Tucatinib Triplet Prolongs Time to Deterioration of HRQOL in HER2+ Breast Cancer With Brain Metastases

Carey K. Anders, MD

Tucatinib (Tukysa) IN COMBINATION with trastuzumab (Herceptin) and capecitabine significantly prolonged the time to deterioration of health-related quality of life (HRQOL) in patients with HER2- positive metastatic breast cancer with brain metastases, according to the results of an analysis of the HER2CLIMB study presented during the 2020 San Antonio Breast Cancer Symposium (SABCS).¹

Results showed no notable differences in HRQOL between patients who received tucatinib, trastuzumab, and capecitabine and those who received placebo, trastuzumab, and capecitabine. Moreover, the addition of tucatinib was found to significantly delay time to worsening of EQ-5D-5L health score compared with placebo. Patients who received the tucatinib regimen experienced a 49% reduction in the risk of deterioration versus those who received placebo plus trastuzumab/ capecitabine (HR, 0.51; 95% CI, 0.28-0.93). The median time to worsening of HRQOL was not reached in the tucatinib arm versus 5.5 months in the placebo arm.

Although no noticeable changes with regard to mobility, usual activities, pain and discomfort, self-care, and depression and anxiety were observed in patients during the course of treatment, investigators noted deterioration in mobility, usual activities, pain and discomfort, and self-care following treatment discontinuation in both arms.

“The addition of tucatinib to trastuzumab and capecitabine among patients with HER2-positive breast cancer and brain metastases confirms improved time to deterioration of HRQOL,” Carey K. Anders, MD, a medical oncologist at Duke University, said during a poster presentation of the findings. “Coupled with the improvements to progression-free survival and overall survival, this is a clinically meaningful outcome.”

In April 2020, the FDA approved the use of tucatinib in combination with trastuzumab and capecitabine in patents with unresectable, locally advanced, or metastatic HER2-positive breast cancer, including those with brain metastases. The approval was based on early HER2CLIMB data, which were presented during the 2019 SABCS.²

Results from the primary analysis showed a benefit with the tucatinib triplet in patients, regardless of whether they had brain metastases.

After a median duration of exposure of 7.3 months in the tucatinib arm and 4.4 months in the placebo arm, tucatinib led to a 46% reduction in risk of progression or death per blinded independent central review (BICR; HR, 0.54; 95% CI, 0.42-0.71; P <.001). Additionally, patients who received the tucatinib combination experienced a 34% reduction in risk of death (HR, 0.66; 95% CI, 0.50-0.88; P = .005). Notably, the triplet resulted in a 52% reduction in risk of progression or death per BICR in patients with brain metastases (HR, 0.48; 95% CI, 0.34-0.69; P <.001).

Disease progression in patients with metastatic breast cancer can have a negative impact on QOL.³ Moreover, patients with HER2-positive disease and brain metastases have an increased chance of having a negative HRQOL versus those without brain metastases.⁴

For the analysis presented at 2020 SABCS, the investigators set out to evaluate the HRQOL impact of tucatinib in patients with brain metastases.

To be eligible for enrollment on the HER2CLIMB study, patients needed to have HER2-positive metastatic breast cancer; have received prior treatment with trastuzumab, pertuzumab (Perjeta), and trastuzumab emtansine (T-DM1; Kadcyla); have an ECOG performance status of 0 or 1; and have a brain MRI at baseline. Notably, 48.3% of patients in the tucatinib arm had brain metastases at baseline; this included patients with previously untreated, treated and stable, or treated and progressing metastases.

Patients (n = 612) were randomized 2:1 to the 2 treatment arms. The experimental cohort (n = 410) received 300 mg of oral tucatinib twice daily followed by 6 mg/kg of trastuzumab given every 3 weeks with an 8-mg/ kg loading dose (cycle 1, day 1) in a 21-day cycle, as well as 1000 mg/m2 of oral capecitabine twice daily on days 1 to 14. The second cohort (n = 202) received placebo in combination with the same trastuzumab/capecitabine dose and schedule as the tucatinib cohort.

Among the total patient population, 331 patients had HRQOL data available; 164 of these patients had brain metastases. Of the patients with brain metastases, 107 were in the tucatinib cohort and 57 were in the placebo cohort. HRQOL assessments were performed at baseline, cycle 3, cycle 5, cycle 7, cycle 9, and during the 30-day follow-up.

Assessments focused on overall health status utilizing the visual analogue scale (VAS), as well as time to deterioration of QOL, which was defined as a decrease of 7 points on VAS. Change from baseline on individual patientreported factors was another focus of the analysis; these factors were mobility, self-care, usual activities, pain and discomfort, and anxiety and depression. Changes in these factors were rated on a scale of 1 to 5, with 1 representing no change and 5 indicating extreme problems.

Baseline patient characteristics were consistent among the total study population, including the total brain metastases population and HRQOL brain metastases population. In the brain metastases population and the HRQOL brain metastases population, patients in the tucatinib arm had a median of 4 prior lines of therapy overall and 2 median lines of therapy in the metastatic setting. The placebo arm had a median of 3 prior lines of therapy for metastatic disease and overall, respectively.

“Future outcomes of interest could include time to and type of future radiation therapy, and subsequent improvements in neurocognition,” Anders concluded.

References

1. Wardley A, Mueller V, Paplomata E, et al. Impact of tucatinib on health-related quality of life in patients with HER2+ metastatic breast cancer with stable and active brain metastases. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Poster PD13-04. https://bit.ly/3qRaqn6
2. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382:597-609. doi:10.1056/NEJMoa1914609
3. Müller V, Nabieva N, Häberle L, et al. Impact of disease progression on health-related quality of life in patients with metastatic breast cancer in the PRAEGNANT breast cancer registry. Breast. 2018;37:154-160. doi:10.1016/j.breast.2017.08.008
4. Hurvitz SA, O'Shaughnessy J, Mason G, et al. Central nervous system metastasis in patients with HER2-positive metastatic breast cancer:pPatient characteristics, treatment, and survival from SystHERs. Clin Can Res. 2019;25(8):2433-2441. doi:10.1158/1078-0432.CCR-18-2366