麻豆传媒

This year's American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium featured many highlights on gastroesophageal, gastric, and gastroesophageal junction (GEJ) cancer. In this exclusive 麻豆传媒 video, Lakshmi Rajdev, MD, of Icahn School of Medicine at Mount Sinai in New York City, discusses several key abstracts from the meeting and their implications for clinical practice.

Following is a transcript of her remarks:

This year at ASCO GI there was a lot of exciting data that was presented that clearly advances therapeutic options for patients with gastric cancer.

The study that probably generated the most interest as it relates to gastric cancer was the SPOTLIGHT trial. So in the SPOTLIGHT trial, previously untreated Claudin 18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma patients were randomized to zolbetuximab plus mFOLFOX6 [leucovorin, fluorouracil, and oxaliplatin] or placebo plus mFOLFOX6.

First-line treatment with zolbetuximab combined with mFOLFOX6 led to significantly longer progression-free survival and overall survival. The primary endpoint of the study was actually progression-free survival, and overall survival was a secondary endpoint and was to be calculated only until progression-free survival was statistically significant. Of note, there was really no difference in the response rate between the two arms.

So just a word about Claudin 18.2, which is a type of transmembrane protein found in normal gastric cells and is a major component of epithelial and endothelial tight junctions, and it controls the flow of molecules between cells. It's been shown that Claudin 18.2 expression becomes more and more exposed and accessible to targets as a gastric cancer develops.

Now, Claudin 18.2 is expressed in multiple GI cancers. It's also been known to be expressed in gastric cancer and pancreatic cancer amongst other GI cancers. Claudin 18.2 is not expressed in any healthy tissues, with the exception of the gastric mucosa.

In this particular study, about 38% of patients screened positive for Claudin 18.2 tumors, and tumors were defined as being positive if they had expression of Claudin 18.2 in greater than 75% of tumor cells with strong to moderate staining intensity based on a validated immunohistochemistry assay.

Zolbetuximab acts by binding to Claudin 18.2 on cancer cells' surface of gastric epithelial cells, and it initiates death by activating two distinct immune system pathways -- antibody-dependent cellular toxicity and complement-dependent.

The most frequent side effects of this combination are nausea, vomiting, and loss of appetite. And these are really considered on-target Claudin 18.2 effects. It's important to treat the nausea and vomiting early as these effects often occur earlier in earlier treatment cycles and they are often managed by dose adjustment or interruption. And over time in the latest cycles, these effects actually appear to decrease.

Interestingly, in the SPOTLIGHT trial the longest survival in gastric cancer in a phase III trial was reported with a median overall survival of about 15 months in the control arm. And in the investigational arm it was 18 months.

The is evaluating the efficacy of zolbetuximab plus capecitabine and oxaliplatin. That's the CAPOX regimen. And that study has also been reported as being positive.

Zolbetuximab is being studied in combination with immunotherapy agents in patients with Claudin 18.2-positive metastatic or advanced unresectable gastric and GEJ cancer in the study.

Now, clearly, Claudin 18.2 is an important target in gastric cancer. Notably, last year there was a report of Claudin 18.2-targeted CAR T cells in patients with previously treated Claudin 18.2-positive digestive system cancers. Now, in particular in patients with gastric cancer, the overall response rate was 57%, and the disease control rate was 75% and 6-month overall survival was 81%. So this really establishes Claudin 18.2 as an important target in gastric cancer.

There were two other studies which I found interesting. One was the , and this study was conducted to determine if treatment with regorafenib improves overall survival in patients with refractory advanced GE junction cancer. So patients were randomized in a 2:1 fashion to regorafenib plus best supportive care versus best supportive care. And it resulted in an overall survival hazard ratio of 0.68 and a 12-month survival rate of 19% compared to 6% for the placebo arm. Regorafenib also delayed deterioration in global quality of life compared with control.

There's another study being planned comparing regorafenib plus nivolumab to investigator's choice of chemotherapy in patients with advanced GE junction cancer.

Another interesting study was the . So this was a multicenter single-arm, two-cohort, phase II trial that was investigating the activity and safety of tremelimumab and durvalumab as neoadjuvant therapy in patients with MSI [microsatellite instability]-high and mismatched repair deficient and EBV [Epstein Barr virus]-negative resectable gastric or gastroesophageal junction adenocarcinoma.

The Cohort 2 plans to look at this same treatment as definitive therapy. So patients in Cohort 1 received a single high dose of tremelimumab and durvalumab for three cycles. The primary endpoint was pCR [pathological complete response] with negative ct [circulating tumor]DNA after these three cycles. Among 15 evaluable patients, one had disease progression and 14 underwent resection. So the pCR rate was about 60%, and major complete pathologic response of less than 10% viable cells was 80%.

All patients who had a pCR had a negative ctDNA status; pCR rate was actually only 17% in patients with T4 disease and almost 90% in T2 to T3 disease. And interestingly, there was no correlation to baseline nodal status or PD-L1 CPS [combined positive score]. And it was a nonsignificant trend of TMB [tumor mutational burden] correlation with pCR. Three patients had greater than Grade 3 immune-related adverse events, but they resolved the treatment with high-dose steroids and did not really impair surgery.

So the study validates the activity of neoadjuvant immunotherapy in this patient population. The [study] excluded patients with T4 disease and in the next cohort. We really need additional follow-up to evaluate the durability of these outcomes. Additionally, the number of patients are very small in this trial and in the trial that was presented last year.

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