FDA has granted full approval to pembrolizumab, an anti-PD-1 therapy, for the treatment of adult and paediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumours, as determined by an FDA-approved test, that have 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 2 KEYNOTE-158, KEYNOTE-164 and KEYNOTE-051 trials and includes data in 504 adult and paediatric 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 tumour type.

“This approval reinforces the important role of pembrolizumab in certain patients with MSI-Hor dMMR solid tumours 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.”

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time during or after treatment with pembrolizumab, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation.

Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions. Early identification and management of immune- mediated adverse reactions are essential to ensure the safe use of pembrolizumab.

Based on the severity of the adverse reaction, pembrolizumab should be withheld or permanently discontinued and corticosteroids administered if appropriate.

Pembrolizumab can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, pembrolizumab can cause foetal harm when administered to a pregnant woman. For more information, see “Selected Important Safety Information” below.

"Today’s 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-tumour 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 personalising treatment strategies for patients.”

Data supporting the approval

The full approval was based on data from three multicenter, non-randomised, 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 tumours (Cohort K) or retrospectively identified in one of 10 solid tumour cohorts (Cohorts A-J). KEYNOTE-051 (NCT02332668) enrolled seven paediatric 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 tumour status was determined using polymerase chain reaction (local or central) or immunohistochemistry (local or central), respectively.

Adult patients received pembrolizumab 200 mg administered intravenously every three weeks (paediatric 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, an assessment of tumour status was performed every nine weeks through the first year, then every 12 weeks thereafter. In KEYNOTE‑051, assessment of tumour 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, pembrolizumab 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), pembrolizumab 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 tumours (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), pembrolizumab 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 pembrolizumab 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).

Source: Merck