Efficacy of pembrolizumab and biomarker analysis in patients with WGS-based intermediate to high tumor mutational load: results from the Drug Rediscovery Protocol
Birgit S. Geurts, Laurien J. Zeverijn, Lindsay V.M. Leek, Jade M. van Berge Henegouwen, Louisa R. Hoes, Hanneke van der Wijngaart, Vincent van der Noort, Joris van de Haar, Annemiek van Ommen-Nijhof, Marleen Kok, Paul Roepman, Anne M.L. Jansen, Wendy W.J. de Leng, Maja J. A. de Jonge, Ann Hoeben, Carla M.L. van Herpen, Hans M. Westgeest, Lodewyk F.A. Wessels, Henk M.W. Verheul, Hans Gelderblom, Emile E. Voest- Cancer Research
- Oncology
Abstract
Purpose: To evaluate efficacy of pembrolizumab across multiple cancer types harboring different levels of Whole-Genome Sequencing (WGS)-based tumor mutational load (TML; total of non-synonymous mutations across the genome) in patients included in the Drug Rediscovery Protocol (NCT02925234). Patients and methods: Patients with solid, treatment-refractory, microsatellite-stable tumors were enrolled in cohort A: breast cancer TML 140-290, cohort B: tumor-agnostic cohort TML 140-290, and cohort C: tumor-agnostic cohort TML >290. Patients received pembrolizumab 200 mg every three weeks. Primary endpoint was clinical benefit (CB: objective response or stable disease (SD) ≥16 weeks). Pre-treatment tumor biopsies were obtained for WGS and RNA-sequencing. Results: Seventy-two evaluable patients with 26 different histotypes were enrolled. 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 cohort A and B. In cohort A, CB was significantly associated with mutations in the chromatin remodeling gene PBRM1, while in cohort B, CB was significantly associated with expression of MICA/MICB and butyrophilins. CB and clonal TML were not significantly associated. Conclusion: While in cohort A pembrolizumab lacked activity, cohort B and cohort C met the study’s primary endpoint. Further research is warranted to refine selection of patients with tumors harboring lower TMLs and may benefit from a focus on innate immunity.