Angela M. DeMichele, MD
The combination of ado-trastuzumab emtansine (T-DM1) and pertuzumab was superior to the combination of paclitaxel and trastuzumab as neoadjuvant treatment for women with HER2-positive breast cancer, according to an analysis the adaptively randomized I-SPY 2 Trial.
The probability was 99.5% that the rate of pathologic complete response (pCR) was superior with the T-DM1 combination, which should now advance into a phase III study, said Angela M. DeMichele, MD, at the AACR Annual Meeting. The I-SPY 2 Trial was designed to use biological markers to help screen women for receptivity to drugs and allow reliable testing with smaller sets of patients, thereby accelerating trial activity and lowering cost.
The toxicity profiles differed between T-DM1/pertuzumab and paclitaxel/trastuzumab, with hypertension, neuropathy, and alopecia much less common in patients assigned to T-DM1/pertuzumab. “I would argue that these are side effects of treatment that really matter to women, that can really affect their day-to-day function,” said DeMichele, professor of medicine and epidemiology, University of Pennsylvania, Philadelphia.
Paclitaxel plus HER2-directed therapy with trastuzumab has demonstrated improved outcomes in HER2-positive breast cancer compared with chemotherapy alone, and it is considered the standard treatment in this setting. A pCR at the time of surgery is an excellent surrogate for long-term survival outcomes in HER2-positive breast cancer. I-SPY 2 tested the ability of T-DM1 plus pertuzumab to improve pCR rates over standard therapy.
I-SPY 2 has numerous simultaneously running experimental arms in which therapies are matched with breast cancer subtypes based on hormone receptor (HR) status and the cancer’s profile on the MammaPrint 70-gene signature. The goal of I-SPY 2 is to identify drugs and combinations of drugs to take to phase III. A drug or combination “graduates” by reaching a threshold predictive probability of success in a subsequent phase III trial.
The branch of I-SPY 2 presented at AACR included patients with HER2-positive advanced breast cancer ≥2.5 cm and adequate organ function and performance status. Patients were randomized to control (paclitaxel, 80 mg/m2
, plus trastuzumab, 4 mg/kg followed by 2 mg/kg, both given weekly for 12 doses) or T-DM1, 3.6 mg/kg, plus pertuzumab, 840-mg load followed by 420 mg, both administered every 3 weeks for four doses, or other HER2-directed arms. Upon completion, each arm proceeded to chemotherapy with doxorubicin and cyclophosphamide followed by surgery.
Overall, 1540 patients were screened for the trial; 878 met the eligibility criteria and were randomized. Of these, 249 had HER2-positive disease. One hundred sixty-five were randomized to five other investigational arms, leaving 52 who were assigned to T-DM1/pertuzumab and 32 who were assigned to paclitaxel/trastuzumab. Approximately two-thirds in each arm were HR-positive.
For all HER2-positive patients, the pCR rate in the control group was estimated at 22%, compared with 52% in the patients assigned to T-DM1/pertuzumab. “That led to a probability that T-DM1/pertuzumab was superior to [paclitaxel/trastuzumab] of 99.5%, and our probability that it would be successful in a subsequent phase III trial of 94%,” said DeMichele.
HR subtypes were analyzed separately. For the HR-negative patients, the estimated pCR rate in the control arm was 33%, compared with 64% in the T-DM1/pertuzumab arm, with a probability of 98% that T-DM1/pertuzumab was superior to control, and a probability of 90% that it would be successful in this subtype in a phase III trial. Among HR-positive patients, estimated pCR rates were 17% and 46% for control and T-DM1, respectively, with a 99% probability that T-DM1/pertuzumab was superior to control in this subgroup, and a 93% probability of success in phase III.
During the experimental portion of the trial, there were very few grade 3 or 4 adverse events in either arm. There were greater rates of hypertension (45% vs 4%), neuropathy (45% vs 0%), and alopecia (58% vs 0%) among women assigned to paclitaxel/trastuzumab compared with T-DM1/pertuzumab. As expected, elevations of alanine aminotransferase and aspartate aminotransferase levels occurred in patients randomized to T-DM1/pertuzumab “but was low grade, and not clinically significant,” said DeMichele.