FDA Grants Keytruda Priority Review for Cervical Cancer Treatment

Keytruda (pembrolizumab) was granted a priority review by the Food and Drug Administration (FDA) for the treatment of patients with advanced cervical cancer with disease progression or after chemotherapy.

The agency has set a Prescription Drug User Fee Act (PDUFA) date of June 28, 2018, meaning that the FDA must make a decision on the agent’s approval by that date.

Merck, the developer of Keytruda, 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, M.D., senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories, said in a statement.

Merck filed the supplemental biologics license application based on results from the phase 2 KEYNOTE-158 trial. The ongoing global, open-label, nonrandomized, multicohort, multicenter KEYNOTE-158 study is evaluating Keytruda 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 percent among the first 82 patients in the advanced cervical squamous cell cancer cohort, with 3 complete responses and 7 partial responses. All 10 responses were ongoing at the data cutoff. Seventeen patients had stable disease and 44 had progressive disease.

ORR was 14 percent among 71 patients with PD-L1—positive tumors, with three complete responses and 7 partial responses. Fourteen patients had stable disease and 37 experienced progression. None of the nine PD-L1–negative patients responded to treatment.

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

Patients received 200 mg of Keytruda every three 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 overall and in the PD-L1 positive group. The median duration of response was not reached in both groups.

Median patient age was 45.5 (range, 27-73), but 94 percent of patients were under 65 years. Seventy-three patients had received one or more prior treatment.

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

In data published in November from the phase 1b KEYNOTE-028 study, the ORR for 24 patients with advanced cervical cancer was 17 percent, comprising four confirmed partial responses. Three patients had stable disease and 16 had progressive disease as best response.

Patients received 10 mg/kg of IV Keytruda every two 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 Keytruda treatment of up to one 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 percent), lungs (38 percent), pelvis (38 percent) and liver (25 percent). Twenty-two (92 percent) patients had received prior radiation therapy and 23 had received prior platinum-based chemotherapy. Ten patients had received prior Avastin (bevacizumab).. Fifteen (63 percent) patients had received two or more prior lines of therapy for advanced disease.

PD-L1 positivity was defined as at least percent 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 percent) were positive in the tumor only and six (25 percent) 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 percent) 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 percent CI, 2-3). Six-month PFS was 21 percent and 12-month PFS was 4 percent.

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

All patients discontinued treatment during the study, 4 (17 percent) because of adverse events (AEs), 1 (4 percent) because of physician decision, and 19 (79 percent) because of progressive disease. Eighteen (75 percent) patients experienced treatment related TRAEs. Only rash (21 percent) and pyrexia (17 percent) occurred in 10 percent or more 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 percent) 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 (two patients; grade 3), colitis (one patient; grade 3), Guillain-Barré syndrome (one patient; grade 3), hyperthyroidism (one patient; grade 2), and hypothyroidism (one patient; grade 2).