FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication

On May 23, 2017, the U.S. Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA, Merck & Co.) for adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options or with MSI-H or dMMR colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

This is the FDA’s first tissue/site-agnostic approval.

The approval was based on data from 149 patients with MSI-H or dMMR cancers enrolled across five uncontrolled, multi-cohort, multi-center, single-arm clinical trials. Ninety patients had colorectal cancer and 59 patients were diagnosed with one of 14 other cancer types. Patients received either pembrolizumab, 200 mg every 3 weeks, or pembrolizumab, 10 mg/kg every 2 weeks. Treatment continued until unacceptable toxicity, or disease progression that was either symptomatic, rapidly progressive, required urgent intervention, or associated with a decline in performance status. A maximum of 24 months of treatment was administered.

The major efficacy outcome measures were objective response rate (ORR) assessed by blinded independent central radiologists’ review according to RECIST 1.1, and response duration. ORR was 39.6% (95% CI: 31.7, 47.9). Responses lasted six months or more for 78% percent of those who responded to pembrolizumab. There were 11 complete responses and 48 partial responses. ORR was similar irrespective of whether patients were diagnosed with CRC (36%) or a different cancer type (46% across the 14 other cancer types).

The identification of MSI-H or dMMR tumor status for the majority of patients (135/149) was prospectively determined using local laboratory-developed, investigational polymerase chain reaction (PCR) tests for MSI-H status or immunohistochemistry (IHC) tests for dMMR. For 14 of the 149 patients, MSI-H status was determined in a retrospective assessment of 415 patients’ tumor samples using a central laboratory-developed PCR test.

The most common adverse reactions to pembrolizumab include fatigue, pruritus, diarrhea, decreased appetite, rash, pyrexia, cough, dyspnea, musculoskeletal pain, constipation, and nausea. Pembrolizumab is associated with immune-mediated side effects, including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.

The prescribing information for pembrolizumab includes a “Limitation of Use” stating that the safety and effectiveness of pembrolizumab in pediatric patients with MSI-H central nervous system cancers have not been established.

The recommended pembrolizumab dose for this indication is 200 mg for adults or 2 mg/kg (up to a maximum of 200 mg) for children, administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Full prescribing information for pembrolizumab is available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s014lbl.pdf

FDA granted this application priority review status and accelerated approval. Further studies are required to confirm clinical benefit of pembrolizumab for this indication. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.

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 by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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