Novel Regimen Outperforms Standard Chemotherapy in HER2 Breast Cancer

June 2016, Vol 7, No 5

An ongoing clinical trial of a novel strategy to evaluate new chemotherapy regimens for patients with early-stage breast cancer has identified another neoadjuvant combination therapy worthy of a phase 3 clinical trial involving patients with HER2-positive breast cancer.

According to results from a phase 2 study, the combination of ado-trastuz­umab emtansine (Kadcyla, also known as T-DM1) and pertuzumab (Perjeta) resulted in an estimated pathologic complete response (CR) rate of 52% compared with 22% for the combination of trastuzumab plus paclitaxel, said Angela M. DeMichele, MD, MSCE, Associate Professor of Medicine and Epidemiology, University of Pennsylvania, Philadelphia, at the 2016 American Association for Cancer Research meeting.

Improved Outcomes, Lower Toxicity Profile

The novel regimen had a 94% likelihood of success in a phase 3 comparison against the standard chemotherapy combination. Similar advantages for the novel combination were observed in patients with hormone receptor (HR)-positive and HR-negative breast cancer.

“On the basis of these results, the probability that the novel combination of T-DM1 and pertuzumab is superior to trastuzumab and paclitaxel combination is greater than 99%, and the probability of success versus trastuzumab and paclitaxel in a phase 3 trial is 94%. T-DM1 and pertuzumab graduated [to phase 3], both in the overall HER2-positive patient population, as well as in both hormone receptor subsets,” said Dr DeMichele.

The novel combination “had a very different toxicity profile than that seen with the standard of care. Neuropathy, hypertension, and alopecia were much less common [with T-DM1 plus 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,” Dr DeMichele added.

These findings are the latest from the ongoing I-SPY 2 clinical trial. The biomarker-driven adaptive clinical trial design relied on genetic and biomarker data derived from the patients’ tumors to inform treatment choices for subsequent patients.

The study objective was to identify effective neoadjuvant regimens for specific biomarker-defined breast cancer “signatures.” Investigators at multiple sites simultaneously evaluated several different regimens in small phase 2 studies. Novel regimens that demonstrated superiority versus current standard therapies qualified to graduate to phase 3 clinical trials.

Dr DeMichele reported findings from a phase 2 study involving 249 patients with HER2-positive breast cancer, 84 of whom were randomized to T-DM1 plus pertuzumab (N = 52) or trastuzumab plus paclitaxel (N = 32). The patients also received doxorubicin and cyclophosphamide. The remaining patients were randomized to other investigational neoadjuvant regimens.

T-DM1 plus Pertuzumab Superior to Standard Therapy

A subgroup analysis of patients with HR-negative disease yielded an estimated pathologic CR rate of 64% with pertuzumab plus T-DM1 versus 33% with trastuzumab plus paclitaxel. The probability of superiority was 98%, and the likelihood of success in a phase 3 clinical trial was 90%.

In the HR-positive subgroup, the estimated pathologic CR rates were 46% with the novel regimen and 17% with the conventional therapy. The probability of success for the novel regimen was 99% in the phase 2 study and 93% in a phase 3 clinical trial.

The frequency and severity of adverse events were similar for the 2 regimens. When the doxorubicin and cyclophosphamide component of the regimens was included, patients in the T-DM1 plus pertuzumab arm had higher rates of neutropenia, thrombocytopenia, and elevated liver enzymes (alanine transaminase and aspartate transaminase) compared with the trastuzumab plus paclitaxel arm; however, combination therapy with trastuzumab plus paclitaxel was associated with higher rates of hypertension, neuropathy, and alopecia.

“These results demonstrate the benefit of the adaptive trial design and the standing platform of the I-SPY 2 trial, and show that we can see this benefit in a relatively modest number of patients. Using the standard platform, where we continuously evaluate drugs, enables us to get results out very quickly,” concluded Dr DeMichele.

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