Shuichi Hironaka, MD
The triplet of nivolumab (Opdivo), ramucirumab (Cyramza) and paclitaxel showed promising antitumor activity with durable responses in a phase II study of patients with advanced gastric cancer. The overall response rate (ORR) was 37.2% among patients treated with this combination, with all responders having a partial response (PR).1
The median progression-free survival (PFS) in the overall cohort of 43 patients was 5.1 months, and was not influenced by the combined positive score (CPS), lead author Shuichi Hironaka, MD, Chiba Cancer Center, Japan, said at the 2020 Gastrointestinal Cancers Symposium. The median overall survival (OS) was 13.1 months, and similarly did not appear different between cohorts with low versus high CPS.
“The impact of PD-L1 expression on the clinical outcome for this combination is not clear,” Hironaka said. “Long-term overall survival [OS] was promising for further investigation of this combination.”
Nivolumab has already shown a significant survival benefit in the salvage setting for patients with advanced gastric cancer,2
while ramucirumab demonstrated enhanced survival in combination with paclitaxel as second-line treatment.3
Simultaneous blockade of PD-1 and VEGFR-2 with PD-1 inhibition, taxanes, and VEGFR-2 blockers has been reported to have synergistic antitumor effects, Hironaka said.
The phase I/II study tested the effect of the triplet for the treatment of advanced gastric cancer in patients who were refractory or intolerant to first-line platinum and fluoropyrimidine doublet chemotherapy. To be eligible, patients had to have measurable lesions, an ECOG performance status of 0 or 1, and disease progression on the above chemotherapy regimen.
At level 0 in phase I, patients received nivolumab (1 mg/kg on days 1 and 15) combined with paclitaxel (80 mg/m2
on days 1, 8, and 15) and ramucirumab (8 mg/kg on days 1 and 15) every 4 weeks. At dose level 1 (phase II), nivolumab was dosed at 3 mg/kg on days 1 and 15 and the other drugs were dosed as per level 0. After feasibility was established in 6 patients (phase I portion), an additional 37 patients were enrolled in the phase II portion, with 6-month PFS rate as the primary endpoint.
Results were stratified according to the CPS, defined as the number of PD-L1–positive cells (tumor cells, macrophages, and lymphocytes) divided by the total number of viable tumor cells.
The median patient age was 66 years and 60.5% had CPS ≥1. Three-fourths (74.4%) of patients had stage IV cancer and 25.6% had recurrent disease. About half (51.2%) had 2 metastatic sites and 27.9% had ≥3 metastatic sites. Some 60.5% were positive for peritoneal metastasis. Mismatch repair status was proficient in 88.4% and unknown in the remaining 11.6%.
Of the 16 responders (37.2%), all had a PR. Another 46.5% had stable disease for a disease control rate (DCR) of 83.7%. The ORR by CPS was as follows
- In the 13 patients with CPS <1, the ORR was 30.8%, with 4 responses being a PR, compared with 46.2% (all 12 being PR) in the 26 patients with CPS ≥1.
- In the 32 patients with CPS <10, the ORR was 37.5%, with all 12 responses a PR, compared with 57.1% in the 7 patients with CPS≥10, all 4 responses a PR
With a median follow-up of 23.2 months, 6-month PFS rate was 46.5% (80% CI, 36.4%-55.8%; P
= .067) The 6-month PFS was not significantly different according to CPS cutoffs.
The median OS was 13.1 months (95% CI, 8.0-16.6). The 12- and 18-month OS rates were 55.8% (95% CI, 39.8%-69.1%) and 32.1% (95% CI, 18.2%-46.8%), respectively. As with PFS, OS was not significantly different between low and high CPS.
As presented previously, tolerability of the regimen was good, said Hironaka. Dose-limiting toxicities were observed in 2 patients at dose level 1; one patient had febrile neutropenia and 1 other had neutropenia over a period of 8 days.
Further biomarker analyses are ongoing.
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- Hironaka S, Kadowaki S, Izawa N, et al. A phase I/II study of nivolumab, paclitaxel, and ramucirumab as second-line in advanced gastric cancer. Presented at GI Cancers Symposium; January 23-25, 2020; San Francisco, CA. Abstract 352.
- Kang YK, Boku N, Satoh T, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;390:2461-71.
- Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 2014;15:1224-35.