FDA Approval Summary: Pembrolizumab for the Treatment of Microsatellite Instability-High Solid Tumors

Abstract

The FDA approved pembrolizumab on May 23, 2017, 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 prior treatment and who have no satisfactory alternative treatment options and for the treatment of unresectable or metastatic MSI-H or dMMR colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. The FDA granted the approval based on an understanding of the biology of MSI-H/dMMR across different tumors along with the clinically important effects on overall response rate (ORR) observed in patients who were enrolled in 1 of 5 single-arm clinical trials. The ORR was 39.6% among 149 patients with 15 different tumor types (95% confidence interval, 31.7-47.9), with a 7% complete response rate. The duration of response ranged from 1.6þ months to 22.7þ months, with 78% of responses lasting !6 months. Overall, the adverse event profile of pembrolizumab was similar to the adverse event profile observed across prior trials that supported the approval of pembrolizumab in other indications. This approval of pembrolizumab is the first time that the FDA has approved a cancer treatment for an indication based on a common biomarker rather than the primary site of origin.

Hyperprogression and Immune Checkpoint Inhibitors: Hype or Progress?

“…Immunotherapy in the form of checkpoint blockade has resulted in impressive responses for several previously refractory tumor types. Indeed, the U.S. Food and Drug Administration (FDA) has now approved seven checkpoint inhibitors: pembrolizumab, nivolumab, durvalumab, avelumab, atezolizumab, cemiplimab, and ipilimumab . Immune checkpoint inhibitors mediate responses by reactivating the immune system.…”

An overview of precision oncology basket and umbrella trials for clinicians

“…For example, pembrolizumab, a programmed cell death protein 1 inhibitor, is the first tumor‐agnostic therapy that received an accelerated approval from the FDA in March 2017 for adult and pediatric patients who have unresectable or metastatic solid tumors with microsatellite instability‐high (MSI‐H) or deficient mismatch repair (dMMR) . This approval was based on a pooled analysis of tumor response rate and duration observed from 149 patients with 15 different tumors from 5 single‐arm trials: KEYNOTE‐016 (Study of MK‐3475 in Patients With Microsatellite Unstable [MSI] Tumors [Cohorts A, B, and C]; clinicaltrials.gov identifier NCT01876511), KEYNOTE‐164 (Study of Pembrolizumab [MK‐3475] as Monotherapy in Participants With Previously Treated Locally Advanced Unresectable or Metastatic Colorectal Cancer; NCT02460198), KEYNOTE‐158 (Study of Pembrolizumab [MK‐3475] in Participants With Advanced Solid Tumors; NCT02628067), KEYNOTE‐012 (Study of Pembrolizumab [MK‐3475] in Participants With Advanced Solid Tumors; NCT01848834), and KEYNOTE‐028 (Study of Pembrolizumab [MK‐3475] in Participants With Advanced Solid Tumors; NCT02054806) . The patients across these trials had common unifying risk factors in the form of MSI‐H and dMMR mutations.…”

“…46 ANVIL, conversely, plans to recruit 714 patients to detect a 30% improvement in OS and/or a 33% reduction in disease-free survival favoring nivolumab. 45 Table 2 [47][48][49][50][51][52][53][54][55][56][57][58] highlights several of the key targeted precision oncology therapies that have been recently approved by the FDA. Currently, there are 3 FDA-approved tumor-agnostic therapies.…”

“…However, it is important to note that the evidence used for these approvals closely followed the core assumption of basket trials: the unification of disease. For example, pembrolizumab, a programmed cell death protein 1 inhibitor, is the first tumor-agnostic therapy that received an accelerated approval from the FDA in March 2017 for adult and pediatric 47,48 The patients across these trials had common unifying risk factors in the form of MSI-H and dMMR mutations. Larotrectinib, a tropomyosin kinase receptor (TRK) inhibitor, is the second tumor-agnostic therapy to be approved by the FDA.…”

Cancer-specific associations of driver genes with immunotherapy outcome

“…Several ICI biomarkers have been identified, but only a few are in routine clinical use: PD-L1 expression levels in tumor and immune cells, and deficient mismatch repair (dMMR)/ microsatellite instability-high (MSI-H) have been incorporated into FDA-approved indications for some ICIs. However, these are still imperfect predictors; response rates among MSI-H patients in the clinical trials leading to the FDA approval of this biomarker were just under 40% 3 . Tumor mutation burden (TMB) is emerging as another predictive biomarker but has not been widely implemented due to a lack of standardized definitions and thresholds 4 .…”