First FDA Approval Based on a Tumor Marker – Pembrolizumab for MSI-H Cancers

The immunotherapy drug Keytruda, containing pembrolizumab, received accelerated approval on May 23, 2017 for tumors with particular genetic features (MSI-H), regardless of their organ of origin, from the FDA (United States Food and Drug Administration). Previously, approved drugs were generally given according to the organ where cancer arose. Pembrolizumab is the first drug approved in this way.

What Is MSI-H?

MSI-H means high microsatellite instability, a condition in which microsatellite regions in DNA show abnormally high variability. Microsatellites are short repeated nucleotide sequences within DNA. Microsatellite instability (MSI) occurs when cells tend to make errors copying or repairing DNA. This can produce abnormal genes contributing to cancer cell formation and growth.

MSI-H tumors are particularly common in colorectal cancer, occurring in approximately %15 of cases. They can also occur in other cancers, including endometrial (uterine), stomach, pancreatic, ovarian and bile duct cancer. Determining MSI-H status is important for predicting the efficacy of particular treatments such as immunotherapy.

Cancers with high genomic instability respond well to immunotherapy treatments

Full Approval Through Three Clinical Trials

Full approval is based on data from three multicenter, nonrandomized, open-label, multicohort studies.

KEYNOTE-164 included advanced MSI-H/dMMR colorectal cancer treated with fluoropyrimidine and oxaliplatin or irinotecan, or anti-VEGF/EGFR monoclonal antibody-based treatment, in 124 patients.

KEYNOTE-158 enrolled 373 patients with advanced MSI-H/dMMR noncolorectal cancers progressing after prior treatment. Patients were either enrolled prospectively with MSI-H/dMMR tumors (Cohort K) or identified retrospectively in one of 10 solid tumor cohorts (Cohorts A-J).

KEYNOTE-051 included seven pediatric patients with MSI-H/dMMR cancers.

All studies excluded patients with autoimmune disease or a medical condition requiring 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 intravenous pembrolizumab every 3 weeks at 200 mg, and pediatric patients, until unacceptable toxicity, disease progression or a maximum of 24 months, received it every 3 weeks at 2 mg/kg.

In KEYNOTE-164 and KEYNOTE-158, tumor status was assessed every 9 weeks during the first year and then every 12 weeks. In KEYNOTE-051, assessments during the first 24 weeks occurred every 8 weeks, then every 12 weeks. The main efficacy measures were objective response rate and duration.

Results

In the pooled analysis of the three studies, KEYTRUDA showed an objective response rate of %33,3 (confidence interval [CI] = %29,2-37,6), including %10,3 complete responses and %23,0 partial responses.

Median follow-up was 20,1 months (range = 0,1-71,4 months). Among responding patients (n = 168), %77 had responses lasting 12 months or longer and %39 lasting 36 months or longer. Median response duration was 63,2 months (range = 1,9+ - 63,9+ months).

In MSI-H/dMMR colorectal cancer patients (n = 124), pembrolizumab showed a targeted response rate of %34 (CI = %26-43), with response duration ranging from 4,4 to 58,5+ months. Other MSI-H/dMMR noncolorectal solid tumor patients (n = 380) included endometrial, stomach or gastroesophageal junction, small bowel, brain, ovarian, bile duct and pancreatic cancers, sarcoma, breast and cervical cancers, neuroendocrine tumors, prostate and adrenal cortical cancers, mesothelioma, thyroid cancer, small cell lung cancer, bladder and salivary gland cancers, renal cell carcinoma and other cancers (including anal cancer, head and neck squamous cell carcinoma, nasopharyngeal, retroperitoneal, testicular, vaginal and vulvar cancers, appendix adenocarcinoma, hepatocellular carcinoma, unspecified carcinoma and carcinoma of unknown origin). Pembrolizumab showed an overall targeted response rate of %33 (CI = %28-38), with response duration ranging from 1,9+ to 63,9+ months.

In KEYNOTE-158 and KEYNOTE-164, median KEYTRUDA exposure was 6,2 months (range = 1 day - 53,5 months). In KEYNOTE-051, median exposure was 2,1 months (range = 1 day - 25 months).