Trastuzumab emtansine disappoints in HER2-positive advanced gastroesophageal cancer

Last Updated: 2017-04-14

By Will Boggs MD

NEW YORK (Reuters Health) - The HER2-targeted monoclonal antibody trastuzumab coupled with the tubulin inhibitor emtansine is no better than taxane against previously treated, HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma, according to results from the GATSBY study.

The antibody–drug conjugate trastuzumab emtansine is approved for the treatment of HER2-positive metastatic breast cancer, and its efficacy in that cancer provided the rationale for testing it in patients with HER2-positive gastric cancer.

Dr. Yoon-Koo Kang from Ulsan College of Medicine, Seoul, South Korea and colleagues compared outcomes with trastuzumab emtansine versus taxane in 345 patients with previously treated HER2-positive advanced gastric cancer, in a randomized open-label phase 2/3 study.

During median follow-ups of 17.5 months for trastuzumab emtansine and 15.4 months for taxane, median overall survival (the primary endpoint) was 7.9 months in the trastuzumab emtansine group and 8.6 months in the taxane group (p=0.86).

As reported March 23rd online in Lancet Oncology, survival outcomes were similar in all the clinical and biomarker subgroups.

Trastuzumab emtansine showed antitumor activity, but it did not prolong progression-free survival compared with taxane treatment (median, 2.7 months versus 2.9 months, respectively).

The incidence of grade 3 or higher adverse events was lower with trastuzumab emtansine (60%) than with taxane (70%), although the proportion of patients discontinuing treatment because of an adverse event was the same in both groups (14%).

“Trastuzumab emtansine was not superior to taxane in patients with previously treated, HER2-positive advanced gastric cancer,” the researchers conclude. “There is still an unmet need in this patient group and therapeutic options remain limited.”

“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 note.

“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,” writes Dr. Hanna K. Sanoff from University of North Carolina, Chapel Hill, North Carolina in a related editorial. “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 (NCT01702558).”

“For now, we will have to be satisfied with knowing that HER2 is a valid target after progression on trastuzumab, and that trastuzumab emtansine is an active-and probably important-drug in HER2-positive gastroesophageal cancer,” she said.

Dr. Daisuke Takahari from Japanese Foundation for Cancer Research, Tokyo, Japan told Reuters Health by email, “HER2 overexpression functions differently in second-line gastric cancer compared with breast cancer.”

“Further research is needed, such as genomic alterations before and after trastuzumab, loss of HER2 overexpression, and using trastuzumab beyond progression,” Dr. Takahari said.

F Hoffman-LaRoche funded the trial, employed four of the 15 authors, and had various relationships with four other authors, including Dr. and Kang.

Dr. Kang did not respond to a request for comments.

SOURCE: http://bit.ly/2nE3dFd and http://bit.ly/2naNiD9

Lancet Oncol 2017.