Low-dose Paclitaxel with Pembrolizumab Enhances Clinical and Immunologic Responses in Platinum-refractory Urothelial Carcinoma.

PURPOSE: Single-agent checkpoint inhibition is effective in a minority of patients with platinum-refractory urothelial carcinoma; therefore, the efficacy of combining low-dose paclitaxel with pembrolizumab was tested. MATERIALS AND METHODS: This was a prospective, single-arm phase II trial with key inclusion criteria of imaging progression within 12 months of platinum therapy and Eastern Cooperative Oncology Group ≤1. Treatment was pembrolizumab 200 mg day 1 and paclitaxel 80 mg/m2 days 1 and 8 of a 21-day cycle for up to eight cycles unless progression or unacceptable adverse events (AE). The primary endpoint was overall response rate (ORR) with overall survival (OS), 6-month progression-free survival (PFS), and safety as key secondary endpoints. Change in circulating immune cell populations, plasma, and urinary miRs were evaluated. RESULTS: Twenty-seven patients were treated between April 2016 and June 2020, with median follow-up of 12.4 months. Baseline median age was 68 years, with 81% men and 78% non-Hispanic White. ORR was 33% by intention to treat and 36% in imaging-evaluable patients with three complete responses. Six-month PFS rate was 48.1% [95% confidence interval (CI): 28.7-65.2] and median OS 12.4 months (95% CI: 8.7 months to not reached). Common ≥ grade 2 possibly-related AEs were anemia, lymphopenia, hyperglycemia, and fatigue; grade 3/4 AEs occurred in 56%, including two immune-mediated AEs (pneumonitis and nephritis). Responding patients had a higher percentage of circulating CD4+IFNγ+ T cells. Levels of some miRs, including plasma miR 181 and miR 223, varied in responders compared with nonresponders. CONCLUSIONS: The addition of low-dose paclitaxel to pembrolizumab is active and safe in platinum-refractory urothelial carcinoma. SIGNIFICANCE: We found that combining pembrolizumab with low-dose paclitaxel may be effective in patients with urothelial carcinoma progressing on platinum chemotherapy, with favorable safety profiles.

Circulating immune biomarkers as predictors of the response to pembrolizumab and weekly low dose carboplatin and paclitaxel in NSCLC and poor PS: An interim analysis.

The combination of standard-dose chemotherapy and immunotherapy has been shown to be beneficial for patients with non-small cell lung cancer (NSCLC) with good performance status (PS). However, treatment options for patients with poor PS are limited. In the present study, the feasibility and immunological effects of low-dose chemotherapy with carboplatin and paclitaxel combined with immunotherapy with pembrolizumab were examined in patients with metastatic NSCLC and a poor PS. Patients with advanced NSCLC and a PS of 2 were randomized to single-agent pembrolizumab at 200 mg every 3 weeks or pembrolizumab combined with weekly carboplatin area under the curve 1 and paclitaxel 25 mg/m2. Blood for circulating immune cell phenotyping, soluble program death ligand 1 (sPD-L1) and immune-modulatory microRNAs (miRNAs) was collected prior to treatment and at weeks 4 and 7. Ten patients were randomized to the combination arm and 10 to the single-agent arm. Therapy was well tolerated. Four patients discontinued carboplatin due to hypersensitivity reactions but continued pembrolizumab and paclitaxel treatments. Increases in activated CD4+ T cells and in immune-regulatory miRNA, and decreases in myeloid derived suppressor cells were observed in the blood of patients in the combination arm and not in the single-agent arm. Changes in circulating regulatory T cells and sPD-L1 were not observed. Seven patients in the combination arm manifested a partial response compared with only two in the single-agent arm. Weekly low-dose chemotherapy carboplatin and paclitaxel was well tolerated and immunologically active when combined with pembrolizumab in patients with advanced NSCLC and a PS of 2. This combination merits further study in this patient population.