San Francisco, CA—Second-line treatment with a 3-drug regimen that included the PD-1 inhibitor nivolumab (Opdivo), the VEGF receptor antagonist ramucirumab (Cyramza), and chemotherapy with the taxane paclitaxel, showed durable and impressive response rates, regardless of PD-L1 expression, in patients with advanced gastric cancers. Shuichi Hironaka, MD, PhD, Chiba Cancer Center, Japan, reported the study results at the 2020 Gastrointestinal Cancers Symposium.
In this single-arm phase 1/2 clinical trial, the overall response rate (ORR) with the triplet regimen was 37.2%, and all responses were partial. The median progression-free survival (PFS) was 5.1 months; the PFS was not influenced by the patient’s Combined Positive Score (CPS), which assesses PD-L1 expression in solid tumors. The median overall survival (OS) was 13.1 months, which was not different between the 2 cohorts of patients with low and high CPS, representing the level of PD-L1 expression.
“The impact of PD-L1 expression on the clinical outcome for this combination is not clear,” said Dr Hironaka. “Long-term overall survival was promising for further investigation of this combination.”
Promising Regimen for Advanced Gastric Cancer
This 3-drug combination of nivolumab, paclitaxel, and ramucirumab was investigated in patients with advanced gastric cancer whose disease was refractory to or who were intolerant of first-line combination chemotherapy with platinum and fluoropyrimidine.
“Synergistic antitumor activity had previously been reported with simultaneous blockade of PD-1 and taxanes, as well as PD-1 and vascular endothelial growth factor receptor,” said Dr Hironaka, explaining the rationale for this 3-drug combination.
At baseline, 74.4% of the patients had stage IV gastric cancer, and 25.6% had recurrent disease. Approximately half (51.2%) had 2 metastatic sites, and 27.9% had ≥3 metastatic sites. Mismatch repair deficiency status was proficient in 88.4% and was unknown in the remaining 11.6% of patients.
At level 0 in phase 1 of the study, 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, 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 the phase 1 portion of 6 patients, an additional 37 patients were enrolled in the phase 2 portion, with 6-month PFS rate as the primary end point.
With a median follow-up of 23.2 months, the 6-month PFS rate was 46.4%. When 20 patients who achieved stable disease were considered, the disease control rate was 83.7%.
The results were stratified according to the patients’ CPS. A total of 32 (60.5%) patients had a score ≥1, and 13 (39.5%) had a score <1. In patients with a score of <1, the ORR was 30.8% (4 partial responses) compared with 46.2% (12 partial responses) in patients with a score ≥1. When the score of ≥10 was used as the cut point, the ORR was 37.5% in those with a CPS <10 versus 57.1% in patients with a score of ≥10.
The 6-month PFS was not significantly different based on the CPS cutoffs.
The median OS was 13.1 months. The 12- and 18-month OS rates were 55.8% and 32.1%, respectively. As with the PFS, the OS was not significantly different between patients with low versus high PD-L1 expression, as determined by the CPS. Further biomarker analyses are ongoing.
The tolerability of the 3-drug regimen was good, according to Dr Hironaka. The most common grade 3 or 4 adverse event was a decrease in the neutrophil count, experienced by 33 (76.7%) patients. A total of 20 (46.5%) patients had a decrease in white blood cell count. Dose-limiting toxicities were reported in 2 patients at dose level 1 (1 patient had febrile neutropenia and the other patient had neutropenia for 8 days).