Multicenter phase I/II study of nivolumab combined with paclitaxel plus ramucirumab as the second-line treatment in patients with advanced gastric cancer
Nivolumab (Nivo) has a significant survival benefit in the salvage line for advanced gastric cancer (AGC) patients (pts) (Kang YK, Lancet, 2017). Synergistic anti-tumor effect induced by simultaneous blockade of PD-1 and taxanes, and PD-1 and VEGFR-2 has been reported. A phase I/II study was conducted to investigate the safety and efficacy of Nivo combined with paclitaxel (PTX) plus ramucirumab (Ram), which is the standard treatment as the 2nd line for AGC.
AGC pts with measurable lesions, ECOG PS 0-1, disease progression on the 1st line chemotherapy with fluoropyrimidine and platinum were eligible. Pts received Nivo (3 mg/kg on day 1 and 15) combined with PTX (80 mg/m2 on day 1, 8 and 15) and Ram (8 mg/kg on day 1 and 15) (Level 1), every 4 weeks until unacceptable toxicity or disease progression occurred. After feasibility was evaluated in 6 patients (phase I part), an additional 37 patients were enrolled in a phase II part with the primary endpoint of 6-month progression-free survival (PFS) rate with the threshold of 35%, one-sided alpha of 10% and power of 75%. Secondary endpoints included overall response rate (ORR), disease control rate (DCR), overall survival, and safety. PD-L1 tumor expression was assessed by immunohistochemistry (28-8 pharmDx assay) with a cut-off value for PD-L1 positivity set at 1% in tumor cells.
From February 2017 to July 2018, 43 AGC patients were enrolled. Patient characteristics included median age 66 years, ECOG PS 1 48.8%, prior gastrectomy 25.6%, and PD-L1 positive rate 15.4%. Dose-limiting toxicities were observed in 2 pts in the phase I part, febrile neutropenia and neutropenia over a period of 8 days, and the recommended dose was determined as Level 1. Forty (93.0%) patients experienced grade ≥ 3 AEs: neutropenia (76.7%), febrile neutropenia (16.3%), anemia (14.0%), diarrhea (7.0%), thrombocytopenia (7.0%). Fourteen (32.6%) pts experienced grade ≥ 3 immune-related AEs. There was one treatment-related death related to thrombocytopenia. CR/PR/SD was obtained in 0/16/20 pts respectively with an ORR of 37.2% (95% CI, 23.0-53.5%) and a DCR of 83.7% (95% CI, 69.3-93.2%). With a median follow-up time of 16.8 months, 6-month PFS rate was 46.4% (80% CI, 36.4-55.8%) (P=.067) and median PFS was 5.1 months (95%CI, 4.5-6.5 months).
Nivo combined with PTX plus Ram demonstrated promising antitumor activity as the 2nd-line treatment for AGC pts with manageable toxicities. (UMIN000025947)
