Current and Future Drug Combination Strategies Based on Programmed Death-1/Programmed Death-Ligand 1 Inhibitors in Non-Small Cell Lung Cancer
Lung cancer remains the leading cause of cancer-related morbidity and mortality worldwide. In recent years, immune checkpoint inhibitors (ICIs), particularly those targeting the programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) pathways, have revolutionized the treatment landscape of non-small cell lung cancer (NSCLC). While PD-1/PD-L1 inhibitor monotherapy initially broke the treatment pattern for NSCLC, its benefits at the population level are limited, and it is associated with a hyper-progressive phenomenon in some patients. To expand the therapeutic efficacy and broaden the population benefiting from immunotherapy, combination strategies involving PD-1/PD-L1 inhibitors have emerged as a focal point of research. This article provides a comprehensive review of current and future drug combination strategies based on PD-1/PD-L1 inhibitors in NSCLC.
Introduction
The advent of PD-1/PD-L1 inhibitors marked a significant breakthrough in lung cancer treatment. Initially used as second-line therapies, these inhibitors have now been upgraded to first-line treatments for advanced and unresectable locally advanced NSCLC. Immunotherapy is also moving toward neoadjuvant and adjuvant treatments for early-stage NSCLC. However, the population benefiting from single-agent ICI therapy is limited, and some patients experience hyper-progressive disease. To address these challenges, combination immunotherapy strategies have been developed, including ICIs combined with chemotherapy, anti-angiogenic therapy, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, radiotherapy, and novel target drugs. These strategies aim to improve treatment efficacy and expand the population benefiting from immunotherapy, particularly for patients without driver gene mutations.
Current Status of Combined Immunotherapy Strategies for NSCLC
Combination Therapies for Advanced NSCLC
ICIs in Combination with Chemotherapy
Platinum-based doublet chemotherapy was the standard first-line treatment for advanced NSCLC without driver oncogene mutations before the introduction of ICIs. Combining ICIs with chemotherapy has become one of the earliest and most commonly used strategies. Studies have shown that chemotherapy positively affects the tumor immune microenvironment by reducing T-regulatory cell (Tregs) activity, depleting myeloid-derived suppressor cells (MDSCs), and inducing antigen-presenting cell maturation. These mechanisms enhance the antitumor activity of ICIs.
The phase II KEYNOTE-021 cohort G study evaluated pembrolizumab combined with pemetrexed plus carboplatin versus pemetrexed plus carboplatin as a first-line treatment in patients with advanced non-squamous NSCLC without EGFR and ALK mutations. The results demonstrated significant improvements in objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in the ICI plus chemotherapy group, regardless of PD-L1 expression levels. Based on these findings, the FDA accelerated the approval of pembrolizumab in combination with pemetrexed plus carboplatin as a first-line treatment for non-squamous NSCLC. The KEYNOTE-189 study further confirmed that pembrolizumab combined with chemotherapy significantly prolonged OS and PFS compared to chemotherapy alone in patients with metastatic NSCLC, with a 3-year OS rate of 31.3% versus 17.4%.
Similarly, the IMpower130 study showed that atezolizumab combined with carboplatin and nab-paclitaxel significantly improved OS and PFS compared to chemotherapy alone. However, the IMpower132 study only reached the co-primary endpoint for PFS but not OS when atezolizumab was combined with pemetrexed and cisplatin or carboplatin.
In squamous NSCLC, the KEYNOTE-407 study demonstrated that pembrolizumab combined with paclitaxel or albumin-bound paclitaxel and carboplatin significantly improved PFS and OS in patients with advanced squamous NSCLC. The FDA approved this combination as a first-line treatment for metastatic squamous NSCLC based on these results, with a 3-year OS rate of 29.7% versus 18.2%. However, the IMpower131 study only reached the PFS endpoint without OS benefit, possibly due to differences in subsequent treatment rates between the groups.
Several phase III studies evaluating Chinese-developed PD-1 inhibitors, such as camrelizumab, sintilimab, and tislelizumab, have also reported improved PFS and good tolerance when combined with chemotherapy. These findings suggest that ICIs combined with chemotherapy are applicable to patients with advanced NSCLC without driver gene mutations, regardless of PD-L1 expression or histological type, making this combination a standard first-line treatment for advanced NSCLC.
ICIs in Combination with Anti-Angiogenic Agents and Chemotherapy
Tumor angiogenesis is a hallmark of cancer, and anti-angiogenic agents can normalize tumor blood vessels, increase immune cell infiltration, and enhance the killing activity of immune effector cells. The IMpower150 study was the first phase III trial to evaluate atezolizumab combined with bevacizumab, paclitaxel, and carboplatin (ABCP) versus bevacizumab combined with paclitaxel and carboplatin (BCP) in non-squamous NSCLC. The ABCP group showed significantly prolonged OS (19.2 months vs. 14.7 months) compared to the BCP group, leading to FDA approval of this combination for first-line treatment of advanced non-squamous NSCLC without EGFR or ALK mutations. Patients with liver metastasis, large tumor size, and KRAS mutations were more likely to benefit from this combination.
The LEAP-006 study evaluated lenvatinib combined with pembrolizumab plus pemetrexed and carboplatin in advanced NSCLC, showing an ORR of 69.2% and manageable safety. Another phase Ib study of sintilimab combined with anlotinib reported an ORR of 72.7% and a median PFS of 15 months, suggesting that ICIs combined with small-molecule anti-angiogenesis drugs may be a promising strategy.
Double-Immune Checkpoint Blockades
Combining PD-1/PD-L1 inhibitors with CTLA-4 inhibitors can enhance T-cell activity against tumors through complementary mechanisms. The CheckMate 227 study was the first phase III trial to evaluate nivolumab combined with ipilimumab versus chemotherapy in advanced NSCLC. The dual immunotherapy significantly improved PFS and OS in patients with high tumor mutational burden and PD-L1 expression ≥1%, leading to FDA approval of this combination as a first-line treatment for advanced NSCLC without EGFR and ALK mutations. However, the MYSTIC study did not show improved OS or PFS with durvalumab plus tremelimumab compared to chemotherapy.
The CheckMate 9LA study addressed the issue of early disease progression in dual immunotherapy by adding two cycles of platinum-based chemotherapy to nivolumab and ipilimumab. This combination significantly improved OS (15.6 months vs. 10.9 months) and was also approved by the FDA. Although dual immunotherapy combined with chemotherapy increased toxicity, it was generally manageable.
ICIs in Combination with Targeted Therapies
Targeted therapies using EGFR-TKI and ALK-TKI are standard treatments for NSCLC with EGFR mutations or ALK rearrangements. However, combining ICIs with targeted therapies has shown mixed results. The CheckMate 012 trial reported an ORR of 19% with nivolumab plus erlotinib but a high incidence of grade 3–4 adverse events (AEs). The TATTON trial evaluated durvalumab plus osimertinib but was terminated due to a high risk of interstitial lung disease. Similarly, combining ICIs with ALK inhibitors has shown efficacy but also significant toxicity, making this strategy less feasible for patients with EGFR and ALK mutations.
Combination Immunotherapy Strategies for Unresectable Locally Advanced NSCLC
Radiotherapy plays a crucial role in unresectable locally advanced NSCLC, and combining ICIs with radiotherapy can enhance antitumor immunity. The PACIFIC study was the first phase III trial to show that durvalumab consolidation therapy after concurrent chemoradiotherapy significantly improved PFS (17.2 months vs. 5.6 months) and OS (47.5 months vs. 29.1 months) in patients with unresectable locally advanced NSCLC, establishing this combination as a standard treatment.
The KEYNOTE 799 study evaluated pembrolizumab combined with concurrent radiotherapy and chemotherapy, showing an ORR of 69.6% and 70.5% in two cohorts with manageable toxicity, including a low incidence of grade ≥3 pneumonia (8.0% and 7.9%). This suggests that simultaneous use of ICIs with radiochemotherapy may further improve treatment efficacy.
Combination Immunotherapy Strategies for Early-Stage NSCLC
Immunotherapy is also being explored in early-stage NSCLC. The CheckMate 159 study was a milestone in neoadjuvant immunotherapy, showing that nivolumab achieved a major pathological response (MPR) in 45% of patients with resectable NSCLC. The NEOSTAR study evaluated nivolumab alone or combined with ipilimumab, showing an MPR of 20% and 43%, respectively, suggesting that dual immunotherapy may be more effective.
The NADIM study evaluated nivolumab combined with paclitaxel and carboplatin in stage IIIA NSCLC, achieving an MPR of 83% and a pathological complete response (pCR) of 63%, with a 24-month PFS of 77.1%. These results indicate that ICIs combined with chemotherapy may be a promising neoadjuvant strategy for early-stage NSCLC.
Future of Combined Immunotherapy Strategies
ICIs Combined with Novel Immune Target Drugs
New immune target drugs, including those targeting co-inhibitory receptors, co-stimulatory molecular receptors, and immunosuppressive cells, are emerging as promising strategies. The phase II CITYSCAPE study evaluated tiragolumab (a TIGIT inhibitor) combined with atezolizumab, showing an ORR of 31.3% and a PFS of 5.4 months compared to 16.2% and 3.6 months with atezolizumab alone, suggesting that this combination may enhance antitumor activity with manageable toxicity.
Bispecific antibodies, such as M7824, which targets PD-L1 and transforming growth factor-beta (TGF-β), have shown promising antitumor activity in early clinical studies. M7824 achieved an ORR of 27.5% and a median OS of 17.1 months in second-line NSCLC treatment, and ongoing studies are evaluating its efficacy in unresectable locally advanced and first-line NSCLC.
Precisely Combined Immunotherapy Based on Cancer Immune Phenotypes
The tumor microenvironment can be classified into three main phenotypes: immune-desert, immune-excluded, and inflamed. Each phenotype is associated with specific biological mechanisms that may prevent effective antitumor immunity. Future strategies aim to adopt precise and individualized immune combination therapies based on these phenotypes. For immune-desert tumors, strategies may include chemotherapy, radiotherapy, DNA repair-based therapies, and cancer vaccines to transform cold tumors into hot tumors. For immune-excluded tumors, ICIs combined with anti-angiogenesis drugs, epigenetic regulators, and TGF-β inhibitors may be effective. For inflamed tumors, ICIs combined with immunosuppressive receptor inhibitors or co-stimulatory receptor agonists may further enhance antitumor immunity.
Conclusion
ICI combination therapies have significantly advanced the treatment of NSCLC, offering new hope for patients with advanced, unresectable locally advanced, and early-stage disease. Current strategies, including ICIs combined with chemotherapy, anti-angiogenic agents, dual immunotherapy, and targeted therapies, have become standard treatments for advanced NSCLC. In unresectable locally advanced NSCLC, ICIs consolidation therapy after concurrent chemoradiotherapy has established a new standard of care. In early-stage NSCLC, neoadjuvant immunotherapy combined with chemotherapy shows promising efficacy and safety. Emerging strategies, such as ICIs combined with novel immune target drugs and precise immunotherapy based on cancer immune phenotypes, hold great potential for further improving outcomes in NSCLC. As research continues, these combination strategies will likely play an increasingly important role in the fight against lung cancer.
doi.org/10.1097/CM9.0000000000001560
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