Trastuzumab emtansine ‘not superior’ to taxanes in advanced HER2-positive gastric cancer
medwireNews: The GATSBY trial finds no significant difference in outcomes between patients with advanced human epidermal growth factor receptor 2 (HER2)-positive gastric cancer given second-line trastuzumab emtansine and those given a taxane.
These results indicate that the antibody–drug conjugate is “not superior” to taxanes in this setting, say the investigators. “There is still an unmet need in this patient group and therapeutic options remain limited.”
In the first stage of the phase II/III trial, patients with unresectable, locally advanced, or metastatic gastric cancer who had progressed during or after first-line treatment with a platinum agent plus fluoropyrimidine were randomly assigned to receive trastuzumab emtansine at one of two doses – 3.6 mg/kg every 3 weeks (n=70) or 2.4 mg/kg once a week (n=75) – or a taxane (n=37), either docetaxel or paclitaxel at the physician’s discretion.
After the independent data monitoring committee selected the 2.4 mg/kg dose based on a prespecified interim analysis, an additional 153 patients were randomly assigned to receive trastuzumab emtansine at this dose while a further 80 were given a taxane.
In the intention-to-treat population comprising all patients who received the selected dose of trastuzumab emtansine or a taxane, the primary endpoint of overall survival (OS) did not differ significantly between treatment arms, at a median of 7.9 and 8.6 months, respectively.
And there was no OS benefit of trastuzumab emtansine over taxane in any clinical or biomarker subgroup, such as patients previously treated with trastuzumab or not.
Trastuzumab emtansine treatment did not significantly improve any of the secondary endpoints either compared with taxane therapy, achieving, for instance, comparable progression-free survival (median 2.7 vs 2.9 months) and objective response rates (20.6 vs 19.6%) between the groups.
Yoon-Koo Kang (University of Ulsan College of Medicine, Seoul, Korea) and fellow researchers say that their results suggest that “HER2 overexpression functions differently in second-line advanced gastric cancer compared with metastatic breast cancer,” where trastuzumab emtansine has been shown to significantly improve survival relative to standard therapies.
Unlike breast cancer, “HER2 overexpression in gastric cancer is often heterogeneous and it is not clear how focal HER2 expression might affect the activity of trastuzumab emtansine,” the team writes in The Lancet Oncology.
Despite the negative results, commentator Hanna Sanoff, from the University of North Carolina in Chapel Hill, USA, does not consider GATSBY a failure, believing that it offers “meaningful lessons.”
“[T]he trial unequivocally proved that trastuzumab emtansine is an active agent in gastroesophageal cancer,” and as shown by the subgroup analyses, its efficacy is not modified by prior trastuzumab treatment, indicating that “HER2 remains a relevant target” for some patients after progression on trastuzumab, she notes.
The commentator does think, however, that in some ways the trial was “a missed opportunity.”
“Had a combination arm of trastuzumab emtansine plus chemotherapy been included in the phase 2 lead-in stage, we would have had a better idea of whether trastuzumab emtansine is worth pursing in trastuzumab-refractory disease,” Sanoff writes.
She continues: “However, as there will probably be little desire to initiate another massive international effort in third-line treatment, trastuzumab emtansine’s place in gastroesophageal cancer remains uncertain as we await the results of ongoing single-arm trials investigating the combination of trastuzumab emtansine with chemotherapy or immunotherapy.”
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