The Lynx Group

Tucatinib Fills Unmet Need in Heavily Pretreated HER2-Positive Metastatic Breast Cancer, Including Brain Metastasis

April 2020, Vol 11, No 2

San Antonio, TX—The investigational oral drug tucatinib reduced the risk for death by 33% and the risk for disease progression or death by 50% when added to trastuzumab (Herceptin) plus capecitabine (Xeloda) in patients with heavily pretreated advanced HER2-positive breast cancer, with or without brain metastasis.

The phase 3 HER2CLIMB clinical trial represents the first study to show that a drug can prevent or delay disease progression in this patient population, said experts at the 2019 San Antonio Breast Cancer Symposium, where these data were presented. The results were published (Murthy RK, et al. N Engl J Med. 2020;382:597-609) to coincide with the meeting.

“HER2CLIMB is the first randomized trial to include patients 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 investigator Rashmi K. Murthy, MD, MBE, Assistant Professor, Department of Breast Medical Oncology, M.D. Anderson Cancer Center, Houston, TX.

“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.

Tucatinib is an oral, highly selective inhibitor of the HER2 tyrosine kinase with minimal inhibition of epidermal growth factor receptor. It is distinct from trastuzumab in its binding to the internal domain of the HER2 protein, whereas trastuzumab binds to the external domain.

HER2CLIMB Study Details

The international, prospective, randomized, placebo-controlled, double-blind HER2CLIMB trial was conducted in 15 countries. The study included 615 patients with metastatic HER2-positive breast cancer, of whom 47.5% had brain metastasis; the patients were randomized to tucatinib 300 mg twice daily plus trastuzumab and capecitabine (N = 410) or to trastuzumab plus capecitabine and placebo (N = 202).

At a median follow-up of 14 months, 33% of patients in the tucatinib group were alive, with no disease worsening, compared with 12% (P <.001) of patients in the control group. The median progression-free survival (PFS) was 7.8 months and 5.6 months, respectively. The 2-year overall survival rates from treatment initiation were 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 1 year after beginning treatment versus none of those in the control group (P <.001). The median PFS 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.

The side effects of tucatinib were manageable and included diarrhea, palmar- plantar erythrodysesthesia, nausea, fatigue, and vomiting. Grade ≥3 diarrhea and elevated liver enzyme levels were more common with tucatinib treatment than with placebo. Diarrhea was manageable with short courses of antidiarrheal agents, and elevated liver enzymes were transient and reversible. Treatment discontinuation rates were 6% in the tucatinib arm and 3% in the placebo arm. Approximately 10% of patients in each arm discontinued capecitabine.

Expert Commentary

“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 thirdline but 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,” said Adam M. Brufsky, MD, PhD, FACP, Co-Director, Magee-Womens Breast Cancer Program, UPMC Hillmen Cancer Center, Pittsburgh, PA, in an interview.

“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,” noted senior researcher of the article referenced here, Eric P. Winer, MD, Chief, Division of Breast Oncology Center, Susan F. Smith Center for Women’s Cancers, Dana-Farber Cancer Institute, Boston, MA, in a news release from Dana-Farber Cancer Institute.

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