Abstract 192P
Background
Evidence suggests baseline ATB and PPI exposure negatively impacts immune checkpoint inhibitor (ICI) outcomes in solid tumors, likely via gut microbiome disruption.
Methods
The PACIFIC trial (NCT03519971) randomized (2:1) patients (pts) to receive 12 months durvalumab or placebo maintenance. We conducted a post-hoc analysis to evaluate the impact of baseline ATB and PPI use on progression-free survival (PFS) and overall survival (OS) depending on the treatment strategy. Log-rank test and Cox regression were used for univariable and multivariable analysis.
Results
After excluding 45 pts due to lack of consent for post-hoc analyses, 450 (durvalumab) and 214 (placebo) were included. PPI exposure (262 patients) was associated with age >65 (47.1% vs 36.9%, p=0.01), ECOG-PS 1 (56.5% vs 48.0%, p=0.04), and PD-L1>1% (44.2% vs 40.8%, p=0.05). ATB exposure (70 patients) was linked to a higher rate of partial response to cCTRT (50.0% vs 48.0%, p=0.01). Median follow-up was 62.4 months. Among durvalumab-treated patients, ATB exposure was significantly associated with reduced PFS (5.68 vs 16.8 months, p=0.03) with no impact in placebo-treated pts (p=0.5; interaction p=0.39). Similarly, PPI exposure was associated with reduced PFS in the durvalumab group (10.7 vs 18.1 months, p=0.017) but not in the placebo group (p=0.12; interaction p=0.01). Multivariable analysis including age, gender, smoking status, PD-L1 expression, tumor histology, EGFR status, ECOG-PS, TNM stage as adjusting covariates confirmed ATB (HR 1.69, 95%CI: 1.12–2.55) and PPI exposure (HR 1.31, 95%CI: 1.02–1.68) as independent predictors of shorter PFS in durvalumab-treated pts. No significant OS impact was observed for either ATB or PPIs.
Conclusions
Baseline ATB and PPI exposure may detrimentally affect outcomes in pts receiving durvalumab after cCTRT. Further studies are warranted to explore mechanisms and mitigation strategies in the early stage setting.
Editorial acknowledgement
This publication is based on research using data from AstraZeneca that has been made available through Vivli, Inc. Vivli has not contributed to or approved, and is not in any way responsible for, the contents of this publication.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
H.Wakelee: Financial Interests, Personal, Advisory Board, Served on a DSMC, completed November 2022: Mirati; Financial Interests, Personal, Invited Speaker, Develop and present a series of lectures: Fishawack Facilitate LTD; Financial Interests, Personal, Invited Speaker, Series of CME lectures: Medscape, Research to Practice; Financial Interests, Personal, Other, Discussion of new data at conferences: Curio Science; Financial Interests, Personal, Invited Speaker, Series of lectures/webinars for PER/OncLive: MJH Holdings; Financial Interests, Personal, Invited Speaker, CME lecture: Axis Medical Education, ParadigmMC, Prova Education; Financial Interests, Personal, Advisory Board: IOBiotech; Financial Interests, Personal, Invited Speaker, Facilitated speaking at several virtual conferences: Shanghai Bird Translation and Consulting; Financial Interests, Personal, Invited Speaker, Invited speaker at virtual symposium: China International Medical Foundation; Financial Interests, Personal, Invited Speaker, Invited to speak and moderate at JLCS meetings: Japanese Lung Cancer Society; Financial Interests, Personal, Invited Speaker, Presented at several CME conferences: Medical Educator Consortium; Financial Interests, Personal, Invited Speaker, Facilitated discussion of recent data: IDEOlogy Health; Financial Interests, Personal, Invited Speaker, Invited CME lecture: Vindico Medical Education; Financial Interests, Personal, Invited Speaker, Invited speaker at symposium: Taiwan Association for the Study of Lung Cancer (TASLC); Financial Interests, Personal, Royalties, I receive royalties for a chapter I wrote for UpToDate: UpToDate; Financial Interests, Institutional, Invited Speaker, Clinical Trial Conduct: AstraZeneca/Medimmune, BMS, Genentech/Roche, Merck, Seagen, Xcovery; Financial Interests, Institutional, Invited Speaker, clinical trial conduct: Helsinn; Financial Interests, Institutional, Invited Speaker, IIT for single site: Bayer; Financial Interests, Personal, Invited Speaker, uncompensated steering committee member: Merck, AstraZeneca, Genentech/Roche; Financial Interests, Personal, Other, uncompensated advisory board participation: BMS; Non-Financial Interests, Personal, Officer, Past President: International Association for the Study of Lung Cancer (IASLC); Non-Financial Interests, Personal, Leadership Role, Executive Committee: ECOG-ACRIN. M.C. Garassino: Financial Interests, Personal, Advisory Board: Eli Lilly, SeaGen International GmbH, Eli Lilly, Incyte, GSK, Bayer Healthcare Pharmaceuticals, Blueprint Medicines, AstraZeneca and Daiichi Sankyo Oncology Teams, Roche, Daiichi Sankyo, Mirati Therapeutics, Inc, Daiichi Sankyo/AstraZeneca, AstraZeneca Poland, Daiichi Sankyo, Inc., MSD, Eli Lilly, Pfizer, AstraZeneca/MedImmune, Sanofi Genzyme corporation, Sanofi/Prex, Regeneron Pharmaceuticals, Eli Lilly, Mirati Therapeutics, Inc., Janssen pharmaceutical, io biotech, Merck, Novocure, Nuvation, Pfizer, Revolution Medicine, Roche, Merck, AstraZeneca, Bayer, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Gilead, Mirati; Financial Interests, Personal, Invited Speaker: WebMD, WebMD Oncology/Takeda, MSD Italia, Srl, GrupoPacifico-Secretaria Técnica ICAPEM/AstraZeneca, S. O.S S.r.l, Medscape, ecancer, Ideology, Gilead, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker, Global Experts Meeting: AstraZeneca; Financial Interests, Personal, Other, AstraZeneca Spain: Invitation to a lung cancer investigator meeting: AstraZeneca; Financial Interests, Personal, Advisory Board, Advisory Boards: Takeda, Daiichi Sankyo, BeiGene; Financial Interests, Personal, Other, PACIFIC-R Global Scientific Committee: AstraZeneca; Financial Interests, Personal, Other, Steering Committee member and Co-chair at the AstraZeneca Lung Cancer Summit 2019: AstraZeneca; Financial Interests, Personal, Other, MK-3475 KN671 Steering Committee.: MSD; Financial Interests, Personal, Other, Pacific 6 International Coordinating Investigator: AstraZeneca; Financial Interests, Personal, Other, Janssen Scientific Advisory Board and Therapeutic Area Steering Committee Meeting on Lung Cancer: Janssen; Financial Interests, Personal, Expert Testimony: AstraZeneca UK; Financial Interests, Personal, Other, Pfizer Global Lung Cancer Educational Programme - Steering Committee: Pfizer; 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S. Ramella: Non-Financial Interests, Institutional, Funding: AstraZeneca, Roche, Merck MSD; Non-Financial Interests, Institutional, Invited Speaker: AstraZeneca, Roche, Merck MSD; Non-Financial Interests, Institutional, Advisory Board: AstraZeneca, Roche, Merck MSD; Non-Financial Interests, Institutional, Other, Travel: Elekta, Tema Sinergie; Non-Financial Interests, Institutional, Writing Engagements: AstraZeneca. B. Routy: Financial Interests, Personal, Advisory Board: BMS, Merck, AstraZeneca; Financial Interests, Institutional, Funding: AstraZeneca, Merck, BMS. All other authors have declared no conflicts of interest.