Trastuzumab Duocarmazine Shows Superiority Over Physician’s Choice for HER2+ Breast Cancer

The antibody-drug conjugate (ADC) vic-trastuzumab duocarmazine (SYD985) was found to significantly improve progression-free survival (PFS) over physician’s choice of treatment in patients with pretreated HER2-positive unresectable locally advanced or metastatic breast cancer, meeting the primary end point of the phase 3 TULIP trial (NCT03262935).¹

PFS was defined as the time from the date of randomization to the date of first documented disease progression or death because of any cause, whichever happened first. Topline data from the study also showed preliminary supportive overall survival benefit with the ADC.

Detailed data from the study will be shared at future scientific meetings, according to Byondis B.V., the drug developer. The clinical-stage biopharmaceutical company plans to submit a biological license application for the agent before the end of 2021.

“There is considerable unmet medical need in patients with HER2-positive metastatic breast cancer and [vic-]trastuzumab duocarmazine represents a promising potential clinical advance,” Jan Schellens, MD, PhD, chief medical officer of Byondis, stated in a press release. “We are excited by the topline results of TULIP and indebted to all patients who participated in the clinical studies.”

Trastuzumab duocarmazine is comprised of the monoclonal antibody trastuzumab (Herceptin) and valine-citrulline-seco-duocarmycin-hydroxybenzamide-azaindole, a cleavable-linker drug. The antibody portion of the agent binds to HER2 on the cancer cell surface, and the drug is then internalized by the cell. After proteolytic cleavage of the linker, cytotoxin is activated and DNA damage is elicited, which leads to cancer cell death. The agent is considered to be a form of targeted chemotherapy.

In the phase 3 TULIP trial, investigators compared the ADC with physician’s choice of treatment in 436 patients with histologically confirmed, unresectable locally advanced or metastatic breast cancer.

To be eligible for enrollment, patients needed to have either progressed during or after at least 2 HER2-targeted treatment regimens for locally advanced or metastatic disease or progressed during or after ado-trastuzumab emtansine (T-DM1; Kadcyla). Patients also needed to be at least 18 years of age, have HER2 positivity, evaluable disease per RECIST v1.1 criteria, an estimated life expectancy of over 12 weeks, as well as acceptable organ function and blood cell counts.²

Participants were randomized 2:1 to receive the ADC or physician’s choice of treatment, which could include lapatinib plus capecitabine, trastuzumab plus capecitabine, trastuzumab plus vinorelbine, or trastuzumab plus eribulin. Treatment was given until either progressive disease or intolerable toxicity.

The primary objective of the trial was to compare PFS per blinded, independent, central review between the arms. Key secondary objectives included comparing the 2 arms with regard to OS, objective response rate per independent central review, investigator-assessed PFS, patient-reported outcomes, as well as safety and tolerability.

Previously, when evaluated in heavily pretreated patients with metastatic breast cancer as part of a phase 1 trial (NCT02277717), trastuzumab duocarmazine was found to elicit an ORR of 33% (n = 16/48); this included 29% (n = 11/38) of those who had previously received T-DM1.³ In 30 patients with HER2-low/hormone receptor (HR)–positive disease, the ORR achieved with the ADC was 27% (n = 8). Among 15 patients with triple-negative breast cancer (TNBC), the ORR was 40% (n = 6).

Additionally, the median PFS with the ADC was 9.4 months (95% CI, 4.5-12.4) in the HER2-positive subgroup, 8.3 months (95% CI, 4.1-15.0) in those who previously received T-DM1, 4.1 months (95% CI, 2.4-5.4) in the HER2-low/HR-positive subgroup, and 4.4 months (95% CI, 1.0-7.1) in the TNBC subgroup.

The safety and efficacy of the ADC is also under examination in patients with HER2-expressing recurrent, advanced, or metastatic endometrial cancer as part of the phase 2 SYD985.003 trial (NCT04205630).⁴ In the single-arm study, patients will be given trastuzumab duocarmazine intravenously every 3 weeks. The primary end point of the research is ORR, while secondary end points comprise PFS, OS, and safety. The first patient was dosed on July 15, 2020.

The synergistic effects of the ADC and niraparib (Zejula) in patients with HER2-expressing locally advanced or metastatic solid tumors is under evaluation in a phase 1 study (NCT04235101); a new arm of the I-SPY 2 trial is evaluating the neoadjuvant use of trastuzumab duocarmazine in patients with HER2-low, early-stage breast cancer; and a phase 1 trial (NCT04602117) is examining the ADC in combination with paclitaxel in patients with solid tumors.

References

1. Byondis announces positive topline results of pivotal phase III TULIP study in patients with HER2-positive unresectable locally advanced or metastatic breast cancer. News release. Byondis B.V. June 8, 2021. Accessed June 8, 2021. https://prn.to/3gj1oef
2. SYD985 vs. physician’s choice in participants with HER2-positive locally advanced or metastatic breast cancer (TULIP). ClinicalTrials.gov. Updated June 2, 2021. Accessed June 8, 2021. https://clinicaltrials.gov/ct2/show/NCT03262935
3. Saura C, Thistlethwaite F, Banerji U, et al. A phase I expansion cohorts study of SYD985 in heavily pretreated patients with HER2-positive or HER2-low metastatic breast cancer. J Clin Oncol. 2018;36(suppl 15):1014. doi:10.1200/JCO.2018.36.15_suppl.1014
4. Byondis initiates phase II study of antibody-drug conjugate [vic-]trastuzumab duocarmazine in advanced endometrial cancer. News release. Byondis B.V. July 15, 2020. Accessed June 8, 2021. https://bit.ly/3ixgeNG