NEW ORLEANS — Neoadjuvant treatment with ado-trastuzumab emtansine and pertuzumab appeared more beneficial than standard paclitaxel plus trastuzumab among women with HER-2–positive invasive breast cancer, according to results of the I-SPY 2 trial presented at the American Association for Cancer Research Annual Meeting.
Researchers observed the benefit regardless of hormone receptor status.
“We are encouraged by this and look forward to adding new combinations to [ado-trastuzumab emtansine] as a less toxic backbone, including immunotherapies and other targeted therapies,” Angela DeMichele, MD, MSCE, professor of medicine and epidemiology at Perelman School of Medicine at University of Pennsylvania, said during a press conference. “It gives us an opportunity to start thinking about tailoring therapy, particularly in the neoadjuvant setting. ... It could help us start to give up some of the more toxic chemotherapies like paclitaxel that we have used in the past.”
Women who achieve pathologic complete response (pCR) defined as no residual invasive cancer detected in the breast tissue or lymph nodes at the time of surgery is an excellent surrogate for long-term clinical outcomes among women with HER-2–positive breast cancer. However, not every patient achieves pCR, and researchers hope to identify new trials that increase the pCR rate in this population.
Researchers involved with I-SPY 2 a phase 2, adaptively-randomized trial established to identify specific drugs or combinations that could be advanced to phase 3 assessed whether ado-trastuzumab emtansine (Kadcyla, Genentech) plus pertuzumab (Perjeta, Genentech) could help more women with HER-2–positive invasive breast cancer achieve pCR.
The analysis included 83 patients with invasive HER-2–positive disease at least 2.5 cm in size. All patients had adequate organ function and performance status.
Fifty-two patients received ado-trastuzumab emtansine 3.6 mg/kg, plus pertuzumab administered in an 840-mg loading dose followed by 420 mg every 3 weeks. The 31 patients in the control group received paclitaxel 80 mg/m2, plus trastuzumab administered in a 4-mg/kg loading dose followed by subsequent weekly doses of 2 mg/kg.
Treatment continued for 12 weeks. After that, all patients received standard doxorubicin and cyclophosphamide.
Treatment arms were well balanced with regard to age, race, ethnicity and MRI tumor diameter at the time of diagnosis. Approximately two-thirds of women in each group had hormone receptor-positive disease.
DeMichele and colleagues used Bayesian predictive probabilities to estimate the likelihood that patients would achieve a pCR. They also calculated the probability of success that the investigational arm would be superior to the control arm, as well as the probability that the probability that it would succeed in a subsequent phase 3 trial.
Results showed the combination of ado-trastuzumab emtansine and pertuzumab was associated with a higher estimated pCR rate than the control regimen among all women with HER-2–positive disease (52% vs. 22%). Estimated pCR rates for the investigational regimen were higher among women with hormone receptor-negative disease (64% vs. 33%) and those with hormone receptor-positive disease (46% vs. 17%).
Researchers calculated a 99.5% probability that the investigational regimen would be superior to the control arm for all women with HER-2–positive disease. They calculated superiority probabilities of 98% for women with hormone receptor-negative disease and 99% for those with hormone receptor-positive disease.
The probabilities that the investigational regimen would be successful in a phase 3 trial were 94% for all women with HER-2–positive disease, 90% for those with hormone receptor-negative disease and 93% for those with hormone receptor-positive disease.
During the experimental agent portion of the study, women who received the control regimen experienced higher rates of hypertension (any grade, 45% vs. 17%; grade 3 or higher, 10% vs. 4%), neuropathy (any grade, 45% vs. 17%) and alopecia (any grade, 58% vs. 8%).
“[These] are side effects that really matter to women and can really affect their day-to-day function,” DeMichele said.
Women assigned ado-trastuzumab emtansine plus pertuzumab experienced higher rates of elevated alanine transaminase level (25% vs. 13%) and aspartate transaminase level (25% vs. 13%), but the majority were low grade and not clinically significant, DeMichele said.
Adverse event rates calculated during the entire study period followed a similar pattern.
Several phase 3 trials are ongoing to help establish the role of ado-trastuzumab emtansine with or without pertuzumab in the neoadjuvant setting, and those results are eagerly awaited, DeMichele said.
“What we ultimately want to achieve is to get the greatest proportion of patients to a pathologic complete response,” DeMichele said. “If we can use trials like I-SPY 2 to identify ways to do that without using more toxic chemotherapy, that is going to be a win for patients.” – by Mark Leiser
DeMichele, AM. Abstract CT-042. Presented at: American Association for Cancer Research Annual Meeting; April 16-20, 2016; New Orleans.
DeMichele reports institutional research funding from Calithera, Genentech, Incyte, Johnson & Johnson, Novartis and Pfizer, as well as scientific advisory board roles with Novartis and Pfizer. Please see the full study for a list of all other researchers’ relevant financial disclosures.