In topline findings from the phase II DESTINY-BreastO1 study, [fam-] trastuzumab deruxtecan demonstrated encouraging responses in patients with unresectable and/or metastatic HER2-positive breast cancer that has been previously treated with ado-trastuzumab emtansine.
Jose Baselga, MD
In topline findings from the phase II DESTINY-BreastO1 study, [fam-] trastuzumab deruxtecan (DS-8201) demonstrated encouraging responses in patients with unresectable and/or metastatic HER2-positive breast cancer that has been previously treated with ado-trastuzumab emtansine (T-DM1; Kadcyla).1
These encouraging responses, which were assessed by an independent review committee, confirm the phase I findings previously reported in an international, heavily pretreated HER2-positive breast cancer population. The safety and tolerability of the agent were also consistent with prior results.
Based on these study findings, AstraZeneca, which manufactures the antibody-drug conjugate with Daiichi Sankyo, stated in a press release that it plans to submit a biologics license application to the FDA in the second half of 2019.
“We are encouraged to see positive data from [fam-] trastuzumab deruxtecan, with the DESTINY-Breast01 trial now reinforcing what earlier data have shown,” José Baselga, MD, PhD, executive vice president, R&D Oncology, AstraZeneca, said in the press release. “We believe this antibody-drug conjugate has the potential to redefine the treatment of patients with HER2-expressing cancers, and we are eager to bring it as quickly as possible to patients with refractory HER2-positive breast cancer who continue to have high unmet medical need.”
[Fam-] trastuzumab deruxtecan is comprised of a humanized HER2 antibody that is attached to a novel topoisomerase I inhibitor by a tetrapeptide-based linker; the drug overall is designed to target and deliver chemotherapy inside cancels and reduce exposure to the cytotoxic payload.
In the open-label, international, multicenter, two-part, phase II DESTINY-BreastO1 trial of [fam-] trastuzumab deruxtecan, researchers first identified the optimal dose as 5.4 mg/kg. Part 2 of the study evaluated the efficacy and safety of that dosage in patients with HER2-positive breast cancer who have failed or discontinued prior therapy with T-DM1.
The FDA previously granted [fam-] trastuzumab deruxtecan a breakthrough therapy designation in August 2017 for the treatment of patients with HER2-positive, locally advanced, or metastatic breast cancer who have been treated with trastuzumab (Herceptin) and pertuzumab (Perjeta) and have disease progression on T-DM1.
The designation was based on preliminary data from an ongoing, dose-escalation/dose-expansion phase I study, which showed promising antitumor activity and a tolerable safety profile with the ADC in patients with HER2-positive and -expressing cancers.2
In part 1 of the trial, a modified continuous reassessment method was used to identify the expansion dose in patients with HER2-positive breast or gastric cancer, while part 2 evaluated the safety and efficacy in 4 expansion cohorts: HER2-positive breast cancer previously treated with T-DM1, HER2-positive gastric cancer treated with trastuzumab, low-HER2expressing breast cancer, and other HER2-expressing solid tumors.
Results of part 1 showed that there were no dose-limiting toxicities and the maximum-tolerated dose was not reached. The part 2 dose was identified as 6.4 mg/kg and 5.4 mg/kg every 3 weeks.
Findings from part 2 of the trial, which were recently published inLancet Oncology, included 115 patients who received at least 1 dose of [fam-] trastuzumab deruxtecan, of which 111 were evaluable for confirmed response. Patients enrolled on this part of the study had a median 7 lines of prior therapy, including trastuzumab and T-DM1, as well as pertuzumab in 86% of cases.
Data showed that the overall response rate was 59.5% (95% CI, 49.7-68.7) and the disease control rate was 93.7% (95% CI, 87.4-97.4) with [fam-] trastuzumab deruxtecan.3Additionally, the median duration of response was 20.7 months (0.0-21.8), the median progression-free survival was 22.1 months (0.8-27.9), and the median overall survival has not yet been reached in the trial. As of the data cutoff of August 10, 2018, 55 (48%) patients remained on [fam-] trastuzumab deruxtecan.
Regarding safety, data for 115 patients with HER2-positive metastatic disease who received ≥1 dose of [fam-] trastuzumab deruxtecan at 5.4 or 6.4 mg/kg in part 1 or 2 of the trial were reported. The most common all-grade adverse events (AEs; ≥30%) included nausea, decreased appetite, vomiting, alopecia, fatigue, anemia, diarrhea, and constipation.
Fifty percent of patients experienced a grade ≥3 AE and 19% had a serious AE; this included 2 earlier reported cases of grade 5 treatment-related pneumonitis. Additionally, reported cases of interstitial lung disease or pneumonitis in the clinical development program for this agent are evaluated by an independent adjudication committee. A formal monitoring and management program is also in place to help determine the risk of these toxicities.