Phase II trial of nab-paclitaxel plus ramucirumab in combination with nivolumab for unresectable advanced or recurrent gastric cancer after progression on first-line treatment including fluoropyrimidine, platinum, and anti-PD-1/PD-L1 antibody (PADDLE).

Background: Patients with advanced gastric cancer (AGC) have poor survival after first-line treatment containing an anti-programmed death-1/ligand 1 (PD-1/PD-L1) antibody. Accumulating evidence suggests rationales for continuing immunotherapy beyond progression, synergistic effects between immune checkpoint inhibitors and angiogenesis inhibitors, and a preferable combination of steroid-free chemotherapy with immunotherapy. These rationales imply that nanoparticle albumin-bound (nab)-paclitaxel plus ramucirumab in combination with nivolumab (anti-PD-1 antibody) may enhance anti-tumor effects as second-line treatment. Therefore, we hypothesized that this triplet regimen may improve clinical outcomes in patients with AGC who experienced disease progression on first-line treatment including anti-PD-1/PD-L1 antibody.

Methods: The PADDLE trial, which is sponsored by Ono Pharmaceutical, is an investigator-initiated, multicenter, open-label, single-arm, prospective phase II trial conducted at six institutions in Japan. Key eligibility criteria are as follows: (1) advanced gastric or esophagogastric junction cancer, (2) histologically confirmed diagnosis of adenocarcinoma, (3) refractory to first-line treatment including fluoropyrimidines, platinum, and an anti-PD-1/PD-L1 antibody, (4) performance status of 0-1, and (5) at least one measurable lesion. Patients are to receive nab-paclitaxel (100 mg/m weekly, with a 1-week rest after 3 consecutive weeks), ramucirumab (8 mg/kg every 2 weeks), and nivolumab (240 mg/body every 2 weeks). The primary endpoint is 6-month progression-free survival (PFS) rate. The target number of patients was set at 45 based on threshold and expected 6-month PFS rates of 35% and 60%, respectively, with a one-sided alpha error of 0.05 and power of 0.95. Secondary endpoints include objective response rate, disease control rate, PFS, overall survival, duration of response, time to response, and safety. Biomarker analyses of serial blood and tumor samples are planned to clarify predictive markers and molecular mechanisms underlying treatment resistance by multifaceted analytical methods (e.g., flow cytometry, DNA sequencing [DNAseq]/RNA sequencing [RNAseq]). Recruitment started in November 2022.

Discussion: The PADDLE trial is expected to clarify the efficacy of nab-paclitaxel plus ramucirumab in combination with nivolumab as second-line treatment in patients with AGC refractory to first-line treatment including an anti-PD-1/PD-L1 antibody and to identify potential biomarkers for predicting clinical responses in patients with AGC undergoing this triplet regimen.

Trial Registration: jRCT2031220448.