Immunotherapy for special populations

At the recent WCLC, two investigator-initiated clinical trials were presented, both addressing clinically relevant but often underexplored patient populations. Despite negative results for their primary endpoints, the studies provide important insights into therapeutic strategies for elderly patients and for those with brain metastases, as discussed by Prof Brandao and Dr Hendriks.

The first study, the French IFCT-1805 ELDERLY trial, enrolled patients aged 70 to 89 years with good PS (0–1) and adequate organ function. Participants underwent cognitive screening and were randomised 2:1 to receive chemo-immunotherapy or chemotherapy alone. The chemotherapy backbone consisted of four-weekly carboplatin and weekly paclitaxel, chosen to minimise haematologic toxicity. The primary endpoint, OS, was not met: no benefit was observed in the experimental arm, including across predefined subgroups. However, PFS favoured the chemo-immunotherapy combination. More than 50% of patients in the chemotherapy arm subsequently crossed over to immunotherapy, which may have influenced outcomes. The absence of survival benefit raises questions regarding patient selection, comorbidity burden, and the role of geriatric assessment in guiding treatment. The lack of correlation with PD-L1 status was unexpected, given consistent trends in prior immunotherapy trials. Overall, the study highlights the complexity of treating elderly patients, underlining the need for personalised strategies that account for biological rather than chronological age.

The second trial, NIVIPI Brain, investigated the CheckMate 9LA regimen in patients with untreated brain metastases. Two cohorts were defined: asymptomatic patients not requiring steroids, and oligosymptomatic patients receiving up to 4 mg/day dexamethasone. Treatment was non-randomised, with DCR at 5–6 months as the primary endpoint. Objective responses occurred in ~40% of patients, but median OS remained modest and DCR fell below the predefined threshold. Notably, a subset of patients achieved durable benefit, reflected in a plateau in survival curves, although predictive factors remain unclear. Trial inclusion criteria excluded patients amenable to stereotactic radiotherapy, but definitions of ineligibility were vague, complicating interpretation. These findings raise important questions regarding optimal integration of systemic therapy and stereotactic radiotherapy for brain metastases.

To address these issues, the EORTC is initiating the IVO BRAIN trial, a randomised phase II study enrolling patients with up to ten brain metastases (≤30 mL total volume). Patients will be randomised to either upfront stereotactic radiosurgery followed by systemic therapy or systemic therapy with deferred radiosurgery as needed. The primary endpoint will be intracranial PFS, with secondary endpoints including OS, time to next CNS intervention, and systemic treatment duration.

Together, these studies underscore the challenges of managing vulnerable patient populations in lung cancer. They highlight the necessity of refined patient selection, integration of geriatric assessments, and optimised sequencing of local and systemic therapies.