Treatment for HER2-positive breast cancer with trastuzumab emtansine (T-DM1) plus pertuzumab yielded a higher risk of event-free survival (EFS) events compared with trastuzumab, pertuzumab, and chemotherapy, according to a phase III trial. There was a similar risk of invasive disease–free survival (IDFS) events, though, suggesting that chemotherapy may be unnecessary in some patients.
The standard of care for HER2-positive breast cancer is chemotherapy along with dual HER2 blockade with trastuzumab and pertuzumab, which offers pathologic complete response (pCR) rates ranging from 46% to 62%. “Despite the good outcomes we have with dual HER2 blockade in the neoadjuvant setting, 15% of patients will relapse or die” within 3 to 5 years, and systemic chemotherapy is associated with systemic toxicity, said Sara A. Hurvitz, MD, of the David Geffen School of Medicine at UCLA. “There still is a need for effective, less toxic therapy.”
T-DM1 is an antibody-drug conjugate consisting of HER2-targeted cytotoxic chemotherapy along with trastuzumab; combining it with pertuzumab could improve the toxicity profile of combination regimens. Hurvitz presented the final results of the phase III KRISTINE trial at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting (abstract 500). It was previously reported that the chemotherapy and dual blockade combination resulted in a superior pCR rate compared with T-DM1 plus pertuzumab, but the latter regimen had a better safety profile.
The study included 444 patients, and patients were followed for a median of approximately 37 months. The 3-year EFS rate was 94.2% with trastuzumab, chemotherapy, and pertuzumab, compared with 85.3% with T-DM1 and pertuzumab, for a hazard ratio (HR) of 2.61 (95% CI, 1.36–4.98). This was primarily driven by an increased number of locoregional recurrences, with 15 in the T-DM1 group compared with none in the chemotherapy group.
Fourteen of those with locoregional progression were evaluable for HER2 mRNA expression, and all 14 had expression below the median, compared with 47.1% of those without locoregional progression.
The 3-year IDFS rates were 92.0% with chemotherapy and 93.0% with T-DM1, for an HR of 1.11 (95% CI, 0.52–2.40).
Serious adverse events were more frequent with chemotherapy, occurring in 32.4% of patients compared with 13.5% of patients receiving T-DM1. Adverse events leading to discontinuation of any study drug, however, were more common with T-DM1, in 20.2% of patients compared with 11.0% of chemotherapy patients. Hurvitz noted that patient-reported outcomes including global health status favored the T-DM1 group during neoadjuvant treatment, but no differences were seen during adjuvant therapy.
“The similar risk of an IDFS event with T-DM1 plus pertuzumab and [trastuzumab, chemotherapy, and pertuzumab] suggests that systemic chemotherapy might be unnecessary for some patients, but of course identification of these patients is going to be critical in determining who can have a de-escalation approach,” Hurvitz concluded.
Mark D. Pegram, MD, of the Stanford School of Medicine, was the discussant for the abstract. “Recall that T-DM1 retains all the known mechanisms of action of trastuzumab,” he said, adding that the dose in this trial was lower with T-DM1 than with trastuzumab. “If any of these [mechanisms] are important attributes of T-DM1 action … then there may be a compromise with the dose of T-DM1.”
