Overall survival also extended with conjugate treatment

In a small, phase II trial, patients with advanced gastric cancer were far more likely to respond to conjugate therapy with trastuzumab deruxtecan (Enhertu) than with chemotherapy regimens, researchers reported in the New England Journal of Medicine and at the virtual annual meeting of the American Society of Clinical Oncology.

About 51% of patients treated with the conjugate agent achieved an objective response to therapy compared to 14% of gastric cancer patients who were treated with irinotecan or paclitaxel (P<0.001), reported Kohei Shitara, MD, chief of experimental therapeutics and gastrointestinal oncology at the National Cancer Center Hospital East, Tokyo, and colleagues.

They also reported that overall survival in the pre-treated patients who were assigned trastuzumab deruxtecan was 12.4 months compared with a median overall survival of 8.4 months for patients treated with chemotherapy (P=0.01).

“Overall, treatment with trastuzumab deruxtecan led to a significantly higher percentage of patients with an objective response and to longer overall survival than conventional chemotherapy among patients with HER2-positive, advanced gastric or gastroesophageal junction cancer,” Shitara said in his report. “Antitumor activity was noted in patients who had had disease progression while they had been receiving regimens including trastuzumab.”

The phase II DESTINY-Gastric01 trial included patients with HER2-expressing, locally advanced or metastatic gastric or gastroesophageal junction cancer that had progressed after the patient had received at least two previous treatment regimens, which included a fluoropyrimidine, a platinum agent, and trastuzumab or an approved biosimilar agent. HER2 levels were documented as high — a score of 3-plus on immunohistochemical analysis or score of 2-plus with positive results on in situ hybridization — or low — a score of 2-plus with negative results on in situ hybridization or a score of 1-plus.

Shitara and colleagues enrolled 187 patients with advanced gastric cancer, and 125 were assigned to receive trastuzumab deruxtecan while 62 patients were assigned to the chemotherapy regimens. They reported that 101 of 187 patients died: 62 of 125 patients (50%) in the trastuzumab deruxtecan group, and 39 of 62 (63%) in the physician’s choice group. The estimated overall survival was 80% in the trastuzumab deruxtecan group and 66% in the physician’s choice group at 6 months and was 52% and 29%, respectively, at 12 months.

“In DESTINY-Gastric01, patients treated with trastuzumab deruxtecan demonstrated a statistically significant and clinically meaningful improvement in objective response rate as assessed by an independent review committee as well as in overall survival compared to patients treated with investigator’s choice of chemotherapy,” Wasif Saif, MD, deputy physician-in-chief and medical director at the Northwell Health Cancer Institute, Lake Success, New York, told BreakingMed when asked to comment on the research. “Whereas combination chemotherapy has been shown to improve survival and tumor related symptoms in the front-line setting, second-line therapy has been subject to much debate in the oncology community, mainly because of the debilitating effects of gastric cancer, which would impede the administration of cytotoxic therapy.”

He added: “Trastuzumab deruxtecan has the potential to meaningfully advance the treatment of patients with HER2 positive metastatic gastric cancer as the first ever antibody drug conjugate approved to treat this type of cancer. It is expected to be tested in first-line treatment as well as in combination with other agents.”

Saif noted that gastric cancer is the fifth most common cancer worldwide and the third leading cause of cancer mortality. “Approximately one in five gastric cancers are HER2 positive,” Saif said. “Gastric cancer is usually diagnosed in the advanced stage, but even when diagnosed in earlier stages of the disease the survival rate remains modest. Current recommended first-line treatment for HER2 positive advanced or metastatic gastric cancer is combination chemotherapy plus trastuzumab, an anti-HER2 medicine, which has been shown to improve outcomes when added to chemotherapy.

“However, neither trastuzumab nor other approved HER2 targeting agent has shown benefit in patients with gastric cancer who has progressed on first line treatment,” he added.

Shitara reported that the patients were recruited from Nov. 2017-May 2019 at 48 sites in Japan and 18 sites in South Korea. The characteristics of the patients were balanced across the two groups, the researcher said. The median age was 65 years old and 24% were women. All the patients fell in ECOG performance status of 0-1, and about 77% of patients were in the high HER2-positive group; patients had received a median of two previous systemic therapies for advanced or metastatic disease, and 31 patients (17%) had received at least four previous therapies; 72% of the patients had previously received ramucirumab, and 86% had received taxanes. The median time since the last administration of trastuzumab was 5.9 months among patients in the trastuzumab deruxtecan group and 6.5 months among those in the physician’s choice group.

At the data cutoff in Nov. 2019, 22% of the patients in the trastuzumab deruxtecan group and 5% of those in the physician’s choice group were continuing to receive treatment. The median duration of treatment was 4.6 months in the trastuzumab deruxtecan group and 2.8 months in the physician’s choice group.

“In this trial,” Shitara noted, “the notable adverse events occurring with trastuzumab deruxtecan were myelosuppression and interstitial lung disease, which were managed by appropriate dose reduction or interruption. Although most gastrointestinal events were of low grade, hematologic events were more frequently of grade 3 or higher with trastuzumab deruxtecan than with chemotherapy.

“These toxic effects were often addressed with dose modification. Although HER2-targeted therapies, including trastuzumab, have been associated with cardiotoxic effects, this was not observed in our trial,” he said.

The trial was sponsored and designed by Daiichi Sankyo and was approved by the institutional review board at each participating site. Data were analyzed and interpreted by the sponsor and authors. In March 2019, AstraZeneca entered into a collaboration agreement with Daiichi Sankyo for trastuzumab deruxtecan. AstraZeneca was not involved in data collection but was involved in data interpretation as well as review of the manuscript and approval of its submission for publication.

  1. In this phase II trial, treatment of HER2 positive locally advanced or metastatic gastric or gastroesophageal junction cancers with trastuzumab deruxtecan was associated with a greater response rate than with standard chemotherapies.

  2. The trial also revealed that a 4 month improvement in overall survival was observed in these patients who had already gone through at least 2 lines of therapy.

Edward Susman, Contributing Writer, BreakingMED™

The DESTINY trial was funded by Daiichi Sankyo.

Shitara reported grants and non-financial support from Daiichi Sankyo, during the conduct of the study; grants and personal fees from Astellas Pharma, grants and personal fees from Eli Lilly and Company, personal fees from Bristol-Myers Squibb, personal fees from Takeda Pharmaceuticals, personal fees from Pfizer Inc, grants and personal fees from Ono Pharmaceutical, personal fees from Novartis , personal fees from AbbVie Inc, personal fees from Yakult, grants from Dainippon Sumitomo Pharma, grants from Daiichi Sankyo, grants and personal fees from Taiho Pharmaceutical, grants from Chugai Pharma, grants and personal fees from Merck Pharmaceutical, grants from Medi Science, and personal fees from GlaxoSmithKline outside the submitted work.

Saif disclosed no relevant relationships with industry.

Cat ID: 122

Topic ID: 78,122,730,122,935,192,925,172