Last month, Revolution Medicines’ RAS inhibitor doubled survival in a Phase 3 pancreatic cancer trial. On the biotech’s heels are Immuneering, Actuate Therapeutics, Erasca and more, looking to improve on that result with increased tolerability—and more time for patients.
Just over a month ago, Revolution Medicines stunned the oncology space, revealing that its RAS inhibitor doubled survival in a Phase 3 trial for pancreatic cancer—a deadly malignancy with just a 13% five-year survival rate. Two weeks later, the good news continued to flow, with competitor Erasca announcing positive early-stage data for its own candidate.
“I think there’s kind of finally a glimmer of hope on the horizon for patients who have really been waiting a long time for developments,” Ben Zeskind, CEO of Immuneering, which is developing a deep cyclic inhibitor for pancreatic cancer, told BioSpace. As for why this is happening now, Zeskind said it’s the result of many years of scientific toil. “The understanding of the biology and the pathway that really drives most of pancreatic cancer has really been growing over the years.”
In terms of its developmental journey, Daniel Schmitt, CEO of Actuate Therapeutics, compared pancreatic cancer to testicular cancer.
“For a very long time, [testicular cancer] was a death sentence, until investigators at the University of Indiana came up with a target [a chemotherapy regimen], and now it’s like 90% curable,” he told BioSpace. “It’s really about unlocking the keys and getting much more information.”
The key to pancreatic cancer appears to be the KRAS gene, which is mutated in around 92% of these malignancies. These mutations can lead to overactivation of the MAP kinase (MAPK) signaling pathway, contributing to the progression of pancreatic, colorectal and lung cancers.
When asked if he sees a future where pancreatic cancer is a disease patients can live with, Schmitt said, “That is the hope. We want to make these processes druggable, tolerable and with beneficial, long-term outcomes.”
Therein lies the challenge—and an opportunity for Revolution, Erasca, Immuneering, Actuate and the multitude of other biopharmas trying to unlock the enigma that is pancreatic cancer.
A ‘profound’ step forward
“There hasn’t been a major step forward in pancreatic cancer” since the 2013 approval of Abraxane (nab-paclitaxel) in combination with gemcitabine—a regimen known as GnP—in late-stage disease, Schmitt said.
That’s part of why Revolution’s recent results were met with so much fanfare. In a Phase 3 trial, daraxonrasib, an oral RAS(ON) multi-selective inhibitor, helped patients with advanced pancreatic cancer who had progressed on at least one other treatment survive for 13.2 months compared to 6.7 months for comparators on chemotherapy. The company’s shares jumped 40% the day the results were announced.
Daraxonrasib is the first RAS inhibitor that has succeeded in a Phase 3 trial, according to Anna Berkenblit, chief scientific and medical officer at the Pancreatic Cancer Action Network (PanCAN). “The first in class is not necessarily going to be the best in class, Berkenblit said, “but . . . this is a profound, profound step forward for pancreatic cancer.”
Revolution, which will present “detailed results” from that trial at ASCO later this month, has stated its intention to file with global regulatory authorities based on the Phase 3 data. Having been awarded a Commissioner’s National Priority Voucher (CNPV) in October last year, daraxonrasib should enjoy a 1–2 month review period, as opposed to the usual 10–12 months once the FDA accepts the application.
For now, the FDA earlier this month moved to make daraxonrasib available to more patients. On May 1, the agency approved an expanded access treatment protocol for patients with previously treated pancreatic cancer. Daraxonrasib is also in registrational trials for first-line disease.
But while daraxonrasib appears to be extremely efficacious, it comes with some pretty gnarly side effects.
Former Nebraska Sen. Ben Sasse exposed one clear adverse effect of the treatment—which he has confirmed he’s taking for stage 4 pancreatic cancer—in a recent 60 Minutes interview. The former lawmaker credited daraxonrasib, which he called a “miracle drug,” with decreasing his pain and reducing his tumor volume by 76%, USA Today reported. But a rash was evident on Sasse’s face—revealing a common side effect of the drug.
“That picture is worth a thousand words,” Berkenblit said. However, while it is known that the majority of patients develop a rash, it is mild to moderate in severity for most patients, she said.
Moreover, Berkenblit is optimistic that the sector is moving toward high levels of efficacy and better tolerability. “There’s a thought that the side effect profile of these multi-targeted RAS inhibitors may be different from those that are targeting just one specific mutation that is only found in the tumor.”
The next step: tolerability and time
Several companies are in early- to mid-stage trials for pancreatic cancer with candidates that show potential to minimize side effects and give patients more time.
San Diego–based Erasca is developing ERAS-0015, a RAS inhibitor currently in Phase 1. The biotech revealed dose-escalation data last month touting a 62% unconfirmed overall response rate in the third-line setting.
Meanwhile, Immuneering and Actuate are taking different approaches, also with tolerability and increased survival in mind.
Immuneering’s atebimetinib seeks to inhibit the MEK protein kinase, which is lower down in the MAPK funnel, Zeskind said. By targeting MEK, which Zeskind explained is located at a narrower part of the funnel, “it’s a little bit harder for the tumor to get around it.”
This approach also contributes to the drug’s positive tolerability profile, Zeskind said. In addition to its involvement in certain cancers, the MAPK pathway plays a role in helping healthy cells to grow and divide “at the right pace.” Because they “basically shut down this pathway 24/7,” RAS treatments inhibit this process as they fight cancer, he explained. Immuneering’s asset only shuts down the pathway for “several hours a day,” then releases it to guide healthy cells properly.
In January, Immuneering reported results from a Phase 2a study showing that atebimetinib plus modified GnP elicited 64% overall survival at 12 months in first-line pancreatic cancer—nearly doubling the survival seen in a pivotal study of standard of care GnP. Additionally, there were “only two categories of adverse events observed at the Grade 3 level in more than 10% of patients,” according to the January release.
Imuneering’s three-pronged approach, which focuses on durable tumor shrinkage, weight maintenance (a key challenge in pancreatic cancer) and minimizing side effects “enable us to deliver the kind of survival that we showed in January, together with the kind of tolerability we’re seeing,” Zeskind said.
Immuneering will present data from an expanded cohort of this trial at the upcoming American Society of Clinical Oncology (ASCO) conference in June.
Over in Texas, Actuate Therapeutics is working on a novel GSK-3 inhibitor called elraglusib.
“Cancer cells are known for three things: they grow, they don’t die, and they refuse to be treated into death,” Schmitt said.
GSK-3 is a “master regulator” in cancer cells that sits upstream of a group of proteins called NF-κB, which mediate the survival of those cells, he explained. In targeting GSK-3, elraglusib downregulates NF-κB activity, making the cells susceptible to treatment. It was also designed to be very specific, Schmitt said. “That’s why we don’t have a lot of off-target effects.”
Actuate’s approach is unique from those of Revolution and Immuneering, which target what Schmitt called driver mutations.
“Their focus is very important, and we believe that those pathways are very important, but they’re not curing anybody, and patients often progress,” he said. That progression is associated with the NF-κB pathway. Schmitt expects to see “synergy” between elraglusib and drugs like daraxonrasib and atebimetinib.
“People ask us, how do we compete? We don’t. We’re going to be a combination agent,” he said. “To get even more benefit for patients, the combination makes scientific sense.”
In a Phase 2 trial published in Nature Medicine last month, elraglusib plus chemo doubled the rate of survival compared to the standard first-line regimen of GnP alone in first-line pancreatic cancer.
Elraglusib has so far only been tested as an IV treatment, but Schmitt said Actuate will be advancing an oral formulation of the asset into trials later this year.
Berkenblit is encouraged by the recent wins in pancreatic cancer, but she also noted the remaining challenges. “It is still underfunded when you look at all of the different cancer types,” she said, with prostate and breast cancers drawing more dollars from the National Institutes of Health.
“Part of the problem is it’s a terrible disease,” Berkenblit continued. “It seems like everybody knows somebody with pancreatic cancer who’s been diagnosed but it’s still not so common that it doesn’t quite get the attention that we at PanCAN think it deserves.”
