The challenge of immunotherapy resistance in non-small cell lung cancer (NSCLC) has prompted researchers to explore innovative therapeutic approaches, as multiple phase 3 clinical trials have been unable to improve upon standard-of-care treatments for patients who experienced disease progression on or after immunotherapy.
Limited Success with Current Approaches
The prospective phase 3 Pragmatica-Lung (SWOG S2302) study examined ramucirumab in combination with pembrolizumab versus standard-of-care for patients with stage IV or recurrent NSCLC who previously received immunotherapy. Results presented at the 2025 ASCO Annual Meeting showed that patients receiving the combination (n = 419) did not achieve a significant benefit in overall survival compared with the standard-of-care 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]," commented Hossein Borghaei, DO, MS, chief of the Division of Thoracic Medical Oncology at Fox Chase Cancer Center.
Bispecific Antibodies Show Promise
Despite these setbacks, encouraging efficacy signals have emerged using bispecific antibodies. The phase 3 HARMONi-A study demonstrated that the novel PD-1/VEGF bispecific antibody ivonescimab plus chemotherapy improved progression-free survival compared with placebo plus chemotherapy in patients with nonsquamous NSCLC.
The median progression-free survival in the combination arm (n = 161) was 7.1 months (95% CI, 5.9-8.7) versus 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.
"[These data] come from a slightly different patient population: patients with EGFR-positive disease," Borghaei noted. "[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."
JAK Inhibition Strategy
Combined JAK inhibition and anti-PD-1 therapy has shown promising results in a phase 2 study of treatment-naive metastatic NSCLC. Patients 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 progression-free survival 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 explained.
Cancer Vaccines and Novel Approaches
The new generation of cancer vaccines shows more promise compared to previous iterations. A phase 1 trial demonstrated that intratumoral adenovirus-IL-12 in combination with atezolizumab was safe and showed promising clinical benefit in patients with metastatic NSCLC following disease progression.
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 progression-free survival of 2 months. The median overall survival was 10.5 months, with no instances of grade 4 or 5 adverse effects or treatment discontinuation due to treatment-related adverse events.
Additionally, the therapeutic cancer vaccine OSE2101 is being compared with docetaxel for patients with metastatic NSCLC with secondary resistance to immunotherapy in a phase 3 study currently recruiting patients in North America and Europe.
Advanced Bispecific Antibody Development
Further evidence for bispecific antibodies comes from a phase 1a/1b study of the first-in-class PD-1/IL-2a-bias bispecific antibody IBI363 in patients with advanced NSCLC who previously received immunotherapy.
At a median follow-up of 11.3 months, patients with nonsquamous disease who received the agent at 3 mg/kg (n = 31) achieved a median progression-free survival of 9.3 months (95% CI, 6.2-11.7). The median overall survival was not calculable (95% CI, 10.4-NC) and the 12-month OS rate was 70.9%.
For patients with EGFR wild-type disease treated with IBI363 at 3 mg/kg (n = 25), the median progression-free survival was 5.6 months (95% CI, 3.1-9.4) at a median follow-up of 10.1 months. The median overall survival was not calculable (95% CI, 9.4-NC), and the 12-month OS rate was 71.6%.
Understanding Resistance Mechanisms
Research has identified multiple mechanisms of resistance to immunotherapy, which can be broadly categorized as cancer cell dependent, immune related, and host related. These mechanisms include tumor heterogeneity, neoantigen depletion, altered signaling pathways, interferon signaling defects, epigenetic modifications, and microenvironmental suppression.
Primary resistance is characterized by a lack of therapeutic response and is influenced by the tumor's molecular and immunological features as well as the composition of the tumor microenvironment. Acquired resistance develops in patients who initially respond to therapy but subsequently exhibit declining therapeutic efficacy.
Future Directions
"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," Borghaei concluded.
The integration of artificial intelligence and machine learning in predicting patient responses, along with microbiome-modulating therapies, represents additional promising avenues for enhancing immunotherapy efficacy. These approaches aim to identify biomarkers such as tumor mutational burden and microsatellite instability that correlate with patient responsiveness to therapy.
"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 noted, emphasizing the potential of these innovative approaches to transform treatment outcomes for patients with immunotherapy-resistant NSCLC.
