Will a new treatment option be introduced for gastric cancer

...the 2 studies that receive attention at ASCO 2023

[ASCO 2023] Clinical results of zolbetuximab and Keytruda released

Zolbetuximab offers a new targeted therapy option... improved PFS by 2 times

Keytruda demonstrates positive effects in patients with CPS between 1-4

Unlike lung cancer and breast cancer, gastric cancer has been regarded as one type of cancer that has not benefited from the development of new anticancer drugs.

 

For the past decade, chemotherapy has been the standard first-line treatment for patients with HER2 gene-negative metastatic gastric cancer.

 

This means that there were no suitable new drugs other than HER2-targeting anticancer drugs available for its treatment.

 

However, changes have recently occurred in the treatment of gastric cancer.

 

The immuno-oncology drug ‘Opdivo’ emerged as a first-line option, another immuno-oncology drug 'Keytruda' also obtained positive results.

 

A targeted therapy that targets a new protein is also expected to enter the market.

 

Two noteworthy studies in the field of gastric cancer were presented at the ‘2023 ASCO Annual Meeting (ASCO 2023)’ that was held for 5 days from the 2nd (local time).

 

The two were: results from the Phase III trial of ‘zolbetuximab,’ a targeted anticancer drug that targets CLDN18.2 (Claudin 18.2), and results from a Phase III trial that reviewed the first-line treatment of Keytruda in gastric cancer.

 

Primary endpoint results of Phase III GLOW trial on zolbetuximab (Data: ASCO)

Zolbetuximab is a new drug being developed by Astellas that targets CLDN18.2 for the first time among anticancer drugs.

 

Claudin 18.2 is a protein mainly present on the surface of gastric cancer cells.

 

Although the protein is also present in normal cells, it is expressed at high levels in certain malignant tumors.

 

Claudin 18.2 is known to be involved in the proliferation, differentiation, and metastasis of cancer cells.

 

The GLOW clinical trial that was announced this year, compared zolbetuximab + CAPOX (capecitabine + oxaliplatin) combination therapy with just CAPOX in 507 patients with advanced·metastatic gastric cancer who were CLDN18.2 positive.

 

Of those involved, 78% had a PD-L1 combined positive score (CPS) less than 5.

 

Min-Hee Ryu, Professor of Oncology at Asan Medical Center

The primary endpoint, median progression-free survival was significantly higher - 8.2 months - in the zolbetuximab group compared with the 6.8 months in the placebo group (HR=0.69).

 

At 24 months, the PFS rate in the zolbetuximab group was 14%, twice higher than the 7% in the placebo group.

 

The secondary endpoint, overall survival (OS) was 14.4 months in the zolbetuximab group and 12.2 months in the placebo group, demonstrating a 23% reduction in risk of death with zolbetuximab (HR=0.77).

 

In addition, the objective response rate was 53.8% and the duration of response was 6.3 months in the zolbetuximab group.

 

During an interview with Dailypharm, Min-Hee Ryu, Professor of Oncology at Asan Medical Center, said, “Zolbetuximab is expected to bring a positive effect as it has demonstrated superiority in OS as well as PFS.

 

In terms of side effects, although the frequency of nausea and vomiting, which was different from those of existing drugs, was high with zolbetuximab, but appears to be at a manageable level.

 

I believe the side effects arise because the targeted claudin protein is also present in normal cells.” Another noteworthy clinical trial is the Phase III KEYNOTE-859 that was conducted to evaluate Keytruda’s effect as a first-line treatment for gastric cancer.

 

This clinical trial is significant in that MSD succeeded in changing the design of the KEYNOTE-062 clinical trial, which had previously failed in the first-line, and was led by Korean medical staff.

 

The clinical trial compared Keytruda with the chemotherapy CAPOX or 5-FU (5-fluorouracil) to chemotherapy alone in patients with HER2-negative gastric cancer.

 

The trial also measured the therapy’s effect according to the patient’s PD-L1 CPS score.

 

The primary endpoint was overall survival (OS).

 

Primary endpoint results of KEYNOTE-859 study on Keytruda as first-line therapy in gastric cancer (Data: ASCO)

Trial results showed that the median overall survival (OS) of the Keytruda group was 12.9 months, reducing the risk of death by 22% compared with placebo (HR=0.78).

 

Keytruda’s effect increased with the increase in CPS.

 

The hazard ratio was 0.83 in the patient group with a CPS score of 1 to 10, and the hazard ratio was 0.64 in the patient group with a CPS score of 10 or more.

 

This means that in patients with a CPS score of 10 or higher, Keytruda lowered the risk of death by 35%.

 

In addition, the Keytruda group demonstrated significant efficacy in secondary key endpoints as well, including PFS.

 

Sun-Young Rha, Professor of Oncology at Yonsei Cancer Hospital,

Another immuno-oncology drug, 'Opdivo,' had proven its efficacy in patients with a CPS score of 5 or higher and obtained an indication for the first-line treatment of gastric cancer.

 

Although Keytruda succeeded in demonstrating its effect later than Opdivo, it is meaningful as the results included PD-L1 CPS 1-4 point patients.

 

Sun-Young Rha, Professor of Oncology at Yonsei Cancer Hospital, said, “The fact that Keytruda showed an improvement with a hazard ratio of 0.83 even in patient groups that include patients with CPS 1 to 4, demonstrates that patients with a CPS of 1 or more may use the immunotherapy.” They agreed that it will become necessary to devise an effective treatment strategy according to the CPS score when zolbetuximab is introduced in the future.

 

Professor Ra said, "Our task for the future in gastric cancer is to reach a consensus on how to treat patients who are both CLDN18.2 positive and PD-L1 positive." Professor Rhu added, “There is some overlap between the areas for the use of zolbetuximab and immuno-oncology drugs.

 

in patients with CPS between 5 to 10, the effects of the two drugs are likely to be similar, so the side effect aspect should be considered.

 

For those with a CPS of 10 or higher, immuno-oncology drugs are definitely more effective."