Key data: Oncogene-driven NSCLC

New considerations for NSCLC treatment decisions

The second plenary session at the World Conference of Lung Cancer (WCLC) 2025 in Barcelona on Sunday, September 7 saw leading experts in non–small-cell lung cancer (NSCLC) present the latest key findings in the area. Data on targeted therapies from the FLAURA2, HARMONi, ARROS-1, and E4512 trials provide new considerations for treatment decision-making in clinical practice, and guide further investigations.

EGFR-mutated NSCLC: FLAURA2 final OS

David Planchard (Gustave Roussy Villejuif, France) presented the overall survival (OS) results of the FLAURA2 phase 3 study in locally advanced or metastatic epidermal growth factor receptor mutation–positive (EGFRm) NSCLC, highlighting a shift toward osimertinib plus chemotherapy as a first-line treatment decision.

He first reminded attendees of the previously published primary findings: a statistically significant and clinically meaningful 23% improvement in progression-free survival (PFS) with osimertinib in combination with chemotherapy (n=279) versus osimertinib monotherapy (n=278).

The median OS in the combination arm was 47.5 months, which he said was the longest in a global phase 3 study of this kind. Median OS in the monotherapy arm was 37.6 months.

Planchard noted OS was consistent across all subgroups, and the results comparable to those in the FLAURA trial. There were no new safety signals, and the rate of adverse events (AEs) leading to discontinuation of osimertinib remained low.

In his commentary, Daniel Tan (National Cancer Centre Singapore) highlighted the need to prioritize biomarker discovery to identify populations who will benefit the most from combination therapies. Tan left attendees with a question: “Does intensity matter for these therapies when it comes to side-effect profiles?”

HARMONi results and the post-TKI treatment gap

Does ivonescimab have the potential to fill a major post–tyrosine kinase inhibitor (TKI) treatment gap? Jonathan Goldman (David Geffen School of Medicine at UCLA, Los Angeles, California, USA) presented HARMONi data for patients with locally advanced and metastatic EGFR-mutated NSCLC who progressed following third-generation EGFR–TKI treatment.

Ivonescimab plus chemotherapy (n=219) had a statistically significant and clinically meaningful benefit on PFS, which was a median of 6.8 months versus 4.4 months for those given placebo plus chemotherapy (n=219).

This amounted to a 48% difference favoring ivonescimab, which was broadly consistent across subgroups. However, Goldman noted a potentially larger benefit of ivonescimab in patients with brain metastases at baseline, who had a 66% improvement in PFS, compared with a 41% improvement in those without brain metastases.

Study commenter Suresh Ramalingam (Winship Cancer Institute of Emory University, Atlanta, Georgia, USA) highlighted more favorable efficacy in Asian patients, as seen in HARMONi-A, noting that the inclusion of non-Asian patients in HARMONi may have diluted this benefit.

Goldman pointed out a nonsignificant, favorable trend in OS (HR, 0.79; P=0.057) but noted that follow-up is immature.

There were no new safety findings, and rates of treatment-related AEs (TRAEs), discontinuation, and death were all similar in both study arms.

In his commentary, Ramalingam noted that although ivonescimab targets both programmed cell death protein 1 (PD-1) and vascular endothelial growth factor (VEGF), and has an adverse-event profile in line with this dual blockade, its efficacy is similar to that of other VEGF inhibitors, with no clear evidence of additional benefit from PD-1 inhibition.

ARROS-1 efficacy and safety data

Alexander Drilon (Memorial Sloan Kettering Cancer Center, New York, USA) presented the results of the phase 1/2 ARROS-1 trial, investigating zidesamtinib for advanced/metastatic proto-oncogene tyrosine-protein kinase ROS–positive (ROS1+) NSCLC.

The primary endpoint, objective response rate (ORR), was 44% in all 117 patients treated with any previous TKI, 51% for the 55 with one prior TKI (either crizotinib or entrectinib), and 38% in the 58 treated with two or more TKIs.

Durable responses were observed in those pre-treated with up to four TKIs, including repotrecitinib or taletrectinib, for whom no targeted therapy is currently approved.

In 35 TKI-naive patients, the ORR was 89%, and responses were durable up to 14 months in those who remained on therapy.

The safety population included 432 patients, with the most common treatment-emergent AEs being peripheral edema, constipation, increased blood creatine phosphokinase, fatigue, and dyspnea. Dose reduction and discontinuation rates were 10% and 2%, respectively.

Commentator Anne-Marie Dingemans (Erasmus Medical Center, Rotterdam, The Netherlands) stressed that, given half of the study population did not respond to zidesamtinib, “it’s really important in the pre-treated setting to identify patients who will benefit from this treatment.”

Targeted therapy for resected early-stage ALK+ NSCLC

The final trial in the session, presented by David Gerber (UT Southwestern Medical Center, Dallas, Texas, USA), assessed the role of targeted therapy in post-surgical management in patients with surgically resected stage 2A–3B anaplastic lymphoma kinase–positive (ALK+) NSCLC.

E4512, a 10-year study, is the first to investigate adjuvant crizotinib as an ALK-targeted therapy in post-surgical management

Gerber explained that adjuvant crizotinib (n=75) did not prolong disease-free survival compared with observation (n=79) over a median follow-up of 58.3 months. There was no meaningful difference in OS.

Toxicities were similar to those observed in advanced ALK+ NSCLC, and Gerber noted that more than 25% of treatment discontinuations were attributed to TRAEs.

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