Japanese regulators have granted a Sakigake designation to trastuzumab deruxtecan (DS-8201), for the treatment of patients with HER2-positive gastric cancer that is refractory to trastuzumab (Herceptin), according to Daiichi Sankyo, the manufacturer of the antibody-drug conjugate.
The Sakigake designation from the Ministry of Health, Labor and Welfare gives trastuzumab deruxtecan prioritized consultation, a dedicated review system to support the development and review process, and a reduced review time from the normal 12 months to 6 months.
“There are no HER2-targeting treatment options currently available for patients with HER2-positive gastric cancer whose tumors are no longer controlled by trastuzumab,” Koichi Akahane, PhD, executive officer, head of Oncology Function, R&D Division, Daiichi Sankyo, said in a statement.
“We look forward to working closely with the Japan Ministry of Health, Labor and Welfare under the terms of the Sakigake program to accelerate the development of trastuzumab deruxtecan, particularly since Japan has one of the highest incidence rates of gastric cancer worldwide,” added Akahane.
The Sakigake designation was granted based on findings for the novel investigational HER2-targeting antibody-drug conjugate presented 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 with heavily pretreated HER2-expressing gastric cancer. Among 23 patients who received prior irinotecan treatment, the ORR and DCR were 43.5% and 82.6%, respectively.
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 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 led to the pivotal phase II DESTINY-Gastric01 trial, in which the efficacy and safety of trastuzumab deruxtecan are being explored in patients with HER2-expressing unresectable and/or metastatic gastric cancer that has progressed despite 2 prior lines of therapy.
In August 2017, the FDA granted trastuzumab deruxtecan a breakthrough therapy designation for the treatment of patients with HER2-positive, locally advanced, or metastatic breast cancer who have been treated with trastuzumab and pertuzumab (Perjeta) and have disease progression after ado-trastuzumab emtansine (T-DM1; Kadcyla).
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.