Adagrasib (Ada) + cetuximab (Cetux) for <i>KRAS</i> ^G12C -mutated metastatic colorectal cancer (mCRC): Longer follow-up analysis from KRYSTAL-1.

Abstract

131 Background: KRAS G12C mutations occur in 3%–4% of CRC cases and are associated with poor prognosis. In the phase 1/2 KRYSTAL-1 study (NCT03785249), at a median follow-up of 11.9 months (mo), Ada (irreversible inhibitor of KRAS G12C ) in combination with Cetux (anti-EGFR antibody) demonstrated promising clinical activity (objective response rate [ORR] of 34% per blinded independent central review [BICR] and 43% per investigator [INV]) and was well tolerated in patients (pts) with previously treated KRAS G12C -mutated mCRC. Based on these findings, Ada + Cetux was granted accelerated approval in the United States for these pts. Here, we present longer-term follow-up analyses from this study. Methods: Adults with previously treated KRAS G12C -mutated mCRC and ECOG performance status of 0 or 1 were treated with Ada (600 mg BID) in combination with Cetux (400 mg/m 2 followed by 250 mg/m 2 QW or 500 mg/m 2 Q2W) until disease progression, unacceptable toxicity, withdrawal of consent, or death, in separate phase 1 and phase 2 cohorts. Primary endpoints were safety (phase 1) and ORR per BICR (phase 2). Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety (phase 2). Results: A total of 94 pts received Ada + Cetux. The median number of prior lines of systemic therapy was 3 (range, 1–9); 23 pts (24%) had received ≥ 4 prior lines of systemic therapy. The most frequent sites of metastases at baseline were the lung (71%) and liver (64%). At a median follow-up of 20.4 mo, ORR per INV was 43% (95% CI 32–53) and all were partial responses; median DOR was 5.9 (95% CI 5.5–7.6) mo. Disease control rate per INV was 86% (95% CI 78–92). Median PFS per INV was 6.9 (95% CI 5.9–7.4) mo; 6- and 12-mo PFS rates were 61% and 19%, respectively. Median OS was 16.0 (95% CI 13.3–18.8) mo; 6- and 12-mo OS rates were 88% and 66%, respectively. Any-grade treatment-related adverse events (TRAEs) were reported in 100% of pts, 28% of which were grade 3/4. TRAEs led to discontinuation in 10% of pts. Efficacy analyses by BICR, subgroup analyses, and additional safety results will be presented. Conclusions: In heavily pretreated pts with KRAS G12C -mutated mCRC, Ada + Cetux continued to demonstrate clinically meaningful activity and tolerable safety with longer follow-up. These updated results are consistent with those from the primary analysis and constitute the longest duration of follow-up for dual KRAS G12C /EGFR blockade in this setting. Efficacy of second-line Ada + Cetux vs chemotherapy in KRAS G12C -mutated mCRC is being investigated in the phase 3 KRYSTAL-10 study (NCT04793958). Clinical trial information: NCT03785249 .