The drug napabucasin—that inhibits stem cell activity—was found to improve outcomes when used as a companion agent together with docetaxel in heavily pre-treated patients with metastatic breast cancer in a phase II study reported at the 2017 ASCO Annual Meeting (Abstract 1084).
“We found very encouraging anti-cancer signs of activity,” said co-author Matthew Hitron, MD, an internist and researcher in Boston. He noted that napabucasin was the first therapeutic agent in its class with the ability to inhibit “stemness in cancer stem cells”—STAT3-driven gene transcription and spherogenesis.
The study was a phase II “expansion cohort” in patients with previously treated metastatic breast cancer who had run out of therapy options. “These were women who [had] exhausted reasonable therapies and [were] good candidates for single agent taxane,” said lead author W. Jeff Edenfield MD, Medical Director of the Institute for Translational Oncology Research in Greenville, S.C.
“The response rate was 24 percent in the evaluable population—those who received both a pre-and on-study scan, and 20 percent in the intent-to-treat population—including 100 percent regression in several patients. [There was an] increased median progression-free survival of 2.7 months and median overall survival of 7.8 months.”
Thirty-four out of the 50 patients who took part in the trial had triple-negative disease with no history of positive receptor status. Nine were positive for ER, PR, or HER2 and refractory to targeted agents, and in the remaining seven patients the disease had become triple-negative from pathology that had previously been positive for ER, PR, or HER2.
Therapy Options Exhausted
“These [patients] were heavily pretreated,” said Hitron. “They had received a median of five prior lines of therapy. Which is a lot! These include several lines of taxanes. So when you combine our agent with a taxane again, it is suggesting that we could be sensitizing to the effects of taxane again.
“Treatments for patients with triple negative breast cancer and for those with hormone receptor positive breast cancer who had exhausted their targeted treatments represented unmet medical needs,” noted Hitron. “For triple negative breast cancer there are no targeted treatments available and so we were investigating napabucasin in combination with weekly paclitaxel [for] a new mechanism of action for patients.”
He described the targeting of STAT-3–dependent gene transcription as the “master control” for stemness genes. “Cancer stem cells are quiescent. They have a lot of immune evasion mechanisms up-regulated so they ‘hide out’ in the tumor. Traditional chemotherapy will kill the bulk of cells but these stem cells can remain, and they can cause relapse and treatment failure,” Hitron explained.
So it was logical to combine an antagonist to stemness with an agent like docetaxel that could simultaneously—and perhaps synergistically—control proliferation.
“Our preclinical data points to very strong synergy with paclitaxel. And perhaps the role of a cancer stem cell agent could be in combination with a chemotherapy that takes care of all the bulk cells while the stem cell agent is eradicating those hard-to-treat stem cells in the tumor. So we think the combination approach could provide the most potential benefit to patients,” Hitron stated.
He also said napabucasin discriminated between stem cell functions that are needed for normal physiology and those that could cause cancer. “When we say cancer stem cells we are specifically talking about stem cells within a tumor. Hematopoietic or precursor cells—myeloid progenitor cells—are not affected by napabucasin. In fact, in our phase I and phase III trials in monotherapy, there was no effect on white blood cells, neutrophils, or red blood cells at all.”
Edenfield added that because metastatic and advanced cancers had enriched populations of stem cells—which divided relatively infrequently—these could become the main drivers of carcinogenesis.
“Over time, when they become heavily pretreated, this population of stem cells becomes an issue one has to deal with. And napabucasin uniquely inhibits STAT3—that's over expressed in stem cells—and inhibits their growth. So it's a way of tackling the residual problem. If taxanes can address the proliferating group of cells then maybe the ‘stem cell poison’ can affect the non-populating cells,” he explained.
But was it safe to target stem cells? “It seems to be,” said Edenfield. “We haven't seen any safety signals of other organs at risk after a lot of study in many different tumor types.” He noted the responses “kind of surprised everyone.” But the team found that toxicity—mainly gut toxicity—was manageable and they were learning to get better at managing the diarrheal component of it. “But to have about 20 percent of your patients benefit and stabilize in a heavily pretreated population is interesting.
“The gut toxicity needs to be managed. And what we learned with these drugs is that the persons who are really going to have trouble are identified early. Within a few doses of the stem cell drug, we can identify the people who are going to need help with either dose reductions [or] dose delays for management of their diarrhea,” said Edenfield.
“I think the take-home message is [that] we've not attended well to stem cell biology before, and this is a glimpse as to what one might expect if you could affect the stem cell compartment uniquely—which is unaffected by chemotherapy.”
However, Edenfield emphasized that stem cell targeting wasn't a new potential paradigm in breast cancer treatment. “I have always seen this as an add-on therapy. I don't think it's going to be a stand-alone therapy because you're going to have to address the proliferation compartment, too. But I think addressing the stem cell department—which might be the source of subsequent metastasis—makes perfect sense to try this earlier on in the course of disease. That's why the tolerability has got to be okay.”
Peter M. Goodwin is a contributing writer.