Vic-trastuzumab duocarmazine markedly improved progression-free survival vs physician’s choice of treatment in patients with HER2-positive metastatic breast cancer who had received 2 prior treatment regimens or ado-trastuzumab emtansine in the metastatic setting, according to data from the phase 3 TULIP trial.
Vic-trastuzumab duocarmazine (SYD985) markedly improved progression-free survival (PFS) vs physician’s choice of treatment in patients with HER2-positive metastatic breast cancer who had received 2 prior treatment regimens or ado-trastuzumab emtansine (T-DM1; Kadcyla) in the metastatic setting, according to data from the phase 3 TULIP trial (NCT03262935).
Results, which were presented during the 2021 ESMO Congress, showed that treatment with the antibody-drug conjugate (ADC) resulted in a median PFS of 7.0 months (95% CI, 5.4-7.2) vs 4.9 months (95% CI, 4.0-5.5) with physician’s choice, per central review (hazard ratio [HR], 0.64; 95% CI, 0.49-0.84; P = .002). Similarly, the investigator-assessed PFS in the investigative and control arms 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).
“Trastuzumab duocarmazine can provide a new treatment option for patients with pretreated, locally advanced, or metastatic HER2-positive breast cancer,” Cristina Saura, MD, PhD, lead study author, principal investigator of the Breast Cancer & Melanoma Group at Vall d´Hebron Institute of Oncology, and head of the Breast Cancer Program at Vall d´Hebron University Hospital in Barcelona, Spain, said during a presentation on the data.
Trastuzumab duocarmazine is a HER2-targeted ADC that is based on trastuzumab (Herceptin) and has a cleavable linker-doucramycin payload that includes active toxin alkylates DNA, and a drug to antibody ratio that ranges from 2.4 to 2.8.
The ADC has a 3-way mechanism of action that includes the uptake of the ADC by internalization and intracellular release of the payload, proteolytic cleave and subsequent release of the payload in the tumor microenvironment, and diffusion of the active payload to neighboring tumor cells.
For the TULIP study, investigators sought to examine trastuzumab duocarmazine in patients with HER2-positive, locally advanced or metastatic breast cancer. To be eligible for enrollment, patients had to have received at least 2 prior therapies for metastatic disease or T-DM1 in the metastatic setting. Notably, those who had been treated for brain metastases were permitted.
A total of 437 patients were randomized 2:1 to receive either intravenous trastuzumab duocarmazine (n = 291) at a dose of 1.2 mg/kg every 21 days, or physician’s choice of treatment (n = 146) until disease progression or unacceptable toxicity. Physician’s choice of treatment could include lapatinib (Tykerb) plus capecitabine (Xeloda), trastuzumab plus capecitabine, trastuzumab plus vinorelbine, or trastuzumab plus eribulin.
Patients were stratified by region (Europe and Singapore vs North America), the number of prior treatments they received (1 or 2 vs more than 2), and whether they had received prior treatment with pertuzumab (Perjeta).
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 trial was powered to detect a HR of 0.65 at the P < .05 significance level, assuming a median time to progression of 4.1 months in the physician’s choice group, as well as a 20% drop out in the control group and a 30% drop out in the investigative group. The assumptions were updated in September 2019 to 30% drop out in the control group, and 40% drop out in the investigative group. Drop out was defined as patients not having an event of interest during the observation period for any reason.
Among patients enrolled to the study, the median age was 57 years (range, 24-86), and baseline characteristics were similar between the treatment arms. Most patients in the investigative and control 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 (60.8% vs 57.5%).
The median time from metastatic breast cancer diagnosis was 3.6 years (range, 0.0-18.6) in the trastuzumab duocarmazine arm vs 2.9 years (range, 0.0-19.5) in the physician’s choice arm, and the median number of prior metastatic breast cancer treatments received was 4.0 (range, 1-16) and 5.0 (range, 1-14), respectively.
Additional data showed that trastuzumab duocarmazine treatment yielded a median OS of 20.4 months (95% CI, 18.0-23.7) 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).
Moreover, 252 patients in the trastuzumab duocarmazine arm and 122 patients in the physician’s choice arm had measurable disease at baseline. Among those in the investigative and control arm, the ORRs were 27.8% and 29.5%, respectively, and the clinical benefit rates were 38.5% and 32.2%, respectively. Additionally, 70.2% of those treated with the ADC experienced a reduction in their target lesion size vs 58.2% of those treated with physician’s choice.
In terms of safety, 52.8% of those in the investigative group reported a treatment-related adverse effects (TRAE) of grade 3 or higher vs 48.2% of those in the physician’s choice group. The most common grade 3 or higher TRAEs in the ADC arm were keratitis (12.2%), conjunctivitis (5.6%), and neutropenia (4.9%). The most frequent grade 3 or higher TRAEs in the physician’s choice group included neutropenia (18.2%), palmar-plantar erthrodyseasthesia syndrome (3.6%), and diarrhea (2.2%).
Eye toxicity was reported in 78.1% of patients in the trastuzumab duocarmazine arm and 29.2% in the physician’s choice arm. Moreover, 20.8% of those treated with the ADC discontinued treatment due to eye toxicity; 22.9% required a dose modification. Mitigation factors included excluding those with prior keratitis, administering prophylactic eye drops, and performing regular eye examines. Those with grade 3 or higher keratitis stopped treatment, and those with grade 3 conjunctivitis delayed treatment until it reduced to grade 2.
Interstitial lung disease (ILD) and pneumonitis were reported by 7.6% of patients in the investigative arm (2.4% with grade 3 or higher) vs 0% in the control arm. ILD/pneumonitis led to treatment discontinuation in 5.2% of those treated with the ADC, and dose modifications in 2.1%. Mitigation strategies included excluding those with prior pneumonitis, evaluating tumor scans for lung changes, and conducting full diagnostic workups of new or worsening respiratory symptoms. Those with grade 2 or higher pneumonitis stopped treatment, and those with grade 1 pneumonitis delayed treatment until resolution.
Six fatalities were reported on the trastuzumab duocarmazine arm vs none on 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 reported between the 2 arms.