Abstract 426P
Background
Predictive biomarkers for immune checkpoint blockade (ICB) are desperately needed. Retrospective studies demonstrate that tsMHC-II positivity is a strong predictive biomarker for anti-PD-1 activity in melanoma, Hodgkins disease and breast cancer. Deficient mismatch repair (dMMR) CRC responds readily to anti-PD-1 and has significantly higher tsMHC-II expression than pMMR CRC but some pMMR patients have strong primary tsMHC-II positivity and it is prognostic. We report here a prospective trial of nivolumab in locally advanced and metastatic tsMHC-II positive pMMR CRC (NCT03981146).
Methods
pMMR CRC patients who had progressed on all standard of care therapies and whose tumors exhibited >1% tsMHC-II were prospectively treated with 480mg nivolumab every 4 weeks. Primary outcome measure was durable clinical benefit (DCB – no progression at 27 weeks), key secondary outcomes were objective response (OR), progression-free survival time (PFS) and overall survival (OS).
Results
Of 455 patients screened, 12.8% were tsMHC-II positive (8.6% ≥5% and 0.7% >50% staining). Of 35 patients treated, 65.7% has tsMHC-II ≥5%, 2.9% >50%. Liver metastases were present in 62.9%. At a median follow-up time of 57 weeks, only 1 patient was still on treatment. 3/35 (8.6%) had DCB, none of whom had liver metastases; of 9 patients remaining on therapy >18 weeks, 7 had no liver metastases. The OR was 0%. Currently mPFS is 9.1 weeks (95% Confidence Interval (CI): 9.0, 9.8) and mOS 29.6 weeks (95% CI: 17.3, 42.1). The one patient with tsMHC-II expression >50% remained on treatment for one cycle. Staining of matched primaries and secondaries showed discordance is common with <40% tsMHC-II positive primaries giving rise to positive secondaries. There were no new safety signals.
Conclusions
In this first prospective trial of tsMHC-II as a predictive biomarker for anti-PD-1 we show that tsMHC-II expression is not a useful stratifier in advanced pMMR CRC. We discuss likely reasons for this which include the liver predominance of metastatic CRC, the discordance of tsMHC-II status by site and the nature of the IFNg producing T cells in those with tsMHC-II positive pMMR primaries that subsequently relapse.
Clinical trial identification
EudraCT Number: 2018-000318-39, NCT03981146, ISRCTN40245896.
Editorial acknowledgement
Legal entity responsible for the study
University of Birmingham.
Funding
Bristol-Myers Squibb.
Disclosure
G. Middleton: Financial Interests, Institutional, Research Grant: Plexxikon, AstraZeneca, Merck Sharp & Dome, Bristol-Myers Squibb; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Merck Sharp & Dome, Bristol-Myers Squibb, Servier, Roche; Financial Interests, Personal, Invited Speaker: Merck Sharp & Dome, Bristol-Myers Squibb, Boehringer Ingelheim, Roche; Financial Interests, Personal, Advisory Role: Merck Sharp & Dome, Bristol-Myers Squibb, D2G Oncology, Boehringer Ingelheim, Roche; Financial Interests, Personal, Advisory Board: Mina Therapeutics. J.A. Bridgewater: Financial Interests, Personal, Advisory Board: TAIHO, BMS, Incyte, Basilea; Financial Interests, Institutional, Funding: Incyte. P. Ross: Financial Interests, Personal, Advisory Board, Chair of UK Advisory Board: Amgen; Financial Interests, Personal, Advisory Board, Chaired & participated in UK Advisory Boards: Sirtex; Financial Interests, Personal, Advisory Board, Participated in Advisory Boards: Roche; Financial Interests, Personal, Invited Speaker, Talks at meetings: Roche, Servier, Eisai; Financial Interests, Personal, Advisory Board, Participated in advisory boards: Eisai; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Other, Support to attend meetings: Roche, Servier, Bayer; Financial Interests, Personal, Advisory Board: AstraZeneca, Pierre Fabre; Financial Interests, Institutional, Research Grant, Educational grant to support conduct of an Investigator Initiated trial: Sanofi; Financial Interests, Institutional, Research Grant, Educational grant to undertake a national audit: Bayer; Financial Interests, Personal, Other, Chair of IDMC: Beigene; Non-Financial Interests, Sponsor/Funding, Support for departmental awayday: Merck. M.P. Saunders: Financial Interests, Personal, Invited Speaker: Servier, Amgen, Merck. R. Plummer: Financial Interests, Personal, Advisory Board: Pierre Faber, Bayer, Novartis, BMS, Cybrexa, Ellipses, CV6 Therapeutics, Astex Therapetics, Sanofi Aventis, Immunocore, Genmab, Medivir, Onexo; Financial Interests, Institutional, Royalties, Royalties relating to rucaparib licencing: Clovis Oncology; Financial Interests, Personal, Other, Honorarium as member of IDMC: SOTIO, Alligator Biosciences; Financial Interests, Personal, Other, Honoraria as member of IDMC: GSK. V. Coyle: Financial Interests, Personal, Invited Speaker, producing educational material: Servier; Financial Interests, Institutional, Research Grant, Pre-clinical research funding and support for clinical trial: Astex Pharmaceuticals; Other, Other, Hospitality/conference attendance support: Servier. A. Thomas: Financial Interests, Personal, Advisory Role: Bristol-Myers Squibb; Financial Interests, Personal, Speaker’s Bureau: Bristol-Myers Squibb; Financial Interests, Personal, Expert Testimony: Bristol-Myers Squibb. All other authors have declared no conflicts of interest.