Safety and Efficacy of Durvalumab and Tremelimumab Alone or in Combination in Patients with Advanced Gastric and Gastroesophageal Junction Adenocarcinoma

Abstract

Purpose: This randomized, multicenter, open-label, phase Ib/II study assessed durvalumab and tremelimumab in combination or as monotherapy for chemotherapy-refractory gastric cancer or gastroesophageal junction (GEJ) cancer. Patients and Methods: Second-line patients were randomized 2:2:1 to receive durvalumab plus tremelimumab (arm A), or durvalumab (arm B) or tremelimumab monotherapy (arm C), and third-line patients received durvalumab plus tremelimumab (arm D). A tumor-based IFNg gene signature was prospectively evaluated as a potential predictive biomarker in second-and third-line patients receiving the combination (arm E). The coprimary endpoints were objective response rate and progression-free survival (PFS) rate at 6 months. Results: A total of 113 patients were treated: 6 in phase Ib and 107 (arm A, 27; arm B, 24; arm C, 12; arm D, 25; arm E, 19) in phase II. Overall response rates were 7.4%, 0%, 8.3%, 4.0%, and 15.8% in the five arms, respectively. PFS rates at 6 months were 6.1%, 0%, 20%, 15%, and 0%, and 12-month overall survival rates were 37.0%, 4.6%, 22.9%, 38.8%, and NA, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 4%, 42%, 16%, and 11% of patients, respectively. Conclusions: Response rates were low regardless of monotherapy or combination strategies. No new safety signals were identified. Including use of a tumor-based IFNg signature and change in baseline and on-treatment circulating tumor DNA are clinically feasible and may be novel strategies to improve treatment response in this difficult-to-treat population.

Durvalumab and tremelimumab combination therapy versus durvalumab or tremelimumab monotherapy for patients with solid tumors

“…[ 28 – 32 ] All the selected studies were included in the systematic review, and 3 of 5 were included in the meta-analysis. [ 28 – 30 ]…”

“…In the eligible studies, for advanced gastric and gastroesophageal junction adenocarcinoma, the combining durvalumab and tremelimumab displayed a numerically higher ORR than durvalumab monotherapy. [ 30 ] Nevertheless, durvalumab plus tremelimumab showed similar efficacy to durvalumab monotherapy in recurrent or metastatic head and neck squamous cell carcinoma and pancreatic ductal adenocarcinoma. [ 28 , 29 ] It is important to assess what factors might have contributed to the failure of combinatorial therapy.…”

Immune checkpoint inhibitor combination therapy for gastric cancer: Research progress (Review)

“…NCT02340975 is a randomized, multicenter, open-label, phase 1b/2 study, which assessed durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA-4) in combination or as monotherapies for the treatment of chemotherapy-refractory gastric cancer. Response rates were low regardless of monotherapy or combination strategies (27). Although the preliminary observations did not detect an obvious benefit of the combined treatment regimen for patients with advanced gastric cancer, the overall safety profiles still provide support for the study of dual ICI combination therapy.…”

Prediction of immune checkpoint inhibition with immune oncology-related gene expression in gastrointestinal cancer using a machine learning classifier

“… 2 3 However, data exploring the correlation between RNA signatures and GI cancers, particularly esophageal cancer and colorectal cancers, are still limited. 14 Moreover, a prospective evaluation of the IFN-γ signature was performed in patients with gastric cancer, 15 and the results showed that it failed to guide patient selection, possibly due to the great tumor heterogeneity and complexity of the TME.…”