A phase Ib study evaluated neoadjuvant nivolumab or nivolumab–relatlimab in combination with chemoradiotherapy in patients with resectable stage II/III oesophageal/gastro-oesophageal junction cancer together with an in-depth evaluation of pathological, molecular and functional immune responses. Findings demonstrate the safety and feasibility of this approach in the neoadjuvant setting and suggest that circulating tumour DNA (ctDNA) clearance is associated with systemic expansion of neoantigen-specific T-cells, thus capturing systemic tumour burden and outcome-linked residual disease after neoadjuvant immunotherapy.
The results from the first study incorporating PD1 and LAG3 inhibition plus chemoradiotherapy in the neoadjuvant setting for patients with resectable oesophageal/gastro-oesophageal junction cancers are published by Drs. Ronan J. Kelly of the The Charles A. Sammons Cancer Center, Baylor University Medical Center in Dallas, TX, US, and Valsamo Anagnosou and Vincent K. Lam of The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine in Baltimore, MD, US and colleagues on 19 March 2024 in the Nature Medicine.
The authors wrote in the background that early stage gastro-oesophageal tumours may express high levels of PD-L1, indicating the presence of an adaptive immune resistance mechanism that may be reversed by anti-PD1 therapy. Preclinical and human studies have indicated that neoadjuvant chemoradiotherapy may have a PD-L1 priming effect in operable oesophageal/gastro-oesophageal junction cancers, supporting the rational combination of chemoradiotherapy with immune checkpoint inhibitors (ICI). LAG3 is a co-inhibitory receptor that is highly expressed in gastro-oesophageal cancers; therefore, combined anti-LAG3 and anti-PD1 therapy has the potential to modulate immune checkpoint pathways, re-invigorate exhausted T-cells and thus enhance antitumour immune responses.
Assessments of systemic tumour burden by analyses of ctDNA may accurately and rapidly determine tumour regression with neoadjuvant ICI in conjunction with pathologic and functional T-cell responses. Preoperative ctDNA assessments may identify individuals more likely to attain pathologic complete response (pCR) with neoadjuvant ICI and postoperative ctDNA detection may identify patients with minimal residual disease and an increased risk of disease relapse that may benefit from sequential therapy. Nevertheless, the predictive versus prognostic role of ctDNA remained unclear, with no studies to date in patients with gastro-oesophageal cancer treated in the neoadjuvant immuno-chemoradiotherapy setting.
In the article published in the Nature Medicine, the authors present safety, feasibility and efficacy, alongside pathological response, circulating tumour burden contraction and systemic neoantigen-specific T-cell responses during neoadjuvant treatment with nivolumab or nivolumab plus relatlimab combined with chemoradiotherapy in patients with operable stage II/III oesophageal/gastro-oesophageal junction cancer.
In the study, 16 patients with resectable stage II/III oesophageal/gastro-oesophageal junction cancer received neoadjuvant nivolumab in arm A and 16 patients nivolumab–relatlimab in arm B in combination with chemoradiotherapy. Primary endpoint was safety; the secondary endpoint was feasibility; exploratory endpoints included pCR and major pathological response (MPR), recurrence-free survival (RFS) and overall survival (OS).
The study met its primary safety endpoint in arm A, although arm B required modification to mitigate toxicity. pCR and MPR rates were 40% and 53.5% for arm A and 21.4% and 57.1% for arm B. Most common adverse events were fatigue, nausea, thrombocytopenia and dermatitis.
Overall, 2-year RFS and OS rates were 72.5% and 82.6%, respectively. Higher baseline PD-L1 and LAG3 expression were associated with deeper pathological responses. Exploratory analyses of ctDNA showed that patients with undetectable ctDNA post-ICI induction, preoperatively and postoperatively had a significantly longer RFS and OS; ctDNA clearance was reflective of neoantigen-specific T-cell responses.
The authors concluded that neoadjuvant nivolumab plus chemoradiotherapy is an active regimen for patients with operable oesophageal/gastro-oesophageal junction cancer, resulting in higher pCR and 2-year OS rates compared to historical chemoradiotherapy controls. The addition of relatlimab to nivolumab did result in a higher rate of immune-related adverse effects than nivolumab plus chemoradiotherapy alone, but promising long-term efficacy suggests that future studies should further evaluate the optimal sequencing of dual ICI when given concurrently with chemoradiotherapy.
Overall, the study findings provide insights into the safety profile of combined PD1 and LAG3 blockade in gastro-oesophageal cancer and highlight the potential of ctDNA analysis to dynamically assess systemic tumour burden during neoadjuvant ICI that may open a therapeutic window for future intervention.
The study was funded by Bristol Myers Squibb. The funder had no role in study design, data collection and analysis and decision to publish. The translational work was supported in part by the US National Institutes of Health grants, a Cancer Research Institute Torrey Coast Foundation GEMINI CLIP award, the Bloomberg-Kimmel Institute for Cancer Immunotherapy, the ECOG-ACRIN Thoracic Malignancies Integrated Translational Science Center grant, the Mark Foundation for Cancer Research, the Conquer Cancer Foundation of ASCO Career Development Award, Swim Across America and the W.W. Caruth Jr. Foundation.
Reference
Kelly RJ, Landon BV, Zaidi AH, et al. Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal/gastroesophageal junction cancer: a phase Ib trial and ctDNA analyses. Nature Medicine; Published online 19 March 2024. DOI: https://doi.org/10.1038/s41591-024-02877-z