Over the past 38 years, I have devoted my professional career to the practice of breast cancer-specific medical oncology. During these years of discovery, I personally feel the most exciting and compelling story began when Dennis Slamon, MD, PhD, recognized the unique clinical behavior of the HER-2/neu–positive variant of breast cancer. I have been fortunate to have participated in most of the clinical trials since about 1994 that have brought four molecules specifically targeting HER-2–positive disease into clinical practice.
The recent FDA approval of pertuzumab, as the first agent ever approved for neoadjuvant use in selected breast cancer patients, is a welcome addition to its prior approval in the metastatic disease setting. This perspective was written in an attempt to very briefly mention some of the other neoadjuvant trials in this patient subset and to speculate on future developments in HER-2–directed therapies.
There are other pertinent neoadjuvant trials that include dual blockade. Although the NeoSphere trial dealt with only single-agent docetaxel, the TRYPHAENA trial evaluated more aggressive chemotherapy regimens with pertuzumab and trastuzumab (Herceptin, Genentech). The pathologic complete response rates appeared even more impressive than the single-agent docetaxel trial; however, cross-trial comparisons are difficult to interpret. NeoSphere was presented in San Antonio at the same time as the Neo-ALTTO trial, which used chemotherapy with trastuzumab but with lapatinib (Tykerb, GlaxoSmithKline) instead of pertuzumab. The results were equally impressive in terms of efficacy in the Neo-ALTTO trial as in NeoSphere; however, there was a relatively high patient discontinuation rate in the Neo-ALTTO trial because of drug toxicity related to lapatinib.
We now have approval for pertuzumab in the metastatic setting and the neoadjuvant setting. Moving forward, the APHINITY trial is a major adjuvant trial evaluating chemotherapy of different types with trastuzumab alone or trastuzumab plus pertuzumab. If that trial is positive, then the next step would be more widespread use of chemotherapy plus dual blockade with curative potential in the adjuvant setting.
Although pertuzumab is already approved in metastatic disease , we’ve just finished the VELVET trial, in which a less-toxic chemotherapy, vinorelbine, was substituted for docetaxel with trastuzumab and pertuzumab. There are no overall results of this trial yet, but one of my patients has had a beautiful response of widespread liver metastases. The relative lack of toxicity of this regimen was noteworthy.
Looking to the future, we now have trastuzumab, pertuzumab, lapatinib and ado-trastuzumab emtansine (Kadcyla, Genentech) approved as HER-2–targeting agents, with only pertuzumab approved to date outside of the metastatic disease setting. We’re anxiously awaiting results from the MARIANNE trial, which includes trastuzumab and docetaxel — the standard prior to the availability of pertuzumab — vs. ado-trastuzumab emtansine alone or in combination with pertuzumab.
In several years, it’s very possible that the backbone of therapy for HER-2–positive disease could ultimately end up being ado-trastuzumab emtansine plus pertuzumab. However, at this time we don’t even have the results of MARIANNE in metastatic disease, nor any adjuvant ado-trastuzumab emtansine data to support this interesting concept. With the increasing use of these targeted agents in combination, it could even be that — for HER-2–positive disease, relatively nontoxic, chemotherapy-free regimens will dominate clinical care within this decade.
Charles L. Vogel, MD, FACP
Sylvester Comprehensive Cancer Center
University of Miami
Disclosures: Vogel reports past advisory roles with and research support from Amgen, AstraZeneca, Aveo, Bristol-Myers Squibb, Clarient, Genentech, GlaxoSmithKline, Merck Sharp Dome, Novartis and Roche.