Trastuzumab Deruxtecan or Ramucirumab plus Paclitaxel in Gastric Cancer

Author(s): Kohei Shitara, M.D.¹; Eric Van Cutsem, M.D., Ph.D.^2,3; Mahmut Gümüş, M.D.^4,5; Sara Lonardi, M.D.⁶; Christelle de la Fouchardière, M.D.⁷; Clélia Coutzac, M.D., Ph.D.⁷; Jeroen Dekervel, M.D., Ph.D.^2,3; Daniel Hochhauser, M.D., Ph.D.⁸; Lin Shen, M.D., Ph.D.^9,10; Wasat Mansoor, M.D., Ph.D.¹¹; Bo Liu, M.D., Ph.D.¹²; Lorenzo Fornaro, M.D.¹³; Min-Hee Ryu, M.D., Ph.D.^14,15; Jeeyun Lee, M.D.¹⁶; Cátia Faustino, M.D.¹⁷; Jean-Philippe Metges, M.D.¹⁸; Josep Tabernero, M.D., Ph.D.^19,20; Fábio Franke, M.D.²¹; Yelena Y. Janjigian, M.D.²²; Fabricio Souza, M.D.²³; Lori Jukofsky, M.S.²³; Yumin Zhao, Ph.D.²³; Takahiro Kamio, M.D.²³; Aziz Zaanan, M.D., Ph.D.^24,25; Filippo Pietrantonio, M.D.²⁶; for the DESTINY-Gastric04 Trial Investigators*;

Source: DOI: 10.1056/NEJMoa2503119

Dr. Anjan Patel's Thoughts

The DESTINY-Gastric04 trial compared trastuzumab deruxtecan (T-DXd) vs ramucirumab + paclitaxel as second-line therapy for HER2+ advanced gastric or gastroesophageal junction (GEJ) cancer, showing significant improvements in progression-free survival (PFS) (7.1 vs 5.7 months) and overall survival (OS) (13.6 vs 10.2 months). The antibody-drug conjugate (ADC) also achieved a higher objective response rate (43.6% vs 28.4%). This is no surprise as this T-DXd seems to be a game changer in many diseases. Toxicities were as expected.

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.

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; ³University of Leuven, Leuven, Belgium; ⁴Istanbul Medeniyet University, Istanbul, Turkey; ⁵Prof. Dr. Suleyman Yalcin City Hospital, Istanbul, Turkey; ⁶Veneto Institute of Oncology IRCCS, Padua, Italy; ⁷Centre Leon Berard, Lyon, France; ⁸University College Hospital Macmillan Cancer Centre, London; ⁹State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing; ¹⁰Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing; ¹¹Christie NHS Foundation Trust, Manchester, United Kingdom; ¹²Shandong Cancer Hospital, Jinan City, China; ¹³Azienda Ospedaliero–Universitaria Pisana, Pisa, Italy; ¹⁴Asan Medical Center, Seoul, South Korea; ¹⁵University of Ulsan College of Medicine, Seoul, South Korea; ¹⁶Samsung Medical Center, Seoul, South Korea; ¹⁷Instituto Português de Oncologia do Porto, Porto, Portugal; ¹⁸Institut de Cancérologie et d’Imagerie, Arpego Network, Centre Hospitalier Universitaire de Brest, Brest, France; ¹⁹Vall d’Hebron Hospital Campus and Institute of Oncology, Barcelona; ²⁰University of Vic–Central University of Catalonia, Barcelona; ²¹Oncosite-Oncoclínicas, Ijuí, Brazil; ²²Memorial Sloan Kettering Cancer Center, New York; ²³Daiichi Sankyo, Basking Ridge, NJ; ²⁴Department of Gastroenterology and Digestive Oncology, Paris-Cité University, Paris; ²⁵George Pompidou European Hospital, Paris; ²⁶Fondazione IRCCS Istituto Nazionale dei Tumori, Milan;

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