The ACROSS 2 trial comparing aumolertinib, a third-generation EGFR-TKI, with and without platinum-based chemotherapy, found that combination therapy improved progression-free survival (PFS) for patients with EGFR-mutated non-small cell lung cancer (NSCLC) who also had co-mutated tumor suppressor genes (TSGs).
The PFS benefit was modest, 19.8 months for combination therapy versus 16.5 months for aumolertinib monotherapy, and varied by activating EGFR-mutation. Overall survival (OS) results for the trial were immature at the data cutoff for the analysis presented at the 2025 World Conference on Lung Cancer (WCLC).
“This is the first trial to compare aumolertinib monotherapy and combination therapy in patients with both EGFR mutations and TSGs,” said Jie Wang, MD, Chair of the Chinese Academy of Medical Sciences and Chief Physician at Peking Union Medical College, Beijing, China. Typically, individuals with co-mutated EGFR and TSGs have shorter PFS and OS with EGFR-TKI monotherapy.
Similar trials comparing other third-generation EGFR-TKIs as mono- and combination therapy generally show superior efficacy for combination therapy, but there are no clear parameters for combination therapy patient selection.
Presidential Symposium 1 with Lectureship Award Presentations
It’s not too late! With on-demand access, registered WCLC 2025 attendees can still watch Jie Wang, MD, and others present much-awaited data during the first of two Presidential Symposia. LEARN MORE
ACROSS 2 recruited 126 patients with locally advanced or metastatic NSCLC with EGFR and TSG mutations who were treatment naïve across 26 sites in China. TSGs in the cohort included: TP53, RB1, APC, PTEN, BRCA2, BRCA1, CHEK2, ATM, CHEK1, PALB2, and RAD51C. Of the 118 patients, 54 were treated with aumolertinib plus carboplatin-pemetrexed and 64 were treated with aumolertinib alone.
The primary endpoint was PFS as assessed by investigators. Secondary endpoints included overall response rate (ORR), disease control rate (DCR), duration of response (DoR), OS, and safety.
At data cutoff in August 2025, 37% of patients in the combination therapy arm remained on treatment compared to 25% in the monotherapy arm. More patients in the monotherapy arm discontinued treatment due to disease progression (62.5%) than in the combination therapy arm (42.6%).
After a median follow-up of 25.3 months, combination therapy showed a statistically significant PFS advantage, hazard ratio (HR) 0.55 (95% confidence interval [CI] 0.34 – 0.91, p = 0.021), although the numerical advantage was small at only 3.3 months across the cohort. Subgroup analysis showed heterogeneous results by EGFR activating mutation: TP53 HR 0.55 (95% CI 0.33 –0.93, p = 0.024); 19DEL HR 0.46 (95% CI 0.21 – 0.98, p = 0.055); L858R HR 0.63 (95% CI 0.35 – 1.20, p = 0.154).
The ORR favored combination therapy by a small margin, 70.5% versus 67.2% for monotherapy, as did DCR, 92.6% and 98.4% respectively. Dr. Wang noted that the small sample size likely affected both numerical and statistical results.
Most adverse events were grade 1 and 2, most commonly anemia, reduction in white blood cell count, and increases in both AST and ALT. Adding chemotherapy to the treatment regimen did not alter aumolertinib’s known safety profile, and there were no new safety signals seen in either arm, Dr. Wang said.
