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Phase III Trial Explores Combination of Tucatinib and T-DM1 in HER2+ Breast Cancer

Lisa Astor
Published Online:9:00 PM, Thu October 10, 2019
Roger Dansey, MD
Roger Dansey, MD
A phase III trial, HER2CLIMB-02, has been initiated to investigate the combination of tucatinib and ado-trastuzumab emtansine (T-DM1, Kadcyla) in patients with locally advanced or metastatic HER2-positive breast cancer (NCT03975647).1 The results of the trial will support registration for tucatinib in the United States.

“We are building a comprehensive strategy for tucatinib in combination with other medicines across a range of HER2-positive cancers,” Roger Dansey, MD, chief medical officer at Seattle Genetics, the company developing tucatinib, said in a press release. “We are pleased to advance this tucatinib clinical trial with the vision of improving combination outcomes for patients with HER2-positive metastatic breast cancer who receive T-DM1. This trial has the potential to support tucatinib use in earlier lines of therapy.”

Tucatinib is an oral HER2-specific small molecule tyrosine kinase inhibitor. The randomized, double-blind phase III HER2CLIMB-02 trial is exploring the potential of the tucatinib/T-DM1 combination versus T-DM1 alone in patients with unresectable locally advanced or metastatic HER2-positive breast cancer.

Eligible patients will have previously received trastuzumab and a taxane, and prior pertuzumab is permitted. Patients with untreated brain metastases not needed immediate therapy or previously treated and stable brain metastases were able to enroll in the trial. 

Patients in the trial are randomized 1:1 to either 300 mg tucatinib twice daily or placebo plus 3.6 mg/kg intravenous T-DM1 in 21-day cycles. Already the first patient has been dosed in the trial and 460 total patients are expected to be enrolled.

The primary endpoint is progression-free survival (PFS) by RECIST v1.1 criteria and secondary endpoints include overall survival, objective response rate (ORR), duration of response (DOR), clinical benefit rate (CBR), and safety.

The enrolling phase III trial is based off of the results of a phase Ib trial, in which the agent demonstrated an acceptable safety profile in combination with T-DM1 in patients with HER2-positive metastatic breast cancer.2

The open-label, multicenter, dose-escalation study enrolled 57 women with HER2-positive metastatic breast cancer with or without stable brain metastases who had previously been treated with trastuzumab (Herceptin) and a taxane. Patients received 300 or 350 mg of oral tucatinib twice per day plus 3.6 mg/kg of intravenous T-DM1 once in every 21-day cycle.

Patients had a median age of 51 (range, 44-63) and most had an ECOG performance status of 1. Fifty patients were treated with 300 mg tucatinib twice daily, and in this cohort, patients had received a median of 2 prior HER2-directed agents (range, 1-3). Sixty percent of these patients had brain metastases and 62% had not received radiotherapy for their brain metastases. In the 350 mg cohort, the median number of prior HER2-targeted therapies was 1 (range, 1-2) and only 2 patients (29%) had brain metastases and had undergone whole-brain radiation.

Three dose-limiting toxicities were observed in 7 patients at the 350-mg dose, consisting of drug hypersensitivity, fatigue, and vomiting. As such, the 300 mg twice daily dose was set as the maximum tolerated dose (MTD).

Among the 50 patients treated at the MTD, the median PFS was 8.2 months (95% CI, 4.8-10.3); patients who had previously received both trastuzumab and pertuzumab (Perjeta), however, had a median PFS of 6.5 months (95% CI, 4.1-9.2).

The ORR in 34 evaluable patients with measurable disease was 47%, including 1 complete response and 15 partial responses. Among 48 evaluable patients, the CBR was 58%. The median DOR was 6.9 months (95% CI, 2.8-19.8).

In the patients with brain metastases treated at the MTD (n = 30), the median PFS was 6.7 months (95% CI, 4.1-10.2) and the DOR was 6.9 months (95% CI, 1.45-19.48). Of 14 of these patients with measurable brain metastases, the brain-specific ORR was 36%.

The most common treatment-emergent adverse events (TEAEs) among patients treated at the MTD were nausea (72%), diarrhea (60%), fatigue (56%), epistaxis (44%), headache (44%), constipation (42%), vomiting (42%), and decreased appetite (40%). Frequent adverse events considered to be related to tucatinib included nausea, diarrhea, fatigue, increased AST levels, vomiting, decreased appetite, increased ALT levels, and hypokalemia.

Grade ≥3 TEAEs included thrombocytopenia, hypokalemia, increased ALT levels, increased AST levels, fatigue, and hypophosphataemia. Serious adverse events were observed in 37%, with 6 of these events potentially related to tucatinib treatment: cardiac failure and fatigue, pyrexia and drug hypersensitivity, vomitinib and hypokalemia, and pneumonia.

Dose interruptions for tucatinib were needed in 32 patients and 5 patients discontinued tucatinib due to an adverse event.
  1. Seattle Genetics Announces Initiation of Phase 3 Clinical Trial of Tucatinib in Combination with Ado-trastuzumab Emtansine (T-DM1, Kadcyla®) for Patients with Advanced or Metastatic HER2-Positive Breast Cancer [press release]. Bothell, WA: Seattle Genetics Inc; October 10, 2019. https://bwnews.pr/33i2fnm. Accessed October 10, 2019.
  2. Borges VF, Ferrario C, Aucoin N, et al. Tucatinib Combined With Ado-Trastuzumab Emtansine in Advanced ERBB2/HER2-Positive Metastatic Breast Cancer: A Phase 1b Clinical Trial. JAMA Oncol. 2018;4(9):1214-1220. doi: 10.1001/jamaoncol.2018.1812.

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