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Pembrolizumab Granted Accelerated FDA Approval in Merkel Cell Carcinoma

Gina Columbus
Published Online:8:18 PM, Wed December 19, 2018
FDA
Pembrolizumab (Keytruda) has been granted an accelerated approval by the FDA as a treatment for adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC).

The FDA based its decision on findings from the phase II CITN-09/KEYNOTE-017 trial (NCT02267603), in which pembrolizumab elicited an overall response rate (ORR) of 56% (95% CI, 41%-70%) and a complete response rate of 24% in patients who did not previously receive systemic therapy for their advanced disease.


In the multicenter, single-arm, open-label trial, 50 treatment-naïve patients with recurrent locally advanced or metastatic MCC received pembrolizumab at 2 mg/kg every 3 weeks. Patients were enrolled between January 2015 and May 2017, and could not have received prior systemic therapy. The median patient age was 70 years (range, 46-91), with 80% of patients aged ≥65 years. Fourteen percent (n = 7) of patients had recurrent locally advanced MCC, and 86% (n = 43) had distant metastatic MCC. Sixty-four percent of patients had tumors that were positive for Merkel cell polyomavirus (MCPyV), with the remaining 36% being negative.

The primary endpoints were ORR and response duration, as assessed by blinded independent central review per RECIST v1.1 criteria. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and duration of response. 

At a median follow-up of 14.9 months (range, 0.4-36), results of the trial showed that the median DOR was not reached (range, 5.9-34.5+). Among the 28 patients with responses, 96% had a DOR ≥6 months and 54% had a DOR ≥12 months. An additional 5 patients (10%) had stable disease. Sixteen patients (32%) had progressive disease and 1 patient was not assessed for response.

The median PFS was 16.8 months with pembrolizumab, which was higher than historical data for chemotherapy controls, for which the median PFS ranges from 3.1 to 4.6 months. This was also true for median OS, which had not been reached for pembrolizumab compared with historical data ranging from 9.5 to 10.2 months with frontline chemotherapy in MCC.

The median time to response was 2.8 months (range, 1.5-9.7). Most responses had occurred by 12 weeks and most were also ongoing at the time of the data cutoff of February 6, 2018. Responses were observed regardless of MCPyV status. The ORR was 59% among MCPyV-positive patients and 53% among MCPyV-negative patients.

The FDA noted that the recommended pembrolizumab dose for MCC is 200 mg administered intravenously (IV) every 3 weeks for adults. For pediatric patients, the PD-1 inhibitor should be given at 2 mg/kg, up to a maximum of 200 mg, IV every 3 weeks for patients <18 years of age.

The most common adverse events (AEs) of pembrolizumab reported in at least 20% of patients who received single-agent pembrolizumab were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. Overall, 96% (n = 48) of patients experienced all-grade treatment-related adverse events (TRAEs), with 14% (n = 7) of patients discontinuing treatment due to TRAEs. Grade ≥3 TRAEs were reported for 14 patients (28%), and there was 1 treatment-related death.

The accelerated approval of pembrolizumab in this setting is contingent on the results of a confirmatory trial. Pembrolizumab has FDA-approved indications in melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large B-cell lymphoma, and microsatellite
 
 
References:
  1. FDA approves pembrolizumab for Merkel cell carcinoma. FDA. Published December 19, 2018. https://bit.ly/2BvqX7D?rel=0" . Accessed December 19, 2018.
  2. Nghiem P, Bhatia S, Lipson EJ, et al. Durable tumor regression and overall survival (OS) in patients with advanced Merkel cell carcinoma (aMCC) receiving pembrolizumab as first-line therapy. J Clin Oncol. 2018;36 (suppl; abstr 9506).


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