Can T-DM1 Match Chemotherapy Plus Dual Blockade in HER2+ Breast Cancer?

A randomized phase II trial found no differences in response rates between a regimen consisting of docetaxel, trastuzumab, and pertuzumab, and trastuzumab emtansine (T-DM1) for the neoadjuvant treatment of HER2-positive breast cancer. The latter treatment had substantially less toxicity than the chemotherapy and HER2 blockade regimen.

“Trastuzumab emtansine is apparently quite a powerful drug, because a patient failing after 2 or more lines of anti-HER2 therapies had a median survival [gain] of almost 7 months,” said Jonas C. S. Bergh, MD, PhD, of the Karolinska Institutet and University Hospital in Sweden, citing previous research. He presented results of the new phase II PREDIX HER2 trial at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting (abstract 501).

The study included 199 patients with HER2-positive breast cancer. Patients were randomized to receive either docetaxel, trastuzumab, and pertuzumab (100 patients), or T-DM1 (99 patients), as neoadjuvant therapy. All patients received epirubicin and cyclophosphamide in the adjuvant setting, followed by 11 courses of trastuzumab.

Patients had a median age of 51 years in the combination group and 53 years in the T-DM1 group. Approximately half the cohort was premenopausal, and almost all patients had an ECOG performance status of 0 (98%).

In the combination group, 47% of patients had a pathologic complete response, compared with 45% in the T-DM1 group (P = .359). Though they still did not differ by treatment, pCRs were more frequent among patients with estrogen receptor (ER)- and progesterone receptor (PR)-negative disease; in these patients, the pCR rate was 67% with docetaxel and HER2 blockade, and 59% in the T-DM1 group (P = .502). Among ER- and/or PR-positive patients, the pCR was 36% in both groups (P = .929). When stratified by T stage, there was still no difference in pCR between the two regimens.

A total of 18 patients switched from the combination treatment to the T-DM1 treatment; 14 of these were due to toxicity, while 4 were due to no change or progression after 2 or 4 courses of treatment. Nine patients switched in the opposite direction; four because of no change or progression after two courses, three after four courses, and two patients switched due to toxicity. One patient in each of these groups experienced a pCR after switching.

Toxicity was significantly worse with docetaxel and dual HER2 blockade. Among the adverse events that were more frequent with that therapy were grade 3/4 febrile neutropenia (26% vs 3%), grade 1/2 diarrhea (59% vs 7%), and grade 1/2 sensory neuropathy (30% vs 17%), among others. Liver toxicity was more common with T-DM1, at 14% for grade 1/2 compared with 3% in the combination group.

“Neoadjuvant T-DM1 plus or minus pertuzumab is better tolerated than dual HER2 antibody therapy in combination with cytotoxics, and is associated with better quality-of-life metrics,” said Mark D. Pegram, MD, of the Stanford School of Medicine, who was the discussant for the abstract. Based on this and other recent research, he said that “early adopters may consider neoadjuvant T-DM1 in patients who are perhaps not candidates for chemotherapy, due to comorbidities, age, etc, or those patients who frankly refuse chemotherapy.”