Open-label, Phase I Study of Nivolumab Combined with nab-Paclitaxel Plus Gemcitabine in Advanced Pancreatic Cancer

Abstract

Purpose: Assess safety and efficacy of nivolumab plus nabpaclitaxel and gemcitabine in patients with locally advanced/metastatic pancreatic cancer in a two-part, open-label, phase I trial. Patients and Methods: Fifty chemotherapy-naive patients received nab-paclitaxel 125 mg/m 2 plus gemcitabine 1,000 mg/m 2 (days 1, 8, and 15) and nivolumab 3 mg/kg (days 1 and 15) in 28day cycles. The primary endpoints were dose-limiting toxicities (DLTs; part 1) and grade 3/4 treatment-emergent adverse events (TEAEs) or treatment discontinuation due to TEAEs (parts 1/2). Secondary efficacy endpoints were progression-free survival (PFS), overall survival (OS), and response. Assessment of programmed cell death-ligand 1 (PD-L1) expression was an exploratory endpoint; additional biomarkers were assessed post hoc. Results: One DLT (hepatitis) was reported in part 1 among six DLT-evaluable patients; 48 of 50 patients experienced grade 3/4 TEAEs and 18 discontinued treatment due to TEAEs. One grade 5 TEAE (respiratory failure) was reported. Median [95% confidence interval (CI)] PFS/OS was 5.5 (3.25-7.20 months)/9.9 (6.74-12.16 months) months, respectively [median follow-up for OS, 13.6 months (95% CI, 12.06-23.49 months)]. Overall response rate (95% CI) was 18% (8.6%-31.4%). Median PFS/OS was 5.5/9.7 months (PD-L1 <5%) and 6.8/11.6 months (PD-L1 ≥5%), respectively. Proportion of peripheral Ki67 þ CD8 þ /CD4 þ cells increased significantly from baseline to cycle 3; median peak on-treatment Ki67 þ CD8 þ T-cell values were higher in responders than in nonresponders. Conclusions: The safety profile of nivolumab plus nab-paclitaxel and gemcitabine at standard doses in advanced pancreatic cancer was manageable, with no unexpected safety signals. Overall, the clinical results of this study do not support further investigation.

Prognostic significance and therapeutic potential of the immune checkpoint VISTA in pancreatic cancer

“…Pancreatic ductal adenocarcinoma (PDAC) is the most lethal type of human cancer, with a low 5-year survival rate of 6-10% (Yao et al 2020). Recently, although programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blocking therapy has been used successfully in several types of malignancies (Brahmer et al 2012;Hagi et al 2020;Rao et al 2020;Tomita et al 2019), the response rate is low in PDAC patients (Brahmer et al 2012;Tomita et al 2019;Wainberg et al 2020). Thus, it is imperative to investigate the mechanism of immune escape in PDAC and potential alternate therapeutic strategies.…”

Immunotherapy is Associated with a Survival Benefit in Patients Receiving Chemotherapy for Metastatic&nbsp;Pancreas Cancer

“…[19] A recent phase I trial examining the safety of nivolumab, nab-paclitaxel, and gemcitabine in patients with advanced PDAC did not show a survival bene t as compared to historic survival data without nivolumab. [28] De ciencies in mismatch repair with subsequent microsatellite instability (MSI) are often found in cancers and cause numerous genetic mutations, activating a patient's anti-tumor immune response. [29] A pivotal trial administered pembrolizumab (a PD-1 antagonist) to patients with metastatic cancer and demonstrated a disease control rate of 75% and a reported objective response rate of 62% in those with pancreatic cancer.…”

Pancreas cancer: Therapeutic trials in metastatic disease

“…A phase Ib/II study of 19 patients with PDAC treated with pembrolizumab, gemcitabine, and nab‐paclitaxel did not meet its prespecified primary endpoint of complete response greater than 15% in 15 patients with evaluable responses 70 . A phase I trial of 50 patients with PDAC treated with nivolumab, gemcitabine, and nab‐paclitaxel demonstrated an ORR of 18% (95% CI, 8.6%–31.4%) with a median PFS of 5.5 months (95% CI, 3.3–7.2 months) in the first‐line setting, which did not lead to further investigation 71 . Combination of CTLA‐4 and PD‐1 blockade with durvalumab and tremelimumab were associated with a low ORR (3.1%; 95% CI, 0.1%–16.2%) in the second‐line setting, 72 and there were no objective responses (ORR, 0%; 95% CI, 0%–10.6%) in patients randomized to durvalumab monotherapy in this trial.…”