[Vic-]trastuzumab duocarmazine safe and effective in pre-treated HER2-positive locally advanced or metastatic breast cancer
[Vic-]trastuzumab duocarmazine (SYD985) is a novel HER2-targeting antibody–drug conjugate comprised of trastuzumab bound to a linker drug containing duocarmycin. The phase III TULIP study, assessing SYD985 vs. physician’s choice of chemotherapy in patients with HER2-positive locally advanced or metastatic breast cancer, met its primary endpoint of progression-free survival, demonstrating a statistically significant improvement over physician’s choice.
TULIP study design
The TULIP trial randomly assigned HER2-positive locally advanced or metastatic breast cancer (mBC) patients who received ≥ 2 previous mBC regimens or previous mBC treatment with T-DM1 in a 2:1 ratio between SYD985 (1.2 mg/kg intravenously Q3W) and physician’s choice (PC) treatment. This PC could consist of either lapatinib plus capecitabine, trastuzumab plus capecitabine, trastuzumab plus vinorelbine or trastuzumab plus eribulin. Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) by blinded central review, with secondary objectives including investigator-assessed PFS, overall survival (OS), objective response rate (ORR), and health-related quality of life (HRQoL).
In total, 437 patients from 11 countries were randomised to SYD985 (N= 291) or PC (N= 146). The median age of study participants was 57 years and they received a median of 4 or 5 prior treatment lines in the SYD985 [range 1-16] and PC arm [range 1-14], respectively. The centrally reviewed median PFS was 7.0 months for SYD985 and 4.9 months for PC (HR[95%CI]: 0.64[0.49-0.84], p= 0.002), rendering SYD985 statistically significant superior to treatment of physician’s choice. The PFS benefit was consistent across all subgroups. Investigator-assessed PFS was also significantly improved (6.9 months vs. 4.6 months, HR[95%CI]: 0.60[0.47-0.77], p< 0.001). At the time of the first interim OS analysis, the median OS was reported at 20.4 months in the SYD985 arm, as compared to 16.3 months in the PC arm. The hazard ratio was 0.83 without a statistically significant p-value at this timepoint (p= 0.153). In the patients with measurable disease at baseline, the ORR was 27.8% in the SYD985 arm and 29.5% in the PC arm. However, 70.2% and 58.2% of patients respectively had a reduction in target lesion measurement. The clinical benefit rate was also higher in the SYD985 group than in the PC group (38.5% vs. 32.2%). There were no significant differences between study arms in terms of HRQoL.
The most frequently reported adverse events of all grade for SYD985 were conjunctivitis (38.2%), keratitis (38.2%) and fatigue (33.3%), for PC these were diarrhoea (35.8%), nausea (31.4%) and fatigue (29.9%). Interstitial lung disease (ILD)/ pneumonitis was reported for 7.6% of patients treated with SYD985, including grade ≥3 in 2.4% of patients, but were not reported in the PC arm. Eye toxicity was reported in 78.1% of patients treated with SYD985 and in 29.2% of patients receiving PC treatment. Grade ≥3 eye toxicity was present in 21.2% of SYD985 patients. Six deaths were reported in the SYD985 arm, of which three were deemed treatment-related (respiratory failure [N= 1], pneumonia [N= 1] and pneumonitis [N= 1]).
PFS was significantly improved with SYD985 treatment in comparison with standard physician’s choice treatment in patients with HER2-positive mBC with two prior regimens or T-DM1 in the metastatic setting. Ocular toxicity is the most prevalent safety event while ILD/pneumonitis of grade 3 or worse was reported in 2.4% of patients. SYD985 can provide a new treatment options for patients with pre-treated locally advanced or metastatic HER2-positive breast cancer.
Manich CS, 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. Presented at ESMO 2021; Abstract LBA15.