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TULIP trial shows extended survival in HER2+ metastatic breast cancer



Based on significant progression-free survival benefits in the phase III TULIP trial, trastuzumab duocarmazine may provide a new treatment option among pretreated HER2-positive metastatic breast cancer patients, according to Cristina Saura Manich, MD, Hospital Universitario Valle de Hebrón, Barcelona. In TULIP, trastuzumab duocarmazine (SYD985, Byondis B.V., NL) was compared with physician’s choice of chemotherapy, Dr. Saura said at the virtual European Society for Medical Oncology Congress 2021 on Sept. 18 (abstract LBA15).

Trastuzumab duocarmazine, Dr. Manich noted, is a novel HER2-targeting antibody–drug conjugate based on trastuzumab and a cleavable linker-duocarmycin (vc-seco-DUBA) payload. Its three-way mechanism of action includes uptake of the antibody–drug conjugate by internalization and intracellular release of the payload, and two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.

Two or more prior therapies for metastatic breast cancer

TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to SYD985 (1.2 mg/kg IV every 21 days [n = 291]) or physician’s choice (PC) [n = 146] of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.

Longer progression-free survival with SYD985

Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed progression-free survival was significantly longer in the SYD985 group at 7.0 months (5.4-7.2) versus 4.9 months (4.0-5.5) for PC (hazard ratio [HR], 0.64, 95% confidence interval [CI], 0.49-0.84, P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for SYD985 over physician choice across all categories (except for ECOG status 2). Analysis of progression-free survival by investigators showed a similar benefit for SYD985 (6.9 months versus 4.6 months, HR, 0.60, P < .001).

A first look at median overall survival showed a nonsignificant advantage for SYD985 (20.4 months versus 16.3 months (HR, 0.83, 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for SYD985 and 29.5% for PC, with reductions in target lesion measurement at 70.2% and 32.2% for SYD985 and physician choice, respectively. The clinical benefit rates were 38.5% for SYD985 and 32.2% for physician choice.

Ocular toxicity

Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for SYD985 were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%), and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with SYD985, including two grade 5 events. Eye toxicity led to discontinuations in 20.8% of SYD985 patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of SYD985 patients. Six fatalities (2.1%) were reported in the SYD985 group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.

Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.

Another option

“It is encouraging to observe clinically meaningful and potentially practice changing PFS improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, of Massachusetts General Hospital and Harvard Medical School, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years – including T-DXd, neratinib, tucatinib, and margetuximab – and [vic-]trastuzumab duocarmazine could eventually be another option.”

“At this time, there is only a minor 2-month difference in progression-free survival and a nonsignificant overall survival difference,” said Fatima Cardoso, MD, of Champalimaud Cancer Center, Lisbon, Portugal. “With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”

Dr. Manich concluded, “SYD985 can provide a new treatment option for patients with pretreated locally advanced or metastatic HER2-positive metastatic breast cancer.”

The study was funded by Byondis B.V. The authors disclosed numerous pharmaceutical-related financial interests.

This article was updated Sept. 24, 2021.

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