AACR 2016: Neoadjuvant Trastuzumab Emtansine Plus Pertuzumab May Improve Outcomes for Women With HER2-Positive Breast Cancer
Results from the I-SPY 2 TRIAL show that a neoadjuvant therapy combination of the antibody-drug conjugate ado-trastuzumab emtansine (Kadcyla) and pertuzumab (Perjeta) was more beneficial than paclitaxel plus trastuzumab for women with HER2-positive invasive breast cancer, according to research presented by DeMichele et al at the 2016 AACR Annual Meeting (Abstract CT042).
Traditional trials have simply added new drugs to the existing regimens, but paclitaxel has some very bothersome and disabling symptoms, including neuropathy, lowering of blood counts, and hair loss, said lead author and presenter, Angela DeMichele, MD, MSCE, Professor of Medicine and Epidemiology at the Perelman School of Medicine at the University of Pennsylvania. “Being able to offer patients a more effective and less toxic regimen would be extremely beneficial to patients’ overall prognosis, and quality of life.”
In this portion of the I-SPY2 TRIAL, the investigators tested if ado-trastuzumab emtansine plus pertuzumab could bring a substantially greater proportion of patients to the primary endpoint of pathological complete response compared with paclitaxel plus trastuzumab. They also examined whether this combination could meet that goal without the need for patients to receive paclitaxel.
Study Findings
Prior studies have shown that a combination of ado-trastuzumab emtansine and pertuzumab was safe and effective against advanced, metastatic HER2-positive breast cancer, Dr. DeMichele said. In this trial, the investigators tested whether this combination would also be effective if given earlier in the course of treatment, before surgery.
Using a statistical approach called the Bayesian probability of superiority vs control, patients whose HER2-positive invasive breast cancers were 2.5 cm or bigger were adaptively randomly assigned to 12 weekly cycles of paclitaxel plus trastuzumab (control) or ado-trastuzumab emtansine plus pertuzumab (test). Following this, all patients received four cycles of the chemotherapies doxorubicin and cyclophosphamide, and surgery.
Patients’ tumors were determined to have one of three biomarker signatures: HER2-positive, HER2-positive and hormone receptor–positive, and HER2-positive and hormone receptor–negative.
“The combination of ado-trastuzumab emtansine and pertuzumab graduated from I-SPY 2 in all biomarker signatures tested,” said Dr. DeMichele, meaning that it substantially improved pathologic complete response for all subgroups of HER2-positive breast cancers compared with those in the control group, and would be likely to succeed in a confirmatory 300-patient, neoadjuvant, phase III, randomized trial testing this combination against paclitaxel plus trastuzumab. “This could, in turn, result in fewer women developing recurrent, metastatic breast cancer without the short- and long-term toxicity of taxane therapy.”
At the time of assessment, there were 52 patients in the test arm and 31 patients in the control arm. The trial’s unique statistical method confirmed that, based on pathologic complete response data, there is a 90% to 94% chance that ado-trastuzumab emtansine plus pertuzumab combination will deliver positive results in a 300-patient phase III trial in women with HER2-positive breast cancers with any of the three biomarker signatures aforementioned.
“These data provide a possible new treatment option for patients with newly diagnosed breast cancer that can not only effectively shrink the tumor in the breast but potentially reduce the chance of the cancer coming back later, in another part of the body, which is an incurable situation,” Dr. DeMichele said. “This also shows that by replacing older, nontargeted therapies with more effective, less-toxic new therapies, we have the potential to both improve outcomes and decrease side effects,” she added.
“While these results are promising, a phase III confirmatory study is necessary. In addition, since pertuzumab received accelerated approval in the neoadjuvant setting, many patients now receive a taxane with both trastuzumab and pertuzumab [THP]. The THP regimen was also tested in I-SPY2, and is also superior to standard paclitaxel and trastuzumab. Though we found both ado-trastuzumab emtansine plus pertuzumab and the THP regimen to be superior to paclitaxel plus trastuzumab, our trial was not designed to compare THP to ado-trastuzumab emtansine plus pertuzumab directly,” Dr. DeMichele said. “However, the toxicity seen in the ado-trastuzumab emtansine plus pertuzumab arm was clearly less than with paclitaxel plus trastuzumab or THP.”
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