FDA Approves Tucatinib for HER2+ Breast Cancer


The FDA has approved tucatinib for use in combination with trastuzumab and capecitabine for the treatment of patients with unresectable locally advanced or metastatic HER2-positive breast cancer.

The FDA has approved tucatinib (Tukysa) for use in combination with trastuzumab (Herceptin) and capecitabine (Xeloda) for the treatment of patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including patients with brain metastases, following at least 1 prior anti-HER2-based regimen in the metastatic setting.1

The approval is based on data from the phase II HER2CLIMB trial, which were presented at the 2019 San Antonio Breast Cancer Symposium (SABCS).2,3 The results showed that the tucatinib triplet reduced the risk of death by 34% compared with trastuzumab and capecitabine alone in heavily pretreated patients with unresectable locally advanced or metastatic HER2-positive breast cancer.

The median overall survival (OS) was 21.9 months (95% CI,18.3-31.0) with the tucatinib triplet compared with 17.4 months (95% CI, 13.6-19.9) with trastuzumab and capecitabine alone (HR, 0.66; 95% CI, 0.50-0.88; P  = .0048). The 1- and 2-year OS rates were 76% versus 62% and 45% versus 27% in the tucatinib and control arms, respectively. The OS benefit was upheld across all prespecified subgroups.

The addition of the small molecule TKI tucatinib also led to a 46% reduction in the risk of disease progression or death compared with trastuzumab and capecitabine alone, with a median progression-free survival (PFS) of 7.8 months (95% CI, 7.5-9.6) versus 5.6 months (95% CI, 4.2-7.1), respectively (HR, 0.54; 95% CI, 0.42-0.71;&#8239;P &#8239;<.00001). The 6-month and 1-year PFS rates were 63% versus 46% and 33% versus 12%, respectively. The PFS benefit was upheld across all clinically significant prespecified subgroups.

Notably, the tucatinib triplet reduced the risk of disease progression or death by 52% (HR, 0.48; 95% CI, 0.34-0.69;&#8239;P &#8239;<.00001) in patients with brain metastases at baseline. The median PFS in this subpopulation with high unmet medical need was 7.6 months with tucatinib versus 5.4 months in the control arm. The 1-year PFS rates were 25% versus 0%, respectively. Subgroup analysis also indicated an OS benefit with tucatinib in this subgroup (HR, 0.58, 95% CI, 0.40-0.85).

“With highly significant and clinically important results for overall and progression-free survival, the addition of Tukysa to trastuzumab and capecitabine has the potential to become a standard of care for people with HER2-positive metastatic breast cancer after having received one or more previous anti-HER2 therapies in the metastatic setting,” Eric P. Winer, MD, chief of the Division of Breast Oncology, Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute, said in a press release.4

"Cancer spreads to the brain in up to half of patients with HER2-positive metastatic breast cancer; and this approval is based on a unique clinical trial that included patients with active brain metastases, either untreated or progressing. Tukysa is well tolerated by patients and is a valuable addition to the agents we have for HER2-positive metastatic breast cancer,” added Winer.

The FDA approved tucatinib under its Project Orbis program, a collaboration with the Australian Therapeutic Goods Administration, Health Canada, Health Sciences Authority (Singapore), and Swissmedic (SMC, Switzerland).

“The FDA’s Project Orbis provides a framework for concurrent submission and review of oncology drug applications among the FDA’s international collaborators. We are pleased to work with our Singapore and Switzerland colleagues for the first time, and to continue working alongside our Australian and Canadian colleagues as we facilitate new treatment options for patients — like today’s first new molecular entity under Project Orbis,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, said in a press release.

“This approval represents an additional targeted treatment option for patients with HER2-positive breast cancer. The clinical trial supporting this approval enrolled and specifically studied patients with active brain metastases in addition to the overall population enrolled, which also demonstrated benefit in this subgroup,” added Pazdur.

The international, double-blind, placebo-controlled HER2CLIMB trial (NCT02614794) included 612 patients with unresectable locally advanced or metastatic HER2-positive breast cancer who were previously treated with trastuzumab, pertuzumab (Perjeta), and ado-trastuzumab emtansine (T-DM1; Kadcyla). Patients were randomized 2:1 to receive trastuzumab and capecitabine combined with either tucatinib (n = 410) or placebo (n = 202).

Tucatinib was administered orally at 300 mg twice daily during each 21-day cycle. In both arms, patients received capecitabine at 1000 mg/m2&#8239;orally twice daily on days 1 to 14 of each 21-day cycle, and trastuzumab at 8 mg/kg intravenously on day 1 of cycle 1, followed by 6 mg/kg thereafter on day 1 of each 21-day cycle.

The primary endpoint was PFS, with secondary endpoints including OS, PFS in patients with brain metastases, and confirmed objective response rate (ORR). The primary PFS endpoint was measured in the first 480 patients enrolled. Through an early amendment to the study protocol, the target population was increased from 480 to 600 patients to provide adequate power to the secondary endpoint of PFS in patients with brain metastases.

Key baseline characteristics were well balanced between the 2 arms. The median patient age was around 55, 99% of patients were female, and there was about a 50/50 split in each treatment arm between patients with an ECOG performance score of 0 or 1. About two-thirds of patients in each arm were ER- and/or PR-receptor positive. Patients in both arms had received a median of 4 prior therapies overall and a median of 3 prior therapies in the metastatic setting.

In the tucatinib arm, 48% (n = 198) of patients had brain metastases at baseline and 46% (n = 93) of patients in the control arm had them. “HER2CLIMB is the first randomized trial completed in patients with HER2-positive metastatic breast cancer that included patients with untreated or previously treated, progressing brain metastases,” lead study author Rashmi K. Murthy, MD, assistant professor, Department of Breast Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, said when presenting the data at SABCS.

The data cutoff date was September 4, 2019, and the median follow-up was 14 months. The confirmed objective ORR was 41% in the tucatinib arm compared with 23% in the control arm (P&#8239;= .00008). The ORR in the tucatinib group comprised a 1% complete response (CR) rate and 40% partial response (PR) rate. The stable disease (SD) rate 46% and the progressive disease (PD) rate was 8%. In the control group, the CR rate was 1%, the PR rate was 22%, the SD rate was 59%, and the PD rate was 14%.

The safety population comprised patients who received at least 1 dose of study treatment (n = 601). The median duration of treatment exposure was 5.8 months in the tucatinib arm and 4.4 months in the placebo arm. At the data cutoff, 29% of patients remained on treatment in the tucatinib group compared with 14% in the placebo group. In both arms, disease progression was the main reason for treatment discontinuation at 49% versus 66%, respectively.

Grade ≥3 adverse events (AEs) occurred in 55% of the tucatinib arm compared with 49% of the control arm. There were 6 AE-related deaths in the tucatinib group and 5 in the control group.

Diarrhea was the most frequently occurring all-grade AE in both arms at 81% (13% grade ≥3) versus 53% (9% grade ≥3) in the tucatinib versus control arms, respectively; however, antidiarrheal prophylaxis was not required.

All-grade palmar-plantar erythrodysesthesia syndrome was also common in both arms at 63% (13% grade ≥3) versus 53% (9% grade ≥3) with the triplet versus trastuzumab and capecitabine alone, respectively. “Palmar-plantar erythrodysesthesia is a clinically well-known side effect of capecitabine. Longer duration of exposure in the tucatinib arm contributed to the observed difference in rates,” explained Murthy.

Regarding liver transaminase elevations, Murthy noted that AST and ALT increases were, “mostly low-grade, transient, and reversible.”

“We recognize that patients with cancer constitute a vulnerable population at risk of contracting the coronavirus disease. In this critical time, we remain steadfast in our commitment to patients with cancer and doing everything we can to expedite oncology product development. Tukysa was approved four months prior to the FDA goal date, providing an example of this commitment and showing how our regular work in reviewing treatments for patients with cancer is moving forward without delay,” Pazdur concluded in the press release.


  1. FDA Approves First New Drug Under International Collaboration, A Treatment Option for Patients with HER2-Positive Metastatic Breast Cancer Published April 17, 2020. https://bit.ly/2RKhVwv. Accessed April 17, 2020.
  2. Murthy R, 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 (HER2CLIMB). Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14; San Antonio, TX. Abstract GS1-01.
  3. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer [published online December 11, 2019]. N Engl J Med. doi: 10.1056/NEJMoa1914609.
  4. Seattle Genetics Announces U.S. FDA Approval of TUKYSA™ (tucatinib) for People with Advanced Unresectable or Metastatic HER2-Positive Breast Cancer. Accessed April 17, 2020. https://bit.ly/3eyiYcr. Published April 17, 2020.
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