Novel Anti-HER2 Drugs ‘Impressive’ in Advanced Biliary Cancer

— Response charges reached 41-47% with various approaches in uncommon disease

by
Ian Ingram, Managing Editor, MedPage At the moment
June 3, 2023

CHICAGO — In a pair of mid-stage trials, newer centered therapies demonstrated major levels of recount against HER2-obvious biliary tract cancers in pretreated sufferers with evolved disease.

Cohort 1 of the area HERIZON-BTC-01 word, which integrated 80 treatment-refractory sufferers, showed that 41.3% (95% CI 30.4-52.8) responded to zanidatamab, an investigational bispecific monoclonal antibody that targets two obvious HER2 epitopes, in conserving with Shubham Pant, MD, of the MD Anderson Cancer Center in Houston.

Zanidatamab triggered “rapid and sturdy responses,” he mentioned right here at the American Society of Scientific Oncology (ASCO) annual meeting.

And in a smaller word, the twin HER2-centered procedure of tucatinib (Tukysa) plus trastuzumab triggered responses in 46.7% (90% CI 30.8-63.0) of the 30 sufferers with metastatic disease, reported Yoshiaki Nakamura, MD, PhD, of the National Cancer Center Sanatorium Japan East in Kashiwa.

“Tucatinib and trastuzumab demonstrated clinically major recount and favorable tolerability,” he mentioned. “Furthermore, extra than one HER2 sorting out modalities were shown to be reliable in identifying sufferers who may presumably maybe maybe simply be eligible for this treatment routine.”

The median length of response (DOR) within the fragment II trials ranged from 6 months with tucatinib-trastuzumab to 13 months with zanidatamab.

“Impressive,” “thrilling,” mentioned ASCO-invited discussant Andrew Ko, MD, of the University of California San Francisco Cancer Center, in characterizing the outcomes.

Even supposing no HER2-directed agents are approved in biliary tract cancer — where HER2 is overexpressed as much as twenty% of the time — several agents are rapid in guidelines, mentioned Ko. Prior trials in this inhabitants appreciate reported response charges of 16% with neratinib (Nerlynx), 23% with trastuzumab plus pertuzumab (Perjeta), and 36% with trastuzumab deruxtecan (Enhertu).

Ko cautioned, alternatively, that every and every trial had variations in eligibility requirements and definitions for HER2-obvious disease, with activating HER2 mutations (customarily now now not related with overexpression) accepted for eligibility in some tyrosine kinase inhibitor trials.

Furthermore, he mentioned, now now not all forms of biliary cancers narrate HER2 the identical manner. Overexpression is extra regularly noticed in extrahepatic cholangiocarcinomas and gallbladder cancer, as an example.

“I place now now not are looking to point out that we clearly know whether one centered agent or combination is better than any other,” he mentioned. “But appropriate now what I’m able to whisper is that every affected person that we appreciate now got with evolved biliary cancer, whose treatment is deliberate, must be tested for HER2 expression and no doubt for HER2 mutations as effectively.”

HERIZON-BTC-01

From September 2020 to March 2022, the HERIZON-BTC-01 trial enrolled 87 sufferers with locally evolved or metastatic HER2-amplified biliary cancers right by 32 sites in Asia, Europe, North The US, and South The US. Patients received zanidatamab at an IV dose of 20 mg/kg every 2 weeks.

Cohort 1 integrated 80 sufferers with HER2 expression outlined as an immunohistochemistry (IHC) rating of two+ or 3+, with about three-fourths having IHC 3+. Central affirmation of HER2 amplification modified into once required by fluorescence in-situ hybridisation (FISH), and sorting out modified into once easiest allowed on tumor tissue. Cohort 2 integrated seven sufferers with IHC 0 or 1+; none of these sufferers responded to treatment.

The word’s main endpoint modified into once the confirmed response fee in cohort 1, as assessed by impartial central review, and the facts from cohort 1 modified into once the main target of Pant’s presentation.

Median affected person age modified into once 64, 56% were girls folks, 65% were Asian, and 29% were white. For tumor form, 51% had gallbladder cancer, 29% had intrahepatic cholangiocarcinoma, and 20% had extrahepatic cholangiocarcinoma. Most (89%) had stage IV disease at baseline, and sufferers had a median of one prior line of systemic treatment within the locally evolved or metastatic environment.

On central review, partial responses were recorded in 32 sufferers (40%), as modified into once one full response (1.3%). Yet any other 22 sufferers (28%) had staunch disease, ensuing in a disease control fee (DCR) of 69%. Investigator-assessed responses were an identical overall, nonetheless showed extra full responders.

Responses with zanidatamab were predominantly viewed within the IHC 3+ subset (51.6%), with appropriate one in every of 18 sufferers (5.6%) within the IHC 2+ crew responding, per central review. Responses were in any other case customarily consistent right by subgroups.

Median DOR per central review reached 12.9 months, and the median time to response modified into once 1.8 months. Median progression-free survival (PFS) modified into once 5.5 months, whereas median overall survival (OS) facts were now now not weak. The OS fee at 9 months modified into once 70%.

Zanidatamab had a manageable and tolerable safety profile, mentioned Pant, with mostly low-grade diarrhea and infusion-living reactions that were reversible. Excessive treatment-related harmful events (TRAEs) were reported in 8.8%, and 2.5% stopped treatment ensuing from drug-related toxicity. Grade ≥3 TRAEs took place in 19%, and no deaths were deemed related to treatment.

SGNTUC-019

Nakamura presented facts from a fragment II basket trial (SGNTUC-019) that integrated 30 pretreated sufferers with HER2-obvious biliary tract cancer. All received as a minimum one dose of oral tucatinib and IV trastuzumab. Median apply-up modified into once 10.8 months.

Contributors had a median age of 68.5, 50% were male, and most were Asian (77%). Gallbladder tumors were most overall, in 15 sufferers, adopted by extrahepatic cholangiocarcinomas in eight sufferers and intrahepatic cholangiocarcinomas in seven. Patients had a median of two prior lines of treatment for his or her metastatic disease, with most (60%) having been within the start identified with stage IV disease.

One full response (3.3%) modified into once noticed within the trial along with 13 partial responses (43.3%), with a median time to response of two.1 months and DOR of 6.0 months (90% CI 5.5-6.9). There were also nine cases of staunch disease (30%) following treatment with the mix, yielding a DCR of 76.7%. Overall, 70% of sufferers had some stage of low cost in tumor burden.

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-emergent harmful events (TEAEs) integrated nausea, diminished appetite, and cholangitis each and every in three sufferers (10%); diarrhea, anemia, elevated alanine transaminase (ALT), and elevated aspartate transaminase (AST) each and every in two sufferers (6.7%); and fatigue, hyponatremia, will enhance in blood creatinine, COVID-19, and peculiar hepatic feature in one affected person each and every (3.3%).

HER2 positivity within the trial modified into once resolute either by amplification in blood or tissue samples. Patients had to appreciate HER2 3+ overexpression or amplification, with the latter assessed either by tumor tissue or next-generation sequencing (NGS) from circulating tumor DNA (ctDNA).

Concordance charges between local and central test outcomes were 87.5% for each and every FISH and IHC (with reflex to FISH), nonetheless appropriate 76% with blood-based fully NGS. None of the sufferers stumbled on to be HER2-negative on central review responded to treatment, including seven sufferers that tested obvious locally by ctDNA.

“It serves as a reminder that we should be cautious in interpreting HER2-obvious outcomes on ctDNA in scientific practice for biliary cancer,” mentioned Ko.