Combination Anti-HER2 Therapies the Wave of the Future
San Antonio, TX—It turns out that for women with HER2-overexpressing breast cancer, treatment with trastuzumab (Herceptin)—which cuts the risk of recurrence by half—may be just the beginning.
At the annual San Antonio Breast Cancer Symposium, several key studies evaluated “combined HER2 blockade,” showing impressive outcomes in the preoperative (neoadjuvant) setting. In these studies, rates of pathologic complete response (pCR)—which means that tumors not only shrink but tumor cells become undetectable—exceeded 50%. The studies used various combinations of trastuzumab, lapatinib (Tykerb), and pertuzumab, a novel monoclonal antibody akin to trastuzumab.
Neil Spector, MD, director of Translational Oncology Research at the Duke Cancer Institute in North Carolina, remarked that, “Combinations of targeted drugs is the future of oncology. This is a very exciting area. We have gone from HER2-overexpressing disease being the most lethal type of breast cancer to a subtype that we are talking about curing.”
In the 4-arm NeoSphere trial, triple therapy with pertuzumab, trastuzumab, and docetaxel (Taxotere) produced 50% more pCRs (46%) than were achieved with other doublets. In addition, the completely “chemotherapyfree” combination of pertuzumab plus trastuzumab eradicated tumors in 17%, leading investigator Luca Gianni, MD, of Milan, to suggest that a subset of patients might benefit from targeted ther apy minus the more toxic chemotherapy. In the NeoALLTO trial, treatment with trastuzumab plus lapatinib (Tykerb), given with paclitaxel, produced a 51% pCR rate compared with 25% for lapatinib and 29% for trastuzumab.
View larger version
Moving Beyond Trastuzumab
It is clear that other agents targeting the HER2 protein are needed, beyond trastuzumab. Although trastuzumab is highly effective, in the advanced-disease setting patients generally develop resistance to the drug within 1 year.
“But HER2 is still a relevant target, once this happens, since HER2 overexpression is still maintained,” Dr Spector said in a plenary lecture. “In fact, patients who have tumor progression on HER2 targeted therapies benefit from continued HER2 blockade.”
Using the agents that were evaluated in these trials, Dr Spector acknowledged that cost would be very high with trastuzumab plus lapatinib, higher yet with trastuzumab plus pertuzumab, and essentially unimaginable should the 3 drugs be combined.
He remarked that “if money were abundant” he would like to use trastuzumab, lapatinib, and pertuzumab together, because they “act differently but at the same target.”
“But in doing so we would bust the economy, and I can’t imagine this will go over well with payers,” he said. “If only 5 of 100 patients can afford this blockade, we will need to rethink this approach.”
Jose Baselga, MD, codirector of the Massachusetts General Cancer Institute, Boston, said at a press conference, “No question, the cost of these therapies will be higher, but you have to put this in context with the therapeutic benefit, with the fact that many more patients will not require treatment for disease recurrence. This is a sea change in how we explore these therapies.”
More anti-HER2 combinations will be evaluated, Dr Spector said in his presentation, including trastuzumab paired with novel agents targeting PI3- kinase, mTOR, insulin growth factor receptor, and heat shock protein 90. The immunoconjugate TDM-1 is also highly promising.
He predicted the most affordable approach may be anti-HER2 vaccines, which essentially generate trastuzu mab-and pertuzumab-like antibodies directly in patients. Laboratory experiments now under way have shown that an HER2 vaccine plus lapatinib significantly diminished tumor volume. If this pans out, complete HER2 blockade would become “more affordable and therefore more accessible” to the 30% or so of patients with breast cancer with this subtype.