Updated Zanidatamab Data Shows Durable Response in Biliary Tract Cancer

Shubham Pant, MD, MBBS

Updated data from the phase 2b HERIZON-BTC-01 trial (NCT04466891) revealed that zanidatamab (ZW25) given to patients with pretreated, advanced, unresectable, or metastatic HER2-amplified (HER2+) biliary tract cancer (BTC) led to a clinical benefit.¹

Longer-term follow-up data from the study presented during the 2024 American Society of Clinical Oncology Annual Meeting showed that the confirmed objective response rate (cORR) with zanidatamab was 41.3%. The disease control rate (DCR) was 68.8%, which was maintained from the study’s primary analysis. With 1 more patient achieving a complete response (CR) with longer follow-up, 2 patients have now shown a CR in the study.² Further, the median duration of response was 14.9 months (95% CI, 7.4-not reached).¹

For overall survival (OS), the median OS in the cohort of patients with immunohistochemistry (IHC) 2+ or 3+ was 15.5 months (95% CI, 10.4-18.5). At 6 and 12 months, the OS rates were 80.3% (95% CI, 69.4%-87.6%) and 56.2% (95% CI, 44.3%-66.5%), respectively.

Zanidatamab’s safety profile remained generally consistent with previous reports. Most patients (96.6%) experienced treatment-emergent adverse effects (TEAEs), with 51.7% experiencing grade 1 or 2 treatment-related AEs (TRAEs) and 20.7% experiencing grade 3 or 4 TRAEs. Serious TRAEs were observed in 9.2% of patients. Common all-grade and grade 3 to 4 TRAEs included diarrhea (36.8%; 4.6%), infusion-related reactions (IRR; 33.3%; 1.1%), decreased ejection fraction (10.3%; 3.4%), nausea (9.2%; 1.1%), and increases in alanine transaminase (ALT; 6.9%; 1.1%) and aspartate aminotransferase (AST; 6.9%; 2.3%).

Additional AEs of special interest were IRRs (33.3% all-grade; 1.1% grade 3-4), cardiac events (5.7%; 3.4%), and noninfectious pulmonary toxicities (1.1%). TRAEs leading to dose reductions included grade 3 diarrhea, grade 1 diarrhea and nausea, and grade 2 weight loss, affecting 1 patient each. One patient reported serious TRAEs of increased ALT and AST, with no new treatment discontinuations due to TRAEs since the last analysis, keeping the overall discontinuation rate at 2.3%.

In an interview with Targeted Oncology^TM, Shubham Pant, MD, MBBS, professor in the Department of Gastrointestinal Medical Oncology with a joint appointment in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, discussed zanidatamab and the HERIZON-BTC-01 trial in HER2+ biliary tract cancer treatment.

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Targeted Oncology: Can you provide some background on zanidatamab and the phase 2b trial investigating it?

Pant: Zanidatamab is a bispecific anti–HER2-directed antibody that binds to 2 domains on HER2 called ICD2 and ICD4. Last year, we presented findings from the phase 2b HERIZON BTC-01 trial, a global trial in patients with HER2+ biliary tract cancers. We presented data on 80 patients [with HER2+ disease], defined as IHC 3+ or IHC 2+ with [in situ hybridization] positivity. Patients in the trial received zanidatamab via [intravenous (IV)] infusion every 2 weeks. The primary end point was overall response rate, with secondary end points including progression-free survival, overall survival, and toxicity. This year, we [presented] updated results with long-term follow-up data from that trial.

The initial HERIZON-BTC-01 data showed promising ORR with zanidatamab. Can you share updated data on the cORR with longer follow-up?

Last year, our confirmed overall response rate was 41.3%, [and] we had a duration of response of about 12.9 months. We followed those patients out, and now, the median duration of follow-up is 21.9 months. And again, the confirmed overall response rate remained the same, which is good, 41.3%. For comparison, let's say FOLFOX [leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin], which is chemotherapy in the second-line setting for BTC, has a response rate of 5%. This was obviously very promising.

Beyond ORR, are there any updated efficacy data you can present, such as DCR or progression-free survival with longer follow-up?

What we have seen is that the confirmed overall response rate remained the same, but the duration response increased to 14.9 months, so that actually improved, and we were happy about that. The median overall survival that we could report the data out [for, and] that we did not have the data mature last year, is about 15.5 months, so promising for these patients.

Can you discuss the safety profile of zanidatamab with longer follow-up?

We also [presented] the updated safety analysis, in which there were no new safety signals. In the original trial, we saw some diarrhea, which was the main [AE] that stayed, but we did not see any updated safety parameters.

What are the main takeaways from this updated part of the study?

I think it is an exciting study, and another way to target biliary tract cancer. For the community oncologists, I would say they need to do next-generation testing—I am sure most of them are doing it in [patients with] biliary tract cancer. That is how we can identify the target. [This is a] phase 2 trial, [so] again, we should take it with a grain of salt because [it was a] single arm. The response rates are higher than what we see with just chemotherapy, so that was very promising. Overall survival in this pretreated patient population of 15.5 months was promising. I think the duration of response is important because if the patients respond and they progress within 4 months, that is not very clinically relevant to them. But if they respond and they stay on for a prolonged duration, that is important.

There is no chemotherapy here; it is targeted therapy, so it is relatively well tolerated. And [for] any of the [adverse] effects, we could give [patients] medications and…control the [adverse] effects of this agent. Those are the main take-home points for the community oncologist.

Based on these updated findings, are there any ongoing or planned phase 3 trials evaluating zanidatamab in HER2+ BTC?

We do have an ongoing, randomized, phase 3 trial in frontline patients who have never been treated. Patients are going to get zanidatamab in combination with standard-of-care therapy in the frontline setting for patients. It is a randomized trial, and we are excited to take the next step in this journey of this drug.

REFERENCES:

1. Pant S, Fan J, Oh D-Y, et al. Zanidatamab in previously-treated HER2-positive (HER2+) biliary tract cancer (BTC): Overall survival (OS) and longer follow-up from the phase 2b HERIZON-BTC-01 study.J Clin Oncol. 2024;42(suppl 16; abstr 4091). doi:10.1200/JCO.2024.42.16_suppl.4091

2. Harding JJ, Fan J, Oh D-Y, et al. Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study. Lancet Oncol. 2023;24(7):772-782. doi:10.1016/S1470-2045(23)00242