526O - High activity of nivolumab in patients with pathogenic exonucleasic domain POLE (edPOLE) mutated Mismatch Repair proficient (MMRp) advanced tumours

Background

Hotspot edPOLE mutations (mut) generate proofreading defects and hypermutated genomic profiles. While rare in the advanced setting, most edPOLE mut pathogenicity and derived sensitivity to anti-PD-1 (aPD1) agents remains unclear. We aimed to investigate the efficacy of nivolumab in MMRp tumours with edPOLE mut.

Methods

ACSé immunotherapy is a nationwide program launched by the French National Cancer Institute (INCa) and sponsored by the French network of comprehensive cancer centres (Unicancer) investigating the efficacy and tolerance of aPD1 in multiple phase II single arm cohorts in rare tumours. We report here the initial results of the edPOLE cohort, which is the first trial selecting patients on a prospective assessment of missense POLE mut pathogenicity by an ad hoc molecular tumour board. nivolumab (240 mg IV q2w) was administered until disease progression (PD), toxicity or for up to 2 years. The primary endpoint was the objective response rate (ORR) assessed by RECIST v1.1 at 12 weeks.

Results

From Apr 2018 to Jan 2020, 15 pts (mean age, 59 years) were included with colorectal (6), endometrial (4), gastric (2), pancreas (1), biliary (1) and glial (1) tumours. Mean number of previous lines of treatment was 2.7. Median follow up was 74 days (Q1-Q3= 40.5-188.5). At the date of submission, nivolumab safety was in accordance with data reported in other tumour types. ORR at 12 weeks in 10 evaluable patients was 30% (PR: n=3; SD: n=4; PD: n=3). Pathogenicity of edPOLE mut was confirmed by the ad hoc committee in 7 cases (47%): 2 P286R, 2 N363K, 2 V411L, 1 A463V. In the pathogenic mut group, ORR was 50% (3/6), disease control rate was 83% (5/6) and median progression-free survival (mPFS) was 161 days. Responses were observed in MMRp colorectal and endometrial cancers with P286R and V411L mutations. Conversely, in the non-pathogenic group (n=4), only 2 SD were observed as best response and 2 pts died before first evaluation. mPFS in this group was 47 days.

Conclusions

We report the first clinical trial assessing aPD1 in POLE mutated MMRp tumours. Nivolumab activity appears promising in edPOLE mutated MMRp advanced cancer pts but activity is limited to pathogenic mutations, underlining the need for individual mutational functional assessment by a molecular tumour board. We will include the tumour evaluation of the last 5 additional patients at the ESMO 2020 Virtual Congress.

Clinical trial identification

NCT03012581.

Editorial acknowledgement

Legal entity responsible for the study

UNICANCER.

Funding

BMS.

Disclosure

B.J-C. Rousseau: Advisory/Consultancy, Speaker Bureau/Expert testimony: Bayer; Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Travel/Accommodation/Expenses: Servier; Travel/Accommodation/Expenses: Astellas; Speaker Bureau/Expert testimony: Gilead. V. Simmet: Honoraria (self): Lilly; Honoraria (self): Servier; Travel/Accommodation/Expenses: Amgen; Travel/Accommodation/Expenses: Novartis. D. Pouessel: Honoraria (self): Ipsen; Honoraria (self), Honoraria (institution): BMS; Honoraria (self), Honoraria (institution), Travel/Accommodation/Expenses: AstraZenca; Honoraria (self): Sanofi; Honoraria (self), Travel/Accommodation/Expenses: Pfizer; Honoraria (self): Merck; Honoraria (self): Astellas; Honoraria (self), Honoraria (institution), Travel/Accommodation/Expenses: Janssen; Honoraria (institution): MSD; Honoraria (institution): Incyte. A. Bruyas: Speaker Bureau/Expert testimony: BMS. F. Rolland: Advisory/Consultancy: Merck KGaA; Advisory/Consultancy: MSD; Advisory/Consultancy: BMS. E. Saada-Bouzid: Advisory/Consultancy: Merck KGaA; Advisory/Consultancy: MSD; Advisory/Consultancy: BMS. R. Cohen: Honoraria (self): Servier; Honoraria (self): Amgen; Honoraria (self): Sanofi. O. Bouche: Honoraria (self), Travel/Accommodation/Expenses: Roche; Honoraria (self): Merck; Honoraria (self), Speaker Bureau/Expert testimony: Amgen; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Bayer; Speaker Bureau/Expert testimony: Pierre Fabre; Speaker Bureau/Expert testimony: Servier; Travel/Accommodation/Expenses: Lilly. A. Marabelle: Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: Roche/Genentech; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: BMS; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: MSD; Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Lytix pharma; Research grant/Funding (institution): Eisai; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca/Medimmune; Research grant/Funding (institution): Tesaro; Research grant/Funding (institution): Chugai; Advisory/Consultancy: GSK; Advisory/Consultancy: Innate pharma; Advisory/Consultancy: Novartis; Advisory/Consultancy: Bayer. All other authors have declared no conflicts of interest.