Tucatinib Granted FDA Breakthrough Designation for Treatment of Metastatic HER2-Positive Breast Cancer

The FDA has granted Breakthrough Therapy Designation to the addition of tucatinib to trastuzumab (Herceptin) and capecitabine for the treatment of patients with locally advanced unresectable or metastatic HER2-positive breast cancer, including those with brain metastases who received prior treatment with trastuzumab, pertuzumab (Perjeta), and T-DM1 (Kadcyla), according to a press release from Seattle Genetics.¹

The designation is based on positive results from the HER2CLIMB trial of tucatinib/trastuzumab/capecitabine versus placebo/trastuzumab/capecitabine, which were presented at the 2019 San Antonio Breast Cancer Symposium (SABCS) on December 11, 2019, and then published in theNew England Journal of Medicine.

The data showed that the addition of tucatinib to trastuzumab in HER2CLIMB met its primary end point of progression-free survival (PFS) by reducing the risk of disease progression or death by 46% in patients with locally advanced unresectable or metastatic HER2-positive breast cancer (HR 0.54; 95% CI, 0.42-0.71;P<0.00001). The combination also improved survival in the study subjects, with a 34% reduction in the patients who received the experimental combination. Tucatanib/trastuzumab also showed a superior PFS to the comparator combination of trastuzumab and capecitabine, by achieving a 52% decrease in the risk of disease progression or death (HR 0.48, 95% CI, 0.34-0.69;P<0.0001).²

Based on these data, the investigators concluded that the combination of tucatinib and trastuzumab led to a clinically significant improvement in PFS and a 4.5-month extension in OS, compared with placebo plus capecitabine plus trastuzumab.³

Adverse events (AEs) were observed with both tucatinib combination and the placebo combination, with the most common being diarrhea (80.9% vs 53.3 %), PPE syndrome (63.4 % vs 52.8%), nausea (58.4 % vs 43.7%), fatigue (45.0% vs 43.1%), and vomiting (35.9 % vs 25.4 %), respectively. There were 223 grade 3 or higher AEs seen in patients treated with tucatinib/trastuzumab and 96 AEs in the group of patients treated with the placebo combination. Diarrhea was also the most common grade or higher grade AEs.³

Patients experienced elevations in their alanine aminotransferase (ALT) and aspartate aminotransferase levels (AST), however, these events were low grade and considered to be transient and reversible. High-grade elevations in ALT and AST occurred in 5.4% of patients in the tucatanib/trastuzumab group and 4.5% of those in the placebo combination group. There were also elevations in bilirubin levels, which were 18.6% and 10.2, respectively. Fewer patients in the tucatinib combination group experienced grade 3 or higher bilirubin level elevations than in the placebo combination group.

In the study, 215 deaths occurred, most commonly because of disease progression in both study arms. AEs including cardiac arrest, cardiac failure, dehydration, multiple-organ dysfunction syndrome, sepsis, and septic shock, led to death in 6 patients treated with tucatinib plus trastuzumab. Five patients treated with the placebo combination also died as a result of AEs, which include, cardiac arrest, multiple-organ dysfunction syndrome, myocardial infarction, sepsis, and systemic inflammatory response syndrome.

In the HER2CLIMB study, patients were randomized 2:1 to receive either tucatinib 300 mg twice daily or placebo twice daily, both in combination with trastuzumab 6 mg per kilogram of body weight) and capecitabine 1000 mg per square meter of the body surface area. Treatment lasted for 21-day cycles.

The secondary end points of the study were PFS in patients with baseline brain metastases OS, objective response rate, duration of response, clinical benefit rate, the incidence of AEs, incidence of health resources utilization, quality of life, and pharmacokinetics.

Candidates to enroll in the study were those with histologically confirmed HER2-positive breast cancer, the progression of unresectable advanced or metastatic disease, measurable or non-measurable disease, an ECOG performance status of 0 or 1, left ventricular ejection fraction &ge; 50%, adequate hepatic function, and adequate renal function. Patients were permitted to have received prior treatment with trastuzumab, pertuzumab, and T-DM1. Patients with brain metastases were also permitted to enroll if they met certain sub-requirements.

People with clinically significant cardiopulmonary disease, known chronic liver disease, known dihydropyrimidine dehydrogenase deficiency and those who were HIV positive, carriers of hepatitis B or C did not meet the criteria for enrollment in the study. Individuals were also excluded from HER2CLIMB if they had received prior treatment with lapatinib (Tykerb) within 12 months of the start of the trial, neratinib (Nerlynx), afatinib (Gilotrif), or other investigational HER2 or EGFR inhibitors at any time, and capecitabine for metastatic disease within 12 months prior to beginning treatment in the study.

The HER2CLIMB study is ongoing but is no longer recruiting patients. The study will conclude in July 2021. Following the positive results and the FDA Breakthrough Therapy Designation, Seattle Genetics plans to submit a supplemental New Drug Application to the FDA for tucatinib approval in the United States. The submission of a marketing authorization application to the European Medicines Agency (EMA) is also planned.

&ldquo;The addition of tucatinib to the commonly used combination of trastuzumab and capecitabine demonstrated superior activity compared with trastuzumab and capecitabine alone in patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including those with and without brain metastases,&rdquo; said Roger Dansey, MD, chief medical officer at Seattle Genetics. &ldquo;The decision by the FDA to grant Breakthrough Therapy designation to tucatinib recognizes the urgent need for new medicines that can impact the lives of those with HER2-positive metastatic breast cancer. We intend to submit a New Drug Application to the FDA and an MAA to the EMA by the first quarter 2020, with the goal of making tucatinib available to patients in this setting as soon as possible.&rdquo;

References

1. Seattle Genetics Announces U.S. FDA Grants Breakthrough Therapy Designation for Tucatinib in Locally Advanced or Metastatic HER2-Positive Breast Cancer [press release]. Bothell, Washington: Seattle Genetics; December 18, 2019.https://bit.ly/2Z5mZhs. Accessed December 18, 2019.
2. Seattle Genetics Announces Positive Topline Results from Pivotal Trial of Tucatinib in Locally Advanced or Metastatic HER2-Positive Breast Cancer [press release]. Bothell, Washington: Seattle Genetics; October 21, 2019.https://bit.ly/2M9ImZx. Accessed December 18, 2019.
3. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer.N Engl J Med. 2019. doi: 10.1056/NEJMoa1914609.