Investigators Hope to Build on Early Efficacy in KRAS G12C-Mutated CRC

Christopher Lieu, MD

Investigators have explored the potential of KRAS inhibition in patients with colorectal cancer (CRC), and early results have established the pathway as a prime target for drug development. For example, sotorasib (Lumakras) monotherapy and adagrasib (MRTX849) alone or in combination with cetuximab (Erbitux) can inhibit KRAS, long thought to be an “undruggable” target.

Christopher Lieu, MD, associate director for clinical research and codirector of gastrointestinal medical oncology at the University of Colorado Cancer Center, and an associate professor of medicine-medical oncology at the University of Colorado Medicine in Aurora, discussed new developments in CRC during the 7th Annual School of Gastrointestinal Oncology^®.¹

“We’re starting to find that KRAS is druggable,” he said. “We’ve always said that KRAS is undruggable. This GTP binding of KRAS is 1000 times stronger than, say, the EGFR TKIs [tyrosine kinase inhibitors] that are approved in lung cancer. That’s why we thought that we can never really fit anything in this binding pocket to competitively inhibited but we can with G12C, and of course, there are 2 drugs now that are G12C inhibitors that have been studied and there are others that are coming on.”

In phase 1 of the CodeBreaK100 trial (NCT03600883), sotorasib, a specific, irreversible KRAS G12C protein inhibitor, showed clinical activity in KRAS G12C-mutated solid tumors, including CRC. In phase 2 of the trial, investigators enrolled adult patients with KRAS G12C-mutated advanced solid tumors from 59 medical centers in 11 countries.²

Eligible patients had at least 1 measurable lesion per RECIST 1.1 criteria and an ECOG performance status of 1 or lower. All patients in the trial progressed after receiving fluoropyrimidine, oxaliplatin, and irinotecan treatment.

Patients received once daily oral sotorasib at 960 mg until disease progression, development of unacceptable adverse effects, withdrawal of consent, or death. The primary end point was objective response rate (ORR) as assessed by blinded independent central review.

Among the 62 patients who received at least 1 dose of sotorasib monotherapy as of the March 1, 2021, data cutoff, 9.7% (95% CI 3.6%-19.9%) had an objective response, all of which were partial responses (PRs).

“What you’re seeing is modest activity, right?” Lieu said. “[We saw] progression-free survival [PFS] of 4 months, overall survival of 10 months, with a response rate of [approximately] 10%, but there is some activity here.”

Six (10%) patients experienced grade 3 treatment-related adverse events (TRAEs), most often diarrhea (3%). One (2%) patient experienced grade 4 blood creatine phosphokinase increase. Investigators did not observe any fatal events. Two patients experienced serious TRAEs, 1 incident of back pain and 1 incident of acute kidney injury.

The other promising KRAS inhibitor Lieu discussed was adagrasib (MRTX849). In the phase 1/2, multiarm KRYSTAL-1 trial (NCT03785249), investigators assigned patients with previously treated KRAS G12C-mutated CRC to 600 mg daily adagrasib monotherapy or adagrasib plus 400 mg/m² cetuximab. End points include safety, pharmacokinetics, and clinical activity.³

As of the May 25, 2021, data cutoff, 45 patients who received the monotherapy were evaluable for efficacy. The ORR in the monotherapy arm was 22%, including 1 unconfirmed PR who remains on study. The disease control rate (DCR) was 87%. Median duration of response (DOR) was 4.2 months, and the median PFS was 5.6 months.

As of the July 9, 2021, data cutoff, 28 of 32 patients assigned to adagrasib plus cetuximab were evaluable for efficacy. The ORR was 43% including 2 unconfirmed partial responses who remain on study. The DCR was 100%.

“[This is a] small study,” Lieu said. “We’re only taking a look at 28 patients here, but the response rate of 43% is significantly improved. And this is the combination regimen that we’re going to see move forward [in] future studies.”

Investigators are currently evaluating the combination in the second-line setting in a phase 3 trial of patients with KRAS G12C-mutant CRC (NCT04793958).

Despite the early signals of success in CRC, the 2 agents approved and under review for non–small cell lung cancer (NSCLC) indications. In May 2021, the FDA granted an accelerated approval to sotorasib for the treatment of advanced KRAS G12C–mutant NSCLC based on results from the CodeBreaK 100 trial. Patients who had progressed following treatment with an immunotherapy and/or chemotherapy assigned to 960 mg daily oral sotorasib had an ORR of 36% (95% CI, 28%-45%).⁴

In February 2022, the FDA accepted a new drug application for adagrasib for patients with KRAS G12C-mutated NSCLC who have previously received at least 1 prior systemic therapy.⁵ In topline results from the NSCLC cohort of KRYSTAL-1, twice-daily adagrasib induced an ORR of 43% and a DCR of 80%. The Prescription Drug User Fee Action date is December 14, 2022.⁶

Lieu noted that, just a decade ago, physicians treating CRC had only a handful of treatment options and even fewer genomic markers. “It would be just have been KRAS and we would have sat here and talked about it for about 20 minutes and called it a day.”

Today, oncologists have 15 FDA-approved agents to choose from and more than a dozen markers to target. Genomic information is invaluable in newly diagnosed patients, he said, but it is also important later. Lieu implored his audience to conduct genomic testing on their patients.

“There are others in this audience who have actually reported on the biomarker testing rates,” he said. “And even now we’re still looking at percentages in the 60% to 70%. [Genomic testing is] still not being done early and often enough.”

References

1. Liu C. Novel targeted therapies in refractory mCRC: a target-rich environment? Presented at 7th Annual School of Gastrointestinal Oncology; March 26, 2022. Accessed April 12, 2022. bit.ly/3LLQDiC
2. Fakih MG, Kopetz S, Kuboki Y, et al. Sotorasib for previously treated colorectal cancers with KRASG12C mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial. Lancet Oncol. 2022;23(1):115-124. doi:10.1016/S1470-2045(21)00605-7
3. Weiss J, Yaeger RD, Johnson ML, et al. KRYSTAL-1: Adagrasib (MRTX849) as monotherapy or combined with cetuximab (Cetux) in patients (Pts) with colorectal cancer (CRC) harboring a KRASG12C mutation. Ann Oncol. 2021;32(suppl_5): S1283-S1346. doi: 10.1016/annonc/annonc741
4. FDA approves first targeted therapy for lung cancer mutation previously considered resistant to drug therapy. News release. FDA; May 28, 2021. Accessed April 7, 2022. bit.ly/3c172Ah
5. US Food and Drug Administration (FDA) accepts Mirati Therapeutics’ new drug application for adagrasib as treatment of previously treated KRASG12C-mutated non-small cell lung cancer. News release. Mirati Therapeutics, Inc; February 15, 2022. Accessed April 7, 2022. prn.to/3HWi0oJ
6. Mirati Therapeutics announces positive phase 2 topline results for investigational adagrasib in patients with KRAS G12C-mutated advanced non-small cell lung cancer. News release. Mirati Therapeutics, Inc; September 20, 2021. Accessed April 7, 2022. bit.ly/3HWGZYY