Immuno-oncology (IO) has revolutionized the treatment landscape for non-small cell lung cancer (NSCLC), providing durable responses and survival benefits across different disease stages. The success of immune checkpoint inhibitors (ICIs), including PD-(L)1 and CTLA-4 inhibitors, has paved the way for dual immune checkpoint blockade (ICB) therapy, aiming to enhance antitumor immunity. While clinical trials such as KEYNOTE-024 and KEYNOTE-189 have demonstrated significant benefits with ICI monotherapy or ICI combined with chemotherapy in advanced NSCLC, overcoming treatment resistance and improving five-year overall survival (OS) remain key challenges.

Recent studies have identified promising biomarkers such as LAG-3 (Lymphocyte Activation Gene 3) and TIGIT (T-cell immunoreceptor with Ig and ITIM domains). LAG-3 is often co-expressed with PD-L1 and suppresses T-cell activity through interactions with MHC class II molecules. TIGIT, highly expressed on T cells and natural killer (NK) cells, is linked to immune evasion and poor prognosis. These biomarkers hold potential for patient stratification and treatment optimization in IO therapy. However, additional evidence is required to validate their clinical utility.

Assessing LAG-3 Inhibition in Advanced NSCLC: Insights from the RELATIVITY-104 Trial

The RELATIVITY-104 trial (NCT04623775) is the first randomized phase II study evaluating the addition of the LAG-3 inhibitor relatlimab to nivolumab and platinum-based chemotherapy (PDCT) as first-line treatment for stage IV or recurrent NSCLC. The study builds on the success of RELATIVITY-047 in melanoma and explores the potential role of LAG-3 inhibition in NSCLC. However, its results require careful interpretation, particularly regarding efficacy and subgroup benefits.

The RELATIVITY-104 study enrolled 309 patients, randomized in a 1:1 ratio to receive either nivolumab plus relatlimab with platinum-doublet chemotherapy or nivolumab with platinum-doublet chemotherapy alone. The primary endpoint was objective response rate (ORR) by blinded independent central review (BICR). Secondary endpoints included progression-free survival (PFS), PD-L1 stratified PFS, and ORR. The safety profile of the relatlimab-containing regimen was consistent with expectations, with no significant increase in adverse events compared to the control group.

The primary endpoint analysis showed an ORR of 51.3% in the relatlimab group compared to 43.7% in the control group. Median PFS was 6.7 months versus 6.0 months (HR = 0.88; 90% CI: 0.71–1.1). These results suggest that not all patients benefit from adding relatlimab.

Subgroup analysis revealed that the majority of PFS and ORR benefits occurred in PD-L1-positive patients. There was a statistically significant interaction between histology subtypes, with PFS differing between squamous and non-squamous NSCLC (P = 0.023). Furthermore, the Kaplan-Meier survival curves at 12 months showed a crossover, raising concerns about the durability of benefit.

Exploratory analyses from RELATIVITY-104 identified two potential subgroups that might benefit from the addition of relatlimab: patients with PD-L1 expression greater than 1% and non-squamous NSCLC, and those with PD-L1 expression between 1% and 49% with non-squamous NSCLC. While these findings are promising, they remain hypothesis-generating due to the small sample size and exploratory nature of the analysis.

Ongoing phase III trials are essential to confirm the role of relatlimab in dual ICI therapy. Relatlimab may enhance antitumor response by restoring or preserving effector T-cell function. If validated, the combination of nivolumab, relatlimab, and platinum-doublet chemotherapy could become an effective first-line treatment for advanced NSCLC. However, further research is required to clarify relatlimab’s precise role in NSCLC immunotherapy.

The Emerging Role of TIGIT Inhibition in NSCLC Treatment: Insights from the GALAXIES Lung-201 Trial

Despite advances in immunotherapy for advanced non-small cell lung cancer (NSCLC), the question remains whether patients with high PD-L1 expression can achieve durable remission with immunotherapy alone. Anti-TIGIT therapies such as belrestotug, tiragolumab, and other investigational agents are being explored as potential complements to immune checkpoint inhibitors (ICIs) in NSCLC treatment.

The GALAXIES Lung-201 trial is a large, randomized, dose-ranging phase II study evaluating the efficacy of belrestotug (anti-TIGIT monoclonal antibody) combined with dostarlimab (anti-PD-1 monoclonal antibody) in treatment-naïve advanced NSCLC patients with PD-L1 expression ≥50%. Interim analysis demonstrated a significant improvement in the objective response rate (ORR) across all three dose levels of belrestotug in combination with dostarlimab compared to dostarlimab monotherapy. The study identified 400 mg belrestotug as the optimal dose, yielding a confirmed ORR of 59.4% in high PD-L1 expressors, along with substantial tumor burden reduction and a dose-dependent decline in circulating tumor DNA (ctDNA). Safety analysis indicated manageable toxicity, with immune-related adverse events primarily affecting the skin and subcutaneous tissues.

The PERLA trial conducted a head-to-head comparison of dostarlimab plus chemotherapy versus pembrolizumab plus chemotherapy. The results showed that dostarlimab was non-inferior to pembrolizumab, reinforcing its potential as a competitive PD-1 inhibitor with strong prospects for combination with TIGIT inhibitors in future clinical development.

Similarly, the CITYSCAPE trial assessed tiragolumab (anti-TIGIT) in combination with atezolizumab (anti-PD-L1). The study reported an ORR of 66% in patients with PD-L1 expression ≥50%, compared to 24% in patients receiving atezolizumab monotherapy.

While the CITYSCAPE trial highlighted the clinical benefit of TIGIT inhibition in improving PFS, the GALAXIES Lung-201 trial underscored dose optimization and the potential role of ctDNA as a predictive biomarker. Ongoing phase III trials, such as SKYSCRAPER, will be pivotal in defining the role of TIGIT blockade in response rates and overall survival (OS). These findings will help refine biomarker-driven treatment strategies, improving patient selection and personalizing therapeutic approaches.

As the most effective and safest TIGIT-based therapies are identified, the development of bispecific antibodies targeting both PD-(L)1 and TIGIT may offer a transformative approach to dual immune checkpoint blockade. PD-(L)1/TIGIT bispecific antibodies have the potential to overcome the limitations of current therapies and improve clinical outcomes for NSCLC patients.

Future Directions and Research Priorities

The GALAXIES Lung-201 and RELATIVITY-104 trials represent significant advancements in NSCLC treatment by incorporating TIGIT and LAG-3 inhibitors to enhance dual immune checkpoint blockade. These strategies go beyond conventional PD-1/PD-L1 inhibition, offering new hope for patients with advanced NSCLC.

While early findings on dual immune checkpoint blockade are promising, challenges remain in understanding the interplay between tumor histology, biomarker expression, and T-cell dynamics to optimize treatment strategies. Future research must focus on refining biomarker-driven patient selection, improving safety management, and enhancing the cost-effectiveness of dual immune checkpoint blockade. If these strategies prove successful, their clinical implementation must be carefully managed to ensure accessibility and maximize therapeutic benefit for NSCLC patients.