Effect of prior anti-EGFR therapy and baseline ctDNA profiling on the efficacy of pertuzumab plus trastuzumab in HER2-amplified metastatic colorectal cancer: an integrated analysis of TRIUMPH/MyPathway.
Matsubara Y., Wakabayashi M., Okamoto W., Kato T., Esaki T., Kato K., Komatsu Y., Masuishi T., Nishina T., Bando H., Misumi T., Fukui M., Matsuda S., Ikeda Y., Malato J., Schulze K., Price R., Sato A., Yoshino T., Nakamura Y.
BACKGROUND: HER2-amplified metastatic colorectal cancer (mCRC) is a clinically relevant subgroup for HER2-targeted therapy. The TRIUMPH and MyPathway studies demonstrated the activity of pertuzumab plus trastuzumab (PER + TRA) in that population. Our integrated analysis assessed the effect of prior anti-epidermal growth factor receptor (EGFR) therapy on PER + TRA efficacy and explored the role of baseline circulating tumor DNA (ctDNA) profiling. MATERIALS AND METHODS: The analysis enrolled patients with HER2-amplified mCRC from TRIUMPH and MyPathway who had baseline ctDNA available. Anti-EGFR resistance alterations were defined as RAS, BRAF, or PIK3CA mutations; EGFR ectodomain mutation; or MET amplification. Clinical outcomes with PER + TRA were analyzed in patients who had tissue-based RAS wild-type tumors, stratified by prior anti-EGFR therapy and the presence of resistance alterations. RESULTS: Of 66 enrolled patients, 47 had received prior anti-EGFR therapy. Prior anti-EGFR therapy was associated with inferior overall survival (OS) [median: 10.9 versus 19.7 months; hazard ratio (HR): 2.01] and numerically shorter progression-free survival. ctDNA profiling identified anti-EGFR resistance alterations in 18 patients (27.3%), with an associated absence of objective response (0% versus 31.3%) and a significantly shorter OS (median: 7.6 versus 16.5 months; HR: 2.15). Outcomes were markedly poorer (including shorter OS and lower response rates) in patients with either prior anti-EGFR therapy or resistance alterations than in patients with neither factor. CONCLUSIONS: Prior anti-EGFR therapy and resistance alterations detected by baseline ctDNA profiling are associated with reduced efficacy of PER + TRA in HER2-amplified mCRC. Integrating treatment history with baseline ctDNA profiling might enable improved patient selection for dual HER2-targeted therapy.