On October 13,2021, the Food and Drug Administration approved pembrolizumab (Keytruda, Merck) in combination with chemotherapy, with or without bevacizumab, for patients with persistent, recurrent or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1), as determined by an FDA-approved test.
FDA also granted regular approval to pembrolizumab as a single agent 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. In June 2018, FDA had granted accelerated approval to this indication with the companion diagnostic, PD-L1 IHC 22C3 pharmDx (Dako North America Inc.).
KEYNOTE-826 (NCT03635567), a multicenter, randomized, double-blind, placebo-controlled trial, examined pembrolizumab with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab. The trial enrolled 617 patients with persistent, recurrent, or first-line metastatic cervical cancer who had not been treated with chemotherapy. Patients were enrolled irrespective of PD-L1 expression status. Patients were randomized (1:1) to one of two treatment groups: pembrolizumab 200 mg plus chemotherapy with or without bevacizumab or placebo plus chemotherapy with or without bevacizumab. Pembrolizumab was continued until disease progression, unacceptable toxicity, or 24 months of treatment.
The main efficacy outcome measures were overall survival (OS) and progression-free survival (PFS) assessed by the investigator using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional outcome measures were ORR and duration of response (DoR). For patients with tumors expressing PD-L1 (CPS ≥1, N=548), the median OS was not reached (95% CI: 19.8, NR) in the pembrolizumab arm and was 16.3 months (95% CI: 14.5, 19.4) in the placebo arm (HR 0.64; 95% CI: 0.50, 0.81; 1-sided p-value = 0.0001). Median PFS was 10.4 months (95% CI: 9.7, 12.3) in the pembrolizumab arm and 8.2 months (95% CI: 6.3, 8.5) in the placebo arm (HR 0.62; 95% CI: 0.50, 0.77; 1-sided p-value< 0.0001). The objective response rates were 68% (95% CI: 62, 74) and 50% (95% CI: 44, 56) with median DoR of 18.0 and 10.4 months in the pembrolizumab and placebo arms, respectively.
The most common adverse reactions (≥20%) in patients treated with pembrolizumab, chemotherapy, and bevacizumab were peripheral neuropathy, alopecia, anemia, fatigue/asthenia, nausea, neutropenia, diarrhea, hypertension, thrombocytopenia, constipation, arthralgia, vomiting, urinary tract infection, rash, leukopenia, hypothyroidism, and decreased appetite.
The recommended pembrolizumab dose is 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicity, or up to 24 months.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Australian Therapeutic Goods Administration (TGA), Health Canada, and Switzerland’s Swissmedic. The application reviews are ongoing at the other regulatory agencies.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application 4 months ahead of the FDA goal date.
This application was granted priority review 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.
For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.
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