631P - Using the unique somatic mutation profile of POLE loss of proof-reading mutation helps in selection of patients who may benefit from immunotherapy

Background

It has been reported that POLE mutant tumors are likely to respond to immune therapy, however, most POLE mutations are passenger mutations and do not induce a hypermutated phenotype. Current methods to classify POLE mutations are limited in both accuracy and completeness complicating the selection of patients (pts) most likely to benefit from immunotherapy.

Methods

A curated list of 13 known loss of proof-reading (LOP) POLE mutations was used to identify 66 tumors with POLE LOP mutation from which we extracted somatic mutation signatures, these averaged together defined a positive control POLE LOP signature. POLE mutant tumors with mutational signatures highly correlated with the positive control (> 0.7) were determined to be LOP.

Results

A total of 1467 POLE mutations (mut) were identified from 50962 tumors accessed from cBioPortal. Correlation with the positive control POLE LOP signature was sensitive (all tumors with known POLE LOP mutation from literature were recovered) and specific (92/97 = 94.8% had high TMB, a hallmark feature of POLE LOP). In addition to recovering known LOP mut found in the exonuclease region, several new LOP were discovered including R705W mut, which is in the DNA polymerase domain and positioned to interface with the binding to DNA. To evaluate POLE LOP as a predictive biomarker a cohort of pts with POLE mutant mCRC treated with immunotherapy (IO) (n=29) was identified from institutional databases. All 7 pts with POLE LOP achieved clinical benefit (3 CR, 3 PR, 1 SD) and remain on immunotherapy at the time of submission (median follow up time = 36 months). In contrast, none of the 7 MSS pts with Non-LOP POLE mut achieved an objective response to IO therapy (2 SD, 5 PD), and had disease progression with median PFS of 3.6 months (log-rank p<0.0003). For the other 15 pts with Non-LOP POLE mut response was supported by MSI-H status.

Conclusions

Identifying of the subset of POLE mut that cause LOP is critical in order to correctly identify pts most likely to benefit from immune therapy. CRC tumors with LOP POLE mutation were found to have deep, sustained response to IO therapy, in contrast to those with non-LOP POLE mutations.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

MD Anderson Cancer Center.

Funding

MD Anderson Cancer Center.

Disclosure

M.J. Overman: Financial Interests, Personal, Advisory Board: Roche, Bristol Myers Squibb, MedImmune, Merck, Amgen, Takeda, Janssen, Pfizer, Array, Gritstone, Nouscom, Atreca, Bayer; Financial Interests, Institutional, Coordinating PI: Roche, Lilly, Merck, Bristol Myers Squibb, Phanes, Nouscom. E.S. Kopetz: Financial Interests, Personal, Advisory Board: Roche, EMD Serono, Merck, Novartis, Lilly, Boehringer Ingelheim, Boston Biomedical, AstraZeneca, Bayer, Pierre Fabre, Redx Pharma, Ipsen, Daiichi Sankyo, Natera, HalioDx, Jacobio, Pfizer, Repare Therapeutics, GSK, Jazz, Xilis, AbbVie, Gilead, Mirati, Flame, Servier, Carina, Bicara, Endeavor BioMedicines, Numab Pharma, Janssen; Financial Interests, Personal, Other, Research: Inivata, Guardant Health, Sanofi, Biocartis, Array BioPharma, Genentech/Roche, EMD Serono, MedImmune, Novartis; Financial Interests, Personal, Other, Consultant: Genomic Health, Frontier Medicines, Replimune, Taiho Pharmaceutical, Cardiff Oncology, Ono Pharmaceutical, Bristol Myers Squibb-Medarex, Amgen, Tempus, Foundation Medicine, Harbinger Oncology, Takeda, CureTeq, Zentalis, Black Stone Therapeutics, NeoGenomics Laboratories, Accademia Nazionale Di Medicina; Financial Interests, Personal, Stocks/Shares: Lutris, Iylon, Navire, Xilis; Financial Interests, Personal, Ownership Interest: Frontier Medicines. J.P.Y. Shen: Financial Interests, Personal, Other, general consultation and expert testimony: ShenJPMD Inc; Financial Interests, Personal, Other, advisory board: Engine Biosciences, NaDeNo Nanosciences; Financial Interests, Institutional, Coordinating PI, research project: Celsius Therapeutics; Financial Interests, Institutional, Other, research funding for pilot project: BostonGene. All other authors have declared no conflicts of interest.