Astellas' first Claudin18.2 antibody Zolbetuximab was successfully clinically successful in the treatment of Cldn18.2-positive gastric adenocarcinoma or gastroesophageal junction adenocarcinoma stage III

On November 16, 2022, Astellas announced positive top-line results from a Phase 3 SPOTLIGHT clinical trial evaluating the efficacy and safety
of Claudin18.
2 antibody zolbetuximab in combination with mFOLFOX6, a drug combination regimen including oxaliplatin, calcium folinate, and fluorouracil 。 The SPOTLIGHT trial enrolled 566 patients
with cldn 18.
2-positive, HER2-negative, locally advanced unresectable or metastatic gastric adenocarcinoma or gastroesophageal junction (GEJ) adenocarcinoma.
This is also the first positive outcome of a drug targeting Claudin18.
2 in a registered clinical trial
.

Zolbetuximab (claudiximab) is a first-in-class chimeric monoclonal immunoglobulin G1 antibody that recognizes and binds to Claudin 18.
2 (CLDN18) with high specificity without cross-binding with other CLDNs, mediating tumor cell death
through antibody-dependent cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
Claudin 18.
2 is a gastric-specific membrane protein that is considered a potential therapeutic target for gastric cancer and various other solid tumors
.
About 50% of gastric cancer patients have this mutation
.

CLDN18.
2 was initially found to be consistently and stably expressed in a variety of gastric cancer tissues, but subsequent studies have shown that it can also be abnormally activated and overexpressed in a variety of primary malignancies such as breast, colon, liver, head and neck, bronchial cancer and non-small cell lung cancer, especially in malignant tumors of the digestive system, including gastric cancer (70%), pancreatic cancer (50%), esophageal cancer (30%), etc
.

In this phase III clinical trial codenamed SPOTLIGHT (NCT03504397), a total of 566 patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction cancer (GEJ) with CLDN18.
2+/HER2- were enrolled, with Zolbetuximab+mFOLFOX6 in the experimental group and placebo+mFOLFOX6
in the control group.
Both the primary clinical endpoint PFS and the secondary clinical endpoint OS reached significance, and the adverse reactions were mainly gastrointestinal reactions
such as nausea, vomiting, and loss of appetite.

The study met its primary endpoint, namely that zolbetuximab + mFOLFOX6-treated patients had a statistically significant progression-free survival (PFS) compared to placebo + mFOLFOX6; In addition, the study also met the secondary endpoint that the overall survival (OS) of patients treated with zolbetuximab + mFOLFOX6 was statistically significant
compared to placebo + mFOLFOX6.
In patients treated with zolbetuximab in combination with mFOLFOX6, the most common treatment-urgent adverse events were nausea, vomiting, and loss of appetite
.
Detailed results will be presented
at a future scientific conference.

Zolbetuximab has two phase II clinical trials, ILUSTRO and FAST studies
.

The FAST results were published last year in
the Annals of Oncology.
The FAST study included tumor cells
with medium to strong Claudin 18.
2 expression ≥ 40% in patients with advanced gastric/gastroesophageal junction cancer and esophageal adenocarcinoma (age ≥18 years).
Patients received either first-line epirubicin + oxaliplatin + capecitabine (EOX, group 1, n=84) every 3 weeks (Q3W), or Zolbetuximab + EOX (loading dose, 800 mg/m2, then 600 mg/m2 Q3W) (group 2, n=77).

Group 3 (exploratory) was added after enrollment began (Zolbetuximab + EOX 1000 mg/m2 Q3W, n=85).

The primary endpoint was progression-free survival (PFS), with overall survival (OS) as the secondary endpoint
.

The results showed that the median PFS of Zolbetuximab plus EOX was 7.
5 months (n=77) in the entire patient population compared to 5.
3 months (n=84; heart rate, 0.
44; 95% confidence interval 0.
29-0.
67; P<0.
0005)
in the EOX group alone 。 In patients with Claudin 18.
2-positive cells accounting for 70% or more, median PFS were 9.
0 months (n=57) and 5.
7 months (n=59), respectively (HR 0.
38; 95% confidence interval 0.
23-0.
62; P<0.
0005).

Among Claudin 18.
2-positive tumor cells accounted for 40%~69%, the median PFS was 4.
3 months (n=20) and 4.
1 months (n=20), respectively (HR was 0.
71; 95% CI, 0.
32-1.
57; P=0.
497).

Across the patient population, median OS was 13.
0 months in the Zolbetuximab plus EOX group compared with 8.
3 months in the EOX alone group (HR, 0.
55; 95% confidence interval 0.
39–0.
77; P<0.
0005).

Claudin 18.
2-positive cells accounted for more than 70% of patients, and median survival was 16.
5 and 8.
9 months, respectively (HR, 0.
50; 95% CI, 0.
33-0.
74; P<0.
0005).

Claudin 18.
2-positive tumor cells accounted for 40%~69%, and the median survival was 8.
3 months and 7.
4 months, respectively (HR 0.
78; 95% confidence interval 0.
40-1.
49; P=0.
401).

The objective effective rate (ORR) for each independent assessment was 39% for the Zolbetuximab combined with EOX group and 25%
for the EOX alone group.
According to the investigators' assessment, the ORRs were 37.
7% and 26.
2%,
respectively.
According to independent assessments, the disease control rates were 83.
1% and 76.
2%, respectively, and according to the investigators' assessment, the disease control rates were 83.
1% and 81%,
respectively.

In terms of safety, any grade of adverse reactions (AEs) were observed in 96.
1% of patients in the Zolbetuximab plus EOX group, compared to 100%
in the EOX group.
Among them, grade 3 and above adverse events accounted for 70.
1% and 64.
3%
respectively.
The most common adverse effects in both groups included nausea, vomiting, neutropenia, and anemia
.
Of note, patients who received Zolbetuximab and underwent total or partial gastrectomy (n=8/21) had a lower incidence of vomiting than patients who did not undergo gastrectomy (n=44/56).

However, the competition for Claudin 18.
2 target drugs is very fierce, see: within half a year, 6 domestic Claudin 18.
2 innovative drugs were approved for clinical trials, and the global research has entered a boom

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Within half a year, 6 domestically produced Claudin 18.
2 innovative drugs were approved for clinical trials, and the global research has entered a boom