Researchers Continue to Explore HER2 Blockade Strategies
Evidence-based clinical practice has evolved and the search for how best to blockade the HER2 receptor in HER2+ breast cancer continues.
SAN ANTONIO—Evidence-based clinical practice has evolved and the search for how best to blockade the HER2 receptor in HER2+ breast cancer continues, said Mothaffer Rimawi, MD, of the Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine in Houston, TX. In a plenary lecture, Dr Rimawi reviewed HER2 therapies for curative intent over the past decade.1
HER2 “became a very attractive target for because of its oncogene addiction,” Dr Rimawi recalled. “It was hoped that agents will shut down the pathway and lead to cell death.”
In 2005, the B31/N9831 Adjuvant Trastuzumab trial found dramatic improvements in disease-free rates associated with trastuzumab. The findings were revolutionary and subsequent studies showed benefits as well.
However, resistance to trastuzumab has been a challenge.
“It is still abundantly clear that there are tumors that are resistant to trastuzumab,” Dr Rimawi said. “One hypothesis is that trastuzumab treatment incompletely blockades the HER receptor, so that with alternative signaling pathways, tumors can develop resistance.”
Dual agent anti-HER2 therapy was studied, combining trastuzumab with pertuzumab or lapatinib. In xenograft studies, dual blockade which led to the “complete disappearance” of tumors, Dr Rimawi noted—“even after treatment ended.” In neoadjuvant clinical trials, pathologic complete response (pCR) rates jumped with the addition of pertuzumab and lapatinib to trastuzumab—from 29% to 30% with trastuzumab alone to 46% with the addition of pertuzumab in the NeoSphere trial and 51% with lapatinib in the NeoALTTO trial, he reported.
This led to the FDA's first-ever neoadjuvant label indication, Dr Rimawi noted. But there were no confirmed benefits in survival outcomes.
“Some patients don't respond well,” he said.
Dr Rimawi explained that it's not necessarily the best approach to “layer on treatment on another” for some patients. “Should we consider de-escalating in selected patients? De-escalation is not a new concept. In breast cancer, we've dialed sown surgery, dialed down radiation.”
Anti-HER2 treatment without therapy was studied in NeoSphere, ADAPT, and other trials, he noted—with positive pCR results for some patients.
“A subgroup of patients may not need chemotherapy—but can we identify them?” he asked. Noting that biomarkers of response and resistance are needed.
2015: The ‘Knowns'
“So—2015, what do we know?” he asked. “We know that one year of trastuzumab is standard, and that two years is not better. We know that six months is inferior.”
Smaller node-negative tumors can be treated with taxane plus trastuzumab while larger or node-positive tumors can be treated with trastuzumab plus pertuzumab with chemotherapy, Dr Rimawi said.
“We know that lapatinib doesn't add to standard adjuvant therapy, and that extended adjuvant therapy with neratinib offers a small but significant benefit.”
More data are needed on managing toxicity, he said.
“HER2 breast cancer is not a single disease,” Dr Rimawi emphasized. “There are several subtypes and we should start thinking scientifically and clinically about that.”
Where To Go From Here
Dr Rimawi also offered a list of “what we don't know,” including the definitive benefits of dual inhibition. “We're awaiting results from the APHINITY trial” for those data, he said.
“Should we be adding PI3Ki to anti-HER2 agents? It's an attractive target, worth studying,” he said. “Can we identify patients who don't need chemotherapy? There are ongoing studies, but more are clearly needed.”
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More research is needed to identify and clarify mechanisms of resistance and to identify early predictors of resistance, Dr Rimawi added. New anti-HER2 agents are needed, including downstream pathway inhibitors like PI3Ki and Akti inhibitors.
Physicians need to “treat patients intelligently” and spare their patients toxicity and cost through therapy de-escalation where possible “One size doesn't fit all,” he concluded.
- Rimawi M. Plenary lecture. Presented at: San Antonio Breast Cancer Symposium 2015. Dec. 11, 2015; San Antonio, TX.