Efficacy and predictors of response of nivolumab in treatment-refractory MSI solid tumors: Results of a tumor-agnostic DRUP cohort.
Authors: Geurts Birgit , Zeverijn Laurien Joanna , Battaglia Thomas W. , van de Haar Joris , van Berge Henegouwen Jade M. , Hoes Louisa Rose , van der Wijngaart Hanneke , Roepman Paul , de Leng Wendy W.J. , Jansen Anne M.L. , van der Noort Vincent , Chalabi Myriam , Devriese Lot A. , Van Herpen Carla M.L.- , Gelderblom Hans , Verheul Henk M.W. , Voest Emile E. 
Published: June 2023

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Background: Microsatellite unstable (MSI) tumors represent 4% of all cancer diagnoses and are known to be sensitive to immune checkpoint inhibitors (ICI). Despite the progress made, a significant proportion of patients with MSI tumors does not respond, highlighting the urgent need to identify additional predictive biomarkers. In this study, we evaluated the efficacy of the PD-1 inhibitor nivolumab across pre-treated solid MSI tumors and performed extensive biomarker analysis to better characterize ICI-effectiveness in this setting. Methods: Adult patients with MSI tumors who exhausted all standard of care treatment options were eligible for inclusion and were enrolled in the Drug Rediscovery Protocol (DRUP), a clinical trial that treats cancer patients with approved targeted- and immunotherapies outside their registered indication, based on their tumor molecular profile (NCT0295234). Patients were treated with nivolumab (four cycles of 240 mg every 2 weeks, followed by 480 mg every 4 weeks) until disease progression or unmanageable toxicity. Primary endpoint was clinical benefit (CB, objective response (OR) or stable disease ≥ 16 weeks). Whole genome sequencing and RNA sequencing were performed on pre-treatment biopsies to reveal potential predictors of response or resistance to anti-PD1. Results: 130 evaluable patients were enrolled with in total 16 different tumor types. CB was observed in 62% (95% CI 46 – 54) ( N = 80) with an OR in 45% (95% CI 53 – 70) ( N = 58). After a median follow-up of 14.5 months (95% CI 13 – 19), median progression free survival was 18 months (95% CI 9 – not reached) and median overall survival was not reached. HLA class I status and mutational burden were not significantly associated with CB. However, in depth biomarker analyses identified that mutational burden was predictive of CB in HLA-wildtype patients (52%) but not in HLA class I mutants (48%). Strikingly, in contrast to the paradigm that neoantigen-specific adaptive immunity is primarily involved in clearing MSI tumors, transcriptomics indicated that, compared to non-CB, CB was characterized by significantly higher expression of key modulators in innate immunity, including non-classical HLA transcripts (P = 4.2x10-3), NKGD2 ligands MICA/MICB (P = 6.4x10-3), killer immunoglobulin-like receptors ( P = 0.047) and butyrophilins ( P = 0.024). Conclusions: Nivolumab proved highly effective in pre-treated, advanced solid MSI tumors. Genomic analysis revealed that neoantigen burden only determined ICI-effectiveness in patients with wildtype HLA class I. Furthermore, transcriptomics revealed a central role of innate immunity in ICI-effectiveness in MSI tumors, which aligns with the fact that these tumors frequently lose HLA class I antigen presentation. Together, these results inform novel biomarker strategies to further refine precision medicine in this patient population. Clinical trial information: NCT0295234 .