Controversy Surrounds FDA Approval of Pembrolizumab for High TMB Solid Tumors
While pembrolizumab (Keytruda) demonstrated a significant and durable response in patients with treatment-refractory cancers and a tumor mutational burden (TMB) greater than 10 mutations per megabase (mut/Mb), concerns have been raised about the breadth of the data used for its FDA approval. The approval, granted last summer, was based on efficacy data from the KEYNOTE-158 study, where 13% of patients had tumors with TMB greater than 10 mut/Mb, showing an overall response rate (ORR) of 29%. However, the study's focus on ORR and duration of response (DOR) has been criticized for neglecting more meaningful clinical endpoints such as survival and quality of life.
Critics, including researchers from the Memorial Sloan Kettering Cancer Centre and Johns Hopkins Medical Institutes, argue that high TMB is not a reliable predictor for improved overall survival (OS) after treatment with immune checkpoint inhibitors (ICI) like pembrolizumab. They highlight that the approval could impact 18% of patients with advanced colorectal cancer (CRC), necessitating a retrospective evaluation of ICI treatment outcomes in these patients.
Further analysis revealed that while patients with advanced CRC and high TMB had longer median OS than those with low TMB after ICI treatment, this benefit was not evident when patients were stratified for mismatch repair–deficiency (MRD) status or pathogenic mutations in polymerase ε (POLE) or polymerase δ1 (POLD1). The study also found that only patients with metastatic head and neck cancer, non–small-cell lung cancer, and melanoma saw an improved OS, compared to other tumor types.
The investigators suggest that MRD is a known biomarker for improved OS in patients on ICI, and pol-d status could also predict benefit with ICIs. They conclude that the FDA's approval based on TMB may be too broad, advocating for a more nuanced approach that considers the cause of high TMB rather than relying solely on an absolute threshold.
Adverse events (AEs) associated with pembrolizumab were consistent with its known profile, including fatigue, musculoskeletal pain, and immune-mediated adverse events. The recommended dosing regimen for adults with high TMB tumors is 200 mg every 3 weeks or 400 mg every 6 weeks, with pediatric patients receiving up to a maximum of 200 mg every 3 weeks.