Groundbreaking Phase III Trial Demonstrates Superior Efficacy of Aumolertinib Plus Chemotherapy in Advanced EGFR-Mutant NSCLC
In a pivotal advancement for the treatment of advanced non-small cell lung cancer (NSCLC), new data from the ACROSS 2 Phase III clinical trial reveal that combining aumolertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), with platinum-pemetrexed chemotherapy significantly enhances progression-free survival in patients harboring EGFR sensitizing mutations alongside concomitant tumor suppressor gene alterations. These findings, unveiled at the prestigious 2025 International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer (WCLC) in Barcelona, mark a potential paradigm shift in managing a particularly challenging subset of lung cancer patients.
Advanced NSCLC patients whose tumors possess EGFR sensitizing mutations often receive targeted therapies that inhibit aberrant signaling pathways driving malignant growth. Although EGFR-TKIs have transformed clinical outcomes dramatically, a considerable fraction of these patients harbor additional tumor suppressor gene mutations that correlate with more aggressive disease phenotypes and poorer clinical prognoses. Until now, standard treatment protocols have inadequately addressed this subgroup’s complexity, leaving oncologists seeking optimized therapeutic strategies that improve durability and depth of response.
Aumolertinib represents an evolution in EGFR-targeted therapy. As an oral, third-generation EGFR-TKI, it selectively inhibits mutant EGFR signaling, including mutations resistant to earlier generations of inhibitors, while sparing wild-type receptors to minimize off-target toxicity. Previous real-world evidence and early-phase studies have demonstrated its efficacy and favorable safety profile, yet exploration of its combinatorial use with chemotherapy in genetically complex tumors remains a frontier in clinical research.
The ACROSS 2 trial, registered under NCT04500717, is the first global, multicenter, open-label, randomized, controlled Phase III study specifically designed to assess whether concomitant administration of aumolertinib and platinum-pemetrexed chemotherapy surpasses aumolertinib monotherapy in prolonging progression-free survival among patients with advanced/metastatic NSCLC harboring both sensitizing EGFR mutations and tumor suppressor gene mutations. Criteria for participation required histologically confirmed stage IIIB to IV disease and performance status allowing robust assessment of therapeutic impact.
In the trial protocol, subjects were randomized in a 1:1 ratio to receive either the combination regimen—comprising daily aumolertinib at 110 mg plus carboplatin dosed by AUC=5 and pemetrexed 500 mg/m² every three weeks—or aumolertinib monotherapy continued until evidence of disease progression. Stratification accounted for key variables including EGFR mutation subtype—exon 19 deletions versus L858R—and the presence of central nervous system (CNS) metastases, ensuring balanced baseline characteristics and mitigating confounding factors in outcome interpretation.
Follow-up data captured over a median period exceeding two years (25.3 months) disclosed a compelling improvement in progression-free survival (PFS) associated with combination therapy. Specifically, median PFS extended to 19.78 months for patients receiving aumolertinib with chemotherapy, compared to 16.53 months observed in those assigned to monotherapy. Statistical analysis quantified this difference with a hazard ratio of 0.55 (95% CI: 0.339–0.910), achieving nominal significance (p=0.0205). These results underscore a clinically meaningful delay in disease progression facilitated by the synergistic anticancer effects of targeted and cytotoxic agents.
Secondary endpoints encompassing objective response rate, disease control rate, duration of response, and overall survival (OS) remain under continued evaluation, with mature OS data not yet available. Importantly, the safety profile of the combination regimen mirrored expectations based on the known pharmacology of the individual agents, with no emergent adverse event signals. Common treatment-related toxicities—hematological abnormalities including leukopenia, neutropenia, thrombocytopenia, and anemia—as well as elevated hepatic enzymes and creatine kinase levels, were observed in alignment with platinum-based chemotherapy exposure.
One of the trial’s paramount findings lies in the retention of aumolertinib’s tolerability despite the addition of chemotherapy. This confirms the feasibility of integrating intensive systemic treatments in patients who frequently present with complex molecular tumor profiles and underscores the potential for this combination to become a new standard of care, pending further validation. The manageable safety spectrum provides reassurance for clinical adoption, balancing efficacy with patient quality of life.
This investigation also highlights the critical importance of molecular stratification in lung cancer therapeutics. Tumor suppressor gene mutations often contribute to resistance mechanisms and worsened outcomes when targeted therapies are utilized in isolation. By addressing these co-mutations, the ACROSS 2 study pioneers a nuanced approach that personalizes treatment intensity in accordance with underlying tumor biology, setting a precedent for future trials exploring combinatorial regimens.
The global collaborative framework of ACROSS 2—a multinational, multicenter endeavor—reflects the growing trend toward inclusive, diverse patient populations in clinical research. Such inclusive enrollment enhances data generalizability and accelerates the translation of trial findings into practice worldwide. The prospective, randomized design further ensures robust, high-quality evidence undergirding the trial conclusions.
Dr. Jie Wang of China’s National Cancer Center, who presented these breakthrough results at the IASLC WCLC, emphasized the trial’s novelty in addressing a long-standing unmet need in NSCLC management. “Our findings demonstrate that aumolertinib plus platinum-pemetrexed chemotherapy effectively extends progression-free survival in a patient population traditionally burdened by poor outcomes, with a safety profile consistent with clinical expectations,” he stated. These insights are poised to influence future treatment guidelines and inspire further investigations into combination strategies within molecularly complex NSCLC.
As lung cancer remains the leading cause of cancer-related mortality globally, innovations such as those derived from the ACROSS 2 trial are imperative to shift therapeutic paradigms. The incorporation of molecular pathology into trial design and treatment selection exemplifies precision oncology’s promise. Going forward, longitudinal data including overall survival and quality of life metrics will be critical to confirm long-term benefits and inform individualized patient care.
In summary, the ACROSS 2 Phase III trial establishes for the first time that integrating aumolertinib with platinum-pemetrexed chemotherapy yields a statistically and clinically significant progression-free survival advantage over EGFR-TKI monotherapy in advanced NSCLC patients harboring EGFR sensitizing and tumor suppressor gene co-mutations. This milestone advances lung cancer treatment by offering a potent, biologically rational combination therapy that addresses tumor heterogeneity and resistance. Oncologists and researchers alike eagerly anticipate further data from this landmark study, which may redefine standards of care and improve outcomes for thousands affected worldwide.
Subject of Research:
Not explicitly detailed, but relates to treatment efficacy of aumolertinib plus chemotherapy in EGFR-mutant NSCLC with tumor suppressor gene mutations.
Article Title:
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News Publication Date:
September 7, 2025
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Keywords:
Lung cancer
