RAS mutations are among the most common drivers in cancer, particularly in pancreatic, colorectal, and lung tumors. Despite that, directly targeting RAS proteins proved extremely difficult for years, and the effort accumulated a long history of failed attempts.
Part of the problem came from the biology itself. RAS proteins have relatively smooth surfaces with few obvious binding pockets for drugs, making it difficult for inhibitors to compete effectively. As a result, much of the work on RAS focused on blocking pathways downstream of the protein rather than targeting RAS directly.
That started to change with the development of KRAS G12C inhibitors. In 2021, Amgen’s sotorasib became the first approved direct KRAS inhibitor for previously treated KRAS G12C-mutated non-small cell lung cancer, followed by Bristol Myers Squibb’s adagrasib.
But the field has already moved beyond the initial question of whether RAS can be targeted at all. It is now about which RAS mutations are realistically druggable, which tumor types respond best, how resistance emerges, and whether combinations will matter more than monotherapy. The landscape is also diversifying beyond KRAS G12C toward newer approaches, including KRAS G12D inhibitors, pan-RAS and RAS(ON) inhibitors, degraders, and combination strategies, particularly in pancreatic cancer.
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Why RAS matters in cancer
RAS proteins are involved in several cell signaling pathways. In normal cells, they work like switches, cycling between an inactive GDP-bound state and an active GTP-bound state in response to upstream signals. Once activated, RAS can pass signals into pathways such as RAF-MEK-ERK and PI3K-AKT, which are important to cell proliferation and survival.
When RAS is mutated, the protein can become locked, or at least strongly biased, toward its active state. Instead of responding to normal control signals, mutated RAS keeps driving growth and survival signaling. This is why RAS mutations are considered oncogenic drivers.
There are three main RAS genes in human cancer: KRAS, NRAS, and HRAS. They do not carry the same weight in drug development. KRAS dominates the therapeutic discussion because it is by far the most commonly mutated RAS gene in solid tumors. KRAS mutations are involved in around 85-90% of pancreatic ductal adenocarcinomas, roughly 40-45% of colorectal cancers, and around 25-30% of lung adenocarcinomas, though this varies by dataset and population.
Lung cancer provided the first clinical alley because KRAS G12C is relatively common in lung adenocarcinoma and became druggable with covalent inhibitors. Colorectal cancer quickly showed that targeting KRAS alone may not be enough, pushing the field toward combinations. In Pancreatic cancer, KRAS mutations are present in the vast majority of cases, but the dominant variants, especially G12D and G12V, have historically been harder to drug than G12C.
NRAS and HRAS are still relevant, but they are more tumor-context specific. NRAS is particularly associated with melanoma and some hematologic malignancies, while HRAS mutations are seen in subsets of head and neck, bladder, and other cancers.
RAS inhibitors: the KRAS G12C breakthrough and its limits
KRAS G12C inhibitors were the first major success in the RAS field. After years of failed attempts to drug RAS directly, sotorasib and adagrasib showed that at least one KRAS mutation could be targeted.
The KRAS G12C mutation creates a reactive cysteine residue that allowed the design of covalent inhibitors capable of binding KRAS in its inactive GDP-bound state, exploiting a pocket that earlier approaches had been unable to target.
This is the strategy that led to the first approvals. Amgen’s sotorasib received accelerated FDA approval in 2021 for previously treated KRAS G12C-mutated non-small cell lung cancer (NSCLC), followed by Bristol Myers Squibb’s adagrasib in 2022.
But the first generation of KRAS inhibitors also quickly revealed the complexity of RAS biology, and its limits. Responses in lung cancer were real, but they were rarely permanent, with resistance mechanisms emerging through secondary KRAS mutations, bypass signaling, and pathway reactivation.
Colorectal cancer has been one of the clearest examples of those limitations. Despite targeting the same KRAS G12C mutation, monotherapy activity was more limited than in NSCLC. One reason is that colorectal tumors can rapidly restore MAPK signaling through EGFR-driven feedback loops, partially bypassing KRAS inhibition.
This is why the field moved toward combination strategies, and this ultimately led to the approval of KRAS G12C combinations in colorectal cancer. In January 2025, the FDA approved sotorasib with panitumumab for previously treated KRAS G12C-mutated metastatic colorectal cancer after the trial showed a median progression-free survival of 5.6 months versus 2 months for standard care. Adagrasib followed a similar path, receiving accelerated approval with cetuximab in 2024 based on data showing a 34% objective response rate.
The regulatory story has also remained more moderate than the early excitement surrounding the field. While sotorasib received accelerated approval in NSCLC, confirmatory data later showed a progression-free survival benefit without a statistically significant improvement in overall survival. The FDA ultimately maintained approval, despite those results.
The second wave: G12D, RAS(ON), and pancreatic cancer
Pancreatic ductal adenocarcinoma is one of the cancers most closely tied to KRAS biology, with KRAS mutations found in the vast majority of cases. But unlike lung cancer, where G12C created the first clear opening for direct KRAS inhibition, pancreatic cancer is dominated by variants such as G12D and G12V, which have been harder to target.
KRAS G12C inhibitors were built around the cysteine residue created by that specific mutation. KRAS G12D does not offer the same opportunity, so companies need to think of different strategies. This led to a more diverse second wave of RAS drugs: inhibitors of active RAS, mutation-selective G12D drugs, multi-selective RAS inhibitors, and targeted protein degraders.
One of the most advanced examples is Revolution Medicines’ daraxonrasib, also known as RMC-6236. Daraxonrasib is a multi-selective RAS(ON) inhibitor designed to inhibit active, GTP-bound RAS across several common oncogenic variants. In April 2026, Revolution Medicines reported positive topline phase 3 data in previously treated metastatic pancreatic ductal adenocarcinoma. According to the company, median overall survival reached 13.2 months with daraxonrasib versus 6.7 months with standard chemotherapy, with the trial also meeting progression-free survival and response-rate endpoints.
If those results hold up under regulatory scrutiny, daraxonrasib could become the first RAS-targeted therapy to make a major impact in pancreatic cancer rather than in a narrower molecular niche. The data also drew strong investor attention, with Revolution Medicines shares rising 40% last month.
Revolution Medicines is also developing a more selective G12D approach with zoldonrasib (RMC-9805), also a RAS(ON) inhibitor. Mutations such as G12D tend to spend more time in the active state than KRAS G12C, making them harder to target with earlier approaches. The candidate remains in early clinical development, but phase 1 data have shown acceptable tolerability and early antitumor activity in KRAS G12D-mutant tumors.
Astellas is taking a different route with setidegrasib, also known as ASP3082. Setidegrasib is a targeted protein degrader designed to bind mutant KRAS G12D and recruit an E3 ligase to degrade the disease-driving protein. A month ago, Astellas dosed the first patient in a phase 3 study of setidegrasib plus chemotherapy in first-line metastatic KRAS G12D-mutated pancreatic ductal adenocarcinoma. The company described it as the first protein degrader targeting a KRAS mutation to enter phase 3 development.
Another important candidate is VS-7375, also known as GFH375, from Verastem Oncology and GenFleet Therapeutics. This is an oral KRAS G12D ON/OFF inhibitor, meaning it is designed to target both active and inactive states of KRAS G12D. Verastem selected it as the lead program from its collaboration with GenFleet, received U.S. IND clearance in 2025, and initiated a phase 1/2a trial. In China, GenFleet has reported early phase 1/2 monotherapy data in advanced KRAS G12D-mutant pancreatic cancer, showing a 41% objective response rate in heavily pretreated patients, though these remain early data.
What comes next in RAS inhibitors: resistance, combinations, and the companies to watch
Resistance remains the main reason RAS inhibition is unlikely to be a straightforward area. Tumors can escape through new KRAS alterations that reduce drug binding, amplification of KRAS signaling, or activation of parallel pathways that restore downstream signaling. This means that even when RAS inhibition works, the pathway can often find a way back on.
The first KRAS G12C drugs proved that direct inhibition was possible, but the field is now focused on whether RAS inhibitors can move into first-line settings, work in pancreatic cancer, and target mutations beyond G12C.
One company to watch here is Eli Lilly, with olomorasib, its next-generation KRAS G12C inhibitor. Lilly is already pushing olomorasib into phase 3 first-line NSCLC trials in combination with pembrolizumab and chemotherapy.
Roche/Genentech is also a collaboration to keep an eye on with divarasib, another KRAS G12C inhibitor that could help define whether the class can improve on first-generation drugs. Roche is running phase 3 studies in KRAS G12C-mutated NSCLC, including first-line combinations with pembrolizumab. The two companies announced today that they would present clinical data about multiple programs, including divarasib, at ASCO in a couple of weeks.
Another company involved in the field is Bayer, through its 2025 collaboration with Kumquat Biosciences around KQB548/BAY 3771249, an investigational KRAS G12D inhibitor. The program is still early, with a phase 1 study initiated in October.
Pancreatic cancer is where many of these newer approaches are now converging. Unlike NSCLC, where KRAS G12C created a relatively accessible entry point, pancreatic tumors are dominated by mutations such as G12D and G12V, forcing companies to explore broader RAS inhibition strategies, active-state targeting, and combination approaches much earlier in development.
