Two drug regimens involving an experimental medicine from Celcuity halved the risk of death or disease progression in a late-stage trial in certain people with a type of advanced breast cancer. But the results still fell short of Wall Street expectations, sending the company’s shares plummeting by more than 20%.
Celcuity disclosed last month that its therapy, gedatolisib, succeeded in the latest part of a Phase 3 study evaluating the treatment in breast cancer patients with or without mutations to a gene called PIK3CA. Fresh data presented Tuesday at the American Society of Clinical Oncology’s annual meeting revealed the extent to which patients with those mutations benefited from treatment with Celcuity’s therapy.
In that study, “VIKTORIA-1,” Celcuity enrolled 350 people whose HR-positive, HER2-negative breast tumors were driven by PIK3CA mutations and who’d progressed after prior treatment. Trial participants were randomized to receive a “triplet” involving gedatolisib, hormone therapy and Pfizer’s Ibrance; a “doublet” pairing of gedatolisib and hormone treatment; or Novartis’ targeted therapy Piqray and a hormone drug.
Data presented Tuesday show both the “triplet” and “doublet” regimens halved the risk of disease progression or death. Those combinations held patients’ disease in check for a median of 11.1 months and 11.3 months, respectively, versus 5.6 months for patients treated with Piqray and hormone therapy.
To Celcuity CEO Brian Sullivan, those results are indicative of a paradigm-shifting therapy and progress against a hard-to-drug target, much in the way a Revolution Medicines treatment has proven beneficial against “RAS” mutations.
Revolution “figured out how to drug [RAS]. We think in a lot of ways we're doing the same thing with the PI3K pathway,” Sullivan said in an interview, referring to gedatolisib’s target.
Yet Celcuity didn’t get a positive response from some shareholders. In earlier testing, gedatolisib had slowed disease progression by a median of 14.6 months in 30 patients with PIK3CA mutations. Those findings saddled Celcuity with “lofty expectations” heading into the ASCO readout, leading the new data to likely “disappoint some investors,” Leerink Partners analyst Andrew Berens wrote in a Tuesday note.
The three-drug regimen also didn’t seem more helpful than the doublet either, raising important questions about commercial use, added Jefferies’ Maury Raycroft in a separate note.
However, Sara Hurvitz, a co-principal investigator and head of the Fred Hutchinson Cancer Center’s clinical research division, contended that the findings suggest gedatolisib could “establish a new standard of care” for PIK3CA-mutated breast cancer. Other trials testing a similar type of drug alongside an endocrine therapy produced progression-free survival totals in the range of five and a half to seven months, she said.
“PIK3CA-mutated disease tends to be more aggressive and have poorer outcomes,” Hurvitz said. “Seeing a doubling in the amount of time a patient can live without their disease getting worse is pretty clinically significant.”
The numbers may have “disappointed,” but the drug “cut progression by half compared to one of the two leading PI3K inhibitors, which is a big advance,” said Roderick Wong, a Celcuity investor as well as the Managing Partner and Chief Investment Officer of RTW Investments.
HR-positive, HER2-negative breast cancer is the most common form of the disease, and about 40% of those cases involve a mutation in the PIK3CA gene, according to Celcuity. Multiple treatments, such as Piqray and AstraZeneca’s Truqap, are already available. But they’re associated with tough side effects, like skin rashes and high blood sugar.
Gedatolisib is part of a new wave of therapies designed to be more specific or potent. Unlike Piqray, the drug aims at multiple nodes of a pathway, “PAM,” implicated in cancer growth and survival. Hurvitz also noted how gedatolisib appears different because of its potential to be combined with a “CDK4/6 inhibitor,” like Ibrance, without additive toxicity.
With other, similar therapies, “you can often see pretty high rates of hyperglycemia, as well as diarrhea and rash,” said Hurvitz. “But they were uniquely low in the VIKTORIA-1 study.”
The most common serious side effects seen with in the gedatolisib regimens were low white blood cell counts and a mouth inflammation called stomatitis. One treatment-related death was recorded with the gedatolisib triplet, but was attributed to Ibrance, which is associated with stomatitis and gastrointestinal problems, Hurvitz said.
When clinicians look at the results, they’re going to have to decide who needs Ibrance and whether a two- or three-drug regimen is more appropriate, she added.
Gedatolisib previously succeeded in an earlier part of the Phase 3 trial centered around breast cancer patients without PIK3CA mutations. It’s currently under review in the U.S. as a treatment for those patients, and Celcuity has said it plans to submit the new data in a supplementary application that would expand use.
Sullivan said the new submission should come in the third quarter, around when the drug might reach market. A decision is expected by July 17.
Despite the negative outlook from some investors, Leerink’s Berens wrote that the new data show the “regimen is clearly superior to existing options [for PIK3CA-mutated disease] and likely approvable.”
“Ultimately, input from clinicians will be important” in assessing the drug, “many of whom seem to have lower expectations than the investor community,” Berens wrote.
