A review of clinical studies on antibody-conjugated drugs in the treatment of HER2-positive advanced gastric cancer. A collection of tumor literature

HER2-positive gastric cancer is a special type of gastric cancer.
About 10% to 20% of patients with advanced gastric cancer have HER2 gene amplification or protein overexpression [1]
.

The ToGA study established trastuzumab as the first-line standard treatment for HER2-positive gastric cancer [2], but many subsequent studies on HER2-positive gastric cancer ended in failure.
Monoclonal antibodies such as Pertuzumab and small molecule tyrosine Acid kinase inhibitors such as lapatinib have not achieved good results in HER2-positive advanced gastric cancer [3,4]
.

 Antibody-drugconjugate (ADC) is a new type of therapy
.

ADC is composed of three parts: antibody, linker and cytotoxic drug.
One end is an antibody that specifically recognizes cancer cells, and the other end is connected to cytotoxic chemotherapy drugs.
The antibody can accurately deliver chemotherapy drugs to cancer cells.
Therefore, ADC Combining the powerful lethality of small molecule drugs and the highly targeted properties of monoclonal antibodies, with good curative effects and fewer side effects, it has become a hot field in the research and development of anti-cancer drugs in recent years
.

 At present, a series of studies on ADC treatment of HER2-positive advanced gastric cancer have been carried out at home and abroad, and a variety of drugs have achieved good results
.

This article summarizes the progress of ADC in the treatment of HER2-positive advanced gastric cancer
.

Enmetrastuzumab (T-DM1) T-DM1 is a combination of the classic anti-HER2 targeting drug trastuzumab and the chemotherapeutic drug Maytansine, which inhibits microtubule aggregation, through a thioether linker
.

A number of studies have shown that T-DM1 is effective in HER2-positive breast cancer, and it has become the world's first single-drug ADC approved for solid tumors [5]
.

 T-DM1 has also been explored in HER2-positive gastric cancer
.

The GATSBY study is an international randomized, open-label, phase 2/3 study.
415 patients with HER2-positive advanced gastric cancer or gastroesophageal junction adenocarcinoma were enrolled in the second-line treatment with T-DM1 or paclitaxel
.

The median overall survival of the T-DM1 and paclitaxel treatment groups were 7.
9 months and 8.
6 months, respectively (P=0.
86), and the median progression-free survival were 2.
7 and 2.
9 months (P=0.
31), 3 to 4 The incidence of grade-one adverse events was 59.
8% and 70.
3%, respectively
.

The GATSBY study showed that in the second-line treatment of HER2-positive advanced gastric cancer, the efficacy of T-DM1 is not superior to paclitaxel [6]
.

 The reason for the failure of T-DM1 in the treatment of HER2-positive gastric cancer may be: after trastuzumab treatment, HER2 status may change; HER2 expression in gastric cancer is highly heterogeneous, and there are differences in HER2 expression between metastases and primary tumors ; The linker of T-DM1 is not cleavable, so it will not produce "bystander effect" (that is, after ADC drug lysis, cytotoxic drugs can penetrate the cell membrane and enter adjacent cancer cells to play a bypass killing effect) [7-9]
.

Trastuzumab-deruxtecan (DS-8201, T-DXd) DS-8201 is a new type of ADC drug consisting of humanized anti-HER2 antibody, digested peptide linker and new DNA topoisomerase I inhibitor deruxtecan Composition
.

The cleavable linker is structurally stable in the blood circulation, and the drug shedding rate is low, thereby reducing toxic and side effects, and DS-8201 has an efficient "bystander effect"
.

DS-8201 has currently conducted several studies in breast cancer, gastric cancer, and colorectal cancer, showing good anti-tumor activity
.

 DS8201-A-J101 is a phase 1 study exploring DS-8201 in the treatment of patients with advanced solid tumors
.

This study included 44 patients with advanced HER2-positive gastric cancer or gastroesophageal junction cancer, of which 19 patients (43.
2%; 95% CI, 28.
3%~59.
0%) had a clear objective response to DS-8201 [10]
.

 The DESTINY-Gastric01 study is a multicenter, phase 2 study, enrolling a total of 187 patients with HER2-positive advanced gastric cancer or gastroesophageal junction adenocarcinoma who have previously received at least two regimens of treatment
.

HER2 positive is defined as immunohistochemistry "3+" or immunohistochemistry "2+"/fluorescence in situ hybridization "+"
.

The patients were randomly assigned 2:1 to the DS-8201 6.
4 mg/kg group (n=125) and the physician-selected chemotherapy group (n=62, of which 55 patients were treated with irinotecan and 7 patients were treated with paclitaxel)
.

 The objective response rate and overall survival of the DS-8201 group were significantly better than those of the chemotherapy group: the objective response rates of the two groups were 51% and 14% (P<0.
001), and the median overall survival was 12.
5 months and 8.
4 months, respectively Months (P=0.
01), the median progression-free survival period was 5.
6 months and 3.
5 months
.

The most common adverse reactions of grade 3 and above are decreased neutrophil counts, anemia, and decreased white blood cell counts
.

In addition, 12 patients in the DS-8201 group developed drug-related interstitial lung disease or pneumonia (9 cases of grade 1-2, 3 cases of grade 3-4), and 1 case of drug-related death (due to pneumonia)
.

Based on this research, DS-8201 became the first ADC approved by the US Food and Drug Administration for the treatment of patients with HER2-positive advanced gastric cancer or gastroesophageal junction adenocarcinoma who had received at least 2 regimens [11]
.

 The 2021 European Society of Medical Oncology Annual Meeting (ESMO 2021) reported the results of an open-label, single-arm Phase 2 study (DESTINY-Gastric02)
.

This study enrolled patients with HER2-positive gastric cancer and gastroesophageal junction cancer who had disease progression after first-line trastuzumab treatment to evaluate the efficacy and safety of DS-8201 second-line monotherapy
.

The primary endpoint is the objective response rate
.

 A total of 79 patients were enrolled in this study.
As of April 9, 2021, the objective response rate was 38%, the disease control rate was 81%, the median progression-free survival was 5.
5 months, and the median duration of treatment was 4.
3.
Month (0.
7~15.
9 months)
.

The most common adverse events leading to discontinuation were pneumonia (3.
8%) and interstitial lung disease (2.
5%), and the most common adverse events leading to drug reduction were nausea (7.
6%) and decreased neutrophil count (5.
1%) )
.

DESTINY-Gastric02 provides clinical evidence for DS-8201 as a valuable second-line HER2 targeted therapy option and supports the ongoing phase 3 randomized trial DESTINY-Gastric04 (NCT 04704934)
.

 Vidicituzumab (RC48) Vidicituzumab is a new ADC drug independently developed by China
.

Vidicituzumab is a brand new HER2 antibody with higher affinity to HER2 antigen; the antibody and cytotoxic drug are connected by a cleavable cathepsin linker, which makes it easier to release cytotoxic drugs after being endocytosed by tumor cells
.

 In 2021, Gastric Cancer published a phase 1 study of vedicitumumab in HER2-positive solid tumors
.

The study consisted of two parts: the dose of RC48 in the dose-escalation cohort was 0.
1 mg/kg ~3.
0 mg/kg; the dose of the dose-extended cohort was 2.
0 mg/kg (once every 2 weeks) [12]
.

 A total of 57 patients were enrolled in the study, and the maximum tolerated dose was not reached.
The recommended dose for Phase 2 is 2.
5 mg/kg (once every 2 weeks)
.

RC48 is well tolerated, and the most common adverse events of grade 3 and above include neutropenia (19.
3%), leukopenia (17.
5%), hypoesthesia (14.
0%) and increased conjugated blood bilirubin (8.
8%) )
.

Four patients died in the study, and three of them were thought to be related to RC48
.

 For all 57 patients with evaluable efficacy, including 47 cases of gastric cancer, 4 cases of urothelial cancer and 6 cases of other tumor types, the objective response rate and disease control rate were 21.
1% and 49.
1%, respectively
.

Further analysis showed that patients with HER2 immunohistochemistry “2+”/fluorescence in situ hybridization “−” and immunohistochemistry “2+”/fluorescence in situ hybridization “+” and immunohistochemistry “3+” patients had similar reactions
.

The study showed that vedicitumumab has good tolerance and anti-tumor activity against HER2-positive solid tumors, including gastric cancer with immunohistochemical "2+"/fluorescence in situ hybridization "−"
.

 The C008 study is an open, multi-center phase 2 study that included patients with locally advanced or metastatic gastric cancer with HER2 overexpression in third-line and above
.

This study expanded the definition of HER2-positive population and included patients with immunohistochemistry "2+/3+"
.

As of June 22, 2020, the C008 study enrolled 127 patients with HER2 overexpression gastric cancer or gastroesophageal junction adenocarcinoma who received second-line chemotherapy.
The objective response rate and disease control rate were 24.
4% and 41.
7%, and the progression-free survival and total The survival periods are 4.
1 months and 7.
6 months, respectively.
These data indicate that the drug can effectively treat HER2-positive advanced gastric cancer [13]
.

Based on the C008 study, the China National Medical Products Administration approved the listing of Vidicuzumab
.

 Vidicuzumab not only rewrites the pattern of anti-HER2 late-line therapy for advanced gastric cancer, but also lays the foundation for the expanded use of ADC in HER2-positive gastric cancer
.

 In summary, ADC has received a lot of attention and expectations in the field of tumor treatment
.

Although T-DM1 did not achieve a positive result in HER2-positive gastric cancer, the efficacy of the new drug DS-8201 and the domestic drug vedicitumumab is surprising and brings new hope to patients with advanced HER2-positive gastric cancer
.

References 1.
Gravalos C, Jimeno A.
HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target.
Ann Oncol 2008;19:1523-9.
2.
Bang YJ, Van Cutsem E, Feyereislova A, et al.
Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.
Lancet 2010;376:687-97.
3.
Tabernero J, Ho PM, Shen L, et al.
Pertuzumab plus trastuzumab and chemotherapy for HER2- positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo- controlled phase 3 study.
Lancet Oncol 2018;19:1372-84.
4.
Hecht JR, Bang YJ, Qin SK, et al.
Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor receptor 2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: TRIO-013/LOGiC-a randomized phase III trial.
J Clin Oncol 2016;34:443-51.
5.
Verma S, Miles D, Gianni L, et al.
Trastuzumab emtansine for HER2-positive advanced breast cancer.
N Engl J Med 2012;367:1783-91.
6.
Thuss-Patience PC, Shah MA, Ohtsu A, et al.
Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study.
Lancet Oncol 2017;18: 640-53.
7.
Seo S, Ryu MH, Park YS, et al.
Loss of HER2 positivity after anti-HER2 chemotherapy in HER2-positive gastric cancer patients:results of the gastric cancer HER2 reassessment study 3 (GASTHER3).
Gastric Cancer 2019;22: 527-35.
8.
Creemers A, Ter Veer E, de Waal L, et al.
Discordance in HER2 status in gastro-esophageal adenocarcinomas: a systematic review and meta-analysis.
Sci Rep 2017;7:3135.
9.
Joubert N, Beck A, Dumontet C, et al.
Antibody-drug conjugates: the last decade.
Pharmaceuticals (Basel) 2020;13:245.
10.
Shitara K , Iwata H, Takahashi S, et al.
Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study.
Lancet Oncol 2019;20:827-36.
11.
Shitara K , Bang YJ, Iwasa S, et al.
Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer.
N Engl J Med 2020;382:2419-30.
12.
Xu Y, Wang Y, Gong J, et al.
Phase I study of the recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate RC48-ADC in patients with HER2-positive advanced solid tumors.
Gastric Cancer 2021;24:913-25.
13.
Peng Z, Liu TS, Wei J, et al.
A phase 2 study of efficacy and safety of RC48-ADC in patients with locally advanced or metastatic HER2- overexpressing gastric or gastroesophageal junction cancers.
2020 ASCO, 4560P.
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