FDA Issues CRL to BLA for [Vic-] Trastuzumab Duocarmazine in HER2+ mBC

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

[Vic-] trastuzumab duocarmazine is an anti-HER2 antibody-drug conjugate. In July 2022, the agent received a BLA from the FDA based on data from the phase 3 TULIP trial (NCT03262935). In the study, [vic] trastuzumab duocarmazine met the studies primary end point by generating a significant improvement in progression-free survival (PFS) vs physician’s choice of therapy in this patient population.²

The CRL issued by the regulatory agency has now requested additional information that will require more time and resources extending beyond the current evaluation period.

“We continue to believe that [trastuzumab duocarmazine] can present a meaningful treatment option for patients living with HER2-positive metastatic breast cancer,” said Marco Timmers, PhD, chief executive officer of Byondis, in a press release.¹ “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.”

A total of 436 patients were enrolled in the multicenter, open-label, randomized trial with 291 patients treated with [vic] trastuzumab duocarmazine and 146 given physician’s choice of therapy, which consisted of either lapatinib (Tykerb), capecitabine, trastuzumab (Herceptin), vinorelbine, or eribulin.³

Patients with HER2-positive locally advanced or metastatic breast cancer were enrolled if they had received at least 2 prior lines of therapy for metastatic disease, or ado-trastuzumab emtansine (T-DM1; Kadcyla) for metastatic disease. The study also included patients with treated brain metastases.

Investigators randomized patients in a 2:1 fashion 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.

The primary end point was centrally assessed PFS, and secondary end points were investigator-assessed PFS, overall survival (OS), overall response rate (ORR), and health-related quality of life.

Among those treated with[vic] trastuzumab duocarmazine, the median PFS was 7.0 months (95% CI, 5.4-7.2) per central review compared with 4.9 months (95% CI, 4.0-5.5) for those given physician’s choice of therapy (HR, 0.64; 95% CI, 0.49-0.84; P = .002).2 With [vic] trastuzumab duocarmazine, the investigator-assessed median PFS was 6.9 months (95% CI, 6.0-7.2) 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).

Patients treated with [vic] trastuzumab duocarmazine elicited a median OS of 20.4 months (95% CI, 18.0-23.7) while the median OS was 16.3 months (95% CI, 13.4-22.8) with physician’s choice of therapy (HR, 0.83; 95% CI, 0.62-1.09; P = .153). No significant difference in OS was noted between the 2 arms.

For safety, the most frequently reported adverse events (AEs) in the [vic-] trastuzumab duocarmazine arm included conjunctivitis (38.2%), keratitis (38.2%), and fatigue (33.3%). In the physician’s choice arm, the most common AEs were diarrhea (35.8%), nausea (31.4%), and fatigue (29.9%). Among patients treated with [vic-] trastuzumab duocarmazine, interstitial lung disease and pneumonitis were reported in 7.6% of patients, of which 5.6% were grade 1 or 2 in severity and 2 were grade 5. In either arm, AEs that lead to treatment discontinuation included eye disorders (20.8%), or respiratory disorders (6.3%). Treatment discontinuation occurred in 35.4% of patients in the experimental arm vs 10.2% in the control arm.

REFERENCES:

1. U.S. Food and Drug Administration issues complete response letter for Byondis’ [vic-]trastuzumab duocarmazine. News release. May 15, 2023. Accessed May 18, 2023. https://bit.ly/3MF3HtJ

2. 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

3. SYD985 vs. Physician's choice in participants with HER2-positive locally advanced or metastatic breast cancer (TULIP). ClinicalTrials.gov. Updated October 21, 2023. Accessed May 18, 2023. https://clinicaltrials.gov/ct2/show/NCT03262935