Adagrasiib/cetuximab maintains efficacy in KRAS G12C mutated advanced mCRC

The addition of adagrasib to cetuximab continues to demonstrate clinically meaningful efficacy in severely pretreated KRAS, according to published long-term follow-up analysis of the Phase 1/2 KRYSTAL-1 trial (NCT03785249). Patients with G12C-mutated unresectable or metastatic colorectal cancer (mCRC) had longer follow-up.

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 based on BICR and investigator review included complete response (0%; 0%), partial response (34%; 43%), stable disease (51%; 44%), progressive disease (6%; 5%), and not evaluable (9%; 9%), respectively. The disease control rate (DCR) was 85% (95% CI, 76%-92%) based on BICR and 86% (95% CI, 78%-92%) based on investigator review. The median duration of response (DOR) per BICR was 5.8 months (95% CI, 4.2-8.5); based on investigator review, the median DOR was 5.9 months (95% CI, 5.5-7.6).

With extended follow-up, adagrasibcombination with cetuximab continued to demonstrate clinically meaningful efficacy in heavily pretreated patients with KRAS G12C-mutant CRC. These updated results are consistent with those from the preliminary analysis and represent the longest follow-up period for dual KRAS G12C/EGFR blockade in this setting.

This open-label, non-randomized, multiple expansion cohortPhase 1/2 trial evaluated the safety and efficacy of adagrasiib/cetuximab in patients with unresectable or metastatic KRAS G12C mutant CRC. Eligibility criteria included no available treatment options with therapeutic intent or refusal or ineligibility for phase 1 and 2 standard-of-care treatments; treatment with fluoropyrimidine, irinotecan, oxaliplatin, and VEGF/VEGFR inhibitors in phase 2; and having an ECOG performance status of 0 or 1.

In the first phase of the study, patients (n=32) took 600mgadagrasib twice daily, plus400 mg/m2 of cetuximab, followed by 250 mg/m2 weekly or 500 mg/m2 every 2 weeks. Patients in the phase 2 portion (n=62) received 600 mg of adagrasiib twice daily, plus 500 mg/m2 of cetuximab every 2 weeks. The primary endpoint of the first phase is safety; secondary endpoints are ORR, DOR, progression-free survival (PFS) and overall survival (OS) per BICR. The primary endpoint of Phase 2 is ORR by BICR according to RECIST 1.1 criteria; secondary endpoints include DOR and PFS according to BICR, as well as safety and OS.

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

Based on BICR and investigator review, the median progression-free survival was 6.9 months (95% CI, 5.6-7.4) and 6.9 months (95% CI, 5.9-7.4), respectively. According to BICR, progression-free survival at 6 months and 12 months was 57% and 19%, respectively, and according to investigator review, progression-free survival at 6 months and 12 months was 61% and 19%, respectively. The median OS was 16.0 months (95% CI, 13.3-18.8), and the 6-month and 12-month OS rates were 88% and 66%, respectively.

After longer follow-up, no new safety signals were identified. Most common treatment-related adverse reactions (TRAEs) include nausea, vomiting, diarrhea, acneiform dermatitis, fatigue, dry skin, and rash. Grade 3/4 TRAEs occurred in 28% of patients, and no Grade 5 TRAEs were reported. Of note, TRAEs resulted in dose reductions of adagrasib in 31% of patients and cetuximab in 6% of patients. TRAEs required dose interruption of adagrasib and cetuximab, respectively. Adverse reactions leading to treatment discontinuation were reported in 1% of adagrasib and 9% of cetuximab patients.

Reference materials:https://www.onclive.com/view/adagrasib-cetuximab-maintains-efficacy-in-kras-g12c-mutated-advanced-mcrc