With all randomised patients reaching the primary study endpoint, that is proceeding to surgery within 43 days of initiation of immune checkpoint inhibitor (ICI) therapy, NEOpredict-Lung confirms the feasibility in both study arms to receive two preoperative doses of nivolumab (anti-PD1) with or without relatlimab (anti-LAG3) antibody therapy. Achieving R0 resections in 95% of patients compares favourably with other studies of ICI-based neoadjuvant treatment in patients with non-small cell lung cancer (NSCLC) with operation rates mostly around 80%.
The safety of preoperative nivolumab plus relatlimab was supported with no apparent difference in overall frequency and severity of adverse events (AEs), treatment-related AEs and immune-related AEs compared with the reference nivolumab. Further exploration of dual targeting of PD1 and LAG3 in NSCLC is warranted according to Drs. Martin Schuler of the University Hospital Essen in Essen, Germany, Kristof Cuppens of the Jessa Hospital in Hasselt, Belgium, and colleagues who published the findings on 30 April 2024 in the Nature Medicine.
In the setting of ICI therapy, reinvigoration of a suppressed immune response may be more effective while tumour infiltrating lymphocytes are still present in their native tumour context. Besides demonstrating safety and feasibility, the spectra of clinical and histopathological responses observed in studies with preoperative ICI therapy directed against PD1, PD-L1, CTLA4 and less-established targets in patients with resectable NSCLC, were correlated with exploratory biomarker analyses.
More recently, preoperative PD1/PD-L1 antibodies combined with platinum-based chemotherapy have been explored. Although this approach resulted in impressive histopathological response rates and improved event-free survival, combined chemoimmunotherapy may obscure the contribution of the ICI component at the single patient level. Across larger studies of preoperative chemoimmunotherapy approximately 20% of patients failed to proceed to curatively intended surgery. Further, patients who might have been served perfectly well with ICI therapy alone were exposed to the additional toxicities of chemotherapy.
Based on distinct and potentially synergistic mode of action, combined targeting of the immune checkpoints LAG-3 and PD1 is a rational choice to overcome immune resistance in NSCLC. Both PD1 and LAG-3 are expressed by exhausted T cells. Dual blockade of both immune checkpoints synergistically enhanced T cell function and antitumour activity in preclinical models.
The study NEOpredict-Lung was designed to explore the feasibility and safety of preoperative dual targeting of PD1 and LAG-3 in patients with resectable NSCLC stages IB, II or IIIA. Secondary endpoints include the assessment of pathological and radiographic responses, survival endpoints and quality of surgical resections. Moreover, the study intends to leverage the neoadjuvant setting for exploratory analyses of specific biologies associated with response or resistance. Patients are randomly assigned to nivolumab plus relatlimab or nivolumab monotherapy, the latter serving as a reference for the evaluation of toxicity, clinical activity, and biological impact of dual targeting of PD1 and LAG-3 in resectable NSCLC.
In this ongoing, open-label phase II study, 60 biomarker-unselected, treatment-naïve patients with resectable NSCLC were randomised to receive two preoperative doses of nivolumab with or without relatlimab. The primary study endpoint was the feasibility of surgery within 43 days, which was met by all patients. Curative resection was achieved in 95% of patients. Major pathological (defined as ≤10% viable tumour cells) and objective radiographic responses were achieved in 27% and 10% in nivolumab group and in 30% and 27% in nivolumab plus relatlimab group of patients.
In 100% of patients in nivolumab group and 90% in nivolumab plus relatlimab group of patients, tumours and lymph nodes were pathologically completely resected. With 12 months median duration of follow-up, disease-free survival and overall survival rates at 12 months were 89% and 93% in nivolumab group, and 93% and 100% in nivolumab plus relatlimab group.
Both treatments were safe with grade ≥3 treatment-emergent AEs reported in 10% and 13% of patients per study arm. Exploratory analyses provided insights into biological processes triggered by preoperative immunotherapy.
This study establishes the feasibility and safety of dual targeting of PD1 and LAG-3 before lung cancer surgery. Based on early signals of clinical and biological activity obtained with this and another recently reported study in patients with metastatic NSCLC further exploration of dual targeting of PD1 and LAG-3 in NSCLC is warranted. The authors wrote that negative correlation of histopathological response with the intratumoural representation of suppressive immune cell subsets is a key finding of their study. Another key observation of NEOpredict-Lung is how rapidly ICI-induced immune activation may shape the individual genomic landscapes of NSCLC.
Overall, the study findings suggest that in a subgroup of patients nivolumab with or without relatlimab failed to reinvigorate an immune response that significantly impacts on clonally diverse tumours. In another subgroup four weeks of nivolumab with or without relatlimab were sufficient to empower complete immune eradication of lung cancers, which precluded meaningful longitudinal genomic analyses. In a third subgroup of patients who achieved substantial, but not complete histopathological responses, the enrichment of apparently resistant clones and depletion of sensitive clones was observed under the selective pressure mounted during preoperative ICI therapy. The latter hypothesis is corroborated by selected cases in which emergence of biologically plausible genomic resistance mechanisms, such as copy number gain of MYC and KRAS, and pathogenic variants of IDH1 and STK11, is observed by longitudinal genome sequencing.
Study management and translational research were performed at University Medicine Essen, Jessa Hospital and Antoni van Leeuwenhoek Hospital. The West German Biobank Essen is acknowledged for supporting study biobanking and biomarker analyses, and the University Medicine Essen Study Center GmbH for supporting sponsor oversight and project management. Bristol Myers Squibb provided the study medication and institutional grant support. The West German Cancer Center Essen is supported by grants from the Deutsche Krebshilfe and receives federal and state funding as National Center for Tumor Diseases West and as partner site of the German Cancer Consortium.
Reference
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. Nature Medicine; Published online 30 April 2024. DOI: https://doi.org/10.1038/s41591-024-02965-0