HER2+ molecular insights pave way for targeted agents

SAN ANTONIO-Insight into the molecular workings of HER2-positive breast cancer has paved the way for targeted agents that are showing great promise in clinical trials, according to a presentation at SABCS 2008.

"I think the landscape is really exciting. We have a plethora of agents that are molecularly targeted," said Jos Baselga, MD, chairman of medical oncology, hematology, and radiation oncology at the Vall d'Hebron University Hospital in Barcelona. "We have never had anything like this in the past, so this provides us with a tremendous opportunity to move forward."

One such new agent is pertuzumab (Omnitarg), an antibody that prevents dimerization of HER2. Phase II data have shown impressive rates of response (24%) and clinical benefit (50%) when this agent is added to trastuzumab (Herceptin) in patients with advanced disease that is progressing on the latter agent, Dr. Baselga said.

In the ongoing phase III first-line CLEOPATRA trial, patients with metastatic breast cancer are receiving trastuzumab plus docetaxel (Taxotere), along with either pertuzumab or a placebo. It is important to note that, unlike trastuzumab, pertuzumab has not been associated with cardiotoxicity, he said.

Another new agent in the HER2 armamentarium is trastuzumab-DM1, which uses the receptor-targeting antibody to deliver a highly potent antimitotic compound directly to the tumor. At this year's symposium, researchers will present updated results of a phase II trial of this agent among patients with HER2-positive metastatic breast cancer who previously experienced a progression on trastuzumab and chemotherapy, Dr. Baselga noted. Preliminary data suggest that nearly one-third of patients have a partial response. Trastuzumab-DM1 also appears to have a good safety profile.

Inhibitors of heat shock protein 90 (Hsp-90), which impair the chaperone function of this molecule and thereby induce degradation of HER2, are yielding encouraging results in phase I trials among patients with breast cancer.

"Many companies are developing these compounds, so we should be having data pretty soon on this activity," Dr. Baselga said.

Meanwhile, investigators are also elucidating mechanisms of resistance to anti-HER2 agents and testing strategies to overcome it. For example, data show that the one-third of HER2-positive tumors also having p95HER2, a terminal fragment of the receptor that has kinase activity, are unlikely to respond to trastuzumab, but they still respond to lapatinib and other tyrosine kinase inhibitors.

"This might be a case in which you would want to use small molecules that target the kinase as opposed to molecules that work at the receptor surface," Dr. Baselga said.

Furthermore, phase III trial data released earlier in 2008 suggest that combining lapatinib with trastuzumab in patients with metastatic breast cancer who have a failure of trastuzumab improves both progression-free survival and clinical benefit rate. The dual strategy is also being tested in the Neo-ALTTO trial, a neoadjuvant trial that is randomizing patients to lapatinib plus paclitaxel, trastuzumab plus paclitaxel, or all three agents combined.

Deregulation of the mTOR and PI3 kinase pathway that lies downstream from growth factor receptors has also been implicated in resistance to anti-HER2 therapies, according to Dr. Baselga. Hence, inhibitors of both mTOR (deforolimus, everolimus) and PI3 kinase (NVP-BEZ235) are now being evaluated in early-phase clinical trials, sometimes in combination with other therapies.

"In the field of HER2, we are faced with a plethora of agents that was totally unthinkable just a few years ago," Dr. Baselga concluded.

Given the sheer number of agents, he predicted that the conventional clinical trial approach, involving testing in unselected populations, is unlikely to succeed in identifying patients who will respond. Moreover, testing them after patients have received multiple other therapies adds complexity to the process.

"We clearly need to change the model," he said, recommending instead a neoadjuvant approach entailing biopsies and selection of agents guided by biomarkers. "The (aim) of this approach would be to identify patients up front and give them the combination that they are more likely to benefit from. There are ways to design clinical trials in an adaptive fashion like this."