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*For medical professionals only
The HERB study reveals the therapeutic potential
of novel ADC drugs in biliary tract cancer (BTC).
The prognosis of advanced biliary cancer is poor, and the treatment benefits after existing first-line treatment resistance are often unsatisfactory, can targeted therapy for specific mutations bring greater benefits? At the 2022 ASCO conference, the results of the HERB trial of anti-HER2 star drug DS-8201 for late-stage treatment of BTC [1] were announced, exploring the new possibilities
of advanced BTC treatment.
In response to this research, ADC Academy Online is honored to invite Professor Zhou Jun of Peking University Cancer Hospital to interpret
it in depth.
Synopsis
BTC is a collective term for a series of aggressive adenocarcinomas including cholangiocarcinoma (including intrahepatic, perihilal, and distal cholangiocarcinoma), gallbladder cancer, and ampullary cancer (AVC), which is a low-incidence malignancy in most high-income countries, but has shown an annual increase in the past three decades
.
The incidence rate in China is significantly higher than that in Western developed countries [2], and evidence suggests that patients with gallstones, hepatitis B, and metabolic diseases (such as diabetes) have a higher incidence of biliary tract cancer [3-5].
For BTC, surgery is the cornerstone of
healing.
However, most patients with BTC have progressed to locally advanced disease or metastases (hereinafter collectively referred to as advanced BTC) at the time of diagnosis, and the prognosis is extremely poor
.
Taking cholangiocarcinoma as an example, the 5-year survival rate of metastatic disease is only 2%,
whether it occurs in the liver or outside the liver.
The standard treatment regimen for metastatic BTC is systemic therapy represented by chemotherapy [6], gemcitabine plus cisplatin (GemCis) regimen is the preferred regimen for first-line treatment in patients with advanced BTC, in addition, the 2022 NCCN guideline based on the phase III TOPAZ-1 trial moderate vallelumab plus GemCis may confer a significant benefit in median overall survival (mOS) compared with GemCis alone (mOS: durvalumab+ GemCis 12.
8 months vs placebo + GemCis 11.
5 months, HR 0.
8, 95% CI 0.
66 to 0.
97, p=0.
021), and the addition of divalisumab plus GemCis is also recommended as first-line therapy [7].
The current standard regimen for second-line therapy is the FOLFOX (folic acid, fluorouracil, and oxaliplatin) regimen, with a median OS of 6.
2 months and an objective response rate (ORR) of only 5%.
Table 1.
Systemic treatment regimen and benefit of advanced BTC patients[1]
Despite the above recommendations made by the guidelines for patients with advanced BTC, the benefit of standard therapy is still unsatisfactory
。 Therefore, for patients with specific gene mutations, guidelines recommend targeted therapy in the backline to further enhance the patient's benefit, such as pemitinib or infilgradinib for cholangiocarcinoma patients with FGFR2 fusion or rearrangement; Patients with cholangiocarcinoma with IDH1 mutations can choose ivonib; Others include research and exploration of molecular targets such as BRAF and HER2, but the relevant studies are all late-line therapy exploration, and the patient population is small
.
In general, the application of new targeted therapy in patients with advanced BTC still needs to be explored, among which HER2 variants are relatively common in advanced BTC and the clinical experience is relatively mature, so anti-HER2 targeted therapy has been given high hopes by clinicians in the systematic treatment of advanced BTC
.
Table 2.
Some specific mutation options for advanced BTC and their clinical benefits[1]
HER2 is an important member of the epidermal growth factor receptor (EGFR) tyrosine kinase family encoded by the ERBB2 gene, including gastric cancer, non-small cell lung cancer, colorectal cancer, It is found in a variety of cancers, such as bladder cancer, and plays a key role
in cell proliferation.
HER2 variants include gene mutations, gene amplification, and protein overexpression, and previous research data show that HER2-targeted therapy can be used in patients
with advanced breast and gastric cancer with HER2 mutations.
HER2 variants have also been observed in BTC patients, in approximately 31.
3 percent of gallbladder cancers, 3 to 18.
5 percent of extrahepatic cholangiocarcinoma, 16.
4 percent of ampullary cancers, and 3.
7 percent of intrahepatic cholangiocarcinomas [1], and previous studies suggest that HER2 overexpressing cell lines show enhanced aggressiveness, motility, and proliferative behavior [9].
Therefore, it can be speculated that HER2 variants are associated with the morbidity and prognosis of some BTC patients, and anti-HER2 therapy may be effective in BTC patients with HER2 variants [10-14].
Figure 1.
HER2 expression rate in BTC patients
Introduction to the study
The HERB trial (NCCH1805, JMA-IIA00423) is a investigator-initiated multicenter, single-arm trial to evaluate the efficacy and safety
of DS-8201 in the treatment of patients with BTC who have progressed or are intolerable to resectable or relapse after prior gemcitabine-based chemotherapy with HER2-positive or low-expression BTC.
*HER2 positive: immunohistochemistry (IHC) 3+, or IHC 2+ but fluorescence in situ hybridization (FISH) positive (HER2/CEP17 ratio≥2.
0); **HER2 low expression: IHC/ISH 0/+, 1+/-, 1+/+, or 2+/-
.
Figure 2.
The primary endpoint of the HERB trial was confirmed ORR in HER2-positive patients assessed by the
Blinded Independent Center Review Committee (BICR); Secondary endpoints included ORR, disease control rate (DCR), progression-free survival (PFS), OS, and incidence of treatment-related adverse events (TEAEs) as assessed by local investigator review (LIR) in HER2-positive and HER2-low patients
.
The results of
the HERB trial were presented at this year's ASCO conference.
As of July 2021, a total of 30 patients with advanced BTC were included in the study: 22 were HER2-positive and 8 were HER2-low-expression; BTC primary tumor site: gallbladder cancer 43.
3% (13 cases), extrahepatic cholangiocarcinoma 26.
7% (8 cases), intrahepatic cholangiocarcinoma 20% (6 cases), ampullary cancer 10% (3 cases); 90% (27 cases) had metastatic BTC, 10% (3 cases) had locally progressive tumors, and 70% (21 cases) had previously received second-line or more treatment
.
Figure 3.
The population included in the HERB trial and the baseline characteristic
efficacy data showed that the ORR of the overall patient was 30% (14.
7-49.
4), the ORR of HER2-positive patients was 36.
4% (95% CI 19.
6-56.
1), and the ORR of HER2 low expression was 12.
5% (0.
3-52.
7); The DCR of the overall patients was 80% (61.
4-92.
3), of which 81.
8% (59.
7-94.
8) were HER2-positive patients and 75% (34.
9-96.
8) of patients with HER2 low expression.
Figure 4.
The median PFS of BICR-assessed confirmed ORR (left) and ORR (right) of LIER-assessed ORR2-positive patients was 5.
1 months (3.
0-7.
3), 3.
5 months (1.
2-5.
5) in patients with HER2 hypoexpression, 7.
1 months (4.
7-14.
6) in HER2-positive patients, and 8.
9 months (3.
0-12.
8)
in patients with HER2 hypoexpression
。
Figure 5.
PFS (left) and OS (right) :D S-8201 benefited both HER2-positive and low-expression patients, and post-hoc analysis showed that the median duration of response in HER2-positive patients was 7.
4 months (2.
8-NA), with 50% of patients achieving tumor remission beyond 6 months.
Figure 6.
Post-hoc analysis: The median duration of response in HER2-positive patients can be as long as 7.
4 months
In terms of safety, the safety data of DS-8201 is consistent with previous clinical data, and no new adverse signals
are observed 。 The most common adverse events overall included 1) hematologic toxicity such as anemia (68.
8%, 53.
1% ≥ grade 3), decreased neutrophil count (56.
3%, 31.
3% in grade 3 ≥), thrombocytopenia (43.
8%, ≥grade 3 9.
4%), etc.
; 2) gastrointestinal reactions such as nausea (43.
8%, grade ≥ 3 did not occur), anorexia (37.
5%, 3.
1% of grade ≥ 3), vomiting (21.
9%, grade ≥ 3 did not occur); In addition, there are hair loss (40.
6%, grade ≥ 3 does not occur) and interstitial lung disease (ILD); ILD was an adverse event of particular interest in the study, with a total of 8 patients developing ILD, of which 4 were grade 1 to 2, 2 were grade 3, and 2 were grade 5, with a median time to ILD onset of 124 days (35 to 247)
from initiation of treatment.
Figure 7.
The incidence of overall TEAE (left) and ILD (right) in the HERB study showed the efficacy of DS-8201 in BTC patients with HER2 expression, among which HER2-positive BTC patients were particularly effective, and patients with low HER2 expression also showed some evidence of benefit, which laid the foundation for further exploration and use of DS-8201 in late BTC
。
Article reviews
In recent years, in advanced BTC, the relationship between HER2 variants and prognosis and the treatment targeting HER2 have gradually entered the field of vision of clinicians, and the exploration of existing anti-HER2 therapies includes targeting HER2 amplification and overexpression, as well as HER2 mutations
.
HER2 overexpression is considered an independent predictor of poor BTC prognosis [16], and patients with HER2 mutations or amplifications may have a worse prognosis than other patients [17], suggesting that patients with advanced BTC with HER2 variants may have greater therapeutic urgency
.
Following previous clinical explorations, targeted therapy with anti-HER2 has been confirmed to be a target for patients with advanced BTC [18].
In 2021, a trastuzumab biosimilar combined with GemCis obtained 50% ORR and 100% DCR in advanced BTC, which has better PFS and OS data than clinicians' treatment options, further suggesting that targeting HER2 may become a new direction of concern and may bring greater therapeutic benefit in advanced BTC [19].
In the HERB trial, DS-8201 had an ORR of 36.
4% and a DCR of 81.
8% in HER2-positive BTC patients, which showed better efficacy than the previous advanced BTC first- and second-line standard therapy and anti-HER2 targeted therapy, and also showed significant benefits
for patients with low HER2 expression.
This superior antitumor activity is closely related
to the unique mechanism of DS-8201.
DS-8201 is a novel antibody-drug conjugate (ADC) consisting of trastuzumab and a potent topoisomerase I inhibitor as a cytotoxic carrier conjugated by a cleavage, tetrapeptide-based linker, combining the advantages of
traditional chemotherapy and monoclonal antibodies.
It can not only accurately target tumor cells, but also greatly improve the antitumor activity of DS-8201 due to the high activity of drug carrier and drug-antibody ratio (DAR) reaching 8, and also exert bystander killing effect [20,21].
It is based on these structural and mechanism advantages that it can effectively overcome the influence of HER2 tumor heterogeneity while increasing efficiency and reducing toxicity, and can exert a strong anti-tumor killing effect
on HER2-positive or low-expression BTC patients.
In the HERB study, several patients who received DS-8201 achieved longer-term tumor remission compared to other patients, but due to the small sample size of the study and limited disclosure of study data, it is not known whether these patients are related
to their HER2 expression, tumor origin, previous treatment type, or other factors 。 This suggests that for patients with advanced BTC, while carrying out more DS-8201-related confirmatory clinical trials, it is necessary to further understand the pathophysiology of BTC, so as to accurately segment patients and provide ideas
for further improving the efficacy.
In addition, DS8201 and other ADC drug treatment related to ILD should also be concerned and paid attention to, the specific pathogenesis of ILD is not clear, preclinical studies show that the pulmonary toxicity of DS-8201 may not be caused by the drug carrier that falls off during blood circulation, ADC drug-induced alveolar damage may be related to the non-target-dependent endocytosis of its immune cells, and has nothing to do with
the endocytosis dependent on HER2 protein 。 Similar ADC drugs (datopotamab deruxtecan) targeting TROP-2 with deruxtecan as a drug carrier have also observed the occurrence of ILD (8%, including 3 fatal events) in non-small cell lung cancer studies, further confirming the hypothesis that ILD originates from non-target-dependent endocytosis
。 Although steroid hormone therapy is required after ILD, there will be some differences in screening diagnosis, treatment adjustment and hormone therapy, and the difficulty and severity of pneumonia management caused by different drugs will also be different
.
At present, DS-8201 has achieved very good efficacy in many tumor fields, and the application population is wide, and we should actively pay attention to and manage the ILD caused by it to avoid the occurrence of
serious adverse events.
Commentary:
Professor Zhou Jun, Peking
University Cancer Hospital
- Associate Chief Physician, Department of Gastroenterology
- Member of the Standing Committee of the CSCO Biliary Tract Oncology Expert Committee
- Member of the Standing Committee of the CSCO Pancreatic Cancer Expert Committee
- Member of the CSCO Liver Cancer Expert Committee
- Member of CSPAC of Pancreatic Cancer Professional Committee of Chinese Anti-Cancer Association
- Director General of Oncology Branch of Chinese Geriatrics Society
- Vice Chairman of the Youth Committee of the Digestive Tract Cancer Committee of China Research Hospital
- Member of MDT Professional Committee of Precision Medicine and Oncology of China Research Hospital Association
- Member of the Hepatobiliary and Pancreatic Young and Middle-aged Expert Committee of the Beijing Health Promotion Association
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*This article is only used to provide scientific information to medical professionals and does not represent the views of this platform
