Divarasib Looks to Best Sotorasib/Adagrasib and Solidify a Role in KRAS G12C-Mutated NSCLC

Benjamin Herzberg, MD

Following high response rates observed among patients with KRAS G12C-mutated non–small cell lung cancer (NSCLC) treated with divarasib in a phase 1 trial (NCT04449874), the agent is being compared with standard-of-care agents adagrasib (Krazati) and sotorasib (Lumakras) in the phase 3 KRASCENDO 1 trial (NCT06497556), representing an encouraging trial design, according to Benjamin Herzberg, MD.1

“Regardless of the outcome of this trial, I’m happy to see a sponsor taking this direct comparison on in this way,” Herzberg said in an interview with OncLive®. “For divarasib, the main eyebrow raising piece of information is that its response rate and duration of response [DOR] in the phase 1 study appeared [to be] significantly longer than what we’ve seen before with G12C off-state inhibitors [such as] adagrasib and sotorasib.”

Patients with locally advanced or metastatic NSCLC who received the oral, highly potent, covalent KRAS G12C inhibitor divarasib in the phase 1 study at the 400-mg dose level (n = 44) achieved a confirmed overall response rate of 59.1%. The median DOR was 14.0 months (95% CI, 11.1-24.9) and the median progression-free survival (PFS) was 15.3 months (95% CI, 12.3-26.1).

In the interview, Herzberg detailed new agents in the KRAS G12C-mutated space such as divarasib and how he selects between available therapies for this patient population. Herzberg is an assistant professor of medicine at Columbia University Irving Medical Center and a medical oncologist at Herbert Irving Comprehensive Cancer Center in New York, New York.

OncLive: How is targeting KRAS evolving in NSCLC?

Herzberg: KRAS inhibitors have been a huge area of development in NSCLC over the past few years—really since 2018—and the key take home message is that we’re part of the way there, we have a long way to go, and it’s as exciting as it possibly could be right now. KRAS G12C inhibitors have become a part of daily practice, and [although] the ones that are commercially available have nice response rates and good PFS data, it’s not clear if they’re as strong as other targeted therapies that we’re used to seeing in NSCLC. Several next-generation KRAS G12C approaches look like they might be even better than what we have on the shelf right now. Beyond that, and beyond G12C, we have a whole variety of new drugs that are entering the clinic in this very exciting time to give us new options against non-G12C KRAS.

What unique features of divarasib may make it a standout in the KRAS G12C landscape?

The main standout feature is that the response rate [appears] to be in the 50% to 60% [range], which is 10 to 20 [percentage] points higher than what we’ve seen previously. The DOR is approximately a year, [which] is longer and more robust, and it is starting to approach the profile we expect from other targeted therapies in lung cancer, such as osimertinib [Tagrisso] or lazertinib [Lazcluze]/amivantamab-vmjw [Rybrevant], which we haven’t yet seen with G12C inhibitors [yet]. That’s one very exciting feature of divarasib, and the toxicity profile looks the same [as other agents in this class].

Notably, with divarasib there’s now a registrational trial [comparing] divarasib vs the standard-of-care KRAS G12C inhibitors sotorasib and adagrasib. This is an incredibly encouraging trial design to see as a clinical investigator [because] it’s directly comparing the best [treatment] we have right now with what a sponsor thinks is the best [agent] that is the same generation and same profile. In a world in which trials are often trying to get away with the lowest common denominator comparator that we think is acceptable to the FDA and other regulatory agencies, it’s exciting to see a trial that is going for the heart of the question with this approach.

What is notable about the KRAS G12C-targeted agent olomorasib that is under investigation?

Olomorasib has 2 interesting features. First, it looks to be very well tolerated—the toxicity profile looks to be among the best of the drugs. A cohort of patients who had previously [been treated with a KRAS] G12C inhibitor [also received the drug] and many of those patients responded to olomorasib. It’s to be determined if that’s mechanistic or [it’s] just that this drug is better tolerated than some of the other drugs, but it looks like it might also have a place because of some of those features.

How do you currently select between the available KRAS G12C inhibitors for patients with KRAS G12C-mutated NSCLC?

Amongst our 2 commercially available KRAS G12C inhibitors in NSCLC, sotorasib and adagrasib, there is more in common than there is different, but there are some differences. I say there’s more in common than there is different because the toxicity profiles are quite similar, [and] the response rate profiles are as well. [Regarding] small differences that we do see, adagrasib has slightly more robust data [in terms of] central nervous system [CNS] activity than sotorasib does. There have been retrospective reviews and reviews [for] sotorasib showing that it looks like it does have CNS activity, but we have direct evidence of this for adagrasib. [Therefore], for patients who have brain metastases or who I believe are at high-risk for future brain metastases, I tend to choose adagrasib.

There are small toxicity differences [as well]. Sotorasib may have more liver function test [level] elevation or more difficulty in patients coming off checkpoint inhibitors and for that reason, I tend to choose adagrasib in that situation as well. But [sotorasib] has a bit less nausea, vomiting, and gastrointestinal toxicity, so for patients who want the least amount of toxicity, sometimes sotorasib is more attractive in that setting. There’s also a warning with adagrasib for QTC prolongation and for patients who have cardiac issues or other issues where they’re at risk for arrhythmia, that might lead me to choose sotorasib in that situation. But there are more similarities than differences and are some subtle differences between the two.

Reference

1. Garralda E, Patel MR, Kim TW, et al. Long-term follow-up of single-agent divarasib in patients with KRAS G12C-positive solid tumors. Ann Oncol. 2024;35(2):S494. doi:10.1016/j.annonc.2024.08.683