Regulatory Decision Summary for Keytruda

Authorization was based on results of interim analyses of two single arm, pivotal studies, both of which were enrolled with adult patients with MSI-H/dMMR cancers. In 1 of these studies (Keynote (KN)-164), results were provided for patients in 1 of 2 cohorts (cohort A) who received pembrolizumab monotherapy for the treatment of patients with locally advanced unresectable or metastatic colorectal cancer (mCRC) who had previous treatment with standard therapy which must have included a fluoropyrimidine, oxaliplatin, and irinotecan. The second pivotal study (KN-158) consisted of 10 cohorts of patients (cohorts A-J), each representing a specific histological tumour type (excluding CRC) diagnosed retrospectively as positive for MSI-H/dMMR, as well as a single cohort of patients (cohort K) enrolled if prospectively diagnosed with an MSI-H/dMMR tumour of any histological type (except CRC).

In study KN-164, of 74 patients screened, 61 patients were evaluable and thus analyzed for efficacy and safety. At the time of the interim report, the median follow-up time was 13.2 months (mos) (range 0.2 to 16.9 mos). The objective response rate (ORR) was considered clinically meaningful at 27.9%, though all responses were PRs. Analysis of the duration of response (DOR), progression-free survival (PFS), and overall survival (OS) showed results that were promising but required confirmation with additional patients and longer follow-up for these endpoints. No new safety signals were apparent and the safety profile was comparable to the large safety datasets accumulated over time for the multiple indications already authorized.

In study KN-158, 94 patients were enrolled and evaluable for efficacy and safety. Overall, the ORR for all patients was 37.2% with 4 complete responses (CRs). The most common cancer types (n) and their ORRs (%) were endometrial (24, 54.2%), gastric (13, 46.2%), small intestine (13, 30.8%), and pancreas (10, 10%). All but one of the remaining 16 tumour types were each represented by ≤3 patients. In addition, the median follow-up for all patients was 8.4 mos (range 0.6 to 14.9 mos). The number of patients for each tumour type and the duration of follow-up for responses were insufficient to confidently demonstrate adequate promise of meaningful improvement in primary or secondary endpoints. The frequencies of different types of adverse events (AEs) were similar to that found in the large cumulative safety datasets from multiple previously authorized indications. No new safety signals were reported.

The most current versions of the core Risk Management Plan (RMP) and Canadian Specific Annex (CSA) were submitted and reviewed. No new safety concerns were identified and the RMP and CSA were considered acceptable.

An assessment of the benefits and risks in the two pivotal studies concluded that efficacy and safety data from study KN-164 demonstrated promising efficacy that outweighs the risks of treatment with Keytruda monotherapy in adult patients with unresectable or metastatic MSI-H/dMMR colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Promising efficacy that outweighed the risks of such treatment was also demonstrated in patients with MSI-H/dMMR endometrial cancer in study KN-158. Adequate promise of efficacy could not be demonstrated for patients with other tumour types represented in the submission due to the small number of patients with these tumour types.

As a result, this submission was issued a Notice of Compliance with Conditions (NOC/c) under the NOC/c Policy to authorize the use of Keytruda monotherapy for the treatment of adults with unresectable or metastatic MSI-H/dMMR colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan or MSI-H/dMMR endometrial cancer that has progressed following prior therapy and who have no satisfactory alternative treatment options. Conditions include the enrollment of additional patients to study KN-164 and to study KN-158 with adequate minimum follow-up of responding patients in both studies.