For patients with progressing HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1), no single regimen is an established standard of care. More than 50% of these patients will develop brain metastasis, and thus far, treatments have been suboptimal.

Tucatinib—an investigational oral drug recently granted Breakthrough Therapy designation—may have the potential to meet this unmet need for pretreated patients with metastatic HER2-positive breast cancer, including those with brain metastases. Tucatinib added to trastuzumab/capecitabine reduced the risk of death by one-third and reduced the risk of disease progression or death by one-half in patients with heavily pretreated metastatic HER2-positive breast cancer, including those with untreated or previously treated brain metastasis, according to results from the phase III HER2CLIMB study presented at the 2019 San Antonio Breast Cancer Symposium.¹

Eric P. Winer, MD, FASCO

Senior study author Eric P. Winer, MD, FASCO, Chief of the Division of Breast Oncology at the Susan F. Smith Center for Women’s Cancers, Dana-­Farber Cancer ­Institute, Boston, said, “The results of this trial represent significant progress … including the first evidence from a clinical trial of a targeted agent that can improve survival for patients with HER2-positive breast cancer that has metastasized to the brain.”

Study results were published online in The New England Journal of Medicine to coincide with the presentation.² These results met with universal enthusiasm by breast cancer experts interviewed at the meeting.

“HER2CLIMB is the first completed randomized trial to include patients with [HER2-positive breast cancer with] brain metastases. Tucatinib in combination with trastuzumab and capecitabine has the potential to become a new standard of care in this patient population with and without brain metastases,” said lead author Rashmi K. Murthy, MD, of The University of Texas MD Anderson Cancer Center, Houston, who presented the results in San Antonio.

Rashmi K. Murthy, MD

HER2-positive breast cancer accounts for 15% to 20% of breast cancers. The approval of the first anti-HER2 drug, trastuzumab, markedly improved outcomes for some patients. Pertuzumab, another anti-­HER2 drug, and T-DM1, an antibody-drug conjugate, are established treatments for HER2-positive breast cancer. Although these agents can extend survival, patients eventually develop resistance to them.

Tucatinib is a highly selective inhibitor of HER2 tyrosine kinase with minimal inhibition of epidermal growth factor receptor. The novel targeted compound binds the internal domain of the HER2 protein, whereas trastuzumab binds to the external domain.

Study Details

HER2CLIMB is an international, prospective, randomized, placebo-controlled, double-blind trial that enrolled 612 patients with metastatic HER2-positive breast cancer with or without baseline brain metastasis at 155 sites in 15 countries in North America, Europe, Asia, and Australia. A total of 410 patients were assigned to receive oral tucatinib at 300 mg twice daily plus trastuzumab/capecitabine, and 202 patients were assigned to treatment with trastuzumab/capecitabine plus placebo.

All patients had centrally confirmed HER2-positive disease. Patients with treated or untreated brain metastases composed 47.5% of the study population. Both treatment arms were well balanced for demographic and disease characteristics.

At a median follow-up of 14 months, 33% of patients in the tucatinib group were alive with no worsening of their disease, compared to 12% in the control group (P < .001). Median progression-free survival was 7.8 months with tucatinib plus trastuzumab/capecitabine and 5.6 months with trastuzumab/capecitabine plus placebo.

The 2-year overall survival from the time of treatment initiation was 45% for the tucatinib group and 27% for the placebo group (P = .005). Among patients with brain metastasis at baseline, 25% of those in the tucatinib group were alive with no evidence of disease at 1 year after beginning treatment, compared with none in the control group. (P < .001). Median progression-free survival among these patients was 7.6 months and 5.4 months, respectively.

“The survival benefit was observed with tucatinib in the total HER2CLIMB population and across all subgroups tested,” Dr. Murthy emphasized.

Safety Profile

The most common adverse effects in the tucatinib-treated group were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, and vomiting. Grade 3 or higher diarrhea and elevated liver enzyme levels were more common in the tucatinib group compared with placebo (see editor's note below). Diarrhea was manageable with short courses of antidiarrheal agents, and elevated liver enzymes were transient and reversible.

Despite the toxicity with tucatinib, less than 6% of patients discontinued treatment in the experimental arm compared with 3% in the placebo arm. About 10% of patients in both arms discontinued capecitabine.

“Our results show that for this group of patients, for whom effective standard treatment options are extremely limited, the addition of tucatinib to trastuzumab and capecitabine provided a clinically meaningful reduction in the risk of disease or death,” Dr. Murthy said.

Experts Comment

“These are impressive results with tucatinib in heavily pretreated metastatic HER2-positive breast cancer. Encouraging activity is seen after progression on T-DM1 and other anti-HER2 agents,” said Steven J. Isakoff, MD, PhD, Associate Director of Breast Cancer Clinical Research at Massachusetts General Hospital, Boston.

Steven J. Isakoff, MD, PhD

Adam M. Brufsky, MD, PhD

“These data show that tucatinib does not have as much toxicity as some of the other drugs that are options for heavily pretreated HER2-positive patients; for example, neratinib can cause severe diarrhea. Tucatinib can be given at a higher dose and provides a survival benefit in the third line,” said Adam M. Brufsky, MD, PhD, Professor of Medicine and Co-Director of the Comprehensive Breast Cancer Center at UPMC Hillmen Cancer Center, Pittsburgh.

“Tucatinib and HER2 tyrosine kinase inhibitors like it are likely going to change the standard of care within the next year. Tucatinib will be used in the third-line setting, but it will be studied earlier in the course of disease. HER2-positive patients typically die from brain metastases, and any drug that can prevent or control brain metastasis is a big advance,” he added.

“For the first time, we are starting to see a glimmer of hope for a cure for HER2-positive breast cancer. With each line of treatment, we extend survival further, and now we can envision people living 8 to 10 years from diagnosis. We are ‘kicking the can down the road,’” Dr. Brufsky said.

Amy Tiersten, MD, Professor of Medicine, Oncology, and Hematology at the Icahn School of Medicine at Mount Sinai, New York, told The ASCO Post, “This is the most exciting study presented today at San Antonio…. This trial is the first trial I am aware of that included patients with untreated or progressive brain metastases.”

Amy Tiersten, MD

She continued: “The benefit for the addition of tucatinib was impressive…. Overall, tucatinib reduced the risk of disease progression or death by 50%. I think this regimen may be considered a new standard of care for pretreated HER2-positive metastatic breast cancer.” 

Editor's Note: A correction published in The New England Journal of Medicine² noted the following: “A single patient in the tucatinib-combination group met Hy’s law criteria on the basis of ALT, 152 U per liter (4.8 times the upper limit of normal [ULN]); AST, 128 U per liter (3.6×ULN); total bilirubin, 2.6 mg per deciliter (2.2×ULN); and alkaline phosphatase (ALP), 165 U per liter (1.4×ULN). This patient had an adaptive response, with recovery of laboratory values to baseline after dose modification of both tucatinib and capecitabine and continued treatment with all three drugs for six more cycles until disease progression. An independent expert hepatology review subsequently concluded that the mild AST and ALT elevations and adaptation with retreatment did not qualify this as a true Hy’s law case.”

DISCLOSURE: HER2CLIMB was supported by Seattle Genetics. Dr. Winer owns stock or other ownership interests in Verastem; has received honoraria from Genentech/Roche, Genomic Health, Tesaro, Carrick Therapeutics, Genomic Health, GlaxoSmithKline, Jounce Therapeutics, Leap Therapeutics, Lilly, and Seattle Genetics; and has received institutional research funding from Genentech, Merck, and Novartis. Dr. Murthy has received honoraria from Daiichi Sankyo, Genentech, Puma Biotechnology, and Seattle Genetics; has served in a consulting or advisory role for Daiichi Sankyo, Genentech/Roche, Puma Biotechnology, and Seattle Genetics; has received institutional research funding from Daiichi Sankyo, EMD Serono, Genentech/Roche, Pfizer, and Seattle Genetics; has received contracted research funding from France Foundation; and has been reimbursed for travel, accommodations, and other expenses by Daiichi Sankyo, Genentech, Puma Biotechnology, and Seattle Genetics. Dr. Isakoff has served in a consulting or advisory role for AbbVie, Genentech/Roche, Hengrui Therapeutics, Immunomedics, Myriad Genetics, and Puma Biotechnology; and has received institutional research funding from AbbVie, AstraZeneca/MedImmune, Genentech, Merck, OncoPep, and PharmaMar. Dr. Brufsky has served in a consulting or advisory role for Agendia, Bayer, Bioarray Therapeutics, Biotheranostics, Celgene, Eisai, Genentech/Roche, Genomic Health, Lilly, Merck, Myriad Pharmaceuticals, NanoString Technologies, Novartis, Pfizer, and Puma Biotechnology. Dr. Tiersten has received honoraria from Amgen and Tesaro; has served in a consulting or advisory role for AstraZeneca, Eisai, Immunomedics, Novartis, Puma Biotechnology, and Roche/Genentech; has served on a speakers bureau for Amgen and Tesaro; has received research funding from AstraZeneca and Pfizer; and has been reimbursed for travel, accommodations, or other expenses by Amgen and Tesaro.

REFERENCES

1. Murthy RK, Loi S, Okines A, et al: Tucatinib vs placebo, both combined with capecitabine and trastuzumab, for patients with pretreated HER2-positive metastatic breast cancer with and without brain metastases. 2019 San Antonio Breast Cancer Symposium. Abstract GS-01. Presented December 11, 2019.

2. Murthy RK, Loi S, Okines A, et al: Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. December 11, 2019 (early release online): Correction appears in N Eng J Med 382:586, 2020.