CHICAGO: In two medium-term trials, new targeted therapies have demonstrated degrees of activity opposite to HER2-positive bile duct cancers in pretreated patients with complex diseases.
Cohort 1 of the HERIZON-BTC-01 study, which included 80 treatment-refractory patients, showed that 41. 3% (95% CI 30. 4-52. 8) responded to zanidatamab, an investigational bispecific monoclonal antibody that targets two different HER2 epitopes, according to Shubham Pant, MD, of MD Anderson Cancer Center in Houston.
And in a smaller study, the HER2-targeting strategy of tucatinib (Tukysa) plus trastuzumab elicited responses in 46. 7% (90% CI 30. 8-63. 0) of 30 patients with metastatic disease, reported Yoshiaki Nakamura, MD, PhD, of National Cancer Centre Japan East Hospital in Kashiwa.
“Tucatinib and trastuzumab demonstrated clinically significant activity and favorable tolerability,” he said. “In addition, several HER2 verification modalities have been shown to be reliable in identifying patients who would possibly be eligible for this regimen. “
The median duration of reaction (DOR) in phase II trials ranged from 6 months with tucatinib-trastuzumab to thirteen months with zanidatamab.
“Impressive,” “exciting,” ASCO guest commentator Andrew Ko, MD, of the University of California, San Francisco Cancer Center, characterizes the findings.
While no targeted agent opposed to HER2 is approved in bile duct cancer, where HER2 is overexpressed up to 20 percent of the time, several agents are in the guidelines, Ko said. Previous trials in this population reported reaction rates of 16% with neratinib (Nerlynx), 23% with trastuzumab plus pertuzumab (Perjeta), and 36% with trastuzumab deruxtecan (Enhertu).
Ko cautioned, however, that the trial had differences in eligibility criteria and HER2-positive disease definitions, with HER2-activating mutations (often unrelated to overexpression) used for eligibility in some trials. Tyrosine kinase inhibitors.
In addition, he said, not all types of biliary cancers express HER2 equally. Overexplanation is most noticeable in extrahepatic cholangiocarcinomas and gallbladder cancers, for example.
“Needless to say, we obviously know if one agent or targeted mix is better than another,” he said. “But for now, what I can say is that each and every patient we have with complex biliary cancer, whose remedy is planned, deserves to be tested for HER2 expression and probably also for HER2 mutations. “
HERIZON-BTC-01
From September 2020 to March 2022, the HERIZON-BTC-01 trial enrolled 87 patients with HER2-amplified complex or metastatic biliary cancers at 32 sites in Asia, Europe, North America, and South America. Patients gained zanidatamab at an IV dose of 20 mg/kg each and every 2 weeks.
Cohort 1 included 80 patients with HER2 expression explained as an immunohistochemistry (IHC) score of 2 or 3, with approximately three-quarters having IHC 3. Central confirmation of HER2 amplification via fluorescence in situ hybridization (FISH) is required and testing is only allowed on tumor tissue. Cohort 2 included seven patients with IHC 0 or 1; None of these patients responded to treatment.
The study’s number one endpoint showed the reaction rate in cohort 1, as assessed through an independent central review, and data from cohort 1 were the focus of Pant’s presentation.
The median age of patients was 64 years, 56% were female, 65% were Asian, and 29% were white. For tumor type, 51% had gallbladder cancer, 29% had intrahepatic cholangiocarcinoma, and 20% had extrahepatic cholangiocarcinoma. The majority (89%) had level IV disease at baseline and patients had a median of an earlier line of systemic therapy in the metastatic or locally complex setting.
On central examination, partial reactions were recorded in 32 patients (40%), as well as one complete reaction (1. 3%). Another 22 patients (28%) had solid disease, leading to a disease rate (DCR) of 69%. The reactions assessed by the researcher were very similar, but showed more complete responses.
Zanidatamab responses were observed primarily in the IHC 3 subgroup (51. 6%), and only one of the 18 patients (5. 6%) in the IHC2 organization responded through the central examination. Responses were also consistent across suborganizations.
The median OR consistent with the central examination is 12. nine months and the median time to reaction is 1. 8 months. Median progression-free survival (PFS) was 5. 5 months, while knowledge of median overall survival (OS) was not mature. The ILI rate at nine months 70%.
Zanidatamab had a manageable and tolerable protective profile, Pant said, with more common low-grade diarrhea and reversible infusion site reactions. Drug-related serious adverse events (AERTs) were reported in 8. 8% of patients and 2. 5% discontinued medication due to medications. related toxicity. Grade ≥3 IERTs occurred in 19% of patients, and deaths were not thought to be related to the remedy.
SGNTUC-019
Nakamura presented insights from a Phase II basket trial (SGNTUC-019) that included 30 pretreated patients with HER2-positive bile duct cancer. All earned at least one dose of oral tucatinib and IV trastuzumab. The median follow-up was 10. 8 months.
Participants had a median age of 68. 5 years, 50% were male, and the maximum were Asian (77%). median of two previous lines of remedy for their metastatic disease, with a maximum (60%) first diagnosed with level IV disease.
One complete reaction (3. 3%) as well as thirteen partial reactions (43. 3%) were observed in the trial, with a median time to reaction of 2. 1 months and an OR of 6. 0 months (90% CI: 5. 5-6. 9). There were also nine cases of solid disease (30%) after treatment with the combination, resulting in a DCR of 76. 7%. Overall, 70% of patients had some degree of relief in tumor burden.
The median PFS and OS were 5. 5 months (90% 3. 9-8. 1) and 15. 5 months (90% 6. 5-16. 7), respectively.
Grade ≥3 treatment-related adverse events (TEEs) included nausea, decreased appetite, and cholangitis in 3 patients (10%); diarrhoea, anaemia, elevated alanine transaminase (ALT) and elevated aspartate transaminase (AST) each in two patients (6. 7%); and fatigue, hyponatremia, elevated blood creatinine, COVID-19 and liver serve as in one patient each (3. 3%).
HER2 positivity in the assay was decided through amplification in blood or tissue samples. Patients had to have an overexpression or amplification of HER2 3, the latter assessed through tumor tissue or through next-generation sequencing (NGS) of circulating blood. Tumor DNA (ctDNA).
Concordance rates between local and central control effects were 87. 5% for FISH and IHC (with FISH reflex), but only 76% for blood NGS. positive through ctDNA.
“This reminds us to be cautious when interpreting the positive effects of cDNA HER2 in biliary cancer clinical practice,” Ko said.
Ian Ingram is editor-in-chief of MedPage Today and is helping to cover the site’s oncology.
The HERIZON-BTC-01 study funded by Zymeworks, Jazz Pharmaceuticals and BeiGene. SGNTUC-019 funded by Seagen.
Pant disclosed relationships (including study funding) with Zymeworks, 4D Pharma, Amal Therapeutics, Arcus Biosciences, Astellas Pharma, AskGene Pharma, Boehringer Ingelheim, BioNTech, Bristol-Myers Squibb, Elicio Therapeutics, Framewave, Ipsen, ImmunoMet, Immuneering, Janssen, Lilly, Mirati Therapeutics, NGM Biopharmaceuticals, Novartis, Pfizer, Rgenix and Xencor. The co-authors revealed industry relationships and included workers from Zymeworks and BeiGene.
Nakamura has relationships with Seagen, Chugai Pharma, Guardant Health AMEA, Merck, Genomedia, Roche and Taiho Pharmaceutical.
Ko disclosed its relationships (including institutional funding) with AADi, AbGenomics International, Apexigen, Astellas Pharma, BioMed Valley Discoveries, Bristol-Myers Squibb, Celgene, Clinical Care Options, CrystalGenomics, FibroGen, Genentech, Gerson Lehrman Group, GRAIL, Ipsen, Leap Therapeutics, Merck, Merus and Roche/Genentech.