Study: A new breast cancer drug improves overall survival among people with brain and other metastases

IN-DEPTH REVIEW OF RESEARCH

Study background:

Patients with HER2-positive metastatic breast cancer (MBC) have limited options for treatment. and, on average, survive 2 years. Researchers are seeking treatments that prolong survival or increase survival without cancer progression for better quality of life. Tucatinib is a type of drug known as a tyrosine kinase inhibitor (TKI) that specifically targets HER2. TKI inhibitors act in a different region of HER2 compared to trastuzumab (herceptin) or related drugs. A phase Ib dose study suggested that combination of tucatinib plus trastuzumab and standard chemotherapy might improve outcomes of metastatic breast cancer patients.

Researchers of this study wanted to know:

Whether tucatinibin combination with standard treatment improves progression-free survival and/or overall survival in people with or without brain metastases

Populations looked at in this study:

612 participants were enrolled from February 2016 to May 2019 from 155 locations in 15 countries. Eligible participants were patients 18 years or older with HER2-positive metastatic breast cancer who had previously been treated with trastuzumab (Herceptin), pertuzumab (Perjeta) or trastuzumab emtansine (Kadcyla). Participants included 607 women and 5 men with and without brain metastases with an average age of 54. Participants included 72% white women, 9% black women, 3.7% Asian women and 14% women with unknown racial/ethnic information.

Study design:

The HER2CLIMB study was a randomized double-blind clinical trial. All participants were treated with trastuzumab (Herceptin) and capecitabine (Xeloda) as standard of care. Trastuzumab was given intravenously every 21 days, while capecitabine was given orally on days 1-14 of each 21-day period. The remainder of this review refers to trastuzumab plus capecitabine as the "combination."

Participants were randomly treated with either tucatinib or placebo as a pill twice a day throughout the study:

•  tucatinib (the tucatinib-combination group: 410 participants)
• placebo (the placebo-combination group: 202 participants)

Participants were tested by CT, PET-T or contrast-MRI imaging to measure their disease progression at the time of enrollment, then every 6 weeks for 24 weeks and every 9 weeks thereafter until the end of the study. For participants with brain metastases at the time of enrollment, progression of brain cancer was followed by contrast MRI of the head. All imaging was evaluated by blinded independent review (reviewers did not know which patients or which drug treatment were linked to each image) using Response Evaluation Criteria in Solid Tumors  v. 1.1 as a standard guideline.

Study findings:  

The primary endpoint was progression-free survival (PFS) or the length of time participants experienced before their cancer progressed (grew in size or metastasized further). This analysis was done with an original group of 480 participants.

At 1 year, the risk of disease progression or death was 46% lower in the tucatinib-combination group compared to the placebo group.

• 275 of 480 participants experienced a progression of their cancer:
  • 33% of the tucatinib-combination group survived without their cancer worsening
  • 12% of the placebo-combination group survived without their cancer worsening
• The average participant experienced a longer time until their cancer progressed:
  • 7.8 months for the tucatinib-combination group
  • 5.6 months for the placebo-combination group
• Improved PFS was seen in all sub-groups: hormone receptor-positive and receptor-negative patients, participants younger and older than age 65, white and non-white patients, and those with and without brain metastases.

At 2 years, the risk of death was 34% lower for participants treated with the tucatinib-combination.

• 215 deaths occurred among the enrolled 612 participants:
  • 45% of the tucatinib-combination group survived
  • 27% of the placebo-combination group survived
• The average participant experienced a longer time until death:
  • 22 months for the tucatinib-combination group
  • 17 months for the placebo-combination group
• Improved overall survival was seen in all sub-groups: hormone receptor-positive and receptor-negative patients, participants younger and older than age 65, white and non-white patients, and in those with and without brain metastases.

Participants with brain metastases also benefited from the tucatinib-combination treatment.

• At 1 year, the risk of disease progression or death was 52% lower among participants with brain metastases in the tucatinib-combination group compared to those in the placebo group.
  • 25% of the tucatinib-combination group survived without their cancer worsening
  • 0% of the placebo-combination group survived without their cancer worsening

The average participant experienced a longer time until their cancer progressed:

• 7.6 months for the tucatinib-combination group
• 5.4 months for the placebo-combination group

Objective response rate refers to the rate of patients whose cancer shrink in size or become undetectable. Almost twice as many participants treated with the tucatinib-combination had their cancer shrink or disappear compared to the placebo group.

• Among the 511 participants who had measurable cancer when they enrolled, the objective response rate was:
  • 41% among the tucatinib-combination treated patients
  • 23% among the placebo-combination treated patients

Safety

Adverse events among patients who were treated with the tucatinib-combination were diarrhea, hand-foot syndrome, nausea, fatigue and vomiting. Most of these were not severe. Diarrhea was the most common severe event. Similar types of adverse effects are seen with related TKI drugs, but they appear less frequently with tucatinib. This suggests tucatinib may be a better TKI inhibitor for breast cancer treatment.

Most events did not require discontinuation of therapy; 6% of the tucatinib-combination group and 3% of the placebo-combination group discontinued treatment.

Of the 215 participant deaths during the study, most (96%) were linked to cancer progression: 11 were associated with treatment—6 of 404 (6%) patients in the tucatinib-group and 5 of 157 (2.5%) in the placebo-combination group.

Limitations:

This study reports initial findings of the HER2CLIMB trial of tucatinib. Some participants are still living; additional time is needed to determine final survival rates and outcomes.

While 30% of participants were non-white, a substantial portion of these women were of unknown or undeclared ethnicity/racial background. Non-white participants saw outcome benefits similar to white participants. However, the numbers of participants in specific racial or ethnic groups were too small to conclude if there were differences in outcomes between groups. Treating more women of color with this drug is needed to determine if it is equally helpful in all groups.

While significant improvements in progression-free survival, overall survival and objective response rates were observed, 215 deaths that were attributed to metastatic breast cancer occurred in the first year of treatment. This treatment slows but does not stop cancer for most patients. Further research is needed to improve these results.

Conclusions:

This is a well-designed randomized, double-blind trial. Tucatinib treatment in combination with Herceptin and Xeloda seems to improve outcomes of women with HER2-positive metastatic breast cancer by increasing progression-free survival, overall survival and objective response rates, with relatively modest adverse effects. Tucatinib was approved by the FDA on 04/17/20.

Share your thoughts on this XRAYS article by taking our brief survey. 

Posted 11/20/19 and updated 04/17/20.