Why It Works
In an interview, MOUNTAINEER coinvestigator Tanios S. Bekaii-Saab, MD, from the Mayo Clinic Comprehensive Cancer Center in Phoenix, Arizona, explained why dual HER2 blockade with tucatinib and trastuzumab is an important breakthrough for this population.
“HER2 as a target was already well established in breast cancer and in gastric cancer. In colon cancer we had signals [of anti-HER2 efficacy] but these signals were primarily with dual targeted therapy,” he said.
“What’s unique about tucatinib versus neratinib [Nerlynx], lapatinib [Tykerb] and some of the others is that this is a highly selective tyrosine kinase inhibitor, meaning it is potent just against HER2 and has limited activity against other receptors, classically EGFR, which also goes by the name of HER1,” said MOUNTAINEER trial chair John H. Strickler, MD, of Duke Cancer Center in Durham, North Carolina.
“The reason why that’s valuable is that when you inhibit other receptors like HER1 or EGFR, you can cause significant skin rash and other symptoms that can limit tolerability, which limits your ability to give the full dose. With tucatinib you can more completely inhibit HER2 with fewer side effects,” Dr. Strickler said in an interview.
Dr. Raghav noted that the primary adverse events of therapy with tucatinib have been diarrhea and fatigue, and other common side effects include abdominal pain, fever, nausea, rash, and infusion reactions.
Barriers to Treatment
Dr. Barzi pointed out that in the day-to-day practice setting there are two potential barriers to treatment with tucatinib and trastuzumab for patients with HER2-positive colorectal cancer, hurdles that they would not encounter if they were enrolled in clinical trials.
The first barrier is the requirement for HER2 testing, either through immunohistochemistry or fluorescence in situ hybridization.
“The adoption of HER2 testing in colorectal cancer lags behind other molecular testing, such as testing for KRAS or BRAF, so the provider needs to be aware that HER2 positivity is a possibility,” she said.
The second and more difficult-to-surmount barrier is imposed by the healthcare system. Although the combination is included in National Comprehensive Cancer Network guidelines and, therefore, should not be subject to restrictions or denials by insurers, “the challenge is that this is an oral and IV drug combination,” Dr. Barzi said.
While patients in real-world settings receive intravenous drugs such as trastuzumab in treatment centers, the oral drug component, tucatinib, is dispensed by pharmacies, and patients are often required to shell out high copays for such agents.
Dr. Barzi cited as an example the case of one of her patients who was receiving an oral agent — not tucatinib — for treatment of a different type of colorectal cancer.
“He has very good insurance, and after insurance his out-of-pocket cost on a monthly basis to obtain the drug is $275,” she said.
What’s Next
In colorectal cancer the combination of tucatinib and trastuzumab is approved only in the metastatic setting, but it is also being explored as a first-line therapy in combination with the mFOLFOX6 regimen (5-Fluorouracil, leucovorin, and oxaliplatin) in the MOUNTAINEER-03 trial, which is currently recruiting.
MOUNTAINEER was sponsored by Seagen and Merck. Dr. Strickler reported support from Seagen for the Lancet Oncology manuscript; institutional grants, consulting fees, and travel support from Seagen, and similar relationships with other companies. Dr. Bekaii-Saab reported institutional research and consulting fees from various companies, including Merck, personal consulting fees from various companies, and independent monitoring board/scientific advisory board activities. Dr. Raghav disclosed honoraria and an advisory/consulting role for Seagen and others. Dr. Barzi reported no relevant conflicts of interest.