Combining trastuzumab emtansine (T-DM1) and pertuzumab before surgery was more beneficial than the combination of paclitaxel plus trastuzumab for patients with HER2-positive invasive breast cancer, according to results from the I-SPY 2 trial presented at the American Association for Cancer Research 2016 Annual Meeting.1

This phase of the I-SPY2 trial investigated whether T-DM1 plus pertuzumab could eradicate residual disease (pathological complete response [pCR]) for more patients if administered before surgery to shrink tumors compared with paclitaxel plus trastuzumab. Also, the researchers examined whether the combination could meet that goal without the need for paclitaxel.

Paclitaxel has some very bothersome and disabling side effects including neuropathy that can progress to pain and, in some cases become permanent; low blood counts with a risk of infection or bleeding; and hair loss.

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“The combination of T-DM1 and pertuzumab substantially reduced the amount of residual disease in the breast tissue and lymph nodes for all subgroups of HER2-positive breast cancers compared with those in the control group,” said Angela DeMichele, MD, MSCE, a professor of medicine and epidemiology at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, and lead author of the study.

“Our results suggest a possible new treatment option for patients that can not only effectively shrink tumors in the breast, but potentially reduce the chance of the cancer coming back later. The results also show that by replacing older, nontargeted therapies with more effective and less-toxic new therapies, we have the potential to both improve outcomes and decrease side effects.”

For the study, patients whose tumors were 2.5 cm or bigger were randomly assigned to 12 weekly cycles of paclitaxel plus trastuzumab (control) or T-DM1 plus pertuzumab (test). Following the initial test period, all patients received 4 cycles of the chemotherapies doxorubicin and cyclophosphamide, and surgery. Patients’ tumors were then tested for one of 3 biomarker signatures: HER2-positive, HER2-positive and hormone receptor (HR)-positive, and HER2-positive and HR-negative.

The assessed data included 52 patients in the test arm and 31 patients in the control arm. The unique statistical method of the I-SPY2 trial means it is highly likely that T-DM1 and pertuzumab will have the same positive results in a 300-patient phase III trial in women with HER2-positive breast cancers.

The I-SPY2 trial is a standing platform trial, in which drugs can be evaluated on an ongoing basis, allowing therapies to be tested and discarded more effectively. This is different from traditional trials that simply add new drugs to existing regimens.

“The process of developing cancer drugs currently requires well over $2.5 billion, 12 to 15 years, and the involvement of 1000 to 6000 patient-volunteers to bring 1 drug to market, and despite this high cost, historically, 60% to 70% of drugs fail or do not complete phase III trials,” said Laura Esserman, MD, MBA, a professor of surgery and radiology at the University of California San Francisco, and senior author of the study.

“The I-SPY approach to clinical trials is designed to reduce the cost, time, and number of patients required, in order to identify active drugs and the tumor types most likely to respond and get such drugs to market sooner, as well as to identify inactive drugs that should not be further developed.”


1. Wolf DM, Yau C, Ashish Sanil A, et al.       Combining sensitivity markers to identify triple-negative breast cancer patients most responsive to veliparib/carboplatin: results from the I-SPY 2 TRIAL. Presentation at: American Association for Cancer Research 2016 Annual Meeting; April 16-20, 2016; New Orleans, LA. Abstract 858.