ASCO 2020-NO BENEFIT OF TRASTUZUMAB IN ESOPHAGEAL CANCER

Although HER-targeted therapy represents a standard of care for many HER2-positive malignancies, data supporting its benefit for patients with early-stage HER2-overexpressing esophageal adenocarcinoma are lacking. Results of the RTOG 1010 trial demonstrated that adding trastuzumab both before and after chemoradiotherapy and surgery did not significantly improve disease-free survival (DFS) beyond that achieved with trimodality therapy alone, thus failing to meet the primary study endpoint (Abstract 4500).

“The results of this trial were clearly disappointing,” lead study investigator Howard P. Safran, MD, of Rhode Island Hospital–Brown University, said. Dr. Safran had hoped that RTOG 1010 would establish trastuzumab as a routine component of early-stage cancer care for patients with HER2-positive esophageal adenocarcinoma, just as the ToGA trial had done in the late-stage setting for patients with metastatic HER2-positive gastroesophageal adenocarcinoma.¹

Dr. Barbara Burtness

RTOG 1010 was a randomized phase III trial sponsored by the National Cancer Institute that included 203 patients with newly diagnosed, HER2-overexpressing T1N1-2 or T2-3N0-2 adenocarcinoma of the esophagus. All patients received paclitaxel and carboplatin for 6 consecutive weeks concurrent with fractionated radiotherapy, followed thereafter by surgery. Patients assigned to the experimental arm also received seven weekly doses of trastuzumab prior to surgery, followed by 13 doses of trastuzumab administered every 3 weeks after surgery.

All major outcomes of RTOG 1010 showed no significant differences between the treatment arms. Median DFS, the primary endpoint, reached 19.6 months for the group that received trastuzumab in combination with trimodality therapy as compared with 14.2 months for the group that received only trimodality therapy (HR 0.97, 95% CI [0.69, 1.36]; p = 0.85). Median overall survival (OS) reached 38.5 months in the trastuzumab-containing arm versus 38.9 months in the arm lacking trastuzumab (HR 1.01, 95% CI [0.69, 1.47]; p = 0.95). Likewise, the pathologic complete response rate was 27% for the arm that received trastuzumab as compared with 29% for the arm that did not (p = 0.71).

Notably, the similarities in efficacy also carried over to safety. Incorporation of perioperative trastuzumab with trimodality therapy did not lead to marked increases in grade 3 or higher cardiac toxicity (5% vs. 3%), hematologic events (56% vs. 57%), gastrointestinal disorders (29% vs. 21%), infections (12% vs. 7%), or metabolism and nutrition disorders (13% vs. 20%) when compared with standard trimodality therapy alone.

Irrespective of any potential methodologic weaknesses of the trial, “the lack of any effect on response, DFS, or OS indicates that the main issue here is trastuzumab resistance,” Discussant Barbara Burtness, MD, of Yale School of Medicine and the Yale Cancer Center, said.

Dr. Safran noted that additional analyses of the RTOG 1010 results are underway to identify factors that may have influenced the response to trastuzumab—for example, the degree of HER2 overexpression or the presence of genomic alterations that may confer intrinsic resistance to trastuzumab, such as KRASmutations, PI3K mutations, or PTEN alterations.

Dr. Burtness agreed that these analyses will be important, but she believes “the issue of adaptive resistance with upregulation of HER3 or MET may be more pertinent.”

“Despite the negative results of RTOG 1010, HER2 remains an important target, and it will be important to study in the perioperative setting,” Dr. Burtness said. Toward this end, she mentioned both the JACOB trial² and the PETRARCA trial (Abstract 4502), which evaluated perioperative trastuzumab and pertuzumab in combination with chemotherapy.

“Despite the negative results of RTOG 1010, HER2 remains an important target, and it will be important to study in the perioperative setting.” - Dr. Barbara Burtness

“I think there is evidence from the JACOB trial… that combination trastuzumab and pertuzumab has some success in addressing HER3 expression and HER3-mediated adaptive resistance, and I think a phase III trial in the perioperative setting is warranted,” Dr. Burtness said.

In addition to dual HER2 targeting, Dr. Safran also believes it worthwhile to explore next-generation HER2 inhibitors in esophageal adenocarcinoma, such as antibody-drug conjugates like trastuzumab deruxtecan or HER2-directed immunotherapies like DF1001.

– Kara Nyberg, PhD