Neoadjuvant atezolizumab plus chemotherapy in gastric and gastroesophageal junction adenocarcinoma: the phase 2 PANDA trial.

"data availability the rna and dna sequencing data will be deposited in the european genome-phenome archive under egas50000000168 and these data will be shared on reasonable request for academic use and within the limitations of the provided informed consent and under general data protection regulation law. data availability the rna and dna sequencing data will be deposited in the european genome-phenome archive under egas50000000168"

"Competing interests Y.L.V., J.v.d.H., J.G.v.d.B., J.W.v.S., J.M.v.D., S.B., C.G., M.E.I., A.A.F.A.V., K.J.H., M.A.V., E.C.O., A.B-R., P.d.H., N.F.C.C.d.M. and M.E.v.L. declare no competing interests. L.L.K. reports research funding to the institute from BMS outside the submitted work. A.J., S.S. and E.S. are full-time employees of Natera, Inc. with stocks and/or stock options to own in the company. J.B.A.G.H. has (had) advisory roles with Achilles Therapeutics, AstraZeneca, Bayer, Bristol Myers Squibb, BioNTech, GSK, Immunocore, Iovance Bio, Instil Bio, Ipsen, MSD, Merck Serono, Molecular Partners, Novartis, Neogene Therapeutics, Pfizer, Roche/Genentech, Sanofi, Scenic Bio, T-Knife and Third Rock Ventures and has received research grants not related to this paper from Amgen, Bristol Myers Squibb, MSD, BioNTech, Novartis and Sastra Cell Therapy. All grants were paid to the institutions. T.N.S. is advisor for Allogene Therapeutics, Asher Bio, Celsius, Merus, Neogene Therapeutics and Scenic Biotech; is a stockholder in Allogene Therapeutics, Asher Bio, Cell Control, Celsius, Merus and Scenic Biotech; and is venture partner at Third Rock Ventures, all outside of the current work. E.E.V. reports research funding from BMS outside the current work. M.C. has (had) advisory roles for NUMAB, KINETA, BMS, MSD and Roche/Genentech and received research grants not related to this paper from BMS, MSD and Roche-Genentech. All grants were paid to the institutions."

"We thank Hoffman-La Roche for funding this study. We thank all the patients and their families for participating in the present study. We thank the Core Facility of Molecular Pathology and Biobanking, in particular A. Broeks, S. Cornelissen and M. Alkemade, for their support in processing samples and performing immunohistochemistry; M. Nieuwland, R. Kluin, A. Velds and the Genomics Core Facility for their support with sequencing; I. Seignette for her support in digital imaging analysis using HALO; R. Harkes and Y. Ge for their support in quantification of CD8+ cells using QuPath; L. Al-van Wijck and M. van de Belt from the scientific administration department for data management and for support in trial conduct and management; N. Brandhorst for facilitating sample acquisition and processing; T. Korse, M. Lucas and E. Platte for PBMC acquisition and processing; Y. Hilhorst and M. Warmerdam for patient care; and St Jansdal Hospital, Rode Kruis Hospital, Tergooi Medical Center, Haga Hospital, Noordwest Hospital Group, Gelre Hospitals, Amsterdam UMC, Franciscus Hospital, PoliDirect IJburg, Slotervaart Hospital, Laurentius Hospital and St Antonius Hospital for patient referral. We would also like to acknowledge M.C. Liu and G. Laliotis from Natera for their supervision and critical review of the ctDNA analysis. The present study was funded by Hoffman-La Roche and sponsored by the NKI. The funding source had no role in design and execution of the study, data analysis or writing of the manuscript."

"Gastric and gastroesophageal junction (G/GEJ) cancers carry a poor prognosis, and despite recent advancements, most patients die of their disease. Although immune checkpoint blockade became part of the standard-of-care for patients with metastatic G/GEJ cancers, its efficacy and impact on the tumor microenvironment (TME) in early disease remain largely unknown. We hypothesized higher efficacy of neoadjuvant immunotherapy plus chemotherapy in patients with nonmetastatic G/GEJ cancer. In the phase 2 PANDA trial, patients with previously untreated resectable G/GEJ tumors (n = 21) received neoadjuvant treatment with one cycle of atezolizumab monotherapy followed by four cycles of atezolizumab plus docetaxel, oxaliplatin and capecitabine. Treatment was well tolerated. There were grade 3 immune-related adverse events in two of 20 patients (10%) but no grade 4 or 5 immune-related adverse events, and all patients underwent resection without treatment-related delays, meeting the primary endpoint of safety and feasibility. Tissue was obtained at multiple time points, allowing analysis of the effects of single-agent anti-programmed cell death ligand 1 (PD-L1) and the subsequent combination with chemotherapy on the TME. Twenty of 21 patients underwent surgery and were evaluable for secondary pathologic response and survival endpoints, and 19 were evaluable for exploratory translational analyses. A major pathologic response (≤10% residual viable tumor) was observed in 14 of 20 (70%, 95% confidence interval 46–88%) patients, including 9 (45%, 95% confidence interval 23–68%) pathologic complete responses. At a median follow-up of 47 months, 13 of 14 responders were alive and disease-free, and five of six nonresponders had died as a result of recurrence. Notably, baseline anti-programmed cell death protein 1 (PD-1)+CD8+ T cell infiltration was significantly higher in responders versus nonresponders, and comparison of TME alterations following anti-PD-L1 monotherapy versus the subsequent combination with chemotherapy showed an increased immune activation on single-agent PD-1/L1 axis blockade. On the basis of these data, monotherapy anti-PD-L1 before its combination with chemotherapy warrants further exploration and validation in a larger cohort of patients with nonmetastatic G/GEJ cancer. ClinicalTrials.gov registration: NCT03448835."