HER2-expressing metastatic colorectal cancer: Assessing trastuzumab deruxtecan

An initial report of patients with heavily pre-treated metastatic HER2-expressing colorectal cancer shows particularly efficacy with trastuzumab deruxtecan in patients with high HER2-positivity.

In an initial report of patients with heavily pre-treated metastatic HER2-expressing colorectal cancer, preliminary efficacy was observed with trastuzumab deruxtecan, particularly in patients with the highest degree of HER2-positivity.

Prof. Salvatore Siena (University of Milan's Niguarda Cancer Center, Italy) presented results from the DESTINY-CR101 study, which stratified 3 cohorts of patients [1]. Cohort A had HER2-overexpressing patients who had scores of 3 or higher according to immunohistochemistry testing (IHC 3 plus), as well as a score above 2 by in-situ hybridization (ISH). Cohort B were patients whose tumors were IHC 2 and above but were ISH-negative; cohort C were patients whose tumors were IHC >1. All patients (n=90) enrolled in the trial had tumors that were RAS/BRAF-wildtype and expressed HER2. A single patient had an NRAS mutation. All had received at least two prior lines of therapy, including other HER2-targeting agents such as trastuzumab. Patients had a median of 4 prior therapies.

The primary endpoint of this study was overall response rate (ORR), which was 45.3%. A single patient had a complete response to the treatment and 23 patients had partial responses. Additionally, 20 patients achieved stable disease, resulting in an overall 83% control rate. In cohorts B and C, there were no confirmed responses. The median progression-free survival for patients in cohort A was 6.9 months, although neither the median duration of response nor the median overall survival was reached.

Prof. Siena noted that the absence of any responses in the two cohorts with low HER2 expression suggests that the promising durable activity seen with trastuzumab deruxtecan is likely restricted to those with high levels of HER2 expression.

Testing patients to guide precision treatment strategies is becoming standard practice in mCRC, including mutation screening for KRAS/RAS and BRAF, HER2 amplification, mismatch repair deficiency/microsatellite instability, and NTRK fusions. Although preliminary, these data may indicate the importance of testing for HER2 expression as well in patients with metastatic colorectal cancer.

1. Siena S, et al. A phase II, multicenter, open-label study of trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): DESTINY-CRC01. ASCO Virtual Meeting, 29-31 May 2020, Abstract 4000.