Trastuzumab Deruxtecan or Ramucirumab plus Paclitaxel in Gastric Cancer

Author(s): Kohei Shitara, M.D.1; Eric Van Cutsem, M.D., Ph.D.2; Mahmut Gümüş, M.D.3; Sara Lonardi, M.D.4; Christelle de la Fouchardière, M.D.5; Clélia Coutzac, M.D., Ph.D.5; Jeroen Dekervel, M.D., Ph.D.2; Daniel Hochhauser, M.D., Ph.D.6; Lin Shen, M.D., Ph.D.7; Wasat Mansoor, M.D., Ph.D.8; Bo Liu, M.D., Ph.D.9; Lorenzo Fornaro, M.D.10; Min-Hee Ryu, M.D., Ph.D.11; Jeeyun Lee, M.D.12; Cátia Faustino, M.D.13; Jean-Philippe Metges, M.D.14; Josep Tabernero, M.D., Ph.D.15; Fábio Franke, M.D.16; Yelena Y. Janjigian, M.D.17; Fabricio Souza, M.D.18; Lori Jukofsky, M.S.18; Yumin Zhao, Ph.D.18; Takahiro Kamio, M.D.18; Aziz Zaanan, M.D., Ph.D.19; Filippo Pietrantonio, M.D.20
Source: N Engl J Med 2025;393:336-348
Original Article
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Dr. Anjan Patel's Thoughts

The phase III DESTINY-Gastric04 trial randomized HER2+ metastatic gastric/GEJ adenocarcinoma progressing on trastuzumab to T-DXd versus RAM+PTX, showing a significant overall survival (OS) benefit with T-DXd (14.7 vs 11.4 months) and improved PFS (6.7 vs 5.6 months). Objective response rate (ORR) was higher with T-DXd (44.3% vs 29.1%), and duration of response was longer (7.4 vs 5.3 months). Grade ≥3 AE rates were comparable (50.0% vs 54.1%), though adjudicated ILD/pneumonitis was more frequent with T-DXd (13.9% vs 1.3%, mostly grade 1–2), underscoring the need for vigilant monitoring. Bottom line: T-DXd looks like the new second-line standard for HER2+ disease that stays HER2-positive post-trastuzumab—meaningful survival gains. Please make sure to plan for a repeat biopsy in this setting.

BACKGROUND

On the basis of phase 2 studies, trastuzumab deruxtecan was approved for patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic gastric cancer or gastroesophageal junction adenocarcinoma who had previously received trastuzumab-based therapy. Ramucirumab plus paclitaxel is also a standard second-line treatment option regardless of HER2 status.

METHODS

We conducted an international, randomized, phase 3 trial comparing second-line trastuzumab deruxtecan at a dose of 6.4 mg per kilogram of body weight with ramucirumab plus paclitaxel in patients with HER2-positive metastatic gastric cancer or gastroesophageal junction adenocarcinoma confirmed on tumor biopsy conducted after the patient had progression while receiving trastuzumab-based therapy. The primary end point was overall survival. Secondary end points included progression-free survival, confirmed objective response (complete or partial response lasting ≥4 weeks), disease control, duration of response, and safety. Research Summary Trastuzumab Deruxtecan or Ramucirumab +Paclitaxel in Gastric Cancer

RESULTS

Among 494 patients who had undergone randomization, overall survival was significantly longer with trastuzumab deruxtecan than with ramucirumab plus paclitaxel (median, 14.7 vs. 11.4 months; hazard ratio for death, 0.70; 95% confidence interval, 0.55 to 0.90; P=0.004). Significant results were also seen with regard to progression-free survival (hazard ratio for disease progression or death, 0.74; 95% CI, 0.59 to 0.92) and confirmed objective response (in 44.3% of the patients in the trastuzumab deruxtecan group vs. 29.1% of those in the ramucirumab–paclitaxel group). The incidence of drug-related adverse events of any grade was 93.0% with trastuzumab deruxtecan and 91.4% with ramucirumab plus paclitaxel; the incidence of drug-related adverse events of grade 3 or higher was 50.0% and 54.1%, respectively. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 13.9% of the patients who received trastuzumab deruxtecan (grade 1 or 2 in 33 patients and grade 3 in 1) and in 1.3% of those who received ramucirumab plus paclitaxel (grade 3 in 2 patients and grade 5 in 1).

CONCLUSIONS

Trastuzumab deruxtecan led to significantly longer overall survival than ramucirumab plus paclitaxel among patients with HER2-positive metastatic gastric cancer or gastroesophageal junction adenocarcinoma. Adverse events were common in both groups. Events of interstitial lung disease or pneumonitis with trastuzumab deruxtecan, a known risk, were mainly low-grade. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Gastric04 ClinicalTrials.gov number, NCT04704934.)

Author Affiliations

1National Cancer Center Hospital East, Kashiwa, Japan; 2University Hospitals Gasthuisberg, Leuven, Belgium; 3Istanbul Medeniyet University, Istanbul, Turkey; 4Veneto Institute of Oncology IRCCS, Padua, Italy; 5Centre Leon Berard, Lyon, France; 6University College Hospital Macmillan Cancer Centre, London; 7State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing; 8Christie NHS Foundation Trust, Manchester, United Kingdom; 9Shandong Cancer Hospital, Jinan City, China; 10Azienda Ospedaliero–Universitaria Pisana, Pisa, Italy; 11Asan Medical Center, Seoul, South Korea; 12Samsung Medical Center, Seoul, South Korea; 13Instituto Português de Oncologia do Porto, Porto, Portugal; 14Institut de Cancérologie et d’Imagerie, Arpego Network, Centre Hospitalier Universitaire de Brest, Brest, France; 15Vall d’Hebron Hospital Campus and Institute of Oncology, Barcelona; 16Oncosite-Oncoclínicas, Ijuí, Brazil; 17Memorial Sloan Kettering Cancer Center, New York; 18Daiichi Sankyo, Basking Ridge, NJ; 19Department of Gastroenterology and Digestive Oncology, Paris-Cité University, Paris; 20Fondazione IRCCS Istituto Nazionale dei Tumori, Milan

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