What Clinical Trials Led to the Keytruda Tumor Agnostic FDA Approval in MSI-H tumors?

Exactly how did Merck get a tumor-agnostic FDA approval for Keytruda (pembrolizumab) microsatellite instability-high adult and pediatric tumors?

In May 2017, FDA granted accelerated approval for Keytruda for the treatment of MSI-H or mismatch repair deficient (dMMR) solid tumors that have progressed following previous treatment and who have no satisfactory alternative options.

In March 2023, this was converted to full approval.

These approvals were based on several clinical trials:

KEYNOTE-016: Initiated in 2012, this early-phase study focused on pembrolizumab in patients with advanced solid tumors, specifically highlighting MSI-H colorectal cancer and a selection of other MSI-H tumors. This trial was instrumental in exploring the efficacy of pembrolizumab across different MSI-H cancer types.

KEYNOTE-012: Initiated in 2013, this phase 1b trial evaluated pembrolizumab in patients with advanced triple-negative breast cancer, gastric cancer, and other PD-L1 positive solid tumors. It included a cohort of patients with tumors expressing PD-L1, helping to define the role of pembrolizumab in PD-L1 positive cancer therapies.

KEYNOTE-028: Also started in 2013, this early-phase trial assessed the safety and efficacy of pembrolizumab in patients with PD-L1 positive cancers across 20 different cohorts, including various solid tumors. This trial further supported the potential for pembrolizumab in a wide range of tumor types based on PD-L1 expression rather than the tumor’s location.

KEYNOTE-164: Launched in 2014, this study focused on patients with previously treated metastatic colorectal cancer that exhibited MSI-H or dMMR. The results contributed to the understanding of pembrolizumab’s effectiveness specifically in colorectal cancer patients with these genetic markers.

KEYNOTE-158: Started in 2015 and still recruiting, this trial was pivotal in investigating pembrolizumab in patients with a variety of advanced solid tumors with dMMR or MSI-H that were not specific to colorectal cancer. This broad study across multiple tumor types helped establish the efficacy of pembrolizumab in a tumor-agnostic approach.

KEYNOTE-051: This trial was initiated in 2015. It is a Phase I/II study evaluating pembrolizumab in pediatric patients with advanced melanoma, PD-L1 positive solid tumors, or lymphoma. The trial includes several cohorts based on different tumor types and characteristics, including microsatellite instability-high (MSI-H) and tumor mutational burden-high (TMB-H) solid tumors.

KEYNOTE-177: Initiated in 2015, KEYNOTE-177 was a pivotal Phase III trial focused on pembrolizumab as a first-line treatment for patients with MSI-H or dMMR metastatic colorectal cancer. This study played a crucial role in the 2020 FDA approval of pembrolizumab for this specific indication, marking a significant advancement in the treatment of this patient population.