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Novel Regimen Outperforms Standard Therapy in HER2 Breast Cancer

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

The combination of ado-trastuzumab emtansine (T-DM1) and pertuzumab resulted in an estimated pathologic complete response (pCR) rate of 52% in a phase 2 evaluation, compared with 22% for the combination of trastuzumab and paclitaxel. The novel regimen has a 94% likelihood of success in a phase 3 comparison against the standard combination.

Similar advantages for the novel combination were observed in patients with hormone receptor (HR)-positive and HR-negative disease, as reported at the American Association for Cancer Research Annual Meeting.

“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%,” said Angela M. DeMichele, MD, Associate Professor of Medicine at the University of Pennsylvania in Philadelphia. “T-DM1 and pertuzumab graduated [to phase 3], both in the overall HER2-positive patient population, as well as in both hormone receptor subsets.”

“[The novel combination] had a very different toxicity profile than that seen with the standard of care,” she added. “Neuropathy, hypertension, and alopecia were much less common. I would argue that these are side effects of treatment that really matter to women, that can really affect their day-to-day function.”

The findings are the latest from the ongoing I-SPY2 trial. Investigators in the trial use a biomarker-driven adaptive trial design that relies on genetic and biologic marker data derived from patients’ own tumors to inform treatment choices for subsequent patients enrolled in the trial program.

The underlying objective of the trial design is to identify effective neoadjuvant regimens for specific biomarker-defined breast cancer “signatures” and advance the regimens to phase 3 trials requiring as few patients as possible. Investigators at multiple sites simultaneously evaluate several different regimens in small phase 2 trials. Novel regimens that demonstrate superiority versus current standards qualify to “graduate” to phase 3 trials.

Dr DeMichele reported findings from a phase 2 trial involving 52 patients randomized to T-DM1/pertuzumab and 32 to trastuzumab-paclitaxel. Patients in both groups also received doxorubicin and cyclophosphamide.

In addition to the overall results, subgroup analysis yielded an estimated pCR rate of 64% with the T-DM1/pertuzumab regimen and 33% with the trastuzumab-paclitaxel combination in patients with HR-negative disease. The probability of superiority was 98%, and the likelihood of success in a phase 3 trial was 90%.

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

The frequency and severity of adverse events were similar for T-DM1/pertuzumab and trastuzumab-paclitaxel. When the doxorubicin-cyclophosphamide component of the regimens was included, patients in the T-DM1/pertuzumab arm had higher rates of neutropenia, thrombocytopenia, and elevated liver enzymes (ALT and AST). The trastuzumab-paclitaxel regimen was associated with more hypertension, neuropathy, and alopecia.

The 84 patients in the trial were among 249 with HER2-positive breast cancer. The remaining patients were randomized to other investigational neoadjuvant regimens, results of which have yet to be reported.

“These results demonstrate the benefit of the adaptive trial design and the standing platform of the I-SPY2 trial and show that we can see this benefit in a relatively modest number of patients,” said Dr DeMichele. “Using the standard platform, where we continuously evaluate drugs, enables us to get results out very quickly.”

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