An accelerated filing of a biologics license application is planned for [fam-] trastuzumab deruxtecan (DS-8201) as a treatment for patients with HER2-positive metastatic breast cancer previously treated with ado-trastuzumab emtansine.
Antoine Yver, MD
An accelerated filing of a biologics license application (BLA) is planned for [fam-] trastuzumab deruxtecan (DS-8201) as a treatment for patients with HER2-positive metastatic breast cancer previously treated with ado-trastuzumab emtansine (T-DM1; Kadcyla), according to Daiichi Sankyo, the developer of the investigational HER2-targeted antibody-drug conjugate.1
The submission of the BLA, which was initially planned for 2020, is scheduled for the first half of fiscal year 2019. The application will be based on findings from the phase II DESTINY-Breast01 study, which will be presented at an upcoming medical meeting.
“We are pleased to confirm the acceleration of the [fam-] trastuzumab deruxtecan clinical development program for this potential indication in patients with HER2-positive metastatic breast cancer pretreated with T-DM1 ahead of schedule,” Antoine Yver, MD, MSc, executive vice president and global head, Oncology Research and Development of Daiichi Sankyo, said in a press release. “Simultaneously, we are committed to our aggressive development strategy evaluating the potential of [fam-] trastuzumab deruxtecan across a spectrum of HER2-expressing cancers, including breast, gastric, lung, and colorectal.”
The international, multicenter, open-label, two-part, phase II DESTINY-Breast01 study is evaluating the safety and efficacy of [fam-] trastuzumab deruxtecan in patients with HER2-positive unresectable and/or metastatic breast cancer who were previously treated with T-DM1.
The primary endpoint is objective response rate (ORR); secondary endpoints include duration of response (DOR), disease control rate (DCR), clinical benefit rate, progression-free survival (PFS), and overall survival.
Part 1 of the study includes a pharmacokinetic and a dose-finding stage to determine the recommended dose of the antibody-drug conjugate, which will be evaluated in part 2 of the trial. The second part enrolled patients into cohorts of those who are resistant/refractory to T-DM1 (part 2a) and those who discontinued treatment with T-DM1 for other reasons (part 2b). Enrollment on the trial, which includes approximately 230 patients at more than 100 international sites, was completed in September 2018.
Additionally, Daiichi Sankyo announced that it has entered a global development and commercialization agreement with AstraZeneca for [fam-] trastuzumab deruxtecan.2 Both Daiichi Sankyo and AstraZeneca will jointly develop and commercialize the antibody-drug conjugate as a single agent or in combination internationally, with the exception of Japan, which is where Daiichi Sankyo maintains exclusive rights. Also, Daiichi Sankyo will be solely responsible for the manufacturing and supply of [fam-] trastuzumab deruxtecan.
As part of the terms of the agreement, AstraZeneca will provide Daiichi Sankyo an upfront payment of $1.35 billion. Moreover, contingent payments of up to $5.55 billion include $3.8 billion for achievement of future regulatory milestones and other contingencies and sales-related milestones of up to $1.75 billion. The total payments have the potential to reach up to $6.90 billion.
"[Fam-] trastuzumab deruxtecan is the flagship asset in our oncology pipeline created by our relentless pursuit of science and technology, the most important strengths of our company," George Nakayama, representative director, chairman and CEO of Daiichi Sankyo Company, Limited, said in a press release.
"Through the strategic collaboration with AstraZeneca, a company with a wealth of global experience and expertise in oncology, we will combine our respective skill sets to maximize the value of [fam-] trastuzumab deruxtecan, and accelerate the establishment of our global oncology business. By aiming to provide new treatment options across a wide range of cancers as soon as possible, we will maximize our contribution to patients with cancer and their families around the world," added Nakayama.
[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.
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 findings from an ongoing, dose-escalation/dose-expansion phase I study, which showed promising antitumor activity and a tolerable safety profile in patients with HER2-positive and -expressing cancers.3
In part 1 of the trial, a modified continuous reassessment method 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-HER2—expressing 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.
In patients with breast cancer, the ORR in patients receiving part 2 doses was 42.2%; the DCR was 97.8%. Among patients who had prior treatment with T-DM1, the ORR was 45.7% and the DCR was 100%, and in those with prior T-DM1 plus pertuzumab, the corresponding rates were 46.7% and 100%, respectively. Moreover, the median PFS for patients with breast cancer was 45.4 weeks (95% CI, 32.1—not reached).
Long-term findings of the study, which were presented at the 2018 ASCO Annual Meeting, showed that among 160 evaluable patients, the ORR was 50.6% (n = 81) by RECIST v1.1 criteria, and the highest ORR reported was 54.5% in the HER2-positive breast cancer population; the DCR was 93.9%, the median PFS was not reached, and the median DOR was not reached.4