FDA Grants Pembrolizumab Priority Review for Treatment of Cervical Cancer

Tuesday, March 13, 2018
The FDA has granted priority review to a supplemental biologics license application for Pembrolizumab (Keytruda) for the treatment of advanced cervical cancer with disease progression on or after chemotherapy. It was based on results from the phase II KEYNOTE-158 trial.

The agency has set a Prescription Drug User Fee Act (PDUFA) date, a deadline by which it must complete a review, of June 28, 2018. Merck, the developer of pembrolizumab, reported in a press release that this is the first time the FDA has given a priority review to an anti–PD-1 therapy in this disease.

“Advanced cervical cancer is an illness with a poor prognosis and a high unmet medical need. We look forward to working with the FDA on the review of this application to help bring Keytruda to previously-treated patients with advanced cervical cancer,” Roger Dansey, MD, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories, said in a statement.

The ongoing global, open-label, nonrandomized, multicohort, multicenter KEYNOTE-158 study is evaluating pembrolizumab in patients with multiple types of advanced solid tumors who have progressed on standard of care therapy.

In preliminary data from KEYNOTE-158 presented at the 2017 ASCO Annual Meeting, objective response rate (ORR) was 12% (95% CI, 6-21) among the first 82 patients in the advanced cervical squamous cell cancer cohort, with 3 complete responses and 7 partial responses.1 All 10 responses were ongoing at the data cutoff. Seventeen patients had stable disease and 44 had progressive disease.

ORR was 14% (95% CI, 7-24) among 71 patients with PD-L1–positive tumors, with 3 complete responses and 7 partial responses. Fourteen patients had stable disease and 37 experienced progression. None of the 9 PD-L1–negative patients responded to treatment.

At the time of the presentation, 20 patients were still receiving treatment.

Patients received 200 mg of pembrolizumab every 3 weeks for 24 months or until withdrawal of consent, confirmed radiographic progression, unacceptable toxicity, or investigator decision. Clinically stable patients with radiologic progression could remain on treatment until progression was confirmed by subsequent imaging.

Median time to response was 2.1 months (range, 1.6-4.2) overall and in the PD-L1 positive group. The median duration of response was not reached (range, 4.2+ to 8.7+ months) in both groups.

Median patient age was 45.5 (range, 27-73), but 94% of patients were <65 years. Seventy-three patients had received ≥1 prior treatment.

Ten patients (12%) experienced grade 3/4 treatment-related adverse events (TRAEs).

In data published in November from the phase Ib KEYNOTE-028 study, the ORR for 24 patients with advanced cervical cancer was 17% (95% CI, 5-37), comprising 4 confirmed partial responses. Three patients (13%; 95% CI, 3-32) had stable disease and 16 (67%; 95% CI, 45-84) had progressive disease as best response.2

Patients received 10 mg/kg of IV pembrolizumab every 2 weeks for up to 24 months or until withdrawal of consent, confirmed radiographic progression, unacceptable toxicity, or investigator decision. Participants with stable disease or better on treatment discontinuation could be eligible to restart pembrolizumab treatment of up to 1 year if they exhibited subsequent disease progression.

Median patient age was 42 years (range, 26-62). All patients presented with metastatic disease that was most frequently located in the lymph nodes (67%), lungs (38%), pelvis (38%), and liver (25%). Twenty-two (92%) patients had received prior radiation therapy and 23 had received prior platinum-based chemotherapy. Ten patients had received prior bevacizumab (Avastin). Fifteen (63%) patients had received 2 or more prior lines of therapy for advanced disease.

PD-L1 positivity was defined as ≥1% modified proportion score or interface pattern as assessed using a laboratory-developed prototype immunohistochemistry assay. All patients in the cohort were PD-L1 positive, 18 (75%) were positive in the tumor only and 6 (25%) in the tumor and stroma.

The median follow-up was 11.0 months (range, 1.3-32.2) at the data cutoff. The median time to response for partial responders was 1.9 months (range, 1.7-8.2) and median duration of response was 5.4 months (range, 4.1-7.5). Two of the four patients achieving partial response exhibited a response for over 6 months. All of the responding patients had PD-L1 expression in the tumor only.

Eight (36%) of 22 evaluable patients had a decrease in the sum of diameters of target lesions from baseline according to computed tomography scan. Median overall progression-free survival (PFS) was 2 months (95% CI, 2-3). Six-month PFS was 21% and 12-month PFS was 4%.

Median overall survival (OS) in all patients was 11 months (95% CI, 4-15), with a 6-month OS of 67% and a 12-month OS of 40%.

All patients discontinued treatment during the study, 4 (17%) because of adverse events (AEs), 1 (4%) because of physician decision, and 19 (79%) because of progressive disease. Eighteen (75%) patients experienced treatment related TRAEs. Only rash (21%) and pyrexia (17%) occurred in ≥10% of patients.

Five patients experienced grade 3 TRAEs including neutropenia, rash, colitis, Guillain-Barré syndrome, and proteinuria. There were no grade 4 TRAEs or treatment-related deaths observed in the study.

Four (17%) patients experienced serious TRAEs including 1 case each of rash (grade 3), colitis (grade 3), Guillain-Barré syndrome (grade 3), and pyrexia (grade 2). Two patients discontinued treatment because of grade 3 treatment-related colitis and Guillain-Barré syndrome. The patient with Guillain-Barré syndrome recovered after receiving tegeline.

Six patients experienced immune-mediated AEs including rash (n = 2; grade 3), colitis (n = 1; grade 3), Guillain-Barré syndrome (n = 1; grade 3), hyperthyroidism (n = 1; grade 2), and hypothyroidism (n = 1; grade 2).


  1. Schellens JHM, Marabelle A, Zeigenfuss S, et al. Pembrolizumab for previously treated advanced cervical squamous cell cancer: Preliminary results from the phase 2 KEYNOTE-158 study. J Clin Oncol 35, 2017 (suppl; abstr 5514).
  2. Frenel JS, Le Tourneau C, O’Neil B, et al. Safety and efficacy of pembrolizumab in advanced, programmed death ligand 1–positive cervical cancer: results from the phase Ib KEYNOTE-028 trial. J Clin Oncol. 2017; 35:4035-4041.

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