From a research standpoint, Mills sees the MSI approval of pembrolizumab and the molecularly focused development of larotrectinib as © ©ktsdesign/fotolia.com “incredibly exciting.”
“The key question over the next 6 months to a year is, are we going to be able to leverage them to help the breadth of patients that we should be able to help with these technologies?” Mills said.
Many Building Blocks for MSI Approval
The FDA’s recognition of dMMR as the first predictive biomarker for a targeted therapy across tumor types is built upon a “strong biologic rationale, availability of commercially used diagnostics for patient identification, and the urgent, unmet medical needs of patients with refractory cancers,” Flaherty et al contended.3
Specifically, the FDA has granted an accelerated approval to pembrolizumab for the treatment of adult and pediatric patients with unresectable or metastatic MSI-H or dMMR solid tumors that have progressed after prior treatment and who have no satisfactory alternative treatment options, as well as for patients with MSI-H or dMMR colorectal cancer (CRC) following progression on a fluoropyrimidine, oxaliplatin, and irinotecan.
The approval for the PD-1–targeting immunotherapy agent was based on data from 149 patients with MSI-H or dMMR cancers enrolled across 5 single-arm clinical trials. Ninety patients had CRC and the remaining 59 had 1 of 14 other tumor types (Figure).
Overall, the objective response rate (ORR) with pembrolizumab was 39.6% (95% CI, 31.7%-47.9%), including 11 (7.4%) complete responses (CRs) and 48 (32.2%) partial responses (PRs). The ORR was 36% in patients with CRC; it ranged from 27% to 83% in patients with other tumor types (Table, page 19; Figure). The median duration of response for the entire population was not yet reached (range, 1.6 -22.7 months). Among patients who responded to pembrolizumab, 78% had responses that lasted for at least 6 months.
“This is an important first for the cancer community,” said Richard Pazdur, MD, acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and director of the FDA’s Oncology Center of Excellence, in a statement announcing the approval. “Until now, the FDA has approved cancer treatments based on where in the body the cancer started—for example, lung or breast cancers. We have now approved a drug based on a tumor’s biomarker without regard to the tumor’s original location.”
The pivotal data for the approval included patients from the KEYNOTE-016 (n = 58), KEYNOTE-164 (n = 61), KEYNOTE-012 (n = 6), KEYNOTE-028 (n = 5), and KEYNOTE-158 (n = 19) trials. Pembrolizumab was administered at 200 mg every 3 weeks or 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity, or a maximum of 24 months.
The median age among the 149 patients was 55 years, with 36% aged 65 or older. Across the population, 77% of patients were white, 56% were male, 36% had an ECOG performance status (PS) of 0, and 64% had an ECOG PS of 1.
Two percent of patients had locally advanced, unresectable disease, and 98% of patients had metastatic disease. Among patients with metastatic or unresectable disease, the median number of prior therapies was 2. In patients with metastatic CRC, 84% had received at least 2 prior lines of therapy compared with 53% in patients with other solid tumors.
Among the majority (n = 135) of the 149 patients, MSI-H or dMMR tumor status was determined prospectively with immunohistochemistry tests for dMMR or laboratory-developed, investigational polymerase chain reaction (PCR) tests for MSI-H status. For the remaining 14 patients, MSI-H status was determined through a retrospective evaluation of 415 tumor samples using a central laboratory-developed PCR test.
In its statement on the approval, the FDA listed common adverse events (AEs) of pembrolizumab, including fatigue, pruritus, diarrhea, decreased appetite, rash, pyrexia, cough, dyspnea, musculoskeletal pain, constipation, and nausea. Immune-mediated AEs associated with pembrolizumab include pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.4
The FDA also noted that the label for pembrolizumab includes a “Limitation of Use” indicating that the efficacy and safety of pembrolizumab have not been established in pediatric patients with MSI-H central nervous system cancers. The accelerated approval for pembrolizumab in this setting is contingent on the results of a confirmatory trial. The approval was preceded by a breakthrough therapy designation the FDA granted to pembrolizumab in November 2015 as a treatment for patients with MSI-H metastatic CRC.
“The main data here are showing that in CRC and non-CRC, we’re seeing response rates with pembrolizumab that are quite impressive,” Luis A. Diaz Jr, MD, whose research helped paved the way for the pembrolizumab approval, said in an interview. “The progression-free survival and overall survival are quite durable, and it’s recapitulated in entirely different studies. I believe that is what led to the FDA approval.