Phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma

Abstract

Background A single center phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab (GNP) to evaluate the safety and efficacy in metastatic pancreatic adenocarcinoma (PDAC) was conducted (NCT02331251). Methods PDAC patients (pts) with measurable disease, biopsy proven metastasis, adequate laboratory tests, and KPS ≥ 70% received GNP until progression or toxicity. Safety monitoring, RECIST 1.1, and irRECIST assessments were conducted. Response imaging was performed prior to cycle 4, then every 3 months. Changes in tumor cell-free DNA copy number instability (CNI) was retrospectively evaluated. Results 17 pts. with a median age of 56 were treated. 11 were women and all had a KPS of at least 80%. Grade 3 events occurred in 53% of patients. The phase II portion was completed for chemotherapy naïve PDAC pts. Of the 11 evaluable chemotherapy naïve PDAC, the disease control rate (partial response [PR] + stable disease[SD]) was 100%. There were 3 with PR on treatment for 8+, ~11, and 15 months; respectively. The primary endpoint of >15% complete response was not met. The median progression-free survival (PFS) and overall survival (OS) was 9.1 and 15.0 months for chemotherapy naïve treated patients. Of 9 patients evaluable for CNI change, a greater reduction in CNI correlated with longer PFS and improved OS. Conclusions GNP can be safely given to chemotherapy naïve PDAC patients. Efficacy appears to be slightly improved over previously reported results for standard weekly × 3 every 28 day gemcitabine and nab-paclitaxel dosing. CNI change may be prognostic for OS.

Prognostic impact of gene copy number instability and tumor mutation burden in patients with resectable gastric cancer

“…Recently, plasma CNI has been increasingly used as a prognostic marker for pancreatic cancer [9] and head and neck squamous cell carcinoma [10]. In accordance with these results, we found that a high CNI could be an independent marker for unfavorable prognosis in patients with resectable GC.…”

“…All patients had undergone adjuvant chemotherapy with capecitabine plus oxaliplatin (XELOX). The median number of chemotherapy cycles was 6 (range, [3][4][5][6][7][8][9][10][11][12]. Overall survival (OS) was defined as the time from surgery to death or the last follow-up.…”

Combination systemic therapies with immune checkpoint inhibitors in pancreatic cancer: overcoming resistance to single‐agent checkpoint blockade

“…The CTLA-4 inhibitor tremelimumab in combination with weekly gemcitabine demonstrated preliminary efficacy and tolerability with the most common grade 3-4 toxicities being asthenia (11.8%) and nausea (8.8%) in a phase Ib trial enrolling treatment-naïve metastatic pancreatic cancer patients [48]. A dose-finding, multi-arm phase Ib trial enrolled patients with advanced solid tumors to 6 different treatment arms; in the metastatic PDAC cohort, a final 17 patients with treatment-naïve or previously-treated disease received combination pembrolizumab, gemcitabine, and nab-paclitaxel with responses observed only in those who were previously untreated (Table 2) [49,50]. Notably, gemcitabine and nab-paclitaxel were reduced to 800 mg/m 2 and 100 mg/ m 2 in the pretreated cohort, which was ultimately closed 2 PRs with OS after onset of therapy of 13 and 5 mos due to futility [50].…”

“…A dose-finding, multi-arm phase Ib trial enrolled patients with advanced solid tumors to 6 different treatment arms; in the metastatic PDAC cohort, a final 17 patients with treatment-naïve or previously-treated disease received combination pembrolizumab, gemcitabine, and nab-paclitaxel with responses observed only in those who were previously untreated (Table 2) [49,50]. Notably, gemcitabine and nab-paclitaxel were reduced to 800 mg/m 2 and 100 mg/ m 2 in the pretreated cohort, which was ultimately closed 2 PRs with OS after onset of therapy of 13 and 5 mos due to futility [50]. Immune-related AEs (all grades) were seen in 47.1%.…”

Harnessing the Immune System in Pancreatic Cancer

“…• Weiss et al reported findings from the metastatic PDA patient arm of the NCT02331251 trial [11]. In this phase I/II study, 17 patients were treated with the combination of gem, nab, and pembrolizumab.…”