Negative trial but positive lesson: reframing immunotherapy resistance from one-size-fits-all to precision strategies.

Immune checkpoint inhibitors combined with platinum-based chemotherapy have become the first-line backbone for advanced, driver-negative non-small cell lung cancer (NSCLC), delivering meaningful survival gains; yet for most, disease control ultimately erodes, making immunotherapy resistance one of the most pressing unmet needs. To date, primary resistance to chemoimmunotherapy is defined as Response Evaluation Criteria in Solid Tumours (RECIST) progression within 6 months of treatment initiation after a minimum exposure of 6–8 weeks (approximately two cycles of the immunotherapy component); conversely, secondary resistance is defined as RECIST progression beyond 6 months in patients who have received >6 months of therapy.1
Over the past decade, numerous combination strategies have been proposed to overcome immune resistance, often supported by compelling biological rationale and encouraging early-phase signals. Among the most widely explored approaches to immunotherapy resistance is the combination of PD-(L)1 (programmed death 1 (PD-1) and programmed cell death ligand 1) blockade with a receptor tyrosine kinase (RTK) inhibitor.2 From a mechanistic standpoint, by targeting the specific RTK receptors, an immunosuppressive tumour microenvironment (TME) is converted to an immune-supportive TME, which may improve response to immune checkpoint inhibitors (ICIs) and overcome resistance.3
This approach, although biologically attractive, failed to translate into clinical benefit in a subset of large global studies. Trials including the CONTACT-01 study,4 SAPPHIRE study5 and LEAP-008 study,6 using combined anti-PD-(L)1 monoclonal antibodies with RTK inhibitors, all failed to demonstrate superior efficacy over docetaxel alone for patients who progressed on checkpoint inhibitor and platinum-based chemotherapy. Results from the more recent randomised SAFFRON-301 study further added to the existing evidence against combining ICIs with RTK inhibitors in this patient population.7
To address this unmet need, future strategies will need to introduce the concept of prior immunotherapy efficacy stratification and mechanism-informed interventions. Primary resistance to checkpoint inhibitors may suggest an alternative coinhibitory immune checkpoint as clinically actionable regulators of T-cell exhaustion. For example, the phase III clinical trial of the anti-cytotoxic T lymphocyte-associated antigen-4 (anti-CTLA-4) antibody, gotistobart (ONC-392/BNT316) in patients with metastatic NSCLC resistant to immunotherapy is on the way (NCT05671510); moreover, the clinical validation of lymphocyte activation gene-3 blockade (LAG-3) demonstrates that non-redundant inhibitory pathways can be therapeutically exploited.8 At the same time, these results underscore the context-dependent nature of immune modulation and the need for appropriate biological selection to maximise benefit. On the contrary, acquired resistance to ICIs may indicate adaptive immune evasion of cancer cells that could be addressed by adding potent cytotoxic regimens, such as antibody–drug conjugate (ADC). Recent approvals of multiple ADCs in NSCLC showcased a complementary strategy by integrating targeted cytotoxic delivery with immune sensitisation (NCT04656652 and NCT04154956). Growing evidence indicates that ADCs might increase the efficacy of immunotherapeutic agents by inducting immunogenic cell death, dendritic cell maturation, increasing T lymphocyte infiltration, as well as potentiation of immunological memory and expression of immune-regulatory proteins.9 For example, in the TROPION-Lung01 study, datopotamab deruxtecan showed a higher objective response rate and progression-free survival in patients previously exposed to immunotherapy or targeted therapies, although the survival benefit remains unclear.10 Alternatively, bispecific antibodies offer a more flexible and synergistic method of immune modulation. Encouraging data have been reported for PD-1xVEGF bispecific antibody in treatment-naïve patients, and there is a growing landscape of bispecific antibodies targeting vascular endothelial growth factor (VEGF) and PD-1 in NSCLC, although their efficacy in immune-resistant populations is not well established. Additionally, investigations in other combinations of target such as PD-1xCTLA-4 are also ongoing.
Concomitantly, application of integrated multiomics approaches, incorporating genomic, transcriptomic, proteomic and spatial immune profiling, offers a path towards defining distinct resistance phenotypes and tailoring therapy accordingly. With refinement in biomarker selection and risk stratification, there is an opportunity to bring more clinically meaningful improvement to anti-tumour efficacy of existing and upcoming therapies.
In conclusion, recent clinical experience reinforces a growing recognition: immunotherapy resistance is driven by biological complexity rather than insufficient treatment intensity. Findings from studies such as SAFFRON-301 contribute to a clearer understanding of where current strategies fall short. Future progress might depend on patterns of resistance to immunotherapy and mechanism-derived approaches aligning therapeutic innovation with the underlying mechanisms of resistance, guided by more precise biological insight and patient stratification.