On March 29, the U.S. Food and Drug Administration (FDA) granted full approval to the anti–PD-1 therapy pembrolizumab for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) solid tumors, as determined by an FDA-approved test, whose disease has progressed following prior treatment and who have no satisfactory alternative treatment options. The conversion from an accelerated to a full (regular) approval is based on results from the phase II KEYNOTE-158, KEYNOTE-164, and KEYNOTE-051 trials and includes data from over 500 adult and pediatric patients across more than 30 types of cancer. This marks the first full approval for an immunotherapy based on a predictive biomarker, regardless of solid tumor type.
Luis A. Diaz, Jr, MD
“This approval reinforces the important role of pembrolizumab for certain patients with MSI-H or dMMR solid tumors facing a variety of cancers,” said Luis A. Diaz, Jr, MD, Head of the Division of Solid Tumor Oncology at Memorial Sloan Kettering Cancer Center. “These data also further underscore the need for biomarker testing to identify patients who may be eligible for this therapy.”
Data Supporting the Full Approval
The full approval was based on data from three multicenter, nonrandomized, open-label multicohort trials. KEYNOTE-164 (ClinicalTrials.gov identifier NCT02460198) enrolled 124 patients with advanced MSI-H/dMMR colorectal cancer that progressed following treatment with fluoropyrimidine and either oxaliplatin or irinotecan with or without anti-VEGF/EGFR monoclonal antibody–based therapy. KEYNOTE-158 (ClinicalTrials.gov identifier NCT02628067) enrolled 373 patients with advanced MSI-H/dMMR noncolorectal cancers who had disease progression following prior therapy. Patients were either prospectively enrolled with MSI-H/dMMR tumors (Cohort K) or retrospectively identified in one of 10 solid tumor cohorts (Cohorts A–J). KEYNOTE-051 (ClinicalTrials.gov identifier NCT02332668) enrolled seven pediatric patients with MSI-H/dMMR cancers. All trials excluded patients with autoimmune disease or a medical condition that required immunosuppression. Regardless of histology, MSI or MMR tumor status was determined using polymerase chain reaction (local or central) or immunohistochemistry (local or central), respectively.
Adult patients received 200 mg of pembrolizumab administered intravenously every 3 weeks and pediatric patients received 2 mg/kg every 3 weeks until unacceptable toxicity, disease progression, or a maximum of 24 months. In KEYNOTE‑164 and KEYNOTE‑158, assessment of tumor status was performed every 9 weeks through the first year, then every 12 weeks thereafter. In KEYNOTE‑051, assessment of tumor status was performed every 8 weeks for 24 weeks, and then every 12 weeks thereafter. The major efficacy outcome measures were objective response rate and duration of response as assessed by blinded independent central review according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ in KEYNOTE-158) and as assessed by the investigator according to RECIST version 1.1 in KEYNOTE-051.
In a pooled analysis of the three trials, KEYTRUDA demonstrated an objective response rate of 33.3% (95% confidence interval [CI] = 29.2%–37.6%), including a complete response rate of 10.3% and partial response rate of 23.0% at a median follow-up time of 20.1 months (range = 0.1–71.4 months). Of the responding patients (n = 168), 77% had responses lasting 12 months or longer, and 39% had responses lasting 36 months or longer. Median duration of response was 63.2 months (range = 1.9+ to 63.9+ months).
In patients with MSI-H/dMMR colorectal cancer (n = 124), pembrolizumab demonstrated an objective response rate of 34% (95% CI = 26%–43%) with a duration of response ranging from 4.4 to 58.5+ months. In patients with other MSI-H/dMMR noncolorectal solid tumors (n = 380), which included endometrial cancer, gastric or gastroesophageal junction cancer, small intestinal cancer, brain cancer, ovarian cancer, biliary tract cancer, pancreatic cancer, sarcoma, breast cancer, cervical cancer, neuroendocrine tumors, prostate cancer, adrenocortical cancer, mesothelioma, thyroid cancer, small cell lung cancer, bladder cancer, salivary cancer, renal cell carcinoma, and other cancers (including anal cancer, head and neck squamous cell carcinoma, nasopharyngeal cancer, retroperitoneal cancer, testicular cancer, vaginal cancer, vulvar cancer, appendiceal adenocarcinoma, hepatocellular carcinoma, carcinoma not-otherwise-specified, and carcinoma of unknown origin), pembrolizumab demonstrated an overall objective response rate of 33% (95% CI = 28%–38%) with a duration of response ranging from 1.9+ to 63.9+ months.
In KEYNOTE-158 and KEYNOTE-164, the median duration of exposure to KEYTRUDA was 6.2 months (range = 1 day to 53.5 months). In KEYNOTE-051, the median duration of exposure was 2.1 months (range = 1 day to 25 months).
"[This] approval builds on the 2017 accelerated approval of pembrolizumab as the first immunotherapy with a tumor agnostic indication and supports the role of pembrolizumab as an effective immunotherapy option based on a pan-tumor predictive biomarker," said Scot Ebbinghaus, MD, Vice President, Global Clinical Development at Merck Research Laboratories.
