Jian-Chun Duan, Jia Zhong, Bo-Yang Sun, Wen-Hua Zhao, Lin Wu, Kai-Lun Fei, Qian Chu, Qi-Sen Guo, Qi-Bin Song, Yan Yu, Da-Xing Zhu, Xin-Yan Liu, Jun Zhao, Zhi-Xiang Zhan, Shi Li, Lei Nie, Jie Lin, Xiao-Dong Peng, Dian-Sheng Zhong, Jin Zhou, Li-Hua Li, Yun-Fang Chen, Chen Hu, Tony Mok, Zhi-Jie Wang, Jie Wang
Third-generation epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs) are standard first-line therapy for advanced, EGFR-mutated nonsmall cell lung cancer (NSCLC). However, their benefit is limited in patients who have co-existing tumor suppressor gene (TSG) mutations, highlighting a need for intensified strategies to improve outcomes. ACROSS2 (ClinicalTrials.gov identifier NCT04500717) is the first prospective, multicenter, randomized phase 3 study to compare the third-generation EGFR-TKI aumolertinib in combination with carboplatin–pemetrexed versus aumolertinib monotherapy in patients who had NSCLC with EGFR mutations and concomitant TSG mutations. In total, 126 patients were enrolled and randomly assigned to either combination therapy (n = 62) or monotherapy (n = 64). The primary end point was median progression-free survival (PFS). At a median follow-up of 25.3 months, combination therapy significantly prolonged median PFS compared with monotherapy (19.78 vs 16.53 months; hazard ratio, 0.58; 95% confidence interval, 0.34–0.97). Landmark PFS rates at 12, 18, and 24 months were 78.7% versus 65.3%, 67.2% versus 40.8%, and 41.0% versus 29.9%, respectively. Subgroup analyses demonstrated a clear PFS benefit in patients who had co-existing tumor protein p53 (TP53) mutations. Grade 3 or greater adverse events occurred in 25.9% of patients who received combination therapy versus 17.2% of those who received monotherapy; no drug-related deaths were observed. Overall survival data were immature (data maturity, 4%). The ACROSS2 trial provides the first prospective evidence supporting a genotype-directed, chemotherapy-targeted intensification approach favoring aumolertinib plus carboplatin–pemetrexed for this molecularly defined population.
{"title":"Aumolertinib with carboplatin–pemetrexed versus aumolertinib for nonsmall cell lung cancer with EGFR and concomitant tumor suppressor genes (ACROSS2): An open-label, multicenter, randomized phase 3 study","authors":"Jian-Chun Duan, Jia Zhong, Bo-Yang Sun, Wen-Hua Zhao, Lin Wu, Kai-Lun Fei, Qian Chu, Qi-Sen Guo, Qi-Bin Song, Yan Yu, Da-Xing Zhu, Xin-Yan Liu, Jun Zhao, Zhi-Xiang Zhan, Shi Li, Lei Nie, Jie Lin, Xiao-Dong Peng, Dian-Sheng Zhong, Jin Zhou, Li-Hua Li, Yun-Fang Chen, Chen Hu, Tony Mok, Zhi-Jie Wang, Jie Wang","doi":"10.3322/caac.70071","DOIUrl":"https://doi.org/10.3322/caac.70071","url":null,"abstract":"Third-generation epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs) are standard first-line therapy for advanced, <i>EGFR</i>-mutated nonsmall cell lung cancer (NSCLC). However, their benefit is limited in patients who have co-existing tumor suppressor gene (TSG) mutations, highlighting a need for intensified strategies to improve outcomes. ACROSS2 (ClinicalTrials.gov identifier NCT04500717) is the first prospective, multicenter, randomized phase 3 study to compare the third-generation EGFR-TKI aumolertinib in combination with carboplatin–pemetrexed versus aumolertinib monotherapy in patients who had NSCLC with <i>EGFR</i> mutations and concomitant TSG mutations. In total, 126 patients were enrolled and randomly assigned to either combination therapy (<i>n</i> = 62) or monotherapy (<i>n</i> = 64). The primary end point was median progression-free survival (PFS). At a median follow-up of 25.3 months, combination therapy significantly prolonged median PFS compared with monotherapy (19.78 vs 16.53 months; hazard ratio, 0.58; 95% confidence interval, 0.34–0.97). Landmark PFS rates at 12, 18, and 24 months were 78.7% versus 65.3%, 67.2% versus 40.8%, and 41.0% versus 29.9%, respectively. Subgroup analyses demonstrated a clear PFS benefit in patients who had co-existing tumor protein p53 (<i>TP53</i>) mutations. Grade 3 or greater adverse events occurred in 25.9% of patients who received combination therapy versus 17.2% of those who received monotherapy; no drug-related deaths were observed. Overall survival data were immature (data maturity, 4%). The ACROSS2 trial provides the first prospective evidence supporting a genotype-directed, chemotherapy-targeted intensification approach favoring aumolertinib plus carboplatin–pemetrexed for this molecularly defined population.","PeriodicalId":137,"journal":{"name":"CA: A Cancer Journal for Clinicians","volume":"18 1","pages":"e70071"},"PeriodicalIF":254.7,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147439895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Krishna S. Gunturu, Hina Khan, Gilberto de Lima Lopes
<p>The treatment landscape for <i>EGFR</i>-mutated nonsmall cell lung cancer (NSCLC) continues to evolve with welcome speed. With the advent of third-generation tyrosine kinase inhibitors (TKIs) like osimertinib, treatment has improved systemic and central nervous system control. However, patients who have NSCLC harboring concomitant tumor suppressor gene alterations, particularly <i>TP53</i> mutations, represent a biologically distinct subgroup with a poor prognosis and limited therapeutic options. TP53 co-mutations in <i>EGFR</i>-mutated NSCLC range from 40% to 68% in the real-world setting. These <i>co-mutated</i> tumors often behave aggressively, relapse earlier, and exhibit shorter lasting responses to targeted monotherapy.<span><sup>1, 2</sup></span> In one retrospective study, 5753 patients with <i>EGFR</i>-mutant NSCLC specimens were molecularly profiled.<span><sup>3</sup></span> Patients younger than 50 years who had classical <i>EGFR</i> mutations had the longest median overall survival (OS) with osimertinib compared with both older adults with classical <i>EGFR</i> mutations (40 vs. 32 months; hazard ratio [HR], 0.692; <i>p</i> < .01) and older adults with atypical <i>EGFR</i> mutations (40 vs. 21 months; HR, 0.47; <i>p</i> < .0001), independent of <i>TP53</i> mutation status. However, compared with older adults (older than 50 years) with atypical <i>EGFR</i> mutations, older adults with classical mutations had longer OS only in the absence of concurrent <i>TP53</i> mutations (median OS, 39 vs. 28 months; HR, 0.735; <i>p</i> < .0001). In addition, <i>TP53</i> co-mutations were enriched in the younger adult population (younger than 50 years; 76% vs. 62%, <i>q</i> < .05) compared with older adults.</p>