1334P - Activity of first line immunotherapy or chemo-immunotherapy in advanced NSCLC with SMARCA4 deficiency

Background

SMARCA4 deficient (SMARCA4d) non-small cell lung cancer (NSCLC) has a poor prognosis. The activity of first line immune-checkpoint blockers (ICB) or chemo-ICB and the potential impact of co-mutations is scarcely explored in patients with SMARCA4d NSCLC.

Methods

This is a monocentric, retrospective study evaluating patients with advanced NSCLC, screened for SMARCA4 alterations and treated with first line chemo-ICB or ICB alone. SMARCA4d was defined as loss of BRG1 in immunohistochemistry or the presence of deleterious SMARCA4 in liquid or tissue biopsies assessed by next-generation sequencing. Progression-free survival (PFS), overall survival (OS) and the impact of co-mutations (STK11, KEAP1) were compared between patients with or without SMARCA4d.

Results

A total of 128 patients were included: 36 with SMARCA4d (12 in IHC, 31 in NGS, 7 both) and 92 without SMARCA4d (control group). Patients with SMARCA4d had a median age of 57 years, were male in 64% cases and smokers in 94% cases, similar to the control group. Histology type was adenocarcinoma in 53% versus 82% (p<0.001) in control, with more cases of undifferentiated or large cell neuroendocrine carcinoma in the SMARCA4d group. TMB value was 13 vs 5 mut/Mb (p<0.001), median PD-L1 expression was 0 vs 5% (p=0.3) in SMARCA4d versus control, with no differences in immune blood counts. STK11 and KEAP1 mutations were frequently co-mutated with SMARCA4d (53% vs 26%, p= 0,01; 37% vs 13%, p= 0,01, respectively. The median PFS under ICB+/- chemotherapy was 4.0 months (CI 95% 2.87- 7.7) vs 7.37 months (CI 95% 6.53-11.3) (p= 0.005) in SMARCA4d versus control, and the median OS was 9.3 months (CI 95% 7.0 – NR) vs 27.6 months (CI 95% 27.3 - NA) (p< 0.0001), respectively. In patients with STK11/KEAP1 mutations, median OS was 7 months (95% CI 5-NR) versus 13.3 months (95% CI 10.5-35.8) (p=0.19) in SMARCA4 and control, respectively.

Conclusions

SMARCA4d seems to negatively impact survival outcomes and the efficacy of ICB, despite high TMB. Novel treatments are rapidly needed.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

J. Remon Masip: Financial Interests, Personal, Invited Speaker: Roche, MSD, Boehringer Ingelheim; Financial Interests, Personal, Writing Engagement: Pfizer; Financial Interests, Personal, Advisory Board: AstraZeneca, Ose Immunotherapeutics, BMS, Janssen, Takeda, Sanofi; Financial Interests, Institutional, Invited Speaker: Merck Portugal; Non-Financial Interests, Principal Investigator, PI of PECATI trial in Thymic malignancies endorsed by a grant by MSD: MSD; Non-Financial Interests, Other, Co-PI of APPLE trial (EORTC-1525): AstraZeneca; Non-Financial Interests, Member, Secretary of the Lung Cancer Group at the EORTC: EORTC. A. Levy: Financial Interests, Institutional, Invited Speaker: Pharma Mar; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Coordinating PI: BeiGene. F. Barlesi: Financial Interests, Institutional, Advisory Board: AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, Mirati, MSD, Pierre Fabre, Pfizer, Sanofi Aventis, Seattle Genetics, Takeda, AbbVie, Acea, Amgen, Eisai, Ignyta; Non-Financial Interests, Principal Investigator: AstraZeneca, BMS, Merck, Pierre Fabre, F. Hoffmann-La Roche Ltd., Innate Pharma, Mirati. D. Planchard: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Samsung, Celgene, AbbVie, Daiichi Sankyo, Janssen, Seagen, Gilead, Pierre Fabre; Financial Interests, Personal, Invited Speaker: AstraZeneca, Novartis, Pfizer, priME Oncology, Peer CME, Samsung, AbbVie, Janssen; Non-Financial Interests, Principal Investigator, Institutional financial interests: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Daiichi Sankyo, Sanofi-Aventis, Pierre Fabre; Non-Financial Interests, Principal Investigator: AbbVie, Sanofi, Janssen. B. Besse: Financial Interests, Institutional, Funding: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, GSK, Janssen, Onxeo, Ose Immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals; Financial Interests, Institutional, Research Grant: Genzyme Corporation, Chugai Pharmaceutical, Eisai, Inivata, Ipsen, Turning Point Therapeutics. All other authors have declared no conflicts of interest.