After Immunotherapy Resistance: Lessons from Israeli Lung Cancer Research

A patient whose lung cancer progresses after immunotherapy may appear to fit a familiar trial category. Yet that description leaves important questions unanswered. Which treatment did the patient receive? Was there an initial response? Did progression occur during treatment or after discontinuation? And can the patient complete screening before another treatment decision becomes necessary?

For clinical development teams, these distinctions influence both the population being studied and the feasibility of enrolling it. Israeli lung cancer research offers useful examples of how investigator-led studies and population-level evidence can sharpen those decisions.

Start with a clearer definition of resistance

The Society for Immunotherapy of Cancer has distinguished primary resistance, secondary resistance and progression following treatment discontinuation. Its consensus work also recognises that resistance definitions need to reflect the regimen received, including whether a checkpoint inhibitor was administered alone or with chemotherapy. 1, 2

These frameworks help study teams describe comparable populations. They also highlight why a treatment history deserves more attention than a single eligibility label. Progression after initial benefit and discontinuation because of toxicity are different clinical histories. Applying the same shorthand to both can obscure the question a trial intends to answer.

For feasibility discussions, the practical starting point is a treatment timeline: drugs, exposure, best response, progression and reason for stopping. Investigators can then assess how that history maps to the proposed protocol, while identifying records or assessments that may be missing.

A small study with an important design lesson

CORAL-Lung examined a strategy for advanced non-small cell lung cancer (NSCLC) following progression on or after first-line checkpoint inhibitor treatment. The Israeli team, including Jair Bar, Alona Zer, Amir Onn and colleagues, evaluated durvalumab, tremelimumab and radiotherapy in an open-label, single-arm phase 2a study. 3

The results, reported as an ASCO 2026 meeting abstract, were limited. Ten patients entered the initial efficacy cohort, with a response rate of 10%, leading to study closure. Three of nine participants in the safety run-in discontinued treatment because of grade 3 diarrhoea. The investigators concluded that the regimen did not demonstrate meaningful activity in this unselected population and identified better patient selection as an area for further investigation.

The study's value includes the questions it raises. Which patients should enter a combination trial? How should prior treatment and toxicity inform eligibility? What early evidence should determine whether expansion is justified?

Its small size and single-arm design limit broader conclusions. The findings concern this regimen and population; they do not establish that other approaches to immunotherapy resistance will behave similarly.

Real-world evidence adds the patient pathway

LUMINATE-101-Maccabi provides a different perspective. Published in 2026, the retrospective study by Sarah Sharman Moser, Alona Zer, Jair Bar and colleagues examined Israeli patients with metastatic, non-squamous NSCLC without actionable genetic alterations. It used de-identified Maccabi Healthcare Services data from a historical treatment cohort identified between 2017 and 2020. 4

Among 176 patients receiving second-line or later treatment, 30.7% received third-line therapy. The study described treatment sequences and generally poor outcomes, documenting the clinical challenge beyond first-line treatment.

For trial planning, such evidence helps frame questions about where patients move through care and when another treatment opportunity arises. However, this was not a cohort selected specifically for resistance to first-line immunotherapy. Many patients received chemotherapy first and immunotherapy second. Historical treatment patterns also differ from contemporary practice.

The study therefore supports an informed feasibility discussion, rather than a current recruitment forecast. Today's eligible population requires fresh assessment against the actual protocol, available treatments and competing trials.

Figure 1. A practical discussion framework for post-immunotherapy NSCLC feasibility. The four areas are complementary checks, not a recruitment model or a substitute for protocol-defined eligibility.

Connect the scientific question to site readiness

Together, these studies suggest a useful sequence for investigator discussions. First, establish the treatment history and resistance setting. Next, assess current clinical eligibility. Finally, examine whether the centre can deliver the required assessments within the patient's treatment window.

That discussion should consider tissue availability, imaging, molecular results, performance status, recovery from prior toxicity and the timing of the next clinical decision. At centre level, it should also examine coordination between oncology, radiology, pathology and research staff.

An investigator may identify a scientifically relevant population while also explaining why only a smaller group can practically enter a particular study. Capturing that distinction early can help teams choose sites more carefully and make recruitment assumptions more explicit.

The contribution illustrated by this Israeli research is a combination of clinical questioning and evidence about patient care. Bringing those perspectives into planning gives sponsors a firmer basis for deciding what to study, where to study it and which uncertainties still need investigation.

Pharma Clinical is an independent Israeli CRO supporting clinical research through investigator-informed feasibility, regulatory coordination, site activation, monitoring and project management. Its international capabilities extend through established partners in Europe and North America, with services scoped to each programme's requirements.

Sources

1. Kluger HM et al. Defining tumor resistance to PD-1 pathway blockade. Journal for ImmunoTherapy of Cancer. 2020;8.

2. Rizvi N et al. SITC consensus definitions for resistance to combinations of immune checkpoint inhibitors with chemotherapy. Journal for ImmunoTherapy of Cancer. 2023;11.

3. Bar J et al. CORAL-Lung. Journal of Clinical Oncology. 2026;44(suppl 16):8583. ASCO meeting abstract; not a full-length trial publication.

4. Sharman Moser S et al. LUMINATE-101-Maccabi. Expert Review of Anticancer Therapy. 2026;26(7):961-969.