Trastuzumab deruxtecan leads to longer overall survival than ramucirumab plus paclitaxel in HER2-positive gastric cancer

1. In this randomized controlled trial, among adults with HER2-positive unresectable or metastatic gastric cancer who had previously progressed on trastuzumab-based therapy, it was found that trastuzumab deruxtecan resulted in longer overall survival than ramucirumab plus paclitaxel.

2. The overall incidence of adverse events was similar between the two groups, although trastuzumab deruxtecan was associated with a greater risk of interstitial lung disease or pneumonitis.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Among all types of cancer, gastric cancer ranks fifth in both prevalence and mortality. The current standard first-line therapy for patients with advanced HER2-positive gastric cancer is chemotherapy plus trastuzumab. For second-line therapy following progression during trastuzumab-based therapy, ramucirumab plus paclitaxel is an established treatment option. Trastuzumab deruxtecan is a novel antibody-drug conjugate that has been shown in phase two trials to produce a better response and longer overall survival compared to paclitaxel as second-line or later treatment of advanced HER2-positive gastric cancer. However, while trastuzumab deruxtecan has been approved in multiple countries as second- or third-line therapy for such patients, a confirmatory phase three trial of trastuzumab deruxtecan as second-line therapy is needed to allow for broader access to this treatment. The present trial assessed the efficacy and safety of trastuzumab deruxtecan compared with ramucirumab plus paclitaxel as second-line therapy in patients with HER2-positive unresectable or metastatic gastric cancer. Trastuzumab deruxtecan was found to be superior to ramucirumab plus paclitaxel with respect to overall survival, progression-free survival, and objective response. Additionally, with regard to safety, the incidence of adverse events was generally similar between the two groups. However, trastuzumab deruxtecan was associated with a greater risk of interstitial lung disease or pneumonitis. The trial was limited by its inability to assess significance within subgroups. Nevertheless, these findings show that trastuzumab deruxtecan has superior efficacy as second-line therapy in patients with advanced HER2-positive gastric cancer compared with the established treatment of ramucirumab plus paclitaxel.

Click to read the study in NEJM

In-Depth [randomized controlled trial]: This international, randomized, phase three trial compared the efficacy and safety of trastuzumab deruxtecan with that of ramucirumab plus paclitaxel as second-line treatment for HER2-positive unresectable or metastatic gastric cancer. Adults with HER2-positive unresectable or metastatic gastric cancer confirmed via a tumor biopsy conducted following progression during trastuzumab-based therapy and who had an Eastern Cooperative Oncology Group (ECOG) performance-status score of zero or one were included. Participants were randomly assigned in a 1:1 ratio to receive trastuzumab deruxtecan or ramucirumab plus paclitaxel. The primary efficacy outcome was overall survival. Secondary efficacy outcomes included progression-free survival, confirmed objective response, disease control, and duration of response. The primary safety outcome was adverse events, with interstitial lung disease or pneumonitis and left ventricular dysfunction considered to be adverse events of special interest. A total of 494 patients were included in the study, with 246 assigned to the trastuzumab deruxtecan group and 248 to the ramucirumab plus paclitaxel group. The median overall survival was 16.8 months in the trastuzumab deruxtecan group (95% Confidence Interval [CI], 14.0 to 20.0) compared with 14.4 months in the ramucirumab-paclitaxel group (95% CI, 13.1 to 19.7). Thus, overall survival was significantly longer in the trastuzumab deruxtecan group than in the ramucirumab-paclitaxel group (hazard ratio for death, 0.70; 95% CI, 0.55 to 0.90; p=0.004). Median progression-free survival was also significantly longer with trastuzumab deruxtecan (6.7 months) than with ramucirumab plus paclitaxel (5.6 months). A confirmed objective response was achieved in 44.3% of patients in the trastuzumab deruxtecan group compared with 29.1% of participants in the ramucirumab-paclitaxel group, and the median duration of response was 7.4 months and 5.3 months, respectively. With regards to safety, while a high percentage of patients in the trial had adverse events, the incidence of adverse events was generally similar between the two groups. In summary, trastuzumab deruxtecan was found to result in significantly prolonged overall survival when used as second-line therapy for HER2-positive unresectable or metastatic gastric cancer compared with the established treatment of ramucirumab plus paclitaxel.

Image: PD

©2025 2 Minute Medicine, Inc. All rights reserved. No works may be reproduced without expressed written consent from 2 Minute Medicine, Inc. Inquire about licensing here. No article should be construed as medical advice and is not intended as such by the authors or by 2 Minute Medicine, Inc.