Combination Strategies of Immunotherapy in Non-Small Cell Lung Cancer: Facts and Challenges
Introduction
Lung cancer remains the most commonly diagnosed cancer and the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 80% of cases. Over the past decade, 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 NSCLC. Agents such as pembrolizumab, nivolumab, atezolizumab, and durvalumab have received FDA approval for various stages of NSCLC, demonstrating significant clinical benefits. However, despite these advancements, challenges such as acquired resistance and suboptimal response rates persist, prompting the exploration of combination strategies to enhance treatment efficacy and safety.
Immunotherapy Combined with Other Treatments
Efficacy of ICIs When Combined with Chemotherapy
Chemotherapy has been shown to augment the immunologic effects of ICIs through mechanisms such as immunogenic cell death, which releases tumor-associated antigens and danger-associated molecular patterns, thereby enhancing T-cell infiltration and downregulating immunosuppressive cells. Clinical trials have demonstrated the efficacy of combining ICIs with platinum-based chemotherapy. For instance, the KEYNOTE-021 trial showed that pembrolizumab combined with carboplatin-pemetrexed significantly improved objective response rate (ORR) and progression-free survival (PFS) compared to chemotherapy alone. Similarly, the KEYNOTE-189 trial validated these findings, with pembrolizumab plus chemotherapy demonstrating prolonged overall survival (OS) in untreated metastatic non-squamous NSCLC patients. The IMpower130 trial also highlighted the benefits of atezolizumab combined with chemotherapy, showing improved OS and PFS in non-squamous NSCLC patients, except in subgroups with liver metastases or EGFR/ALK mutations.
Efficacy of ICI Combinations
Combining different ICIs has also been explored to enhance treatment outcomes. The CheckMate 012 trial demonstrated that nivolumab plus ipilimumab improved outcomes, particularly in patients with positive PD-L1 expression. The CheckMate 227 trial further supported this combination, showing improved OS in patients with PD-L1 expression ≥1%. However, the KEYNOTE-598 trial found that adding ipilimumab to pembrolizumab did not improve efficacy in patients with PD-L1 tumor proportion score ≥50% and was associated with greater toxicity. Similarly, the MYSTIC trial, which evaluated durvalumab with or without tremelimumab, did not meet its primary endpoints, raising questions about the optimal combination strategies.
Efficacy of ICIs When Combined with Anti-Angiogenics
Anti-angiogenic agents, such as bevacizumab, have immunomodulatory effects that enhance T-cell infiltration and dendritic cell maturation. The IMpower150 trial demonstrated that atezolizumab plus bevacizumab and chemotherapy (ABCP) improved PFS and OS in chemotherapy-naïve non-squamous NSCLC patients, including those with EGFR mutations. Ongoing trials, such as LEAP-006 and WJOG11218L/APPLE, are further exploring the combination of ICIs with anti-angiogenics and chemotherapy.
Efficacy of ICIs Combined with TKIs
For NSCLC patients with EGFR or ALK alterations, tyrosine kinase inhibitors (TKIs) remain the standard treatment. However, combining ICIs with TKIs has shown mixed results. The KEYNOTE-021 trial reported improved PFS with pembrolizumab plus TKIs, but the TATTON study was terminated due to high rates of interstitial pneumonia. Similarly, the CheckMate 370 trial observed severe hepatic toxicities with nivolumab plus crizotinib. These findings suggest that the combination of ICIs and TKIs may be associated with significant toxicities, warranting further investigation.
Efficacy of ICIs Combined with Radiotherapy
Radiotherapy can enhance the immunogenicity of tumors by promoting the release of pro-inflammatory mediators and increasing T-cell infiltration. The PACIFIC trial demonstrated that durvalumab as a consolidation therapy after chemoradiotherapy significantly improved OS and PFS in patients with unresectable stage III NSCLC. The KEYNOTE-799 trial also showed promising anti-tumor activity with pembrolizumab plus chemoradiotherapy in stage III NSCLC patients.
Efficacy of ICIs When Combined with Other Agents
Emerging compounds targeting co-stimulatory/inhibitory receptors are being explored in combination with ICIs. For example, TIM-3 inhibitors, IDO inhibitors, and OX40 agonists are being tested in clinical trials to overcome resistance to PD-1/PD-L1 inhibitors. Additionally, chimeric antigen receptor (CAR)-T-cell therapy and histone deacetylase inhibitors are being investigated for their potential to enhance the efficacy of ICIs.
Comments and Future Challenges
Patient Selection
PD-L1 expression remains the primary biomarker for ICI therapy, but its predictive value is limited. Tumor mutational burden (TMB) and neoantigens have emerged as potential biomarkers, with high TMB levels associated with improved outcomes in some trials. However, challenges such as sample adequacy and cost limit the widespread application of TMB testing. Tumor-infiltrating lymphocytes (TILs) and genomic features, such as microsatellite instability and STK11/LKB1 mutations, are also being explored as predictive biomarkers. The gut microbiome has shown promise in influencing immunotherapy outcomes, but further research is needed to validate its role in NSCLC.
Treatment of Special Populations
Patients with EGFR/ALK alterations generally do not benefit from ICIs, but the IMpower150 trial suggested that anti-angiogenic agents may enhance the efficacy of ICIs in this population. Elderly patients and those with liver metastases present unique challenges, with some studies showing comparable benefits in older patients and improved outcomes with anti-angiogenics in patients with liver metastases.
Treatment-Related Adverse Events
Immune-related adverse events (irAEs) are a significant concern with ICI therapy, with checkpoint inhibitor-associated pneumonitis (CIP) being a particularly severe complication. Combination strategies may increase the risk of irAEs, necessitating careful monitoring and management.
Selection of the Optimal Combination Strategy
The choice of combination therapy depends on factors such as efficacy, toxicity, and cost. Ongoing research aims to identify the most effective and tolerable combination strategies, with a focus on optimizing drug selection, dosage, and sequencing.
Future Challenges
The future of NSCLC treatment lies in the development of more effective and precise immunotherapy combinations. Key challenges include improving treatment efficiency, enhancing precision medicine, prolonging therapeutic benefits, and ensuring the safety of immunotherapy. The integration of novel immunomodulatory agents, such as CAR-T-cell therapy, and the exploration of comprehensive predictive models will be critical in advancing the field.
In conclusion, combination immunotherapy represents a promising approach to improving outcomes in NSCLC patients. However, significant challenges remain, and ongoing research is essential to optimize treatment strategies and overcome barriers to efficacy and safety.
doi.org/10.1097/CM9.0000000000001610
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