Radiotherapy Regimen Shows Responses in Anti–PD-1–Refractory NSCLC

Adding subablative radiotherapy to ipilimumab (Yervoy) and nivolumab (Opdivo) induced objective clinical responses in a small subset of patients with metastatic non–small cell lung cancer (NSCLC) and low or negative PD-L1 expression who had progressed on first-line anti–PD-1 therapy, according to findings from the phase 2 RECLAIM trial (EudraCT 2020-001097-29) published in the Journal for ImmunoTherapy of Cancer. Treatment was also associated with strong peripheral T-cell activation, improved overall survival (OS) among responders, and an acceptable safety profile.

What did the RECLAIM trial show?

Among 31 patients in the intention-to-treat population, the objective response rate (ORR)—assessed in non-irradiated tumor lesions—was 7% at 6 weeks and 10% at 12 weeks, reaching 29% as the best response. The disease control rate (DCR) was 58% at 6 weeks and 39% at 12 weeks. OS differed significantly by best response, with a median OS of 3.1 months (95% CI, 1.6-4.6) for patients with progressive disease, 13.5 months (95% CI, 8.8-18.3) for those with stable disease, and 22.5 months (95% CI, 16.1-28.8) for those with a partial or complete response (P <.001).

The median progression-free survival (PFS) was 4.2 months (95% CI, 1.4-9.7) among patients with PD-L1–negative disease and 2.9 months (95% CI, 1.5-8.2) in patients with PD-L1–positive disease (P = .577). Across each respective group, the median OS was 10.1 months (95% CI, 4.8-28.4) and 8.6 months (95% CI, 3.2-22.5; P = .776).

Baseline sum of longest diameters, age, blood inflammatory markers, and albumin levels were prognostic of treatment response. Early T-cell activation in peripheral blood at day 8 was detectable and more pronounced in responders than in patients who progressed.

What was the safety profile?

All patients experienced treatment-related adverse events (TRAEs). Grade 3 was the highest severity observed, occurring in 8 patients (26%); no higher-grade events were reported as the maximum severity. Immune-related AEs led to treatment discontinuation in 5 patients (16%). The investigators reported that the regimen carried an acceptable safety profile in this pretreated population.

“This prospective phase 2 trial showed that the combination of [ipilimumab/nivolumab] with subablative [radiotherapy] yielded favorable response rates in patients with metastatic NSCLC with PD-L1 low or negative tumors who had progressed on first-line anti-PD1 therapy. The regimen was well tolerated, with a safety profile consistent with prior dual [immune checkpoint inhibitor] studies,” lead study investigator Ezgi B. Ulas, MD, PhD, from the Department of Pulmonary Medicine at Amsterdam UMC Location VUmc, Cancer Center Amsterdam, and Amsterdam Institute for Immunology and Infectious Diseases, wrote with coauthors in the publication.¹ “These results support the feasibility of this multimodal strategy in a population with limited therapeutic options. Prospective studies, including randomized controlled trials, are warranted to confirm these results, refine patient selection, [radiotherapy] dosing, and treatment sequencing, and enable broader clinical adoption.”

What was the RECLAIM trial design?

RECLAIM was a single-arm, prospective phase 2 trial that aimed to enroll 30 evaluable patients with metastatic NSCLC exhibiting low or negative PD-L1 tumor expression who had progressed after first-line anti–PD-1 therapy. Treatment consisted of ipilimumab at 1 mg/kg every 6 weeks and nivolumab at 240 mg every 2 weeks for 6 weeks, combined with subablative radiotherapy delivered as 3 fractions of 8 Gy to 1 to 4 lesions. Afterwards, ipilimumab at 1 mg/kg every 6 weeks and nivolumab at 360 mg every 3 weeks were continued.

The primary end points were safety, DCR, and ORR at 6 and 12 weeks, each assessed in non-irradiated lesions. Secondary end points included PFS and OS.

Across all 31 evaluable patients, the mean age was 66.3 years (SD, 9.9), and most were male (58.1%). Additionally, most patients had a former history of smoking (64.5%), an ECOG performance status of 1 (54.8%), adenocarcinoma histology (74.2%), a tumor PD-L1 expression status of less than 1% (54.8%), and prior treatment with pembrolizumab (Keytruda; 87.1%).

Reference

Ulas EB, Purcell ND, Houda I, et al. Rescue by radiotherapy and anti-CTLA4/PD-1 after failure of anti-PD-1 therapy in patients with metastatic NSCLC: the phase II RECLAIM trial. J Immunother Cancer. 2026;14(6):e014724. doi:10.1136/jitc-2025-014724