Abstract

<div>AbstractPurpose:<p>To evaluate the efficacy of pembrolizumab across multiple cancer types harboring different levels of whole-genome sequencing–based tumor mutational load (TML; total of nonsynonymous mutations across the genome) in patients included in the Drug Rediscovery Protocol (NCT02925234).</p>Patients and Methods:<p>Patients with solid, treatment-refractory, microsatellite-stable tumors were enrolled in cohort A: breast cancer cohort harboring a TML of 140 to 290, cohort B: tumor-agnostic cohort harboring a TML of 140 to 290, and cohort C: tumor-agnostic cohort harboring a TML >290. Patients received pembrolizumab 200 mg every 3 weeks. The primary endpoint was clinical benefit [CB; objective response or stable disease (SD) ≥16 weeks]. Pretreatment tumor biopsies were obtained for whole-genome sequencing and RNA sequencing.</p>Results:<p>Seventy-two evaluable patients with 26 different histotypes were enrolled. The CB rate was 13% in cohort A [3/24 with partial response (PR)], 21% in cohort B (3/24 with SD; 2/24 with PR), and 42% in cohort C (4/24 with SD; 6/24 with PR). In cohort C, neoantigen burden estimates and expression of inflammation and innate immune biomarkers were significantly associated with CB. Similar associations were not identified in cohorts A and B. In cohort A, CB was significantly associated with mutations in the chromatin remodeling gene <i>PBRM1</i>, whereas in cohort B, CB was significantly associated with expression of MICA/MICB and butyrophilins. CB and clonal TML were not significantly associated.</p>Conclusions:<p>Although pembrolizumab lacked activity in cohort A, cohorts B and C met the study’s primary endpoint. Further research is warranted to refine the selection of patients with tumors harboring lower TMLs and may benefit from a focus on innate immunity.</p><p><i><a href="https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-24-1261" target="_blank">See related commentary by Hsu and Yen, p. 3652</a></i></p></div>

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