A new world has been opened.

On October 19, Astellas announced that the U.S. FDA has approved its Claudin18.2 (CLDN18.2) targeted antibody Zolbetuximab for first-line treatment of adults with locally advanced unresectable or metastatic, HER2-negative gastric cancer or gastroesophageal junction adenocarcinoma, in combination with fluoropyrimidine and platinum-based chemotherapy regimens. According to internal predictions from Astellas, Zolbetuximab's peak sales are expected to reach between 100 billion and 200 billion Japanese yen (approximately 6.67-13.34 billion USD) by 2030. This is the first Claudin18.2 targeted drug approved by the FDA globally, signifying its importance and highlighting the vast market opportunities it presents.

The Untapped Market for Gastric Cancer

According to the WHO data from 2020, gastric cancer ranks fifth in incidence and third in mortality worldwide. In China, there were 478,000 new cases (accounting for 43.9%) and 373,000 deaths (accounting for 48.5%), making it the country with the highest number of gastric cancer cases and deaths globally. Early-stage gastric cancer can be cured through surgery, with a five-year survival rate exceeding 90%. 

However, a considerable number of patients in China are diagnosed at an advanced stage, with statistics indicating that 31.7% of patients are stage III and 42.4% are stage IV at the time of diagnosis (with late-stage gastric cancer accounting for 74%, a very high percentage). 

Overall, advanced gastric cancer (including gastroesophageal junction cancer) remains one of the cancers with the worst prognosis, with a five-year survival rate of only about 6%.

According to the 2023 CSCO guidelines for first-line treatment options for advanced metastatic gastric cancer, the use of multi-drug combination therapy largely revolves around HER2 monoclonal antibodies and PD-1 monoclonal antibodies. However, even with first-line therapies like PD-1 monoclonal antibodies, the median survival time for patients remains around one year, indicating a significant unmet clinical need in this indication area. Existing studies show that approximately 22% of gastric cancer patients are HER2-positive, while the remaining are HER2-negative, which means the population of HER2-negative gastric cancer patients is even larger.

Recently, the FDA's Oncology Drug Advisory Committee (ODAC) held a meeting where experts opposed the use of PD-1 inhibitors in patients with HER2-negative, PD-L1 ≤ 1% gastric and gastroesophageal junction adenocarcinoma. Currently, Keytruda (K drug) and Opdivo (O drug) have been approved in the U.S. for first-line treatment of HER2-negative gastric cancer (regardless of PD-L1 expression). Given the limited efficacy of existing drugs and the restricted patient population for PD-1 inhibitors, this clearly provides more room for new generation gastrointestinal cancer targets like CLDN18.2 to break through.

CLDN18.2: A New Target

As a subtype of the tight junction protein family, CLDN18.2 is expressed in nearly all gastric cancer patients and has no expression in normal human tissues. In comparison, while HER2 is highly expressed in only 20% of gastric cancer patients, the high expression rate of CLDN18.2 among gastric cancer patients can reach 50%-60%. Frost & Sullivan forecasts that the global gastric cancer drug market will grow from $22.1 billion in 2024 to $36.4 billion by 2030, with a CAGR of 8.7%. Regarding the CLDN18.2 antibody market, it is projected that from 2025 to 2035, the antibody markets in the U.S. and China will grow from $252 million and $200 million to $4.036 billion and $3.744 billion, respectively, with CAGRs reaching 32.0% and 33.5%; gastric cancer will contribute significantly to market growth.

Market Gap Left by Zolbetuximab

Astellas' Zolbetuximab, as the first CLDN18.2 drug to hit the market globally, is expected to enjoy at least a two-year market exclusivity based on its global development progress. Despite Zolbetuximab's first-mover advantage, it has many "imperfections" from various dimensions, leaving significant competitive space for subsequent CLDN18.2 developments. The FDA's early approval of Zolbetuximab for the treatment of HER2-negative gastric cancer or gastroesophageal junction adenocarcinoma is primarily based on the positive results from the SPOTLIGHT and GLOW Phase III clinical trials. The SPOTLIGHT trial was designed to compare "Zolbetuximab + mFOLFOX6" (oxaliplatin, leucovorin, and fluorouracil combination chemotherapy) with "placebo + mFOLFOX6," while the GLOW trial compared "Zolbetuximab + CAPOX" (capecitabine and oxaliplatin chemotherapy) with "placebo + CAPOX." The primary endpoint of the trials was progression-free survival (PFS), with key secondary endpoints including overall survival (OS).

Data from the SPOTLIGHT study indicated that compared to the control group, "Zolbetuximab + mFOLFOX6" extended the median PFS by 1.94 months (10.61 months vs. 8.67 months, HR=0.75) and the median OS by 2.69 months (18.23 months vs. 15.54 months, HR=0.75). Data from the GLOW study indicated that compared to the control group, "Zolbetuximab + CAPOX" extended the median PFS by 1.41 months (8.21 months vs. 6.8 months, HR=0.687) and the median OS by 2.23 months (14.39 months vs. 12.16 months, HR=0.771).

In terms of safety, the most common serious adverse events in both studies included nausea, vomiting, and decreased appetite. The incidence of the most common serious adverse events was similar and consistent with trends from previous studies. After analyzing the trial data, it appears that Zolbetuximab may face the most competition in three areas: the mid-low expression population, efficacy, and safety risks. The approved indication for Zolbetuximab is limited to patients with high expression of CLDN18.2 (≥75%), and statistics indicate that only about 20% of gastric cancer patients have high CLDN18.2 expression (data may vary), meaning the drug clearly cannot meet the clinical needs of patients with mid-low CLDN18.2 expression. 

Additionally, in the SPOTLIGHT and GLOW studies, the total survival benefit was no more than three months, indicating limited potential for improvement. Furthermore, Zolbetuximab's lack of specificity for its target has resulted in relatively high safety risks in clinical practice, with ≥ Grade 3 treatment-emergent adverse events (TEAEs) exceeding 69% in both Phase III studies, leaving more optimization space for subsequent developers.

Diverse Domestic CLDN18.2 Targeted Drugs

In China, the development pipeline for CLDN18.2 targeted drugs is flourishing, with a variety of drug types including monoclonal antibodies, bispecific antibodies, ADCs, and CAR-T therapies. In terms of progress, CLDN18.2 monoclonal antibodies are at the forefront, followed closely by CLDN18.2 ADCs. Among monoclonal antibodies, TST001 from Chuangsheng Group stands out as it has initiated a global Phase III clinical trial (TranStar 301) combining O drug and chemotherapy for first-line treatment of HER2-negative, CLDN18.2-expressing gastric cancer or gastroesophageal junction adenocarcinoma. According to the latest data presented at ASCO 2023, 64 patients were enrolled in the TST001 treatment group, with a median duration of response (DOR) of 9.9 months and a median progression-free survival (PFS) of 9.5 months. The highlights of this trial are: 

1) The patient population is not limited to those with high CLDN18.2 expression, as its definition of CLDN18.2 positivity is broader (covering 55% of gastric cancer patients), showing benefits across different expression groups; 

2) The efficacy data of the combined CAPOX regimen show superior potential compared to Zolbetuximab (mPFS 9.5 months vs. 8.21 months, for reference).

Another noteworthy monoclonal antibody is ASK589 from OSAI, which is currently in Phase III clinical trials in China. The latest published Phase I/II data shows that among 24 patients with high expression of CLDN18.2 receiving ≥6 mg/kg doses, the objective response rate (cORR) was 79.2%, and the disease control rate (DCR) reached 95.8%, with efficacy being dose-dependent. Notably, most adverse events in this trial were of grades 1-2 and related to chemotherapy toxicity, highlighting promising safety potential.

The rapid progress of domestic CLDN18.2 ADCs has been praised by investors, with four drugs currently in Phase III clinical trials: IBI343 from Innovent Biologics, CMG901 from Kangnoa, LM-302 from Lixin Pharmaceuticals, and SHR-A1904 from Heng Rui Pharmaceuticals. The indications for these CLDN18.2 ADCs in Phase III trials differ from those of CLDN18.2 monoclonal antibodies, primarily targeting second-line and beyond patients with advanced or metastatic gastric and gastroesophageal junction adenocarcinoma. Some molecules have already shown remarkable potential in early data: 

1) CMG901 from Kangnoa reported a median PFS of 4.8 months and a median OS of 11.8 months in 93 patients with high expression CLDN18.2 gastric cancer/gastroesophageal junction adenocarcinoma in Phase I data; 

2) IBI343 from Innovent Biologics showed excellent efficacy in high expression CLDN18.2 gastric or gastroesophageal junction adenocarcinoma, with a 36.7% ORR and a median PFS of 6.8 months in the 6 mg/kg dose group with 30 patients in the Phase I study; 

3) LM-302 from Lixin Pharmaceuticals showed an ORR of 30.6%, a DCR of 75.0%, and a median PFS of 7.16 months in 36 patients with second-line or beyond gastric or gastroesophageal junction adenocarcinoma in the Phase I/II data.

Besides CLDN18.2 monoclonal antibodies and ADCs, domestic bispecific antibodies and CAR-T therapies also have bright prospects, with early positive data reported for IBI-389 from Innovent Biologics, ABL111 from Tianjing Biologics, and CT041 from Keji Biologics.

Conclusion

The past lack of effective innovative treatment drugs has resulted in a short survival period for patients with advanced gastric cancer, likely limiting the expansion of the gastric cancer drug market. With Astellas' Zolbetuximab breaking through first, it is believed that more innovative targeted drugs will see breakthroughs, and China, as a country with a high incidence of gastrointestinal cancers, is clearly a breeding ground for relevant blockbuster products and resilient biotech companies.