FDA Grants Trastuzumab Deruxtecan Priority Review for HER2+ Breast Cancer

José Baselga, MD, PhD

The FDA has granted a priority review designation to a biologics license application (BLA) for [fam-] trastuzumab deruxtecan (DS-8201) for the treatment of patients with HER2-positive metastatic breast cancer.¹

The BLA is supported by data from a phase I trial² and the pivotal phase II DESTINY-Breast01 trial.³ Under the Prescription Drug User Fee Act, the action date for the BLA is in the second quarter of 2020, according to AstraZeneca and Daiichi Sankyo, the companies developing the antibody-drug conjugate.

“Trastuzumab deruxtecan has the potential to transform the treatment landscape for patients with HER2-positive metastatic breast cancer who have limited treatment options today. This priority review draws on the strength and the consistency of results seen in the phase I and phase II trials and is a critical step on the journey to deliver this potential new medicine to patients,” José Baselga, MD, PhD, executive vice president, Oncology R&D, AstraZeneca, said in a press release.

Phase I Trial

In part I of the phase I 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 ado-trastuzumab emtansine (T-DM1; Kadcyla), HER2-positive gastric cancer treated with trastuzumab (Herceptin), 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.

Findings from part 2 of the trial 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.³ Additionally, 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.

Phase II DESTINY-Breast01 Study

In the open-label, international, multicenter, two-part, phase II DESTINY-Breast01 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.

According to AstraZeneca, “The response rate observed in DESTINY-Breast01, as assessed by an independent review committee, validated the clinical activity observed in the phase I trial.”1 The results of the trial are scheduled to be presented in December at the 2019 San Antonio Breast Cancer Symposium.

“We are pleased that the FDA has accepted the application and granted priority review, as we believe trastuzumab deruxtecan has the potential to redefine the treatment of patients with HER2-positive metastatic breast cancer. Following the recent regulatory submission in Japan, we look forward to working closely with regulatory authorities to bring trastuzumab deruxtecan to patients in the US and Japan as soon as possible,” Antoine Yver, MD, MSc, executive vice president and global head, Oncology Research and Development, Daiichi Sankyo, said in the press release.

References

1. Trastuzumab deruxtecan granted FDA Priority Review for treatment of patients with HER2-positive metastatic breast cancer. AstraZeneca. Published October 17, 2019. Accessed October 17, 2019. https://bit.ly/32AJcVe.
2. Tamura K, Tsurutani J, Takahashi S, et al. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study. Lancet Oncol. 2019 Jun;20(6):816-826. doi: 10.1016/S1470-2045(19)30097-X.
3. Trastuzumab deruxtecan demonstrated clinically-meaningful response in patients with refractory HER2-Positive Metastatic breast cancer, a population with high unmet need. AstraZeneca. Published May 8, 2019. Accessed October 17, 2019. https://bit.ly/2Q1SuEF.