Neoadjuvant dual immuno-combination therapy with anti-LAG3 and anti-PD-1 antibodies is feasible and safe for resectable non-small cell lung cancer

We would like to comment on Schuler et al., on their well-designed randomized phase II NEOpredict-Lung study (NCT04205552) which was published in Nature Medicine. The main objective of this study was to investigate the feasibility and the efficacy of neoadjuvant anti-lymphocyte-activation gene 3 (LAG3) antibody in combination with anti-programmed cell death-1 (PD-1) antibody for resectable non-small cell lung cancer (NSCLC) (1). The paper evaluated 60 patients, enrolled across three institutions, between March 2020 and July 2022. They concluded novel neoadjuvant dual immuno-combination therapy with relatlimab and nivolumab established feasibility and safety in patients with resectable NSCLC stages IB, II and IIIA with promising outcomes including a 1-year disease-free survival (DFS) of 93% and a 1-year overall survival (OS) of 100%. Furthermore, this study achieved a pathological complete response (pCR) in 17%, and major pathological response (MPR) in 30% of patients.

Currently, neoadjuvant or perioperative chemo-immunotherapies were established by several phase III studies [CheckMate-816 (2), CheckMate-77T (3), KEYNOTE-671 (4), AGEAN (5) and NEOTORCH (6)]. In consensus recommendation of International Association for the Study of Lung Cancer (IASLC), neoadjuvant chemo-immunotherapy is strongly preferred to upfront surgery for medically operable patients with resectable clinical stage IIIA or IIIB NSCLC, irrespective of programmed cell death-ligand 1 (PD-L1) expression level (expert panel agreement 94%) (7). The standard regimen is anti-PD-1 antibody in combination with platinum based cytotoxic chemotherapy. However, the combination therapy is not feasible for all resectable NSCLC patients, especially, in those with higher age or comorbidities such as renal dysfunction. NSCLC patients with resectable stage are aging, therefore the tolerability of neoadjuvant chemo-immunotherapies is an important issue. In previous pivotal phase III studies, grade 3 ≥ treatment-related adverse events (TRAEs) consistently developed in over 30%, even in patients with good performance status (PS) treated with neoadjuvant chemo-immunotherapies. In contrast, neoadjuvant relatlimab in combination with nivolumab revealed good tolerability in the NEOpredict-Lung study (Table 1). Neoadjuvant dual immuno-combination therapy could potentially replace chemo-immunotherapy for older patients with renal dysfunction who cannot tolerate platinum doublet chemotherapy.

Speaking on the efficacy, pCR rate of dual immuno-combination therapy with relatlimab and nivolumab was relatively lower than chemo-immunotherapy despite promising survival results such as 1-year DFS of 93% and a 1-year OS of 100%. It is debatable whether pCR rate is an acceptable surrogate endpoint for neoadjuvant therapy in resectable NSCLC. A recent single-arm phase II study, the INCREASE study, investigated the feasibility of neoadjuvant ipilimumab plus nivolumab with chemoradiotherapy (CRT) in patients with resectable and borderline resectable NSCLC (8). The INCREASE study demonstrated remarkable efficacy that achieved a pCR rate of 50%, and a MPR rate of 63.3% in their cohort. However, grade 3 ≥ TRAEs developed in 70.0% of patients. Although multimodality neoadjuvant therapy is a promising strategy, further modification is needed in future studies.

From the point of view of surgical outcomes, definitive surgery and R0 resection rate was numerically higher than neoadjuvant chemo-immunotherapies. We summarized safety and surgical outcomes of pivotal studies according to the treatment strategy in Table 1. Notably, surgical delay was not present in the NEOpredict study. Low TRAEs in dual immuno-combination therapy could give a positive impact to avoid surgical delay compared to chemo-immunotherapy.

Furthermore, the authors produced a well-designed, exploratory biomarker/translational research in the NEOpredict-Lung study. Interestingly, expression of the immune checkpoint gene LAG3 was significantly induced by nivolumab monotherapy group, but not by the combination group. Further biomarker studies could give novel insights and appropriate patient selection of neoadjuvant anti-LAG3 antibody in combination with anti-PD-1 antibody.

References

1. Schuler M, Cuppens K, Plönes T, et al. Neoadjuvant nivolumab with or without relatlimab in resectable non-small-cell lung cancer: a randomized phase 2 trial. Nat Med 2024;30:1602-11. [Crossref] [PubMed]
2. Forde PM, Spicer J, Lu S, et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med 2022;386:1973-85. [Crossref] [PubMed]
3. Cascone T, Awad MM, Spicer JD, et al. Perioperative Nivolumab in Resectable Lung Cancer. N Engl J Med 2024;390:1756-69. [Crossref] [PubMed]
4. Wakelee H, Liberman M, Kato T, et al. Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer. N Engl J Med 2023;389:491-503. [Crossref] [PubMed]
5. Heymach JV, Harpole D, Mitsudomi T, et al. Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer. N Engl J Med 2023;389:1672-84. [Crossref] [PubMed]
6. Lu S, Zhang W, Wu L, et al. Perioperative Toripalimab Plus Chemotherapy for Patients With Resectable Non-Small Cell Lung Cancer: The Neotorch Randomized Clinical Trial. JAMA 2024;331:201-11. [Crossref] [PubMed]
7. Spicer JD, Cascone T, Wynes MW, et al. Neoadjuvant and Adjuvant Treatments for Early Stage Resectable NSCLC: Consensus Recommendations From the International Association for the Study of Lung Cancer. J Thorac Oncol 2024;19:1373-414. [Crossref] [PubMed]
8. Bahce I, Dickhoff C, Schneiders FL, et al. Single-arm trial of neoadjuvant ipilimumab plus nivolumab with chemoradiotherapy in patients with resectable and borderline resectable lung cancer: the INCREASE study. J Immunother Cancer 2024;12:e009799. [Crossref] [PubMed]

Publication: Furuya N, Homma T, Saji H. Neoadjuvant dual immuno-combination therapy with anti-LAG3 and anti-PD-1 antibodies is feasible and safe for resectable non-small cell lung cancer. J Thorac Dis 2025;17(2):528-530. doi: 10.21037/jtd-24-1789