Fam-trastuzumab deruxtecan-nxki improves outcomes in gastric cancer subset
Fam-trastuzumab deruxtecan-nxki significantly improved outcomes compared with chemotherapy among patients with HER2-positive gastric cancer, according to study results presented during the ASCO20 Virtual Scientific Program.
Results of the randomized phase 2 DESTINY-Gastric01 trial were published simultaneously in The New England Journal of Medicine.
“Fam-trastuzumab deruxtecan-nxki [Enhertu; AstraZeneca, Daiichi Sankyo) is the first drug that has shown statistically significant and clinically meaningful improvement in response rate and OS [among patients with HER2-positive gastric cancer] who were treated with chemotherapy and trastuzumab [Herceptin, Genentech],” Kohei Shitara, MD, chief of the department of gastrointestinal oncology at National Cancer Center Hospital East in Chiba, Japan, told Healio. “This is extremely important in the context that there have been several failures — including [ado-trastuzumab emtansine (Kadcyla, Genentech)] and lapatinib [Tykerb, Novartis] after trastuzumab, as well as trastuzumab continuation beyond progression — in the past.”
Approximately 15% of patients with gastric cancer have overexpression or amplification of HER2. Although chemotherapy plus trastuzumab is the standard of care for HER2-positive gastric cancer, several randomized studies with other HER2-targeting agents failed to show a survival benefit.
“In addition, other available agents such as irinotecan, taxanes, ramucirumab [Cyramza, Eli Lilly] and immune checkpoint inhibitors have limited efficacy,” Shitara said. “Therefore, there is still an unmet need for patients with HER2-positive gastric cancer, especially after trastuzumab-containing therapy.”
Fam-trastuzumab deruxtecan-nxki is a novel antibody-drug conjugate with three components: a humanized anti-HER2 immunoglobulin G1 monoclonal antibody with the same amino acid sequence as trastuzumab; a topoisomerase 1 inhibitor payload; and a tetrapeptide-based cleavable linker.
DESTINY-Gastric01 included 187 patients from Japan and South Korea with HER2-expressing advanced gastric cancer or gastroesophageal junction adenocarcinoma who had progressed on two or more prior treatment regimens, including fluoropyrimidine and platinum chemotherapy and trastuzumab.
Shitara and colleagues randomly assigned 125 patients (median age, 65 years; range, 34-82) to fam-trastuzumab deruxtecan-nxki dosed at 6.4 mg/kg once every 3 weeks. The other 62 patients (median age, 66 years; range, 28-82) received investigator’s choice of chemotherapy, which consisted of paclitaxel (n = 7) or irinotecan monotherapy (n = 55).
ORR as assessed by independent review committee served as the primary endpoint. Secondary endpoints include OS, PFS, duration of response, disease control rate and time to treatment failure, as well as pharmacokinetic and safety endpoints.
Results showed a higher ORR (51.3% vs. 14.3%; P < .001) and a higher confirmed ORR (42.9% vs. 12.5%) in the fam-trastuzumab deruxtecan-nxki group. Eleven patients assigned fam-trastuzumab deruxtecan-nxki achieved complete response.
Several other outcomes also favored fam-trastuzumab deruxtecan-nxki, including median duration of response (11.3 months vs. 3.9 months), median OS (12.5 months vs. 8.4 months; HR = 0.59; 95% CI, 0.39-0.88), 1-year OS (52% vs. 29%), median PFS (5.6 months vs. 3.5 months; HR = 0.47; 95% CI, 0.31-0.71) and 1-year PFS (30% vs. 0%).
Researchers observed a higher rate of grade 3 or higher adverse events in the fam-trastuzumab deruxtecan-nxki group (85.6% vs. 56.5%), including decreased neutrophil count (51.2% vs. 24.2%), anemia (37.6% vs. 22.6%) and decreased white blood cell count (20.8% vs. 11.3%).
Twelve patients assigned fam-trastuzumab deruxtecan-nxki experienced drug-related interstitial lung disease and pneumonitis, including two grade 3 cases and one grade 4 case. One treatment-associated death occurred in the fam-trastuzumab deruxtecan-nxki group.
“Fam-trastuzumab deruxtecan-nxki holds promise for becoming a new treatment option among patients with advanced gastric cancer previously treated with trastuzumab,” Shitara said. “To confirm this encouraging activity of fam-trastuzumab deruxtecan-nxki, the single-arm phase 2 DESTINY-Gastric02 study is ongoing in the U.S. and Europe to evaluate the agent in the second-line setting after first-line trastuzumab. In addition, the phase 1b/phase 2 DESTINY-Gastric03 study of the safety and efficacy of fam-trastuzumab deruxtecan-nxki in advanced HER2-positive gastric cancer is now being planned.”