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Add-On Tucatinib Ups Survival in Breast Cancer With Brain Mets

— TKI plus trastuzumab-capecitabine reduced risk of death by nearly half

MedpageToday

Adding tucatinib (Tukysa) to a trastuzumab-capecitabine (Herceptin-Xeloda) regimen significantly improved central nervous system (CNS) outcomes versus placebo plus trastuzumab-capecitabine in patients with HER2-positive metastatic breast cancer and brain metastases at baseline, researchers reported.

In the HER2CLIMB study, the risk of intracranial progression or death was cut by 68% in the tucatinib arm (hazard ratio 0.32, 95% CI 0.22-0.48, P<0.0001), according to Nancy Lin, MD, of the Dana-Farber Cancer Institute and Harvard Medical School in Boston.

The median CNS progression-free survival (PFS) was 9.9 months in the tucatinib arm versus 4.2 months in the placebo control arm, she reported at the American Society of Clinical Oncology (ASCO) virtual meeting. The study results were simultaneously published in the.

Also, median overall survival (OS) was 18.1 versus 12.0 months. The risk of death was reduced by 42% in the tucatinib arm (OS HR 0.58, 95% CI 0.40-0.85, P=0.005), according to Lin and colleagues.

And the intracranial overall response rate was higher in the tucatinib arm (47.3%, 95% CI 33.7%-61.2%) versus the control arm (20.0%, 95% CI 5.7%-43.7%), they stated.

Finally, the estimated 1-year OS rate was 70.1% (95% CI 62.1%-76.7%) in the tucatinib arm and 46.7% (95% CI 33.9%-58.4%) in the control arm.

ASCO discussant Aleix Prat, MD, PhD, of the University of Barcelona, noted that the last decade has shown major improvements in survival among breast cancer patients with advanced disease. "But we still have work to do," he said, especially for the treatment of brain metastases.

"Today we've seen the results of tucatinib in patients with brain metastases," Prat stated in a pre-recorded comment. "These were patients recruited in the HER2CLIMB, which is a randomized double-blind pivotal trial of patients with HER2-positive advanced disease who received prior trastuzumab/pertuzumab [Perjeta] and T-DM1 [Kadcyla] and who had the brain MRI at baseline. About 48% of patients had brain metastases at baseline, and than among them, 60% had active brain metastases, meaning untreated brain metastases or progressing brain metastases."

Prat highlighted the fact that the investigators looked at CNS PFS only, and that the risk of progression was reduced by 68%, with "an absolute increase in progression-free survival of 5.4 months. So overall, very impressive results of tucatinib in patients with central nervous system disease," he said.

Prat suggested that future studies could determine if tucatinib, a small-molecule tyrosine kinase inhibitor that is highly selective for HER2, can be used upfront as a preventive agent.

"Up to 50% of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer will develop brain metastases during the course of their disease. Initial therapy for brain metastases typically consists of locally directed therapy with surgical resection, stereotactic radiosurgery, and/or whole-brain radiation therapy. Unfortunately, the rate of intracranial progression within 6 to 12 months with these therapies is high," noted Lin.

"In the absence of randomized, prospective data demonstrating a benefit of switching systemic agents at the time of brain progression, ASCO clinical practice guidelines currently recommend that patients with stable systemic disease at the time of brain progression continue treatment with the same systemic treatment after local therapy and until further progression," she added.

For HER2CLIMB, patients were randomly assigned 2:1 to tucatinib or placebo, in combination with trastuzumab and capecitabine. All patients underwent baseline brain MRI, and those with brain metastases were classified as active or stable. Brain MRI was required every 6 weeks for the first 24 weeks and every 9 weeks thereafter. Eligible patients did not require immediate local therapy for CNS lesions.

The median patient age was 50, all had an ECOG performance status of 0-1, and 40% initially presented with de novo metastatic breast cancer. Lin said 97% of the patients had coexisting extracranial disease; 70% of patients had received prior radiotherapy; and 14%-16% had previously been treated with CNS-directed surgery.

Patients received oral tucatinib at 300 mg twice daily, plus trastuzumab-capecitabine (n=410) or placebo plus trastuzumab-capecitabine (n=202).

Trastuzumab was given at a loading dose of 8 mg/kg on day 1 of cycle 1 if needed and then at a maintenance dose of 6 mg/kg on day 1 of 21-day cycles thereafter. Capecitabine was given at 1,000 mg/m2 orally twice daily on days 1 through 14 of every 21-day cycle.

Patients were treated until disease progression or unacceptable toxicity.

"To our knowledge, this is the first regimen to demonstrate improved antitumor activity against brain metastases in patients with HER2-positive breast cancer in a randomized, controlled trial," Lin said.

"A unique subset was the group of 66 patients with untreated [brain metastases] who elected to enter HER2CLIMB in lieu of radiation therapy. Although the overall numbers were small, median CNS-PFS was 8.1 months in the tucatinib arm, suggesting this strategy merits further exploration, because it may delay the need for radiation therapy," Lin and colleagues pointed out.

Results from the phase III trial supported the of tucatinib-trastuzumab-capecitabine in advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.

Disclosures

HER2CLIMB was supported by Seattle Genetics.

Lin disclosed relevant relationships with Genentech/Roche, Seattle Genetics, Puma Biotechnology, Daiichi Sankyo, Pfizer, and Merck.

Prat disclosed relevant relationships with Novartis, Amgen, Daiichi Sankyo, Lilly, MSD Oncology, Pfizer, Roche, AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, NanoString Technologies, Oncolytics Biotech, Puma Biotechnology, and Incyte.

Primary Source

Journal of Clinical Oncology

Lin N, et al "Intracranial Efficacy and Survival With Tucatinib Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer With Brain Metastases in the HER2CLIMB Trial" J Clin Oncol 2020; DOI: 10.1200/JCO.20.00775.