Key NSCLC Trials From WCLC 2025 

Balazs Halmos, MD Albert Einstein College of Medicine | Rahul Gosain, MD, MBA Wilmot Cancer Institute | Rohit Gosain, MD Roswell Park Comprehensive Cancer Center

Key Points

• The FLAURA2 trial showed an overall survival (OS) benefit by adding chemotherapy to frontline osimertinib in EGFR-mutated non-small cell lung cancer (NSCLC).

• Ivonescimab, a bispecific antibody against PD-1 and VEGF, fell short of a statistically significant OS benefit for advanced NSCLC in the HARMONi trial.

• Data from the ALCHEMIST trial showed adjuvant immunotherapy did not improve survival compared with observation after surgical resection in ALK-positive NSCLC.

WCLC 2025 Conference Highlights

The Oncology Brothers podcast cohosts, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, joined with Balazs Halmos, MD, of Montefiore Einstein Cancer Center, to highlight presentations from the 2025 World Conference on Lung Cancer (WCLC), including the FLAURA2, HARMONi, and ALCHEMIST trials.

FLAURA2: Frontline Osimertinib

One of the most anticipated presentations at WCLC 2025 was the final OS data from the FLAURA2 trial, which compared osimertinib plus chemotherapy with osimertinib alone in the frontline treatment of EGFR-mutated advanced NSCLC. The combination regimen showed a statistically significant improvement in OS with a hazard ratio (HR) of 0.77 (95% CI, 0.61-0.96; P = .02).

In the osimertinib plus chemotherapy group, the median follow up was 51.2 months (range, 0.2-60.4), and the median OS was 47.5 months (95% CI, 41.0-not calculable). The 24-month, 36-month, and 48-month survival rates were 79.7% (95% CI, 74.5-84.0), 63.1% (95% CI, 57.1-68.5), and 49.1% (95% CI, 43.0-55.0), respectively. 

In the osimertinib monotherapy group, the median follow up was 51.3 months (range, 0.1-60.1), and the median OS was 37.6 months (95% CI, 33.2-43.2). The 24-month, 36-month, and 48-month survival rates were 71.5% (95% CI,65.8-76.5), 50.9% (95% CI, 44.8-56.6), and 40.8% (95% CI, 34.9-46.6), respectively.

“With FLAURA2, we’re entering a new era, so all of us have to practice those nuancing skills, precision medicine is definitely here to stay, and in fact is expanding how we need to use our armamentarium,” said Dr. Halmos.

FLAURA2 and MARIPOSA Impact

The FLAURA2 OS data were presented one day after OS data from the MARIPOSA trial on amivantamab and lazertinib were published, and both trials reported similar OS outcomes. Based on this evidence, the typical patient should be considered for combination therapy with osimertinib plus chemotherapy or amivantamab plus lazertinib, and the choice should be an informed, shared decision with each patient, said Dr. Halmos.

Osimertinib monotherapy may still be appropriate for some patients, including the very elderly, those with very limited burden of disease, or those with favorable molecular profiles. Additionally, the average duration of chemotherapy in the FLAURA2 trial was eight months, suggesting it may be reasonable to halt or adjust the chemotherapy component of maintenance if a patient is struggling.

HARMONi Data Unveiled

The HARMONi trial evaluated ivonescimab plus chemotherapy versus placebo plus chemotherapy in patients with EGFR-mutated NSCLC whose disease progressed on a third-generation tyrosine kinase inhibitor (TKI). The combination previously showed a progression-free survival (PFS) benefit, but subsequent press releases were unclear on OS benefit.

In the WCLC 2025 presentation, the median OS was 16.8 months in the ivonescimab group versus 14 months in the placebo group (HR, 0.79; 95% CI, 0.62-1.01). The OS benefit was short of statistical significance with a P value of 0.057. Ivonescimab was unlikely to get an approval based on the HARMONi data, but a separate trial had shown a PFS benefit with ivonescimab versus pembrolizumab in wild-type NSCLC, said Dr. Halmos.

TreatingALK-Positive NSCLC in ALCHEMIST

The ALCHEMIST trial evaluated postoperative crizotinib after surgical resection in patients with early-stage ALK-positive NSCLC. The trial was stopped when the FDA approved adjuvant alectinib for this population based on the ALINA trial, and crizotinib was largely replaced by alectinib and other newer-generation TKIs in practice. 

At a median follow-up of 58.3 months, the crizotinib group had a median disease-free survival (DFS) of 72.8 months versus 75.1 months in the observation arm (HR, 1.06; 90% CI, 0.63-1.77; P = .86). Neither group reached median OS (HR, 0.49; 90% CI, 0.18-1.37; P = .26). The “stunningly negative” primary DFS finding could be due to many participants dropping crizotinib due to toxicities and the weaker efficacy of crizotinib compared with newer agents, said Dr. Halmos. 

While the negative outcome of the trial doesn’t detract from the successes of alectinib and other newer-generation tyrosine kinase inhibitors in the NSCLC space, it served as a warning for “simply broadening, without data, the adjuvant use of other targeted therapies,” said Dr. Halmos.