The European Society for Medical Oncology (ESMO) Congress 2025 in Berlin featured many important trials with the potential to significantly influence clinical practice and improve outcomes for patients with multiple tumor types. These studies highlighted the benefits of novel treatment combination regimens, immunotherapies, and innovative approaches to the treatment of solid tumors. Here we highlight some of the key trials reported in genitourinary cancers, breast cancer, non-small cell lung cancer, gastrointestinal cancers, and ovarian cancer.
GUEST EDITOR
Sumanta Pal, MD, FASCO
Dr. Pal is Co-director, Kidney Cancer Program; Professor, Department of Medical Oncology & Therapeutics Research; and Vice Chair of Academic Affairs, Department of Medical Oncology & Therapeutics Research at City of Hope Comprehensive Cancer Center in Duarte, California.
Genitourinary Cancers
Attendees to ESMO 2025 responded enthusiastically to the results from the phase III KEYNOTE-905/EV-303 study presented by Christof Vulsteke, MD, PhD, Head of Integrated Cancer Center Ghent and Guest Professor at the University of Antwerp, Belgium.1
In the study, first-line perioperative enfortumab vedotin-ejfv plus pembrolizumab significantly improved event-free survival, overall survival, and pathologic complete response rates in patients with muscle-invasive bladder cancer who were ineligible for or declined cisplatin chemotherapy.
The combination demonstrated a median overall survival of not reached vs 41.7 months with surgery alone and a pathologic complete response rate of 57.1% vs 8.6%, establishing it as the first perioperative regimen to improve outcomes in this difficult-to-treat patient population.
In the global phase III open-label POTOMAC trial, the PD-L1–targeting monoclonal antibody durvalumab in combination with bacillus Calmette-Guérin (BCG) therapy was evaluated in 1,018 patients with BCG-naive high-risk non–muscle-invasive bladder cancer from more than 120 sites in 12 countries.
The study was presented by Maria De Santis, MD, Head of the Interdisciplinary Uro-Oncology Section at Charité–Universitätsmedizin, Berlin, Germany. 2
The addition of 1 year of the PD-L1 inhibitor durvalumab to standard induction and maintenance BCG infusions led to a statistically significant and clinically meaningful improvement in disease-free survival compared with BCG induction alone, reported Dr. De Santis.
The addition of the targeted radionuclide therapy lutetium-177–labeled PSMA-617 (vipivotide tetraxetan; 177Lu-PSMA-617) to standard-of-care androgen deprivation therapy and an androgen receptor pathway inhibitor significantly improved radiographic progression-free survival in patients with prostate-specific membrane antigen (PSMA)-positive metastatic hormone-naive prostate cancer. Scott T. Tagawa, MD, MS, FACP, FASCO, Richard A. Stratton Associate Professor in Hematology and Oncology and an Associate Professor of Clinical Medicine & Urology at Weill Cornell Medicine in New York City, presented the findings of the PSMAddition trial. 3
These results mark the first time a targeted radionuclide therapy has demonstrated benefit in this patient population, Dr. Tagawa reported, noting that the results suggest a potential novel option in early-line treatment strategies.
Study discussant Arun Azad, MBBS, PhD, FRACP, expressed some concerns, however. Dr. Azad is a Medical Oncologist and Translational Researcher at Peter MacCallum Cancer Centre in Melbourne, Australia. He acknowledged the significance of the trial but raised several critical issues about its broad applicability. Chief among these issues was the lack of overall survival benefit at the first interim analysis. Due to the trial’s crossover design, overall survival benefit would likely be diluted with longer follow-up, Dr. Azad theorized, drawing parallels to metastatic hormone-resistant prostate cancer trials (PSMAfore, PR21) where early 177Lu-PSMA-617 use did not improve overall survival.
Breast Cancer
A planned interim analysis of the phase III DESTINY-Breast05 study of 1,635 high-risk patients found that treatment with the antibody drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd) led to a statistically significant and clinically meaningful improvement in invasive disease–free survival, the primary endpoint, over another antibody-drug conjugate, ado-trastuzumab emtansine (T-DM1), the current standard.
Results of the trial were presented as a late-breaking abstract by Charles Geyer, MD, Professor of Medicine at the University of Pittsburgh.4 Dr. Geyer reported that in DESTINY-Breast05, treatment with T-DXd yielded nearly a 9% absolute improvement in 3-year invasive disease–free survival over T-DM1. He added that findings from the phase III DESTINY-Breast05 trial are positioning T-DXd as a new standard of care for patients treated with neoadjuvant therapy for HER2-positive early breast cancer with residual invasive cancer after neoadjuvant therapy who are at high risk for recurrence.
Non-Small Cell Lung Cancer
In the phase III HARMONi-6 trial, conducted in China, the bispecific antibody ivonescimab given with chemotherapy improved progression-free survival over the PD-1 inhibitor tislelizumab-jsgr plus chemotherapy, representing a 40% reduction in risk as first-line treatment of advanced squamous non–small cell lung cancer (NSCLC).
Shun Lu, MD, PhD, presented the interim analysis, noting that the addition of ivonescimab to chemotherapy showed significant improvement in efficacy with a manageable safety profile.5 Dr. Lu is Professor and Chief of the Shanghai Lung Cancer Center at Shanghai Chest Hospital in China.
Tislelizumab has been approved by the European Medicines Agency and China’s National Medical Products Administration as a first-line treatment of advanced squamous NSCLC. Ivonescimab targets PD-1 and VEGF and is approved in China for patients who have nonsquamous NSCLC and experience disease progression on EGFR-targeted tyrosine kinase inhibitors, as well as a first-line therapy for patients with PD-L1–expressing advanced NSCLC.
In another NSCLC study, Li Zhang, MD, of Sun Yat-sen University Cancer Center, Guangzhou, China, presented results of the randomized, multicenter, phase III OptiTROP-Lung04 study.6 Sacituzumab tirumotecan, a novel TROP2 antibody-drug conjugate, was found to significantly improve both progression-free and overall survival compared with platinum-based chemotherapy in patients with EGFR-mutated NSCLC who had experienced disease progression following EGFR tyrosine kinase inhibitor therapy. Data were presented during the ESMO 2025 Congress and simultaneously published in TheNew England Journal of Medicine.These data position sacituzumab tirumotecan as a potential new standard of care for this challenging patient population.
Dr. Zhang reported that the phase III OptiTROP-Lung04 study demonstrated a highly statistically significant and clinically meaningful improvement across key efficacy endpoints. He added that the safety profile was manageable, with no unexpected signals and notably no reported cases of interstitial lung disease or pneumonitis.
Gastrointestinal Cancers
Josep Tabernero, MD, PhD, FASCO, presented the final report from the global phase III MATTERHORN trial in patients with resectable gastric and gastroesophageal junction adenocarcinomas, showing that the addition of durvalumab to perioperative FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) resulted in a significant improvement in overall survival, with benefit seen regardless of PD-L1 status.7
Dr. Tabernero is with Vall d’Hebron Institute of Oncology, Barcelona.
The analysis also showed improved event-free survival regardless of the extent of pathologic response or node involvement. The results appear to support perioperative durvalumab plus FLOT as a new global standard of care.
In a separate study in gastrointestinal cancers, Sun Young Rha, MD, PhD, reported findings of the phase III FORTITUDE-101 trial.8 Dr. Rha is Professor of Medical Oncology and Director of the Songdang Institute for Cancer Research at the Yonsei University College of Medicine, Seoul, South Korea.
Dr. Rha reported that the addition of the anti-FGFR2b antibody bemarituzumab to mFOLFOX6 chemotherapy met its primary endpoint and significantly improved overall survival in patients with FGFR2b-overexpressing unresectable, locally advanced or metastatic gastric or gastroesophageal junction cancer.
Ovarian Cancer
In the phase III ENGOT-ov65/KEYNOTE-B96 trial, first-line pembrolizumab plus weekly paclitaxel, with or without bevacizumab, significantly improved investigator-assessed progression-free survival in both the PD-L1 CPS (combined positive score) ≥ 1 and overall populations of patients with platinum-resistant recurrent ovarian cancer.9
The findings of the first and second interim analyses were presented by Nicoletta Colombo, MD, PhD, of the University of Milan-Bicocca, and Director of the Gynecologic Oncology Program at the European Institute of Oncology. The regimen also demonstrated a statistically significant and clinically meaningful improvement in overall survival in the PD-L1 CPS ≥ 1 population with subsequent confirmation of overall survival benefit in the overall population in a later analysis. Dr. Colombo noted that this regimen achieved one of the longest reported overall survivals in this setting and demonstrated a manageable safety profile.
Additional details on each of these studies are included in the individual reports in this supplement to The ASCO Post. For more information and video interviews with some of the investigators, visit ASCOPost.com/newsreels.
Disclosure: Dr. Pal reported receiving support from CRISPR, Ipsen, and Exelixis.
References
1. Vulsteke C, Kaimakliotis H, Danchaivijitr P, et al: Perioperative enfortumab vedotin plus pembrolizumab in participants with muscle-invasive bladder cancer who are cisplatin-ineligible: The phase 3 KEYNOTE-905 study. ESMO Congress 2025. Abstract LBA2. Presented October 18, 2025.
2. De Santis M, Palou J, Nishiyama H et al: Durvalumab in combination with Bacillus Calmette-Guerin (BCG) for BCG-naive, high-risk non-muscle-invasive bladder cancer: Final analysis of the phase III, open-label, randomised POTOMAC trial. ESMO Congress 2025. Abstract LBA108. Presented October 17, 2025.
3. Tagawa ST, Sartor O, Piulats JM, et al: Phase 3 trial of [177Lu]Lu-PSMA-617 combined with ADT + ARPI in patients with PSMA-positive metastatic hormone-sensitive prostate cancer (PSMAddition). ESMO Congress 2025. Abstract LBA6. Presented October 19, 2025.
4. Geyer CE, et al: ESMO Congress 2025. Abstract LBA1. Presented October 18, 2025.
5. Lu S, Yang F, Jiang Z, et al: Phase III study of ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy as first-line treatment for advanced squamous non-small cell lung cancer (HARMONi-6). ESMO Congress 2025. Abstract LBA4. Presented October 19, 2025.
6. Zhang L, Fang W, Wu L, et al: Sacituzumab tirumotecan vs platinum-based chemotherapy in EGFR-mutated non-small cell lung cancer following progression on EGFR-TKIs: Results from the randomized, multi-center phase 3 OptiTROP-Lung04 study. ESMO Congress 2025. Abstract LBA5. Presented October 19, 2025.
7. Tabernero J, Al-Batran SE, Wainberg ZA, et al: Final overall survival and the association of pathological outcomes with event-free survival in MATTERHORN: A randomised, phase III study of durvalumab plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) in resectable gastric/gastroesophageal junction adenocarcinoma. ESMO Congress 2025. Abstract LBA81. Presented October 17, 2025.
8. Rha SY, Pazo Cid RP, Montes AF, et al: Bemarituzumab plus chemotherapy for advanced or metastatic FGFR2b-overexpressing gastric or gastroesophageal junction cancer: FORTITUDE-101 phase III study results. ESMO Congress 2025. Abstract LBA10. Presented October 20, 2025.
9. Colombo N, Zsiros E, Sebastianelli A, et al: Pembrolizumab vs placebo plus weekly paclitaxel ± bevacizumab in platinum-resistant recurrent ovarian cancer: Results from the randomized double-blind phase III ENGOT-ov65/KEYNOTE-B96 study. ESMO Congress 2025. Abstract LBA3. Presented October 18, 2025.
