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Pre-Op Immunotherapy Combo Makes Headway in Select Gastric Cancers

— Plus, novel bispecific antibody tested as first-line therapy for advanced gastric/GEJ cancer

Ƶ MedicalToday

This article is a collaboration between Ƶ and:

SAN FRANCISCO -- In patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma, a checkpoint inhibitor combination showed promise in the preoperative setting, while a bispecific antibody added to upfront chemotherapy elicited responses in two-thirds of patients with advanced disease, according to a pair of early-phase trials.

In the first -- the study -- investigators found that neoadjuvant therapy with nivolumab (Opdivo) and ipilimumab (Yervoy) appeared to be effective in patients with resectable microsatellite instability-high/mismatch repair deficient (MSI/dMMR) gastric/GEJ cancers.

The combination, followed by surgery, led to a pathologic complete response in 59% of patients with MSI/dMMR gastric or GEJ adenocarcinoma, reported Thierry Andre, MD, of Sorbonne University in Paris.

In a , a combination of the next-generation PD-1/CTLA-4 bispecific antibody AK104 and chemotherapy demonstrated an objective response rate of 65.9% as a first-line therapy for patients with advanced gastric or GEJ cancer, according to Jiafu Ji, MD, PhD, Peking University Cancer Hospital in Beijing.

The two studies were presented during a fast abstract session at the Gastrointestinal Cancers Symposium.

GERCOR NEONIPIGA

In explaining the rationale behind the study, Andre noted that patients with locally advanced MSI/dMMR gastric and GEJ adenocarcinomas have a better prognosis compared with MMR-proficient cases.

"Perioperative chemotherapy with fluoropyrimidines combined with platinum salt offers questionable benefit in this population and might decrease both event-free and overall survival," he added, and pointed out that dMMR status is predictive for the efficacy of immune checkpoint inhibitors and that using them in this population before and/or after radical surgery might improve outcomes.

The study enrolled 32 patients (median age 65.5 years). Most patients (n=22) had initial stage usT3Nx disease, while four had usT2Nx and six had disease that was not evaluable on ultrasound.

Patients were treated with nivolumab 240 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks, followed by radical surgery 5 weeks after the last injection of nivolumab. Patients with Becker tumor regression grade (TRG) <3 were treated with adjuvant nivolumab 480 mg every 4 weeks.

Of the 32 patients, 29 underwent surgery, two had complete endoscopic response with tumor-free biopsies and refused surgery, and one had a metastatic progression and did not undergo surgery.

Of the 29 patients who underwent surgery, 17 had a pathological complete response (TRG 1a as per Becker grade), four had TRG 1b (<10% residual tumor per tumor bed), two had TRG 2 (10-50% of residual tumor), and six had TRG 3 (˃50% of residual tumor).

With a median follow-up of 12 months, 30 patients were alive and without relapse.

As for safety, 25% of patients had grade 3/4 treatment-related adverse events (TRAEs), while 17 patients had perioperative and/or postoperative complications (up until 90 days after surgery).

The study "raises the question whether surgery can be delayed or avoided for some patients with localized MSI/dMMR gastric or [GEJ] adenocarcinoma if immune checkpoint inhibitors are effective," Andre said.

AK104

In their phase Ib/II study, Ji and his colleagues included 96 patients (median age 62.7 years, 70.8% male, 62.5% with ECOG PS 1, and 44.8% with liver metastasis) with unresectable advanced gastric or GEJ adenocarcinoma (regardless of PD-L1 status) and with a history of no prior therapy. Patients with known HER2-positive status were excluded.

Enrolled patients received AK104 (4 mg/kg, 6 mg/kg, 10 mg/kg, once every 2 weeks, or 10 mg/kg, 15 mg/kg once every 3 weeks), plus chemotherapy (either modified XELOX once every 2 weeks, or XELOX once every 3 weeks).

At a median follow-up of 9.95 months, 88 of the 96 patients had at least one post-baseline tumor evaluation. Of those 88 patients, 56 had a partial response, while two had a complete response. Stable disease was reported in another 23 patients, accounting for a disease control rate of 92.0%.

The median duration of response was 6.93 months, with a median time to response of 1.46 months.

Median progression-free survival was 7.1 months (95% CI 5.5-10.48), while median overall survival was 17.41 months (bottom limit of 95% CI 12.35).

TRAEs occurred in 97.9% of patients, the most frequent of which were decreased platelet count (60.4%), decreased white blood cell count (58.3%), reduced neutrophil count (56.3%), anemia (47.9%), nausea (30.2%), vomiting (30.2%), and increased aspartate aminotransferase (30.2%). Grade ≥3 TRAEs occurred in 62.5% of patients.

"AK104 plus chemo presents a potential new first-line treatment option for these patients," observed Ji, who added that a phase III study of AK104 combined with chemotherapy as a first-line therapy for gastric or GEJ cancer is ongoing.

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    Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.

Disclosures

Andre reported honoraria from AMGEN; Bristol-Myers Squibb; GlaxoSmithKline; Pierre Fabre; Roche/Genentech; SERVIER; Ventana Medical Systems. Consulting or advisory roles with Amgen; Astellas Pharma; AstraZeneca/MedImmune; Bristol-Myers Squibb; GamaMabs Pharma; GlaxoSmithKline; Gritstone Oncology; Kaleido Biosciences; MSD Oncology; Pierre Fabre; Seattle Genetics; Tesaro; Transgene. Travel accommodations, expenses from MSD Oncology.

Ji had no disclosures.

Primary Source

Gastrointestinal Cancers Symposium

Andre T, et al "Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in patients (pts) with localized microsatellite instability-high (MSI)/mismatch repair deficient (dMMR) oeso-gastric adenocarcinoma (OGA): The GERCOR NEONIPIGA phase II study" GiCS 2022.

Secondary Source

Gastrointestinal Cancers Symposium

Ji J, et al "A phase Ib/II, multicenter, open-label study of AK104, a PD-1/CTLA-4 bispecific antibody, combined with chemotherapy (chemo) as first-line therapy for advanced gastric (G) or gastroesophageal junction (GEJ) cancer" GiCS 2022.