Phase 3 data shift NSCLC landscape

Phase 3 NSCLC: What do the data say?

What were the latest phase 3 trial results in non–small-cell lung cancer (NSCLC) shared at the World Conference of Lung Cancer (WCLC) 2025 in Barcelona, Spain? Leading experts presented key abstracts in the presidential plenary sessions, including the first interim analysis of a trial of adjuvant chemo-immunotherapy in early-stage NSCLC, data building on the PACIFIC trial in unresectable stage 3 NSCLC, and a precision medicine study in epidermal growth factor receptor mutation (EGFRm) NSCLC.

NADIM ADJUVANT phase 3 results

Mariano Provencio (Hospital Universitario Puerta de Hierro Majadahonda, Spain) presented the first interim analysis of the NADIM ADJUVANT study, a phase 3 open-label academic trial investigating a chemo-immunotherapy combination in the adjuvant setting in early-stage NSCLC. The study had two arms: adjuvant nivolumab plus chemotherapy followed by nivolumab maintenance for 6 months (n=103) versus adjuvant chemotherapy only plus observation for 6 months (n=103).

There was a clinically meaningful reduction in relapse rates with nivolumab plus chemotherapy versus chemotherapy alone

Overall survival (OS) and disease-free survival (DFS) data remain immature, and no significant differences were observed. However, relapse rates were markedly lower in the nivolumab arm compared with the control arm, at 20.4% versus 38.8%. Also, an exploratory sensitivity analysis of cancer-specific DFS showed a significant difference between the arms (HR, 0.54; CI, 0.32–0.93; P=0.025).

Study commentator Tina Cascone (The University of Texas MD Anderson Cancer, Houston, USA) said this is “meaningful and thoughtful” but further analysis may be needed at later time points.

Safety and tolerability were manageable and consistent with previous data on combination chemo-immunotherapy. There were six early deaths in the experimental arm, of which three were attributed to cardiac issues and four were in patients 70+ years old. There was one treatment-related toxicity death in the adjuvant phase of the experimental arm.

More than 90% of patients had comorbidities, and 15% were 75+ years old. Cascone noted the higher rate of cardiac comorbidities in the experimental arm may have impacted the results.

Provencio stressed that NADIM ADJUVANT provides a real-world evidence perspective due to the inclusion of patients following surgery and concluded that the results contribute to the growing evidence that could potentially define standard treatments in the future.

EA5181: Building on PACIFIC in unresectable stage 3 NSCLC

While the past 4 decades have seen great progress in the treatment of unresectable stage 3 NSCLC, more than 50% of patients experience progressive disease in the 2 years following concurrent chemotherapy

John Varlotto (Edwards Comprehensive Cancer Center, Huntington, West Virginia, USA) presented results of EA5181, a randomized study of concurrent plus consolidation durvalumab (n=335) versus consolidation durvalumab only (n=327) for unresectable stage 3 NSCLC. This builds on the PACIFIC trial, which established consolidation durvalumab as a standard treatment in this setting.

There was no difference in OS between the two groups, or in progression-free survival (PFS), response rate (about 50% per arm), or overall response rate (ORR).

There were no significant differences in adverse events (AEs) or discontinuation, with over 91% of both arms completing the chemotherapy stage.

Study commentator Corinne Faivre-Finn (University of Manchester, UK) reminded the audience that the PACIFIC study remains the standard of care in this setting, but looked forward to future studies of chemo-immunotherapy prior to concurrent chemotherapy. Varlotto noted future projects will investigate toxicity analyses, prognosis, and local and distant recurrence factors.

EGFRm plus tumor suppressor genes: ACROSS 2 results

Could aumolertinib plus chemotherapy be an approach for patients with NSCLC with co-mutations in tumor suppressor genes (TSG)?

Jie Wang (Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China) discussed the open-label phase 3 study, ACROSS 2, which investigated aumolertinib plus chemotherapy (n=54) versus aumolertinib monotherapy (n=64) in locally advanced or metastatic epidermal growth factor receptor mutated (EGFRm) NSCLC in the presence of TSGs.

Wang explained there was a median follow-up of 25.3 months in which 63 (53.4%) PFS events occurred. The combination group had a significantly higher median PFS (19.8 months) compared with the monotherapy group (16.5 months). OS data were immature.

ORR was 70.4% in the combination group versus 67.2% for monotherapy. The disease control rates in the combination and monotherapy groups were 92.6% and 98.4%, respectively.

Most AEs were of low grade, and no new safety signals were observed.

TP53 was the most commonly mutated TSG in ACROSS 2. Commentator Jordi Remon (CIOCC Barcelona – HM Nou Delfos, Spain) said he is “not completely convinced” whether the results support TP53 mutation status as a biomarker for making treatment decisions. He said the role of TSGs as predictive biomarkers still needs to be clarified, and the optimal combination partner with an EGFR TKI requires further investigation.

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