BRUSSELS – Now that dual combinations of targeted breast cancer drugs are standard treatment, researchers see up-front triple drug combinations as the next treatment frontier.
“Doublets are simply not enough,” Dejan Juric, MD, said at a breast cancer conference sponsored by the European Society of Medical Oncology. Triple-drug combinations offer the possibility of substantially-reduced rates of resistance development and the possibility of reducing dosages to improve tolerability.
Mitchel L. Zoler/Frontline Medical News
Dr. Nicholas Turner (from left), Dr. Dejan Juric, and Dr. René Bernards
One way to leverage the potential of a triple regimen is to target all three drugs at the same oncogenic pathway. “If we target a pathway with multiple drugs do we still need the maximally-tolerated dose of each? Clearly no,” said René Bernards, PhD, a professor at the Netherlands Cancer Institute in Amsterdam.
Dr. Bernards said he has as-yet unpublished evidence that individual-drug dosages can be cut when using a combination regimen that joins treatments targeted to the sequential signaling steps of Raf, MEK, and ERK in a key signaling cascade tied to the epidermal growth factor receptor (BBA Mol Cell Res. 2007 Aug;1773[8]:1263-84). “We now have drugs for all these [targets]. You can use 10% of the effective dose of each of these drugs and get complete inhibition of the pathway and not make cells resistant to these low-doses,” he declared.
Having drugs that work well together is critical, agreed Dr. Juric. “We need to keep searching for drugs where you can achieve nice inhibition by the triplet.” The goal is to “completely shut down a pathway,” he said. While “upfront combination is always superior to a sequential strategy, we hope that a new combination is not just more hits at the goal but a new quality.” The conventional concept of first-line, second-line, and third-line treatments is an “obstacle” to development of the most rational combinations.
A challenge when testing a triple regimen as first-line treatment is deciding which patients to target, as some hormone-receptor positive patients can do well on just an aromatase inhibitor.
“I don’t know which patients will do well on a single agent and who will need a combination,” said Dr. Juric. Given that uncertainty, his priorities are testing combination regimens that are both tolerable and cost effective. He also stressed the need to “better understand the tumor we are dealing with, using blood and biopsies, and use an adaptive approach” based on each tumor’s combination of characteristics.
As long as tolerability is possible, preclinical models suggest that the biggest impact from combination regimens comes in treatment naive patients. That would mean targeting patients with high-risk, estrogen–receptor positive breast cancer “where we know the risk continues for 20, 30 years and the long-term prognosis for relapse is very poor,” said Nicholas Turner, MD, a molecular oncologist at the Institute of Cancer Research and the Royal Marsden Hospital, both in London. “Perhaps a triple combination, if tolerable, would have the most potential to change the prognosis of these patients.”
Dr. Juric has been a consultant to Eisai, EMD, Novartis, and Serono. Dr. Bernards owns a portion of Agendia, a company that markets a breast cancer genetic test he codeveloped. Dr. Turner has received honoraria from Lilly, Novartis, Pfizer, and Roche.
On Twitter @mitchelzoler