By Deborah Borfitz

May 22, 2024 | A consortium of pancreatic cancer researchers sharing information in real time has shown that an oral pan-RAS inhibitor known as RMC-7977, developed by Revolution Medicines, effectively targets the common cancer-causing RAS proteins while minimally impacting normal cells—and did so across a comprehensive range of preclinical models in a series of similar experiments. Notably, the finding held when the drug was subsequently tested on separate cohorts of triple-transgenic animals run independently at two separate institutions, according to Kenneth Olive, Ph.D., associate professor of medicine at Columbia University’s Vagelos College of Physicians and Surgeons and Herbert Irving Comprehensive Cancer Center. 

The published study, which appeared recently in Nature (DOI: 10.1038/s41586-024-07379-z), addresses the reproducibility question head on, he says. This focus is on the most common form of pancreatic cancer, human pancreatic ductal adenocarcinoma (PDAC), which develops from the exocrine portion of the pancreas responsible for generating and secreting digestive enzymes into the gastrointestinal tract. 

PDAC is one of the most aggressive cancers where often little can be done besides treatment with a cocktail of two or more cytotoxic chemotherapies, and the tumor almost invariably returns, says Olive. An enduring collegiality in the pancreatic cancer research community focused on helping patients live longer, if not eradicate their tumors entirely, gave birth to the data-sharing mindset between experts at five academic institutions. 

The goal is to, at minimum, see the pan-RAS inhibitor produce a more frequent and durable set of responses in patients with PDAC. But if the agent only proves its equivalency to the current standard of care, it could still simplify the process of running clinical trials by having monotherapy as its backbone, Olive says. 

Multiple phase 1 clinical trials are already underway using RMC-6236—a related clinical compound of Revolution Medicines with similar pharmacology and biochemistry as RMC-7977—to treat patients with RAS-mutant tumors. These include a high percentage of pancreatic and lung and colorectal cancers. 

Last fall, Revolution Medicines announced some preliminary but promising anti-tumor and safety data for RMC-6236 in patients with previously treated non-small cell lung cancer (NSCLC) and PDAC. At the recent annual meeting of the American Association for Cancer Research, the company also shared its plans to launch a phase 3 trial at the end of the year, says Olive, adding that the creation of the preclinical compound that was broadly distributed “massively expedited the process of drug development” because the lessons learned were transferable to the clinical agent. 

Lengthy Quest

RAS genes are among the most frequently mutated genes cancers, putting investigators on a decades-long quest for an effective RAS inhibitor. KRAS alone is implicated in more than 90% of PDAC cases, and together with NRAS and HRAS isoforms of the RAS oncogene account for between 20% and 30% of human cancers, says Olive.  

For a long time, RAS was considered an “undruggable” target, he continues. That all changed a few years ago with U.S. Food and Drug Administration (FDA) approval of Lumakras (sotorasib) and Krazati (adagrasib), targeted therapies for a lung cancer mutation previously considered resistant to drug therapy. The inhibitors are intended to be a second-line treatment for adult patients with NSCLC whose tumors have a specific type of genetic mutation called KRAS G12C. “Unfortunately, this mutation is only found in about one percent of PDAC patients, so it wasn’t until the recent development of new agents capable of targeting more prevalent RAS mutations that their effects could be thoroughly investigated in this setting,” Olive says.  

The difference now is that data in the preclinical setting is qualitatively and quantitatively better than ever before, he adds, referring to his work with RMC-7977. “It’s a completely different experience for me as a scientist from anything I have done over the past two decades.” 

In the latest study, investigators examined multiple examples of virtually every class of preclinical model—including human PDAC cell lines, organoids, explants, implanted models, xenografts, allografts, and genetically engineered mouse—to head off questions about whether the right one was used, says Olive. “The weaknesses of one model are often the strengths of another and covering the whole ground... we got a consistent message from all of them.”   

Extrapolating from preclinical models to patients, RMC-7977 may deliver a deep but “not necessarily permanent” treatment response in most cases, says Olive. This is because 12 of the 13 tumors in the mice developed resistance and recurred (the final mouse died from an unrelated cause). Recurrence has already been observed in many of the rare PDAC cases treated with G12C-selective inhibitors. “It remains to be seen whether pan-RAS inhibitors will prove to have a more durable set of responses, and that the tumors... must find an entirely novel pathway or approach toward acquiring resistance. 

“While we hope that tumor responses are as long as possible in patients, we are already preparing how to overcome possible resistance mechanisms,” he continues, which makes the mission of the moment figuring out the best combinations of drugs to use. 

Question of Why

About 15 years ago at various meetings, Olive ran into Mallika Singh, now Revolution Medicine’s vice president of translational research. “In my mind, she has always been my industry counterpart [since] we both trained in laboratories using genetically engineered mouse models of cancer and worked on similar problems [pancreatic and lung cancer],” he says. 

So, when Singh told him that her company had invented a new class of inhibitors with the potential to target all RAS mutations, he was at once curious and skeptical. The two quickly established a collaboration, says Olive. 

“I have always been convinced that KRAS was the right target,” he adds. “The convincing came in believing that this drug would perform as advertised from a pharmacological standpoint” given the many shots on goal in trying to create a true RAS inhibitor. “There are currently no targeted therapies that are FDA-approved for treatment of PDAC as a monotherapy, and my hope is that this [RMC-6236] will be the first.” 

It has been widely assumed that targeting wild-type RAS in humans would prove intolerable, says Olive. So, to convince themselves that the preclinical form of the drug could inhibit all the mutant and wild-type forms of RAS while selectively targeting tumors, researchers examined the normal tissues in the treated animals and found that they were minimally impacted. The tumor cells proved to be uniquely sensitive to the inhibitor. 

The question is why. While there are multiple explanations, he continues, it is ultimately “a combination of the rather interesting pharmacology of the drug combined with the fact that tumor cells react violently when you take away this driving oncogene, even for a few hours.” 

In normal physiology, explains Olive, RAS proteins are part of the machinery that tells cells to proliferate, but even the rapidly growing cells—the ones found in hair follicles, the skin, lining of the gut, and the immune system—"are not cycling every single hour of every day.” Rather, they are responding to extrinsic cues related to, for example, their exposure to nutrients or the stage of their growth cycle. “They are used to RAS being turned on and being turned off,” so when cells get the message to stop growing for a bit they don’t suddenly explode or lose their function. 

Epithelial cells within a pancreatic tumor, on the other hand, have been receiving a “nonstop constitutive growth signal from the mutations in KRAS all along and they have adapted and evolved their entire regulatory framework and underlying molecular logic to depend on that... signal,” he says. Consequently, these cells undergo apoptosis very rapidly after just a couple hours of turning off RAS. 

“As a result, even though the drug is close to equally impacting the chemistry of these different mutant and wild-type proteins, the effect of that inhibition in malignant cells is much greater than it is in normal cells,” Olive says. And that is why this broad-spectrum RAS inhibitor is tolerable in the clinic. 

Parallel Paths

Revolution Medicines has adopted an innovative pathway to the development of its agents, which Olive says other companies might do well to emulate. The approach effectively protects commercial interests while advancing science more quickly. 

Many drug companies are “extremely reluctant to give out their flagship clinical compounds because of the potential for problems when it comes to filing for FDA approval,” he says. That’s because every single experiment done with a compound is potentially reportable to the FDA, including any bad ones done by an academic collaborator. 

What Revolution Medicines has done here is create two nearly identical drugs, one designated RMC-7977 that is given out broadly to investigators and the clinical agent RMC-6236 that progressed into clinical trials two years ago. For a little extra investment up front to create and characterize the preclinical compound, the benefits are massive, says Olive.  

To that end, Revolution Medicines readily embraced Olive’s idea to set up the consortium for the latest preclinical study and established a confidential disclosure agreement between across five academic institutions—Columbia University as well as the Dana-Farber Cancer Institute, the University of Pennsylvania, the Broad Institute of Harvard and MIT, and Memorial Sloan Kettering Cancer Center. It also assigned a consortium manager to run quarterly Zoom meetings to keep the collaborating institutions apprised of progress.  

The company now has multiple phase 1 studies underway, including two studies where Columbia University is a recruiting location. One trial is studying a combination of RMC-6236 with another agent (RMC-6291) for the treatment of advanced KRAS G12C mutant solid tumors and the other use of RMC-6236 in patients with solid tumors harboring specific RAS mutations. 

Olive says he hopes to be working with some of the samples that emerge from these clinical trials and ones that are likely to follow. “If cancer is coming back, we need to understand and find the drug combinations that make more durable responses or, to be hopeful, lead to tumor eradication. We also need to make sure that the mechanisms of resistance that are showing up in human patients with pancreatic cancer are the same as what we see in mice.” 

‘Exploding Field’

While Olive is focused largely on the pan-RAS inhibitor from Revolution Medicines, there is also an “exploding field of research on additional mutation-selective inhibitors,” he says. Beyond those being explored by Revolution Medicines, Bristol Myers Squibb (thanks to last fall’s acquisition of Mirati) is working on Krazati as well as MRTX1133 targeting the KRAS mutation implicated in PDAC, NSCLC, and colorectal cancer. 

Of particular interest are drugs aimed at the more common mutations in pancreatic cancer such as KRAS and G12C, says Olive. “I’ll be super-interested to learn how the ones that target the mutation specifically fair versus those that broadly target all forms of RAS.”  

Olive, a decided optimist, says that “hope is coming in a much faster way than has been true over the recent decades. Twenty years ago, there was an entire generation of oncologists who had seen their careers go by with almost no progress in outcomes for patients and I don’t think that will continue to be the case. We are starting to see blips on the radar in terms of agents that have some modest impact in really difficult-to-treat preclinical models, and as those start to progress into the clinic and to be combined in unique ways, I think we are going to see a true acceleration in terms of [longer survival] for patients.”