Introduction and Highlights
The therapeutic landscape for resectable non-small-cell lung cancer (NSCLC) has undergone a paradigm shift with the introduction of neoadjuvant and perioperative immunotherapy. While chemo-immunotherapy combinations have become the standard of care based on landmark trials, the quest for chemotherapy-free regimens continues, particularly for patients who may not tolerate or require cytotoxic agents. The NEOpredict-Lung trial (NCT04205552) was designed to evaluate the feasibility and efficacy of preoperative nivolumab (anti-PD-1) alone or in combination with relatlimab (anti-LAG-3). Following the initial reports of feasibility, the long-term outcomes recently published in the European Journal of Cancer provide critical insights into the durability of response and the prognostic value of pathological downstaging.
Key Highlights
- The 3-year Overall Survival (OS) rates remained remarkably high, exceeding 88% in both the monotherapy and doublet immunotherapy arms.
- Dual checkpoint inhibition (nivolumab plus relatlimab) demonstrated a superior nodal downstaging rate of 66.7% compared to 28.6% with nivolumab alone.
- Major Pathological Response (MPR) showed a strong trend toward improved Disease-Free Survival (DFS), with a Hazard Ratio of 0.35.
- Short-course immunotherapy (only two doses) proved sufficient to induce deep responses without delaying surgical intervention.
Background: The Evolution of Neoadjuvant Therapy in NSCLC
Historically, the management of stage IB to IIIA NSCLC relied on surgical resection followed by adjuvant chemotherapy, which offered a modest 5% absolute improvement in 5-year survival. The advent of immune checkpoint inhibitors (ICIs) changed this trajectory. Trials such as CheckMate 816 demonstrated that adding nivolumab to neoadjuvant chemotherapy significantly increased pathological complete response (pCR) rates and event-free survival. However, chemotherapy carries a burden of systemic toxicity. The NEOpredict-Lung study explores whether a ‘pure’ immunotherapy approach—specifically targeting two distinct immune checkpoints, PD-1 and LAG-3—could provide sufficient anti-tumor activity to improve surgical outcomes and long-term survival while sparing patients the side effects of chemotherapy.
Study Design: Evaluating the PD-1/LAG-3 Axis
NEOpredict-Lung was a randomized, phase II trial enrolling 60 patients with resectable NSCLC (stages IB-IIIA). Participants were randomized into two cohorts:
Arm A: Nivolumab Monotherapy
Patients received two doses of nivolumab (240 mg) administered intravenously every two weeks prior to surgery.
Arm B: Nivolumab plus Relatlimab Doublet
Patients received two doses of nivolumab (240 mg) combined with relatlimab (80 mg) every two weeks.Relatlimab is a first-in-class antibody that binds to Lymphocyte-activation gene 3 (LAG-3), an inhibitory receptor expressed on T cells. LAG-3 and PD-1 are often co-expressed on tumor-infiltrating lymphocytes, and their simultaneous blockade has shown synergistic effects in other malignancies, most notably melanoma. The primary endpoints were feasibility (defined by the absence of surgical delays) and safety, while the secondary endpoints included OS, DFS, pathological response rates, and patterns of recurrence.
Key Findings: Survival, Recurrence, and Downstaging
The analysis conducted in December 2024, with a median follow-up of 37.4 months, reveals several critical outcomes regarding the efficacy of this short-course preoperative intervention.
Overall and Disease-Free Survival
The long-term survival data is highly encouraging. In Arm A (Nivolumab), the 3-year OS was 88.4% and the 3-year DFS was 73.3%. In Arm B (Nivolumab + Relatlimab), the 3-year OS was 88.9% and the DFS was 60.3%. While the DFS in the doublet arm was numerically lower than the monotherapy arm, the study was not powered for a direct comparison of these rates, and the high OS in both groups suggests that many patients who recur can be successfully managed with subsequent lines of therapy.
Pathological Response and Downstaging
One of the most striking findings was the impact on tumor staging. Downstaging was confirmed in 53.3% of patients in Arm A and 66.7% in Arm B. More importantly, in patients with baseline nodal involvement, nodal downstaging occurred in 66.7% of those receiving the doublet (Arm B) compared to only 28.6% in the monotherapy group. This suggests that the addition of relatlimab may be particularly effective at clearing micrometastatic disease in regional lymph nodes.
Predictors of Outcome
The study confirmed that the depth of pathological response is a valid surrogate for long-term outcomes. Patients achieving a Major Pathological Response (MPR), defined as ≤10% viable tumor cells in the resected specimen, trended toward significantly better DFS (HR 0.35; 95% CI, 0.1-1.19).
Recurrence Patterns
Out of the 60 patients, 15 experienced disease recurrence. The majority of these (11 patients) were metastatic recurrences, while 4 were locoregional. This highlights that while preoperative immunotherapy is potent, the risk of systemic escape remains a challenge in a subset of patients.
Expert Commentary: Navigating the Chemo-Free Paradigm
The NEOpredict-Lung trial provides a compelling argument for the feasibility of chemotherapy-free neoadjuvant strategies. The 3-year OS rates of nearly 89% are comparable, if not superior, to some chemo-immunotherapy regimens reported in larger phase III trials.
Mechanistic Insights
The superior nodal downstaging observed with the addition of relatlimab underscores the biological importance of the LAG-3 pathway in NSCLC. LAG-3 functions by inhibiting T-cell activation and cytokine secretion; blocking it alongside PD-1 appears to ‘reinvigorate’ exhausted T cells more effectively than PD-1 blockade alone. This is particularly relevant in the neoadjuvant setting, where the primary tumor is still present to serve as a reservoir for neoantigens, allowing for a more robust priming of the systemic immune response.
Clinical Implications and Limitations
From a clinical perspective, a short course of only two doses of immunotherapy is highly attractive. It minimizes the window of time before surgery and reduces the cumulative toxicity risk. However, the study’s small sample size (n=60) means that the survival percentages should be interpreted with caution. The numerically lower DFS in the doublet arm, despite better downstaging, is a curious finding that may be due to chance or differences in baseline risk factors between the small cohorts. It also raises questions about whether some patients require more than two doses or adjuvant therapy to maintain a disease-free state.
Conclusion and Summary
The 3-year follow-up of the NEOpredict-Lung trial reinforces the potential of preoperative nivolumab and relatlimab as a viable treatment path for resectable NSCLC. By achieving significant nodal downstaging and excellent overall survival without the need for concurrent chemotherapy, this regimen offers a glimpse into a future of de-escalated yet highly effective thoracic oncology. While larger randomized trials are needed to definitively establish the role of LAG-3 inhibition in this setting, NEOpredict-Lung provides a strong foundation for the continued exploration of dual checkpoint blockade in early-stage lung cancer.
Funding and ClinicalTrials.gov
This study was investigator-initiated and supported by Bristol Myers Squibb. ClinicalTrials.gov Identifier: NCT04205552.
References
1. Cuppens K, Wiesweg M, Baas P, et al. Long-term outcomes of preoperative nivolumab with or without relatlimab in patients with resectable non-small-cell lung cancer (NEOpredict-Lung). Eur J Cancer. 2026 Jan 17;233:116165. doi: 10.1016/j.ejca.2025.116165. 2. Forde PM, Spicer J, Lu S, et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med. 2022;386(21):1973-1985. 3. Lipson EJ, Madan RA, et al. LAG-3 and PD-1 Blockade with Relatlimab and Nivolumab: A New Standard of Care? Cancer Discov. 2022;12(6):1414-1416.
