The Lancet Oncology: New bispecific antibodies are expected to become a weapon against various HER2-positive solid tumors!

Targeted therapy for HER2 is one of the most successful targeted therapies at present, and the iconic monoclonal antibody-based targeted drug trastuzumab has been widely used in the treatment of gastric and breast cancer, and has significantly prolonged the survival time of breast and gastric cancer patients [1].

As an oncogene, HER2 also has gene over-amplification or protein overexpression in cholangiocarcinoma, colorectal cancer, bladder cancer, salivary gland cancer, and non-small cell lung cancer [2], but monoclonal antibody targeted drugs have poor therapeutic effects on tumors other than breast and gastric cancer [3], so more innovative drugs for HER2 targets are needed, and various new drugs are constantly emerging
.

Recently, a research team led by Professor Funda Meric-Bernstam of the University of Texas Anderson Cancer Center published an important research result
in The Lancet Oncology 。 The study found that Zanidatamab, a bispecific antibody HER2, was well tolerated in clinical treatment, and the objective response rate in patients with advanced tumors (mainly cholangiocarcinoma and colorectal cancer) with HER2 overexpression or overamplification could reach 37% [4], suggesting that Zanidatamab has a good initial efficacy in the treatment of gastric cancer and tumors other than breast cancer
.

Figure 1.
Screenshot of the article cover

Zanidatamab targets the extracellular domain and dimerization domain of HER2 and binds to two non-overlapping HER2 epitopes ECD4 (trastuzumab-targeting domain) and ECD2 (pertuzumab targeting domain) simultaneously, thereby blocking dual HER2 signaling and eliminating HER2 proteins on the cell surface[5].

In addition, Zanidatamab inhibits growth factor-dependent tumor cell proliferation and activates antibody-dependent cytotoxicity, cytophagocytosis, and complement-dependent cytotoxicity[6].

Preclinical studies have shown that Zanidatamab has strong anti-tumor activity in a variety of HER2 overexpressed or over-amplified tumors [5], or can be successfully applied to the clinical treatment
of cholangiocarcinoma, colorectal cancer and other cancers.

The clinical study of the published results was divided into two phases, the dose escalation trial and the expansion trial, which were used to determine the maximum tolerated dose and optimal therapeutic dose of Zanidatamab, respectively, and to observe the initial therapeutic effect of Zanidatamab (Figure 2).

In the first phase, a total of 46 patients (mainly gastric and breast cancer patients) were enrolled and divided into 7 dose groups, with a maximum dose of 30 mg/kg (Figure 2).

The most common adverse reactions in all dose groups were diarrhoea and infusion reactions, occurring in 52% and 43%, respectively; Only 7% of patients experienced grade 3 adverse effects, mainly joint pain, fatigue and hypophosphatemia, decreased appetite, and hypertension; Of the 46 patients, none experienced serious adverse effects
.
It can be seen that Zanidatamab has high clinical tolerability
.

Figure 2.
Dose-escalation phase study design

Based on the first phase, the researchers determined the optimal therapeutic dose of 20 mg/kg (every two weeks), and to further determine the safety of Zanidatamab at this dose and initially study its therapeutic effect, the researchers included 86 patients with advanced cancer with HER2 overexpression (22 cases of cholangiocarcinoma or gallbladder cancer, 28 cases of colorectal cancer, and 36 cases of non-small cell lung cancer, ovarian cancer and other cancers) (Figure 3).

Figure 3.
Amplification phase study design

In the second stage, diarrhea is still the most common adverse reaction in patients, and most of the adverse reactions are grade 1-2, and only one case of grade 3 adverse reaction (diarrhea), so Zanidatamab, which is administered once every two weeks at 20mg/kg, has a good safety profile in clinical treatment, but its therapeutic effect on solid tumors such as cholangiocarcinoma and colorectal cancer is unknown
.

Of these 86 patients, a total of 83 patients were assessable for disease remission: objective response rates (ORRs) of 38%, 38%, and 36% for cholangiocarcinoma, colorectal cancer, and other cancers, respectively, and an overall ORR of 37%; The median duration of response (DoR) was 8.
5 months for cholangiocarcinoma, 5.
6 months for colorectal cancer, and 9.
7 months for other cancers, with some patients having a duration of response greater than one year (Figure 4).

Figure 4.
Duration of remission of Zanidatamab in different cancers

In addition, the median progression-free survival was 5.
4 months (95% CI: 3.
7-7.
3) for all patients, with 3.
5 months (95% CI: 1.
8-6.
7) for cholangiocarcinoma, 6.
8 months (95% CI: 3.
5-7.
8) for colorectal cancer, and 5.
5 months (95% CI: 3.
6-8.
3)
for other cancers.

Of the 83 patients with evaluable response, 63 (76%) had tumor shrinkage (Figure 5), of which 14 had been treated with trastuzumab or pertuzumab, 1 in cholangiocarcinomac, 3 in colorectal cancer, and 10 in other tumors (Figure 6).

It can be seen that Zanidatamab is not only suitable for cancers other than gastric cancer and breast cancer, but also is expected to be used in patients
treated with HER2 monoclonal antibody.

Figure 5.
Effect of Zanidatamab on volume reduction of different tumor lesions

Figure 6.
Efficacy of Zanidatamab in patients who have received HER2-targeted therapy for other cancers (K: emmetrituzumab; T: trastuzumab; P: pertuzumab; L: Lapatinib)

In conclusion, this study found that HER2 bispecific antibody Zanidatamab also has a good therapeutic effect on cancers other than breast and gastric cancer, and has a high safety profile, and according to the news just announced, Zanidatamab has achieved the success of the phase 2b key trial for the treatment of HER2 overexpression or excessive amplification of cholangiocarcinoma, with an objective response rate of 41.
9% and a median DoR of more than one year, and the relevant indications are expected to be approved based on the results of this study
。

At present, the phase III clinical trial of Zanidatamab in the treatment of advanced HER2-positive breast cancer or adenocarcinoma at the gastric/gastroesophageal junction (CTR20210237) has also been carried out in China at the same time, which is expected to provide more adequate evidence for the clinical application of Zanidatamab, and also expects new good news
from this study.

References:

[1] Duranti S, Fabi A, Filetti M, et al.
Breast Cancer Drug Approvals Issued by EMA: A Review of Clinical Trials.
Cancers (Basel).
2021 Oct 16; 13(20):5198.
doi: 10.
3390/cancers13205198.

[2] Yan M, Schwaederle M, Arguello D, et al.
HER2 expression status in diverse cancers: review of results from 37,992 patients.
Cancer Metastasis Rev.
2015 Mar; 34(1):157-64.
doi: 10.
1007/s10555-015-9552-6.

[3] Siena S, Di Bartolomeo M, Raghav K,et al.
Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): a multicentre, open-label, phase 2 trial.
Lancet Oncol.
2021 Jun; 22(6):779-789.
doi: 10.
1016/S1470-2045(21)00086-3.

[4] Meric-Bernstam F, Beeram M, Hamilton E, et al.
Zanidatamab, a novel bispecific antibody, for the treatment of locally advanced or metastatic HER2-expressing or HER2-amplified cancers: a phase 1, dose-escalation and expansion study.
Lancet Oncol.
2022 Nov 15:S1470-2045(22)00621-0.
doi: 10.
1016/S1470-2045(22)00621-0.

[5] Dixit S, Abraham L, Weiser N, et al.
Super-resolution imaging studies of zanidatamab: providing insights into its bispecific mode of action.
American Association of Cancer Research, 2021; Virtual: AACR; Cancer Research; 2021 (abstr 1032).

[6] Weisser N, Wickman G, Abraham L, et al.
The bispecific antibody zanidatamab's (ZW25's) unique mechanisms of action and durable anti-tumor activity in HER2-expressing cancers.
Proceedings of the American Association for Cancer Research Annual Meeting; 2021 Apr 10-15 and May 17-21; Virtual: AACR; Cancer Res 2021 (abstr 1005).