1803P - Analysis of samples from the SCLC REACTION trial: Discovery of biomarkers to optimize treatment

Background

The addition of immunotherapy (ICI) to chemotherapy (CT) as frontline treatment for extensive stage small-cell lung cancer (SCLC) significantly improved survival (OS). However, its benefit remains still limited. SCLC subtypes have been described according to differential expression of transcription factors (TFs). Methylation profiling of SCLC circulating cell-free tumour DNA (ctDNA) has been shown to identify these subtypes, providing a promising modality for monitoring responses and stratifying treatment strategies.

Methods

We examined 38 tissue biopsies and 145 serial blood samples (baseline (C1), after 2 cycles of CT (C2, etoposide and platinum), during CT-ICI (C3, addition of pembrolizumab) and at progression (C4)) from 57 patients (pts) participating in the EORTC REACTION trial (NCT02580994) to determine whether ctDNA predicts response to therapy and to determine TF subtype (ASCL1, NEUROD1 or double negative). We correlated TF subtypes defined by ctDNA methylation with immunohistochemistry (IHC).

Results

We measured the level of tumour-specific methylation at each timepoint and then derived a methylation score (MS). ctDNA levels were higher at baseline and progression, compared to samples taken on treatment. Kaplan–Meier analysis of the score showed that pts with low score at C2 or C3 had significantly longer OS (p=0.0015 and p<0.0001 respectively). In 22 pts, ctDNA methylation profiles at baseline categorized in SCLC subtype as follow: ASCL1 (17 pts - 77%), NEUROD1 (3 pts - 14%) and ASCL1 and NEUROD1 negative (2 pts - 9%). Of the 38 tissue biopsies available for TF IHC subtyping, 18 were ASCL1 positive (47%), 9 double positive (ASCL1 and NEUROD1) (24%), 1 NEUROD1 positive (3%) and 10 ASCL1 and NEUROD1 negative (26%). We had 24 paired tissue / ctDNA samples for TF subgroups comparison and obtained a matched subtyping for 18 patients (75%).

Conclusions

ctDNA methylation profiling has potential clinical utility in SCLC by allowing sensitive blood-based tumour detection and providing prognostic information, circumventing the challenges encountered by biopsies. ctDNA methylation can identify TF subtypes and potentially bring insights into the longitudinal biological behaviour of SCLC.

Clinical trial identification

This is a translational research on samples from patients participating to REACTION trial (NCT02580994).

Editorial acknowledgement

Legal entity responsible for the study

P. Lavaud.

Funding

Gustave Roussy.

Disclosure

P. Lavaud: Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca, BMS, SanofI; Financial Interests, Personal, Other, Travel accommodation: Daiichi; Financial Interests, Personal, Advisory Board, Travel accommodation: Pfizer, Janssen; Financial Interests, Institutional, Local PI: Amgen. J. Menis: Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Roche, MSD, Novartis; Financial Interests, Institutional, Other, Travel grant: Ipsen; Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, MSD, Novartis. A.C. Dingemans: Financial Interests, Institutional, Advisory Board: Roche, Amgen, Bayer, AstraZeneca, Boehringer Ingelheim, Janssen, Mirati; Financial Interests, Institutional, Invited Speaker: Lilly, Janssen; Financial Interests, Institutional, Other, IDMC: Roche; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Local PI: Lilly, Amgen, Daiichi, JNJ, Mirati; Financial Interests, Institutional, Coordinating PI: Roche; Financial Interests, Institutional, Steering Committee Member: Roche; Non-Financial Interests, Other, Chair EORTC lung cancer group: EORTC; Non-Financial Interests, Member: IASCL, ASCO, AACR. B. Besse: Financial Interests, Institutional, Advisory Board: Amgen, AstraZeneca, BeiGene, Blueprint Medicine, Cergentis, Chugai pharmaceutical, Daiichi Sankyo, F. Hoffmann-La Roche, Inivata, Pfizer, PharmaMar, Sanofi Aventis, Springer Healthcare Ltd, 4D Pharma, AbbVie, Da voltera, Eli Lilly, Ellipse pharma Ltd, F-Star, GSK, Janssen, Onxeo, Ose Immunotherapeutics, Socar research, Taiho oncology, Turning Point Therapeutics; Financial Interests, Institutional, Invited Speaker: Genzyme Corporation, Hedera Dx, Medscape, MSD; Financial Interests, Institutional, Local PI: AbbVie, Amgen, Blueprint Medicines, Daiichi Sankyo, Pfizer, Roche-Genentech, Turning Point Therapeutics, Nuvalent, Enliven, Prelude therapeutics; Financial Interests, Institutional, Coordinating PI: AstraZeneca, OSE immunotherapeutics, Sanofi, Taiho; Financial Interests, Institutional, Steering Committee Member: BeiGene, GSK, Janssen, Takeda, Genmab; Financial Interests, Institutional, Funding: Cristal Therapeutics. C. Dive: Financial Interests, Institutional, Research Funding: AstraZeneca, Astex Pharmaceuticals, Bioven, Amgen, Carrick Therapeutics, Merck AG, Taiho Oncology, GSK, Bayer, Boehringer Ingelheim, Roche, BMS, Novartis, Celgene, Epigene Therapeutics Inc., Angle PLC, Menarini, Clearbridge Biomedics, Thermo Fisher Scientific, Neomed Therapeutics; Financial Interests, Personal, Advisory Board: Biocartis, Merck, AstraZeneca, GRAIL, Boehringer Ingelheim. All other authors have declared no conflicts of interest.