In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 2590-2590
Abstract:
2590 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 .
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/JCO.2023.41.16_suppl.2590
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2023
detail.hit.zdb_id:
2005181-5
Bookmarklink