The PD-1/CTLA-4 bispecific antibody, AK104, plus chemotherapy represents a potential new first-line treatment option for patients with advanced gastric or gastroesophageal junction (GEJ) cancer. Results from a phase 1b/2 study showed an overall response rate of 65.9% when a capecitabine (Xeloda) plus oxaliplatin (Eloxatin; XELOX) regimen was combined with AK104 in patients with untreated, inoperable, advanced gastric/GEJ adenocarcinoma regardless of PD-L1 status, reported Jiafu Ji, MD, PhD, FACS, President, Peking University Cancer Hospital, School of Oncology, Beijing, China, at the 2022 ASCO Gastrointestinal Cancers Symposium.
In the full data set of 96 patients, the median progression-free survival was 7.1 months, and the median overall survival (OS) was 17.41 months.
By itself, platinum/fluoropyrimidine-based combination therapy as first-line treatment in patients with advanced gastric/GEJ cancer has limited clinical benefit, with an overall response rate of 35% and an OS of approximately 1 year.
“Two previous studies demonstrated synergy between immune checkpoint inhibitors and chemotherapy in gastric/GEJ cancer worldwide,” said Dr Ji. “Compared with anti–PD-1 monotherapy, co-treatment with an anti–PD-1 agent and an anti–CTLA-4 agent has consistently shown a higher response but greater toxicity.”
The phase 1b/2 study evaluated AK104 in combination with XELOX or modified XELOX in the first-line setting of gastric/GEJ cancer. It represents the first clinical trial of a PD-1/CTLA-4 bispecific in combination with chemotherapy in the first-line setting.
The study consists of a dose escalation and expansion phase (phase 1b) to determine the recommended phase 2 dose for AK104 in combination with XELOX, and a dose confirmation phase (phase 2) that further characterizes the treatment of AK104 in combination at the recommended phase 2 dose. In the phase 1b portion, the dose of AK104 was escalated from 4 mg/kg every 2 weeks to 6 mg/kg every 2 weeks, 10 mg/kg every 2 weeks to 15 mg/kg every 3 weeks, combined with modified XELOX every 2 weeks or XELOX every 3 weeks, followed by dose extension. Phase 2 was dose confirmation of AK104 at either 6 mg/kg every 2 weeks or 10 mg/kg every 3 weeks.
The primary tumor location was GEJ in 12.5% of patients and gastric in 87.5%. Some 89.6% of patients had metastatic disease at enrollment and 10.4% had locally advanced disease. A total of 18 (18.8%) patients had undergone surgery. PD-L1 staining showed a combined positive score (CPS) ≥5 in 16.7% and <5 in 83.3%. Median follow-up time was 9.95 months.
Approximately 88 patients had at least 1 post-baseline tumor evaluation. Best overall response was a complete response in 2 (2.3%) patients, a partial response in 56 (63.6%), and stable disease in 23 (26.1%), for a disease control rate of 92.0%. The median time to response was 1.46 months and the median duration of response was 6.93 months.
Median OS was 14.65 months in the patient subgroup with CPS ≥1, was not reached in those with a CPS ≥5 and was 17.08 months in those with a CPS <5. Median progression-free survival in these subgroups was 6.83, 9.6, and 6.83 months, respectively, and the median duration of response was 10.05, not reached, and 5.82 months, respectively.
Approximately two-thirds (62.5%) of patients had grade ≥3 treatment-related adverse events (TRAEs) and 41.7% had serious TRAEs. In 6 (6.3%) patients, a TRAE led to permanent discontinuation of study drugs and led to death in 4 (4.2%). The most frequent TRAEs were decreased platelet count (28.1%; 6.3% grade ≥3), decreased white blood cell count (22.9%; 3.1% grade ≥3), decreased neutrophil count (22.9%; 2.1% grade ≥3%), and anemia (26.0%; 3.1% grade ≥3%).
A phase 3 trial of the AK104/chemotherapy combination as first-line therapy in this patient population is ongoing, said Dr Ji.