A combination of neoadjuvant atezolizumab plus chemotherapy led to a major pathologic response (MPR) in 70% and a pathologic complete response (pCR) in 45% of patients with previously untreated resectable gastric and gastro-oesophageal junction cancer included in the phase II PANDA study. Importantly, pathologic response showed an excellent correlation with survival, with 13 of 14 responders without disease recurrence after a median follow-up of 47 months.
Although previous studies in gastric and gastro-oesophageal junction cancer have shown an association between response to neoadjuvant chemotherapy or chemoradiotherapy and outcome, these data indicate that the association may be stronger and more like in patients receiving neoadjuvant immunotherapy for non-small cell lung cancer, melanoma, colon, and bladder cancer, where patients with MPR and pCR have a negligible risk of disease recurrence. The authors observed an association between ctDNA and recurrence risk. In addition, presurgical ctDNA status was associated with pathologic response. Findings are published by Dr. Myriam Chalabi of the Netherlands Cancer Institute in Amsterdam, the Netherlands, and colleagues on 8 January 2024 in the Nature Medicine.
The authors explained in the background that gastric and gastro-oesophageal junction cancers carry a poor prognosis, and despite recent advances, most patients die of their disease. Although immune checkpoint blockade became part of the standard-of-care for patients with metastatic gastric and gastro-oesophageal junction cancers, its efficacy and impact on the tumour microenvironment in early disease remain largely unknown. They hypothesized higher efficacy of neoadjuvant immunotherapy plus chemotherapy in patients with non-metastatic gastric and gastro-oesophageal junction cancer.
PANDA study investigated the safety, efficacy, and immunologic correlates of atezolizumab plus chemotherapy in patients with resectable, non-metastatic gastric and gastro-oesophageal junction adenocarcinoma. A total of 21 patients received one cycle of monotherapy atezolizumab followed by four cycles of atezolizumab combined with docetaxel, oxaliplatin and capecitabine. Tumour biopsies were obtained through endoscopy at baseline, after monotherapy atezolizumab and after the first combination treatment. Surgery was performed 6–9 weeks after the last treatment cycle, and tissue was obtained from surgical resection specimens.
The primary objective was safety and feasibility. Secondary objectives included efficacy assessed by histopathologic regression, changes in the tumour microenvironment and clinical outcomes. Pathologic response was defined as ≤10% residual viable tumour (RVT), consisting of MPR (≤10% RVT) and pCR (0% RVT). An important purpose of this study design was to allow separate dissection of the effects of PD-L1 blockade alone and the subsequent combination with chemotherapy on the tumour microenvironment, as well as their association with clinical response.
Treatment was well tolerated. There were grade 3 immune-related adverse events in 2 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.
In total, 20 of 21 patients underwent surgery and were evaluable for secondary pathologic response and survival endpoints, and 19 were evaluable for exploratory translational analyses. MPR was observed in 14 of 20 patients (70%, 95% confidence interval [CI] 46–88%) patients, including 9 pCRs (45%, 95% CI 23–68%). At a median follow-up of 47 months, 13 of 14 responders were alive and disease-free, and 5 of 6 non-responders had a recurrence and died.
Notably, baseline anti-PD1+CD8+ T cell infiltration was significantly higher in responders versus non-responders, and comparison of tumour microenvironment alterations following anti-PD-L1 monotherapy versus the subsequent combination with chemotherapy showed an increased immune activation on single-agent blockade.
In the PANDA study, the study investigators observed a 3-year recurrence rate of 27%, whereas the expected recurrence rate for gastric and gastro-oesophageal junction cancers following FLOT chemotherapy is about 50% at 3 years. Despite the limitations of cross-trial comparisons and small patient cohort, these findings warrant validation in larger cohorts.
The authors emphasized when considering only intestinal-type tumours in the PANDA study, MPR and pCR rates were 80% and 60%, respectively. Albeit in a small cohort, these pathologic responses compare favourably to historical data in similar patient populations.
Notably, the translational work associated with this study strongly supports the added value of atezolizumab in neoadjuvant regimens for gastric and gastro-oesophageal junction cancers. Overall, the promising high pathologic response rate and the excellent survival of responders after neoadjuvant atezolizumab plus chemotherapy in gastric and gastro-oesophageal junction adenocarcinoma warrant validation in a randomised controlled study. Additionally, based on the observation that atezolizumab monotherapy leads to prominent changes in the tumour microenvironment, the question of whether selective absence of chemotherapy during the first treatment cycle is causally related to the observed high response rate may be explored.
The study was funded by Hoffman-La Roche and sponsored by the Netherlands Cancer Institute. The authors acknowledged Natera for supervision and review of the ctDNA analysis.
Reference
Verschoor YL, van de Haar J, van den Berg J, et al. Neoadjuvant atezolizumab plus chemotherapy in gastric and gastroesophageal junction adenocarcinoma: the phase 2 PANDA trial. Nature Medicine; Published online 8 January 2024. DOI: https://doi.org/10.1038/s41591-023-02758-x