Second-Line Trastuzumab Emtansine Fails To Boost Advanced HER2-Positive Gastric Cancer OS

GATSBY trial participants given second-line trastuzumab emtansine did not have better overall survival than their taxane-treated counterparts

medwireNews: Final analysis of the GATSBY trial has failed to demonstrate an overall survival (OS) benefit for trastuzumab emtansine in the second-line setting for patients with human epidermal growth factor receptor 2 (HER2)-positive, locally advanced and metastatic gastric or gastro-oesophageal junction carcinoma.

“The findings from this trial suggest that trastuzumab emtansine is not superior to taxane treatment in patients with previously treated HER2-positive gastric cancer”, say Yoon-Koo Kang, from Asan Medical Center in Seoul, South Korea, and co-investigators.

“Thus, there is still no HER2-targeted standard treatment regimen for this patient group and therapeutic options remain limited”, they conclude in The Lancet Oncology.

The GATSBY trial employed a “unique seamless adaptive design” that allowed “instantaneous transition” from the phase II dose-finding stage to the phase III stage, the researchers explain, and at the pre-planned interim analysis a trastuzumab emtansine dose of 2.4 mg/kg per week was chosen for subsequent participants.

Intention to treat analysis for the 228 patients randomly assigned to receive trastuzumab emtansine at this dose gave a median OS of 7.9 months and this did not significantly differ from the 8.6 months in the 117 patients who were given docetaxel 75 mg/m2 every 3 weeks or paclitaxel 80 mg/m2 per week.

“Overall, the absence of a superiority in overall survival in patients with advanced gastric cancer treated with trastuzumab emtansine compared with those treated with taxanes cannot be explained by imbalances in demographic or baseline disease characteristics, toxicity, or drug administration”, the researchers say.

Hanna Sanoff, from the University of North Carolina in Chapel Hill, USA, writes in an accompanying comment that “[e]ven the theoretically improved toxicity profile of trastuzumab emtansine was not sufficiently benign to warrant continued development of single-agent trastuzumab emtansine as second-line treatment for gastroesophageal cancer.”

Specifically, trastuzumab emtansine 2.4 mg/kg per week was associated with fewer grade 3 or more severe adverse events than taxane therapy (60 vs 70%) but a similar incidence of adverse events leading to death (4 vs 4%), serious adverse events (29 vs 28%) and adverse events leading to discontinuation (14 vs 14%).

Nevertheless, she notes that the trial was still a “success” in some ways, demonstrating that trastuzumab emtansine is an active agent in gastro-oesophageal cancer including patients who had previously received trastuzumab therapy.

Summarising that “HER2 overexpression functions differently in second-line advanced gastric cancer compared with metastatic breast cancer”, Yoon-Koo Kang et al suggest that the heterogeneous and focal expression of HER2 in gastric cancer may contribute to the GATSBY trial outcome.

“The results of future clinical trials will clarify whether targeting the HER2 pathway with combination therapy, instead of monotherapy, or with activation of immune cells will improve efficacy after failure of first-line HER2-targeted therapy”, they conclude.

References

Thuss-Patience PC, Shah MA, Ohtsu A, et al. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction carcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol; Advance online publication 23 March 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30111-0

Sanoff HK. Targeting HER2 beyond progression in gastroesophageal cancer. Lancet Oncol; Advance online publication 23 March 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30102-X

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