KRAS G12C and Beyond: KRAS Targeted Agents of Interest Under Development in NSCLC

Benjamin Herzberg, MD

As investigators are exploring many approaches to inhibit KRAS, such as RAS(ON), degradation, and new allele-specific strategies, the research sector is exciting and busy with questions, according to Benjamin Herzberg, MD.

“We’ve seen novel types of pharmacology tackling non-G12C KRAS. One example is the KRAS G12D degrader ASP3082 that instead of inhibiting KRAS, latches onto KRAS and uses the normal cellular machinery to degrade KRAS completely. This works only for G12D, but we’ve seen responses in patients with lung and pancreatic cancers [harboring] G12D mutations treated with this drug. This is exciting not just because it’s targeting a new KRAS allele, but because it’s doing it in a new way,” Herzberg said in an interview with OncLive®.

At the July 8, 2024, data cutoff, data from the phase 1 study of ASP3082 (NCT05382559) demonstrated that patients with non–small cell lung cancer (NSCLC) who received the agent at 300 to 600 mg (n = 13) experienced an overall response rate of 23.1% and a disease control rate of 84.6%.1 Degradation of the KRAS G12D mutant protein was dose-dependent and no grade 3 or 4 treatment-related adverse effects were observed.

In the interview, Herzberg highlighted novel therapies in the KRAS-mutated NSCLC landscape and ongoing questions research is seeking to answer, which he also detailed in a presentation given at an OncLive State of the Science Summit he chaired. Herzberg is an assistant professor of medicine at Columbia University Irving Medical Center and an oncologist at Herbert Irving Comprehensive Cancer Center in New York, New York.

OncLive: What notable research is ongoing in KRAS-mutated NSCLC?

Herzberg: KRAS is one of the premier areas of small molecule-based drug development right now [which] results in all sorts of medicinal chemistry, pharmacologic, and scientific creativity that’s pouring into ways to do new targeting of KRAS. The key questions with KRAS are [will] the drugs be allele-specific targeting 1 specific mutation like G12C, G12D, or G12V, or are we making drugs that can target all potential KRAS mutations or even RAS mutations? How are those different approaches going to play out in terms of toxicity, activity, and success?

There are a series of medicines now that are targeting not just the off state or the GDP-bound state of the protein, which is what all of our approved molecules do, but there are also molecules that are targeting the on state of the protein. Some of these are straight inhibitors [whereas] others are molecular glue inhibitors where they bind KRAS to something else which it doesn’t normally bind and that blocks KRAS from being active. [The] tri-complex inhibitors from Revolution Medicine [include] both allele-specific—G12C and G12D—directed molecules and pan-RAS molecules [which] shut off any RAS mutation.

We’ve seen promising responses across [patients with] RAS mutations in some of the clinical trials that have reported on these compounds, [and] this is just 2 of them; there are dozens of others that are doing this in all sorts of unique ways.

Are there any particular agents you have your eye on?

ASP3082 is interesting because its shown activity and it’s this completely new mechanism of action that is slowly making its way into other areas of oncology because it is a very interesting proof of principle. RMC-6291 is a KRAS G12C-specific molecule that showed a response rate of approximately 40% to 50% in a small phase 1 clinical trial [NCT05462717]. It also showed responses amongst previously KRAS G12C inhibitor-treated patients, which is very interesting.

The pan-RAS molecule RMC-6236, now named daraxonrasib, looks like it has a lot of activity across KRAS mutations. It also has a slightly different toxicity profile, we see a lot more rash with this than we’re accustomed to seeing with the allele-specific molecules, and that’s an area to watch [regarding] whether that becomes a toxicity issue that prevents full use of the drug. But for now, it’s been surprisingly well tolerated at the doses we’ve tested, showing lots of responses, and is very interesting.

There are a whole series of molecules coming up, [such as] pan-KRAS inhibitors coming out from several companies [that] are just entering phase 1 studies now at our center and other centers, so we’ll see what they end up showing. But it’s an incredibly exciting time and out of all these molecules, I believe some are likely to show real activity for new KRAS alleles that we haven’t yet been able to target.

What questions still need to be answered regarding KRAS in this patient population?

There are a couple of major open questions on KRAS. One is what combinations with KRAS inhibitors are going to be the future of KRAS inhibition for both G12C and non-G12C alleles? These drugs are [going to] be tested with chemotherapy, immunotherapy, and other [agents].

Other than combinations with EGFR inhibitors such as cetuximab [Erbitux] and panitumumab [Vectibix], the data that we’ve seen so far on combinations, to my eye, have not really shown synergistic activity. We’ve seen some reports of immunotherapy plus KRAS G12C inhibitors having nice response rates, but those rates look like they’re response rates of the immunotherapy plus the response rate of the KRAS G12C inhibitor added together.

[Therefore], major questions are going to be what combinations are tolerable, what can be used, and then what combinations are very good or synergistic/better than just using the drugs individually? Those are somewhat separate questions that tend to get lumped together, but we have a number of trials ongoing that are trying to answer those questions. We’ll see readouts for trials [examining] immunotherapy with adagrasib [Krazati] in patients with frontline PD-1-high [disease and] chemotherapy with sotorasib [Lumakras] for patients with PD-1-low [disease] in the coming months or years, and that will help inform us as to what combinations are important.

Likewise, a major question is going to be once we develop these next generation molecules that have pan-KRAS or pan-RAS properties, can we combine different targeting to either get deeper responses or more long-lived responses? In the limited data that have been published so far about why patients become resistant to KRAS G12C inhibitors, we’ve often seen them develop new KRAS mutations [such as] G12A, G12B, [or] G12D. This makes a lot of scientific sense, and if we have pan-KRAS or pan-RAS inhibitors, we might be able to abrogate that resistance and keep patients on these drugs longer and more successfully, which is a very exciting concept.

We’re going to see a lot of this [research] over the next few years, some of which is going to be good and exciting, and some of which is going to end up in the trash as we find out that it doesn’t work. But in either case, it’s an exciting time to be working in these cancers as my suspicion is we’ll get a lot more novel, unique, and interesting strategies.

Reference

Targeted protein degradation. Progress on ASP3082, a first-in-class KRAS G12D selective protein degrader. Astellas. Accessed March 25, 2025. https://www.astellas.com/en/system/files/6e02b237de/pf_tpd_asp3082_ir_call_presentation_240927_en.pdf