Study discussant Shanu Modi, MD, of Memorial Sloan Kettering Cancer Center, New York, commented, “Neither T-DM1 [Kadcyla] nor T-DM1 plus pertuzumab [Perjeta] proved to be superior to the old standard of care, taxane plus trastuzumab [Herceptin]. MARIANNE was a valiant trial, but THP (taxane, trastuzumab, and pertuzumab) remains our first-line standard of care, with T-DM1 a preferred second-line option.”

Dr. Modi emphasized that toxicity and health-related quality of life did appear more favorable with the ado-trastuzumab emtansine–containing regimens. In particular, rates of grade 3/4 neutropenia, febrile neutropenia, and diarrhea were lower in these arms, as was the occurrence of alopecia, and patient-reported outcomes remained positive for much longer. “It would be very informative to reassess these toxicities based on the taxane delivered,” she offered, “knowing that weekly paclitaxel has a very low febrile neutropenia rate and may be the preferred partner.”

She also questioned why pertuzumab provided no additional benefit, since in CLEOPATRA, the addition of this drug greatly improved survival, compared with an HT (trastuzumab [Herceptin] and taxane) arm.¹ The role of pertuzumab in adjuvant breast cancer is being explored further in the phase III ­APHINITY trial, she added.

Assessing the future for ado-trastuzumab emtansine, Dr. Modi suggested, “Given no progression-free survival advantage for T-DM1 or T-DM1 plus pertuzumab in the first-line metastatic setting, it is unlikely to show a survival advantage in the early-stage setting (neoadjuvant or adjuvant).” A number of adjuvant trials, however, are currently testing its potential in early-stage patients.

Unanswered Questions

Regarding the treatment of HER2-positive advanced breast cancer in general, Dr. Modi said a number of questions remain unanswered: What is the value of combining therapies? Is there an optimal combination? Does every case warrant multiple targeted agents? Can we avoid chemotherapy for some patients? What is the ideal trial setting for evaluating these treatments, and what are the right endpoints in these trials?

Based on current evidence, she concluded, “For the time being, taxane/trastuzumab/pertuzumab remains our preferred first-line therapy for HER2-positive metastatic breast cancer, and our treatment guidelines for 2015 remain unchanged.” ■

Disclosure: Dr. Modi reported no potential conflicts of interest.

Reference

1. Swain SM, Kim SB, Cortés J, et al: Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): Overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 14:461-471, 2013.