Oncologists Find Controversary With Pembrolizumab Approval in TMB-High Solid Tumors


Physicians published a new analysis that challenges the FDA approval of pembrolizumab for patients with treatment-refractory cancers and a high tumor mutational burden.

While pembrolizumab (Keytruda) showed 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), a new analysis suggests that the data used for its approval were too broad and neglect decreased survival data in certain tumor types.1

The FDA gave accelerated approval to pembrolizumab last summer for this treatment population based on efficacy data from the KEYNOTE-158 (NCT02628067) study.2 Thirteen percent of patients (n = 102) in the study had tumors with TMB greater than 10 mut/Mb and of these patients the overall response rate (ORR) was 29% (95% CI, 21-39). The ORR was the main efficacy outcome of the study along with duration of response (DOR); however, median DOR was not reached. Responses lasted for 12 months or more in 57% of patients and 50% had a response duration of 24 months or more.

“This approval, given purely on the basis of response rate, also neglects more meaningful clinical end points, including survival and quality of life, and slows the development of more effective therapies for this patient population,” wrote first author Benoit Rousseau, MD, PhD, and other investigators from the Memorial Sloan Kettering Cancer Centre in New York, NY and Johns Hopkins Medical Institutes in Baltimore, MD, in a correspondence in the New England Journal of Medicine discussing the approval.3 The investigators stated that high TMB was not a predictor for improved overall survival (OS) after treatment with immune checkpoint inhibitors (ICI) like pembrolizumab. Moreover, 18% of patients with advanced colorectal cancer (CRC) will be impacted by the FDA approval and the outcome of ICI treatment in 137 patients with CRC will have to be retrospectively evaluated.

Median OS was longer in patients with advanced CRC and high TMB, as defined by 10 mut/Mb, than in patients with low TMB after ICI treatment (HR, 0.40; 95% CI, 0.24-0.65).1 When patients were then stratified for mismatch repair–deficiency (MRD) status, pathogenic mutations in polymerase ε (POLE) or polymerase δ1 (POLD1), all titled pol-d in the study, OS benefit was not evident (HR 1.17; 95% CI, 0.59-2.32).

The investigators expanded the analysis to include 1,661 patients with various tumors and were treated with ICIs and found that patients with TMB with 10 mut/Mb had improved OS but only in the subgroup of patients with MRD–proficient tumors. For patients with MRD–proficient tumors that had a low TMB of less than 10 mut/Mb they had a median OS of 12.1 months (95% CI, 9.61-15.3) compared to similar patients with tumors that have a high TMB had a median OS of 10.6 months (95% CI, 4.41-22.2).3 Patients with metastatic head and neck cancer, non–small-cell lung cancer, and melanoma were the only cancer types to see an improved OS (HR 0.52; 95% CI, 0.31 to 0.64) compared to 10 other tumor types that had MRD–proficient or pol-d intact (HR, 0.84; 95% CI, 0.63-1.11).

According to the investigators, MRD is a known biomarker for improved OS for patients on ICI and pol-d status could also predict benefit with ICIs. The only other patients with hypermutated tumors who benefited with ICI had cancers associated with environmental carcinogens, such as, chronic exposure to ultraviolet radiation or tobacco.

The new analysis did not look again at adverse events (AEs) but in the initial FDA approval of pembrolizumab, AEs were consistent with the drug as a single agent.2 The most common of these AEs included fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. Other immune-mediated adverse events that include pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and skin adverse reactions. The recommended dose regimen for patients with TMB high tumors was 200 mg every 3 weeks or 400 mg every 6 weeks for adults. Pediatric patients were given up to a maximum of 200 mg every 3 weeks.

“The current FDA approval granted on the basis of tumor mutational burden may be too broad, and immune checkpoint inhibitors should be considered in the context of the cause of the high tumor mutational burden and not based solely on an absolute threshold,” Rousseau et al concluded.2


1. Physicians Debate Recent FDA Approval of an Immune Checkpoint Inhibitor in Hypermutated Tumours. News Release. ESMO Oncology News. March 31, 2021. Accessed April 5, 2021. https://bit.ly/31UAcM1

2. Rousseau B, Foote MB, Maron SB, et al.The Spectrum of Benefit from Checkpoint Blockade in Hypermutated Tumors. N Engl J Med. 2021; 384:1168-1170. doi: 10.1056/NEJMc2031965

3. FDA approves pembrolizumab for adults and children with TMB-H solid tumors. US Food and Drug Administration. June 16, 2020. Accessed April 5, 2021. https://bit.ly/3sYIVZw

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