FDA grants priority review to Enhertu for gastric cancer subset
The FDA granted priority review to fam-trastuzumab deruxtecan-nxki for treatment of HER2-positive metastatic gastric cancer or gastroesophageal junction adenocarcinoma.
Fam-trastuzumab deruxtecan-nxki (Enhertu; AstraZeneca, Daiichi Sankyo) 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 (Herceptin, Genentech); a topoisomerase 1 inhibitor payload; and a tetrapeptide-based cleavable linker.
The agent is approved in the United States for treatment of adults with unresectable or metastatic HER2-positive breast cancer who received two or more prior anti-HER2-based regimens in the metastatic setting.
A supplemental biologics license application that seeks approval for the gastric cancer indication is based on results of the randomized phase 2 DESTINY-Gastric01 trial, which included 187 patients from Japan or South Korea with HER2-expressing advanced gastric or gastroesophageal junction adenocarcinoma. All patients had progressed on two or more prior treatment regimens, including fluoropyrimidine and platinum chemotherapy and trastuzumab.
Researchers 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).
Objective response rate 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.
As Healio previously reported, results showed a statistically significant improvement in ORR (51.3% vs. 14.3%; P < .001) among patients assigned fam-trastuzumab deruxtecan-nxki. 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%).
The most common grade 3 or higher treatment-emergent adverse events reported among patients assigned fam-trastuzumab deruxtecan-nxki included decreased neutrophil count, anemia, decreased white blood cell count and decreased appetite.
Twelve patients (9.6%) developed confirmed treatment-related interstitial lung disease or pneumonitis. Two cases were grade 3 and one case was grade 4. All others were grade 1 or grade 2.
The FDA is expected to make a decision on approval of fam-trastuzumab deruxtecan-nxki for this indication in the first quarter of 2021.
“Once patients with HER2-positive metastatic gastric cancer progress following initial treatment with an anti-HER2 regimen, there are no approved HER2-directed medicines,” José Baselga, MD, PhD, executive vice president for oncology research and development with AstraZeneca, said in a company-issued press release. “The prognosis for these patients is poor, as available treatment options offer only limited clinical benefit. This milestone brings us one step closer to delivering a potentially practice-changing medicine to patients with gastric cancer in the U.S.”