Abstract 1219P
Background
Immune checkpoint blockade improves clinical outcomes for patients with G/GEJ cancers, but its efficacy and impact on the tumor microenvironment (TME) in the neoadjuvant setting remains largely unknown. Peri-operative FLOT chemotherapy, currently standard of care, leads to pathologic complete responses (pCR) and major pathologic responses (MPR) in 16% and 37% of patients, respectively. An important open question is whether anti-PD-L1 monotherapy can prime the TME prior to combination with chemotherapy.
Methods
In the phase II PANDA study (NCT03448835), 20 patients with resectable G/GEJ adenocarcinoma were neoadjuvantly treated with a single cycle of atezolizumab (anti-PD-L1), followed by 4 cycles of atezolizumab plus docetaxel, oxaliplatin and capecitabine (A-DOC) and subsequent surgery. Tumor tissue was obtained at baseline, after atezolizumab monotherapy, after first A-DOC and at surgery. The primary endpoint was safety. Disease-free survival, pCR rate and biomarker assessments were prespecified exploratory endpoints.
Results
Treatment was well-tolerated and safe, and all patients underwent timely surgery. MPR (≤10% viable tumor rest) was observed in 14/20 patients (70%), including 9 pCR (45%). At a median follow-up of 29 months, 15 patients (75%) were disease-free, including all patients with an MPR. Using gene expression analysis, PD-1 was significantly higher at baseline in responders vs nonresponders, while neutrophil signature was significantly higher in nonresponders vs responders. TMB and PD-L1 CPS were not associated with response. Immune activation was already observed after one cycle of atezolizumab monotherapy, as evidenced by increases in CD4+ and CD8+ T cell infiltration, PD-1, CXCL13 and IFN-γ signatures compared to baseline. This was significant only in responders.
Conclusions
Neoadjuvant atezolizumab plus chemotherapy leads to promising pathologic responses in G/GEJ cancer. Baseline PD-1 and neutrophil signature were associated with response. Biomarker analyses after a single dose of atezolizumab showed immune activation in responders and may be used as an early indicator of response. These data should be validated in a large randomized controlled trial.
Clinical trial identification
EudraCT number: 2017-003854-17.
Editorial acknowledgement
Legal entity responsible for the study
Netherlands Cancer Institute.
Funding
Roche-Genentech.
Disclosure
T.N. Schumacher: Financial Interests, Personal, Other, Consultant: Third Rock Ventures; Financial Interests, Personal, Advisory Board: Allogene Therapeutics, Merus, Celsius Therapeutics; Financial Interests, Personal, Other, Founder, advisor: Asher Bio, Neogene Therapeutics; Financial Interests, Personal, Invited Speaker: Neogene Therapeutics; Financial Interests, Personal, Stocks/Shares: Third Rock Ventures, Allogene Therapeutics, Asher Bio, Merus, Neogene Therapeutics, Celsius Therapeutics. J.B.A.G. Haanen: Financial Interests, Institutional, Advisory Board: Bristol Myers Squipp, Achilles Therapeutics, Immunocore, Gadeta, Ipsen, Merck Sharpe & Dohme, Merck Serono, Pfizer, Molecular Partners, Novartis, Roche, Sanofi, Third Rock Venture, Iovance Biotherapeutics; Financial Interests, Institutional, Advisory Board, SAB member: BioNTech, Instil Bio, PokeAcel, T-Knife; Financial Interests, Personal, Advisory Board, SAB member: Neogene Therapeutics; Financial Interests, Personal, Stocks/Shares: Neogene Therapeutics; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, BioNTech US, Merck Sharpe & Dohme, Amgen, Novartis, Asher Bio; Non-Financial Interests, Member: ASCO, AACR, SITC; Other, Other, Editor-in-Chief IOTECH: ESMO; Other, Other, Editorial Board ESMO Open: ESMO; Other, Other, Editorial Board: Kidney Cancer. E.E. Voest: Financial Interests, Personal, Advisory Board, Hourly rate, to charity: Biogeneration Ventures; Financial Interests, Institutional, Advisory Board, Hourly rate, no compensation in 2019-2020: InteRNA; Financial Interests, Institutional, Invited Speaker, DRUP trial: Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Clovis Oncology, Eisai, Ipsen, MSD, Novartis, Pfizer, GSK, Seattle Genetics; Financial Interests, Institutional, Invited Speaker, DRUP trialDRUG Access Protocol: Bayer, Roche; Financial Interests, Institutional, Invited Speaker, DRUG Access Protocol: Sanofi; Non-Financial Interests, Other, Supervisory Board: HMF – Hartwig Medical Foundation; Non-Financial Interests, Principal Investigator, Senior group leader: Oncode Institute; Non-Financial Interests, Advisory Role, Editorial Board: JAMA Oncology; Non-Financial Interests, Leadership Role, Board of Directors: Cancer Core Europe. All other authors have declared no conflicts of interest.