FDA Grants Full Approval to Pembrolizumab for Select Patients With MSI-H or dMMR Solid Tumors

The FDA has granted full approval to pembrolizumab (Keytruda) for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) solid tumors that have progressed following previous treatment and who have no satisfactory alternative options.¹

The conversion to a regular approval was supported by findings from the multicenter, non-randomized, open-label, multicohort, phase 2 KEYNOTE-158 (NCT02628067), KEYNOTE-164 (NCT02460198), and KEYNOTE-051 (NCT02332668) trials and comprises data from 504 adult and pediatric patients with over 30 kinds of cancer.

Data from a pooled analysis of the trials showed that at a median follow-up of 20.1 months (range, 0.1-71.4), pembrolizumab elicited an objective response rate (ORR) of 33.3% (95% CI, 29.2%-37.6%), which comprised a 10.3% complete response rate and a 23.0% partial response rate.

More than half (77%) of those who responded to the agent (n = 168) experienced responses that lasted for at least 12 months; 39% responded for 36 months or longer. The median duration of response (DOR) was 63.2 months (range, 1.9+ to 63.9+).

The regulatory decision represents the first full approval for an immunotherapy agent based on a predictive biomarker, irrespective of solid cancer type, according to a press release issued by Merck.

“This approval reinforces the important role of KEYTRUDA in certain patients with MSI-Hor dMMR solid tumors facing a variety of cancers,” Luis A. Diaz, Jr., MD, head of the Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, stated in a press release. “These data also further underscore the need for biomarker testing to identify patients who may be eligible for this therapy.”

A total of 124 patients with advanced MSI-H/dMMR colorectal cancer (CRC) what progressed after fluoropyrimidine and oxaliplatin or irinotecan with or without a VEGF/EGFR monoclonal antibody–based therapy were enrolled to KEYNOTE-164. For KEYNOTE-158, 373 patients with advanced MSI-H/dMMR non-CRC who progressed after previous treatment were included. Notably, patients were prospectively enrolled with MSI-H dMMR tumors to cohort K or retrospectively identified in 1 of 10 solid tumor cohorts (cohorts A-J). Lastly, the KEYNOTE-051 trial enrolled 7 pediatric patients with MSI-H/dMMR cancers.

Notably, none of the trials enrolled those with autoimmune disease or a medical condition that needed to be treated with immunosuppressive drugs.

MSI status was determined by utilizing local or central polymerase chain reaction, and MMR status was identified by local or central immunohistochemistry.

Adult participants were administered intravenous pembrolizumab at 200 mg every 3 weeks, and pediatric patients received the immunothreapy at 2 mg/kg every 3 weeks. Treatment continued until intolerable toxicity, progressive disease, or for up to 24 months.

For KEYNOTE-164 and KEYNOTE-158, investigators conducted tumor assessments every 9 weeks through the first year of treatment and then every 12 weeks thereafter. For KEYNOTE-051, tumor assessments were performed every 8 weeks for the duration of 24 weeks and every 12 weeks thereafter.

ORR served as the major efficacy outcome measure of the trials, as well as DOR per blinded independent central review and in accordance with RECIST v1.1 criteria.

In KEYNOTE-158, this was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. For KEYNOTE-051, these outcome measures were assessed by study investigators according to RECIST v1.1 criteria.

In the KEYNOTE-158 and KEYNOTE-164 trials, patients were exposed to the immunotherapy for a median of 6.2 months (range, 1 day-53.5 months). In the KEYNOTE-051 trial, the median duration of exposure to pembrolizumab was 2.1 months (range, 1 day-25 months).

Additional data indicated that among the 124 patients with MSI-H/dMMR CRC, pembrolizumab induced an ORR of 34% (95% CI, 26%-43%), with a DOR that ranged from 4.4 months to over 58.5 months.

For the patients with other MSI-H/dMMR non-colorectal solid tumors (n = 380), the immunotherapy elicited an ORR of 33% (95% CI, 28%-38%), with a DOR that ranged from 1.9+ months to 63.9+ months. This population included those with 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, and renal cell cancer, among others.

Immune-mediated adverse effects can occur at any time during or following treatment with pembrolizumab; these effects can include pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and allogeneic hematopoietic stem cell transplantation complications.

In May 2017, the FDA granted an accelerated approval to pembrolizumab for adult and pediatric patients with unresectable or metastatic, MSI-H or dMMR solid tumors that progressed after previous treatment and who have no satisfactory alternative options, or those with MSI-H or dMMR CRC that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.²

The decision was supported by 5 uncontrolled, multicohort, multicenter, single-arm clinical trials that included 90 patients with CRC and 59 patients with one of 14 other tumor types. These patients had received pembrolizumab at 200 mg every 3 weeks or 10 mg/kg every 2 weeks.

These earlier data showed that the immunotherapy induced an ORR of 39.6% (95% CI, 31.7%-47.9%), with responses lasting for at least 6 months in 78% of responders. A total of 11 CRs and 48 PRs were reported. It was noted that ORRs were comparable, irrespective of whether patients had CRC (36%) or another solid tumor (46%).

In terms of safety, the most common toxicities reported with pembrolizumab were 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.

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

References

1. FDA converts to full approval indication for Keytruda (pembrolizumab) for certain adult and pediatric patients with advanced microsatellite instability-high (MSI-H) or mismath repair deficient (dMMR) solid tumors. News release. Merck. March 29, 2023. Accessed March 29, 2023. https://www.merck.com/news/
2. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. FDA. May 23, 2017. Accessed March 29, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/