Current and Future PD-1/PD-L1 Combination Therapies for Non-Small Cell Lung Cancer
Lung cancer is the leading cause of cancer death worldwide, responsible for more than 1.8 million deaths annually. Non-small cell lung cancer (NSCLC)—which includes adenocarcinoma and squamous cell carcinoma—makes up 85% of cases. For decades, chemotherapy was the main treatment for advanced NSCLC, but in the 2010s, immune checkpoint inhibitors (ICIs) targeting programmed death-1 (PD-1) or its ligand (PD-L1) revolutionized care. These drugs “unlock” the immune system to recognize and attack cancer cells, but they have limits: only a subset of patients benefit, and some experience rapid tumor growth (called hyperprogressive disease). To expand access to immunotherapy and improve outcomes, researchers are testing combination therapies that pair PD-1/PD-L1 inhibitors with other treatments. A 2021 review by Ying Cheng and colleagues from Jilin Cancer Hospital in China summarizes the latest progress in these strategies, offering hope for more effective NSCLC care.
Current Combination Strategies for Advanced NSCLC
The goal of combination therapy is to enhance the immune system’s ability to fight cancer while overcoming the limitations of single-agent ICIs. Below are the most studied and approved approaches:
1. PD-1/PD-L1 Inhibitors + Chemotherapy
Chemotherapy kills cancer cells directly, but it also primes the immune system: it reduces suppressive immune cells (like T-regulatory cells and myeloid-derived suppressor cells) and activates antigen-presenting cells (which help T cells recognize cancer). For non-squamous NSCLC (the most common type), the KEYNOTE-021G trial (phase II) showed that pembrolizumab (a PD-1 inhibitor) plus pemetrexed and carboplatin doubled the objective response rate (ORR: 56.7% vs. 30.2%) and extended progression-free survival (PFS: 13 vs. 8.3 months) compared to chemotherapy alone. The larger KEYNOTE-189 trial (phase III) confirmed these benefits: 3-year overall survival (OS) was 31.3% with combination therapy vs. 17.4% with chemotherapy. The FDA approved this regimen as first-line treatment for non-squamous NSCLC—regardless of PD-L1 levels.
For squamous NSCLC, the KEYNOTE-407 trial found that pembrolizumab plus paclitaxel/carboplatin improved OS (15.9 vs. 11.3 months) and ORR (58.4% vs. 35%). This combination is now standard for squamous NSCLC.
2. PD-1/PD-L1 Inhibitors + Anti-Angiogenic Therapy
Tumors grow new blood vessels (angiogenesis) to get nutrients. Anti-angiogenic drugs like bevacizumab (a monoclonal antibody that blocks VEGF, a protein driving blood vessel growth) normalize these vessels, helping immune cells reach the tumor. The IMpower150 trial tested atezolizumab (a PD-L1 inhibitor) plus bevacizumab, paclitaxel, and carboplatin in non-squamous NSCLC. The combination extended OS to 19.2 months vs. 14.7 months with chemotherapy/bevacizumab alone. Even patients with liver metastases or EGFR mutations (who usually don’t respond to ICIs) benefited.
Smaller trials of small-molecule anti-angiogenics (like lenvatinib or anlotinib) plus ICIs show promise: a phase Ib study of sintilimab plus anlotinib reported a 72.7% ORR and 15-month PFS in first-line NSCLC. These combinations need more data but could become future options.
3. Dual Immune Checkpoint Blockade (PD-1 + CTLA-4)
PD-1/PD-L1 and CTLA-4 are two checkpoints that cancer uses to hide from the immune system. PD-1 blocks active T cells from attacking cancer; CTLA-4 stops T cells from activating in the first place. Blocking both has synergistic effects. The CheckMate 227 trial (phase III) was the first to show success: nivolumab (PD-1) plus ipilimumab (CTLA-4) improved OS (17.1 vs. 14.9 months) in patients with PD-L1 ≥1%. However, some patients had early progression, so the CheckMate 9LA trial added two cycles of chemotherapy to the dual blockade. This boosted OS to 15.6 months vs. 10.9 months with chemotherapy alone—leading to FDA approval. While effective, dual therapy has more side effects (33% grade 3+ adverse events vs. 27% with chemotherapy), so doctors weigh risks carefully.
4. PD-1/PD-L1 Inhibitors + Targeted Therapies
For NSCLCs with driver mutations (like EGFR or ALK), targeted therapies (e.g., erlotinib, crizotinib) are standard. But combining them with ICIs has been risky: early trials showed severe toxicities. The TATTON trial of osimertinib (EGFR inhibitor) plus durvalumab (PD-L1) had a 64% rate of interstitial lung disease in treatment-naive patients—leading to trial termination. While some combinations (like alectinib plus atezolizumab) show high ORRs (81%), the toxicities make them less feasible for now.
Combination Strategies for Unresectable Locally Advanced NSCLC
Locally advanced NSCLC (stage III) is too big to remove surgically but hasn’t spread to distant organs. Radiotherapy plus chemotherapy (chemoradiotherapy) was standard, but ICIs have improved outcomes:
- The PACIFIC trial (phase III) found that durvalumab (PD-L1) given after chemoradiotherapy doubled PFS (17.2 vs. 5.6 months) and quadrupled 4-year OS (47.5% vs. 29.1%). This is now the standard of care.
- The KEYNOTE-799 trial (phase II) is testing simultaneous chemoradiotherapy and pembrolizumab. Early results show high ORRs (69.6–70.5%) with manageable lung toxicity (8% grade 3+ pneumonia).
Early-Stage NSCLC: Neoadjuvant Combination Therapy
Immunotherapy is moving to early-stage disease, where neoadjuvant (pre-surgery) treatment can shrink tumors and improve surgical outcomes. Key trials:
- NEOSTAR: Nivolumab plus ipilimumab led to a 43% major pathological response (MPR)—meaning ≥90% of tumor cells were dead after treatment—vs. 20% with nivolumab alone.
- NADIM: Nivolumab plus chemotherapy led to an 83% MPR and 63% complete pathological response (pCR) (no live tumor cells) in stage IIIA NSCLC.
These results suggest combination neoadjuvant therapy could become standard, especially after the CheckMate 816 trial (first phase III neoadjuvant ICI combination to show superior pCR).
Future Directions: Novel Targets and Personalization
The next frontier in NSCLC immunotherapy is novel immune targets and personalized treatment based on tumor biology:
1. Novel Immune Targets
- TIGIT: A receptor that suppresses T and NK cells. The CITYSCAPE trial found that tiragolumab (anti-TIGIT) plus atezolizumab improved ORR (31.3% vs. 16.2%) and PFS (5.4 vs. 3.6 months) in PD-L1+ NSCLC.
- Bispecific Antibodies: Drugs that target two antigens at once. M7824 (which targets PD-L1 and TGF-β, a protein that suppresses immunity) showed a 27.5% ORR in second-line NSCLC in phase I trials.
2. Personalized Therapy Based on Tumor Immune Phenotypes
Tumors have different immune “signatures” that predict response to immunotherapy:
- Hot: Lots of immune cells—respond well to ICIs.
- Cold: Few immune cells—need therapies to “heat up” the tumor (e.g., chemotherapy, vaccines).
- Excluded: Immune cells can’t get in—anti-angiogenics or TGF-β inhibitors can help.
By matching treatment to a tumor’s phenotype, doctors can deliver more effective, less toxic care.
Conclusion
PD-1/PD-L1 combination therapies have transformed NSCLC treatment, expanding benefits to more patients and improving survival. From chemotherapy to dual checkpoints, these strategies are now standard for advanced, locally advanced, and early-stage disease. The future lies in novel targets (like TIGIT) and personalized therapy—tailoring treatment to a patient’s tumor biology. As Cheng and colleagues note, these advances could one day make immunotherapy accessible to all NSCLC patients—regardless of their tumor’s characteristics.
doi.org/10.1097/CM9.0000000000001560
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