FDA Review Continues for Pembrolizumab in MSI-H Cancer

A supplemental biologics license application (sBLA) for pembrolizumab (Keytruda) for previously treated patients with advanced microsatellite instability-high (MSI-H) cancer remains under review by the FDA, according to a statement from Merck, the manufacturer of the anti—PD-1 agent.

UPDATE 5/23/2017: FDA Approves Pembrolizumab for Microsatellite Instability-High and Mismatch Repair Deficient Cancers

Merck announced in November 2016 that pembrolizumab had received a priority review from the FDA for use in this setting, with a final decision expected under the Prescription Drug User Fee Act (PDUFA) by March 8, 2017. The company now reports that it has submitted further data and analyses supporting the pending sBLA. The new PDUFA action date for the FDA to make its decision is June 9, 2017.

The sBLA for pembrolizumab is based on results from 5 open-label, multicohort phase I/II trials that evaluated pembrolizumab in patients with MSI-H tumors. The specific regimen would be a fixed dosed of 200 mg of pembrolizumab every 3 weeks.

In November 2015, the FDA granted a breakthrough therapy designation to pembrolizumab 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 pembrolizumab 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.^1,2

In the findings presented at ASCO, the objective response rate (ORR) was 62% with pembrolizumab in MMR-deficient mCRC compared with 0% 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 3-arm study that was the basis for the new designation, pembrolizumab was administered at 10 mg/kg every 2 weeks to patients with CRC who were MMR-deficient (n = 13) and MMR-proficient (n = 25). Additionally, a separate arm looked at pembrolizumab in patients with MMR-deficient non-CRC malignancies (n = 10). 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% 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% compared with 16% 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% and the DCR was 70%.

OS and PFS were not reached in the MMR-deficient group versus a median PFS of 2.3 months (HR, 0.10; 95% CI, 0.03-0.37; P <.001) and an OS of 7.6 months in the MMR-proficient group (HR, 0.22; 95% CI, 0.05-1.00; P = .05).

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

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

Interestingly, patients with Lynch syndrome (n = 11) 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% with pembrolizumab compared with 100% in those with MMR that was unrelated to Lynch syndrome (n = 6).

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%) 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 pembrolizumab produced an ORR of 47% in a phase II trial of patients with noncolorectal GI cancers whose tumors were mismatch repair-deficient.³

The phase II study enrolled 3 patient cohorts. The first 2 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 pembrolizumab at 10 mg/kg every 2 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: 4 patients with ampullary cancer, 4 with pancreatic cancer, 3 with biliary cancer, 3 with small bowel cancer, and 3 with gastric cancer. Their median age was 60 years; 29% were female, 29% had an ECOG performance score of 0, and 100% had metastatic disease. The median number of prior regimens was 2.

The rate and type of treatment-related AEs were similar to those in prior pembrolizumab studies. Seventy-six percent of patients developed treatment-related AEs. Most were low grade; 2 patients developed short-lived grade 3/4 AEs that did not require steroid therapy. The most common AEs were fatigue (24%), thyroid disorders (24%), and rash/pruritus (41%).

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

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 4 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 >18 months owing to excellent systemic disease control.

Confirmatory studies are currently evaluating pembrolizumab monotherapy for patients with advanced MSI-H or mismatch repair deficient tumors. The first, the phase II KEYNOTE-164 study, is examining the agent in previously treated patients with advanced CRC and the second, the phase III KEYNOTE-177, is exploring pembrolizumab for treatment-naive patients with CRC. A separate phase II study, the KEYNOTE-158 trial, is exploring pembrolizumab for patients with non-CRC MSI-H tumors.

Pembrolizumab has approvals in melanoma, lung cancer, and head and neck cancer. Other applications for approval are pending with the FDA in bladder cancer and Hodgkin lymphoma, as a monotherapy, and in combination with chemotherapy for patients with lung cancer.

References

1. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch repair deficiency. J Clin Oncol. 2015;(suppl; abstr LBA100).
2. Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015; 372:2509-2520.
3. Le DT, Uram JN, Wang H, et al. PD-1 blockade in mismatch repair deficient non-colorectal gastrointestinal cancers. J Clin Oncol. 2016;34(suppl 4S; abstr 195).