Adagrasib/Cetuximab Combo Marks the Beginning of the RAS-Targeting Era in CRC

Rona Yaeger, MD

Following promising efficacy seen in heavily pretreated patients with KRAS G12C–mutated colorectal cancer (CRC) who received combination therapy with adagrasib (Krazati) and cetuximab (Erbitux), the door is now open for a new era of targeting RAS in CRC, according to Rona Yaeger, MD.

“[The FDA approval of this combination] provides a new treatment for these patients,” Yaeger said in an interview with OncLive^®. “These patients were excluded from receiving EGFR inhibitors because of the KRASmutation, and now they have a treatment. It gives them a new line of treatment [that] is, overall, well tolerated and most patients responded very quickly [to it in the pivotal trial]. It provides a new line of therapy and hopefully a new paradigm for targeting RAS in CRC.”

Findings from the phase 1/2 KRYSTAL-1 study (NCT03785249), which supported the June 2024 approval of adagrasib plus cetuximab for adult patients with KRAS G12C–mutated locally advanced or metastatic CRC who received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, revealed that patients treated with the doublet (n = 94) achieved an overall response rate of 34% (95% CI, 25%-45%).1Additional data revealed that the median overall survival was 15.9 months (95% CI, 11.8-18.8) and no treatment-related adverse effects (AEs) led to discontinuation of adagrasib.²

In the interview with OncLive, Yaeger detailed how the doublet’s approval will push the field forward for patients with KRAS G12C–mutated CRC. Yaeger is an associate attending physician as well as a gastrointestinal medical oncologist and early drug development specialist at Memorial Sloan Kettering Cancer Center in New York, New York.

OncLive: What is the significance of this approval?

Yaeger: With this approval, we have a treatment for patients who have a KRAS G12C mutation within the colorectal tumor. Most directly, it means that those patients have a targeted therapy [option], but it also opens the door to targeting RAS, which is a big goal because KRAS mutations and NRAS mutations are common. Approximately 45% of [patients with] CRC [have KRAS mutations], and this has been a very difficult protein to target, so this is a first step. [Adagrasib] specifically targets the KRAS G12C mutation [which provides] an option for patients who have that mutation and creates a paradigm to hopefully target more RAS mutations in the future.

What was the rationale for the KRYSTAL-1 trial?

KRYSTAL-1 was a large phase 1/2 study looking at adagrasib in patients with different cancers with KRASG12C mutations; there was an expansion [cohort] for patients with CRC with adagrasib monotherapy and a cohort of patients who received the agent with cetuximab. The FDA approval is for the combination of adagrasib and cetuximab, an anti-EGFR antibody, [and] is based on data that I was lucky to be part of [in] a collaboration. We showed that there is reactivation of signaling through EGFR—inhibiting KRAS is not enough, if you block KRAS, you can still have input into the system through EGFR.

KRYSTAL-1 had some expansion cohorts to look at safety and secondarily efficacy with the monotherapy, and then for the combination with cetuximab in CRC.

What efficacy and safety findings are important to note with the doublet?

In the combined cohort, the response rate for patients [treated with] the combination of adagrasib and cetuximab was 34% [and] the median duration of response was 5.8 months. The median progression-free survival [PFS] was 6.9 months, [and patients experienced] a median survival of over a year. Those are meaningful results. Nearly all patients had clinical benefit. In this heavily treated population, the results are very meaningful.

Nothing new [was observed] in terms of the safety when the 2 drugs were combined. Cetuximab is associated most commonly with rash and can also cause diarrhea or affect some electrolytes. Those were the common AEs seen, and adagrasib can also cause some gastrointestinal toxicity. The rate of grade 3 or higher treatment-related toxicities was 27.7% in the study.

What could be done to address the unmet needs that remain for patients with KRAS G12C–mutated CRC?

For patients who have a KRAS G12C mutation, this is a great first step, and it’s great to have the treatment, but over time patients develop resistance. Resistance develops to targeted therapy in nearly all cases. It seems that resistance is largely mediated by reactivating the pathway, so the tumor can develop new alterations that activate the pathway despite [therapy with the] drug.

In terms of future needs, we have to figure out ways to address that. There may be a way to give treatment so that we can prevent or delay resistance, or perhaps there’s a way to sequence treatments or combinations. A lot of studies are looking at that, and there is a lot going on in the space [with the] development of KRAS G12C and RAS inhibitors. There will be time [spent] sorting them out [examining] how to best give the treatment, what the best combination is, and [if] are there sequential lines [that should be given]. Perhaps we can learn from lung cancer where they are able to [give] sequential lines of targeted therapy.

What are the next steps with targeted agents for this patient population?

The most important thing is that for all patients with metastatic CRC, genomic testing is [performed]. Biomarker testing can identify patients who could respond to this treatment, and you wouldn’t know if you didn’t test. [Additionally], the mutation in KRAS is important, since these drugs are selective for the KRAS G12C mutation. I’m excited to have this new combination, and I’m hopeful that we’ll be able to continue to develop [it] in the space and look at some of the other RAS mutations that are more common than KRAS G12C.

The KRAS G12C mutation [occurs in] approximately 3% to 4% of CRC cases, [and] there’s data looking at outcomes for standard treatment that suggest patients [with the mutation] may do worse [vs those without]. This provides a new treatment that’s targeted for them. I was lucky to be part of the FDA approval of adagrasib and cetuximab, and I’m excited to have that option.

There’s [also] potential for other approvals [such as with] the phase 3 CodeBreak300 trial [NCT05198934] that looked at sotorasib [Lumakras] and panitumumab [Vectibix]. Sotorasib is another KRAS G12C inhibitor, it works similarly, and it’s combined with the EGFR antibody panitumumab. That study may also lead to an approval.

References

1. FDA grants accelerated approval to adagrasib with cetuximab for KRAS G12C-mutated colorectal cancer. FDA. June 21, 2024. Accessed August 14, 2024. bit.ly/4f31swm
2. Yaeger R, Uboha NV, Pelster MS, et al. Efficacy and safety of adagrasib plus cetuximab in patients with KRASG12C-mutated metastatic colorectal cancer. Cancer Discov. 2024;14(6):982-993. doi:10.1158/2159-8290.CD-24-0217