HR Status in HER2+ Breast Cancer Does Not Impact Efficacy of HER2CLIMB Regimen

Erika P. Hamilton, MD

The FDA approval of tucatinib (Tukysa) 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, has changed breast cancer practice for the better. Still, there is a subgroup of patients with unresectable locally advanced or metastatic HER2-positive breast cancer who are also hormone receptor (HR)–positive, and subset analysis of the HER2CLIMB trial (NCT02614794) was needed to assess whether the combination was also beneficial for these patients.

In the study, tucatinib plus trastuzumab and capecitabine was administered to a group of 612 patients, 370 of whom had HR-positive status and 242 who had HR-negative status. The characteristics of the patients in these 2 arms were well balanced at baseline. Mirroring the primary analysis of the HER2CLIMB trial, progression-free survival (PFS) per RECIST 1.1 by blinded independent central review was evaluated in the first 480 patients included. Then in the patients who had brain metastases at baseline, the study investigators assessed PFS and overall survival (OS).

Results from the study revealed tucatinib combined with trastuzumab and capecitabine led to clinically meaningful improvements of PFS, OS, and even objective response rate irrespective of HR negativity or positivity. The benefit was similar for the group of patients with brain metastases at baseline.

In an interview with Targeted Oncology, Erika P. Hamilton, MD, director, Breast and Gynecologic Cancer Research, oncologist/investigator, Breast and Gynecologic Program, Sarah Cannon Research Institute, explained how HR status in patients with HER2-positive breast cancer was affected by treatment with the HER2CLIMB regimen of tucatinib plus trastuzumab and capecitabine.

TARGETED ONCOLOGY: What have we seen so far with the HER2CLIMB trial?

Hamilton: HER2CLIMB is that pivotal trial that led to the approval of tucatinib. The trial is designed with capecitabine and trastuzumab given with or without the addition of tucatinib. Patients in the clinical trial had received first- and second-line therapy. These were traditional third-line patients that had already been pre-treated with T-DM1 (Kadcyla), pertuzumab (Perjeta), and a taxane.

What we saw on the HER2CLIMB trial was an improvement across the board in all the end points, including PFS, overall response rate (ORR), OS, [and efficacy in] patients with brain metastases.

The thing that was unique about this trial is that it was one of the first trials to allow a more inclusive population of patients that had brain metastases. We're very used to seeing brain metastases being allowed if they're stable and treated to come on to a trial, but HER2CLIMB also allowed patients that had brain metastases that were asymptomatic and untreated. The study also allowed for brain metastases that had been treated and were subsequently progressive. Two of 3 of these categories were much more high risk, with more aggressive brain disease than we typically see on trials. It was very encouraging to see. Almost 50% of patients ended up coming onto the study with brain metastases and there was a clear improvement in that population.

TARGETED ONCOLOGY: In the study, there was a subset analysis for the HR-positive population. Can you discuss the results from that analysis?

Hamilton: For the subset analysis we looked at patients that also had HR expression. Patients were stratified to determine what [outcomes] looked like if they were HR-negative or HR-positive or so called triple positive along with the HER2-positive status. Investigators looked at all of the markers, including PFS, OS, ORR, and brain metastases. The trial wasn’t designed to break things up this way, so some things observed were not statistically significant. But numerically, there was a benefit across the board in the HR-positive and HER-negative patients.

Some of the things that stood out were in the HR-negative space, and that’s probably because those tumors are a little more aggressive and also have worse outcomes. Specifically, in that subset of patients with HR-negative, HER2-positive breast cancer, OS improved from 14 months to up to 31 months [with the addition of tucatinib]. It’s a striking improvement. In patients with HR-negative disease and brain metastases, we also saw that OS improved from 11.5 months to 18.5 months, which is clinically meaningful.

TARGETED ONCOLOGY: What is the key message you and the other investigators hope to convey with this research?

Hamilton: The key message is that tucatinib is active in HER2-positive patients with brain metastases, without brain metastases, and regardless of the HR status. I think it's just practice affirming that we should be considering this option for all of our patients with HER2-positive disease.

_Reference:

_{Hamilton E, Reinisch M, Loi R, et al. Tucatinib vs placebo in combination with trastuzumab and capecitabine for patients with locally advanced unresectable or HER2-positive metastatic breast cancer (HER2CLIMB): Outcomes by hormone receptor status. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Abstract PD3-08.}