New Strategies Emerge to Tackle Immunotherapy Resistance in NSCLC

Advancements in the treatment of non-small cell lung cancer (NSCLC) may be on the horizon, as researchers explore novel strategies to address challenges associated with immunotherapy resistance. According to Dr. Hossein Borghaei, an expert in thoracic oncology at Fox Chase Cancer Center, traditional phase 3 trials have struggled to enhance standard-of-care (SOC) treatments for patients whose disease progresses post-immunotherapy. However, innovative approaches, including JAK2 inhibitors, bispecific antibodies, and cancer vaccines, show promise for future treatment options.

In a presentation at the 26th Annual International Lung Cancer Congress, Borghaei discussed the mechanisms of resistance observed in patients experiencing disease progression after immunotherapy. “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,” he stated. These mechanisms can be grouped into cancer cell-dependent, immune-related, and host-related factors.

Borghaei reported findings from the prospective phase 3 Pragmatica-Lung study, which examined the effectiveness of ramucirumab (Cyramza) combined with pembrolizumab (Keytruda) against SOC for patients with stage IV or recurrent NSCLC who had previously undergone immunotherapy. Results presented during the 2025 ASCO Annual Meeting indicated that the combination did not significantly improve overall survival (OS) compared to SOC (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 remarked.

Despite this setback, Borghaei highlighted positive efficacy signals from bispecific antibodies. Data from the phase 3 HARMONi-A study demonstrated that the PD-1/VEGF bispecific antibody ivonescimab, when paired with chemotherapy, significantly improved progression-free survival (PFS) compared to a placebo. The median PFS in the combination arm was 7.1 months (95% CI, 5.9-8.7) versus 4.8 months (95% CI, 4.2-5.6) in the placebo arm (HR, 0.46; 95% CI, 0.34-0.62; P < .001). The study met its primary endpoint of PFS per independent radiologic review committee, indicating a strong efficacy signal in a typically challenging patient population. Borghaei also reviewed data from a phase 2 study examining combined JAK inhibition and anti-PD-1 therapy. Results showed that treatment-naive patients with metastatic NSCLC and tumor PD-L1 levels of at least 50% who received pembrolizumab alongside the selective JAK1 inhibitor itacitinib achieved a 12-week overall response rate of 62%. With a median follow-up of 27.6 months, the median PFS reached 23.8 months (95% CI, 4.9-not applicable), showcasing a potential clinical benefit when JAK inhibitors are timed after checkpoint inhibitors. The presentation also covered the emerging landscape of cancer vaccines. Borghaei noted that new-generation agents appear more promising than their predecessors. A phase 1 trial involving intratumoral adenovirus–IL-12 combined with atezolizumab (Tecentriq) reported a disease control rate of 50% among patients with metastatic NSCLC following disease progression. Patients in the trial had a median OS of 10.5 months with no severe adverse events reported. Additionally, the therapeutic cancer vaccine OSE2101 is currently under investigation in a phase 3 study comparing it with docetaxel for patients experiencing secondary resistance to immunotherapy. The primary endpoint of this study focuses on OS and is actively recruiting participants across North America and Europe. Borghaei emphasized the importance of ongoing studies, stating, “These are going to be important studies for us to pay attention to because they could offer a potential step forward.” He concluded his presentation by reiterating the potential of bispecific antibodies to overcome resistance in NSCLC. “I believe something happens biologically when you engage multiple tumor antigens. Bispecifics could change the calculus,” he noted, expressing hope that further research may lead to significant advancements in treatment options for patients facing this challenging disease. As the field continues to evolve, the exploration of these innovative therapies signals a commitment to improving outcomes for NSCLC patients and addressing the complexities of immunotherapy resistance.