Neoadjuvant dual immuno-combination therapy with anti-LAG3 and anti-PD-1 antibodies is feasible and safe for resectable non-small cell lung cancer
Naoki Furuya1
, Takahiro Homma2
, Hisashi Saji2
Keywords: Anti-LAG3 antibody; neoadjuvant immunotherapy; resectable non-small cell lung cancer (resectable NSCLC)
Submitted Oct 20, 2024. Accepted for publication Jan 08, 2025. Published online Feb 27, 2025.
doi: 10.21037/jtd-24-1789
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.
Table 1
| Neoadjuvant IO therapy | Trial | Treatment | Efficacy | Safety | Surgical outcomes | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| pCR (%) |
MPR (%) | Grade 3 ≥ TRAEs (%) | Definitive surgery | Pneumonectomy | R0 resection | Surgical delay ≥43 days | |||||
| Dual IO | NEOpredict-Lung (phase II) | Rela + Nivo (n=30) | 17 | 30 | 13 | 93.3% (28/30) | NA | 96.4% (27/28) | 0% | ||
| Nivo alone (n=30) | 13 | 27 | 10 | 100% (30/30) | NA | 100% (30/30) | 0% | ||||
| NEOSTAR (phase II) | Ipi + Nivo + CT (n=22) | 18.2 | 50.0 | 45.5 | 90.9% (20/22) | 5.0% (1/20) | 95.0% (19/20) | 10.0% (2/20) | |||
| INCREASE (phase II) | Ipi + Nivo + CRT (n=30) | 50.0 | 63.3 | 70.0 | 86.7% (26/30) | 3.8% (1/26) | 100% (26/26) | NA | |||
| IO + CT | CheckMate-816 (phase III) | Nivo + CT (n=179) | 24.0 | 36.9 | 33.5 | 83.2% (149/179) | 16.8% (25/149) | 83.2% (124/149) | 20.8% (31/149) | ||
| CheckMate-77T (phase III) | Nivo + CT (n=229) | 25.3 | 35.4 | 32.5 | 77.7% (178/229) | 9.0% (16/178) | 89.3% (159/178) | 20.2% (36/178) | |||
| KEYNOTE-671 (phase III) | Pembro + CT (n=397) | 18.1 | 30.2 | 44.9 | 81.9% (325/397) | 11.4% (37/325) | 92.0% (299/325) | NA | |||
| AEGEAN (phase III) | Dur + CT (n=366) | 17.2 | 34.2 | 32.4 | 77.6% (284/366) | 9.5% (27/284) | 94.7% (269/284) | 20.4% (58/284)† | |||
| NEOTORCH (phase III) | Tori + CT (n=202) | 24.8 | 48.5 | 63.4 | 82.2% (166/202) | 9.0% (15/166) | 95.8% (159/166) | NA | |||
†, definition of surgical delay was defined as surgery occurring more than 40 days after the last dose of study treatment in the neoadjuvant period in AGEAN study. IO, immune-oncology; NSCLC, non-small cell lung cancer; pCR, pathological complete response; MPR, major pathological response (>10% viable tumor cells); TRAEs, treatment related adverse events; Rela, relatlimab; Nivo, nivolumab; NA, not available; Ipi, ipilimumab; CT, chemotherapy; CRT, chemoradiotherapy; Pembro, pembrolizumab; Dur, durvalumab; Tori, toripalimab.
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.
Acknowledgments
The authors wish to thank Mr. Jason Tonge from St. Marianna University School of Medicine for reviewing the language of this article.
Footnote
Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Thoracic Disease. The article has undergone external peer review.
Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1789/prf
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1789/coif). The authors have no conflicts of interest to declare.
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