Trastuzumab Emtansine Plus Tucatinib for Patients With HER2-Positive Early Breast Cancer

Ciara O’Sullivan, MD, Mayo Clinic, Rochester, Minnesota, outlines the objectives of the CompassHER2 RD trial which aims to evaluate trastuzumab emtansine (T-DM1) plus tucatinib in a cohort of patients with high-risk, HER2-positive early breast cancer. 

Transcript: 

Good afternoon, my name is Ciara O'Sullivan, I'm an associate professor of medical oncology at the Mayo Clinic in Rochester, Minnesota, and I want to talk about a poster that I've presented at the recent San Antonio Breast Cancer Symposium in 2024 entitled the Alliance CompassHER2 RD: Post-neoadjuvant T-DM1 plus tucatinib/placebo in patients with residual HER2-positive invasive breast cancer. 

By way of background, patients with HER2-positive early breast cancer and invasive residual disease after neoadjuvant systemic chemotherapy have a higher risk of relapse than patients who experience a complete pathologic response. Although post-neoadjuvant T-DM1 has improved invasive disease-free survival [iDFS] outcomes, patients with estrogen receptor-negative and or node-positive residual disease have suboptimal outcomes, as well central nervous system [CNS] relapses are a challenge and signify the need for therapies with better CNS penetration in this population. We know that from the HER2CLIMB study tucatinib, trastuzumab, and capecitabine improved progression-free survival and overall survival compared with trastuzumab and capecitabine in patients with pretreated HER2-positive metastatic breast cancer and importantly, this study included almost 50% of patients who had breast cancer but also brain metastases. 

The CompassHER2 trials, which includes the A011801 I'm leading as well as EA1181/CompassHER2 pCR, these are 2 separate but scientifically related studies that leverage pCR or the response to new adjuvant systemic therapy as a tool to determine whether we should escalate or de-escalate systemic therapy in patients with HER2-positive early breast cancer. The primary objective of the study is to determine if invasive disease-free survival with T-DM1 and tucatinib is superior to invasive disease-free survival with T-DM1 and placebo. Secondary endpoints are to see whether T-DM1 and tucatinib versus T-DM1 and placebo improves breast cancer-free survival, distant recurrence-free survival, distant disease-free survival, brain metastasis-free survival, and overall survival. And a really important end point is just to see whether the combination of T-DM1 and tucatinib compared with T-DM1 and placebo reduces the instance of breast cancer brain metastases. 

We also have a number of correlative objectives of the study which are looking to evaluate the association of [tumor-infiltrating lymphocyte] TIL levels in the primary tumor and residual disease with invasive disease-free survival, as well as to determine if there are differential treatment benefits of T-DM1 and tucatinib versus T-DM1 and placebo in high versus low TIL cancers. In one of our upcoming protocol amendments contingent on that, we'll plan to evaluate the association between invasive disease-free survival and the presence of detectable ctDNA at baseline, at the completion of study therapy, and 1 year after completion of study therapy, we'll also determine the difference in the absolute magnitude of benefit of tucatinib in terms of iDFS in the subgroup of patients with detectable ctDNA at baseline and a subgroup of patients without detectable ctDNA at baseline. We'll characterize the [pharmacokinetics] PK of T-DM1 in all patients as well as characterize the PK of in tucatinib treated patients. We'll also look to investigate exposure effect relationships in tucatinib treated patients. We also have a number of local regional, [patient-reported outcome] PRO, and exploratory objectives in the study. 

We have quite standard eligibility criteria: we're including patients with HER2-positive invasive residual breast cancer irrespective of hormone receptor status. Patients can have clinical T1 through T4 and 0 to 3 disease at diagnosis. Patients with ER-negative disease can have any amount of residual disease to qualify, whereas patients with ER-positive disease need lymph node positive disease postoperatively to qualify. As well, patients must have received a minimum of 6 cycles of chemotherapy, either all preoperatively or a combination of pre-op and post-op, which must include at least 9 weeks of neoadjuvant taxane in trastuzumab prior to registration. We have a number of eligibility criteria: key ones include patients who have had prior treatment with HER2-targeted [tyrosine kinase inhibitors]TKIs or [antibody-drug conjugates] ADCs as well as patients with triple-positive residual disease that is lymph node negative for the surgical pathology report. 

The trial questions essentially do patients who receive T-DM1 plus tucatinib experience a reduced risk of breast cancer recurrence compared with those patients who receive T-DM1 plus placebo? This study is a prospective, double-blind, multicenter phase 3 superiority trial. We're targeting to enroll 1031 patients, 981 evaluable patients across the US and Canada. Randomization is 1-to-1 T-DM1 plus placebo versus T-DM1 plus tucatinib. Of course, adjuvant radiation therapy with or without endocrine therapy are indicated as per standard of care depending on the patient. Primary objective is to determine if the invasive disease-free survival is ≥ 5% higher with the addition of T-DM1 to tucatinib in patients with early stage HER2-positive breast cancer with residual disease after neoadjuvant systemic therapy. In terms of stratification factors, these are receipt of post-operative chemotherapy, hormone receptor status, and pathologic lymph node status. In terms of updates regarding this study, we activated originally in January of 2021, it's still available for site activation at the NCTN member sites at ctsu.org. As of the 14th of December 2024, the study had enrolled 897 patients it's open in Canada via the CT CTG, and we've enrolled 18 patients there and the projected accrual completion date is June of 2025. 

We're excited to complete accrual on this important study, [and] we hope that it will help us evaluate whether this combination of T-DM1 plus tucatinib will improve iDFS outcomes and very importantly, reduce the instance of brain metastasis in patients with high-risk disease compared with the standard of care with T-DM1 plus placebo, and I also hope that the correlative analysis of PK and [quality of life] QOL studies from this protocol will inform clinical decision making and future research endeavors in the post neoadjuvant HER2-positive space.

Source: 

Ballman KV, McCall LM, Zelma TJ, et al. A011801 (CompassHER2 RD): Post-neoadjuvant T-DM1 tucatinib/placebo in patients with residual HER2-positive invasive breast cancer. Presented at the 2024 San Antonio Breast Cancer Symposium. San Antonio, Texas. Abstract 1013