Second-line treatment with adagrasib plus cetuximab demonstrates manageable safety but results in no statistically significant improvement in both progression-free (PFS) and overall survival (OS) in previously treated patients with KRAS G12C-mutated metastatic colorectal cancer (mCRC) compared with chemotherapy, results of the KRYSTAL-10 trial have shown.
A total of 461 patients were randomized to receive adagrasib 600 mg twice daily plus cetuximab 500 mg/m2 every 2 weeks (n=231) or chemotherapy (FOLFIRI or mFOLFOX6 ± VEGF/VEGFR inhibitors; n=230), with one and 24 patients withdrawing before receiving treatment, respectively. At 26.4 months of follow-up for OS, 17 patients (7 percent) in the adagrasib plus cetuximab group remained on treatment.
At data cutoff, 206 patients treated with chemotherapy stopped treatment, while 89 (43 percent) discontinued their entire study regimen without radiographic progression, according to lead author Dr Josep Tabernero, Vall d’Hebron Hospital Campus & Institute of Oncology, Barcelona, Spain.
Some 156 patients (68 percent) in the adagrasib plus cetuximab group and 163 (71 percent) in the chemotherapy group received subsequent anticancer therapy. A significantly greater proportion of patients in the chemotherapy group received subsequent KRASG12C inhibitors (4 percent vs 30 percent).
Survival
The dual primary endpoints of PFS and OS did not significantly differ between the adagrasib plus cetuximab group and the chemotherapy group. The median PFS was 7.5 vs 8.1 months (hazard ratio [HR], 0.89, 95 percent confidence interval [CI], 0.71‒1.13; p=0.3241), while the median OS was 21.6 vs 21.7 months (HR, 0.83, 0.67‒1.03; p=0.0938), respectively. [ESMO GI 2026, abstract LBA1]
Notably, patients treated with adagrasib plus cetuximab had higher objective response rate (47 percent vs 16 percent), with higher complete response rates (7 percent vs <1 percent) than those who received chemotherapy.
“Together, while KRYSTAL-10 did not meet its primary endpoints, these results support the clinical activity of the adagrasib plus cetuximab combination therapy in previously treated patients with KRAS G12C-mutated mCRC,” Tabernero said.
Safety profile
Any-grade treatment-related treatment-emergent adverse events (TEAEs) occurred in 225 (98 percent) patients in the adagrasib plus cetuximab group and in 198 (96 percent) patients in the chemotherapy group. Grade 3‒5 TEAEs were reported in 105 (46 percent) and 113 (55 percent), respectively.
Six (3 percent) patients treated with adagrasib plus cetuximab and four (2 percent) with chemotherapy discontinued regimen due to any-grade TEAE, with one death recorded in the chemotherapy group.
The most common treatment-related TEAEs in the adagrasib plus cetuximab group were diarrhoea (n=146, 64 percent), nausea (n=103, 45 percent), dermatitis acneiform (n=97, 42 percent), vomiting (n=72, 31 percent), rash (n=68, 30 percent), and dry skin (n=59, 26 percent).
Other TEAEs included fatigue (n=55, 24 percent), decreased appetite (n=51, 22 percent), AST increased (n=50, 22 percent), ALT increased (n=48, 21 percent), pruritus (n=35, 15 percent), stomatitis (n=19, 8 percent), decreased neutrophil count (n=3, 1 percent), and neutropenia (n=2, 1 percent).
“Safety of adagrasib plus cetuximab was manageable, and no new safety signals were observed,” Tabernero said.
Limitations
High informative censoring due to initiation of subsequent therapies prior to blinded independent central review confirmation limited the interpretation of PFS, and the higher proportion of chemotherapy-treated patients receiving subsequent KRAS G12C inhibitors may have confounded OS outcomes, according to Tabernero.
Moreover, the “[o]pen-label design may have introduced bias in efficacy assessment, [and] treatment discontinuation was disproportionately higher in the chemotherapy group,” he added.