FDA Accepts BLA for Trastuzumab Duocarmazine for Advanced HER2+ Breast Cancer

FDA

The FDA has accepted for review a 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

The BLA is based on findings from the pivotal phase 3 TULIP trial (NCT03262935), where trastuzumab duocarmazine led to a significant improvement in progression-free survival (PFS) vs physician’s choice of therapy in this patient population, meeting the primary end point of the trial.²

The results showed a median PFS of 7.0 months (95% CI, 5.4-7.2) with trastuzumab duocarmazine vs 4.9 months (95% CI, 4.0-5.5) with physician’s choice per central review (HR, 0.64; 95% CI, 0.49-0.84; P = .002). Similarly, the investigator-assessed PFS was 6.9 months (95% CI, 6.0-7.2) vs 4.6 months (4.0-5.6), respectively (HR, 0.60; 95% CI, 0.47-0.77; P < .001).

The regulatory agency is scheduled to decide on the BLA by May 12, 2023, under the Prescription Drug User Fee Act.

“Women with HER2-positive breast cancer generally have a more aggressive disease, greater likelihood of recurrence and poorer prognosis,” Jan Schellens, MD, PhD, chief medical officer of Byondis, stated in a press release. “[The trastuzumab duocarmazine] BLA acceptance by the FDA is an important step forward toward our goal of providing a much-needed alternative for these patients.”

Trastuzumab duocarmazine is an investigational next-generation, HER2-directed antibody-drug conjugate (ADC) that received fast track designation from the FDA in January 2018 based on phase 1 data (NCT02277717) in heavily pretreated patients with HER2-positive metastatic breast cancer.³

The multi-center, open-label, randomized TULIP trial enrolled patients who had received at least 2 prior therapies or ado-trastuzumab emtansine (T-DM1; Kadcyla) in the metastatic setting. Patients who received treatment for brain metastases were eligible.

Patients were randomized 2:1 to 1.2 mg/kg of intravenous trastuzumab duocarmazine (n = 291) every 21 days, or physician’s choice of treatment (n = 146) until disease progression or unacceptable toxicity. Physician’s choice of treatment included lapatinib (Tykerb) plus capecitabine (Xeloda), trastuzumab (Herceptin) plus capecitabine, trastuzumab plus vinorelbine, or trastuzumab plus eribulin.

The primary end point of the study was centrally assessed PFS. Secondary end points included investigator-assessed PFS, overall survival (OS), overall response rate (ORR), and health-related quality of life (HRQoL).

The median patient age was 57 years (range, 24-86). Most patients in the trastuzumab duocarmazine and physician’s choice arms, respectively, were White (69.4% vs 65.1%) and had received prior treatment with trastuzumab (89.3% vs 86.3%), T-DM1 (87.6% vs 87.7%), and pertuzumab ([Perjeta] 60.8% vs 57.5%). The median number of prior therapies was 4 (range, 1-16) and 5 (range, 1-14), respectively.

Additional results from the study, which were presented at the 2021 ESMO Congress, demonstrated a median OS of 20.4 months (95% CI, 18.0-23.7) with trastuzumab duocarmazine vs 16.3 months (95% CI, 13.4-22.8) with physician’s choice of treatment (HR, 0.83; 95% CI, 0.62-1.09; P = .153).

The ORR was 27.8% with trastuzumab duocarmazine vs 29.5% with physician’s choice, and the clinical benefit rates were 38.5% and 32.2%, respectively.

Regarding safety, approximately half of patients in the trastuzumab duocarmazine (52.8%) and physician’s choice (48.2%) arms experienced grade 3 or higher treatment-related adverse effects (TRAEs). The most common grade 3 or higher TRAEs with trastuzumab duocarmazine were keratitis (12.2%), conjunctivitis (5.6%), and neutropenia (4.9%). The most common grade 3 or higher TRAEs with physician’s choice included neutropenia (18.2%), palmar-plantar erthrodyseasthesia syndrome (3.6%), and diarrhea (2.2%).

Eye toxicity occurred in 78.1% of patients in the trastuzumab duocarmazine arm vs 29.2% in the physician’s choice arm. Notably, 20.8% of patients who received the ADC discontinued treatment due to eye toxicity, and 22.9% required a dose modification.

Interstitial lung disease (ILD) and pneumonitis occurred in 7.6% of patients in the trastuzumab duocarmazine arm (grade ≥3, 2.4%) vs 0% in the control arm. ILD/pneumonitis led to treatment discontinuation in 5.2% of patients who received trastuzumab duocarmazine and dose modifications in 2.1%.

Six deaths were recorded in the trastuzumab duocarmazine arm vs none in the physician’s choice arm. Four of these deaths were attributed to treatment-related respiratory failure (n = 1), pneumonia (n = 1), and pneumonitis (n = 2). Two deaths were attributed to unrelated acute respiratory failure (n = 1) and COVID-19 pneumonia (n = 1).

In terms of HRQoL, no significant differences were noted between the 2 arms.

“With our proprietary technologies, we aim to offer antibody-drug conjugates with a novel mechanism-of-action, which are still efficacious when other ADC therapies have been exhausted,” Marco Timmers, PhD, chief executive officer of Byondis, stated in a press release. “[Trastuzumab duocarmazine] combines a HER2-targeting antibody with a novel and potent cytotoxic drug in a way that limits damage to healthy tissue.”

References

1. 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 July 12, 2022. https://prn.to/3caWgdX
2. Saura 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):1283-S1346. doi:10.1016/annonc/annonc741
3. Synthon’s [vic-]trastuzumab duocarmazine (SYD985) granted FDA fast track designation for pre-treated HER2-positive metastatic breast cancer. News release. Synthon Biopharmaceuticals. January 25, 2018. Accessed July 12, 2022. https://bwnews.pr/34xA3Rb