Trastuzumab Deruxtecan Active in HER2-Expressing Gastric Cancer

Toshihiko Doi, MD, PhD

The novel investigational HER2-targeting antibody-drug conjugate trastuzumab deruxtecan (DS-8201a) showed promising antitumor activity in heavily pretreated patients with HER2-expressing gastric cancer, according to an ongoing phase I trial presented at the at the 2018 Gastrointestinal Cancers Symposium.

In the first-in-human trial, the confirmed objective response rate (ORR) per RECIST v1.1 criteria was 45.5% and the disease control rate (DCR) was 81.8% among 44 evaluable patients. Among 23 patients who received prior irinotecan treatment, ORR and DCR were 43.5% and 82.6%, respectively. The toxicity profile was manageable.

“Gastric cancer can be difficult to treat due to its molecular complexity, and currently there are no HER2-targeted therapies or antibody-drug conjugates approved for HER2-positive advanced gastric cancer that progresses following treatment with trastuzumab,” senior study author Toshihiko Doi, MD, PhD, Department of Experimental Therapeutics, National Cancer Center Hospital East, said in a statement. “These phase I results are encouraging and demonstrate the importance of continuing to study the potential of DS-8201 in treating HER2-positive gastric cancer. The pivotal phase II study is currently underway.”

Trastuzumab is the only HER2-targeted therapy to demonstrate an overall survival (OS) benefit in patients with HER2-positive gastric cancer. Previous clinical trials of the newer HER2-targeted therapies trastuzumab emtansine and lapatinib failed to significantly improve OS compared with standard chemotherapy in this setting, according to lead presenter Satoru Iwasa, MD, from the National Cancer Center Hospital Chuoku, Tokyo.

Trastuzumab deruxtecan has a topoisomerase I inhibitor payload, a proprietary drug linker, and a high drug-to-antibody ratio (DAR) of 7 to 8. The high DAR and the permeable payload may lead to more potent antitumor activity in a heterogeneous tumor microenvironment and in low HER2-expressing cancers, as demonstrated in preclinical work, explained Iwasa.

At the time of data cutoff for the presentation, 45 patients with gastric or gastroesophageal junction adenocarcinoma were treated in an open-label fashion with trastuzumab deruxtecan at a dosage of 5.4 or 6.4 mg/kg. Four were included in the dose escalation phase (part 1)—3 dosed with 5.4 mg/kg and 1 with 6.4 mg/kg. In part 2 of the study, 17 were dosed with 5.4 mg/kg and 24 with 6.4 mg/kg. The median patient age was 68 years; 73.3% had Eastern Cooperative Oncology Group (ECOG) performance status of 0 and 26.7% had an ECOG Performance Status of 1.

Forty three of the 44 evaluable patients had HER2-positive tumors. HER2 expression was 3+ on immunohistochemistry in 80% of patients. More than one-fourth (26.7%) of patients had received 5 or more prior anticancer regimens. Forty-four of the 45 had prior trastuzumab and 24 (53.3%) had received irinotecan previously. The median number of lines of therapy was 3.

The median progression-free survival was 5.8 months in the overall evaluable population and 4.1 months in those treated with irinotecan previously. The median duration of response was 7.0 months in the efficacy evaluable patients, and 6.9 months in those with prior irinotecan exposure. The vast majority (83%) of patients experienced tumor shrinkage.

Most treatment-emergent adverse events (TEAE) were grade 3 or lower. Four patients had a grade 3 nonhematologic TEAE; 1 with nausea and 3 experienced decreased appetite. The most common nonhematologic TEAEs overall were nausea (71%), decreased appetite (64.4%), constipation (31.1%), vomiting (22.2%), diarrhea (22.2%), and pyrexia (22.2%).

Grade ≥3 hematologic TEAEs were anemia (24.4%), thrombocytopenia (17.8%), leukopenia (15.5%), and neutropenia (20%). Hematologic TEAEs of any grade included anemia in 35.6% of patients, thrombocytopenia in 33.3%, leukopenia in 33.3%, and neutropenia in 28.9%. Three patients discontinued treatment due to a TEAE (pneumonia, decreased appetite, and pneumonitis).

Other adverse events included 1 case of a grade 2 reduction in ejection fraction and 2 potential cases of interstitial lung disease that need to be confirmed by an independent adjudication committee.

The promising safety and efficacy data support a pivotal phase II trial called DESTINY-Gastric01, in which the efficacy and safety of trastuzumab deruxtecan is being explored in patients with HER2-expressing unresectable and/or metastatic gastric cancer that has progressed despite 2 prior lines of therapy, Iwasa said.

Iwasa S, Shitara K, Takahashi S, et al. Updated results of phase 1 study of DS-8201a in subjects with HER2-expressing gastric cancer. Presented at: 2018 Gastrointestinal Cancers Symposium; January 18-20, 2018; San Francisco, Calif. Abstract 118.

<<< View more from the 2018 GI Cancer Symposium