Positive Responses Demonstrated by Adagrasib and Cetuximab in KRAS G12C-Mutant mCRC

At a longer follow-up, adagrasib with cetuximab maintained meaningful efficacy and elicited an ORR of 34%, results from the phase 1/2 KRYSTAL-1 showed.

Long-term follow-up results from the phase 1/2 KRYSTAL-1 trial (NCT03785249) shared at the 2025 Gastrointestinal Cancer Symposium reported that adagrasib (Krazati) and cetuximab (Erbitux) maintained positive and significant efficacy in heavily pretreated patients who have KRAS G12C–mutated unresectable or metastatic colorectal cancer (mCRC).

At a median follow-up of 20.4 months, updated data showed that the overall response rate (ORR) was 34% (95% CI, 25%-45%) per blinded independent central review (BICR) and 43% (95% CI, 32%-53%) when assessed by investigator review. Best overall response per BICR and investigator review, respectively, included complete response (0%; 0%), partial response (34%; 43%), stable disease (51%; 44%), progressive disease (6%; 5%), and not evaluable (9%; 9%). The disease control rate (DCR) was 85% (95% CI, 76%-92%) per BICR; the DCR was 86% (95% CI, 78%-92%) per investigator review. The median duration of response (DOR) was 5.8 months (95% CI, 4.2-8.5) per BICR; the median DOR was 5.9 months (95% CI, 5.5-7.6) per investigator review.

“With longer follow-up, adagrasib plus cetuximab continued to demonstrate clinically meaningful efficacy in heavily pretreated patients with KRAS G12C–mutated CRC,” lead study author Rona Yaeger, MD, said in a poster presentation on the data. “These updated results are consistent with those from the primary analysis and represent the longest follow-up for dual KRAS G12C/EGFR blockade in this setting.”

Yaeger is an associate attending physician and gastrointestinal medical oncologist and early drug development specialist at Memorial Sloan Kettering Cancer Center in New York.

KRYSTAL-1 Background and Trial Design

The FDA granted accelerated approval to adagrasib/cetuximab in June 2024 for the treatment of adult patients with KRAS G12C–mutated locally advanced or mCRC who were previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.²

The open-label, nonrandomized, multiple-expansion cohort phase 1/2 trial evaluated the safety and efficacy of adagrasib/cetuximab in patients with unresectable or metastatic KRAS G12C–mutated CRC.¹ Eligibility criteria included having no available treatment options with curative intent or refusing or being ineligible for standard of care treatment in phase 1 and 2; receiving previous treatment with fluoropyrimidine, irinotecan, oxaliplatin, and a VEGF/VEGFR inhibitor in phase 2; and having a ECOG performance status of 0 or 1.

In the phase 1 portion of the study, patients (n = 32) were treated with 600 mg of adagrasib twice daily plus 400 mg/m² of cetuximab, which was followed by 250 mg/m² every week or 500 mg/m² every 2 weeks administration thereafter. Patients in the phase 2 portion (n = 62) were treated with 600 mg of adagrasib twice daily plus 500 mg/m² of cetuximab every 2 weeks.

The primary end point of phase 1 was safety; secondary end points were ORR, DOR, and progression-free survival (PFS) per BICR, and overall survival (OS). The primary end point of phase 2 was ORR by BICR per RECIST 1.1 criteria; secondary end points included DOR and PFS per BICR, and safety and OS.

Patient Baseline Demographics

The median age was 57 years (range, 24-75) in the overall adagrasib/cetuximab cohort (n = 94), and women consisted of 53% of the patient population. Regarding race, 71% were White, 14% were Black or African American, and 5% were Asian; 80% identified as not Hispanic or Latino/a, 17% were Hispanic or Latino/a, and ethnicity data were missing in 3%. Patients had an ECOG performance status of 0 (51%) or 1 (49%). Prior lines of therapy included 1 (9%), 2 (36%), 3 (31%), and 4 or more (24%). Metastatic disease sites per BICR were the lung in 71% of patients and the liver in 64%. Concurrent molecular alterations included the TP53 mutation (74%), PIK3CA mutation (18%), EGFR amplification (2%), and NTRK fusion (1%).

Additional Efficacy and Safety Data

In the subgroup analysis of ORR per BICR among patients from the overall adagrasib/cetuximab cohort (n = 94), patients 65 years of age or younger had an ORR of 37% (95% CI, 25%-50%) vs those 65 years of age or older who had an ORR of 29% (95% CI, 14%-48%). The ORR in men was 32% (95% CI, 19%-48%) vs 36% (95% CI, 23%-51%) in women. The ORR at a baseline ECOG performance status of 0 was 44% (95% CI,30%-59%) compared with 24% (95% CI, 13%-39%) in those with an ECOG performance status of 1. Those with lung metastases at baseline had an ORR of 35% (95% CI, 24%-48%) compared with 32% (95% CI, 16%-52%) in those without lung metastases at baseline. Regarding patients with liver metastases at baseline, the ORR was 35% (95% CI, 23%-48%) vs 32% (95% CI, 17%-51%) in those without. Patients with positive TP53 mutation status had an ORR of 37% (95% CI, 25%-51%) vs 24% (95% CI, 8%-47%) in those with negative TP53 mutation status. Those with positive PIK3CA mutation status had an ORR of 36% (95% CI, 13%-65%) vs 32% (95% CI, 21%-44%) in those with negative PIK3CA mutation status. In patients treated with 2 or fewer prior systemic therapies, the ORR was 24% (95% CI, 12%-40%) vs 42% (95% CI, 29%-59%) in those treated with 2 or more prior systemic therapies.

The median PFS was 6.9 months (95% CI, 5.6-7.4) and 6.9 months (95% CI, 5.9-7.4) per BICR and investigator review, respectively. The 6- and 12-month PFS rates were 57% and 19%, respectively, per BICR vs the 6- and 12-month PFS rates of 61% and 19%, respectively, per investigator review. The median OS was 16.0 months (95% CI, 13.3-18.8), with 6- and 12-month OS rates of 88% and 66%, respectively.

No new safety signals were identified with longer follow-up. The most common treatment-related adverse effects (TRAEs) included nausea (any grade, 61%; grade 3/4, 2%), vomiting (any grade, 51%; grade 3/4, 0%), diarrhea (any grade, 49%; grade 3/4, 1%), dermatitis acneiform (any grade, 48%; grade 3/4, 2%), fatigue (any grade, 44%; grade 3/4, 1%), dry skin (any grade, 35%; grade 3/4, 0%), hypomagnesemia (any grade, 29%; grade 3/4, 3%), headache (any grade, 27%; grade 3/4, 3%), and rash (any grade, 22%; grade 3/4, 2%). Grade 3/4 TRAEs occurred in 28% of patients and no grade 5 TRAEs were reported. Of note, TRAEs led to dose reductions of adagrasib in 31% of patients and cetuximab in 6%. Dose interruptions of adagrasib and cetuximab because of TRAEs were required by 37% and 35% of patients, respectively. TRAEs leading to treatment discontinuations were reported in 1% of patients with adagrasib and 9% with cetuximab.

“These longer follow-up results further support the FDA approval of adagrasib/cetuximab as a standard of care in patients with previously treated KRAS G12C–mutated advanced mCRC,” Yaeger concluded in the poster presentation. “The efficacy of second-line adagrasib plus cetuximab vs chemotherapy in this patient population is currently being investigated in the phase 3 KRYSTAL-10 study [NCT04793958].”

References

1. Yaeger R, Uboha NV, Klempner SJ, et al. Adagrasib + cetuximab for KRAS G12C–mutated metastatic colorectal cancer: longer follow-up analysis from KRYSTAL-1. J Clin Oncol. 2025;43(suppl 4):131. doi:10.1200/JCO.2025.43.4_suppl.131
2. FDA grants accelerated approval to adagrasib with cetuximab for KRAS G12C-mutated colorectal cancer. FDA. June 21, 2024. Accessed January 25, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-cetuximab-kras-g12c-mutated-colorectal-cancer