A randomized phase II study of trastuzumab and pertuzumab (TP) compared to cetuximab and irinotecan (CETIRI) in advanced/metastatic colorectal cancer (mCRC) with HER2 amplification: S1613.

Abstract

TPS3620 Background: Despite advances in systemic therapy, few patients are cured, creating a large unmet need for strategies targeting novel signaling and resistance pathways. The HER2 pathway, which has been successfully targeted in breast and gastric cancer, is one such unique potential target in mCRC. HER2 amplifications (HER2amp) have been identified in a small but distinct subset (6-8%) of KRAS wild-type mCRC. HER2amp is associated with resistance to anti-EGFR therapy (cetuximab/panitumumab) and short progression-free survival (PFS) ( < 3 mos.) (Raghav ASCO 2016). Preliminary clinical data (MyPathway Study) has shown promising activity of dual-anti-HER2 inhibition using TP in HER2amp and KRAS wild-type mCRC (Response rate 52%, 95% CI 31 - 72%; and median PFS 5.7 months, 95% CI 4 – 12 mos.) (Hurwitz GIASCO 2017). Methods: S1613 is a multicenter, randomized phase 2 study assessing efficacy of TP relative to CETIRI in HER2amp mCRC. This is a 2 step study. All anti-EGFR naïve mCRC patients (pts) without known activating mutations in KRAS/NRAS/BRAF will be screened in step 1 for HER2amp by a central lab using immunohistochemistry and dual-probe in-situ hybridization. Screening can be performed at any time, even during treatment on 1st/2nd line of therapy. If HER2amp positive, pts will be randomized in step 2 after progression on 1st/2nd lines of therapy to either TP [pertuzumab (840mg loading dose + 420mg every 3 weeks) and trastuzumab (8mg/kg loading dose + 6mg/kg every 3 weeks)] or CETIRI [irinotecan (180 mg/m2 IV every 14 days) and cetuximab (500 mg/m2 IV every 14 days)]. Prior irinotecan is allowed. Crossover to TP will be allowed after progression on CETIRI arm. A total of 122 eligible patients will provide 80% power to detect an increase in median PFS to 5.1 months from 3 months (HR 0.59) based on a two-sided type I error of 5%, 33 months of accrual and 7 months of follow-up. The primary endpoint of PFS will be analyzed in all eligible patients per intent-to-treat. Randomization will be stratified by prior use of irinotecan and HER2/CEP17 ratio. The study is now activated and open to enrollment to all NCI - NCTN institutions. Clinical trial information: NCT03365882.