Among heavily pretreated patients with KRAS G12C-mutant unresectable or metastatic colorectal cancer (mCRC), the combination of Krazati (adagrasib) and Erbitux (cetuximab) has shown clinically meaningful efficacy, as displayed by longer-term follow-up analysis from the phase 1/2 KRYSTAL-1 trial presented at the 2025 Gastrointestinal Cancers Symposium.
At a median follow-up of 20.4 months, updated data showed that the overall response rate (ORR) was 34% per blinded independent central review (BICR) and 43% 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% per BICR; the DCR was 86% (per investigator review. The median duration of response (DOR) was 5.8 months per BICR; the median DOR was 5.9 per investigator review.
“With longer follow-up, [Krazati] plus [Erbitux] continued to demonstrate clinically meaningful efficacy in heavily pretreated patients with KRAS G12C–mutated CRC,” lead study author Dr. Rona Yaeger 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 Krazati/Erbitux 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.
The open-label, nonrandomized, multiple-expansion cohort phase 1/2 trial evaluated the safety and efficacy of Krazati/Erbitux in patients with unresectable or metastatic KRAS G12C–mutated CRC. 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 (32 patients) were treated with 600 milligrams (mg) of Krazati twice daily plus 400 mg/m2 of Erbitux, which was followed by 250 mg/m2 every week or 500 mg/m2 every two weeks administration thereafter. Patients in the phase 2 portion (62 patients) were treated with 600 mg of Krazati twice daily plus 500 mg/m2 of Erbitux every 2 weeks.
Patient Baseline Demographics
The median age was 57 years in the overall Krazati/Erbitux cohort (94 patients), 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 one (9%), two (36%), three (31%) and four 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 Krazati/Erbitux cohort (94 patients), patients 65 years of age or younger had an ORR of 37% versus those 65 years of age or older who had an ORR of 29%. The ORR in men was 32% versus 36% in women. The ORR at a baseline ECOG performance status of 0 was 44% compared with 24% in those with an ECOG performance status of 1. Those with lung metastases at baseline had an ORR of 35% compared with 32% in those without lung metastases at baseline. Regarding patients with liver metastases at baseline, the ORR was 35% versus 32% in those without. Patients with positive TP53 mutation status had an ORR of 37% versus 24% in those with negative TP53 mutation status. Those with positive PIK3CA mutation status had an ORR of 36% versus 32% in those with negative PIK3CA mutation status. In patients treated with two or fewer prior systemic therapies, the ORR was 24% versus 42% in those treated with two or more prior systemic therapies.
The median progression-free survival (PFS) was 6.9 months and 6.9 months 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 months, 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 side effects included nausea (any grade, 61%; grade 3 (severe)/4(life-threatening), 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 treatment-related side effects occurred in 28% of patients and no grade 5 (fatal) treatment-related side effects were reported. Of note, treatment-related side effects led to dose reductions of Krazati in 31% of patients and Erbitux in 6%. Dose interruptions of Krazati and Erbitux because of treatment-related aide effectw were required by 37% and 35% of patients, respectively. Treatment-related side effects leading to treatment discontinuations were reported in 1% of patients with Krazati and 9% with Erbitux.
“These longer follow-up results further support the FDA approval of [Krazati]/[Erbitux] 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 [Krazati] plus Erbitux versus chemotherapy in this patient population is currently being investigated in the phase 3 KRYSTAL-10 study.”
Reference:
“Adagrasib + cetuximab for KRAS G12C–mutated metastatic colorectal cancer: longer follow-up analysis from KRYSTAL-1” by Dr. Rona Yaeger et al., J Clin Oncol.
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