1323MO - Immune evasion across space and time in patients with lung cancer enrolled in the PEACE autopsy study

Background

Checkpoint inhibitors (CPIs) improve survival of patients with metastatic non-small cell lung cancer (NSCLC). However, in many patients the duration of response is limited, and some patients derive no benefit at all. Among key determinants of CPI response are genomic alterations that impair the anti-tumour immune response. In primary NSCLC these alterations are common. However, due to challenges collecting metastasis samples, the prevalence and distribution of these alterations across metastases within patients, and how this impacts response to CPI is not known.

Methods

The PEACE autopsy study in tandem with the TRACERx study enables multi-region tumour sampling from diagnosis of NSCLC to death, allowing immune evasive capacity to be tracked across space and time. We performed exome sequencing on 84 primary tumour regions and 320 metastases from 21 patients recruited to these studies. Mutations and copy number alterations were called with our bioinformatic pipeline and used to infer tumour clones in each sample, their phylogenetic relationship and metastatic migration history. The neoantigen landscape and genomic alterations in genes involved in immune evasion (‘IE alterations’) were then characterised in each clone.

Results

We find IE alterations are frequent in metastases and emerge via distinct evolutionary paths. In a subset of patients, immune evasive primary tumour clones seed metastases, giving rise to metastases with poor T cell infiltrate that share IE alterations with the primary. In others, primary tumour seeding clones do not harbour IE alterations. Compared to patients with shared IE alterations, these patients’ metastases have higher T cell infiltrate and acquire more metastasis unique IE alterations after seeding. Measuring the radiological growth of individual metastases in 7 of these patients treated with CPIs in the DARWIN II trial, we observe homogenous progression of metastases in patients with shared IE alterations, while patients with metastasis unique IE alterations exhibit heterogeneous metastasis growth rates.

Conclusions

When IE alterations occur in relation to metastatic seeding dictates the distribution of immune evasive capacity across metastases, which impacts metastasis growth during CPI therapy.

Clinical trial identification

PEACE - NCT03004755, TRACERx - NCT01888601, DARWIN II - NCT02314481.

Editorial acknowledgement

Legal entity responsible for the study

UCL Clinical Trials Centre.

Funding

The PEACE study and TRACERx study are funded by Cancer Research UK (grants C416/A21999 and C11496/A17786, respectively). The PEACE study is additionally supported by funding from the Rosetrees Trust (grant A2204). A subset of patients in this work were treated with immunotherapy on the DARWIN II study, which is an academic study sponsored by UCL funded by funded by Hoffman La Roche.

Disclosure

D. Moore: Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Takeda; Financial Interests, Personal, Advisory Role: Thermo Fisher, Eli Lilly, Amgen, Janssen, MIM Software, Bristol Myers Squibb. N. McGranahan: Financial Interests, Institutional, Stocks/Shares: Achilles Therapeutics. C. Hiley: Financial Interests, Personal, Invited Speaker: AstraZeneca. 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. 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. All other authors have declared no conflicts of interest.