Keytruda Granted a Priority Review by the FDA for Advanced Microsatellite Instability-High (MSI-H) Cancer

The U.S. Food and Drug Administration (FDA) has granted a priority review to a supplemental biologics license application (sBLA) for Keytruda (pembrolizumab) for previously treated patients with advanced microsatellite instability-high (MSI-H) cancer, according to a statement from Merck, the manufacturer of the anti—PD-1 agent.

Microsatellite instability is a biomarker in certain kinds of cancer and is caused when a cell is not able to repair DNA sequencing errors (mismatch repairs), leading to more errors in microsatellite repeats after the cells divide.

The sBLA is based on results from five open-label, multicohort phase 1/2 trials that evaluated Keytruda in patients with MSI-H tumors. The specific regimen would be a fixed dosed of 200 mg of Keytruda every three weeks. Under the expedited review, the FDA is scheduled to make a final decision by March 8, 2017.

“The FDA’s acceptance of this application represents an important advance for the field of immuno-oncology and is further evidence of Merck’s commitment to identifying patients most likely to benefit from Keytruda treatment,” Roger M. Perlmutter, M.D., Ph.D., president, Merck Research Laboratories, said in a statement. “We believe that patients whose tumors harbor DNA repair defects may be especially responsive to Keytruda, and we look forward to working with the FDA to bring this important new therapy to these very challenging treatment situations.”

In November 2015, the FDA granted a breakthrough therapy designation to Keytruda as a potential therapy for patients with MSI-H metastatic colorectal cancer (mCRC).

The designation was based on findings from an ongoing phase II study, which demonstrated high response rates with Keytruda in patients with heavily pretreated CRC with mismatch repair (MMR) deficiency, a condition that causes MSI. Findings from the analysis were published in The New England Journal of Medicine (NEJM); however, data that were simultaneously presented at the 2015 ASCO Annual Meeting were from a more up-to-date analysis.

In the findings presented at ASCO, the objective response rate (ORR) was 62 percent with Keytruda in MMR-deficient mCRC compared with 0 percent in patients with MMR-proficient tumors. Median progression-free survival (PFS) and overall survival (OS) were not reached, with many patients responding to treatment for longer than 12 months in the MMR-deficient arm.

In the three-arm study that was the basis for the new designation, Keytruda was administered at 10 mg/kg every two weeks to patients with CRC who were MMR-deficient (13 patients) and MMR-proficient (25 patients). Additionally, a separate arm looked at Keytruda in patients with MMR-deficient non-CRC malignancies (10 patients). MMR and microsatellite instability testing was conducted using PCR and IHC, which are standard tests conducted for patients with CRC in order to detect Lynch syndrome.

Defects in MMR commonly lead to microsatellite instability, which can be found in most cancers, including a majority of patients with hereditary nonpolyposis CRC (Lynch syndrome). Without this repair mechanism, the mutational burden is generally higher, suggesting a higher likelihood of developing cancer. In total, more than 80 percent of patients in the MMR-deficient arm were positive for Lynch syndrome.

The primary endpoint of the study was immune-related PFS and response rate at 20 weeks. Secondary endpoints focused on OS, PFS and disease control rate (DCR; complete response, partial response, plus stable disease). Response and survival were assessed by RECIST criteria in addition to immune-related criteria.

In the 48 patients analyzed from the study for the ASCO presentation, those with MMR-deficient CRC experienced a DCR of 92 percent compared with 16 percent in MMR-proficient tumors. After a median treatment duration of 5.9 months, no patients in the MMR-deficient group who responded had progressed. In patients with MMR-deficient non-CRC tumors, the ORR was 60 percent and the DCR was 70 percent.

OS and PFS were not reached in the MMR-deficient group versus a median PFS of 2.3 months and an OS of 7.6 months in the MMR-proficient group.

In the analysis published in NEJM, which contained data from fewer patients, the ORR with Keytruda was 40 percent in patients with MMR-deficient mCRC (10 patients). In this same group, the PFS rate with Keytruda at 20 weeks was 78 percent.

The adverse events (AEs) seen in the study were consistent with other studies of Keytruda. The most common side effects were rash/pruritus (17 percent), pancreatitis (15 percent) and thyroiditis/hypothyroidism (10 percent).

Interestingly, patients with Lynch syndrome (11 patients) were less likely to respond compared with those with other forms of MMR, according to the data published in NEJM. In those with Lynch syndrome, the ORR was 27 percent with Keytruda compared with 100 percent in those with MMR that was unrelated to Lynch syndrome (six patients).

In total, 1782 somatic mutations were identified per patient in the MMR-deficient arm compared with 73 in those with MMR-proficient tumors. Predominately, these tumors were found to alter amino acids (63 percent) and 578 of the somatic mutations in the deficient arm were associated with the immune system.

Membranous PD-L1 expression was only identified in patients with MMR-deficient tumors. Additionally, tumors with MMR-deficiencies were more likely to contain a greater density of CD8+ lymphoid cells. However, the researchers noted that neither PD-L1 nor CD8 were significantly associated with PFS and OS.

In findings presented in January at the 2016 Gastrointestinal Cancers Symposium, treatment with Keytruda produced an ORR of 47 percent in a phase 2 trial of patients with noncolorectal GI cancers whose tumors were mismatch repair-deficient.

The phase 2 study enrolled three patient cohorts. The first two cohorts were patients with CRC, while the third cohort included 21 patients with any solid gastrointestinal tumor that had mismatch repair deficiency. This cohort was subsequently expanded by 50 patients.

Patients were treated with Keytruda at 10 mg/kg every two weeks. Mismatch repair testing was performed locally using standard immunohistochemistry for mismatch repair deficiency or polymerase chain reaction-based testing for microsatellite instability.

To be eligible for the third cohort, patients had to have histologically proven metastatic or locally advanced mismatch repair-deficient non-CRC solid tumor malignancy, measureable and progressive disease, and an ECOG performance score of 0 or 1, and must have received at least one prior therapy.

Data from 17 patients with non-CRC GI cancers deficient in mismatch repair were available for analysis: four patients with ampullary cancer, four with pancreatic cancer, three with biliary cancer, three with small bowel cancer and three with gastric cancer. Their median age was 60 years; 29 percent were female, 29 percent had an ECOG performance score of 0, and 100 percent had metastatic disease. The median number of prior regimens was two.

The rate and type of treatment-related AEs were similar to those in prior Keytruda studies. Seventy-six percent of patients developed treatment-related AEs. Most were low grade; two patients developed short-lived grade 3/4 AEs that did not require steroid therapy. The most common AEs were fatigue (24 percent), thyroid disorders (24 percent) and rash/pruritus (41 percent).

At a median follow-up of 5.3 months, the ORR was 47 percent: 25 percent had a complete response and 24 percent had a partial response. Twenty-nine percent had stable disease, and the disease control rate was 76 percent.

Clinical benefit was observed across tumors with mismatch repair deficiency including cancers of the colon, stomach, duodenum, pancreas, ampulla, and bile ducts.

Responses ranged from four months to 20 months, and all responders were still on treatment at the time of the data presentation. One patient with duodenal cancer developed a brain metastasis at 5.5 months and is still on therapy for more than 18 months owing to excellent systemic disease control.