May 11, 2020
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FDA grants breakthrough therapy designation to Enhertu for gastric cancer subset

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The FDA granted breakthrough therapy designation to fam-trastuzumab deruxtecan-nxki for treatment of patients with HER2-positive unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma.

The designation applies to use of fam-trastuzumab deruxtecan-nxki (Enhertu; AstraZeneca, Daiichi Sankyo) by patients who received two or more prior regimens, including trastuzumab (Herceptin, Genentech).

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.

The FDA granted accelerated approval to the agent in December for treatment of adults with unresectable or metastatic HER2-positive breast cancer who received at least two prior anti-HER2-based regimens in the metastatic setting.

The FDA based the most recent breakthrough therapy designation in part on results from the phase 2 DESTINY-Gastric01 trial, which included 188 patients from Japan and South Korea with HER2-experssing advanced gastric cancer or gastroesophageal junction adenocarcinoma who had progressed on two or more prior treatment regimens, including fluoropyrimidine and platinum chemotherapy and trastuzumab.

About one in five patients with gastric cancers has HER2-positive disease.

In DESTINY-Gastric01, researchers randomly assigned patients 2:1 to receive fam-trastuzumab deruxtecan-nxki dosed at 6.4 mg/kg once every 3 weeks or investigator’s choice of chemotherapy — paclitaxel or irinotecan monotherapy.

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.

Results showed patients assigned fam-trastuzumab deruxtecan-nxki achieved statistically significant and clinically meaningful improvements in ORR and OS compared with those assigned chemotherapy.

The agent exhibited a safety and tolerability profile consistent with that observed in a phase 1 trial. The most common adverse events were hematologic and gastrointestinal in nature, including decreased neutrophil count, anemia, nausea and decreased appetite.

Researchers observed cases of drug-related interstitial lung disease and pneumonitis. Two were grade 3 and one was grade 4. No patients in the phase 1 or phase 2 trials died due to interstitial lung disease.

Complete results from DESTINY-Gastric-01 will be presented at this year’s ASCO20 Virtual Scientific Program.

José Baselga, MD, PhD
Jose Baselga

“Current therapy options are limited for patients with HER2-positive metastatic gastric cancer and, for those who relapse, there are no approved HER2-targeted medicines,” José Baselga, MD, PhD, executive vice president for oncology research and development at AstraZeneca, said in a company-issued press release. “We look forward to working with the FDA to further explore the potential of Enhertu to become an important new treatment and the first antibody-drug conjugate for this devastating disease.”