Adagrasib Provides New Option for Patients with KRAS G12C–Mutant NSCLC

Alexander I. Spira, MD, PhD, FACP

The FDA’s accelerated approval of adagrasib (Krazati) for adult patients with KRAS G12C–mutated locally advanced or metastatic non–small cell lung cancer (NSCLC) who have received at least 1 prior systemic therapy has provided a second KRAS G12C inhibitor option for patients.1

On December 12, 2022, the regulatory decision, supported by findings from the phase 1/2 KRYSTAL-1 trial (NCT03785249), allowed adagrasib to join sotorasib (Lumakras) in the NSCLC treatment landscape. The multicenter, single-arm, study evaluated the efficacy of adagrasib monotherapy among 112 patients with locally advanced or metastatic NSCLC harboring KRAS G12C mutations who had progression on or after platinum-based chemotherapy and an immune checkpoint inhibitor.

Patients achieved an objective response rate of 43% (95% CI, 34%-53%) with a complete response rate of 0.9%. The median duration of response (DOR) was 8.5 months (95% CI, 6.2-13.8), and 58% of patients achieved a DOR of at least 6 months.²

“The approval of this drug is very important,” Alexander I. Spira, MD, PhD, FACP, said. “Adagrasib opens up another KRAS G12C inhibitor [treatment], and while sotorasib and adagrasib are similar, they do have different [adverse] effect [AE] profiles.”

In an interview with OncLive^®, Spira, co-director of the Virginia Cancer Specialists Research Institute in Fairfax, director of the Thoracic and Phase I Program, and a clinical assistant professor at Johns Hopkins School of Medicine in Baltimore, Maryland, discussed the potential role of adagrasib in the treatment landscape for NSCLC, particularly for patients with untreated brain metastases.

OncLive^®: What is the mechanism of action of adagrasib and how does this agent differ from others in its class?

Spira: [Adagrasib] is a KRAS G12C inhibitor that binds directly to the KRAS G12C protein and keeps it in a locked form. It has a longer half-life, which may bode [well] for different dosing frequencies and possibly different [AEs]. There are some subtle differences, but it's not dramatically different from sotorasib

There are also very strong data [which] show that adagrasib has central nervous system [CNS] penetration, which is important. We don't know about that yet for sotorasib—there are anecdotal reports—but there are good data for adagrasib. It opens up other options for patients, and it's always good to have [different options] for patients to pick based on tolerability and AEs.

In the lung cancer space, adagrasib fulfills a couple of unmet needs. It offers patients a secondary option [as] sotorasib was not well tolerated by everybody. [Adagrasib] is going to be looked at in combination with other therapies, specifically in conjunction with pembrolizumab [Keytruda], and we'll see if we can move it to the frontline space, as well. There are also good data that [show] it works in other diseases in an agnostic way for KRAS G12C–[mutant] tumors, including colorectal cancer, pancreatic cancer, and other cancers . To remind everybody, you can't put somebody on a targeted therapy if you don't test for that target. It's important that we test everybody for all biomarkers, not just KRAS G12C [mutations].

What key efficacy data were reported in the KRYSTAL-1 trial in the cohorts of patients with NSCLC and untreated brain metastases?

[Findings from] the KRYSTAL-1 study showed efficacy [in terms of] response rates, as well as a reasonable DOR. In terms of untreated brain metastases, there were very good data that regression or at least stability of CNS metastases [was observed]. [Prior findings] demonstrated that it had efficacy in patients who had previously treated brain metastases, but what we're really excited about is data presented by Joshua Sabari, MD, at [the] 2022 ASCO Annual Meeting, where they took untreated brain metastases and they saw some impressive responses.

It's very important to include patients with measurable brain target lesions [on clinical trials] so you can measure efficacy. It's easy to put patients on who have treated brain metastases. [However], it's challenging to put patients on [with] untreated brain metastases, especially those that are measurable. It's hard to get these patients both from a clinical standpoint and a trial standpoint, so it's important to include this group of patients if we think there is any evidence of CNS activity.

What does the safety profile look like for this agent?

Adagrasib at 600 mg has some more gastrointestinal AEs [and] has a slightly higher adjustment rate, but the discontinuation rate was the same [as 150 mg and 300 mg doses of adagrasib]. When you get a patient to a tolerable dose, it looks like it'll be about the same tolerability.

There is some hope with a new formulation, tablet vs capsule, [that] it will be a little bit better tolerated. We feel that a dose reduction is probably applicable to a lot of patients, and patients do well with a dose reduction.

How do you see adagrasib fitting into the treatment landscape for this population and how would you use it in the space?

Both sotorasib and adagrasib are good drugs that are approved now for the second-line treatment of NSCLC. It will be a bit of physician's choice based upon [patient] tolerability. I do think [for] patients with brain metastases, I currently lean more toward adagrasib because there are more data [regarding CNS metastases]. We don't [have that] as of now [for] sotorasib, although we're not anticipating any major differences. Both will be good tools to offer patients with [KRAS G12C] mutations in the second-line setting, and then we'll have to see what happens in the frontline setting.

References

1. FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC. FDA. December 12, 2022. Accessed December 15, 2022. bit.ly/3HEfTIR
2. Krazati. Prescribing information. Mirati Therapeutics; December 2022. Accessed December 15, 2022. bit.ly/3YE7Din