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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.


March 22, 2019–Atezolizumab (TECENTRIQ, Genentech Inc.) in combination with carboplatin and etoposide, for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC).

March 8, 2019–Atezolizumab (TECENTRIQ, Genentech Inc.) in combination with paclitaxel protein-bound for adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] of any intensity covering ≥ 1% of the tumor area), as determined by an FDA-approved test (with Pharmacist's Applications to Practice)

December 6, 2018–Atezolizumab (TECENTRIQ, Genentech, Inc.), approved in combination with bevacizumab, paclitaxel, and carboplatin for the first-line treatment of patients with metastatic non-squamous, non-small cell lung cancer (NSq NSCLC) with no EGFR or ALK genomic tumor aberrations.

October 18 2016–Atezolizumab (Tecentriq, Genentech Oncology) approved for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose disease progressed during or following 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 atezolizumab (with Pharmacist's Applications to Practice)

May 18, 2016–Atezolizumab injection (Tecentriq™) approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma (with Pharmacist's Applications to Practice)


March 22, 2019

https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761034s019lbl.pdf

On March 18, 2019, the Food and Drug Administration approved atezolizumab (TECENTRIQ, Genentech Inc.) in combination with carboplatin and etoposide, for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC).

Approval was based on IMpower133 (NCT02763579), a randomized (1:1), multicenter, double-blind, placebo-controlled trial in 403 patients with ES-SCLC who received no prior chemotherapy for extensive stage disease and had ECOG performance status 0 or 1. Patients were randomized to one of the following:

  • atezolizumab 1200 mg and carboplatin AUC 5 mg/mL/min on day 1 and etoposide 100 mg/m2 intravenously on days 1, 2 and 3 of each 21-day cycle for a maximum of 4 cycles, followed by atezolizumab 1200 mg once every 3 weeks until disease progression or unacceptable toxicity, or
  • placebo and carboplatin AUC 5 mg/mL/min on day 1 and etoposide 100 mg/m2 intravenously on days 1, 2, and 3 of each 21-day cycle for a maximum of 4 cycles, followed by placebo once every 3 weeks until disease progression or unacceptable toxicity.

Major efficacy outcome measures were overall survival (OS) and progression-free survival (PFS) as assessed by investigator per RECIST 1.1 in the intent-to-treat population. Median OS was 12.3 months (10.8, 15.9) for patients receiving atezolizumab with chemotherapy and 10.3 months (9.3, 11.3) for those receiving placebo with chemotherapy (hazard ratio 0.70; 95% CI: 0.54, 0.91; p=0.0069). Median PFS was 5.2 months (4.4, 5.6) compared with 4.3 months (4.2, 4.5) in the atezolizumab and placebo arms, respectively (HR 0.77; 0.62, 0.96; p=0.0170).

The most common adverse reactions reported in ≥ 20% of patients who received atezolizumab in IMpower133 were fatigue/asthenia, nausea, alopecia, constipation, and decreased appetite.

The recommended atezolizumab dose for patients with ES-SCLC is 1200 mg intravenously over 60 minutes every 3 weeks. When administered on the same day, atezolizumab should be administered prior to chemotherapy. If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes.

View full prescribing information for TECENTRIQ

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.

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.


March 8, 2019, with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761034s018lbl.pdf

On March 8, 2019, the Food and Drug Administration granted accelerated approval to atezolizumab (TECENTRIQ, Genentech Inc.) in combination with paclitaxel protein-bound for adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] of any intensity covering ≥ 1% of the tumor area), as determined by an FDA-approved test.

FDA also approved the VENTANA PD-L1 (SP142) Assay as a companion diagnostic device for selecting TNBC patients for atezolizumab.

Approval was based on IMpassion130 (NCT02425891), a multicenter, international, double-blinded, placebo-controlled, randomized trial that included 902 patients with unresectable locally advanced or metastatic TNBC who had not received prior chemotherapy for metastatic disease. Patients were randomized (1:1) to receive either atezolizumab (840 mg) or placebo intravenous infusions on days 1 and 15 of every 28-day cycle, plus paclitaxel protein-bound (100 mg/m2) administered via intravenous infusion on days 1, 8, and 15 of every 28-day cycle.

Tumor specimens (archival or fresh) were evaluated prospectively using the VENTANA PD-L1 (SP142) Assay at a central laboratory and the results were used as a stratification factor for randomization and to define the PD-L1 positive population for pre-specified analyses.

In patients whose tumors express PD-L1, median progression-free survival (PFS) was 7.4 months (6.6, 9.2) for patients receiving atezolizumab with paclitaxel protein-bound and 4.8 months (3.8, 5.5) for those receiving placebo with paclitaxel protein-bound. The stratified hazard ratio for PFS was 0.60 (95% CI: 0.48, 0.77; p<0.0001) in favor of the atezolizumab plus paclitaxel protein-bound arm. Objective response rate (ORR) in patients with confirmed responses was 53% compared to 33% for the atezolizumab and the placebo-containing arms, respectively. Overall survival data were immature with 43% deaths in the intent to treat (ITT) population.

The most common adverse reactions (reported in ≥ 20% of patients) with atezolizumab with paclitaxel protein-bound were alopecia, peripheral neuropathies, fatigue, nausea, diarrhea, anemia, constipation, cough, headache, neutropenia, vomiting, and decreased appetite.

This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

The recommended atezolizumab dose for patients with TNBC whose tumors express PD-L1 is 840 mg administered as an intravenous infusion over 60 minutes, followed by 100 mg/m2 paclitaxel protein-bound. For each 28-day cycle, atezolizumab is administered on days 1 and 15, and paclitaxel protein-bound is administered on days 1, 8, and 15 until disease progression or unacceptable toxicity.

View full prescribing information for TECENTRIQ.

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.

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

Atezolizumab for Unresectable Locally Advanced or Metastatic Triple-Negative Breast Cancer

Author: Emma Carroll, PharmD BCOP
University of Chicago Medicine Department of Pharmacy
Chicago, IL

What is the potential role for atezolizumab in the treatment of breast cancer?1-3

Atezolizumab in combination with nanoparticle albumin bound (nab)–paclitaxel is a new treatment option for patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) whose programmed death-ligand 1 (PD-L1) stained tumor-infiltrating immune cells of any intensity cover 1% or more of the tumor area.

  • Approval was based on the IMpassion130 study, a phase 3 randomized double-blind placebo-controlled trial of first-line atezolizumab plus nab-paclitaxel versus placebo plus nab-paclitaxel in patients with locally advanced or metastatic TNBC. The median progression-free survival (PFS) was significantly increased in the atezolizumab plus nab-paclitaxel arm in both the intention to treat (ITT) group (7.2 vs 5.5 months; hazard ratio [HR], 0.8; 95% confidence interval [CI], 0.69–0.92; p = .002) as well as PD-L1-positive patients (7.5 vs. 5 months; HR, 0.62; 95% CI, 0.49–0.78; p < .001). In the subgroup analysis, a 2.5-month increase in median PFS was seen in PD-L1-positive patients receiving atezolizumab, compared to no difference in patients who were PD-L1 negative. The median overall survival (OS) in the ITT group was numerically longer in the atezolizumab plus nab-paclitaxel group but not statistically significant (21.3 vs. 17.6 months; HR, 0.84; 95% CI, 0.69–1.02; p = .08). Although statistics were not performed for OS in PD-L1-positive patients at this point, OS in the atezolizumab plus nab-paclitaxel was 10 months longer at the interim analysis (25 vs. 15.5 months; HR, 0.62; 95% CI, 0.45–0.86).
  • This is the first immunotherapy approved by the U.S. Food and Drug Administration (FDA) for use in treating breast cancer.

What role can the pharmacist play in the management of patients on atezolizumab?1,4-6

  • The atezolizumab dosing and frequency used in treating TNBC differ from that used in treating urothelial or lung cancer; ensure that dosing and schedule are appropriate.
  • Atezolizumab should be administered prior to nab-paclitaxel on days 1 and 15.
  • Infusion time for the first dose of atezolizumab is 60 minutes. Infusion time can be reduced to 30 minutes for subsequent doses if no infusion reactions occurred previously.
  • Atezolizumab is a fully humanized monoclonal antibody with only 1% incidence of infusion-related reactions; however, close monitoring during administration is recommended. Prophylactic administration of antihistamines, antipyretics, or corticosteroids is not recommended.
  • Avoid corticosteroids unless one is intending to treat adverse effects.
  • Monitor for immune-mediated adverse events and use guidelines created by the National Comprehensive Cancer Network, the American Society of Clinical Oncology, and the European Society for Medical Oncology to help manage these toxicities.

Clinical Pearls1-3

  • Dosing for atezolizumab is 840 mg on day 1 and day 15 of a 28-day cycle. This dosing is unique to treatment of TNBC.
  • The FDA approved the Ventana PD-L1 (SP142) assay to detect PD-L1 protein expression levels on tumor-infiltrating immune cells to help determine which patients may benefit from treatment with atezolizumab.
  • FDA approval for atezolizumab in TNBC is under accelerated approval based on PFS. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
  • Nab-paclitaxel was chosen over paclitaxel because of the hypothesized negative effect of steroids (which would be required for premedication [per labeling] with solvent-based paclitaxel) on atezolizumab activity.

References

  1. Tecentriq (atezolizumab) for injection [package insert]. South San Francisco, CA: Genentech, Inc.; May 2019.
  2. Schmid P, Adams S, Rugo HS, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379:2108-2121.
  3. U.S. Food and Drug Administration. FDA approves atezolizumab for PD-L1 positive unresectable locally advanced or metastatic triple-negative breast cancer. Silver Spring, MD: US Food and Drug Administration; updated 2019 March 18; accessed May 20, 2019. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-atezolizumab-pd-l1-positive-unresectable-locally-advanced-or-metastatic-triple-negative
  4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Management of Immunotherapy-Related Toxicities (Management of Checkpoint Inhibitor-Related Toxicities). Version 2.2019. Available at https://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf
  5. Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2018;36(17):1714-1768.
  6. Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment, and follow-up. Ann Oncol. 2017;28(suppl_4):iv119-iv142.

December 6, 2018

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761034s009lbl.pdf

On December 6, 2018, the Food and Drug Administration approved Atezolizumab (TECENTRIQ, Genentech, Inc.), in combination with bevacizumab, paclitaxel, and carboplatin for the first-line treatment of patients with metastatic non-squamous, non-small cell lung cancer (NSq NSCLC) with no EGFR or ALK genomic tumor aberrations.

Approval was based on the IMpower150 trial (NCT02366143), an open-label, randomized (1:1:1), three-arm trial enrolling 1202 patients receiving first-line treatment for metastatic NSq NSCLC. Eighty-seven percent (1045 patients) were identified as not having EGFR or ALK tumor mutations. The trial was designed to conduct comparisons between each of the atezolizumab-containing arms with the control arm. Patients were randomized to receive the following:

  • Atezolizumab, carboplatin, paclitaxel, and bevacizumab (4-drug regimen);
  • Atezolizumab, carboplatin and paclitaxel (3-drug regimen); or
  • Carboplatin, paclitaxel, and bevacizumab (control arm).

Following completion of 4 or 6 cycles of carboplatin and paclitaxel, patients continued to receive bevacizumab in the 4-drug arm and the control arm and continued to receive atezolizumab in the two experimental arms until disease progression or unacceptable toxicity. The major efficacy measures were overall survival (OS) and progression-free survival (PFS).

Among patients with NSq NSCLC without an EGFR or ALK mutation, the estimated median OS was 19.2 months for patients receiving the 4-drug regimen and 14.7 months for those receiving, carboplatin, paclitaxel, and bevacizumab (hazard ratio [HR] 0.78; 95% CI: 0.64, 0.96; p=0.016). The estimated median PFS was 8.5 months for patients receiving the 4-drug regimen and 7.0 months for those in the control arm (HR 0.71; 95% CI 0.59, 0.85; p=0.0002). The overall response rates were 55% in the 4-drug arm and 42% in the control arm. No significant differences in interim OS or final PFS were observed between the 3-drug arm and the control arm.

The most common adverse reactions (reported in ≥ 20% of patients) with atezolizumab administered with carboplatin, paclitaxel, and bevacizumab were fatigue/asthenia, alopecia, nausea, diarrhea, constipation, decreased appetite, arthralgia, hypertension, and neuropathy. Atezolizumab was discontinued for adverse reactions in 15% of patients; the most common adverse reaction resulting in discontinuation of atezolizumab was pneumonitis (1.8%).

The incidence of development antibodies to atezolizumab (anti-drug antibodies, ADA) ranges from 30% to 42% across clinical studies supporting the approved indications. Among 364 patients with NSCLC who received the 4-drug regimen in the IMpower150 study, 36% (n=132) had treatment-emergent antibodies against atezolizumab with the majority (83% of these 132 patients) having ADA prior to receiving the second atezolizumab dose. Patients who tested positive for treatment-emergent ADA had lower systemic atezolizumab exposure compared to those who were ADA negative. In an exploratory analysis, the HR for OS was similar in the ADA-positive (0.69; 95% CI: 0.44, 1.07) and the ADA-negative subgroups (0.64; 95% CI: 0.46, 0.90). The presence of ADA neither increased the incidence nor severity of adverse reactions. Given the high rate of ADA, Genentech has agreed to conduct analyses across the atezolizumab development program to evaluate the effects of ADA on efficacy, safety, and pharmacokinetics.

The recommended atezolizumab dose is 1200 mg intravenously over 60 minutes every 3 weeks.

View full prescribing information for TECENTRIQ.

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.

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.


October 18, 2016, with PAP

http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761041lbl.pdf

On October 18, 2016, FDA approved atezolizumab (Tecentriq, Genentech Oncology) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose disease progressed during or following 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 atezolizumab.

Atezolizumab is a programmed death-ligand 1 (PD-L1) blocking antibody that previously received FDA accelerated approval for the treatment of locally advanced or metastatic urothelial carcinoma that has progressed after platinum-containing chemotherapy.

This approval was based on two international, randomized, open-label clinical trials (OAK and POPLAR) that demonstrated consistent results in efficacy and safety in a total of 1137 patients with NSCLC. Compared with docetaxel, treatment with atezolizumab in the intended patient population in the two trials resulted in a 4.2 and a 2.9 month improvement in overall survival (OS), respectively.

The median OS in OAK was 13.8 months (95% confidence interval [CI] 11.8,15.7) in the atezolizumab arm compared to 9.6 months (95% CI 8.6,11.2) in the docetaxel arm (hazard ratio [HR]=0.74 [95% CI 0.63,0.87]; p=0.0004). The median OS in POPLAR was 12.6 months (95% CI 9.7, 16.0) and 9.7 months (95% CI 8.6, 12.0) (HR=0.69 [95% CI 0.52, 0.92]) for the atezolizumab and docetaxel arms, respectively.

The most common (greater than or equal to 20%) adverse reactions in patients in the primary safety analysis population (POPLAR trial) in patients treated with atezolizumab were fatigue, decreased appetite, dyspnea, cough, nausea, musculoskeletal pain, and constipation. The most common (greater than or equal to 2%) grade 3-4 adverse events in patients treated with atezolizumab were dyspnea, pneumonia, hypoxia, hyponatremia, fatigue, anemia, musculoskeletal pain, AST increase, ALT increase, dysphagia, and arthralgia. Clinically significant immune-related adverse events for patients receiving atezolizumab included pneumonitis, hepatitis, colitis, and thyroid disease.

The recommended atezolizumab dose is 1200 mg administered as an intravenous infusion over 60 minutes every three weeks until disease progression or unacceptable toxicity.

Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761041lbl.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

Atezolizumab for Metastatic Non–Small Cell Lung Cancer

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 atezolizumab in the treatment of metastatic non–small cell lung cancer?

  • Atezolizumab is an option for the second-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose disease progressed during or following platinum-containing chemotherapy.1
  • Approval is based on multiple clinical trials, the largest being the phase 3 OAK trial.2 The median overall survival (OS) was improved by 4.2 months with atezolizumab treatment versus docetaxel.
    • The survival benefit with atezolizumab was observed regardless of PD-L1 status or histology.2

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

  • Patients receiving immunotherapy should be monitored carefully for immune-related adverse effects.
  • Clinically significant immune-related adverse events for metastatic NSCLC patients receiving atezolizumab in clinical trials included pneumonitis, hepatitis, colitis, and thyroid disease.2-5
  • The most common adverse effects (AEs) observed in 20% or more of patients with metastatic NSCLC receiving atezolizumab were fatigue, decreased appetite, dyspnea, cough, nausea, musculoskeletal pain, and constipation.2-4
  • AEs occurring more frequently in the atezolizumab arm included musculoskeletal pain (11% vs. 4% with docetaxel) and pruritus (8% vs. 3%).2

Clinical Pearls

  • The recommended atezolizumab dose is a fixed, non-weight-based dose of 1,200 mg administered as an intravenous infusion over 60 minutes every 3 weeks, until disease progression or unacceptable toxicity.5
  • Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving atezolizumab.1
  • There are no recommendations based on PD-L1 expression of cells using an FDA-approved test.1

References

  1. U.S. Food and Drug Administration. Atezolizumab (Tecentriq). www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm525780.htm. Updated October 19, 2016. Accessed January 27, 2017.
  2. Barlesi F, Park K, Ciardiello F, et al. Primary analysis from OAK, a randomized phase III study comparing atezolizumab with docetaxel in 2L/3L NSCLC. Presented at 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA44.
  3. Besse B, Johnson M, Jänne PA, et al. Phase II, single-arm trial (BIRCH) of atezolizumab as first-line or subsequent therapy for locally advanced or metastatic PD-L1-selected non-small cell lung cancer (NSCLC). Presented at 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 16LBA.
  4. Vansteenkiste J, Fehrenbacher L, Spira AI, et al. Atezolizumab monotherapy vs docetaxel in 2L/3L non-small cell lung cancer: Primary analyses for efficacy, safety and predictive biomarkers from a randomized phase II study (POPLAR). Presented at 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 14LBA.
  5. Tecentriq® [package insert]. Genentech, Inc., South San Francisco, CA; October 2016. www.accessdata.fda.gov/drugsatfda_docs/label/2016/761041lbl.pdf. Accessed Jan 27, 2017.

May 18, 2016, with PAP

http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761034s000lbl.pdf

On May 18, 2016, the U. S. Food and Drug Administration gave accelerated approval to atezolizumab injection (Tecentriq™, Genentech, Inc.) for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.   Atezolizumab is a programmed death-ligand 1 (PD-L1) blocking antibody.

The approval was based on a multicenter, single-arm trial in 310 patients with locally advanced or metastatic urothelial carcinoma. Patients entering this trial had disease progression during or following a platinum-containing chemotherapy regimen or within 12 months of treatment with a neoadjuvant or adjuvant platinum-containing regimen. The study excluded patients who had a history of autoimmune disease or required systemic immunosuppressive medications. Tumor specimens were required in all patients. All patients received an intravenous infusion of atezolizumab, 1200 mg, every 3 weeks. Major efficacy outcome measures included confirmed objective response rate (ORR) as assessed by independent review facility (IRF) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and duration of response (DoR).

Visceral metastases were present in 78% of patients and 40% of patients had received greater than or equal to 2 prior regimens in the metastatic setting. Nineteen percent (19%) of patients had progressed following neoadjuvant or adjuvant therapy.  

The confirmed ORR by independent review was 14.8% (95% CI: 11.1, 19.3) in all treated patients. Median DoR was not reached and response duration ranged from 2.1+ to 13.8+ months. Of the 46 responders, 37 patients had an ongoing response for greater than or equal to 6 months and 6 for greater than or equal to12 months. Tumor specimens were evaluated using the Ventana PD-L1 (SP142) Assay at a central laboratory and the results were used to define subgroups for pre-specified analyses. Patients were considered PD-L1 positive if PD-L1 stained tumor-infiltrating immune cells occupied greater than or equal to 5% of the tumor area. Of the 310 patients, 32% were classified as having PD-L1 expression of greater than or equal to 5% (defined as PD-L1 stained tumor-infiltrating immune cells [ICs] covering greater than or equal to 5% of the tumor area). The remaining 68% of patients were classified as having PD-L1 expression of less than 5% (PD-L1 stained tumor-infiltrating ICs covering less than 5% of the tumor area). The confirmed ORR was 26.0% (95% CI: 17.7, 35.7) in 100 patients whose specimens had PD-L1 expression of greater than or equal to 5% and 9.5% (95% CI: 5.9, 14.3) in 210 patients whose specimens had PD-L1 expression of less than 5%. Response durations in these subgroups were similar to those noted above in all treated patients.

The most common adverse reactions of atezolizumab (greater than or equal to 20% of patients) were fatigue, decreased appetite, nausea, urinary tract infection, pyrexia, and constipation. Grade 3-4 adverse events were seen in 50% of patients. Infection and immune-related adverse events such as pneumonitis, hepatitis, colitis, thyroid disease, adrenal insufficiency, diabetes, pancreatitis, and dermatitis/rash were also seen with atezolizumab.  

The recommended dose of atezolizumab is 1200 mg administered as an intravenous infusion over 60 minutes every 3 weeks until disease progression or unacceptable toxicity. Testing of PD-L1 expression in tumor specimens is not required for the use of atezolizumab, but may guide in patient selection. The Ventana PD-L1 (SP142) Assay is approved for PD-L1 testing on tumor-infiltrating immune cells.

This application was approved before the Prescription Drug User Fee Act (PDUFA) goal date of September 12, 2016. Atezolizumab received Breakthrough Therapy Designation for this indication and the 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/2016/761034s000lbl.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

Atezolizumab for Locally Advanced or Metastatic Urothelial Carcinoma after Progression on a Platinum Agent

Author: Rachel Pritchett, PharmD, PGY2 Oncology Resident
Froedtert & the Medical College of Wisconsin, Milwaukee, WI

What is the potential role for atezolizumab in the treatment of urothelial carcinoma?1-5

  • Atezolizumab is a new treatment option for locally advanced or metastatic urothelial carcinoma following progression with a platinum agent.  At this time, there is no standard of care for this population and a clinical trial is recommended.  Since the development of first-line cisplatin-based combination therapy with methotrexate, vinblastine, doxorubicin, and cisplatin almost three decades ago, there have not been major advances in the treatment of this disease. Other agents currently used in the second-line setting also include taxanes, gemcitabine, and pemetrexed.
  • Various inhibitors of PD-1 and PD-L1 are currently being evaluated for locally advanced or metastatic urothelial carcinoma following progression with a platinum agent, in the adjuvant context following radical cystectomy with or without prior neoadjuvant chemotherapy for muscle-invasive urothelial cancer, as well as the first-line setting in cisplatin-ineligible patients with advanced urothelial carcinoma.

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

  • Atezolizumab is a fully humanized monoclonal antibody with a low incidence of infusion related reactions; however, close monitoring during administration is recommended.
    • Prophylactic administration of antihistamines, antipyretics, or corticosteroids is not recommended at this time.
    • Avoid corticosteroids unless intending to treat adverse effects due to the competitive mechanism of action on T-cells.
  • Preventative treatment for nausea is not recommended at this time.
  • Due to the analogous mechanism of action between PD-1 and PD-L1 inhibitors, monitoring parameters for atezolizumab reflects current FDA approved PD-1 inhibitors.

Clinical Pearls1,2

  • The FDA approved the Ventana® PD-L1 (SP142) assay to detect PD-L1 protein expression levels on tumor-infiltrating immune cells to help determine which patients may benefit from treatment with atezolizumab.
    • PD-L1 immune cell expression status was associated with response to atezolizumab (Table 1); however, the prognostic value of PD-L1 status remains unknown at this time.
    • PD-L1 immunohistochemistry testing is currently not required prior to administration of atezolizumab.
    • More information available at: http://www.fda.gov/CompanionDiagnostics

References

  1. Tecentriq® (Atezolizumab) for injection [package insert]. South San Francisco, CA: Genentech, Inc.; May 2016.
  2. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with a platinum-based chemotherapy: a single-arm, multicenter, phase 2 trial. Lancet. 2016; 387(10031):1909-20.
  3. Lexi-Drugs Online™, Hudson, Ohio: Lexi-Comp, Inc.; 2013; Accessed June 29, 2016.
  4. Bladder Cancer. Version 2.2016. National Comprehensive Cancer Network. Available at: https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf.  Accessed June 29, 2016.
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