Tag: ESMO25

  • ESMO25: Neoadjuvant T-DXd Combo Tops Anthracycline Standard With Less Toxicity in HER2+ eBC

    At the 2025 European Society for Medical Oncology (ESMO) Congress, Nadia Harbeck, MD, of the University of Munich, presented results of the phase 3 DESTINY-Breast11 trial, marking the first randomized evidence that an antibody–drug conjugate–based neoadjuvant regimen can outperform anthracycline-containing chemotherapy in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (eBC).

    The global, open-label phase 3 study randomized 927 patients with HER2-positive eBC to receive (1:1:1) trastuzumab deruxtecan plus docetaxel, trastuzumab, and pertuzumab (T-DXd-THP), dose-dense doxorubicin and cyclophosphamide followed by docetaxel, trastuzumab, and pertuzumab (ddAC-THP), or trastuzumab deruxtecan monotherapy (T-DXd). The primary endpoint of the study was pathologic complete response (pCR) by blinded central review, and key secondary endpoints included event-free survival (EFS), invasive disease-free survival (iDFS), overall survival (OS), and safety.

    Median patient age was 50 years, 73% were hormone receptor (HR)–positive, and 89% had node-positive disease.

    The trial met its primary endpoint with T-DXd-THP achieving a pCR rate of 67.3% compared with 56.3% with ddAC-THP, an absolute difference of 11.2 percentage points (95% CI 4.0–18.3; P = .003). The benefit was observed in both HR-positive and HR-negative groups and independent of menopausal or HER2 status (IHC3+ vs other) status.

    Residual cancer burden (RCB) analyses echoed this finding: 81.3% of patients on T-DXd-THP had RCB 0/1, compared with 69.1% in the control arm.

    Event-free survival data were immature at the time of analysis but trended in favor of T-DXd-THP (HR, 0.56; 95% CI, 0.26–1.17). T-DXd monotherapy showed inferior EFS compared to ddAC-THP and was closed on March 13, 2024, as recommended by the independent data monitoring committee.

    Treatment with T-DXd-containing regimens resulted in fewer grade 3 or higher adverse events (AEs), lower hematologic toxicity, fewer treatment interruptions, and less left-ventricular dysfunction. The incidence of interstitial lung disease (ILD) was comparable between arms. T-DXd-THP treatment resulted in higher rates of nausea but were similar for other gastrointestinal toxicities. Adverse events leading to surgical delay occurred in 3.4% of T-DXd-THP patients vs 2.6% of those receiving ddAC-THP.

    Overall, the DESTINY-Breast11study showed that the combination of T-DXd with THP resulted in the highest pCR rates for a registrational trial to date with lower toxicity for patients with HER2+ eBC and may redefine the neoadjuvant standard for high-risk HER2-positive eBC, but longer-term outcomes are awaited. The study was published simultaneously to presentation in the Annals of Oncology.

    References

    Harbeck N, et al. Trastuzumab deruxtecan–based neoadjuvant therapy in high-risk HER2-positive early breast cancer. Abstract 291O, presented at: ESMO 2025 Congress; October 2025; Barcelona, Spain.

    Harbeck N, Modi S, Pusztai L, et al. Neoadjuvant trastuzumab deruxtecan alone or followed by paclitaxel, trastuzumab, and pertuzumab for high-risk HER2-positive early breast cancer (DESTINY-Breast11): a randomised, open-label, multicentre, phase 3 trial.

  • Four-Year Median OS with Osimertinib/ Chemotherapy Combination in Advanced EGFR-Mutation Positive NSCLC

    he final overall survival (OS) analysis from the FLAURA2 trial was presented during the International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer (WCLC) Presidential Symposium, firmly establishing osimertinib plus chemotherapy as a new first-line standard for patients with advanced epidermal growth factor receptor (EGFR)-mutated non–small cell lung cancer (NSCLC). The final OS analysis showed the longest survival yet reported in this population from a global phase 3 trial.

    FLAURA2 enrolled 557 patients with untreated, locally advanced or metastatic EGFR exon 19 deletion or L858R NSCLC. Patients with stable brain metastases were allowed on study. Participants were randomized to receive osimertinib with carboplatin or cisplatin plus pemetrexed for four cycles followed by maintenance osimertinib–pemetrexed, or osimertinib monotherapy at 80 mg daily. Treatment beyond progression was permitted if investigators judged clinical benefit. Subsequent therapy was at investigator discretion. Progression-free survival (PFS) was the primary endpoint, and OS was a key secondary endpoint.

    At the primary PFS analysis (data cut April 2023), the addition of chemotherapy reduced the risk of progression by 38% (HR 0.62; 95% CI 0.49–0.79; p<0.001), with median PFS of 25.5 months versus 16.7 months for osimertinib alone. These benefits were consistent across prespecified subgroups, including patients with brain metastases and those harboring L858R mutations.

    With extended follow-up to June 2025 (57% maturity), median OS reached 47.5 months in the osimertinib–chemotherapy arm compared with 37.6 months with osimertinib monotherapy (HR 0.77; 95% CI 0.61–0.96; p=0.02). Three-year OS was 63% versus 51%, respectively. The OS advantage was maintained across all predefined subgroups.

    Median osimertinib exposure was 30.5 months with the combination, versus 21.2 months with monotherapy. The median pemetrexed exposure in the experimental arm was 8.3 months, suggesting many patients experienced a prolonged chemotherapy-free interval.

    Patterns of subsequent therapy highlighted clinical practice implications. After progression, platinum-based chemotherapy was the most common second-line treatment in both arms, given to 44% of patients in the combination arm and 72% after osimertinib alone. Importantly, the OS benefit for the upfront combination was preserved despite widespread use of platinum rechallenge after monotherapy.

    Grade ≥3 adverse events (AEs) were more common with the combination (70% vs 34%). Anemia, diarrhea, nausea, and decreased appetite were the most common any-grade AEs.  Adverse events led to discontinuation of osimertinib in 12% of patients in the combination arm and 7% with monotherapy. No new safety signals or treatment-related deaths emerged during longer follow-up.

    These findings build on the FLAURA2 PFS advantage and confirm clinically meaningful OS improvement. Median OS of nearly four years represents the longest survival reported for EGFR-mutated NSCLC in a phase 3 global study. With compelling evidence across subgroups and no excess late toxicity, osimertinib plus chemotherapy is now firmly positioned as the frontline standard of care for EGFR-mutated advanced NSCLC.

    References

    Planchard D, Jänne PA, Kobayashi K, et al. First-line osimertinib plus chemotherapy versus osimertinib monotherapy in EGFR-mutated advanced NSCLC: FLAURA2 final overall survival. Presented at: IASLC World Conference on Lung Cancer (WCLC) 2025; September 7, 2025; Barcelona, Spain. Abstract PL01.06.