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First-line aumolertinib plus platinum-pemetrexed chemotherapy significantly improved progression-free survival (PFS) compared with aumolertinib alone in certain patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) in the randomized, open-label, phase 3 ACROSS 2 trial.

Specifically, combining the third-generation EGFR tyrosine kinase inhibitor (TKI) therapy with chemotherapy extended median PFS by just over 3 months (19.8 vs 16.5 months) in treatment-naïve patients with histologically confirmed stage IIIB-IV NSCLC harboring EGFR-sensitizing mutations and tumor suppressor gene (TSG) co-mutations, Jie Wang, MD, reported at the World Conference on Lung Cancer (WCLC) 2025.

While PFS was only a few months longer in the combination arm, most treatment-emergent adverse events (TEAEs) were substantially higher in that group.

Expert Takes on Findings

The findings are notable given the poorer outcomes demonstrated with EGFR-TKI monotherapy in this patient population in prior studies and the lack of an established standard of care in patients with EGFR and TSG co-mutations in clinical practice, said Wang, chair of the medical oncology division at the National Cancer Center, Cancer Hospital Chinese Academy of Medical Sciences, Beijing.

Prior studies have hinted at a survival benefit with EGFR-TKI therapy plus chemotherapy vs EGFR-TKI monotherapy, but the ACROSS 2 trial is the first global, randomized, phase 3 trial to address the question, she added, stressing that "there is a critical need to improve outcomes for patients with co-mutations." 

A biomarker, such as the presence of a specific TSG co-mutation to help guide treatment decisions, could address that need.

Invited discussant Jordi Remon, MD, PhD, on the other hand, characterized the clinical relevance of the PFS benefit observed in the trial as remaining unclear. The potential reproducibility of the findings in other populations requires more study, continued Remon, of the department of cancer medicine at Gustave Roussy, Villejuif, France.

Methods and Results 

Patients in the ACROSS 2 trial were randomized 1:1 to receive 110 mg of daily oral aumolertinib plus carboplatin (AUC5) on day 1 and pemetrexed (500 mg/m²) every 3 weeks for up to 6 cycles, or aumolertinib monotherapy until disease progression.

At a median follow-up of 25.3 months, median PFS was 19.8 months in 54 patients in the combination therapy arm vs 16.5 months in 64 patients in the monotherapy arm (hazard ratio, 0.55), which was significantly different (P = .0202). Overall survival data remain immature.

Patients in the combination and monotherapy arms were a median age of 55.5 and 59 years, and 57.4% and 64.1% were female. The most common TSG mutation was TP53.

TEAEs: Combination vs Control Arms

Treatment-emergent adverse events (TEAEs) that occurred in at least 20% of patients in both groups included anemia, nausea, constipation, and rash, as well as decreased white blood cell count, neutrophil count, and platelet count, and increased aspartate aminotransferase (AST)/alanine aminotransferase (ALT), creatine kinase, and serum creatinine. Those in the combination arm had a substantially higher incidence of most TEAEs, with the exception of increased creatine kinase and grade ≥3 rash.

For example, all-grade and grade ≥3 anemia occurred in 61.1% and 7.4% of patients in the combination therapy arm and in 10.9% and 1.6% of patients in the monotherapy arm. In the combination therapy vs monotherapy arms, all-grade nausea occurred in 24.1% vs 1.6% and all-grade constipation occurred in 20.4% vs 6.3%.

All-grade and grade ≥3 increased creatine kinase occurred in 27.8% and 1.9% of patients in the combination therapy arm, and in 42.2% and 12.5% in the monotherapy arm; and grade ≥3 rash occurred in 0% of those in the combination therapy arm vs 1.6% in the monotherapy arm.

Adding chemotherapy did not alter the safety profile of aumolertinib, and no new safety signals were observed, Wang reported.

It appears, based on these findings, that adding chemotherapy to aumolertinib improves PFS in this patient population, but more research is needed, said Remon.

TSG co-mutations in EGFR-mutated NSCLC portend a poor prognosis, but are likely confounded by a higher tumor burden, and it is unclear if the observed benefit differs across different TSG mutations or in cases where there are multiple TSG mutations, he continued.

"The 'holy grail' question is whether the results of the ACROSS 2 trial strongly support TP53 as a biomarker for making treatment decisions, and I am not completely convinced," Remon said, noting the absolute PFS benefit was only about 3 months and many questions remain unanswered.

"I think that we need more prospective data to strongly support that TP53 or other tumor suppressor genes, per se, are a potential biomarker, and also to elucidate if chemotherapy is the best partner to EGFR-TKI therapy in this subset of patients with EGFR-mutant tumors."

Wang has reported no relevant financial relationships. Remon has reported receiving grants/research support and/or honoraria or consulting fees from MSD, AstraZeneca, Sanofi, Edimark, Takeda, Roche, and Janssen. 

Sharon Worcester, MA, is an award-winning medical journalist based in Birmingham, Alabama, writing for Medscape, MDedge, and other affiliate sites. She currently covers oncology, but she has also written on a variety of other medical specialties and healthcare topics. She can be reached at sworcester@mdedge.com or on X: @SW_MedReporter.