LBA72 - DARWIN II: Deciphering anti-tumour response and resistance to immunotherapy with intratumour heterogeneity in NSCLC

Background

Patients with metastatic non‒small-cell lung cancer (NSCLC) can receive anti PD-L1/PD-1 immunotherapy as a standard of care. However, prediction of response is challenging with existing biomarkers. Retrospective analyses have identified the clonality of mutations and neoantigens as potential biomarkers. However, the impact of intratumour heterogeneity (ITH) on immunotherapy response in patients with metastatic NSCLC has not been prospectively explored. The DARWIN II trial is a phase II, multi-centre molecularly stratified trial for patients with NSCLC to study the effect of ITH on response to treatment. The study is unique as patients were recruited from the TRACERx Lung Cancer observational cohort study, following relapse with metastatic disease.

Methods

A total of 65 patients from the TRACERx study, with spatially separated multi-region sampling of resected early lung cancer, who relapsed with metastatic disease were enrolled between November 2016 and March 2023 and received immunotherapy. Patients were recruited with any PDL1 tumour proportion score. Patients received atezolizumab or atezolizumab with chemotherapy. Multi-omic analysis, including deep (∼500x) whole exome, RNA, RRBS, and TCR sequencing of multi-region primary tumour samples and relapse biopsies was performed on 355 samples. All samples were processed on a uniform bioinformatic analysis pipeline and results corrected for tumour purity variation.

Results

The median PFS and OS were 4.5 and 10.0 months respectively. The proportion of patients with durable clinical benefit was 37.5 percent. A high clonal mutation burden was associated with a statistically significant improvement in response (OR = 5.7, 95% CI [1.1-45.0], p value = 0.04) whereas high total tumour mutation burden (>10 mut/Mb) was not. Additionally, we identified several associations between novel molecular features and immunotherapy response, including ITH of the transcriptome and DNA hyper-/hypo-methylation frequency.

Conclusions

This is the first trial to demonstrate prospectively that clonal mutations are associated with improved patient outcome and identify novel molecular features, related to ITH, as predictors of immunotherapy response in patients with NSCLC.

Clinical trial identification

NCT02314481.

Editorial acknowledgement

Legal entity responsible for the study

University College London.

Funding

Roche.

Disclosure

C. Hiley: Financial Interests, Personal, Advisory Role: Genesiscare. M.G. Krebs: Financial Interests, Personal, Advisory Board: Bayer, Roche, Janssen, Guardant Health; Financial Interests, Personal, Invited Speaker: Roche, Janssen; Financial Interests, Institutional, Advisory Board: AstraZeneca, Seattle Genetics; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Carrick, Janssen, Pyramid Biosciences; Financial Interests, Institutional, Local PI: Blueprint, Astex, Bayer, BerGenBio, Immutep, Novartis, Nurix, Nuvalent, Roche, Seattle Genetics, Turning Point Therapeutics; Financial Interests, Institutional, Research Grant: Roche, Novartis; Other, Travel expenses for congress: Immutep, Janssen; Other, Travel expenses: Roche. S. Quezada: Financial Interests, Personal, Advisory Board: Medicenna, DROIA oncology, Molecular Partners; Financial Interests, Personal, Full or part-time Employment: Achilles Therapeutics; Financial Interests, Personal, Stocks/Shares: Achilles Therapeutics; Financial Interests, Personal, Royalties: Dartmouth College, MSKCC, UCL. K.R. Litchfield: Financial Interests, Personal, Invited Speaker: Roche Tissue Diagnostics; Financial Interests, Personal, Other, Consulting work: Kynos Therapeutics, Monopteros Therapeutics, Tempus; Financial Interests, Personal, Invited Speaker, Invited speaker: Ellipses Pharma; Financial Interests, Institutional, Research Grant: Ono/LifeArc; Financial Interests, Institutional, Research Grant, Research funding: Genesis Therapeutics; Non-Financial Interests, Institutional, Proprietary Information, Collaboration on data analysis: Bms. A. Hackshaw: Financial Interests, Personal, Advisory Board, AH is an investigator for an academic study (SUMMIT) sponsored by UCL that is funded by GRAIL, Inc.; has received one honorarium for an advisory board meeting for GRAIL, Inc; received a consulting fee from Evidera Inc (for one GRAIL-initiated project): GRAIL Inc; Financial Interests, Personal, Other, For delivering general education/training in clinical trials: AbbVie, Boehringer Ingelheim, Clovis, Ipsen, Takeda, AstraZeneca, Daiichi Sankyo, Merck Serono, MSD, UCB, Kyowa Kirin, Servier, Sobi, Pfizer, Roche; Financial Interests, Personal, Stocks/Shares, Shares were sold in 2020: Illumina, Thermo Fisher; Financial Interests, Institutional, Research Grant, Grant for a UCL-academic sponsored clinical trial: Roche, MSD, Autolus, AstraZeneca, Boehringer Ingelheim, GRAIL Inc, Takeda, Pfizer, Novartis, Bristol Myers Squibb, Janssen; Non-Financial Interests, Principal Investigator, Co-lead academic investigator for an observational study sponsored and conducted by Roche. Unpaid/no honoraria for this role.: Roche; Non-Financial Interests, Advisory Role, AH is on the scientific advisory board for Adela Bio and receives no payments/honoraria for this but has share options available: Adela Bio; Non-Financial Interests, Advisory Role, Unpaid member of advisory board: Navio. M. Jamal-Hanjani: Financial Interests, Personal, Invited Speaker, Invited speaker honorarium: Oslo Cancer Cluster, Astex Pharmaceutical; Financial Interests, Personal, Invited Speaker, Speaker honorarium: Pfizer, Bristol Myers Squibb; Non-Financial Interests, Advisory Role, Scientific Advisory Board and Steering Committee member: Achilles Therapeutics; Other, I am named as co-inventor on patent PCT/US2017/028013 relating to methods for lung cancer detection.: Patent. C. Swanton: Financial Interests, Personal, Invited Speaker, Activity took place in 2016.: Pfizer, Celgene; Financial Interests, Personal, Invited Speaker, October 26th 2020: Novartis; Financial Interests, Personal, Invited Speaker: Roche/Ventana, BMS, AstraZeneca, MSD, Illumina, GSK; Financial Interests, Personal, Advisory Board, AdBoard - November 12th, 2020: Amgen; Financial Interests, Personal, Advisory Board, Current - since 2018: Genentech; Financial Interests, Personal, Advisory Board: Sarah Canon Research Institute; Financial Interests, Personal, Advisory Board, Joined October 2020. Also have stock options: Bicycle Therapeutics; Financial Interests, Personal, Other, Consultancy: Medicxi; Financial Interests, Personal, Advisory Board, Member of the Science Advisory Board. Also had stock options until June 2021: GRAIL; Financial Interests, Personal, Other, Consultancy agreement: Roche Innovation Centre Shanghai; Financial Interests, Personal, Advisory Board, 29 November - 1 December 2022: Novartis; Financial Interests, Personal, Invited Speaker, Oncology Collective - 2nd Nov - 4 Nov 2022 - Atlanta, USA: Roche; Financial Interests, Personal, Advisory Board, ctDNA advisory Board - 24th March 2023: AstraZeneca; Financial Interests, Personal, Invited Speaker, Pfizer Oncology 'Leading the revolution for the future: Pfizer; Financial Interests, Personal, Full or part-time Employment, Chief Clinician since October 2017: Cancer Research UK; Financial Interests, Personal, Ownership Interest, Co-Founder of Achilles Therapeutics. Also, have stock options in this company.: Achilles Therapeutics; Financial Interests, Personal, Stocks/Shares, Stocks owned until June 2021: GRAIL, Apogen Biotechnologies; Financial Interests, Personal, Stocks/Shares: Epic Biosciences, Bicycle Therapeutics; Financial Interests, Institutional, Research Grant, Funded RUBICON grant - October 2018 - April 2021.: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant, Collaboration in minimal residual disease sequencing technologies.: Archer Dx Inc; Financial Interests, Institutional, Research Grant: Pfizer, Boehringer Ingelheim; Financial Interests, Institutional, Trial Chair, Chief Investigator for the MeRmaiD 1and 2 clinical trials and chair of the steering committee.: AstraZeneca; Financial Interests, Institutional, Research Grant, Research grant from Oct 2019 - July 2023 - Genetics of CIN and SCNAs for Targeted Discovery (SCEPTRE): Ono Pharmaceutical; Financial Interests, Institutional, Research Grant, Research Grants from 2015: Roche; Financial Interests, Personal, Other, Co-chief investigator: NHS-Galleri Clinical Trial; Financial Interests, Institutional, Research Grant, from October 2022: Personalis; Non-Financial Interests, Principal Investigator, Chief Investigator for MeRmaiD 1and 2 clinical trials: AstraZeneca; Non-Financial Interests, Member of Board of Directors, From 2019-2022: AACR; Non-Financial Interests, Other, Board of Directors: AACR; Non-Financial Interests, Advisory Role, EACR Advisory Council member: EACR. All other authors have declared no conflicts of interest.