Trastuzumab Plus Pertuzumab Versus Cetuximab Plus Irinotecan in Patients With <i>RAS/BRAF</i> Wild-Type, HER2-Positive, Metastatic Colorectal Cancer (S1613): A Randomized Phase II Trial.

Abstract

<i>ERBB2</i> overexpression/amplification in <i>RAS/BRAF</i> wild-type (WT) metastatic colorectal cancer (mCRC; human epidermal growth factor receptor 2 [HER2]-positive mCRC) appears to be associated with limited benefit from anti-EGFR antibodies and promising responses to dual-HER2 inhibition; however, comparative efficacy has not been investigated. We conducted a randomized phase II trial to evaluate efficacy and safety of dual-HER2 inhibition against standard-of-care anti-EGFR antibody-based therapy as second/third-line treatment in HER2-positive mCRC. Patients with <i>RAS/BRAF</i>-WT mCRC after central confirmation of HER2 positivity (immunohistochemistry 3+ or 2+ and in situ hybridization amplified [HER2/CEP17 ratio >2.0]) were assigned (1:1) to either trastuzumab plus pertuzumab (TP; trastuzumab 6 mg/kg and pertuzumab 420 mg once every 3 weeks) or cetuximab plus irinotecan (CETIRI; cetuximab 500 mg/m² and irinotecan 180 mg/m² once every 2 weeks) until progression or unacceptable toxicity. Crossover to TP was allowed after progression on CETIRI. The primary end point was progression-free survival (PFS). Secondary end points included objective response rate (ORR), overall survival, safety, and <i>HER2</i> gene copy number (GCN ≥20/<20) as a predictive factor. Between October 2017 and March 2022, 54 participants were assigned to TP (n = 26) and CETIRI (n = 28). Median PFS did not vary significantly by treatment: 4.7 (95% CI, 1.9 to 7.6) and 3.7 (95% CI, 1.6 to 6.7) months in the TP and CETIRI groups, respectively. Efficacy of TP versus CETIRI differed significantly by <i>HER2</i> GCN (median PFS, GCN ≥20 [9.9 <i>v</i> 2.9 months] and GCN <20 [3.0 <i>v</i> 4.2 months], respectively; <i>P</i> interaction = .003). On TP, ORR was 34.6% (57.1% with GCN ≥20 <i>v</i> 9.1% with GCN <20) with median GCN of 29.7 versus 13.2 for responders and nonresponders, respectively (<i>P</i> = .004). Grade ≥3 adverse events occurred in 23.1% and 46.1% of participants with TP and CETIRI, respectively. TP appears to be a safe and effective cytotoxic chemotherapy-free option for patients with <i>RAS/BRAF</i>-WT, HER2-positive mCRC. Higher levels of <i>HER2</i> amplification were associated with greater degree of clinical benefit from TP vis-à-vis CETIRI.