FDA Expands Pembrolizumab Label

Pembrolizumab (brand name Keytruda Injection) approval expanded to include initial treatment of patients with unresectable or metastatic melanoma

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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).

Last Updated:
December 21, 2015