Trastuzumab combined with irinotecan in patients with HER2-positive metastatic colorectal cancer: A phase II multicenter single-arm study and exploratory biomarker analysis.
Authors: Ting Xu, Xicheng Wang, Ying Xin, Zhenghang Wang, Yakun Wang, Changsong Qi, Dan Liu, Yanyan Li, Jifang Gong, Jian Li, Depei Huang, Lin Shen
Journal: Journal of Clinical Oncology (2022)

301 Background: HER2 overexpression has proven to be an effective treatment target in several malignancies. Trastuzumab plus chemotherapy showed favorable clinical efficacy and safety in HER2-positive gastric cancer and breast cancers. In this study, we aimed to evaluate the antitumor activity of trastuzumab plus irinotecan in pretreated patients with HER2-postive unresectable metastatic CRC and explore biomarkers for response and resistance to this treatment. Methods: mCRC patients with confirmed HER2 positivity (defined as IHC3+ or IHC2+/FISH+ on archival tissue) and wild-type RAS gene that progressed after ≥ 1 prior systemic treatment were enrolled in this phase II clinical trial. Patients received trastuzumab (6mg/kg q3w) plus irinotecan (120mg/m2, d1,8 q3w) for the first six cycles and trastuzumab (6mg/kg q3w) as maintenance treatment sequentially. Primary end point is objective response rate (ORR) and secondary endpoints are progression-free survival (PFS) and safety. Pretreatment tumor tissue, plasma at baseline and after disease progression were collected and analysed using a customized NGS panel covering 733 cancer-related genes in a CAP/CLIA-approved laboratory (3DMed). Results: Between June 2019 and December 2020, 21 HER2 positive patients were enrolled, with median age 55(30-67). At data cutoff (August 1, 2021), six (28.6%) of 21 patients achieved a partial response, and 12 (57.1%) patients had stable disease. The median progression-free survival was 4.3 months (95% CI, 2.65 to 5.95 months). Treatment-related adverse events of grade 3 or 4 occurred in 9.5% of patients, with the most common being neutropenia. No treatment-related death was reported. HER2 3+ expression and higher tumor tissue HER2 copy number were associated with durable response (p for PFS = 0.09 and 0.019, respectively). Two patients with KRAS amplification and one patient with BRAF amplification and fusion mutation at baseline all experienced primary resistance. In the after-progression plasma samples, heterogeneous and complicated genomic alterations potentially contribute to the acquired resistance were observed, with RAS/MAPK pathway (n = 4), cyclin/CDK-RB-E2F pathway (n = 4), PI3K/AKT/mTOR pathway (n = 3), and HER2 gene (n = 1) involved. Intriguingly, except for the SNV, copy number variation and gene fusion may represent an important resistance mechanism of HER2 targeted therapy. Conclusions: Trastuzumab plus irinotecan showed promising efficacy and well tolerated safety profile in HER2-positive mCRC. This combination therapy might present a feasible option for patients with HER2-positive unresectable metastatic colorectal adenocarcinoma. ctDNA sequencing provides novel insights into genomic alteration underlying HER2 targeted therapy in HER2-positive mCRC. Clinical trial information: NCT03185988.