Patients With HER2+ Breast Cancer and Brain Metastases Achieve Better OS With Tucatinib Triplet Regimen

Article

A triplet regimen of tucatinib, trastuzumab, and capecitabine helped patients with HER2-positive metastatic breast cancer and brain metastases live longer with reduced disease progression compared with trastuzumab and capecitabine alone.

Nancy U. Lin, MD

Nancy U. Lin, MD

The addition of tucatinib (Tukysa) to trastuzumab (Herceptin) and capecitabine has continued to demonstrate an overall survival (OS) benefit compared with trastuzumab/capecitabine alone in patients with HER2-positive metastatic breast cancer who have stable or active brain metastases, according to updated results from the pivotal phase 2 HER2CLIMB trial (NCT02614794).1,2

Updated data, which were presented during the 2021 San Antonio Breast Cancer Symposium, showed that after a median follow-up of 29.6 months, the tucatinib triplet demonstrated a median OS of 21.6 months (95% CI, 18.1-28.5) vs 12.5 months (95% CI, 11.2-16.9) with trastuzumab and capecitabine alone in patients with active and stable brain metastases (n = 291; HR, 0.60; 95% CI, 0.44-0.81).

Among patients with active brain metastases (n = 174), the addition of tucatinib resulted in a median OS of 21.4 months (95% CI, 18.1-28.9) vs 11.8 months (95% CI, 10.3-15.2) with trastuzumab and capecitabine alone (HR, 0.52; 95% CI, 0.36-0.77). Additionally, in those with stable brain metastases (n = 117) a median OS of 21.6 months (95% CI, 15.3-42.4) was experienced by those in the tucatinib arm vs 16.4 months (95% CI, 10.6-21.6) by those in the placebo arm (HR, 0.70; 95% CI, 0.42-1.16).

“The risk of breast cancer spreading to the brain is more pronounced for patients with aggressive subtypes of breast cancer, including HER2-positive breast cancer,” Nancy U. Lin, MD, director of the Metastatic Breast Cancer Program in the Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute, stated in a press release. “These analyses provide a hopeful outcome for patients with HER2-positive metastatic breast cancer when cancer has spread to the brain, as they show that the tucatinib regimen not only helped patients live longer but also slowed disease progression in the brain.”

Tucatinib is an oral TKI of the HER2 protein. In vitro, the agent has been shown to inhibit phosphorylation of HER2 and HER3, which has led to the inhibition of downstream MAPK and AKT signaling and cell growth. The agent has also demonstrated antitumor activity in HER2-expressing tumor cells. Tucatinib has also been found to inhibit the growth of HER2-expressing tumors in vivo. When paired with trastuzumab, the regimen increased antitumor activity in vitro, as well as in vivo vs either agent alone.

Currently, tucatinib is approved for use in 36 countries. In April 2020, the FDA gave the green light to tucatinib for use in combination with trastuzumab and capecitabine in the treatment of patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including those with brain metastases, following at least 1 previous anti-HER2­­­–based regimen in the metastatic setting.3 The regulatory decision was supported by data from HER2CLIMB.

The multinational, randomized, double-blind, placebo-controlled, active comparator, pivotal clinical trial randomized 612 patients 2:1 to receive either oral tucatinib at a twice-daily dose of 300 mg plus intravenous trastuzumab at a loading dose of 8 mg/kg on day 1 of cycle 1 followed by 6 mg/kg every 3 weeks and oral capecitabine at a twice-daily dose of 1000 mg/m2 on days 1 through 14 of each 21-day cycle (n = 410), or placebo plus trastuzumab/capecitabine (n = 202).

To be eligible for enrollment, patients needed to have unresectable, locally advanced or metastatic HER2-positive breast cancer and have previously been treated with trastuzumab, pertuzumab (Perjeta), and ado-trastuzumab emtansine (T-DM1; Kadcyla). Patients needed to have an ECOG performance status of 0 or 1 and a brain MRI at baseline.

Notably, patients with treated, stable brain metastases, untreated metastases that did not require immediate treatment, previously treated progressing metastases that do not require immediate therapy, and those with no evidence of brain metastases were all eligible to participate.

The primary end point of the trial was progression-free survival (PFS) per RECIST v1.1 criteria and blinded independent central review (BICR). Secondary end points included OS and PFS in patients with metastases and confirmed OS in those with measurable disease.

Additional updated data indicated that those with stable and active brain metastases who received the addition of tucatinib experienced an improvement in median central nervous system (CNS)-PFS compared with trastuzumab/capecitabine alone, at 9.9 months (95% CI, 8.4-11.7) and 4.2 months (95% CI, 3.6-5.7), respectively (HR. 0.39; 95% CI, 0.27-0.56).

Moreover, the median CNS-PFS for those with active brain metastases was 9.6 months (95% CI, 7.6-11.1) vs 4.0 months (95% CI, 2.9-5.6) in the tucatinib and placebo arms, respectively (HR, 0.34; 95% CI, 0.22-0.54). Furthermore, those with stable brain metastases experienced a median CNS-PFS of 13.9 months (95% CI, 9.7-24.9) with the tucatinib triplet vs 5.6 months (95% CI, 3.0–not evaluable) with trastuzumab/capecitabine (HR, 0.41; 95% CI, 0.19-0.85).

In terms of safety, serious adverse effects (AEs) occurred in 26% of patients in the tucatinib arm. Serious AEs that experienced by 2% or more of patients who received tucatinib included diarrhea (4%), vomiting (2.5%), nausea (2%), abdominal pain (2%), and seizure (2%). Fatal AEs were reported in 2% of patients who received tucatinib, and included sudden death, sepsis, dehydration, and cardiogenic shock.

Furthermore, AEs led to treatment discontinuation in 6% of patients on the tucatinib arm. Those that occurred in 1% or more patients were hepatotoxicity (1.5%) and diarrhea (1%). AEs that required dose reductions were reported in 21% of patients treated with the agent and included hepatotoxicity (8%) and diarrhea (6%).

Overall, the most common AEs experienced by patients who received tucatinib were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash.

References

  1. Seagen announces updated results from pivotal HER2CLIMB trial evaluating TUKYSA® (tucatinib) in patients with HER2-positive breast cancer with brain metastases. News release. Seagen Inc; December 8, 2021. Accessed December 20, 2021. https://bit.ly/3dzzRUX
  2. Lin NU, Murthy RK, Abramson V, et al. Tucatinib vs placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB). Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; virtual. Abstract 858.
  3. FDA approves first new drug under international collaboration, a treatment option for patients with HER2-positive metastatic breast cancer. News release. FDA; April 17, 2020. Accessed December 20, 2021.

This article was originally published on OncLive as “Tucatinib Triplet Maintains OS Benefit in HER2+ Breast Cancer With Brain Metastases”

Recent Videos
Ann H. Partridge, MD, MPH, in an interview with Oncology Nursing News at 2024 ESMO Congress.
Related Content
© 2024 MJH Life Sciences

All rights reserved.