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.

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.

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 with 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 (cohort A) 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

Highlights Session speaker Autumn McRee, MD, also of Lineberger Comprehensive Cancer Center, said these 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.”

Autumn McRee, MD

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.