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Results of two early-phase trials offered a glimpse of promising new agents in the pipeline for advanced gastroesophageal cancer.

In a phase II study, incorporating an investigational PD-1 inhibitor and anti-T-cell immunoglobulin and ITM domain (TIGIT) monoclonal antibody into standard first-line chemotherapy showed promising activity in advanced gastroesophageal adenocarcinoma, reported Yelena Janjigian, MD, from Memorial Sloan Kettering Cancer Center in New York City.

Addition of the anti-PD-1 and anti-TIGIT drugs (zimberelimab and domvanalimab) to FOLFOX chemotherapy led to a confirmed response rate of 56% and a 6-month progression-free survival (PFS) rate of 77%. And the subset with high PD-L1 tumor expression had numerically higher response and PFS rates as well.

Separately, in updated findings from a phase I study of patients with claudin 18.2 (CLDN 18.2)-positive gastric or gastroesophageal junction (GEJ) cancers who were refractory to standard therapies, single-agent treatment with a CLDN 18.2-targeting antibody-drug conjugate was associated with a median PFS of 4.8 months and an overall survival (OS) rate of 56.4% at 9 months, reported Rui-Hua Xu, MD, PhD, from Sun Yat-sen University Cancer Center in Guangzhou, China.

Additionally, 32.6% of patients had confirmed responses with the first-in-class investigational drug, CMG901, and at the highest dose levels, the median PFS reached 14.5 months while median OS was not reached.

The PFS and OS results were "encouraging for this heavily pretreated population," said Xu.

Investigators detailed findings from the two trials Tuesday during an .

Phase II Study Details

The addition of PD-1 inhibitors to frontline chemotherapy has transformed the standard of care for patients with metastatic gastroesophageal cancer, but resistance to this treatment often develops, presenting a need for additional treatment options.

A total of 41 patients were enrolled in Arm A1 of the ongoing global multiarm EDGE-Gastric trial, which is evaluating various combinations of the anti-TIGIT Fc-silent monoclonal antibody domvanalimab and the PD-1 inhibitor zimberelimab in patients with locally advanced unresectable or metastatic gastric, GEJ, or esophageal adenocarcinoma.

This analysis of Arm A1 studied a combination of the novel agents together with first-line FOLFOX. Median follow-up was 8.1 months. Patients enrolled were from the U.S., France, and Korea. Primary location of the tumor was the stomach in 63%, about a third had liver metastases, and the median time on treatment was 33 weeks.

Out of 39 patients who were available for central PD-L1 testing, the 15 patients with PD-L1-high tumor expression -- defined as tumor area positivity (TAP) ≥5% -- had better results when it came to confirmed overall response rates (ORRs) and 6-month PFS compared with the 24 participants with low PD-L1 expression:

• ORR: 73% vs 46%, respectively
• PFS: 93% vs 66%

"This is a very early look at the data. The results seem to be in line with what we might expect from earlier trials of chemotherapy plus PD-1 [inhibition] and are encouraging in PD-L1-high patients, but it's a small dataset," said invited discussant Elizabeth Catherine Smyth, MD, from Oxford University Hospitals NHS Foundation Trust in England. "We need a lot more research to understand the disease-specific context of TIGIT before this will become a standard of care."

Serious treatment-emergent adverse events (TEAEs) occurred in 24% of patients, with none deemed related to domvanalimab and zimberelimab. In 49% of patients, TEAEs led to permanent withdrawal from any study drug and in 81% led to dose modification/interruption of any study drug.

These preliminary data support the ongoing comparing domvanalimab plus zimberelimab and chemotherapy versus nivolumab (Opdivo) plus chemotherapy as first-line treatment in unresectable or metastatic upper gastrointestinal cancer.

Phase I Study Details

CMG901 is a potential first-in-class CLDN 18.2-specific antibody-drug conjugate carrying monomethyl auristatin E via a protease cleavable linker.

The updated findings were from an open-label dose expansion phase I trial (KYM901) of 113 Asian patients who were refractory/intolerant to standard therapies. They were treated at intravenous doses of 2.2 mg/kg to 3.0 mg/kg every 3 weeks. Eligible patients were those with CLDN 18.2 expression of ≥2+ membrane staining intensity in ≥5% of tumor cells. Median patient age was 56 years, 90% had gastric cancer as their primary site of disease, and 74% had prior anti-PD-1/PD-L1 therapy. They were treated with a median of two prior lines of therapy. Most (83%) participants had CLDN 18.2 expression of ≥2+ membrane staining in at least 20% of tumor cells.

At a median follow-up of 6 months, median OS was not reached in the overall population. Median PFS was 14.5 months at the highest dosing level (3.0 mg/kg), 3.3 months with 2.6 mg/kg, and 4.8 months with 2.2 mg/kg. Median OS at the time of data cutoff was not reached in the higher-dose arms, but was 8.5 months in the 2.6 mg/kg arm.

The confirmed ORR ranged from 24% with 2.6 mg/kg to 42% with 2.2 mg/kg. The disease control rate was 70%, and was similar ranging from 67% to 75% across the three dosage levels. Median durations of response ranged from 5.7 months to 12.6 months across dose levels.

"Objective responses were observed regardless of the number of prior lines of therapy, including in patients with three or more prior lines," said Xu. "A similar ORR was observed regardless of prior taxane or anti-PD-1 therapy."

Maximum tolerated dose was not reached during dose escalation. Grade ≥3 TEAEs occurred in 64% and drug-related grade ≥3 TEAEs in 54%. The most common grade ≥3 TEAEs were a decrease in the neutrophil count (19%), anemia (13%), and vomiting (10%). Treatment was discontinued in 8% due to a TEAE.

"These results provide a strong rationale to further explore CMG901 as an [antibody-drug conjugate] in CLDN 18.2-expressing gastric/GEJ cancer," said Xu.

Discussant Smyth said that very few patients in KYM901 did not experience clinical benefit and very few had immediate progression, as evidenced by the long median duration of response. To put the results into context, she noted that the ORR is 7% to 15% with second-line docetaxel-irinotecan, 28% with ramucirumab (Cyramza)-paclitaxel, and 4% with third-line trifluridine-tipiracil (Lonsurf). And that median duration of response is 3.9 months with chemotherapy and 8.1-11.3 months with trastuzumab-deruxtecan (Enhertu).

She added that she would like to see response rates to CMG901 according to CLDN 18.2 expression, prior anti-claudin therapy, and GEJ versus gastric cancer, as well as in international populations, given that 100% of patients enrolled in KYM901 were Asian who had predominantly gastric cancer. "Overall survival looks encouraging when we compare it to most second- and third-line options," but the numbers are small and the follow-up is short at 6 months, she observed.

"There are no preclinical development publications available for this molecule," Smyth said. "So I look forward to seeing those in due course to understand target binding and drug diffusion characteristics."

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