The landscape of non-small cell lung cancer (NSCLC) treatment continues to evolve beyond PD-1 inhibition, with researchers exploring novel combination approaches to enhance therapeutic outcomes. While PD-1/PD-L1 inhibitors remain the cornerstone of immunotherapy, emerging data suggests that additional targets and combination strategies may help overcome resistance and improve patient responses.
The Current State of PD-1 Inhibition
PD-1 inhibition has transformed NSCLC treatment over the past decade, with pembrolizumab establishing itself as the gold standard for patients with high PD-L1 expression. Long-term data from the KEYNOTE-024 trial demonstrated 5-year overall survival rates of 21.9% with pembrolizumab compared to 10.1% with chemotherapy in patients with PD-L1 expression ≥50%.
However, Dr. Melissa Johnson, director of lung cancer research at Sarah Cannon Research Institute, notes that significant challenges remain: "We're stuck firmly in the middle of asking 'what else can I add to PD-1 inhibition?' We need to identify which patients require more than PD-1 monotherapy and who might benefit from alternative approaches."
Emerging Combination Strategies
Anti-TIGIT Approaches
While initial trials with anti-TIGIT agents produced mixed results, recent data has renewed interest in this pathway. The GALAXIES Lung-201 study evaluating belrestotug plus dostarlimab showed promising response rates of 63-77% across different dose levels, significantly higher than dostarlimab alone (37.5%).
LAG3 Inhibition Shows Promise
The RELATIVITY-104 study demonstrated that adding relatlimab to nivolumab plus chemotherapy improved progression-free survival to 6.7 months compared to 6.0 months with nivolumab/chemotherapy alone. These encouraging results have led to the initiation of the phase 3 RELATIVITY-1093 trial.
Innovative Bispecific Antibodies
The bispecific antibody landscape has yielded particularly exciting results. Ivonescimab, targeting both PD-1 and VEGF pathways, demonstrated significant improvement in progression-free survival compared to pembrolizumab in the HARMONi-2 trial, with a median PFS of 11.14 months versus 5.82 months.
Other notable bispecific antibodies in development include:
- Rilvegostomig (PD-L1/TIGIT inhibitor)
- Volrustomig (PD-L1/CTLA-4 inhibitor)
Novel Combination Approaches
The field is witnessing increased interest in rational combinations that could provide synergistic benefits. The development of bispecific T-cell engagers and their potential combination with other novel agents, such as antibody-drug conjugates, represents a new frontier in NSCLC treatment.
Dr. Johnson emphasizes the importance of innovation in combination approaches: "This shows us how we might start to innovate in new ways. It requires breaking down barriers and figuring out how to work together in innovative ways."
Future Directions
As the field moves forward, key priorities include:
- Identifying predictive biomarkers for combination therapy
- Understanding resistance mechanisms to current immunotherapy
- Developing more effective combination strategies
- Optimizing patient selection for various therapeutic approaches
The evolution of NSCLC treatment beyond PD-1 inhibition represents a critical next step in improving outcomes for patients with advanced disease. While challenges remain, the emerging data from novel combination approaches provides hope for continued progress in this challenging disease.
