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
Kanwal Raghav, Katherine A. Guthrie, Benjamin Tan, Crystal S. Denlinger, Marwan Fakih, Michael J. Overman, Arvind Dasari, Larry Corum, Lee G. Hicks, Mital Patel, Benjamin Esparaz, Syed Mohammad Ali Kazmi, Nitya Alluri, Sarah Colby, Sepideh Gholami, Philip J. Gold, E. Gabriela Chiorean, Scott Kopetz, Howard S. Höchster, Philip A. Philip
Abstract
PURPOSE ERBB2 overexpression/amplification in RAS/BRAF 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. METHODS Patients with RAS/BRAF -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/m 2 and irinotecan 180 mg/m 2 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 HER2 gene copy number (GCN ≥20/<20) as a predictive factor. RESULTS 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 HER2 GCN (median PFS, GCN ≥20 [9.9 v 2.9 months] and GCN <20 [3.0 v 4.2 months], respectively; P interaction = .003). On TP, ORR was 34.6% (57.1% with GCN ≥20 v 9.1% with GCN <20) with median GCN of 29.7 versus 13.2 for responders and nonresponders, respectively ( P = .004). Grade ≥3 adverse events occurred in 23.1% and 46.1% of participants with TP and CETIRI, respectively. CONCLUSION TP appears to be a safe and effective cytotoxic chemotherapy-free option for patients with RAS/BRAF -WT, HER2-positive mCRC. Higher levels of HER2 amplification were associated with greater degree of clinical benefit from TP vis-à-vis CETIRI.