Merck Keytruda gets full USFDA approval for advanced MSI-H or dMMR solid tumors

The full approval was based on data from three multicenter, non-randomized, open-label multi-cohort trials. KEYNOTE-164 (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 mAb-based therapy. KEYNOTE-158 (NCT02628067) enrolled 373 patients with advanced MSI-H/dMMR non-colorectal 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 (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 KEYTRUDA 200 mg administered intravenously every three weeks (pediatric patients received 2 mg/kg every three 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 nine weeks through the first year, then every 12 weeks thereafter. In KEYNOTE‑051, assessment of tumor status was performed every eight weeks for 24 weeks, and then every 12 weeks thereafter. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) as assessed by blinded independent central review according to RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ in KEYNOTE-158) and as assessed by the investigator according to RECIST v1.1 in KEYNOTE-051.

In a pooled analysis of the three trials, KEYTRUDA demonstrated an ORR of 33.3% (95% 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 to 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 DOR was 63.2 months (range, 1.9+ to 63.9+ months).

In patients with MSI-H/dMMR colorectal cancer (n=124), KEYTRUDA demonstrated an ORR of 34% (95% CI, 26%-43%) with a DOR ranging from 4.4 to 58.5+ months. In patients with other MSI-H/dMMR non-colorectal solid tumors (n=380), which included endometrial cancer, gastric or gastroesophageal junction cancer, small intestinal cancer, brain cancer, ovarian cancer, biliary cancer, pancreatic cancer, sarcoma, breast cancer, cervical cancer, neuroendocrine cancer, prostate cancer, adrenocortical cancer, mesothelioma, thyroid cancer, small cell lung cancer, bladder cancer, salivary cancer, renal cell cancer and other cancers (including anal cancer, head and neck squamous cell cancer, nasopharyngeal cancer, retroperitoneal cancer, testicular cancer, vaginal cancer, vulvar cancer, appendiceal adenocarcinoma, hepatocellular carcinoma, carcinoma not-otherwise-specified and carcinoma of unknown origin), KEYTRUDA demonstrated an overall ORR 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).

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD- L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

“This approval reinforces the important role of KEYTRUDA in certain patients with MSI-Hor dMMR solid tumors facing a variety of cancers,” said Dr. Luis A. Diaz, Jr., head of the Division of Solid Tumor Oncology, 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.”

"The approval builds on the 2017 accelerated approval of KEYTRUDA as the first immunotherapy with a tumor agnostic indication and supports the role of KEYTRUDA as an effective immunotherapy option based on a pan-tumor predictive biomarker," said Dr. Scot Ebbinghaus, vice president, global clinical development, Merck Research Laboratories. “This milestone reflects Merck’s longstanding commitment to biomarker research and personalizing treatment strategies for patients.”