The first-line triple therapy for gastric cancer was approved, and four other new drugs opened up a new pattern in the treatment of HER2-positive gastric cancer

Author: Cornflower This article is published by Yimaitong authorized by the author, please do not reprint without authorization.

On May 5, the U.
S.
Food and Drug Administration (FDA) announced the accelerated approval of PD-1 monoclonal antibody pembrolizumab (commonly known as K drug) in combination with trastuzumab and chemotherapy (containing fluorouracil and platinum) for HER2 positive First-line treatment for unresectable locally advanced/metastatic gastric and gastroesophageal junction (GEJ) cancer.

The approval of this regimen means that the triple regimen of drug K combined with trastuzumab + chemotherapy will be expected to rewrite the clinical guidelines for the first-line treatment of HER2-positive gastric cancer.

This approval is based on the interim analysis results of Keynote-811 (NCT03615326) [1] clinical trials.

The trial is a multicenter, randomized, double-blind, placebo-controlled clinical trial.
The patients are all HER2-positive advanced gastric and gastroesophageal junction cancer patients who have not previously received systemic treatment.

These patients were randomized to receive K drug or placebo every 3 weeks in a 1:1 ratio, combined with trastuzumab and fluorouracil + cisplatin or capecitabine + oxaliplatin.

 The results of the interim analysis showed that among the 264 initially enrolled patients, the primary efficacy endpoint objective response rate (ORR) of the K drug group was 74% (95% CI: 66,82), while the placebo group was 52% (95% CI: 66,82).
%CI: 43,61), the unilateral p value is less than 0.
0001, which is statistically significant.

The median duration of response (DoR) in the K drug group was 10.
6 months, while that in the placebo group was 9.
5 months.

The detailed data are as follows: In terms of safety, 6% of patients in both the K drug group and the control group discontinued their participation in the trial due to adverse reactions.

The most common adverse reaction leading to the permanent discontinuation of K drug was pneumonia (1.
4%).

 This approval is an important milestone event.
This is the first time the FDA has approved anti-PD-1 therapy combined with anti-HER2 therapy and chemotherapy as the first-line treatment for patients with HER2-positive gastric cancer, showing clinically significant improvements in ORR.

 HER2-positive gastric cancer is a special type of gastric cancer, accounting for about 20% of all gastric cancer types.

The current recommended first-line treatment is chemotherapy combined with trastuzumab, but the efficacy is limited.
The median overall survival (OS) is 13.
8 months, and the ORR is only 47% [2].

With the deepening of the research on the pathogenic mechanism of gastric cancer, a batch of new drugs for the treatment of HER2-positive gastric cancer has emerged, which is expected to open a new pattern in the treatment of HER2-positive gastric cancer.

 1.
Trastuzumab Deruxtecan (DS-8201) [3] DS-8201 is a new generation of antibody drug conjugate (ADC), through a 4-peptide linker to target HER2 humanized monoclonal antibody trastuzumab The monoclonal antibody is linked with a new type of topoisomerase 1 inhibitor exatecan derivative (DX-8951 derivative, DXd), which can target the delivery of cytotoxic agents to cancer cells.
Compared with usual chemotherapy, it can reduce Systemic exposure to cytotoxic agents.

 The FDA has approved DS-8201 for HER2-positive locally advanced or metastatic gastric cancer and GEJ adenocarcinoma patients treated with trastuzumab.
This approval is based on the Phase II DESTINY-Gastric01 study.

 The study enrolled 189 patients with HER2-positive advanced gastric cancer or gastroesophageal junction adenocarcinoma (defined as: IHC3+ or IHC2+/ISH+) from Japan and South Korea.
These patients had previously received 2 or more regimens (including 5-FU, Platinum chemotherapy, trastuzumab), but the disease progressed.

The patients were randomly assigned at a ratio of 2:1 and received DS-8201 (6.
4 mg/kg) or chemotherapy (paclitaxel or irinotecan monotherapy) selected by the investigator, once every three weeks.

The results showed that the study reached the primary and key secondary endpoints: (1) Compared with the chemotherapy group, the DS-8201 treatment group achieved statistically significant and clinically significant improvements in ORR and OS.

(2) The interim analysis showed that the risk of death in the DS-8201 group was reduced by 41% compared with the chemotherapy group (HR=0.
59; 95%CI: 0.
39-0.
88; p=0.
0097).

The median OS was 12.
5 months in the DS-8201 group and 8.
4 months in the chemotherapy group.

(3) The overall safety and tolerability of DS-8201 are consistent with the previously announced phase I trial.

 2.
ARX788 [4] ARX788 is a precisely designed ADC that is specifically linked to an antibody with trastuzumab as the basic skeleton by two cytotoxins.

Through a series of design and screening of the number, position and chemical bond of the cytotoxin AS269 (a tubulin inhibitor), the activity of ARX788 in preclinical experiments has been maximized.

 The ongoing Phase I clinical trial shows that in patients with metastatic gastric cancer who have been treated with trastuzumab and chemotherapy, ARX788 has shown promising anti-tumor activity.

It is expected that more data from the phase I clinical trial will be released by the end of 2021, and a global phase III clinical trial will be launched in the second half of 2021 to test the efficacy of ARX788 as a second-line therapy for the treatment of HER2-positive gastric cancer.

 3.
ZW25 [5] ZW25 is a bispecific antibody that can simultaneously bind to two non-overlapping epitopes of HER2, called biparatopic binding, and has been proven to be resistant to a variety of tumors.

 Such a new type of bispecific antibody is effective across cancer and has mild side effects, which makes the academic community very excited.

In a phase I clinical trial, 3/4 line treatment of HER2-positive gastric cancer patients (90% received HER2-targeted therapy).

The results showed that ZW25 monotherapy had an ORR of 33% and a disease control rate (DCR) of 61%; combined chemotherapy had a better effect, with an ORR of 54% and a DCR of 79%.

 4.
Margetuximab [6] Margetuximab is an Fc-optimized monoclonal antibody targeting HER2, which has HER2 binding and anti-proliferative effects similar to trastuzumab, but the Fc optimization technology has been engineered to enhance its immune system Participation.

 In an open-label, dose-escalation, and expanded phase II study (NCT02689284) analysis, a total of 95 HER2-positive (IHC3-positive or ICH2-positive/FISH-positive) gastroesophageal cancer patients were included, and 94% of the patients received first-line treatment 6% of patients received ≥2 lines of treatment, and all patients had received trastuzumab treatment, with a median follow-up of 19.
9 months (IQR 10.
7-23.
1).

The primary study endpoint is safety and tolerability, and the secondary study endpoint is ORR.

 The results of the study showed that: DCR was 53%; ORR was 18% (95% CI 11.
15–27.
93); PFS was 2.
73 months (95% CI, 1.
61–4.
34), of which ITT (intention-to-treat population) was 3 months (95% CI 11.
15–27.
93) % CI 2–4); OS was 12.
48 months (95% CI, 9.
07-14.
09), of which ITT was 13 months (95% CI 9-14).

 Subgroup analysis showed that patients with HER2 IHC3+, PD-L1+ and HER2 amplification had better efficacy than HER2 IHC2+, PD-L1- and patients without HER2 amplification, among which patients with HER2 IHC3+, PD-L1+ and HER2 amplification at the same time The best curative effect is 60% ORR and 80% DCR.

 As a tyrosine kinase receptor protein that promotes cell growth, HER2 is expressed on the surface of a variety of tumor cells such as gastric cancer, breast cancer, and lung cancer.
It is often associated with aggressive diseases and poor prognosis.

In summary, the development of drugs for this target, including ADCs, double antibodies, and monoclonal antibodies, has the most potential.
The spring for HER2-positive gastric cancer patients has arrived.

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References: 1.
FDA Approves Merck's KEYTRUDA® (pembrolizumab) Combined With Trastuzumab and Chemotherapy as First-line Treatment in Locally Advanced Unresectable or Metastatic HER2-Positive Gastric or Gastroesophageal Junction Adenocarcinoma.
Retrieved May 5, 2021, from 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.
https ://www.
astrazeneca.
com/media-centre/press-releases/2020/enhertu-us-priority-review-in-gastric-cancer.
html.
4.
Ambrx Granted Orphan Drug Designation for ARX788 for the Treatment of Gastric Cancer.
Retrieved March 17, 2021, from /record/185492/abstract.
6.
Margetuximab plus pembrolizumab in patients with previously treated, HER2-positive gastro-oesophageal adenocarcinoma (CP-MGAH22–05): a single-arm, phase 1b–2 trial.