Immuno-oncology (IO) has revolutionized the treatment of non-small cell lung cancer (NSCLC), delivering durable responses and survival benefits across various disease stages. Immune checkpoint inhibitors (ICIs), including PD-(L)1 and CTLA-4 inhibitors, have paved the way for the development of dual immune checkpoint blockade (ICB) to enhance antitumor immunity.
While trials such as KEYNOTE-024 and KEYNOTE-189 demonstrated significant benefits, they also highlighted a need for strategies to overcome resistance and improve 5-year overall survival (OS) rates, particularly in PD-1-resistant tumors.
Emerging biomarkers, such as LAG-3 (Lymphocyte-activation gene 3) and TIGIT (T cell immunoreceptor with Ig and ITIM domains), offer promising targets for advancing IO therapy. LAG-3, often co-expressed with PD-L1, suppresses T-cell activity through major histocompatibility complex (MHC) class II interaction. In contrast, TIGIT, which is upregulated on T-cells and natural killer cells, drives immune evasion and is associated with poor prognosis.
These biomarkers hold the potential to refine patient selection and enhance the efficacy of IO treatments; however, further evidence is needed to validate their clinical utility.
Evaluating the Efficacy of LAG-3 Inhibition in Advanced NSCLC: Insights from the RELATIVITY-104 Trial
The RELATIVITY-104 trial (NCT04623775) is the first randomized phase II study designed to evaluate the addition of relatlimab, a LAG-3-blocking antibody, to nivolumab and platinum-doublet chemotherapy (PDCT) as first-line treatment for stage IV or recurrent NSCLC.
Building on the success of RELATIVITY-047 in melanoma, this study investigated the broader potential of LAG-3 inhibition.1 However, the trial’s results require careful interpretation, particularly concerning efficacy signals and subgroup benefits.2,3
The study enrolled 309 patients who were randomized in a 1:1 ratio to receive either a combination of nivolumab with relatlimab and platinum doublet chemotherapy or nivolumab with platinum doublet chemotherapy alone. The primary objective endpoint was response rate. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and PFS stratified by PD-L1 expression. The safety profile of the nivolumab and relatlimab combination was consistent with expectations; there was no significant increase in adverse events compared to the nivolumab and PDCT arm.
The challenges in interpreting the results stem from several perspectives. The primary endpoint demonstrated a response rate of 51% in the experimental arm compared to nearly 44% in the control arm. The median PFS was 6.7 months for combination therapy with relatlimab, versus 6 months with nivolumab plus chemotherapy (hazard ratio [HR]: 0.88; 90% confidence interval [CI]: 0.71–1.1). These results suggest that combination therapy with relatlimab does not benefit the all-comer population.
However, subgroup analyses revealed a positive test for interaction (0.023) for PFS but not for ORR based on PD-L1 expression. This suggests that most of the benefit is associated with PD-L1 positivity.
There is no difference in PFS between squamous and nonsquamous histology (interaction test result: 0.023). Additionally, a crossover in the Kaplan-Meier curves at 12 months raises concerns regarding the durability of the benefit.
The exploratory analyses of RELATIVITY-104 aimed to identify populations that might preferentially benefit from the addition of relatlimab. Two subgroups with potential benefits were identified: patients with PD-L1 expression greater than 1% and non-squamous (NSQ) histology, and patients with PD-L1 expression between 1% and 49% with NSQ histology.
While promising, these findings are limited by small sample sizes and their exploratory nature, rendering them hypothesis-generating rather than definitive.
The ongoing phase III trial will be critical in determining the efficacy of relatlimab as part of a dual ICI strategy. Relatlimab may enhance antitumor responses by restoring or preserving the function of effector T-cells.
If validated, the combination of relatlimab, nivolumab, and platinum doublet chemotherapy could establish itself as an effective first-line treatment for advanced NSCLC. Until then, these findings underscore the need for further research to clarify relatlimab’s role in advancing immunotherapy for NSCLC.
Emerging Role of TIGIT Inhibition in NSCLC: Insights from the GALAXIES Lung-201 Trial
Despite advancements in immunotherapy for NSCLC, durable responses in patients with high PD-L1 expression remains elusive. Anti-TIGIT therapies, such as belrestotug, tiragolumab, and many others in pharmaceutical company pipelines, are emerging as promising complements to ICIs.
The GALAXIES Lung-201 trial, a large randomized, dose-ranging phase II study, evaluated the combination of belrestotug (anti-TIGIT) and dostarlimab (anti-PD-1) in treatment-naïve patients with advanced NSCLC whose tumors had PD-L1 expression of at least 50%.
The interim analysis revealed a significant improvement in ORR across all combination cohorts compared to dostarlimab monotherapy.4 The trial identified 400 mg of belrestotug as the optimal dose; this yielded a robust ORR of 69% in patients with high PD-L1 expression, along with notable reductions in tumor burden and a dose-dependent decrease in circulating tumor DNA (ctDNA).
The safety analysis highlighted manageable toxicities, with immune-mediated adverse events primarily affecting the skin and subcutaneous tissue.
Dostarlimab demonstrated non-inferior efficacy compared to pembrolizumab in the PERLA trial, further supporting its potential as a competitive PD-1 inhibitor for combination with TIGIT therapies.5 Similarly, the CITYSCAPE trial, which evaluated tiragolumab (anti-TIGIT) in combination with atezolizumab (anti-PD-L1), reported an ORR of 66% versus 24% for atezolizumab alone in patients with PD-L1 expression of at least 50%.6
While CITYSCAPE underscored the clinical benefits of TIGIT inhibition in improving PFS, GALAXIES emphasized dose optimization and the role of ctDNA as a biomarker for biological synergy.
Upcoming data from phase III trials, such as SKYSCRAPER, are critical for defining the role of TIGIT therapies with respect to both response rates and OS.7 These findings will guide biomarker-driven strategies to optimize patient selection and tailor treatment regimens.
Furthermore, as we identify the safest and most effective TIGIT-based therapies, the development of bispecific antibodies targeting both PD-(L)1 and TGIT may offer a transformative approach to dual immune checkpoint blockade. This strategy could have the potential to overcome the limitations of current therapies and improve clinical outcomes for patients with NSCLC.
Future Directions and Research Priorities
The GALAXIES Lung-201 and RELATIVITY-104 trials highlight innovative advancements in the treatment of NSCLC by introducing dual checkpoint strategies that target TIGIT and LAG-3. These approaches go beyond traditional PD-1/PD-L1 inhibitors, providing new hope for patients with advanced NSCLC.
While the early results are encouraging, some challenges remain in understanding the interplay among histology, biomarker expression, and T-cell dynamics in refining treatment strategies.
Further research is essential to optimize biomarker-driven patient selection, improve safety management, and enhance the cost-effectiveness of these therapies. As these treatments evolve, their integration into NSCLC care will require a nuanced approach to ensure broader accessibility and greater clinical impact.
References:
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