Anthracyclines add toxicity with no evidence of improved survival in patients with HER2-positive breast cancer receiving a neoadjuvant chemotherapy regimen plus dual HER2 blockade, results of a phase 3 trial have suggested.
Event-free survival (EFS) estimates at 3 years were 93% for patients receiving anthracycline-containing chemotherapy plus trastuzumab/pertuzumab and 94% for those receiving an anthracycline-free regimen, according to long-term follow-up results of TRAIN-2, a randomized, phase 3 trial.
There was also “no evidence” that higher-risk patients would benefit from anthracyclines, said investigator Anna Van der Voort of the Netherlands Cancer Institute in Amsterdam.
“Today, anthracyclines are often used, especially in patients with higher risk of recurrence,” said Ms. Van der Voort in her presentation, which was part of the American Society of Clinical Oncology (ASCO) virtual scientific program.
“Importantly, anthracyclines increased the risk of febrile neutropenia, cardiac toxicity, and chemotherapy-associated leukemia, and therefore, a neoadjuvant anthracycline-free regimen with dual HER2 blockade should be considered in all stage II and III HER2-positive breast cancer patients,” she suggested.
With these new results, there are now “great safety data and very promising efficacy data” from two comparative studies favoring nonanthracycline regimens plus HER2 blockade over an anthracycline approach, even in patients with disease thought to be at high risk of recurrence, said Sara A. Hurvitz, MD, associate professor of medicine at the University of California Los Angeles Jonsson Comprehensive Cancer Center.
The other comparative study, BCIRG-006, demonstrated that docetaxel and carboplatin plus trastuzumab (TCH) had similar efficacy, fewer acute toxicities, and less cardiotoxicity and leukemia than did doxorubicin/cyclophosphamide followed by docetaxel (AC-T).
In a follow-up analysis focused on patients with four or more positive lymph nodes, disease-free survival was similar for the nonanthracycline and anthracycline regimens, Dr. Hurvitz noted.
“I would challenge us to think carefully about the standard use of anthracyclines when we have so many targeted therapies available for our patients with HER2-positive disease now,” Dr. Hurvitz said in her commentary on TRAIN-2 that was also part of the virtual ASCO proceedings.
The TRAIN-2 trial included 438 patients in the Netherlands with previously untreated stage II to III HER2-positive breast cancer. Patients randomized to the anthracycline-containing arm received 5-fluorouracil, epirubicin, and cyclophosphamide in three 3-week cycles followed by paclitaxel and carboplatin in six 3-week cycles.
Patients in the anthracycline-free arm received paclitaxel and carboplatin for nine 3-week cycles. Both groups also received trastuzumab and pertuzumab concurrent with chemotherapy.
The pathological complete response (pCR) rate was high with and without anthracyclines, Ms. Van der Voort said, referring to primary results of TRAIN-2 previously published in Lancet Oncology.
In that report, pCR was seen in 67% of patients in the anthracycline group, and 68% in the nonanthracycline group (P = .95), a finding that was consistent regardless of tumor size, nodal status, or hormone receptor status, said Ms. Van der Voort. She added that significantly more febrile neutropenia and hypokalemia were seen in the anthracycline group.
At virtual ASCO, Ms. Van der Voort presented results of the EFS analysis. At the time of analysis, there were 21 events among 219 patients in the nonanthracycline group (10%) and 23 events among 219 patients in the anthracycline group (11%). The corresponding 3-year EFS estimates were 93.5% and 92.7%, with a hazard ratio that favored the nonanthracycline group, though the difference between arms was not statistically significant (hazard ratio, 0.90; 95% confidence interval, 0.50-1.63).
“The results were independent of hormone receptor status, age, tumor size, nodal status, and grade, so we found no evidence that high-risk patients require anthracyclines,” said Ms. Van der Voort. Of note, results divided by nodal status suggested similar or better outcomes in the absence of anthracyclines, even in the highest-risk group, she added.
Estimated 3-year overall survival rates were likewise similar between groups, at 98.2% and 97.7% in the nonanthracycline and anthracycline arms, respectively.
Declines in left ventricular ejection fraction were more frequent in the anthracycline group (36% vs. 22% for the nonanthracycline group; P = .0016), and about one-third of patients did not recover that decline. New malignancies were found in 5% of the anthracycline group and 2% of the nonanthracycline group.
The TRAIN-2 study was sponsored by the Netherlands Cancer Institute and Roche. Ms. Van der Voort said she had no relationships to disclose. Dr. Hurwitz reported institutional research funding from multiple pharmaceutical companies including Genentech/Roche.
SOURCE: Van der Voort A et al. ASCO 2020, Abstract 501.