Trastuzumab Deruxtecan Shows Preliminary Activity in HER2-Positive Gastric/GEJ Cancer

The HER2-targeted antibody-drug conjugate (ADC) trastuzumab deruxtecan (DS-8201a) demonstrated promising activity and manageable safety profile in patients with HER2-positive gastric or gastroesophageal junction (GEJ) cancer, meeting the primary end point of the study, according to a press release.¹

“We are excited to report positive top-line results from this trial,” Gilles Gallant, Senior Vice President, Global Head, Oncology Development, Oncology R&D, Daiichi Sankyo, said. “Our development plan remains on track in gastric cancer, including an initial regulatory application in Japan where gastric cancer is highly prevalent, and where SAKIGAKE designation has been granted for this indication. We are strongly committed to bringing this therapy as rapidly as possible to patients in need.” Sakigake is a strategy promoted by the Japanese Ministry of Health, Labour, and Welfare to lead the world in the accelerated approval process of prompt practical application of innovative medical products, including medical devices.²

The primary end point of the phase II DESTINY-Gastric01 was objective response rate (ORR). Trastuzumab deruxtecan achieved a statistically significant and clinically meaningful ORR, as well as overall survival (OS), which was a key secondary end point. The safety and tolerability profiles were also consistent with previous findings and confirm the findings of the non-randomized phase I trial of trastuzumab deruxtecan. Data from the phase II study will be presented at an upcoming medical meeting.

In the 2-part, first-in-human, open-label, phase I study, the HER2-targeted ADC was evaluated in patients with HER2-positive gastric/GEJ cancer. Data were published inThe Lancet Oncology.³

Overall, 44 patients with HER2-positive gastric or GEJ cancer were assessed in this analysis, of which 3 patients were included in part 1 and 41 in part 2. Nineteen patients received 5.4 mg/kg of the study drug, and 25 patients received 6.4 mg/kg. Treatments were given intravenously once every 3 weeks until either withdrawal of consent, unacceptable toxicity, or progressive disease (PD). Tumors were assessed by CT or MRI scans every 6 weeks for the first 24 weeks and every 12 weeks thereafter.

After a median follow-up of 5.5 months, 19 patients (43.2%) achieved an objective response by investigator assessment (95% CI, 28.3-59.0), and 35 patients (79.5%) achieved disease control (95% CI, 64.7-90.2). The objective response rate (ORR) was 43.2% (95% CI, 28.3-59.0). The median time to response was 1.4 months (95% CI, 1.3-1.6), and the median duration of response was 7.0 months (95% CI, 4.4-16.6).

Nineteen patients (43%) achieved a PR, 16 patients (36%) achieved stable disease (SD), and 9 patients (20%) had PD. The median progression-free survival (PFS) was 5.6 months in all 44 patients (95% CI, 3.0-8.3). The median overall survival (OS) was 12.8 months (95% CI, 1.4-25.4). Of the 19 patients who achieved an objective response, 6 were in the 5.4 mg/kg cohort (31.6%) versus 13 in the 6.4 mg/kg cohort (52.0%).

Investigators also evaluated 24 patients who previously received treatment with irinotecan in a post-hoc analysis. Overall, 10 of these patients (41.7%) had an objective response, and 19 (79.2%) had disease control. Ten patients (42%) had achieved a PR, 9 patients (38%) had SD, and 5 patients (21%) had PD. The ORR was 41.7% (95% CI, 22.1-63.4). The median PFS was 4.1 months (95% CI, 2.4-8.3).

As of the data cutoff on August 10, 2018, 41 out of 44 patients (93%) discontinued treatment, and the most common reasons included progressive disease (73%) and AEs (14%). The median duration of treatment was 4.4 months, overall.

Out of the 44 patients with gastric/GEJ cancer, each patient had at least 1 grade 3 or greater treatment-emergent adverse events (TEAEs), and 11 patients had at least 1 serious TEAE; however, 21 (48%) and 4 (9%) were considered related to trastuzumab deruxtecan. The only serious TEAE that was related to treatment was decreased appetite, observed in 2 patients. Drug-related TEAEs that led to discontinuation included pneumonitis, decreased appetite, and decreased platelet count. An additional 7 patients (16%) received dose reductions due to drug-related TEAEs, and 2 patients died from TEAEs, including pneumonia and progression of disease.

The most common TEAEs of any grade were gastrointestinal (GI) and hematologic events. The most common TEAEs of grade 3 or greater included anemia (30%) and decreased platelet count (18%). One case of ejection fraction decrease was reported, which was grade 2, and 1 patient experienced electrocardiogram QT prolongation of grade 3; however, these events were recovered, and patients continued on treatment.

The study enrolled patients at 8 institutions in the United States, as well as 6 in Japan. Part 1 was a dose-escalation study to determine the dose-limiting toxicities and a maximum tolerated dose for the dose-expansion phase, part 2, of the study. In the second part, the drug was evaluated for safety, tolerability, and activity across 5 cohorts of patients, which included advanced, unresectable, or metastatic HER2-positive breast cancer after trastuzumab emtansine (cohort 2a); HER2-positive gastric or gastroesophageal junction cancer post-trastuzumab (cohort 2b); HER2-low-expressing breast cancer (cohort 2c); other HER2-expressing or HER2-mutant solid tumors (cohort 2d); and HER2-expressing advanced, unresectable, or metastatic breast cancer (cohort 2e).

Patients had to be at least 18 years of age in the United States or 20 in Japan to enroll in this study with an ECOG performance status of 0 or 1. They had to have measurable disease based on RECIST v1.1 criterion and a life expectancy of at least 3 months. HER2 status was assessed with archival samples, but new biopsies prior to treatment were not necessary for DESTINY-Gastric01.

“Several other ongoing studies are investigating the efficacy and safety of trastuzumab deruxtecan in different HER2-expressing solid tumor types, including HER2-positive breast cancer, as monotherapy or in combination with other agents,” study authors wrote. “These studies will further expand our understanding of trastuzumab deruxtecan efficacy and safety in various settings. If the results in gastric cancer are confirmed in subsequent trials, trastuzumab deruxtecan might become a new treatment option for patients with HER2-positive gastric cancer who have previously received trastuzumab.”

References:

1. Phase II DESTINY-Gastric-01 trial of Enhertu versus chemotherapy met primary endpoint [news release]. Cambridge, United Kingdom: Astra Zeneca; January 27, 2020. https://bit.ly/38MHR0i. Accessed January 28, 2020.
2. Ministry of Health, Labour and Welfare. Strategy of sakigake (press release). June 17, 2014.https://bit.ly/36wb5z3. January 28, 2020.
3. Shitara K, Iwata  H, Takahashi S, et al. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, a phase 1 study [Published online: April 29, 2019]. The Lancet. doi.org/10.1016/S1470-2045(19)30088-9.