KRAS Inhibitors in Pancreatic Cancer: Hope on the Horizon?

Pancreatic cancer remains one of the deadliest cancers. 
When the disease is caught earlier, the 5-year survival rates hover around 44%, but once the cancer metastasizes, only about 3% of patients live that long. 
Finding effective treatments for the disease continues to be a challenge. 
No significant new therapies in pancreatic cancer have emerged in the past 20 years, explained John Marshall, MD, a gastrointestinal medical oncologist at Georgetown University in Washington, DC.
Oncology researchers have long eyed a potential holy grail target: the KRAS oncogene. Present in about 90% of patients with pancreatic cancer, KRAS mutations are considered a key driver of the disease. But for decades, KRAS was considered “undruggable.” 
Until recently. 
In the past 2 years, the US Food and Drug Administration has approved two KRAS inhibitors — sotorasib and adagrasib — to treat certain colorectal and lung cancers. 
A pipeline of KRAS inhibitors targeting pancreatic cancer has now emerged, leaving some oncologists feeling optimistic about the future of treating the disease.
“I think KRAS inhibitors — [maybe not alone] but as a foundational agent for combinations — are really poised to transform how we care for patients,” said Andrew Aguirre, MD, PhD, a gastrointestinal medical oncologist at the Dana-Farber Cancer Institute, Boston, who heads a lab focused on RAS signaling and pancreatic cancer. These agents won’t necessarily cure pancreatic cancer but will be “part of the solution” to improve outcomes, Aguirre said.
A Challenging Cancer
Pharmaceutical companies currently have at least eight agents in development and are conducting dozens of KRAS/RAS studies that focus on or include pancreatic cancer.
But it’s still early days on the evidence front.
The investigational drugs are only in phase 1/2 testing, and the reported outcomes have been limited so far. 
The current mainstay frontline options in pancreatic cancer largely center on chemotherapy combinations. These include FOLFIRINOX (irinotecan, fluorouracil, leucovorin, and oxaliplatin), gemcitabine, nab-paclitaxel, and capecitabine. The four-drug chemotherapy combination NALIRIFOX — a slight tweak on FOLFIRINOX — was also recently approved in the first-line setting.
Patient outcomes on these chemotherapy combinations have been modest, with median overall survival in the metastatic setting ranging from 6.7 months to 11.1 months.
And although two KRAS inhibitors, sotorasib and adagrasib, are currently on the US market, neither is approved for pancreatic cancer, and use of these agents to treat pancreatic cancer would be limited. Only about 1%-2% of tumors have the specific KRAS G12C mutation that these drugs target. These KRAS inhibitors have shown limited efficacy in pancreatic cancer.
For instance, a small study evaluating sotorasib in pancreatic cancer found that only 21% of 38 patients with metastatic disease who carried the G12C mutation achieved an objective response, and no patients had a complete response. In the overall population, median progression-free survival was 4 months and median overall survival was 6.9 months, with 19.6% of patients alive at 12 months.
In pancreatic cancer, better targets for KRAS inhibitors include the G12D mutation, carried by about 44% of tumors; G12V, present in 29% of tumors; G12R, present in 20%; and pan-RAS inhibitors, which cover all mutations. 
At this year’s American Society of Clinical Oncology meeting, Aguirre discussed the pipeline of investigational KRAS agents targeting some of these more relevant mutations.
Results from a recent phase 1 study, evaluating the investigational pan-RAS inhibitor RMC-6236 from Revolution Medicines, showed initial promise. The study revealed an objective response rate at 14 weeks of 20% in 76 patients with metastatic pancreatic ductal adenocarcinoma treated in the second line. The disease control rate reached almost 90% at 14 weeks. 
Median progression-free survival was 8.1 months, an improvement over the 2-3.5 months expected with additional chemotherapy. Overall survival was not reached but started at 8.5 months. The rate of grade 3 or higher adverse events — most commonly rash, diarrhea, and thrombocytopenia — was 22%. 
Revolution Medicines is now planning a phase 3 trial.
Other investigational KRAS inhibitors, outside of KRAS G12C agents, are entering or are in early trials, but without results reported yet.
While there’s “room for improvement,” such studies only offer “proof of concept” that KRAS inhibition has potential, Aguirre said. 
Oncologists may ultimately see better outcomes by expanding when and how patients receive these drugs. The research to date has been limited to monotherapy in previously treated patients with metastatic disease, which leaves the door open to explore the inhibitors in earlier lines of treatment; in patients with resectable disease; and in combination with chemotherapy, immunotherapy, or other targeted approaches, Aguirre explained. 
In his own lab, Aguirre and colleagues have data suggesting that combining KRAS inhibitors and chemotherapy may bring more benefit than either treatment alone.
Pancreatic tumors generally comprise a mix of both basal-like and classical cell subtypes, and basal-like cells have shown more resistance to chemotherapy. Aguirre’s team has found that basal-like cells may be more sensitive to KRAS inhibitors, which suggests that combining these inhibitors with chemotherapy could improve patient outcomes. 
Alan Venook, MD, said he “remains to be convinced” about the benefit of KRAS inhibition because he’s seen many other promising approaches, such as pegylated hyaluronidase, show initial potential but then fall flat in phase 3 testing. 
“We tend to get excited about preliminary data,” said Venook, a gastrointestinal medical oncologist at the University of California, San Francisco. “At the moment, there’s no data that suggests [KRAS inhibition] is going to be a game changer.” 
Mutation testing in patients with pancreatic cancer will be critical to identify who might benefit from different KRAS agents, and a subset of patients may do very well.
But with many patients presenting with advanced disease, “I just don’t see how turning off the disease [process] can happen adequately enough to stop it from progressing,” Venook said. And “is it a big advance to keep disease from progressing over 3 or 6 months?” 
Aguirre said he respects the caution. Much work remains to be done, including how to improve response rates and durability and to overcome the resistance that sets in with monotherapy. 
Still, “I think there’s tremendous reason for optimism right now,” Aguirre said.
Although the benefits of these agents may be limited, any improvement in pancreatic cancer treatment would still be a “game changer,” Marshall said. And that’s because “we need a new game.”
Aguirre is an advisor and/or disclosed research funding from companies developing KRAS/RAS inhibitors, including Revolution Medicines, Boehringer Ingelheim, Novartis, and Mirati. Venook did not have any disclosures. Marshall has ties to numerous companies, including Caris Life Sciences, Bayer, Merck, and Pfizer. He is also a Medscape Oncology editorial advisor. 
M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Email: [email protected].
 
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