FDA Approves Pembrolizumab Combination for First-Line Treatment of Cervical Cancer

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 granted (https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-advanced-cervical-cancer-disease-progression-during-or-after-chemotherapy) accelerated approval to the indication with the companion diagnostic PD-L1 IHC 22C3 pharmDx.  

A multicenter, randomized, double-blind, placebo-controlled trial (KEYNOTE-826; NCT03635567) examined pembrolizumab with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab. Researchers enrolled 617 patients with persistent, recurrent, or first-line metastatic cervical cancer who had not been treated with chemotherapy, irrespective of PD-L1 expression status, and randomized them 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 for 24 months or until patients experienced disease progression or unacceptable toxicity.  

The main efficacy outcome measures were overall survival (OS) and progression-free survival (PFS) assessed by the investigator using response evaluation criteria in solid tumors 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional outcome measures were objective response rate (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; p = 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; p < 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 reported in 20% or more of patients treated with pembrolizumab, chemotherapy, and bevacizumab were peripheral neuropathy, alopecia, anemia, fatigue or 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 three weeks or 400 mg every six weeks until patients experience disease progression or unacceptable toxicity, for up to 24 months. 

View the full prescribing information for pembrolizumab (https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125514s121s122lbl.pdf).

The review was conducted under Project Orbis (https://www.fda.gov/about-fda/oncology-center-excellence/project-orbis), an initiative of FDA’s Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For the review, FDA collaborated with the Australian Therapeutic Goods Administration, Health Canada, and Switzerland’s Swissmedic. The application reviews are ongoing at the other regulatory agencies.  

The review used the Assessment Aid (https://www.fda.gov/about-fda/oncology-center-excellence/assessment-aid), a voluntary submission from the applicant to facilitate FDA’s assessment. FDA approved this application four months ahead of FDA’s goal date. 

FDA granted the application priority review designation. A description of FDA expedited programs is in the Guidance for IndustryꟷExpedited Programs for Serious ConditionsꟷDrugs and Biologics (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/expedited-programs-serious-conditions-drugs-and-biologics). 

Healthcare professionals should report all serious adverse events they suspect are associated with the use of any medicine and device to FDA’s MedWatch Reporting System (https://www.accessdata.fda.gov/scripts/medwatch/index.cfm) or by calling 800-FDA-1088. 

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate (https://www.fda.gov/about-fda/oncology-center-excellence/project-facilitate) at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov (mailto:OncProjectFacilitate@fda.hhs.gov).