Analyzing the “RAS Pie” for Methods to Target Mutations in GI Cancers

The acceleration of targeted therapy drug development has led investigators to home in on RAS mutations, aside from KRAS G12C, as agents, such as sotorasib (Lumakras) and adagrasib (Krazati), are approved in colorectal cancer (CRC) for patients with the specific mutation. Tanios Bekaii-Saab, MD, noted that the “RAS pie,” including mutations in KRAS G12D, KRAS G12V, and KRAS G12R, has been an area of recent investigation generating excitement.

Although KRAS mutations are present in approximately 40% of advanced CRCs, the KRAS G12C mutation only occurs in approximately 3% of patients, whereas KRAS G12D, KRAS G12V, and KRAS G13D are more common.¹ Data from the National Cancer Institute indicated that the KRAS G12D mutation is present in approximately 1 in 10 CRC cases and in more than 1 in 3 pancreatic cancers.² Clinical trials are examining EGFR plus KRAS inhibition to target KRAS G12C mutations in gastrointestinal (GI) cancers, and newer trials with RAS(ON) multiselective inhibitors are breaking ground as well.

“There is a lot more to come,” Bekaii-Saab noted on key clinical trials in GI cancer. “There are a number of these studies that are challenging us, clarifying, and complicating our landscape. A conference like the International Symposium of Gastrointestinal Oncology [ISGIO] in October summarizes the findings of the year, digests them, and gives the GI community oncologist a good [idea] of how to best practice in GI oncology.”

The 2024 ISGIO conference occurring October 11-12 in Hollywood, Florida, will present the latest updates in GI cancer from a multidisci- plinary angle via case-based learning, debates, panel discussions, and didactic segments.³ Bekaii-Saab, who is cochair of the event with Eileen M. O’Reilly, MD, of Memorial Sloan Kettering Cancer Center, is the David F. and Margaret T. Grohne Professor of Novel Therapeutics for Cancer Research I, a chair and consultant in the Division of Hematology and Medical Oncology, and a professor at the Mayo Clinic College of Medicine and Science at Mayo Clinic in Phoenix, Arizona.

Sessions such as “The KRAS Revolution,” and “Hitting the Target: Molecular Tumor Board With the Experts” will be of interest, and in anticipa- tion of the live meeting, Bekaii-Saab previewed some of the ongoing research evaluating KRAS- directed therapies and more in an interview with OncologyLive.

EGFR Plus KRAS Inhibition as Part of the “RAS PIE”

EGFR is recognized as a major upstream activa- tor of RAS-MAPK signaling, a proposed crucial mechanism of resistance to KRAS G12C inhibition in CRC.⁴ Data from the phase 1/2 KRYSTAL-1 trial (NCT03785249) revealed that dual KRAS/EGFR inhibition with the irreversible, selective KRAS G12C inhibitor adagrasib plus the EGFR monoclonal antibody cetuximab (Erbitux) resulted in encouraging clinical activity for patients with unresectable or metastatic KRAS G12C–mutated CRC who received a median of 3 prior lines of therapy. The overall response rate (ORR) in patients who received the doublet (n=94) was 34.0% (95% CI, 24.6%-44.5%) per blinded independent central review and 42.6% (95% CI, 32.4%-53.2%) as assessed by investigator; all responses were partial.⁵

The combination received accelerated approval from the FDA in June 2024 for the treatment of patients with KRAS G12C–mutated locally advanced or metastatic CRC who received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.⁶

“Next-generation sequencing testing is a human right, now; everyone should get it because not only do we have agents available that [target] the alterations, but also a lot of stud- ies require [it]. Looking at [mutations such as] HER2 or BRAF, the one that is very interesting and emerging is RAS,” Bekaii-Saab said. “RAS has been a target of interest for decades, and we never thought we would get to the point where we can target it. First, we have the KRAS G12C mutation. I’ve done a lot of work [targeting it] with adagrasib and there’s a lot of work done with sotorasib and other [agents targeting KRAS G12C] as well.”

Adagrasib plus cetuximab is under evaluation vs standard-of-care chemotherapy for the treatment of patients with advanced KRAS G12C–mutated CRC in the second-line setting in the phase 3 KRYSTAL-10 trial (NCT04793958). Additionally, in a phase 1b trial (NCT04449874), patients with KRAS G12C–mutated CRC who were naive to KRAS G12C inhibition achieved an ORR of 62.5% (95% CI, 40.6%-81.2%) when treated with divarasib (GDC-6036) plus cetuximab (n=24). The median duration of response was 6.9 months.⁷

“Though the [data] look consistent with CRC, meaningful outcomes can occur [when] adding an EGFR inhibitor [to treatment as shown in] data published in pancreas and biliary cancers that look very promising,” Bekaii-Saab noted.

Patients with pancreatic ductal adenocarcinoma (PDAC) treated with adagrasib in the KRYSTAL-1 study (n=21) experienced a confirmed ORR of 33.3% with a disease control rate (DCR) of 81.0% observed. Further, the median progression-free survival (PFS) was 5.4 months (95% CI, 3.9-8.2) and the median overall survival (OS) was 8.0 months (95% CI, 5.2-11.8). Those with biliary tract cancer (n=12) experienced a confirmed ORR of 41.7% and a DCR of 91.7%; the median PFS was 8.6 months (95% CI, 2.7-11.3), and the median OS in this patient population was 15.1 months (95% CI, 8.6-not estimable [NE]).⁸

“Adagrasib looks very promising [because] it’s on the National Comprehensive Cancer Network guidelines now for patients with KRAS G12C [mutations], but that’s only a small piece of the RAS pie,” Bekaii-Saab said.

Examining Additional Mutations Making Up the “RAS Pie”

“The RAS pie primarily [consists of] KRAS G12D, KRAS G12V, and KRAS G12R [mutations]. KRAS G12C is the least common but was the easiest alteration to go after. [However,] now we’re seeing an explosion [in exploration]—we’re going after KRAS G12D and KRAS G12V. There are studies looking at RAS(ON) [and] RAS^MULTI(ON) agents that target all the RAS [mutations,] not just 1 specific [RAS mutation]. These [inhibitors] are going to be a bit more challenging in the sense that if you have a target-specific agent, those will most likely get priority over all RAS [mutation–targeted agents] for many reasons. Perhaps that’s a discussion to be had at ISGIO,” Bekaii-Saab said.

Data from the phase 1 AMPLIFY-201 trial (NCT04853017) showed that treatment with the ELI-002 2P vaccine, which enhances lymph node delivery and immune response using amphiphile modification of G12D- and G12R-mutated KRAS peptides together with CpG oligonucleotide adjuvant,⁹ resulted in a tumor biomarker response rate of 84% among 25 patients; 20 patients had pancreatic cancer and 5 had CRC. Investigators noted that the vaccine induced considerable T-cell responses in patients with immunotherapy-recalcitrant KRAS-mutated tumors. AMPLIFY-201 also plans to transition to treatment with the ELI-002 7P vaccine which contains all 7 Amph-peptides of G12D, G12R, G12V, G12A, G12C, G12S, and G13D.¹⁰

The RAS(ON) multiselective inhibitor RMC-6236 was evaluated in the first-in-human phase 1 RMC-6236-001 trial (NCT05379985) as second-line therapy in patients with PDAC and RAS mutations including G12X, G13X or Q61X, and KRAS G12X mutations. At doses ranging from 160 mg to 300 mg orally daily, the median PFS in patients with RAS-mutated disease (n = 56) was 7.6 months (95% CI, 5.3-NE) and 8.1 months (95% CI, 5.9-NE) among those with KRAS G12X–mutated disease (n = 42). Patients who received a first dose of RMC-6236 at least 20 weeks prior to the data cutoff date to allow for 3 potential scans experienced an ORR of 27% in the KRAS G12X–mutated group (n=48) and 26% in the RAS-mutated group (n = 61).¹¹

Safety data revealed that the most common any-grade treatment-related adverse effects (TRAEs) were rash (87%), diarrhea (46%), and nausea (43%). Grade 3 or greater TRAEs occurred in 22% of patients, and 28% of patients expe- rienced a TRAE leading to dose modification. Notably, no TRAEs led to dose discontinuation.¹¹

Following the encouraging data, Revolution Medicines, the manufacturer of RMC-6236, announced that a phase 3 study called RASolute 302 is expected to be initiated in the second half of 2024. The trial will examine RMC-6236 vs chemotherapy in the second-line setting for the treatment of patients with metastatic PDAC.

“The RAS pathway is an example of how we continue to move the needle very aggressively in a positive way to continue to go after targets leading to a significant enhancement of patient outcomes,” Bekaii-Saab said. “Are we there yet? We’re getting closer, but we still have a long way to go. There are mechanisms of resistance we need to understand. We need to understand how to go after these mechanisms of resistance and continue to understand how to best optimize outcomes in a way that will prolong survival for patients with advanced disease.”

References

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8. Pant S, Yaeger R, Spira AI, et al. KRYSTAL-1: activity and safety of adagrasib (MRTX849) in patients with advanced solid tumors harboring a KRASG12C mutation. J Clin Oncol. 2023;41(suppl 36):425082. doi:10.1200/JCO.2023.41.36_suppl.425082
9. Pant S, Wainberg ZA, Weekes CD, et al. Lymph-node-targeted, mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer: the phase 1 AMPLIFY-201 trial. Nat Med. 2024;30(2):531-542. doi:10.1038/s41591-023-02760-3
10. A study of ELI-002 in subjects with KRAS mutated pancreatic ductal adenocarcinoma (PDAC) and other solid tumors (AMPLIFY-201). ClinicalTrials.gov. Updated June 20, 2024. Accessed July 16, 2024. https://clinicaltrials.gov/study/NCT04853017
11. RMC-6236: pancreatic cancer update to support pivotal phase 3 trial. Revolution Medicines. July 15, 2024. Accessed July 16, 2024. bit.ly/3WlVgZ1