Drugging RAS: Moving Beyond KRAS^G12C

In the RAS targeted therapy field, sotorasib (Lumakras; Amgen) and adagrasib (Krazati; Mirati Therapeutics)—both KRAS^G12C inhibitors—have had the lion's share of attention for the last 2 years. But new candidate drugs have begun to emerge, some aimed at a broader range of RAS isoforms and others at different KRAS variants.

“G12C aside, more than 85% of KRAS-mutant cancers still lack effective therapies,” remarked Elena Garralda, MD, of Vall d'Hebron Institute of Oncology in Barcelona, Spain. As well, “response rates to sotorasib and adagrasib are only around 40%, so there's room for improvement all around.”

During the 2023 ESMO Congress in Madrid, Spain, October 20–24, Kathryn Arbour, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, presented preliminary findings from a phase I trial of the pan-RAS inhibitor RMC-6236 (Revolution Medicines). The oral agent targets both mutant and wild-type K/H/NRAS, “including all activating mutations at the G12, G13, and Q61 positions,” she explained. Notably, it is also a first-in-class drug that—unlike the two FDA-approved agents—interacts with RAS in its GTP-bound “on” rather than GDP-bound “off” state.

To date, 46 patients with non–small cell lung cancer (NSCLC) and 65 patients with pancreatic ductal adenocarcinoma (PDAC) have been enrolled in the trial's dose-escalation phase, which starts at 80 mg daily. All had received prior standard therapy and had tumors harboring variants other than KRAS^G12C, which was excluded, “given existing targeted therapy opportunities for these patients,” Arbour said.

KRAS^G12D/V were prevalent in the NSCLC cohort. “Although KRAS mutations tend to be associated with smoking history, G12D in particular is a relatively common driver in never smokers, which I'll note made up 35% of this group,” Arbour said. The objective response rate (ORR) to RMC-6236 among 40 evaluable patients was 38%, and the disease control rate (DCR) was 85%. An 83-year-old patient harboring KRAS^G12V, who had disease progression on prior chemotherapy and dual immune checkpoint inhibition (ICI), achieved a complete response—which continues—within 6 weeks with 300 mg of RMC-6236.

In the PDAC cohort, the ORR was 20% and the DCR was 87% among 46 evaluable patients. Arbour highlighted a 57-year-old patient with KRAS^G12R who received RMC-6236 at 160 mg and has had an ongoing partial response, also within 6 weeks, with lung and liver lesions reduced by 47%.

Circulating tumor DNA analyses are being carried out, Arbour said, and among evaluable patients, eight of 10 with NSCLC and 12 of 13 with PDAC “had a greater than 50% reduction of their mutant KRAS allele.”

RMC-6236’s side effects included rash, nausea, and diarrhea, “but nothing limiting in terms of quality of life,” Arbour noted. “These patients are on therapy and feeling pretty good; I'm frankly surprised at how tolerable it's been.”

Considering that “preclinically, ablating all RAS isoform expression caused death in adult mice, it's good that there were no high-grade or fatal adverse events in this study,” observed Garralda, the study's discussant. “Remember, though, we're inhibiting wild-type RAS, and it's the first time this has been done in the clinic. Long-term toxicities could become apparent later.”

Including KRAS^G12C tumor types in future studies of RMC-6236 “would be interesting,” Garralda added, “to see if this drug could potentially be used to block compensatory NRAS/HRAS activation or secondary mutations.”

For KRAS^G12C, “it's an open question whether a selective or a pan-RAS inhibitor is better—I think both have advantages,” Arbour commented. “We're in early days yet, especially with the latter drug class, but the signal so far is exciting.”

On the selective inhibitor front, the development space for therapies aimed at KRAS^G12D is taking off. At ESMO, Caicun Zhou, MD, PhD, of Shanghai Pulmonary Hospital in China, presented the first phase I data on one such agent, HRS-4642 (Jiangsu Hengrui Pharmaceuticals).

In PDAC, for instance, KRAS^G12D “is the predominant mutated isoform, detected in more than 30% of cases,” Zhou said. “It's structurally challenging to drug, and until now, no clinical trial outcomes for G12D inhibitors have been reported.”

HRS-4642 uses a liposomal formulation, Zhou explained, “for targeted delivery, controlled and sustained drug release, and to decrease systemic toxicity.” To date, 18 patients with advanced solid tumors have been treated—the majority (10) with NSCLC, followed by colorectal cancer (5). All had received prior platinum chemotherapy and, for most, ICI as well.

Zhou disclosed that the DCR was 77.8%: One patient with NSCLC achieved a partial response, and 11 more had stable disease. HRS-4642’s main side effects were hypercholesterolemia, infusion-related reactions, proteinuria, and anemia.

“It's a different toxicity profile with mainly lab abnormalities and no rash or GI [gastrointestinal] issues,” Garralda said. HRS-4642 is given intravenously (IV) due to its formulation, she noted, but “I wonder if there's really continuous target inhibition—which we know is important when it comes to the MAPK pathway—with weekly IV dosing, given that the drug's terminal half-life is approximately 40 hours.”

Garralda pointed out, too, that among patients who experienced stable disease, one who turned out to have KRAS^G12V-mutant NSCLC “had some degree of tumor shrinkage that's ongoing at 18 weeks, so we do need to find out more about this agent's specificity. There's also much we don't know about its structure and binding mode.”

Meanwhile, multiple other RAS drugs are now in or close to clinical evaluation: For instance, Astellas Pharma has two degraders, one that's pan-RAS and the other targeting KRAS^G12D. Mirati's MRTX1133 is another KRAS^G12D inhibitor, as is Revolution's RMC-9805; the latter biotech also has RMC-8839, aimed at KRAS^G13C, in its pipeline.

“We can anticipate that lots more data are on the way,” Garralda concluded, “and I think it's safe to say that, for the field, moving beyond G12C is already a reality.” –Alissa Poh