Updated data from recent clinical trials are shaping the future of targeted therapies for gastric and gastroesophageal junction (GEJ) cancers, refining treatment strategies and balancing efficacy with toxicity. These advancements, highlighted at the 2024 Sylvester Cancer Survivorship Symposium, include findings from the TOPGEAR, KEYNOTE-811, and DESTINY-Gastric03 trials, each addressing critical questions in the treatment paradigm.
TOPGEAR Trial: Evaluating Preoperative Chemoradiation
The phase 3 TOPGEAR trial (NCT01924819) investigated the role of preoperative radiotherapy in addition to perioperative chemotherapy for resectable gastric cancer. The study, predominantly conducted in Australia, randomized patients to receive either standard perioperative chemotherapy or chemotherapy plus preoperative chemoradiation. While the addition of chemoradiation nearly doubled the pathologic complete response (pCR) rate from approximately 8% to 16%, long-term follow-up revealed no improvement in progression-free survival or overall survival. The chemoradiation regimen, based on 5-fluorouracil, presented manageable toxicities, mainly fatigue and mild myelosuppression. These findings suggest that a higher pCR rate does not automatically translate to improved survival outcomes in gastric cancer, cautioning against over-reliance on pCR as a sole indicator of treatment success.
KEYNOTE-811: Pembrolizumab Plus Trastuzumab in HER2-Positive Cancers
KEYNOTE-811 (NCT03615326) is a phase 3, placebo-controlled study evaluating first-line pembrolizumab plus chemotherapy and trastuzumab versus placebo in HER2-positive metastatic GEJ cancers. Initial data from this study led to FDA approval of pembrolizumab for HER2-positive gastric cancer in 2021. The final overall survival (OS) analysis presented at the 2024 ESMO Congress, showed that the addition of trastuzumab and pembrolizumab improves OS. However, subgroup analysis based on the combined positive score (CPS) indicated that patients with higher CPS benefited more from the regimen, while those with lower CPS did not experience significant OS improvement. This suggests that pembrolizumab may be omitted in patients with low CPS, reserving it for those more likely to respond to immunotherapy. The safety profile of pembrolizumab plus trastuzumab and chemotherapy requires careful monitoring for cardiopulmonary adverse effects, such as pneumonitis and heart failure.
DESTINY-Gastric03: Exploring T-DXd Combinations
DESTINY-Gastric03 (NCT04379596) is a phase 1b/2 trial assessing fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) combinations in HER2-positive gastric cancer. The study included patients with unresectable, locally advanced or metastatic esophageal adenocarcinoma, as well as gastric or GEJ adenocarcinoma, all with HER2-positive, treatment-naive disease. Patients received different combinations of T-DXd, with or without chemotherapy and immunotherapy. Preliminary results showed good overall response rates across all groups, indicating that T-DXd combinations are active in the first-line setting. However, the study also reported notable toxicities, including interstitial lung disease (ILD) or pneumonitis, particularly in the group receiving T-DXd at the full dose alongside chemotherapy and immunotherapy. These findings suggest that while T-DXd combinations can produce good responses, careful dose optimization and monitoring for ILD are essential to ensure patient safety.
Implications for Clinical Practice
These trials collectively emphasize a shift toward targeted and systemic treatment strategies in gastric and GEJ cancers. The TOPGEAR trial highlights the importance of validating pCR with long-term survival outcomes, while KEYNOTE-811 refines the use of pembrolizumab based on CPS scores. DESTINY-Gastric03 explores the potential of T-DXd in earlier lines of treatment, balancing efficacy with toxicity. As research continues, these advancements promise to further personalize and improve outcomes for patients with gastric and GEJ cancers.
