Innovative Strategies Target Immunotherapy Resistance in NSCLC

In a significant advance in the fight against non-small cell lung cancer (NSCLC), Dr. Hossein Borghaei, Chief of the Division of Thoracic Medical Oncology at Fox Chase Cancer Center, presented novel approaches aimed at overcoming resistance to immunotherapy during the 26th Annual International Lung Cancer Congress held from July 25 to July 27, 2025, in Huntington Beach, California. As NSCLC remains one of the leading causes of cancer-related deaths globally, addressing the persistent challenges posed by immunotherapy-refractory cases is critical.

Dr. Borghaei emphasized that despite the failure of numerous phase 3 clinical trials to surpass standard-of-care (SOC) treatments for patients who progressed after immunotherapy, new strategies such as JAK2 inhibitors, bispecific antibodies, and cancer vaccines hold promise for future treatment. “Based on small studies, we have a fairly consistent picture of the types of mechanisms of resistance that we can anticipate in patients who have disease progression with immunotherapy,” stated Dr. Borghaei, highlighting the multifaceted nature of resistance, which can be cancer cell dependent, immune related, or host related.

The Pragmatica-Lung (SWOG S2302) study evaluated the combination of ramucirumab (Cyramza) and pembrolizumab (Keytruda) against SOC treatments for patients with stage IV or recurrent NSCLC. The findings, which were presented during the 2025 ASCO Annual Meeting, indicated no significant survival advantage for the combination therapy compared to SOC (HR, 0.99; P = .46) (Dragnev et al., 2025). Dr. Borghaei expressed skepticism about the efficacy of this combination, suggesting that it might not be an optimal approach.

Conversely, data from the phase 3 HARMONi-A study (NCT05184712) showed that the novel PD-1/VEGF bispecific antibody ivonescimab, when combined with chemotherapy, improved progression-free survival (PFS) in nonsquamous NSCLC patients compared to placebo plus chemotherapy. The median PFS was 7.1 months for the combination arm versus 4.8 months for the placebo (HR, 0.46; P < .001) (Zhang et al., 2024). Dr. Borghaei remarked on the efficacy signals observed in this study, noting the potential for bispecific antibodies to enhance treatment outcomes in previously difficult-to-treat patient populations.

Further investigations into JAK inhibition combined with anti-PD-1 therapy have also yielded promising results. A phase 2 study (NCT03425006) demonstrated that patients with treatment-naive metastatic NSCLC and high tumor PD-L1 levels who received pembrolizumab alongside the selective JAK1 inhibitor itacitinib achieved a remarkable 62% overall response rate (Mathew et al., 2024).

In the realm of cancer vaccines, Dr. Borghaei discussed a phase 1 trial (NCT04911166) that explored the safety and efficacy of intratumoral adenovirus–IL-12 combined with atezolizumab in patients with metastatic NSCLC following immunotherapy progression. Results indicated a disease control rate of 50% and a median overall survival of 10.5 months, with no severe treatment-related adverse events reported (Ajmal et al., 2025).

Additionally, the therapeutic cancer vaccine OSE2101 is currently under evaluation in a phase 3 study (NCT06472245) comparing it to docetaxel for patients with secondary resistance to immunotherapy. The study is actively recruiting participants in North America and Europe, with an emphasis on overall survival as the primary endpoint (Liu et al., 2025).

Dr. Borghaei concluded his presentation by reiterating the potential of bispecific antibodies in combating immunotherapy resistance. “I believe something happens biologically when you engage multiple tumor antigens. Bispecifics could change the calculus, and as we learn how these drugs work, we may find new pathways to treatment success,” he stated.

The ongoing research into these innovative treatment modalities represents a crucial step forward in addressing the complex challenges of immunotherapy resistance in NSCLC. As these studies progress, they hold the potential to significantly enhance treatment options for patients and improve clinical outcomes in a field that has seen limited advancements in phase 3 trials against standard therapies.

**References:** 1. Dragnev KH, Redman MW, Reckamp KL, et al. PRAGMATICA-LUNG (SWOG S2302): a prospective, randomized study of ramucirumab plus pembrolizumab versus standard of care for participants previously treated with immunotherapy for stage IV or recurrent non-small cell lung cancer. *J Clin Oncol*. 2025;43(suppl 17):LBA8671. doi:10.1200/JCO.2025.43.17_suppl.LBA8671. 2. Zhang L, Feng W, Zhao Y, et al. Ivonescimab combined with chemotherapy in patients with EGFR-mutant non-squamous non-small cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor treatment (HARMONi-A): A randomized, double-blind, multi-center, phase 3 trial. *J Clin Oncol*. 2024;42(suppl 16):8508. doi:10.1200/JCO.2024.42.16_suppl.8508. 3. Mathew D, Marmarelis ME, Foley C, et al. Combined JAK inhibition and PD-1 immunotherapy for non-small cell lung cancer patients. *Science*. 2024;384(6702):eadf1329. doi:10.1126/science.adf1329. 4. Ajmal Z, Guan J, Joshi J, et al. A phase I trial of intratumoral adenovirus-interleukin-12 (IT-ADV/IL-12) and atezolizumab in metastatic non-small cell lung cancer (NSCLC) progressed on first-line immunotherapy. *J Clin Oncol*. 2025;43(suppl 16):8551. doi:10.1200/JCO.2025.43.16_suppl.8551. 5. Liu SV, Guilbert C, Tostivint EP, et al. Phase 3 trial of the therapeutic cancer vaccine OSE2101 versus docetaxel in patients with metastatic non-small cell lung cancer and secondary resistance to immunotherapy. *J Clin Oncol*. 2025;43(suppl 16):TPS8651. doi:10.1200/JCO.2025.43.16_suppl.TPS8651.