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Trastuzumab duocarmazine active in HER2-positive breast cancer resistant to trastuzumab emtansine
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The HER2-targeting antibody-drug conjugate trastuzumab duocarmazine demonstrated clinical activity and appeared safe among patients with heavily pretreated HER2-expressing metastatic cancer, according to results of a dose-escalation and dose-expansion study published in The Lancet Oncology.
Patients who responded to the two-in-one treatment of trastuzumab (Herceptin, Genentech) linked with the chemotherapy agent duocarmazine included women with HER2-positive breast cancer resistant to trastuzumab emtansine (Kadcyla, Genentech) and those with HER2-low breast cancer.
“The approach used in this study of combining the antibody and drug is a highly successful way of targeting tumors,” Udai Banerji, MD, deputy director of the drug development unit at Institute of Cancer Research in London and Royal Marsden NHS Foundation Trust, said in a press release. “With the antibody acting as a guide to find and target the cancer, the duocarmazine drug can be released directly to the tumor cells, destroying them while minimizing the damage to surrounding healthy cells.”
Banerji and colleagues evaluated the safety, pharmacokinetics and preliminary antitumor activity of trastuzumab duocarmazine (SYD985, Synthon Biopharmaceuticals) among 39 patients (median age, 55 years; interquartile range [IQR], 47-63) in a dose-escalation cohort and 146 patients (median age, 57 years; IQR, 49-65) in a dose-expansion cohort between Oct. 30, 2014, and April 2, 2018. Patients in the dose-escalation cohort had locally advanced or metastatic solid tumors with variable HER2 status and were refractory to standard cancer treatment. Patients in the dose-expansion cohort had breast, gastric, urothelial or endometrial cancer with at least HER2 immunohistochemistry 1+ expression and measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
Patients in the dose-escalation cohort received trastuzumab duocarmazine doses of 0.3 mg/kg to 2.4 mg/kg in a 3 + 3 design on day 1 of each 3-week cycle until disease progression or unacceptable toxicity.
Safety and determination of the recommended phase 2 dose served as the primary endpoints of escalation phase.
Objective response per RECIST version 1.1 criteria served as the primary endpoint of the expansion phase.
Median follow-up was 5 months.
Researchers observed one dose-limiting toxic effect, a death due to pneumonitis, at the highest administered dose (2.4 mg/kg). Another patient who received a dose of 1.5 mg/kg died of disease progression, which researchers attributed to a general decline in health. One-third of patients (33%) in the dose-escalation phase experienced grade 3 or grade 4 treatment-related adverse events, including keratitis (8%) and fatigue (5%).
Researchers established 1.2 mg/kg as the recommended phase 2 dose, which they administered to 146 patients in the dose-expansion cohort.
Among this cohort, researchers observed partial responses in:
- 16 of 48 women (33%; 95% CI, 20.4-48.4) with HER2-positive breast cancer;
- nine of 32 women (28%; 95% CI, 13.8-46.8) with HER2-low, hormone receptor-positive breast cancer;
- six of 15 women (40%; 95% CI, 16.3-67.6) with HER2-low, hormone receptor-negative breast cancer;
- one of 16 patients (6%; 95% CI 0.2-30·2) with gastric cancer;
- four of 16 patients (25%; 95% CI, 7.3-52.4) with urothelial cancer; and
- five of 13 patients (39%; 95% CI, 13·9-68·4) with endometrial cancer.
Sixteen patients in the dose-escalation cohort developed serious treatment-related adverse events, included infusion-related reactions (n = 2) and dyspnea (n = 2). Other treatment-related grade 1 to grade 4 adverse events included fatigue (n = 48), conjunctivitis (n = 45) and dry eye (n = 45).
No patients in the dose-expansion cohort died of treatment-related adverse events. However, four died of disease progression.
Median PFS was 7.6 months (95% CI, 4.2-10.9) among women with HER2-positive breast cancer; 4.1 months (95% CI, 2.4-5.4) among women with HER2-low, hormone-receptor-positive breast cancer; and 4.9 months (95% CI, 1.2 to not estimable) among women with HER2-low, hormone receptor-negative breast cancer.
In the other dose-expansion cohorts, median PFS was 3.2 months (95% CI, 1.6-5.3) among patients with gastric cancer, 4 months (95% CI, 1.3 to not estimable) among patients with urothelial cancer, and 4.3 months (95% CI, 2.4-9.9) among patients with endometrial cancer.
The randomized phase 3 TULIP study is recruiting patients to determine whether trastuzumab duocarmazine is superior to standard chemotherapy combinations for women with HER2-positive breast cancer.
“Trastuzumab duocarmazine has shown promising antitumor activity in [patients with breast cancer] with varying levels of HER2 protein,” Banerji said. “As these cancers often develop resistance to the current standard of care, this treatment could extend the lives of patients who have otherwise run out of options.” – by John DeRosier
Disclosures: Synthon Biopharmaceuticals funded the study. Banerji reports research funding from AstraZeneca, BTG International, Chugai, Onyx Pharmaceuticals and Verastem; and personal fees from Astellas, Astex Pharmaceuticals, Eli Lilly, Karus Therapeutics, Novartis, Phoenix Solutions and Vernalis. Please see the study for all other authors’ relevant financial disclosures.
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