Adagrasib With Cetuximab Moves Into Phase 3 for KRAS G12C–Mutated CRC

Rona Yaeger, MD

Targeted treatment with adagrasib (MRTX849) monotherapy and combination therapy with cetuximab (Erbitux) has shown promise when treating patients with KRAS G12C–mutated colorectal cancer (CRC) according to Rona Yaeger, MD.

Investigators of the phase 3 KRYSTAL-10 (NCT04793958) trial seek to build on early efficacy observed with the dual blockade of KRAS G12C and EGFR in patients who have disease progression following standard firstline therapy. Safety data showed that the combination is tolerable with the most frequent treatment-related adverse events including nausea (63%), diarrhea (56%), vomiting (53%), dermatitis acneiform (47%), fatigue (47%), and dry skin (41%).

“The rationale for the combination is that in CRC we have a high level of basal RTK activation, particularly EGFR, [therefore] treatment with adagrasib or any KRAS G12C inhibitor is likely limited by the activation of these receptors. The idea is by [administering] cetuximab you may inhibit with adagrasib KRAS G12C signaling and then inhibit the reactivation of EGFR and so any rebound in signaling,” Yaeger said.

In an interview with OncologyLive^®, Yaeger, an associate attending physician at Memorial Sloan Kettering Cancer Center in New York, New York, discussed the unmet needs for patients with KRAS G12C mutations and the promising combination therapy of adagrasib and cetuximab.

What is important to know about patients with CRC who progress on a first-line chemotherapy regimen?

Patients with metastatic CRC are treated with a combination of chemotherapy and if appropriate targeted therapies. Patients who have a KRAS mutation are precluded from receiving targeted therapies right now. In terms of subsequent lines of treatment after progression on chemotherapy, they have fewer options and so the patients with KRAS G12C mutations are in need of another treatment.

What is the biggest unmet need in this patient population?

KRAS G12C mutations occur in approximately 3% to 4% of CRC [cases and] [up to] approximately 50% of CRCs have an activating mutation in the RAS genes, either KRAS or NRAS. The frequency is higher for right-sided colon tumors and is a lower on the left side, but overall, it’s nearly 50% and a small portion of those are the KRAS G12C mutations. There’s been a lot of data over the years looking at the prognostic significance of having mutations in the RAS genes and the overall thought is that it’s a modest poor prognostic factor.

Now there’s more of an interest on KRAS G12C because of potential to target it with new drugs. There have been studies that have looked at whether the presence of this mutation affects prognosis. Investigators have looked retrospectively at patients with metastatic disease and those who have a tumor KRAS G12C mutation compared with other KRAS mutations appear to have shorter overall survival [OS] and shorter [time to] progression. In that sense, there’s clearly a need for new therapies and there’s a need for ideally something matched, which is what we’re trying to develop.

These patients can get standard chemotherapy, but they have no targeted treatment and, in some sense, they’re missing a potential for therapy. Now that there are new drugs which are selective for the KRAS G12C mutation, [we] have the potential to give a matched treatment.

What is the mechanism of action of adagrasib?

Adagrasib a selective KRAS G12C inhibitor. KRAS is like a switch in that when it is bound to GTP it is active and when it is bound to GDP is inactive. Adagrasib and the other KRAS G12C inhibitors that are now moving through clinical trials or being used in the clinic are designed to take advantage of the cysteine to bind to the G12C. Adagrasib binds covalently and traps KRAS when it is in the inactive state and by doing that it prevents its activation and the reactivation of KRAS.

These drugs take advantage of the natural cycling of KRAS. There is some natural cycling from the active GTP bound state to the GDP bound state and when KRAS G12C is in the GDP bound state if drug is around it, it can trap it in that state. Adagrasib has a longer half-life of approximately 23 hours; it is given twice daily with the idea of [providing] continuous inhibition of KRAS G12C and to prevent the formation of new, active KRAS molecules. It has central nervous system [CNS] penetration and has been shown to have some activity in tumors with CNS spread such as lung cancer, where we see that more commonly.

What has been observed with adagrasib in combination with cetuximab in this patient population in KRYSTAL-1?

KRYSTAL-1 [NCT03785249] is a phase 1/2 study that has looked at adagrasib alone and in multiple combinations. More mature data were recently reported at the European Society for Medical Oncology [Annual Congress 2022] for the monotherapy cohort as well as the cohort [examining adagrasib in] combination with cetuximab in CRC. In the [phase 2] monotherapy cohort they treated 44 patients and 43 were valuable for a response with an objective response rate of 19% and median PFS [progression-free survival] of 5.6 months.¹

The combination was tested in a phase 1b cohort [where] 32 patients were treated; 28 of them were evaluable for response with a response rate of 46%, 100% disease control rate, and a median PFS of 6.9 months. The activity of the combination is very encouraging and that sets the stage for the potential to develop this further. If you look at targeted therapy in general and in CRC, I think it stacks quite well [with the progress we’ve seen]. We’ve been through this recently for BRAF V600E–mutated CRCs where we see that adding an EGFR antibody improves the activity [of targeted agents] rather than just inhibiting the activated oncogene. When we look at the activity that we’re seeing with KRAS G12C inhibitors, the combination of these drugs with EGFR inhibitors is very encouraging in the context of what we see with targeted therapies for CRC.

Can you expand on the design of the KRYSTAL-10 study and the overall trial objectives?

KRYSTAL-10 is a [phase 3] study looking at [adagrasib and cetuximab] in the secondline setting for patients who have metastatic KRAS G12C–mutated CRC; the KRAS G12C mutation is detected in tissue.

Patients [must] have received first-line treatment with a fluoropyrimidine containing doublet. They are then randomly assigned 1:1 to receive either cetuximab and adagrasib or the fluoropyrimidine containing doublet [they did not previously receive]—mFOLFOX6 or FOLFIRI or vice versa—with an anti-VEGF agent per investigator discretion. The primary end points are PFS and OS; this is really looking to compare adagrasib and cetuximab to standard treatment, but it’s taking place in the second line.

Thinking about recruitment, first, patients need to know their KRAS status and to know if they have a KRAS G12C mutation. It would take many patients to find a large portion of KRAS G12C, but all patients should have KRAS testing done. Being aware of this [is important] prior to the secondline setting. [Clinicians should] not wait until after patients have progressed through all therapies and then look for trials.

Second, patients will have to have had received a fluoropyrimidine containing doublet [in the first-line setting], but some patients may have received triplet therapy, such as FOLFOXIRI. Those patients are not eligible because the goal is to compare standard fluoropyrimidine containing doublet to the targeted therapy.

Patients need to have tissue sequencing results available, but they can do central testing for screening or for confirmation if screening is done locally. The study is open and enrolling internationally.

What main message about KRAS G12C mutations in CRC would you like to impart to colleagues?

This is really exciting; the idea of KRAS being targetable is a whole paradigm shift. It’s a huge deal and in the data we have now, we can see that many patients can benefit from these drugs. Hopefully they will be developed further, and we’ll see [more positive] results in the KRYSTAL-10 study.

What I would like clinicians to take from this is to be alert, to look at the sequencing results for patients, [and] if patients do have a KRAS G12C mutation to consider them for clinical trials and be able to connect them with clinical trials so they have the potential to receive targeted therapies.

Reference

Klempner SJ, Weiss J, Pelster M, et al. KRYSTAL-1: updated efficacy and safety of adagrasib (MRTX849) with or without cetuximab in patients with advanced colorectal cancer (CRC) harboring a KRASG12C mutation. Ann Oncol. 2022;33(suppl 7):S1391. doi:10.1016/ j.annonc.2022.08.020