FDA Issues Complete Response Letter for Trastuzumab Duocarmazine in Advanced HER2+ Breast Cancer

The FDA has issued a complete response letter (CRL) to the biologics license application (BLA) for vic-trastuzumab duocarmazine (SYD985) for the treatment of patients with HER2-positive unresectable, locally advanced or metastatic breast cancer.¹

In the CRL, the regulatory agency requested additional information that will require additional time and resources that extend beyond the current evaluation period, according to an announcement from the drug’s developer, Byondis.

“We continue to believe that [trastuzumab duocarmazine] can present a meaningful treatment option for patients living with HER2-positive metastatic breast cancer,” Marco Timmers, PhD, chief executive officer of Byondis, stated in a news release. “We appreciate the FDA’s guidance and support and will carefully evaluate the CRL and consider potential next steps. We will continue with the [trastuzumab duocarmazine] applications in [the] European Union and United Kingdom, and await the outcome of the review process.”

The BLA was originally accepted by the FDA in July 2022, and the application was based on data from the phase 3 TULIP trial (NCT03262935), which showed that the antibody-drug conjugate elicited a significant improvement in progression-free survival (PFS) compared with physician’s choice of therapy, meeting the primary end point of the study.^2,3

Patients treated with trastuzumab duocarmazine (n = 291) experienced a median PFS of 7.0 months (95% CI, 5.4-7.2) per central review vs 4.9 months (95% CI, 4.0-5.5) for physician’s choice of therapy (n = 146; HR, 0.64; 95% CI, 0.49-0.84; P = .002). The investigator-assessed median PFS was 6.9 months (95% CI, 6.0-7.2) for trastuzumab duocarmazine compared with 4.6 months (95% CI, 4.0-5.6), for physician’s choice of therapy (HR, 0.60; 95% CI, 0.47-0.77; P <.001).

The multicenter, open-label, randomized trial enrolled patients with HER2-positive locally advanced or metastatic breast cancer who received at least 2 prior lines of therapy for metastatic disease, or ado-trastuzumab emtansine (T-DM1; Kadcyla) for metastatic disease. Patients with treated brain metastases were allowed to enroll.

Patients were randomly assigned 2:1 to receive 1.2 mg/kg of trastuzumab duocarmazine once every 21 days or physician’s choice of therapy until disease progression or unacceptable toxicity.

Along with the primary end point of centrally assessed PFS, secondary end points included investigator-assessed PFS, overall survival (OS), overall response rate (ORR), and health-related quality of life.

Additional data showed patients treated with trastuzumab duocarmazine experienced a median OS of 20.4 months (95% CI, 18.0-23.7) compared with 16.3 months (95% CI, 13.4-22.8) for physician’s choice of therapy (HR, 0.83; 95% CI, 0.62-1.09; P = .153).

In the trastuzumab duocarmazine arm, 86.6% of patients had measurable disease at baseline, and the ORR was 27.8%. Additionally, 70.2% of patients experienced a reduction in target lesion measurement, and the clinical benefit rate was 38.5%. In the physician’s choice arm, 83.6% of patients had measurable disease at baseline, and the ORR was 29.5%. Furthermore, 58.2% of patients had a reduction in target lesion measurement, and the clinical benefit rate was 32.2%.

Regarding safety, 52.8% of patients in the trastuzumab duocarmazine arm and 48.2% of patients in the physician’s choice arm experienced grade 3 or higher treatment-emergent adverse effects (TEAEs). The most common grade 3 or higher TEAEs in the trastuzumab duocarmazine group included keratitis (12.2%), conjunctivitis (5.6%), and neutropenia (4.9%). The most common grade 3 or higher TEAEs in the physician’s choice group were neutropenia (18.2%), palmar-plantar erythrodysesthesia syndrome (3.6%), and diarrhea (2.2%).

Three patients (1.0%) in the trastuzumab duocarmazine arm experienced any-grade interstitial lung disease (ILD), including 1 patient (0.3%) who had grade 3 or higher ILD. Additionally, 19 patients (6.6%) had any-grade pneumonitis, including 6 patients (2.1%) who had grade 3 or higher events. No instances of ILD or pneumonitis were reported in patients who received physician’s choice of therapy.

References

1. U.S. Food and Drug Administration issues complete response letter for Byondis’ [vic-]trastuzumab duocarmazine. News release. May 15, 2023. Accessed May 15, 2023. https://www.byondis.com/media/press-releases/us-food-and-drug-administration-issues-complete-response-letter
2. FDA Accepts Byondis’ biologics license application for [vic-]trastuzumab duocarmazine (SYD985) in HER2-positive metastatic breast cancer. News release. Byondis BV. July 12, 2022. Accessed May 15, 2023. https://www.byondis.com/media/press-releases/fda-accepts-byondis-biologics-license-application-for-vic-trastuzumab-duocarmazine
3. Saura Manich C, O’Shaughnessy J, Aftimos PG, et al. Primary outcome of the phase III SYD985.002/TULIP trial comparing [vic-]trastuzumab duocarmazine to physician’s choice treatment in patients with pre-treated HER2-positive locally advanced or metastatic breast cancer. Ann Oncol. 2021;32(5):S1288. doi:10.1016/j.annonc.2021.08.2088