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The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

Along with HOPA’s Publications Committee, members also review new drug updates and provide analysis and research on the application of these new drugs or indications. Pharmacist’s Applications to Practice, or PAP, are listed after drugs that include the additional analysis. If you are interested in helping the Publications Committee with creating a Pharmacist's Application to Practice, please contact Jeff Price at jprice@hoparx.org.

You can also find additional information on FDA Alerts and Updates by listening to FDA Drug Safety Podcasts.


July 30, 2019–Pembrolizumab (KEYTRUDA, Merck) for patients with recurrent, locally advanced or metastatic, squamous cell carcinoma of the esophagus (ESCC) whose tumors express PD-L1 (Combined Positive Score [CPS] ≥10), as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

June 17, 2019–Pembrolizumab (KEYTRUDA, Merck) for patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy.

June 10, 2019–Pembrolizumab (KEYTRUDA, Merck) for the first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC).

April 19, 2019–Pembrolizumab (KEYTRUDA, Merck) plus axitinib for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

April 12, 2019–Pembrolizumab (KEYTRUDA, Merck) for the first-line treatment of patients with stage III non-small cell lung cancer (NSCLC) who are not candidates for surgical resection or definitive chemoradiation or metastatic NSCLC. Patients’ tumors must have no EGFR or ALK genomic aberrations and express PD-L1 (Tumor Proportion Score [TPS] ≥1%) determined by an FDA-approved test.

February 15, 2019–Pembrolizumab (KEYTRUDA, Merck) for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

December 19, 2018–Pembrolizumab (KEYTRUDA, Merck & Co. Inc.) for adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC).

August 20, 2018–Pembrolizumab (Keytruda, Merck & Co., Inc.) in combination with pemetrexed and platinum as first-line treatment of patients with metastatic, non-squamous non-small cell lung cancer (NSqNSCLC), with no EGFR or ALK genomic tumor aberrations.

June 13, 2018— Pembrolizumab (Keytrude, Merck and Co., Inc.) for the treatment of primary mediastinal large B-cell lymphoma (with Pharmacist's Applications to Practice)

June 12, 2018–Pembrolizumab (Keytruda®, Merck and Co. Inc.) for patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.

September 22, 2017–Pembrolizumab (KEYTRUDA®, Merck & Co., Inc.) for patients with recurrent locally advanced or metastatic, gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 as determined by an FDA-approved test.(with Pharmacist's Applications to Practice)

May 23, 2017–Pembrolizumab (KEYTRUDA®, Merck & Co.) for adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options or with MSI-H or dMMR colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.(with Pharmacist's Applications to Practice)

May 18, 2017–Pembrolizumab (KEYTRUDA®, Merck and Co., Inc.) for patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.(with Pharmacist's Applications to Practice)

May 10, 2017–Pembrolizumab (KEYTRUDA®, Merck and Co., Inc.) in combination with pemetrexed and carboplatin for the treatment of patients with previously untreated metastatic non-squamous non-small cell lung cancer (NSCLC).(with Pharmacist's Applications to Practice)

March 14, 2017–Pembrolizumab (Keytruda) for the Treatment of Adult and Pediatric Patients with Refractory Classical Hodgkin Lymphoma or Those Who Have Relapsed After Three or More Prior Lines of Therapy (with Pharmacist's Applications to Practice)

October 24, 2016–Pembrolizumab for Metastatic Non-Small Cell Lung Cancer with Tumors Expressing PD-L1 (with Pharmacist's Applications to Practice)

August 5, 2016–Pembrolizumab (KEYTRUDA® injection, Merck Sharp & Dohme Corp.) for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.

October 2, 2015–Pembrolizumab (KEYTRUDA® Injection, Merck Sharp and Dohme Corporation) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express programmed death ligand 1 (PD-L1) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy.

December 18, 2015–Pembrolizumab (Keytruda® Injection, Merck Sharp & Dohme Corp.) for the treatment of patients with unresectable or metastatic melanoma.


July 30, 2019

http://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125514s055s056lbl.pdf

On July 30, 2019, the Food and Drug Administration approved pembrolizumab (KEYTRUDA, Merck) for patients with recurrent, locally advanced or metastatic, squamous cell carcinoma of the esophagus (ESCC) whose tumors express PD-L1 (Combined Positive Score [CPS] ≥10), as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

FDA also approved a new use for the PD-L1 IHC 22C3 pharmDx kit as a companion diagnostic device for selecting patients for the above indication.

Efficacy was investigated in two clinical trials, KEYNOTE‑181 (NCT02564263) and KEYNOTE‑180 (NCT02559687). KEYNOTE-181 was a randomized, open-label, active-controlled trial that enrolled 628 patients with recurrent locally advanced or metastatic esophageal cancer who progressed on or after one prior line of systemic treatment for advanced or metastatic disease. Patients were randomized (1:1) to receive either KEYTRUDA 200 mg intravenously (IV) every 3 weeks or the investigator’s choice of the following regimens: paclitaxel 80-100 mg/m2 IV on days 1, 8, and 15 of every 4‑week cycle; docetaxel 75 mg/m2 IV every 3 weeks; or irinotecan 180 mg/m2 IV every 2 weeks (control arm). Randomization was stratified by geographic region and histologic subtype (squamous versus adenocarcinoma). PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx kit.

The primary efficacy outcome measure of KEYNOTE-181 was overall survival (OS) in patients with ESCC, patients with tumors expressing PD-L1 CPS ≥10, and all randomized patients. Additional efficacy outcome measures were progression-free survival (PFS), overall response rate (ORR), and response duration. The hazard ratio for OS in patients with ESCC whose tumors expressed PD-L1 CPS ≥10 was 0.64 (95% CI: 0.46, 0.90). Median OS was 10.3 months (95% CI: 7.0, 13.5) and 6.7 months (95% CI: 4.8, 8.6) in the pembrolizumab and control arms, respectively.

KEYNOTE‑180 was a single arm, open-label trial that enrolled 121 patients with locally advanced or metastatic esophageal cancer who progressed on or after at least 2 prior systemic treatments for advanced disease. With the exception of the number of prior lines of treatment, the eligibility criteria were similar to and the dosage regimen identical to KEYNOTE-181.

The major efficacy outcome measures of KEYNOTE-180 were ORR and response duration. In the 35 patients with ESCC expressing PD-L1 CPS ≥10, ORR was 20% (95% CI: 8, 37) and response durations ranged from 4.2 to 25.1+ months, with 71% (5 patients) having responses of 6 months or longer and 57% (3 patients) having responses of 12 months or longer.

Adverse reactions in patients with esophageal cancer were similar to those in 2,799 patients with melanoma or NSCLC treated with single-agent pembrolizumab. Common adverse reactions reported in at least 20% of patients receiving pembrolizumab include fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain.

The recommended pembrolizumab dose for esophageal cancer is 200 mg every 3 weeks.

View full prescribing information for KEYTRUDA.

FDA granted these applications priority review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.


June 17, 2019

https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125514s053lbl.pdf.

On June 17, 2019, the Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA, Merck) for patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy.

Efficacy was investigated in 83 patients with SCLC who had disease progression on or after two or more prior lines of therapy enrolled in one of two multicenter, multi-cohort, non-randomized, open label trials: KEYNOTE-158 (NCT02628067) Cohort G or KEYNOTE-028 (NCT02054806) Cohort C1. Patients received either pembrolizumab 200 mg intravenously every 3 weeks (n=64) or 10 mg/kg intravenously every 2 weeks (n=19). Treatment continued until documented disease progression, unacceptable toxicity, or a maximum of 24 months.

The main efficacy outcome measures were overall response rate (ORR) and duration of response (modified RECIST v1.1) assessed by blinded independent central review. The ORR was 19% (95% CI: 11, 29); the complete response rate was 2%. Responses were durable for 6 months or longer in 94%, 12 months or longer in 63%, and 18 months or longer in 56% of the 16 responding patients.

Adverse reactions in patients who received single-agent pembrolizumab for previously treated SCLC were similar to those occurring in patients with other solid tumors who received pembrolizumab. Common adverse reactions reported in at least 20% of patients include fatigue, decreased appetite, cough, nausea and constipation. Pembrolizumab was discontinued for adverse reactions in 9% of patients and 25% had at least one dose withheld for adverse reactions. Serious adverse reactions occurred in 31%. The most frequent (≥2%) serious adverse reactions were pneumonia and pleural effusion.

The recommended pembrolizumab dose for SCLC is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

View full prescribing information for KEYTRUDA.

Pembrolizumab was granted orphan drug designation for SCLC in October 3, 2017. FDA granted this application priority review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Project Facilitate: The Oncology Center of Excellence program for Expanded Access—For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email This email address is being protected from spambots. You need JavaScript enabled to view it..

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.


June 10, 2019

https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125514s052lbl.pdf.

On June 10, 2019, the Food and Drug Administration approved pembrolizumab (KEYTRUDA, Merck) for the first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC).

Pembrolizumab was approved for use in combination with platinum and fluorouracil (FU) for all patients and as a single agent for patients whose tumors express PD‑L1 (Combined Positive Score [CPS] ≥1) as determined by an FDA‑approved test. The FDA also expanded the intended use for the PD-L1 IHC 22C3 pharmDx kit to include use as a companion diagnostic device for selecting patients with HNSCC for treatment with pembrolizumab as a single agent.

Approval was based on KEYNOTE-048 (NCT02358031), a randomized, multicenter, three-arm, open‑label, active‑controlled trial conducted in 882 patients with metastatic HNSCC who had not previously received systemic therapy for metastatic disease or with recurrent disease who were considered incurable by local therapies.

Patients were randomized (1:1:1) to receive one of the following treatments: pembrolizumab as a single agent; pembrolizumab, carboplatin or cisplatin, and FU; or cetuximab, carboplatin or cisplatin, and FU. Randomization was stratified by tumor PD-L1 expression (Tumor Proportion Score [TPS] ≥50% or <50%), HPV status according to p16 IHC (positive or negative), and ECOG PS (0 vs 1). PD-L1 expression (TPS and CPS) was determined using the PD-L1 IHC 22C3 pharmDx kit.

Overall survival (OS), sequentially tested in the subgroup of patients with CPS ≥20 HNSCC, the subgroup of patients with CPS ≥1 HNSCC and the overall population, was the major efficacy measure.

The trial demonstrated a statistically significant improvement in OS in the overall population for patients randomized to pembrolizumab plus chemotherapy compared with cetuximab plus chemotherapy at a pre-specified interim analysis. The median OS was 13.0 months for the pembrolizumab plus chemotherapy arm and 10.7 months for the cetuximab plus chemotherapy arm (HR 0.77; 95% CI: 0.63, 0.93; p=0.0067). Results were similar in the CPS ≥20 subgroup (HR 0.69; 95% CI: 0.51, 0.94) and CPS ≥1 subgroup (HR 0.71; 95% CI: 0.57, 0.88).

The trial also demonstrated statistically significant improvements in OS for the subgroups of patients with PD‑L1 CPS ≥1 HNSCC and PD-L1 CPS ≥20 HNSCC randomized to pembrolizumab as a single agent compared with cetuximab plus chemotherapy. In the CPS ≥1 subgroup, the median OS was 12.3 months for the pembrolizumab arm and 10.3 months for the cetuximab plus chemotherapy arm (HR 0.78; 95% CI: 0.64, 0.96; p=0.0171). For the CPS ≥20 subgroup, the median OS was 14.9 months for the pembrolizumab arm and 10.7 months for the cetuximab plus chemotherapy arm (HR 0.61; 95% CI: 0.45, 0.83; p=0.0015). At the time of the interim analysis, there was no significant difference in OS between the pembrolizumab as a single agent arm and the cetuximab plus chemotherapy arm for the overall population.

There were no significant differences in progression-free survival for either pembrolizumab-containing arm compared to the cetuximab plus chemotherapy arm in any population.

The most common adverse reactions reported in ≥20% of patients who received pembrolizumab as a single agent in KEYNOTE-048 were fatigue, constipation, and rash. The most common adverse reactions reported in ≥20% of patients who received pembrolizumab in combination with chemotherapy in KEYNOTE-048 were nausea, fatigue, constipation, vomiting, mucosal inflammation, diarrhea, decreased appetite, stomatitis, and cough.

The recommended pembrolizumab dose for HNSCC is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

View full prescribing information for KEYTRUDA.

FDA granted this application priority review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Project Facilitate: The Oncology Center of Excellence program for Expanded Access—For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email This email address is being protected from spambots. You need JavaScript enabled to view it..

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.


April 19, 2019

https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125514Orig1s054lbl.pdf

On April 19, 2019, the Food and Drug Administration approved pembrolizumab (KEYTRUDA, Merck & Co. Inc.) plus axitinib for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Approval was based on KEYNOTE‑426 (NCT02853331), a randomized, multicenter, open-label trial conducted in 861 patients who had not received systemic therapy for advanced RCC. Patients were enrolled regardless of PD-L1 tumor expression status and were randomly allocated to receive either pembrolizumab 200 mg intravenously every 3 weeks in combination with axitinib 5 mg orally twice daily, or sunitinib 50 mg orally once daily for 4 weeks and then off treatment for 2 weeks. Treatment continued until confirmed disease progression or unacceptable toxicity. Pembrolizumab was received for maximum of 24 months.

The main efficacy measures were overall survival (OS) and progression-free survival (PFS), assessed by blinded independent central review (RECIST 1.1.) The trial demonstrated a statistically significant improvement in OS in a pre-specified interim analysis for patients on the pembrolizumab plus axitinib arm (HR 0.53; 95% CI: 0.38, 0.74; p<0.0001). With deaths reported in 18% of patients, the median OS was not reached in either arm. The 12-month OS rate was 90% in the pembrolizumab plus axitinib arm and 78% for those treated with sunitinib. The trial also demonstrated a PFS improvement for patients receiving pembrolizumab plus axitinib (HR 0.69; 95% CI: 0.57, 0.84; p=0.0001). Median PFS was 15.1 and 11.1 months for those receiving pembrolizumab plus axitinib vs. sunitinib, respectively.

Grade 3 or 4 hepatotoxicity occurred in 20% of patients. Hepatotoxicity resulted in permanent discontinuation of pembrolizumab or axitinib in 13% of patients. The most common adverse reactions in > 20% of patients who received pembrolizumab plus axitinib were diarrhea, fatigue/asthenia, hypertension, hypothyroidism, decreased appetite, hepatotoxicity, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation.

The recommended pembrolizumab dose for this indication is 200 mg every 3 weeks with axitinib 5 mg orally twice daily.

View full prescribing information for KEYTRUDA.

FDA granted this application priority review and breakthrough therapy designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.


April 12, 2019

https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125514s047lbl.pdf.

On April 11, 2019, the Food and Drug Administration approved pembrolizumab (KEYTRUDA, Merck Inc.) for the first-line treatment of patients with stage III non-small cell lung cancer (NSCLC) who are not candidates for surgical resection or definitive chemoradiation or metastatic NSCLC. Patients’ tumors must have no EGFR or ALK genomic aberrations and express PD-L1 (Tumor Proportion Score [TPS] ≥1%) determined by an FDA-approved test.

Pembrolizumab was previously approved as a single agent for the first-line treatment of patients with metastatic NSCLC whose tumors express PD-L1 TPS ≥50%.

Approval was based on KEYNOTE‑042 (NCT02220894), a randomized, multicenter, open-label, active-controlled trial conducted in 1274 patients with stage III or IV NSCLC who had not received prior systemic treatment for metastatic NSCLC and whose tumors expressed PD-L1 (TPS ≥1%). PD-L1 expression was determined by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx Kit.

Patients were randomized (1:1) to receive pembrolizumab 200 mg intravenously every 3 weeks or investigator’s choice of a carboplatin-containing regimen with either pemetrexed or paclitaxel. Randomization was stratified by ECOG performance status, histology, geographic region, and PD-L1 expression (TPS ≥50% vs. TPS 1 to 49%).

Overall survival (OS) in the TPS ≥50% NSCLC subgroup, the TPS ≥20% NSCLC subgroup, and the overall population (TPS ≥1%) were the major efficacy measures. The trial demonstrated statistically significant OS improvements for those randomized to pembrolizumab compared with chemotherapy in all three populations.

In the TPS ≥1% population (overall population), the median OS was 16.7 and 12.1 months for the pembrolizumab and chemotherapy arms, respectively (HR 0.81; 95% CI: 0.71, 0.93; p=0.0036). For the TPS ≥ 20% subgroup, the median OS was 17.7 months for the pembrolizumab arm and 13.0 months for the chemotherapy arm (HR 0.77; 95% CI: 0.64, 0.92; p=0.004). For the TPS ≥50% subgroup, the estimated median OS was 20 months and 12.2 months for those receiving pembrolizumab and chemotherapy, respectively (HR 0.69; 95% CI: 0.56, 0.85; p=0.0006). There were no significant differences in progression-free survival or overall response rate between arms in any population.

The most common adverse reactions reported in at least 10% of patients who received pembrolizumab as a single agent in KEYNOTE-042 include fatigue, decreased appetite, dyspnea, cough, rash, constipation, diarrhea, nausea, hypothyroidism, pneumonia, pyrexia, and weight loss.

The recommended pembrolizumab dose for NSCLC is 200 mg as an intravenous infusion over 30 minutes every 3 weeks.

View full prescribing information for KEYTRUDA.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.


February 15, 2019

https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125514s040lbl.pdf.

On February 15, 2019, the Food and Drug Administration approved pembrolizumab (KEYTRUDA, Merck) for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Approval was based on EORTC1325/KEYNOTE‑054 (NCT02362594), a randomized, double-blind, placebo-controlled, trial in 1019 patients with completely resected, stage IIIA (>1 mm lymph node metastasis), IIIB or IIIC melanoma (AJCC 7th ed). Patients with mucosal or ocular melanoma were not eligible. Patients were randomly allocated (1:1) to receive pembrolizumab 200 mg every three weeks or placebo for up to 1 year until disease recurrence or unacceptable toxicity. Enrollment required complete resection of melanoma with negative margins, lymph node dissection, and completion of radiotherapy, if indicated, within 13 weeks prior to starting treatment.

The primary efficacy outcome measure was recurrence‑free survival (RFS), as assessed by investigators per RECIST version 1.1. RFS was defined as the time between the date of randomization and first recurrence (local, regional, or distant metastasis) or death from any cause, whichever occurred first. Patients receiving pembrolizumab experienced fewer recurrences/deaths, 26% (n=135), compared with 43% (n=216) on the placebo arm (hazard ratio 0.57; 95% CI: 0.46, 0.70; p<0.001). The RFS benefit for pembrolizumab compared with placebo was observed regardless of tumor PD-L1 expression. Median RFS was 20.4 months in the placebo arm and not reached for those receiving pembrolizumab.

Seventy-six percent of patients received pembrolizumab for 6 months or longer. Pembrolizumab was discontinued for adverse reactions in 14% of patients. The most common adverse reactions (reported in at least 10% of pembrolizumab-treated patients) were diarrhea, pruritus, nausea, arthralgia, hypothyroidism, cough, rash, asthenia, influenza-like illness, weight loss, and hyperthyroidism.

The recommended pembrolizumab dose and schedule for the adjuvant treatment of melanoma is 200 mg administered as an IV infusion over 30 minutes every 3 weeks until disease recurrence or unacceptable toxicity, for a maximum of 1 year.

View full prescribing information for KEYTRUDA.

FDA granted this application priority review and Breakthrough Therapy designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.


December 19, 2018

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125514s045lbl.pdf.

On December 19, 2018, the Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA, Merck & Co. Inc.) for adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC).

Approval was based on Cancer Immunotherapy Trials Network protocol 9 (CITN-09), also known as KEYNOTE-017 (NCT02267603), a multicenter, non-randomized, open-label trial that enrolled 50 patients with recurrent locally advanced or metastatic MCC who had not received prior systemic therapy for their advanced disease. Patients received pembrolizumab 2 mg/kg every 3 weeks.

The major efficacy outcome measures were overall response rate (ORR) and response duration assessed by blinded independent central review per RECIST 1.1. The ORR was 56% (95% CI: 41, 70) with a complete response rate of 24%. The median response duration was not reached. Among the 28 patients with responses, 96% had response durations of greater than 6 months and 54% had response durations of greater than 12 months.

The most common adverse reactions of pembrolizumab reported in at least 20% of patients who received pembrolizumab as a single agent were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain.

The recommended pembrolizumab dose for MCC is 200 mg administered as a 30-minute intravenous infusion every 3 weeks for adults; 2 mg/kg (to a maximum of 200 mg) administered as a 30-minute intravenous infusion every 3 weeks for patients less than 18 years of age (pediatric patients).

View full prescribing information for KEYTRUDA.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

FDA granted this application priority review and Breakthrough Therapy designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.


August 20, 2018

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125514s035lbl.pdf

On August 20, 2018, the Food and Drug Administration approved pembrolizumab (KEYTRUDA, Merck & Co., Inc.) in combination with pemetrexed and platinum as first-line treatment of patients with metastatic, non-squamous non-small cell lung cancer (NSqNSCLC), with no EGFR or ALK genomic tumor aberrations.

Pembrolizumab was previously granted accelerated approval for this indication in May 2017 based on improvements in overall response rate and progression-free survival for patients randomized to pembrolizumab administered with pemetrexed and carboplatin as compared with pemetrexed and carboplatin alone in the KEYNOTE-021 study.

Today’s approval represents fulfillment of a postmarketing commitment demonstrating the clinical benefit of this product. This action is based on the results of KEYNOTE-189 (NCT02578680), a randomized, multicenter, double-blind, active controlled study enrolling 616 patients receiving first-line treatment for metastatic NSqNSCLC. Patients were randomized (2:1) to receive pembrolizumab (or placebo) in combination with pemetrexed, and investigator’s choice of either cisplatin or carboplatin every 3 weeks for 4 cycles followed by pembrolizumab (or placebo) and pemetrexed. Treatment with pembrolizumab continued until disease progression, unacceptable toxicity, or a maximum of 24 months.

The primary efficacy outcome measures were overall survival (OS) and progression-free survival (PFS), as assessed by a blinded independent committee review (RECIST 1.1.) 

The trial demonstrated a statistically significant improvement in OS for patients randomized to pembrolizumab and chemotherapy (HR 0.49; 95% CI: 0.38, 0.64; p<0.00001) in a pre-specified interim analysis. The median OS was not reached at the time of the data cut-off in the pembrolizumab plus chemotherapy arm and was 11.3 months for those in the chemotherapy arm. The trial also demonstrated an improvement in PFS for patients randomized to pembrolizumab plus chemotherapy (HR 0.52; 95% CI: 0.43, 0.64; p<0.00001). The median PFS was 8.8 months for patients receiving pembrolizumab plus chemotherapy and 4.9 months for those receiving chemotherapy alone. The overall response rate was significantly higher (48% vs. 19%; p=0.0001) for those in the pembrolizumab plus chemotherapy arm and the median response duration was 11.2 months and 7.8 months, respectively.

The most common adverse reactions reported in ≥20% of patients in KEYNOTE-189 were fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, and pyrexia.

The recommended pembrolizumab dose and schedule for NSqNSCLC is 200 mg as an intravenous infusion over 30 minutes every 3 weeks.

View full prescribing information for KEYTRUDA.

This is the second FDA approval using the Real Time Oncology Review pilot program that enabled the FDA review team to begin analyzing data before the application submission.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.


June 13, 2018, with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125514s030lbl.pdf

On June 13, 2018, the Food and Drug Administration granted accelerated approval to pembrolizumab (Keytruda, Merck) for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after two or more prior lines of therapy.

Approval was based on data from 53 patients with relapsed or refractory PMBCL enrolled in a multicenter, open-label, single-arm trial, KEYNOTE‑170 (NCT02576990). Patients were treated with pembrolizumab 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months for patients who did not progress. The overall response rate was 45% (95% CI: 32, 60), including 11% complete responses and 34% partial responses. The median duration of response was not reached within the follow-up period (median 9.7 months).  The median time to first objective response was 2.8 months; pembrolizumab is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

The most common adverse reactions in ≥10% of patients with PMBCL treated in KEYNOTE-170 were musculoskeletal pain, upper respiratory tract infection, pyrexia, fatigue, cough, dyspnea, diarrhea, abdominal pain, nausea, arrhythmia, and headache. Pembrolizumab was discontinued or interrupted due to adverse reactions in 8% and 15% of patients, respectively. Twenty-five percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Serious adverse reactions occurred in 26% of patients.

The recommended pembrolizumab dose for treatment of adults with PMBCL is 200 mg every 3 weeks.  The recommended dose in pediatric patients is 2 mg/kg (up to a maximum of 200 mg) every three weeks.

View full prescribing information for Keytruda.

FDA granted this application priority review. Pembrolizumab also received orphan product designation and breakthrough therapy designation for the PMBCL indication. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

Pharmacist’s Applications to Practice

Pembrolizumab for the Treatment of Primary Mediastinal Large B-Cell Lymphoma

Authors: Margaux Jensen, PharmD
PGY-1 Pharmacy Resident
North Memorial Medical Center
Robbinsdale, MN

Sarah Maryon Hayes, PharmD
Inpatient Hematology/Oncology Pharmacist
North Memorial Medical Center
Robbinsdale, MN

What is the potential role for pembrolizumab in the management of relapsed or refractory primary mediastinal B-cell lymphoma?

  • Pembrolizumab has been approved since 2014 by the U.S. Food and Drug Administration (FDA) for the treatment of various solid tumors and was recently approved in 2017 for the treatment of classic Hodgkin lymphoma (cHL).
  • On June 13, 2018, pembrolizumab received accelerated approval for the treatment of adult and pediatric patients with primary mediastinal large B-cell lymphoma (PMBCL) that is relapsed after, or refractory to, two or more prior lines of therapy (rrPMBCL).1 Pembrolizumab is not recommended if urgent cytoreductive therapy is needed.
  • Pembrolizumab was previously evaluated in 18 rrPMBCL patients in the KEYNOTE-018 trial2 (NCT01953692); the overall response rate was 41%, with 35% of patients achieving stable disease.
  • The phase 2 multicenter open-label single-arm KEYNOTE-170 trial3 (NCT02576690) enrolled 53 patients with PMBCL treated with pembrolizumab 200 mg intravenously over 30 minutes every 3 weeks for up to 24 months, or until the disease progressed or an unacceptable level of toxicity was reached. Baseline programmed death receptor-1 (PD-1) ligand expression was available in 63% of patients; of these available tumor biopsies, 94% were programmed death-ligand 1 (PD-L1) positive. The median time to first objective response was 2.8 months. The overall response rate was 45% (95% confidence interval [CI]: 32–60), with 34% partial responses and 11% complete responses. The median duration of response was not reached within the follow-up period (median of 9.7 months).
  • Pembrolizumab was discontinued in 8% of patients and interrupted in 15% because of adverse events. The most common adverse events (occurring in more than 20% of patients) were musculoskeletal pain, fever, upper respiratory tract infection, cough, fatigue, and dyspnea. The most common laboratory abnormalities observed were hyperglycemia (38%), hypophosphatemia (29%), and elevated transaminases (27%).
  • Serious adverse events occurred in 26% of patients; many were cardiac events, including arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericarditis (2%), and pericardial effusion (2%). Six patients (11%) died within 30 days of study treatment.
  • PMBCL accounts for 2%–4% of non-Hodgkin lymphoma diagnoses, and many patients are cured with front-line CHOP-based (cyclophosphamide, doxorubicin, vincristine, prednisone ± rituximab) therapy; approximately 200 patients per year in the United States are diagnosed with rrPMBCL, with no identified standard of care because of the rarity of the diagnosis.4,5
  • Alternative options for treating rrPMBCL include standard cytotoxic salvage regimens such as ICE (ifosfamide, carboplatin, etoposide ± rituximab), ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin ± rituximab), or DHAP (dexamethasone, cisplatin, cytarabine ± rituximab), and CAR-T therapies (tisagenlecleucel and axicabtagene ciloleucel).6

What role can the pharmacist play in the management of patients on pembrolizumab?

  • The approved dose for cHL and rrPMBCL is 200 mg every 3 weeks for adult patients and 2 mg/kg (up to 200 mg) every 3 weeks for pediatric patients.
  • Ensure that patients on pembrolizumab for cHL or PMBCL do not receive any steroids unless they are necessary to treat immune-mediated reactions.
  • Patients should be monitored for adverse effects and immune-mediated reactions, including pneumonitis, colitis, and abnormal thyroid function. Pembrolizumab should be withheld for any rrPMBCL patient with a grade-4 hematologic toxicity.
  • The Merck Patient Assistance Program (https://www.merckaccessprogram-keytruda.com/hcp/the-merck-patient-assistance-program/) is available for patients who do not have insurance or whose insurance does not cover pembrolizumab. Patients who meet these criteria are eligible to apply for free product and product replacement.

Clinical Pearls

  • Nivolumab and pembrolizumab previously earned FDA approval for the treatment of cHL, but this latest approval is the first for a PD-1-based therapy in non-Hodgkin lymphoma treatment.
  • PMBCL and cHL frequently exhibit genetic alterations on chromosome 9p24, which are associated with increased PD-L1 expression, theoretically rendering them susceptible to treatment employing PD-1 blockade.2,3,5
  • PD-L1 testing is not required prior to initiating pembrolizumab in cHL and PMBCL patients.
  • Accelerated approval of pembrolizumab for rrPMBCL is contingent on confirmatory data in clinical trials.

References

  1. Keytruda (pembrolizumab) for injection [package insert]. Whitehouse Station, NJ: Merck and Co.; 2014. Available at https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf.
  2. Zinzani PL, Ribrag V, Moskowitz CH, et al. Safety and tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma. Blood. 2017;130:267-270.
  3. Zinzani PL, Thieblemont C, Melnichenko V, et al. Efficacy and safety of pembrolizumab in relapsed/refractory primary mediastinal large B-cell lymphoma (rrPMBCL): updated analysis of the Keynote-170 Phase 2 Trial. Blood. 2017;130:2833.
  4. Martelli M, Di Rocco A, Russo E, et al. Primary mediastinal lymphoma: diagnosis and treatment options. Expert Rev Hematol. 2015;8:173-186.
  5. Petkovic I. Current trends in the treatment of primary mediastinal large B-cell lymphoma—an overview. Contemp Oncol (Pozn). 2015;19:428-435.
  6. National Comprehensive Cancer Network. B-Cell Lymphomas. Version 1.2019. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf.

June 12, 2018

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125514s034lbl.pdf

On June 12, 2018, the Food and Drug Administration approved pembrolizumab (Keytruda®, Merck and Co. Inc.) for patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.

The most common adverse reactions in at least 10% of patients with cervical cancer enrolled in KEYNOTE-158 were fatigue, pain, pyrexia, peripheral edema, musculoskeletal pain, diarrhea/colitis, abdominal pain, nausea, vomiting, constipation, decreased appetite, hemorrhage, UTI, infections, rash, hypothyroidism, headache, and dyspnea. Pembrolizumab was discontinued due to adverse reactions in 8% of patients. Serious adverse reactions occurred in 39% of patients. The most frequent serious adverse reactions reported included anemia (7%), fistula (4.1%), hemorrhage (4.1%), and infections (except UTIs) (4.1%).

For more information, please visit: Keytruda


September 22, 2017, with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s024lbl.pdf

On September 22, 2017, the Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA®, Merck & Co., Inc.) for patients with recurrent locally advanced or metastatic, gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 as determined by an FDA-approved test. Patients must have had disease progression on or after two or more prior systemic therapies, including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy.

Approval is based on the results of KEYNOTE 059 (NCT02335411), an open-label, multicenter, non-comparative, multi-cohort trial that enrolled 259 patients with gastric or gastroesophageal junction adenocarcinoma. Among the 259 patients, 55% (n=143) had tumors expressing PD-L1 and either microsatellite stable (MSS), or undetermined microsatellite instability (MSI) or mismatch repair (MMR) status.

PD-L1 expression was evaluated by the PD-L1 IHC 22C3 pharmDx Kit (Dako) and PD-L1 positivity was based on a combined positive score (CPS) ≥ 1. CPS is determined by the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by total number of tumor cells evaluated, multiplied by 100.

For the 143 patients with tumors expressing PD-L1 and who were either MSS or had unknown MSI or dMMR status, the objective response rate was 13.3% (95% CI: 8.2, 20.0); 1.4% had complete responses and 11.9% had partial responses. Among the 19 responding patients, the response duration ranged from 2.8+ to 19.4+ months, with 11 patients (58%) having response durations of 6 months or longer and 5 patients (26%) having response durations of 12 months or longer.

Among the 259 patients enrolled in KEYNOTE 059, 7 (3%) had tumors that were determined to be MSI-high. Responses were observed in 4 of these 7 patients (ORR 57%), with one complete response. The response duration ranged from 5.3+ to 14.1+ months.

Adverse reactions occurring in patients with gastric cancer were similar to those presently described in product labelling. The most common adverse reactions are fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, and constipation. Pembrolizumab is associated with immune-mediated side effects, including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.

The recommended pembrolizumab dose for gastric cancer is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Today, FDA also approved the PD-L1 IHC 22C3 pharmDx (Dako), to select patients with gastric cancer for treatment with pembrolizumab. If PD-L1 expression is not detected in an archival gastric cancer specimen, FDA recommends assessing the feasibility of a fresh tumor biopsy. Information on FDA-approved tests for PD-L1 expression in NSCLC or in gastric cancer is available at:
http://www.fda.gov/CompanionDiagnostics

Full prescribing information is available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s024lbl.pdf

FDA granted pembrolizumab priority review for this indication. As a condition of accelerated approval, further studies are required. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at:
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist’s Applications to Practice – September 22, 2017

Pembrolizumab for Recurrent Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma Expressing PD-L1 with Disease Progression on or After at Least Two Prior Lines of Therapy

Author: Arlene Gao, PharmD
Clinical Pharmacy Specialist, Solid Tumors
WVU Medicine
Morgantown, WV

What is the potential role for pembrolizumab in the management of recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma?1-11

  • Few treatment options have been studied in patients with advanced or metastatic gastric or gastroesophageal junction (GEJ) cancers in the relapsed setting.
    • Historically, no standard treatment options for third-line or later therapy have been available. Regimens used, including single-agent irinotecan or docetaxel, have been based primarily on small studies.
    • Pembrolizumab was approved by the U.S. Food and Drug Administration (FDA) in May 2017 for patients with unresectable or metastatic, microsatellite instability–high (MSI-H) solid tumors that have progressed with no additional alternatives. Notably, MSI-H tumors have been observed in gastric and GEJ tumors.
  • The new indication for pembrolizumab is based on the results of KEYNOTE-059 and has allowed pembrolizumab to be accessible to more patients with recurrent locally advanced or metastatic gastric or GEJ adenocarcinoma.
    • The multicenter multicohort noncomparative phase-2 trial included 259 patients with recurrent locally advanced or metastatic gastric or GEJ adenocarcinoma whose disease had progressed on or after at least two prior lines of therapy.
      • Prior treatment must have included fluoropyrimidine- and platinum-containing chemotherapy and HER2/neu-targeted therapy, if indicated.
      • Programmed death-ligand 1 (PD-L1) expression was present (greater than or equal to 1% tumor or stromal cells) in 143 patients (55%). Only 7 patients (3%) had tumors that were identified as MSI-H.
    • At a median follow-up of 5.4 months, overall response rate (ORR) was 11.2% (1.9% complete response [CR] and 9.3% partial response [PR]). However, differences were seen in patients with tumors expressing PD-L1 (ORR 15.5% with 2% CR and 13.5% PR) vs. no expression (ORR 5.5% with 1.8% CR and 3.7% PR).
    • The majority of patients with tumors expressing PD-L1 in this study were microsatellite stable (MSS) or had unknown MSI status. Therefore, PD-L1 expression rather than MSI status was able to identify additional patients who would respond to pembrolizumab.
  • On October 13, 2017, the National Comprehensive Cancer Network (NCCN) updated its clinical practice guidelines for gastric cancer and esophageal and esophagogastric junction cancers to include pembrolizumab as a third-line or later option in patients with PD-L1-positive gastric, GEJ, and esophageal adenocarcinoma.
    • The rationale for extending the use of pembrolizumab to patients with esophageal cancer is not explicitly addressed. However, activity in PD-L1-positive esophageal cancer has been demonstrated (KEYNOTE-028) and continues to be investigated in other trials (KEYNOTE-180 and KEYNOTE-181).
  • Nivolumab has also been studied in patients with advanced gastric or GEJ cancers after disease progression on at least two prior lines of therapy.
    • Recently published results of the phase-3 ONO-4538-12/ATTRACTION-2 study demonstrated, as its primary end point, an overall survival of 5.26 months for patients receiving weight-based nivolumab every 2 weeks versus 4.14 months with placebo (hazard ratio .63, p < .0001). The benefit with nivolumab was seen in both PD-L1-positive and PD-L1-negative patients.
    • Tumor response data were not available for all included patients; an ORR of 11.2% (all PR) was reported for the subset of patients receiving nivolumab with measurable target lesions.
    • Although the results are promising, it should be noted that the study population comprised only patients in Japan, Korea, and Taiwan, making additional extrapolation challenging.

What role can the pharmacist play in the management of patients on pembrolizumab?4,10

  • The approved dosing is a flat dose of 200 mg administered intravenously every 3 weeks.
  • Patients should be monitored for immune-related adverse effects, including colitis, pneumonitis, hepatitis, and endocrinopathies. Corticosteroids may be required for management.
  • The Merck Access Program (https://www.merckaccessprogram-keytruda.com/hcp/) includes several resources that can be utilized by healthcare providers to help obtain access for patients. For example, the Merck Patient Assistance Program (https://www.merckaccessprogram-keytruda.com/hcp/the-merck-patient-assistance-program/) is available for patients who do not have insurance or whose insurance does not cover pembrolizumab.

Clinical Pearls4,12

  • The FDA-approved companion diagnostic test for identifying patients is the PD-L1 IHC 22C3 pharmDx (Dako). Positive PD-L1 expression is determined by a combined proportion score greater than or equal to 1%. This score takes into account stained tumor cells and inflammatory cells (lymphocytes, macrophages).
    • The same companion diagnostic test is approved for identifying appropriate patients with non-small-cell lung cancer. However, PD-L1 expression is determined by a tumor proportion score, which considers only stained tumor cells.
  • Pembrolizumab was granted accelerated approval for this indication. Additional phase-3 studies are needed for full approval.

References

  1. Doi T, Bennouna J, Shen L, et al. KEYNOTE-181: Phase 3, open-label study of second-line pembrolizumab vs single-agent chemotherapy in patients with advanced/metastatic esophageal adenocarcinoma. Ann Oncol. 2016 Jun;27(suppl 3).
  2. Doi T, Piha-Paul SA, Jalal SI, et al. Updated results for the advanced esophageal carcinoma cohort of the phase Ib KEYNOTE-028 study of pembrolizumab (MK-3475) [ASCO abstract 7]. J Clin Oncol. 2016 Feb;34(4 suppl).
  3. National Comprehensive Cancer Network. Esophageal and Esophagogastric Junction Cancers. Version 4.2017. Updated October 13, 2017. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf
  4. U.S. Food and Drug Administration. FDA grants accelerated approval to pembrolizumab for advanced gastric cancer. Silver Spring, MD. Updated September 22, 2017. Retrieved from https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm577093.htm
  5. U.S. Food and Drug Administration. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. Silver Spring, MD. Updated May 30, 2017. Retrieved from https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm560040.htm
  6. Fuchs CS, Doi T, Jang RWJ, et al. KEYNOTE-059 cohort 1: Efficacy and safety of pembrolizumab (pembro) monotherapy in patients with previously treated advanced gastric cancer [ASCO abstract 4003]. J Clin Oncol. 2017;35(15 suppl):4003.
  7. National Comprehensive Cancer Network. Gastric Cancer. Version 5.2017. Updated October 13, 2017. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf
  8. Kang YK, Boku N, Satoh T, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;Oct 5. doi: 10.1016/S0140-6736(17)31827-5. [Epub ahead of print].
  9. Kang YK, Satoh T, Ryu MH, et al. Nivolumab (ONO-4538/BMS-936558) as salvage treatment after second or later-line chemotherapy for advanced gastric or gastro-esophageal junction cancer (AGC): a double-blinded, randomized, phase III trial [ASCO abstract 2]. J Clin Oncol. 2017;35(4 suppl).
  10. Keytruda [package insert]. Whitehouse Station, NJ: Merck and Co., Inc.; Sept 2017.
  11. Shah MA, Bennouna J, Shen L, et al. Pembrolizumab for patients with previously treated metastatic adenocarcinoma or squamous cell carcinoma of the esophagus: phase 2 KEYNOTE-180 study. Ann Oncol. 2016;27(suppl 2).
  12. U.S. Food and Drug Administration. List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools). Silver Spring, MD. Retrieved from https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm

May 23, 2017, with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s014lbl.pdf

On May 23, 2017, the U.S. Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA®, Merck & Co.) for adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options or with MSI-H or dMMR colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

This is the FDA’s first tissue/site-agnostic approval.

The approval was based on data from 149 patients with MSI-H or dMMR cancers enrolled across five uncontrolled, multi-cohort, multi-center, single-arm clinical trials. Ninety patients had colorectal cancer and 59 patients were diagnosed with one of 14 other cancer types. Patients received either pembrolizumab, 200 mg every 3 weeks, or pembrolizumab, 10 mg/kg every 2 weeks. Treatment continued until unacceptable toxicity, or disease progression that was either symptomatic, rapidly progressive, required urgent intervention, or associated with a decline in performance status. A maximum of 24 months of treatment was administered.

The major efficacy outcome measures were objective response rate (ORR) assessed by blinded independent central radiologists’ review according to RECIST 1.1, and response duration. ORR was 39.6% (95% CI: 31.7, 47.9). Responses lasted six months or more for 78% percent of those who responded to pembrolizumab. There were 11 complete responses and 48 partial responses. ORR was similar irrespective of whether patients were diagnosed with CRC (36%) or a different cancer type (46% across the 14 other cancer types).

The identification of MSI-H or dMMR tumor status for the majority of patients (135/149) was prospectively determined using local laboratory-developed, investigational polymerase chain reaction (PCR) tests for MSI-H status or immunohistochemistry (IHC) tests for dMMR. For 14 of the 149 patients, MSI-H status was determined in a retrospective assessment of 415 patients’ tumor samples using a central laboratory-developed PCR test.

The most common adverse reactions to pembrolizumab include fatigue, pruritus, diarrhea, decreased appetite, rash, pyrexia, cough, dyspnea, musculoskeletal pain, constipation, and nausea. Pembrolizumab is associated with immune-mediated side effects, including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.

The prescribing information for pembrolizumab includes a “Limitation of Use” stating that the safety and effectiveness of pembrolizumab in pediatric patients with MSI-H central nervous system cancers have not been established.

The recommended pembrolizumab dose for this indication is 200 mg for adults or 2 mg/kg (up to a maximum of 200 mg) for children, administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Full prescribing information is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s014lbl.pdf.

FDA granted this application priority review status and accelerated approval. Further studies are required to confirm clinical benefit of pembrolizumab for this indication. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist’s Applications to Practice - May 23, 2017

Pembrolizumab (Keytruda) for Patients with Unresectable, Metastatic Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Solid Tumors That Have Progressed Following Prior Treatment and Who Have No Satisfactory Treatment Options or with MSI-H or dMMR Colorectal Cancer (CRC) That Has Progressed Following Treatment with Fluoropyrimidine, Oxaliplatin, and Irinotecan

Author: Charles Wight, PharmD
PGY-1 Pharmacy Resident
WVU Medicine
Morgantown, WV

What is the potential role for pembrolizumab in the management of MSI-H or dMMR solid tumors and colorectal cancer?1-4

  • On May 23, 2017, pembrolizumab was granted accelerated approval by the U.S. Food and Drug Administration (FDA) for the treatment of adult and pediatric patients with the following unresectable or metastatic MSI-H or dMMR cancers:
    • solid tumors that have progressed following prior treatment in patients who have no satisfactory alternative treatment options
    • colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
  • Programmed cell death-1 (PD-1) pathway is an immune checkpoint inhibitor exploited by tumor cells to suppress antitumor immunity. PD-1 receptors on T-cells bind to their ligands on tumor cells, programmed death-ligand 1 and 2 (PD-L1 and PD-L2), and immune response is suppressed. Overexpression of these ligands, especially in dMMR and MSI-H tumor cells, causes an exaggerated decrease in immune response and uninhibited growth of tumor cells.   
  • Pembrolizumab is a monoclonal antibody that binds to PD-1 with a high affinity, preventing it from interacting with PD-L1 and PD-L2 and thereby allowing for enhanced T-cell recognition and destruction of the tumor cell.
  • Approval was based on data from 5 KEYNOTE studies, totaling 149 patients with MSI-H or dMMR cancer (90 with CRC, 59 with 1 of 14 other types of cancer). Primary response outcomes were objective response rate (ORR) and duration of response.
    • ORR was 39.6% (95% confidence interval [CI]; 31.7–47.9).
    • Complete response rate was 7.4%.
    • Partial response rate was 32.2%.
    • 78% achieved a duration of response of greater than 6 months.
    • ORR for CRC patients was 36%, compared to 46% across all other cancer types.
  • The most common cancer types in these studies were colorectal (n = 90), endometrial (n = 14), biliary (n = 11), gastric (n = 9), and pancreatic cancer (n = 6), all of which achieved results similar to those of CRC patients. However, National Comprehensive Cancer Network (NCCN) guidelines currently do not make a recommendation on the use of pembrolizumab in these other types of cancers.

What role can the pharmacist play in the management of patients on pembrolizumab?1,5

  • Monitor for and counsel patients on the signs and symptoms of the following:
    • immune-mediated reactions, such as hyperglycemia (49%), pneumonitis (3.4%), colitis (1.7%), hepatitis (.7%), and nephritis (.3%), and thyroid disorders, such as hypothyroidism (8.5%) and hyperthyroidism (3.4%)
    • common adverse reactions such as fatigue (26%–43%), pruritus (11%–28%), diarrhea (18%–20%), decreased appetite (20%–22%), rash (20%–24%), musculoskeletal pain (21%–32%), constipation (19%–22%), and nausea (12%– 22%).
  • These reactions may require treatment interruption or discontinuation, and treatment with a corticosteroid:
      • Immune-mediated pneumonitis, colitis, and nephritis
        • Grade 2 or higher: Corticosteroids (prednisone 1–2 mg/kg/day followed by a taper), may require interruption of treatment and/or permanent discontinuation
      • Immune-mediated hepatitis
        • Corticosteroids
          • Grade 2: prednisone .5–1 mg/kg/day, followed by a taper
          • Grade 3 or higher: prednisone 1–2 mg/kg/day, then taper
        • Withhold or discontinue treatment based on severity of liver enzyme elevations.
      • Monitor for changes in renal function, elevated liver enzymes, and signs and symptoms of pneumonitis and colitis.
  • Pembrolizumab can cause fetal harm and should be avoided during pregnancy and breastfeeding. The risks should be discussed with women of child-bearing age.

Clinical Pearls1

  • The Merck Patient Assistance Program (https://www.merckaccessprogram-keytruda.com/hcp/the-merck-patient-assistance-program/) is available for patients who do not have insurance or whose insurance does not cover Keytruda. Patients who meet these criteria are eligible to apply for free product and product replacement.
  • The recommended dose of pembrolizumab for patients with MSI-H cancer:
    • In adults, pembrolizumab 200 mg (flat dose) is administered as an intravenous (IV) infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
    • In children, 2 mg/kg (up to 200 mg) is administered as an IV infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
  • Pembrolizumab is available in two formulations (both should be refrigerated at 2⁰C– 8⁰C):
    • 50-mg single-dose vial containing lyophilized powder for reconstitution and injection
    • 100 mg/4 ml (25 mg/ml) single-dose vial.

References

  1. Keytruda (pembrolizumab) [package insert]. Whitehouse Station, NJ: Merck & co Inc.; 2017.
  2. U.S. Food and Drug Administration. FDA approves first cancer treatment for any solid tumor with a specific genetic feature. https://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm560167.htm. Updated May 23, 2017. Accessed August 10, 2017.
  3. Le D., Uram J., Wang H., Bartlett B., Kemberling H., Eyring A, et al. (2015). PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 372(26), 2509-2520.
  4. Patnaik A, Kang S, Rasco D, et al. Phase I study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res. 2015;21(19):4286-4293.
  5. Abdel-Rahman O, El Halawani H, Fouad M. Risk of cutaneous toxicities in patients with solid tumors treated with immune checkpoint inhibitors: a meta-analysis. Future Oncol. 2015;11(17):2471-2484.

May 18, 2017, with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s017s018lbl.pdf

On May 18, 2017, the U.S. Food and Drug Administration granted regular approval to pembrolizumab (KEYTRUDA®, Merck and Co., Inc.) for patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

FDA also granted accelerated approval to pembrolizumab for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.

The regular approval for the second-line indication was based on data from Trial KEYNOTE-045, a multicenter, randomized, active-controlled trial in patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy. Patients were randomly assigned (1:1) to receive either pembrolizumab 200 mg every 3 weeks (n=270) or investigator’s choice of a chemotherapy regimen (paclitaxel [n=84], docetaxel [n=84], or vinflunine [n=87]) every 3 weeks (n=272). The trial demonstrated statistically significant improvements in overall survival (OS) and objective response rate (ORR) for patients assigned to pembrolizumab as compared to chemotherapy. Median OS was 10.3 and 7.4 months in the pembrolizumab and chemotherapy arms, respectively (HR 0.73; 95% CI: 0.59, 0.91, p=0.004). ORR was 21% for pembrolizumab and 11% for chemotherapy (p=0.002). No statistically significant difference in progression-free survival between the two arms was observed.

The accelerated approval for the first-line indication was based on data from KEYNOTE-052, a single-arm, open-label trial in 370 patients with locally advanced or metastatic urothelial carcinoma who were deemed not eligible for cisplatin-containing chemotherapy. Patients received pembrolizumab 200 mg every 3 weeks. With a median follow-up time of 7.8 months, the ORR was 28.6% (95% CI 24, 34) and the median response duration was not reached (range 1.4+, 17.8+ months).

The most common adverse reactions reported for at least 20% of pembrolizumab-treated patients in either of the two trials included fatigue, musculoskeletal pain, pruritus, decreased appetite, nausea, diarrhea, constipation, and rash. Discontinuation of pembrolizumab secondary to adverse reactions occurred in 8% of patients in KEYNOTE-045 and in 11% in KEYNOTE-052. Dose interruption of pembrolizumab occurred in approximately 20% of patients in either trial. Serious adverse reactions occurred in approximately 40% of pembrolizumab-treated patients. Immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis, and endocrinopathies, were reported in the trials and were managed according to guidelines in Warnings and Precautions of the label.

The recommended pembrolizumab dose and schedule for the treatment of urothelial carcinoma is 200 mg as an intravenous infusion over 30 minutes every 3 weeks.

Full prescribing information is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s017s018lbl.pdf.

FDA granted pembrolizumab priority review status for these indications. Prior to the submission, pembrolizumab received Breakthrough Therapy Designation for the second-line indication. An additional trial is required to confirm clinical benefit of pembrolizumab for the first-line indication. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist’s Applications to Practice – May 18, 2017

Pembrolizumab (Keytruda) for Locally Advanced or Metastatic Urothelial Carcinoma with Progression During or After Platinum-Containing Chemotherapy or as First-Line Treatment for Patients Ineligible for Cisplatin-Containing Chemotherapy

Authors: Jessica Campaign Streeter, PharmD BCOP
Clinical Pharmacist in Genitourinary and Gynecologic Oncology
Huntsman Cancer Institute
Salt Lake City, UT

Charles Wight, PharmD
PGY-1 Pharmacy Resident
WVU Medicine
Morgantown, WV

 

What is the potential role for pembrolizumab in the management of urothelial carcinoma?1-7

  • Standard first-line treatment of advanced or metastatic urothelial carcinoma is cisplatin-based chemotherapy, specifically dose-dense MVAC (methotrexate, vinblastine, adriamycin [= doxorubicin], cisplatin) or cisplatin and gemcitabine. Prior to May 2016 no standard of care was identified for treatment following progression of the disease or recurrence after adjuvant or neoadjuvant platinum-based chemotherapy. Options in this setting consisted primarily of single-agent cytotoxic chemotherapy agents such as paclitaxel, docetaxel, gemcitabine, and pemetrexed.
  • Multiple immune checkpoint inhibitors have been investigated in this population. As of July 2017, the U.S. Food and Drug Administration (FDA) has granted accelerated approval to five of these monoclonal antibodies: two programmed cell death-1 (PD-1) inhibitors (pembrolizumab, nivolumab) and three programmed death-ligand 1 (PD-L1) inhibitors (atezolizumab, durvalumab, avelumab) for the treatment of urothelial carcinoma that has progressed during or after platinum-containing chemotherapy. See Table 1.
  • Pembrolizumab offers a survival benefit over standard chemotherapy (docetaxel, paclitaxel, or vinflunine) in patients with disease progression after platinum-based chemotherapy for advanced disease or recurrence within 12 months after platinum-based adjuvant or neoadjuvant therapy for localized muscle-invasive disease, regardless of PD-L1 expression (median overall survival 10.3 months vs. 7.4 months [hazard ratio (HR) 0.73; 95% confidence interval (CI), .59–.91; p = .002]).
  • Pembrolizumab is a first-line treatment option for patients who are not candidates for standard platinum-containing chemotherapy, for reasons including renal dysfunction, poor performance status, significant neuropathy or ototoxicity, and heart failure.

Table 1. FDA-Approved PD-1/PD-L1 Targeted Therapies for Advanced or Metastatic Urothelial Carcinoma After Platinum Chemotherapy

Target Agent Comparator PD-L1 expression status for primary outcome Phase N Median OS, months Median PFS, months ORR, % Treatment-related adverse events, %
PD-1 pembrolizumab docetaxel/paclitaxel/vinflunine Any 3 542 10.3 vs. 7.4 (p = .002) 2.1 vs. 3.3 (p = .42) 21.1 vs. 11.4 (p = .001) 60.9 vs. 90.2
nivolumab NA Any 2 270 8.7 2.0 19.6 64
PD-L1 atezolizumab docetaxel/paclitaxel/vinflunine 5% or greater 3 931 11.1 vs. 10.6 (p = .41) NR 23 vs 22 70 vs. 89
durvalumab NA Any 1/2 182 NR NR 17.0 NR
avelumab NA Any 1 242 7.4 1.5 17.4* 66.7

*patients with 6 months or longer follow-up
NA = not applicable; NR = not reported; ORR = overall response rate; OS = overall survival; PD-1 = programmed cell death-1; PD-L1 = programmed death-ligand 1; PFS = progression-free survival.

 

What role can the pharmacist play in the management of patients on pembrolizumab? 2,7,8

  • The pharmacist can educate patients and providers about possible symptoms of immune-mediated adverse effects, including colitis (2.3%), pneumonitis (4.1%), dermatitis or rash (0.8%), nephritis (0.8%), and endocrinopathies (hyperthyroidism [3.8%], hypothyroidism [6.4%], adrenal insufficiency [0.4%]). Immune hepatitis, myositis, hypophysitis, and type 1 diabetes have also been reported with pembrolizumab.  Biopsy may aid in diagnosis of these adverse effects.
  • For significant immune-mediated adverse effects, pembrolizumab should be withheld. Corticosteroid treatment may be required (most frequently prednisone 12 mg/kg/day or equivalent).
    • Upon adequate lessening of adverse effect (usually to grade 1 or lower), corticosteroids should be tapered, usually over at least 4 weeks.
    • If a patient requires 20 mg or greater of prednisone equivalent daily for 4 weeks or more, Pneumocystis jirovecii pneumonia prophylaxis should be provided.
  • Pembrolizumab can cause fetal harm and should be avoided in pregnancy and breastfeeding. The risks should be discussed with women of child-bearing age.

Clinical Pearls2,7,8

  • PD-L1 testing is not required for patient selection.
  • Of the multiple recently approved PD-1/PD-L1 checkpoint inhibitors for urothelial carcinoma, as of July 2017, pembrolizumab is the only agent with phase 3 data confirming an improvement in overall survival as compared to standard chemotherapy in patients with disease progression or recurrence following platinum-based chemotherapy, regardless of PD-L1 expression. These results were in patients who received two or fewer prior lines of chemotherapy for advanced disease with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, or ECOG 2 without poor prognostic factors for second-line therapy.
  • Accelerated FDA approval for the first-line indication is based on tumor response rate and duration of response. Full approval for this indication will be contingent upon results of further phase 3 clinical trials.
  • Recommended dosing is 200 mg given intravenously every 3 weeks.
  • Pembrolizumab is available in two formulations, both of which should be refrigerated at 2⁰C–8⁰C.
    • 50 mg single-dose vial containing lyophilized powder for reconstitution and injection
    • 100 mg/4 ml (25 mg/m) single-dose vial
  • The Merck Patient Assistance Program (https://www.merckaccessprogram-keytruda.com/hcp/the-merck-patient-assistance-program/) is available for patients who do not have insurance or whose insurance does not cover Keytruda. Patients who meet these criteria are eligible to apply for free product and product replacement.

References

  1. Bladder Cancer. Version 5.2017. National Comprehensive Cancer Network. Available at: https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf. Accessed July 10, 2017.
  2. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376:1015-26.
  3. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicenter, single-arm, phase 2 trial. Lancet Oncol. 2017;18:312-22.
  4. Powles T, Loriot Y, Duran I, et al. IMvigor211: A phase III randomized study examining atezolizumab vs chemotherapy for platinum-treated advanced urothelial carcinoma. Presented at EACR-AACR-SIC Special Conference 2017, Florence, Italy.
  5. Imfinzi (durvalumab) injection, for intravenous use [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; May 2017.
  6. Apolo AB, Ellerton JA, Infante JR, et al. Updated efficacy and safety of avelumab in metastatic urothelial carcinoma (mUC): pooled analysis from 2 cohorts of the phase 1b Javelin solid tumor study. J Clin Oncol. 2017;35:suppl:abstr 4528.
  7. Balar AV, Castellano DE, O’Donnell PH, et al. Pembrolizumab as first-line therapy in cisplatin-ineligible patients with locally advanced and metastatic urothelial cancer: Results from the total KEYNOTE-052 study population [abstract]. J Clin Oncol. 2017;6S: Abstract 284.
  8. Keytruda (pembrolizumab) for injection [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; May 2017.

May 10, 2017, with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s016lbl.pdf

On May 10, 2017, the U.S. Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA®, Merck and Co., Inc.) in combination with pemetrexed and carboplatin for the treatment of patients with previously untreated metastatic non-squamous non-small cell lung cancer (NSCLC).

Approval was based on a cohort (G1) of patients enrolled in an open-label, multicenter, multi-cohort study (KEYNOTE-021). A total of 123 patients with locally advanced or metastatic non-squamous NSCLC and no prior systemic treatment for metastatic disease were enrolled. Patients were randomized to receive either pembrolizumab, 200 mg every 3 weeks, in combination with pemetrexed and carboplatin (PC) for 4 cycles followed by pembrolizumab for a maximum of 24 months (n=60) compared to PC alone (n=63). At the investigator’s discretion, patients in both arms may have received pemetrexed as maintenance therapy. Randomization was stratified by PD-L1 tumor expression - tumor proportion score [TPS] <1% vs. TPS ≥1%.

The trial demonstrated an improvement in overall response rate (ORR) and in progression-free survival (PFS) for patients randomized to pembrolizumab plus PC. The ORR was 55% (95% CI: 42-68%) for the pembrolizumab plus PC arm and 29% (95% CI: 18-41%) for the PC alone arm (p=0.0032). Among responders, the proportion of patients with response durations of 6 months or longer was 93% in the pembrolizumab-containing arm and 81% in the PC alone arm. The hazard ratio for PFS was 0.53 (95% CI: 0.31, 0.91, p=0.0205) and the median PFS was 13.0 months (95% CI: 8.3, NE) for the pembrolizumab plus PC arm and 8.9 months (95% CI: 4.4, 10.3) for the PC alone arm. Exploratory analyses of ORR were conducted in subgroups defined by PD-L1 tumor expression (TPS <1% and TPS ≥1%). In the TPS <1% subgroup, the ORR was 57% and 13% in the pembrolizumab plus PC and in the PC alone arms, respectively. In the TPS 1% or greater subgroup, the ORR was 54% and 38% in the pembrolizumab plus PC and in the PC alone arms, respectively.

Adverse events (AEs) and serious AEs (SAE) were observed at a higher incidence with the addition of pembrolizumab to PC compared to PC alone in patients from Cohort G1. Serious AEs occurred in 41% of the patients in the pembrolizumab plus PC arm compared with 28% in the PC alone arm. The most common AEs (all grades) in the pembrolizumab + PC arm were fatigue (71%), nausea (68%), and constipation (51%). The most common grade 3-4 adverse reactions were fatigue (3.4%), dyspnea (3.4%), nausea (1.7%), vomiting (1.7%), diarrhea (1.7%), and rash (1.7%). Pembrolizumab was discontinued for adverse reactions in 10% of patients. The most common adverse reaction resulting in discontinuation of pembrolizumab (≥2%) was acute kidney injury (3.4%).

Immune-mediated adverse reactions can occur with pembrolizumab including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. Based on the severity of the adverse reaction, pembrolizumab should be withheld or discontinued and corticosteroids administered when appropriate.

The recommended pembrolizumab dose and schedule for NSCLC is 200 mg as an intravenous infusion every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Full prescribing information is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s016lbl.pdf.

FDA granted pembrolizumab priority review status and accelerated approval for this indication. An additional study is required to confirm clinical benefit of pembrolizumab in combination with chemotherapy for this indication. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist’s Applications to Practice - May 10, 2017

Pembrolizumab (Keytruda) for Non-Small-Cell Lung Cancer in Combination with Carboplatin and Pemetrexed

Author: Alyssa Heiden, PharmD
PGY-2 Oncology Pharmacy Resident
University of Minnesota Medical Center and Fairview Health
Minneapolis, MN

What is the potential role for pembrolizumab in combination with carboplatin and pemetrexed in the management of non-squamous non-small-cell lung cancer (NSCLC)?1-3

  • Pembrolizumab in combination with carboplatin and pemetrexed was granted accelerated approval by the U.S. Food and Drug Administration (FDA) as first-line treatment of patients with metastatic non-squamous NSCLC on the basis of the results of the KEYNOTE-021 trial.
    • KEYNOTE-021 was a phase 2, open-label, randomized, international, multicenter trial that randomized 123 patients in a 1:1 ratio to pembrolizumab plus doublet chemotherapy (pemetrexed and carboplatin) or doublet chemotherapy alone.
  • Prior to this approval, the standard first-line therapy for patients with NSCLC without a targetable genetic aberration was doublet chemotherapy with a platinum agent, and limited data were available on the addition of a third agent, despite numerous trials looking at progression-free survival (PFS) and overall survival (OS).
    • The results of KEYNOTE-021 demonstrated an improvement in overall response rate (ORR) and PFS for patients randomized to pembrolizumab plus doublet chemotherapy. The ORR was 55% for pembrolizumab plus doublet chemotherapy versus 29% for doublet chemotherapy alone (p = .0032). The PFS was 13.0 months for pembrolizumab plus chemotherapy and 8.9 months for doublet chemotherapy (hazard ratio .53, p = .0205).
  • Pembrolizumab is an anti-programmed cell death-1 (PD-1) antibody that has shown efficacy in treating metastatic NSCLC as first-line monotherapy and as monotherapy after progression of metastatic NSCLC following treatment with a platinum agent.
  • New data, including the data seen in KEYNOTE-021, show that the antitumor activity of chemotherapy involves not only cytotoxic effects but also immunologic effects. This means that the combination of chemotherapy and immunotherapy could provide synergistic improvement with anti-PD-1 therapy.

What role can the pharmacist play in the management of patients on pembrolizumab, carboplatin, and pemetrexed?1,2,4-7

  • Pembrolizumab is a fully humanized monoclonal antibody that has a low incidence of infusion reactions and a unique side-effect profile, including immune-mediated side effects that can differ significantly from those of standard chemotherapy.
    • Patients should be monitored for side effects relating to both immunotherapy and chemotherapy during treatment because adverse events and serious adverse events were observed more commonly in the pembrolizumab plus chemotherapy group compared to doublet chemotherapy in KEYNOTE-021.
    • The most common adverse events for patients in the doublet chemotherapy arm were nausea (56%), fatigue (50%), and constipation (37%). The most common grade 3 or 4 adverse events were decreased lymphocyte counts (28%), anemia (19%), thrombocytopenia (10%), and neutropenia (9%).
    • The most common adverse events in the pembrolizumab plus chemotherapy arm were fatigue (71%), nausea (68%), and constipation (51%). The most common grade 3 or 4 adverse events were decreased lymphocyte counts (23%), anemia (17%), neutropenia (14%), and thrombocytopenia (9%).
    • The most common immune-mediated adverse events for the combination of pembrolizumab and chemotherapy were hypothyroidism and/or hyperthyroidism (23%) and pneumonitis (5%).
    • Pembrolizumab was discontinued in 10% of patients because of adverse reactions; the most common was acute kidney injury (3.4%).
  • Pharmacists should educate staff on the administration of standard ancillary medications with combination immunotherapy and chemotherapy. In this trial, patients were given corticosteroids as a premedication for chemotherapy per “local guidelines.”
    • The study protocol cites the Multinational Association for Supportive Care in Cancer (MASCC) guidelines for the prevention of nausea and vomiting, which in this case would include an NK1 receptor antagonist, a 5-HT3 receptor antagonist, and dexamethasone.
    • Per the prescribing information, pemetrexed should be given with dexamethasone twice daily starting 1 day before, the day of, and the day after the infusion to prevent cutaneous toxicities.
    • Some data support the use of single doses of dexamethasone to prevent pemetrexed-induced cutaneous toxicities. Additionally, subsequent decreases in the doses or the omission of corticosteroids altogether may be considered if patients tolerate pemetrexed infusions without reaction.
    • Systemic corticosteroids should typically be avoided during administration of anti-PD-1 therapy because of the competitive mechanism of action on T-cells, and use of dexamethasone as a premedication for carboplatin and/or pemetrexed should be determined on the basis of clinic and health system guidelines, along with input from other healthcare providers.

Clinical Pearls1,2

  • Pembrolizumab, pemetrexed, and carboplatin are given once every 3 weeks for four cycles; then patients should transition to pembrolizumab every 3 weeks for 24 months with or without indefinite pemetrexed maintenance.
    • Pembrolizumab should be given on day 1 prior to the administration of pemetrexed and carboplatin.
    • The dosing for pembrolizumab is a flat-based dose of 200 mg infused over 30 minutes, which is the same dose used for its other NSCLC indications as well as head and neck squamous cell carcinoma and Hodgkin lymphoma in adults. Pembrolizumab dosing is weight based (2 mg/kg) when indicated for melanoma in adults and Hodgkin lymphoma in pediatric patients.
    • The dosing for chemotherapy in this trial was pemetrexed 500 mg/m2 infused over 10 minutes and carboplatin area under the curve 5 mg/ml/min infused over 15–60 minutes.
    • The dose of pembrolizumab and pemetrexed remains the same during maintenance therapy (200 mg and 500 mg/m2, respectively).
  • The benefit of adding pembrolizumab to standard chemotherapy was seen regardless of PD-L1 expression on tumor cells.
    • The sample sizes were small in the subgroup analyses; there were 21 patients (35%) with a programmed death-ligand 1 (PD-L1) tumor proportion score less than 1%, 19 patients (32%) with 1%–49% PD-L1 expression, and 20 patients (33%) with PD-L1 expression greater than or equal to 50%.

References

  1. Langer CJ, Gadgeel SM, Borghaei H, et al; KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508.
  2. Keytruda (pembrolizumab) for injection [package insert]. Whitehouse Station, NJ. Merck and Co., Inc. May 2017.
  3. Non-Small Cell Lung Cancer. Version 8.2017. National Comprehensive Cancer Network. Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf Accessed July 2017.
  4. MASCC/ESMO Antiemetic Guideline 2016. Multinational Association of Supportive Care in Cancer. Available at: www.mascc.org/assets/Guidelines-Tools/mascc_antiemetic_guidelines_english_2016_v.1.2.pdf. Accessed July 2017.
  5. Alimta (pemetrexed) for injection [package insert]. Indianapolis, IN. Eli Lilly and Co. February 2015.
  6. Elsoueidi R, Lander MJ, Richa EM, Adane ED. Single-dose dexamethasone for the prevention of pemetrexed associated cutaneous adverse reactions. J Oncol Pharm Pract. 2016 Apr;22(2):271-274.
  7. Sakurada T, Kakiuchi S, Tajima S, et al. Pemetrexed-induced rash may be prevented by supplementary corticosteroids. Biol Pharm Bull. 2015;38(11):1752-1756.

March 14, 2017, with PAP

http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s015lbl.pdf

On March 14, 2017, The U.S. Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA®, Merck and Co., Inc.) for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or those who have relapsed after three or more prior lines of therapy.

Approval was based on data from 210 adult cHL patients enrolled in a multicenter, non-randomized, open-label clinical trial. Patients had refractory or relapsed disease after autologous stem cell transplantation (ASCT; 129 patients) and/or brentuximab vedotin (175 patients), and received a median of four prior systemic therapies (range: 1, 12). With a median follow-up of 9.4 months (range: 1-15), the overall response rate was 69% (95% CI: 62, 75). This included partial responses in 47% of patients and complete responses in 22%. The estimated median response duration was 11.1 months (range 0+ to 11.1). Efficacy in pediatric patients was extrapolated from results observed in adults.

Safety was evaluated in 210 adults with cHL. In adults, the most common (at least 20%) adverse reactions were fatigue, pyrexia, cough, musculoskeletal pain, diarrhea, rash and hypertransaminasemia. Additional common adverse reactions (at least 10%) included dyspnea, arthralgia, vomiting, nausea, pruritus, hypothyroidism, upper respiratory tract infections, headache, peripheral neuropathy, hyperbilirubinemia and increased creatinine. Other immune-mediated adverse reactions occurring in 0.5%-9% of patients included infusion reactions, hyperthyroidism, pneumonitis, uveitis, myositis, myelitis and myocarditis. Fifteen percent had an adverse reaction requiring systemic corticosteroid therapy. Pembrolizumab was discontinued due to adverse reactions in 5% of patients, and treatment was interrupted due to adverse reactions in 26%.

Safety was also evaluated in 40 children with advanced melanoma, PD-L1 positive solid tumors, or lymphoma. The safety profile in the pediatric patients was similar to that observed in adults. Adverse reactions occurring at a higher rate (difference of 15% or greater) in children than adults included fatigue, vomiting, abdominal pain, hypertransaminasemia and hyponatremia. Pembrolizumab exposure in these pediatric patients at a dose of 2 mg/kg every 3 weeks was comparable to that seen in adults. FDA has required the sponsor to evaluate pembrolizumab’s long-term safety in pre-pubertal patients, and those who have not completed pubertal development.

A new “Warning and Precaution” was added for complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT) after pembrolizumab. Transplant-related deaths have occurred, and health care professionals should follow patients closely for early evidence of transplant-related complications, such as hyperacute graft-versus-host-disease (GVHD), severe (grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions. FDA has required the sponsor to further study the safety of allogeneic HSCT after pembrolizumab therapy.

The recommended dose and schedule of pembrolizumab for cHL is 200 mg every 3 weeks for adults and 2 mg/kg (up to 200 mg) every 3 weeks for pediatric patients.

Full prescribing information for pembrolizumab is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s015lbl.pdf

FDA granted pembrolizumab Orphan Drug Designation for the treatment of HL, and Breakthrough Therapy Designation for the current indication. This application also received priority review status and accelerated approval. Further studies are required to confirm clinical benefit of pembrolizumab for this indication. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Pharmacist's Application to Practice - March 14, 2017

Pembrolizumab (Keytruda) for the Treatment of Adult and Pediatric Patients with Refractory Classical Hodgkin Lymphoma or Those Who Have Relapsed After Three or More Prior Lines of Therapy

Author: Brittany Jensen, PharmD, and Krista E. Foley, PharmD
PGY-2 Oncology Pharmacy Residents
Aurora Health Care
Milwaukee, WI

What is the potential role for pembrolizumab in the management of refractory classical Hodgkin lymphoma?1-4

  • Pembrolizumab (Keytruda) has been on the market since 2014 for the following indications:
    • unresectable or metastatic melanoma
    • metastatic non-small-cell lung carcinoma (NSCLC) with high programmed death-ligand 1 (PD-L1) expression or low PD-L1 expression with disease progression on or after platinum-containing chemotherapy
    • recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.
  • Recent data have shown that pembrolizumab may be effective in children and adults with classical Hodgkin lymphoma (cHL) who have refractory or relapsed disease.
  • In a phase-2 study (Keynote-087) of 210 adults with cHL who had refractory or relapsed disease after an autologous stem cell transplantation and/or brentuximab vedotin and received a median of four prior systemic therapies, pembrolizumab 200 mg was given intravenously (IV) every 3 weeks until unacceptable toxicity or documented disease progression or for up to 24 months. Efficacy results included an overall response rate of 69% (complete remission, 22%; partial remission, 47%) and median response duration of 11.1 months, which is comparable to, if not slightly higher than, the results of current treatment options.
  • Current treatment options for patients with relapsed or refractory cHL who have tried at least three prior therapies are limited and include brentuximab, bendamustine, everolimus, lenalidomid, and nivolumab.
  • Pembrolizumab 200 mg IV over 30 minutes every 3 weeks for up to 24 months or until disease progression is an option for patients who have relapsed or refractory disease after three or more lines of therapy.

What role can the pharmacist play in the management of patients on pembrolizumab?1,5-8

  • The adverse effects of pembrolizumab are immune-mediated and develop by enhancing and reversing the T-cell suppression. These toxicities require evaluation prior to each dose. Patients should be monitored for the following:
    • Pneumonitis (shortness of breath, chest pain, new or persistent cough)
    • Colitis (diarrhea, abdominal pain, blood or mucus in stool)
    • Abnormal thyroid function (weight loss or gain, rapid heart rate, sweating, feeling cold, constipation)—monitor thyroid function (at baseline, periodically during treatment, and as clinically indicated)
  • Hepatitis (yellowing of skin or eyes, dark coloring, bruising or bleeding)—monitor trends in liver function tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and total bilirubin)
  • Nephritis (change in amount or color of urine)—monitor trends in kidney function (serum creatinine and blood urea nitrogen)
  • Hypophysitis (headaches, dizziness or fainting, visual changes).
  • If an immune-mediated adverse reaction occurs, it may require corticosteroids, withholding dose, or permanent discontinuation, depending on the severity. If corticosteroids are indicated, treatment may be required for at least 3 or 4 weeks. It is important to note that, if a patient is on prednisone greater than or equal to 1 mg/kg (or equivalent) for over 1 month, antibiotic prophylaxis with sulfamethoxazole-trimethoprim (Bactrim) may be considered until the steroid dose is less than prednisone 10 mg per day or the equivalent.

Clinical Pearls1-9

  • Pembrolizumab was approved based on phase-2 data, but further studies are comparing its effectiveness to brentuximab in patients previously not treated with brentuximab.
  • Overall response rates have favored pembrolizumab over nivolumab; however, adverse effects (e.g., fatigue, hypothyroidism, and pyrexia) have been more common in the pembrolizumab studies.
  • Dosing is not weight based for this indication.
  • PD-L1 expression testing is not required for relapsed or refractory cHL.
  • Immune-mediated toxicities are generally mild and are reversible with the use of corticosteroids; however, endocrinopathies are generally irreversible.
  • Patients should be counseled about these toxicities prior to initiation of therapy and assessed for these toxicities prior to each dose.

References

  • Keytruda® (pembrolizumab) for injection [package insert]. Whitehouse Station, NJ: Merck & Co.; 2014.
  • Moskowitz CH, Zinzani PL, Fanale MA, et al. Pembrolizumab in relapsed/refractory classical Hodgkin lymphoma: primary endpoint analysis of the phase 2 Keynote-087 study. Presented at the 58th American Society of Hematology (ASH) Annual Meeting. December 4–6, 2016; San Diego, CA. Abstract 1107.
  • National Comprehensive Cancer Network. Hodgkin Lymphoma. Version 1.2017. Retrieved from: https://www.nccn.org/professionals/physician_gls/pdf/hodgkins.pdf. Accessed April 6, 2017.
  • U.S. Food and Drug Administration. Pembrolizumab (KEYTRUDA) for classical Hodgkin lymphoma. Retrieved from: https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm546893.htm. March 15, 2017. Accessed April 8, 2017.
  • Naidoo J, Page DB, Li BT, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol 2015;26(12):2375-91.
  • Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev 2016;44:51-60.
  • Champiat S, Lambotte O, Barreau E, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol 2016;27(4):559-74.
  • Helwick C. Pearls for managing immune-related toxicities. ASCO Post. Retrieved from: http://www.ascopost.com/issues/october-10-2016/pearls-for-managing-immune-related-toxicities. October 10, 2016. Accessed April 8, 2017.
  • Timmerman J, Engert A, Younes A, et al. CheckMate 205 update with minimum 12-month follow up: A phase 2 study of nivolumab in patients with relapsed/refractory classical Hodgkin lymphoma. Presented at the 58th American Society of Hematology (ASH) Annual Meeting. December 4–6, 2016; San Diego, CA. Abstract 1110.

October 24, 2016, with PAP

http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125514s012lbl.pdf

On October 24, 2016, the U.S. Food and Drug Administration approved pembrolizumab (KEYTRUDA, Merck & Co., Inc.) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 as determined by an FDA-approved test.

This is the first FDA approval of a checkpoint inhibitor for first-line treatment of lung cancer. This approval also expands the indication in second-line treatment of lung cancer to include all patients with PD-L1-expressing NSCLC.

The FDA approval added the following indications for pembrolizumab:

  • Patients with metastatic NSCLC whose tumors have high PD-L1 expression (Tumor Proportion Score [TPS] greater than or equal to 50%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and no prior systemic chemotherapy treatment for metastatic NSCLC.
  • Patients with metastatic NSCLC whose tumors express PD-L1 (TPS greater than or equal to 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab.

Approval was based on results of two randomized, controlled trials that demonstrated statistically significant improvements in progression-free survival (PFS) and overall survival (OS) for patients randomized to pembrolizumab compared with chemotherapy.

In a trial of 305 patients who had no prior treatment for metastatic NSCLC and TPS greater than or equal to 50%, those who received pembrolizumab (200 mg every 3 weeks) had a significant improvement in PFS (HR 0.50 [95% CI: 0.37, 0.68]; p<0.001) with a median PFS of 10.3 months versus 6.0 months for those receiving platinum-based chemotherapy. A pre-specified interim analysis demonstrated a statistically significant improvement in OS for patients randomized to pembrolizumab as compared with chemotherapy (HR 0.60 [95% CI: 0.41, 0.89]; p<0.005).

In a three-arm trial of 1033 patients who were previously treated for metastatic NSCLC with a TPS greater than or equal to 1%, those randomized to pembrolizumab 2 mg/kg every 3 weeks (HR 0.71 (95% CI: 0.58, 0.88]; p<0.001) or pembrolizumab 10 mg/kg every 3 weeks (HR 0.61 [95% CI: 0.49, 0.75]; p<0.001) had an improved OS compared with patients receiving docetaxel. The median survival was 10.4 months in the pembrolizumab 2 mg/kg arm, 12.7 months in the pembrolizumab 10 mg/kg arm, and 8.5 months in the docetaxel arm.

The most common side effects of treatment with pembrolizumab included decreased appetite, fatigue, nausea, dyspnea, cough, and constipation. Rare but serious adverse events included immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.

The recommended dose and schedule of pembrolizumab for NSCLC is 200 mg intravenously every three weeks.

FDA granted pembrolizumab breakthrough therapy designation and priority review status, and previously granted accelerated approval. The current approval converts the prior accelerated approval in second-line treatment of metastatic NSCLC patients to regular approval. The application for the first-line indication was approved nearly three months before the PDUFA goal date. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.

Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125514s012lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Pharmacist's Application to Practice - October 24, 2016

Pembrolizumab for Metastatic Non-Small Cell Lung Cancer with Tumors Expressing PD-L1

Author: Carolyn Oxencis, PharmD BCOP BCPS
Clinical Oncology Pharmacist
Froedtert and the Medical College of Wisconsin Department of Pharmacy
Milwaukee, WI

What is the potential role for pembrolizumab in the treatment of metastatic non–small cell lung cancer (NSCLC)?

  • Pembrolizumab has been approved via breakthrough therapy designation and priority review status for first-line treatment and by previously granted accelerated approval for the second-line treatment of patients with NSCLC whose tumors express PD-L1, as determined by an FDA-approved test.1
    • Patients with metastatic NSCLC whose tumors have high PD-L1 expression (Tumor Proportion Score [TPS] greater than or equal to 50%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations and no prior systemic chemotherapy treatment for metastatic NSCLC are candidates for first-line treatment with pembrolizumab.1
    • Patients with metastatic NSCLC whose tumors express PD-L1 (TPS greater than or equal to 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy, are candidates for second-line treatment with pembrolizumab.1
  • This is the first FDA approval of a checkpoint inhibitor for first-line treatment of lung cancer.
  • This approval also expands the indication in second-line treatment of lung cancer to include all patients with PD-L1-expressing NSCLC.1
    • First-line approval is based on data from the phase 3 KEYNOTE-024 trial, where single-agent pembrolizumab improved progression-free survival (PFS) by 4.3 months compared with doublet platinum-based chemotherapy for untreated patients with advanced NSCLC with PD-L1 expression on ≥50% of cells.2
    • Second-line approval is based on data from the KEYNOTE-010 trials.3

What role can the pharmacist play in the management of patients on pembrolizumab?

    • Monitor patients receiving immunotherapy carefully for immune-related adverse effects.5
    • Ensure that PD-L1 expression via an FDA-approved test is completed prior to initiation of first- or second-line therapy with pembrolizumab in this patient population.

Clinical Pearls

  • Pembrolizumab was administered in KEYNOTE-024 at a fixed, non-weight-based dose of 200 mg as an intravenous infusion over 60 minutes every 3 weeks, until disease progression or unacceptable toxicity.2,5
  • Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab.1,5

References

  1. U.S. Food and Drug Administration. Pembrolizumab (Keytruda) Checkpoint Inhibitor. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm526430.htm. Updated October 25, 2016. Accessed January 27, 2017.
  2. Reck M, Rodriguez-Abreu D, Robinson AG, et al. KEYNOTE-024: Pembrolizumab vs platinum-based chemotherapy as first-line therapy for advanced NSCLC with a PD-L1 tumor proportion score (TPS) ≥50%. Presented at 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA8.
  3. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-33.
  4. Herbst RS, Baas P, Kim D-W, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540-50.
  5. Keytruda® [package insert]. Merck and Co., Inc., Whitehouse Station, NJ; September 2014. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125514lbl.pdf. Accessed Jan 27, 2017.

August 5, 2016

http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125514s009lbl.pdf

On August 5, 2016, the U. S. Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA® injection, Merck Sharp & Dohme Corp.) for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.

The approval was based on demonstration of a durable objective response rate (ORR) in a subgroup of patients in an international, multicenter, non-randomized, open-label, multi-cohort study. This subgroup included 174 patients with recurrent or metastatic HNSCC who had disease progression on or after platinum-containing chemotherapy. Patients received intravenous pembrolizumab 10 mg/kg every 2 weeks or 200 mg every 3 weeks.

ORR was determined by an independent review committee according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The ORR for these 174 patients was 16% (95% confidence interval [CI] 11, 22). The median response duration had not been reached at the time of analysis. The range for duration of response was 2.4 months to 27.7 months (response ongoing). Among the 28 responding patients, 23 (82%) had responses of 6 months or longer.        

Safety data was evaluated in 192 patients with HNSCC receiving at least one dose of pembrolizumab 10 mg/kg every 2 weeks or 200 mg every 3 weeks. The most common (greater than or equal to 20%) adverse reactions were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were similar to those occurring in patients with melanoma or NSCLC, with the exception of an increased incidence of facial edema (10% all grades, 2.1% grades 3-4) and new or worsening hypothyroidism (14.6% all grades). The most frequent (greater than or equal to 2%) serious adverse reactions were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. Clinically significant immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, adrenal insufficiency, diabetes mellitus, skin toxicity, myositis, and thyroid disorders.

As a condition of the accelerated approval, Merck is required to conduct a multicenter, randomized trial establishing the superiority of pembrolizumab over standard therapy to verify and describe the clinical benefit of pembrolizumab. Merck has an ongoing multicenter, randomized trial (KEYNOTE 040) in patients with recurrent or met HNSCC with disease progression on or after platinum-containing chemotherapy with a primary endpoint of overall survival.  

The recommended dose and schedule of pembrolizumab for this indication is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks.

The current indication was approved under FDA’s accelerated approval program. This application was granted Priority Review. A description of these expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.

Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125514s009lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


October 2, 2015

http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125514s005lbl.pdf

On October 2, 2015, the U. S. Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA® Injection, Merck Sharp and Dohme Corporation) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express programmed death ligand 1 (PD-L1) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab.

Approval was based on demonstration of a durable objective response rate (ORR) in an international, multicenter, open-label, activity-estimating subgroup within Trial P001. This prospectively identified and retrospectively analyzed subgroup included 61 patients with NSCLC, PD-L1 expression tumor proportion score (TPS) of greater than or equal to 50% tumor cells, and disease progression on or after platinum-containing chemotherapy, and, if appropriate, targeted therapy for ALK or EGFR mutations. Patients received intravenous pembrolizumab 10 mg/kg every 3 weeks or every 2 weeks.

ORR was determined by blinded independent review committee according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The ORR for the 61 patients was 41.0% [95% confidence interval (CI): 28.6%, 54.3%)]. The median response duration was not yet reached at the analysis time. Of the 25 patients with responses, 21 (84%) remained without disease progression, and 11 patients had responses for at least 6 months.

Safety data was evaluated in 550 patients with NSCLC receiving at least one dose of pembrolizumab 10 mg/kg every 2 or every 3 weeks, or 2 mg/kg every 3 weeks. The most common (greater than or equal to 20%) adverse reactions included fatigue, decreased appetite, dyspnea and cough. The most frequent (greater than or equal to 2%) serious adverse drug reactions were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. Clinically significant immune-mediated adverse reactions included pneumonitis, colitis, hypophysitis, and thyroid disorders.

As a condition of this accelerated approval, Merck is required to conduct a multicenter, randomized trial establishing the superiority of pembrolizumab over standard therapy to verify and describe the clinical benefit of pembrolizumab. Merck has an ongoing multicenter, randomized trial in patients with NSCLC (Trial P010) with co-primary endpoints of progression-free survival and overall survival.

An FDA approved companion diagnostic, PD-L1 IHC 22C3 pharmDx, to determine PD-L1 expression is now available.

The recommended dose and schedule of pembrolizumab is 2 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks.

Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125514s005lbl.pdf.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


December 18, 2015

http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125514s004s006lbl.pdf

On December 18, 2015, the U. S. Food and Drug Administration (FDA) expanded the label to include the approval of pembrolizumab (Keytruda® Injection, Merck Sharp & Dohme Corp.) for the treatment of patients with unresectable or metastatic melanoma. This expansion now includes the initial treatment of patients with unresectable or metastatic melanoma with pembrolizumab.

In 2014 pembrolizumab received accelerated approval based on a clinically meaningful, durable objective response rate in patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Two new clinical trials described below verify the clinical benefit of pembrolizumab.

The first trial enrolled 834 patients with unresectable or metastatic melanoma who had not received ipilimumab and who had received no more than one line of prior systemic therapy. Patients were randomized (1:1:1) to pembrolizumab 10 mg/kg intravenously every 2 weeks (Q2W), or pembrolizumab 10 mg/kg every 3 weeks (Q3W), or to ipilimumab 3 mg/kg intravenously Q3W for up to 4 doses. Patients treated with pembrolizumab were treated until disease progression. The trial met its co-primary endpoints of overall survival (OS) and progression-free survival (PFS) as assessed by a blinded independent central review (BICR) per RECIST v1.1. The pembrolizumab 10 mg/kg Q2W and Q3W arms demonstrated statistically significant improvements in OS compared to the ipilimumab arm with hazard ratios (HR) of 0.63 (95% CI: 0.47, 0.83; p<0.001) and 0.69 (95% CI: 0.52, 0.90; p=0.004), respectively. Median OS was not reached in either pembrolizumab arm. As compared to the ipilimumab arm, a significant improvement in PFS was observed in the pembrolizumab 10 mg/kg Q2W and Q3W arms with HR of 0.58 [95% CI 0.46, 0.72]; p<0.001 and 0.58 [95% CI: 0.47, 0.72]; p<0.001, respectively. Median PFS was 5.5 and 4.1 months in the pembrolizumab 10 mg/kg Q2W and Q3W arms, respectively, and was 2.8 months in the ipilimumab arm. The overall response rates were 34 %, 33 %, and 12% for patients in the pembrolizumab 10 mg/kg Q2W, 10 mg/kg Q3W, and ipilimumab arms, respectively. Median response durations were not reached for any treatment arm.

The second trial enrolled 540 patients with unresectable or metastatic melanoma who were refractory to prior ipilimumab and a BRAF inhibitor, if BRAF V600 mutation positive who were randomized (1:1:1) to either pembrolizumab 2 mg/kg, or 10 mg/kg (both Q3W), or to investigator’s choice chemotherapy. Among the 155 patients assigned to investigator choice chemotherapy who experienced progression of disease (PD) on chemotherapy (confirmed by BICR), 55% received pembrolizumab post-progression. The co-primary endpoints were PFS as assessed by a BICR per RECIST 1.1 and OS. The trial demonstrated a statistically significant improvement in BICR-assessed PFS in the pembrolizumab 2 mg/kg arm (HR of 0.57 [95% CI: 0.45, 0.73]; p<0.001) and in the pembrolizumab 10 mg/kg arm (HR of 0.50 [95% CI: 0.39, 0.64]; p<0.001) compared to chemotherapy. There was no statistically significant difference between either pembrolizumab arm compared to the chemotherapy arm in the interim OS analysis.

Safety data was evaluated in 1567 patients with unresectable or metastatic melanoma who received pembrolizumab at 2 mg/kg Q3W, or 10 mg/kg delivered either Q2W or Q3W. The most serious risks of pembrolizumab are immune-mediated adverse reactions (imARs), including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. Other clinically significant imARs included arthritis, exfoliative dermatitis, bullous pemphigoid, uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and inflammatory foci in brain parenchyma resulting in partial seizures. The most common adverse events reported included fatigue, pruritus, rash, constipation, nausea, diarrhea, and decreased appetite.

In exposure-response analyses across the dose range of pembrolizumab 2 mg/kg Q3W and 10 mg/kg Q3W in the second trial, no relationship was observed between efficacy or safety and pembrolizumab exposure.

The recommended dose and schedule for pembrolizumab is 2 mg/kg Q3W administered as an intravenous infusion every 3 weeks until disease progression or unacceptable toxicity.

This application was granted Priority Review. The development program for pembrolizumab for this indication received orphan drug designation and was granted breakthrough therapy designation. A description of the expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.

Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125514s004s006lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


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