Novel Approaches Offer the Potential to Combat Immunotherapy–Refractory NSCLC

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Although multiple phase 3 clinical trials have been unable to improve upon standard-of-care (SOC) treatments for patients with non–small cell lung cancer (NSCLC) who experienced disease progression on or after immunotherapy, novel approaches such as JAK2 inhibitors, bispecific antibodies, and cancer vaccines could provide novel approaches in the future, according to Hossein Borghaei, DO, MS.1

“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],” Borghaei said in a presentation during the 26th Annual International Lung Cancer Congress. “[The mechanisms] can be cancer cell dependent, immune related, [and/or] host related.”

Borghaei is the chief of the Division of Thoracic Medical Oncology, the codirector of the Immune Monitoring Facility, the Gloria and Edmund M. Dunn Chair in Thoracic Oncology, and a professor in the Department of Hematology/Oncology at Fox Chase Cancer Center in Philadelphia, Pennsylvania.

Strategies to Overcome Immunotherapy Resistance

Borghaei began his presentation by highlighting data from the prospective phase 3 Pragmatica-Lung (SWOG S2302) study (NCT05633602). Pragmatica-Lung examined ramucirumab (Cyramza) in combination with pembrolizumab (Keytruda) vs SOC for the treatment of patients with stage IV or recurrent NSCLC who previously received immunotherapy.2

Findings from PRAGMATICA-LUNG presented during the 2025 ASCO Annual Meeting showed that patients who received the combination (n = 419) did not achieve a significant benefit in terms of overall survival (OS) compared with those in the SOC arm (n = 419; HR, 0.99; 95% CI, 0.81-1.22; P = .46). “The OS in this study wasn’t that much better in the [investigational arm] vs SOC chemotherapy; perhaps this isn’t a [good approach],” Borghaei commented.

He noted that there have been some encouraging efficacy signals using bispecific antibodies. Data from the phase 3 HARMONi-A study (NCT05184712) demonstrated that the novel PD-1/VEGF bispecific antibody ivonescimab plus chemotherapy improved progression-free survival (PFS) compared with placebo plus chemotherapy in patients with nonsquamous NSCLC.3 The median PFS in the combination arm (n = 161) was 7.1 months (95% CI, 5.9-8.7) vs 4.8 months (95% CI, 4.2-5.6) in the placebo arm (n = 161; HR, 0.46; 95% CI, 0.34-0.62; P < .001). The 9-month PFS rates were 37.9% and 18.3%, respectively. Notably, the study met its primary end point of PFS per independent radiologic review committee.

“[These data] come from a slightly different patient population: patients with EGFR-positive disease,” Borghaei said. “[However], the [efficacy] signal is strong. In a tumor which we usually think of as being ‘cold’ and molecularly driven, we are seeing a clinical benefit with the addition of a bispecific, [but] we need additional studies.”

Borghaei then discussed data from a phase 2 study (NCT03425006) of combined JAK inhibition and anti–PD-1 therapy in NSCLC.4 Findings from the trial showed that patients with treatment-naive metastatic NSCLC with tumor PD-L1 levels of at least 50% who received pembrolizumab in combination with the selective JAK1 inhibitor itacitinib (n = 21) achieved a 12-week overall response rate of 62%. At a median follow-up of 27.6 months, the median PFS was 23.8 months (95% CI, 4.9-not applicable), and the median duration of response was not reached.

“[These data show] that if you time the administration of the JAK inhibitor [after] priming the immune system with the checkpoint inhibitor…you can have a clinical benefit,” Borghaei commented.

In terms of cancer vaccines, the new generation of agents are more interesting compared with those of the previous generation, which largely did not produce positive data, Borghaei said. Findings from a phase 1 trial (NCT04911166) showed that intratumoral adenovirus–IL-12 in combination with atezolizumab (Tecentriq) was safe and showed a promising clinical benefit in patients with metastatic NSCLC following disease progression.5

At a median follow-up of 22 months, patients who received the combination (n = 12) achieved a disease control rate of 50% and a median PFS of 2 months. The median OS was 10.5 months. There were no instances of grade 4 or 5 adverse effects (AEs) or treatment discontinuation due to treatment-related AEs.

Additionally, the therapeutic cancer vaccine OSE2101 is being compared with docetaxel for the treatment of patients with metastatic NSCLC with secondary resistance to immunotherapy in a phase 3 study (NCT06472245).6 The primary end point of the study is OS. The trial is presently recruiting patients in North America and Europe.

“These are going to be important studies for us to pay attention to because they could offer a potential step forward,” Borghaei said.

Borghaei concluded his presentation by further discussing the potential role of bispecific antibodies in overcoming resistance to immunotherapy in patients with NSCLC. “I believe something happens biologically when you engage [multiple] tumor antigens. Bispecifics could change the calculus. What we have now might be an incremental improvement [vs the SOC], but as we learn how these drugs work and [we learn to target] the right antigens, it’s possible that this is going to be the way forward.”

Findings from a phase 1a/1b study (NCT05460767) demonstrated that treatment with the first-in-class PD-1/IL-2a-bias bispecific antibody IBI363 led to encouraging responses in patients with advanced NSCLC who previously received immunotherapy.7 At a median follow-up of 11.3 months (95% CI, 10.3-11.6), patients with nonsquamous disease who receive the agent at 3 mg/kg (n = 31) achieved an median PFS of 9.3 months (95% CI, 6.2-11.7); the median OS was not calculable (NC; 95% CI, 10.4-NC) and the 12-month OS rate was 70.9%.

At a median follow-up of 10.1 months (95% CI, 6.1-11.2), patients with EGFR wild-type disease treated with IBI363 at 3 mg/kg (n = 25) experienced a median PFS of 5.6 months (95% CI, 3.1-9.4). The median OS was NC (95% CI, 9.4-NC), and the 12-month OS rate was 71.6% (95% CI, 45.9%-86.6%).

“Unfortunately, we haven’t had a lot of progress in phase 3 trials in [besting] the SOC, but the studies and rationale that I’ve [highlighted], I believe, are the way forward,” Borghaei concluded.

References

  1. Borghaei H. How to manage immunotherapy–refractory NSCLC. Presented at: 26th Annual International Lung Cancer Congress; July 25-27, 2025; Huntington Beach, CA.
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. Zhou J, Bai X, Chen Y, et al. First-in-class PD-1/IL-2 bispecific antibody IBI363 in patients (pts) with advanced immunotherapy-treated non-small cell lung cancer (NSCLC). J Clin Oncol. 2025;43(suppl 16):8509. doi:10.1200/JCO.2025.43.16_suppl.8509

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