DESTINY-CRC01 study discussant, Michael S. Lee, MD, Assistant Professor of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, called the findings “most promising” for the subsequent anti-HER2 treatment of HER2-positive metastatic colorectal cancer.
Michael S. Lee, MD
The response rate to fam-trastuzumab deruxtecan-nxki (T-DXd), he added, “looked similar” to data from previous single-arm phase II studies of other anti-HER2 approaches in chemotherapy-refractory patients, including trastuzumab/lapatinib (30%), trastuzumab/pertuzumab (25%–40%), and trastuzumab/tucatinib (52%). Progression-free survival was also similar. Responses to other options—regorafenib and tipiracil/trifluridine—have been much lower, less than 3%, and median progression-free survival has been up to 2 months.
Current Benefit Limited to Patients With RAS Wild-Type, HER2-Amplified Disease
Dr. Lee noted that T-DXd’s activity was shown in patients with refractory RAS wild-type disease, including those with prior anti-HER2 therapy, but not in HER2-low disease. He noted that HER2 positivity is enriched among patients RAS wild-type disease, among whom it comprises 5% to 12% of patients. It is not yet known if the drug is active in the 20% to 25% of HER2-positive disease that is RAS-mutant; therefore, its use is not supported in this subset, he said. The strongly positive group (reflected by cohort A in this trial) constitutes just about 3% of patients.
Some of the questions related to the treatment of patients with HER2-amplified metastatic colorectal cancer will be addressed in the ongoing SWOG S1613 trial, which is evaluating trastuzumab plus pertuzumab. For now, Dr. Lee recommends that HER2-amplified patients enroll in a clinical trial or be treated with a HER2-targeting option as recommended by consensus guidelines from the NCCN, though not yet approved by the U.S. Food and Drug Administration; however, he does acknowledge this could pose regulatory and financial issues.
Additional Commentary
Autumn McRee, MD
Highlights Session speaker Autumn McRee, MD, also of Lineberger Comprehensive Cancer Center, said the DESTINY-CRC01 data have raised the question of “whether a HER2-specific approach is superior to what we would offer to these patients in the standard-of-care setting.”
Dr. McRee continued: “It’s still to be determined how to sequence HER2-targeted therapies and whether an antibody-drug conjugate should be considered as a rescue strategy after trastuzumab vs a first-line therapy. There is also the debate over how to approach patients with RAS-mutated tumors and whether we should even consider them for HER2-targeted therapies.”
Questions aside, Dr. McRee concluded: “Without a doubt, this trial is clinically relevant…. It’s important not to miss these patients; they are rare and perhaps more common in the RAS wild-type patient population. However, I would argue that testing for HER2 amplification in colorectal cancer should be considered standard of care."
DISCLOSURE: Dr. Lee has received travel support from Genentech/Roche and institutional research support from several companies. Dr. McRee has received honoraria from Cor2Ed and OncLive, travel funding from Cor2Ed, and research funding from various companies.
