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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.


February 19, 2018–Durvalumab (Imfinzi, AstraZeneca Inc.) approved for patients with unresectable stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. (with Pharmacist's Applications to Practice)

May 1, 2017–Durvalumab (Imfinzi, AstraZeneca Inc.) for the treatment of patients with locally advanced or metastatic urothelial carcinoma (with Pharmacist's Applications to Practice)


February 19, 2018, with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761069s002lbl.pdf

On February 16, 2018, the Food and Drug Administration approved durvalumab (Imfinzi, AstraZeneca Inc.) for patients with unresectable stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.

Approval was based on a planned interim analysis of progression-free survival (PFS) from PACIFIC (NCT02125461), a randomized double-blind, placebo-controlled trial conducted in 713 patients with unresectable, stage III NSCLC. Patients completed concurrent platinum-based chemotherapy and radiation within 42 days prior to study drug initiation and had WHO performance status of 0 or 1. The major efficacy measures were PFS (blinded independent central review per RECIST 1.1) and overall survival (OS). With approximately 81% of planned events for the final analysis, the trial demonstrated a statistically significant improvement in PFS for durvalumab compared to placebo (HR 0.52; 95% CI: 0.42, 0.65; p<0.00010). The estimated median PFS was 16.8 months for patients receiving durvalumab and 5.6 months for those receiving placebo. Survival results were immature at the interim PFS analysis.

The most common adverse reactions (occurring in at least 20% of patients receiving durvalumab in PACIFIC) were cough, fatigue, pneumonitis/radiation pneumonitis, upper respiratory tract infections, dyspnea and rash.

The recommended dose and schedule for durvalumab for this indication is 10 mg/kg as an intravenous infusion over 60 minutes every two weeks.

Full prescribing information is available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761069s002lbl.pdf

FDA granted this application Priority Review and Breakthrough Therapy designations. 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

Durvalumab for Locally Advanced, Unresectable, Non-Small-Cell Lung Cancer That Has Not Progressed After Chemoradiotherapy

Author: Christina Hoban, PharmD BCOP
Solid Tumor Oncology Clinical Specialist
Mary Babb Randolph Cancer Center
WVU Medicine
Morgantown, WV

What is the potential role for durvalumab in the treatment of non-small-cell lung cancer?

  • Durvalumab is a an antiprogrammed death ligand 1 (PD-L1) monoclonal antibody recently approved by the U.S. Food and Drug Administration (FDA) for use in patients with locally advanced, unresectable, non-small-cell lung cancer (NSCLC) that has not progressed following concurrent platinum-based chemotherapy and radiotherapy.1 Durvalumab was initially approved in May 2017 for treatment of locally advanced or metastatic urothelial carcinoma.
    • Durvalumab was approved by the FDA on the basis of the interim results of the phase 3 placebo-controlled PACIFIC study (N = 713), which evaluated 1 year of treatment with durvalumab after chemoradiation in patients with unresectable stage III NSCLC. Median progression-free survival (PFS) in the durvalumab group was 16.8 months compared to 5.6 months for placebo (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.42–0.65; p < .00010).
    • Compared to placebo, the durvalumab group had an estimated 12-month PFS of 55.9% versus 35.3%, an 18-month PFS of 44.2% versus 27%, a response rate of 28.4% versus 16% (p < .001), and median time to death or distant metastasis 23.2 months versus 14.6 months (p < .001).
    • The frequency of new lesions was lower with durvalumab compared to placebo (20.4% vs. 32.1%), and the frequency of brain metastases was also lower (5.5% vs. 11.0%).
    • The incidence of grade 3 or 4 adverse events in the groups was similar: 29.9% versus 26.1%, and the rate of discontinuation because of adverse events was 15.4% versus 9.8%.
  • Chemoradiation is the standard of care for patients with unresectable stage III disease. However, the median time to progression after treatment is only about 8 months, with 5-year survival rates of approximately 15%. Durvalumab is the first and only agent that has demonstrated improved outcomes in this patient population.2
  • The National Comprehensive Cancer Network (NCCN) added durvalumab to the guidelines for non-small-cell lung cancer as consolidation therapy for patients with unresectable stage III disease, performance status 0–1, and no disease progression after 2 or more cycles of definitive chemoradiation. Durvalumab is the only medication recommended in this setting, and this is a category 2A recommendation.3 Patients with both squamous and nonsquamous histology are eligible for durvalumab, and durvalumab may be given regardless of tumor PD-L1 expression. Durvalumab should not be given to patients whose disease has progressed after chemoradiation.

What role can the pharmacist play in the management of patients on durvalumab?
Pharmacists should be aware of the following:

  • The most common toxicities reported in the PACIFIC trial of durvalumab versus placebo were cough (35.4% vs. 25.2%), pneumonitis and radiation pneumonitis (33.9% vs. 24.8%), fatigue (23.8% vs. 20.5%), and dyspnea (22.3% vs. 23.9%). Grade 3 or 4 reactions in patients receiving durvalumab and placebo occurred in 29.9% and 26.1%, respectively. The most common grade 3 or 4 adverse events were pneumonitis or radiation pneumonitis (3.4% vs. 2.6%), dyspnea (1.5% vs. 2.6%), pneumonia (4.4% vs. 3.8%), and anemia (2.9% vs. 3.4%).2
  • Immune-mediated adverse events were reported in 24.2% of patients receiving durvalumab and in 8.1% of patients receiving placebo. The most frequent immune-mediated adverse events were diarrhea (18.3% vs. 18.8%), pneumonitis (12.6% vs. 7.7%), rash (12.2% vs. 7.3%), and pruritis (12.2% vs. 4.7%).2
  • Compared to patients receiving durvalumab for urothelial carcinoma, patients with NSCLC are more likely to experience pneumonitis and radiation pneumonitis.
  • With the exception of pneumonitis and radiation pneumonitis, durvalumab causes similar rates of adverse effects compared to two other PD-L1 inhibitors, avelumab and atezolizumab. Durvalumab causes fewer infusion reactions (2.2%) than avelumab (25%).4
  • No dosage adjustments exist for durvalumab. If significant toxicity occurs, durvalumab treatment should be interrupted or discontinued, depending on the reaction type and severity.
  • The American Society of Clinical Oncology has collaborated with NCCN to develop guidelines for the management of adverse events from immunotherapy agents, including durvalumab. These guidelines can be found in the Journal of Clinical Oncology and at nccn.org.5,6
  • Premedications may be recommended for patients who experience grade 1 or 2 infusion reactions. Infusion reactions occurred in 2.2% of patients receiving durvalumab in multiple clinical trials for various cancers. Grade 3 reactions occurred in 0.3%.1
  • No drug interactions with durvalumab have been found. In clinical trials, concomitant corticosteroid use was limited to the equivalent of prednisone 10 mg per day or less.
  • No absolute contraindications to receipt of durvalumab exist. However, caution should be used in patients with active or recent autoimmune disorders or a history of primary immunodeficiency; these patients were excluded from clinical trials.
  • In clinical trials, durvalumab was given until the disease progressed, an unacceptable level of toxicity was reached, or for a maximum of 1 year, whichever occurred first.
  • Astra Zeneca may provide medication free of charge for patients who meet eligibility requirements.7

Clinical Pearls

  • Durvalumab is supplied as both a 500-mg and a 120-mg vial, allowing for dose rounding. Durvalumab vials do not contain a preservative and therefore must be stored in a refrigerator between 2°C and 8°C and protected from light. Once punctured, the vial must be used within 4 hours when kept at room temperature up to 25°C, or within 24 hours when kept under refrigeration.
  • Of the 713 patients enrolled in the PACIFIC trial, 679 (95.2%) had experienced either a partial response or stable disease following chemoradiotherapy.
  • Expression of PD-L1 on tumor cells is not required for administration of durvalumab. In the PACIFIC trial, patients were stratified based on PD-L1 expression prior to chemoradiotherapy into 2 groups: PD-L1 less than 25% and PD-L1 25% or greater. A benefit in PFS was observed in both groups.
  • The number of patients with squamous and nonsquamous histology was balanced between study groups in the PACIFIC trial, with both groups experiencing a benefit in PFS.
  • Patients receiving chemoradiotherapy are at increased risk of pneumonitis, and the use of immunotherapy also elevates this risk.

References

  1. Imfinzi (durvalumab) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; February 2018.
  2. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non-small cell lung cancer. New Engl J Med. 2017;377:1919-1929.
  3. National Comprehensive Cancer Network. Non-Small Cell Lung Cancer. Version 3.2018. Available at https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed March 26, 2018.
  4. Bavencio (avelumab) [package insert]. Rockland, MD: EMD Serono, Inc.; October 2017.
  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. Advance online publication. http://ascopubs.org/doi/abs/10.1200/JCO.2017.77.6385. doi:10.1200/JCO.2017.77.6385.
  6. National Comprehensive Cancer Network. 2018. Management of Immunotherapy-Related Toxicities. Version 1.2018. Available at https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Accessed March 29, 2018.
  7. Astra Zeneca Access 360. https://www.myaccess360.com/hcp/hcp-branded-imfinzi/home.html. Accessed March 29, 2018.

May 1, 2017, with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761069s000lbl.pdf

On May 1, 2017, the U.S. Food and Drug Administration granted accelerated approval to durvalumab (IMFINZI™, AstraZeneca UK Limited) for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

The FDA also approved the VENTANA PD-L1 (SP263) Assay (Ventana Medical Systems, Inc.) as a complementary diagnostic for the assessment of the PD-L1 protein in formalin-fixed, paraffin-embedded urothelial carcinoma tissue.

Approval was based on one single-arm trial of 182 patients with locally advanced or metastatic urothelial carcinoma whose disease progressed after prior platinum-containing chemotherapy. Durvalumab, 10 mg/kg intravenously, was administered every 2 weeks. Confirmed objective response rate (ORR) as assessed by blinded independent central review per RECIST 1.1, was 17.0% (95% CI: 11.9, 23.3). At the data cutoff for the ORR analysis, median response duration was not reached (range: 0.9+ to 19.9+ months). ORR was also analyzed by PD-L1 expression status as measured by VENTANA PD-L1 (SP263) Assay. In the 182 patients, the confirmed ORR was 26.3% (95% CI: 17.8, 36.4) in 95 patients with a high PD-L1 score and 4.1% (95% CI: 0.9, 11.5) in 73 patients with a low or negative PD-L1 score.

The most common adverse reactions in at least 15% of patients were fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and urinary tract infection. Grade 3-4 adverse events were seen in 43% of patients. Infection and immune-related adverse events such as pneumonitis, hepatitis, colitis, thyroid disease, adrenal insufficiency, and diabetes were also seen with durvalumab.

The recommended dose of durvalumab is 10 mg/kg, administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

Full prescribing information is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761069s000lbl.pdf.

The FDA granted this application accelerated approval, priority review, and Breakthrough Therapy Designation. As a condition of the accelerated approval, AstraZeneca is required to complete an ongoing clinical trial to confirm clinical benefit of durvalumab. FDA approved this application approximately 6 weeks ahead of the 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.

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

Durvalumab (Imfinzi) for Urothelial Cancer

Author: Amy Kamien, PharmD BCOP
Clinical Pharmacist, Oncology
Aurora Sheboygan Memorial Medical Center Cancer Clinics
Sheboygan, WI

What is the potential role for durvalumab in the treatment of urothelial cancer? 1-9

  • Durvalumab received accelerated approval in locally advanced or metastatic urothelial carcinoma in patients who have disease progression during or following platinum-containing chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.1,2
  • Multiple inhibitors of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are approved for use in advanced or metastatic urothelial carcinoma following progression with platinum therapy, including pembrolizumab, atezolizumab, nivolumab, and avelumab.2 
    • Standard regimens for subsequent therapy for locally advanced disease include the above agents (see Table 1), as well as paclitaxel or docetaxel, gemcitabine, or pemetrexed. Pembrolizumab is considered Category 1 by the National Comprehensive Cancer Network Guidelines.2
    • Select patients may receive subsequent therapy with any of the following: nab-paclitaxel; ifosfamide; methotrexate; ifosfamide, doxorubicin, and gemcitabine; gemcitabine and paclitaxel; gemcitabine and cisplatin; dose-dense MVAC (methotrexate, vinblastine, doxorubicin, cisplatin).2
    • Atezolizumab and pembrolizumab also have indications for primary treatment in cisplatin-ineligible patients, whereas durvalumab, nivolumab, and avelumab do not.2
  • Research continues using PD-1/PD-L1 therapy in bladder cancer, including these8:
    • maintenance therapy after chemotherapy in metastatic disease
    • treatment of high-risk non-muscle-invasive bladder cancer that is unresponsive to bacillus Calmette-Gurein (BCG) therapy and in patients who are ineligible for or refuse radical cystectomy
    • in combination therapy with other treatments for metastatic disease.

Table 1. Comparison of PD-1 and PD-L1 Inhibitors in Second-Line Urothelial Carcinoma

PD-1/PD-L1
Inhibitor
ORRMedian OSMedian PFSAdverse Events (Any Grade)
Durvalumab3 31% NR NR fatigue (13.1%)
diarrhea (9.8%)
decreased appetite (8.2%)
Pembrolizumab5 21.1% 10.3
months*
2.1 months pruritis (19.5%)
fatigue (13.9%)
nausea (10.9%)
Atezolizumab6 15% 7.9 months 2.1 months fatigue (30%)
nausea (14%)
decreased appetite (12%)
pruritis (10%)
Nivolumab7 19.6% 8.74 months 2 months fatigue (17%)
immune-mediated skin reaction (17%)
immune-mediated endocrine (14%)
Avelumab8 18.2% 13.7 months 11.6 weeks fatigue (20.5%)
infusion-related reaction (20.5%)
asthenia (11.4%)
nausea (11.4%)

*denotes statistical significance to comparator (single-agent paclitaxel, docetaxel, or vinflunine Note. ORR, overall response rate/objective response rate; OS, overall survival; PFS, progression-free survival; NR, not reported.

 

What role can the pharmacist play in the management of patients on durvalumab?1

  • Durvalumab is a humanized monoclonal antibody with a low incidence of infusion-related reactions, although monitoring is recommended during the infusion.
    • Premedication with antipyretics, antihistamines, or corticosteroids is not currently recommended.
    • Reserve corticosteroids for adverse-effect treatment because of the competitive mechanism of action on T-cells.
  • When treating immune-mediated adverse effects, resume durvalumab when event is resolved to grade 1 and corticosteroid dose has been reduced to less than 10 mg/day prednisone equivalent.
  • Emetogenic potential is minimal; no prophylactic therapy is recommended.
  • Monitoring parameters are consistent with durvalumab’s toxicity profile and other FDA-approved PD-1 and PD-L1 inhibitors.

Clinical Pearls1,3,4

  • Durvalumab is administered over 60 minutes through tubing with a low-protein binding filter. The admixture expires within 4 hours at room temperature and should be administered immediately after preparation. Refrigeration extends stability to 24 hours.
  • Vetana PD-L1 (SP263) assay received FDA approval at the same time durvalumab was approved. This complementary diagnostic tool can be used for PD-L1 protein detection in formalin-fixed, paraffin-embedded urothelial carcinoma tissues.
    • In clinical trials, PD-L1 status was confirmed as high (greater than or equal to 25% in either cell line) or negative (less than 25% in both cell lines) on tumor cells (TCs) and tumor-infiltrating immune cells (ICs).
    • Although appreciably more patients experienced response in the PD-L1-positive group, some responses were seen in the negative group when the TC and IC status was considered individually (see Table 2).
    • Immunohistochemistry testing for PD-L1 status is not currently required prior to durvalumab therapy.

Table 2. Overall Response Rate Data for Durvalumab3

PD-LI Expression by
Location
PD-LI StatusORRDCR12*
Unselected   13/42 (31%) 20/42 (47.6%)
TCs or ICs PD-L1-positive (greater than or equal to 25% TC or IC) PD-L1-negative (less than 25% TCs and ICs) 13/28 (46.4%)
0/14 (0%)
16/28 (57.1%)
4/14 (28.6%)
TC PD-L1-positive (greater than or equal to 25%) PD-L1-negative (less than 25%) 7/15 (46.7%)
6/27 (22.2%)
8/15 (53.3%)
12/27 (44.4%)
IC PD-L1-positive (greater than or equal to 25%) PD-L1-negative (less than 25%) 10/18 (55.6%)
3/24 (12.5%)
12/18 (66.7%)
8/24 (33.3%)

*DCR12 is defined as confirmed complete or partial response or stable disease. Note. ORR, overall response rate; DCR12, disease control rate at 12 weeks; TC, tumor cell; IC, tumor-infiltrating immune cell.

 

References

  1. Imfinzi™ (Durvalumab) injection [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; May 2017.
  2. Bladder Cancer. Version 5.2017. National Comprehensive Cancer Network. Available at: https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf. Accessed July 17, 2017.
  3. Massard C, MS Gordon, S Sharma, et al. Safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer. J Clin Oncol. 2016; 34:3119-25.
  4. Powles T, O’Donnell PH, Massard C, et al. Updated efficacy and tolerability of durvalumab in locally advanced or metastatic urothelial carcinoma [abstract]. J Clin Oncol. 2017; 35: Abstract 286.
  5. Bellmunt J, de Wit R, Vaughn D, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017; 376:1015-26.
  6. 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 platinum-based chemotherapy: a single-arm, multicenter, phase 2 trial. Lancet. 2017; 387:1909-20.
  7. 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.
  8. Apolo AB, Infante JR, Patel MR, et al. Avelumab, and anti-programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: results from a multicenter, phase 1b study. J Clin Oncol. 2017; 35:2117-24.
  9. ClinicalTrials.gov Registry. National Institutes of Health. Available at: www.clinicaltrials.gov. Accessed July 17, 2017.
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