Patel, Anuj

PURPOSE SWOG S1815 was a randomized, open label phase III trial, evaluating gemcitabine, nab-paclitaxel, and cisplatin (GAP) versus gemcitabine and cisplatin (GC) in patients with newly diagnosed advanced biliary tract cancers (BTCs). METHODS Patients with newly diagnosed locally advanced unresectable or metastatic BTC, including intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) and gallbladder carcinoma (GBC), were randomly assigned 2:1 to either GAP (gemcitabine 800 mg/m 2 , cisplatin 25 mg/m 2 , and nab-paclitaxel 100 mg/m 2 intravenously once per day on days 1 and 8 of a 21-day cycle) or GC (gemcitabine 1,000 mg/m 2 and cisplatin 25 mg/m 2 intravenously once per day on days 1 and 8 of a 21-day cycle). RESULTS Among 452 randomly assigned participants, 441 were eligible and analyzable, 67% with ICC, 16% with GBC, and 17% with ECC. There was no significant difference in overall survival (OS) between GAP versus GC. Median OS with GAP was 14.0 months (95% CI, 12.4 to 16.1) and 13.6 months with GC (95% CI, 9.7 to 16.6); hazard ratio (HR), 0.91 (95% CI, 0.72 to 1.14); P = .41. Median progression-free survival (PFS) was similar between groups with median PFS for GAP being 7.5 months (95% CI, 6.4 to 8.5) versus 6.3 months for GC (95% CI, 4.4 to 8.2); HR, 0.89 (95% CI, 0.71 to 1.12); P = .32. In exploratory subset analyses, the OS and PFS benefits of GAP versus GC treatment were greater in locally advanced disease compared with metastatic disease, although not statistically significant (interaction P = .14 for OS and P = .17 for PFS). Moreover, GAP versus GC showed greater improvement in PFS among participants with GBC than those with ICC or ECC (interaction P = .01), but not OS (interaction P = .28). CONCLUSION The addition of a taxane in the GAP regimen to the standard gemcitabine-cisplatin regimen did not improve OS in newly diagnosed BTC. More toxicity was encountered with GAP versus GC.

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) trials have evaluated CTLA-4 and/or PD-(L)1 blockade in patients with advanced disease in which bulky tumor burden and limited time to develop antitumor T cells may have contributed to poor clinical efficacy. Here, we evaluated peripheral blood and tumor T cells from patients with PDAC receiving neoadjuvant chemoradiation plus anti–PD-1 (pembrolizumab) versus chemoradiation alone. We analyzed whether PD-1 blockade successfully reactivated T cells in the blood and/or tumor to determine whether lack of clinical benefit could be explained by lack of reactivated T cells versus other factors. Experimental Design: We used single-cell transcriptional profiling and TCR clonotype tracking to identify TCR clonotypes from blood that match clonotypes in the tumor. Results: PD-1 blockade increases the flux of TCR clonotypes entering cell cycle and induces an IFNγ signature like that seen in patients with other GI malignancies who respond to PD-1 blockade. However, these reactivated T cells have a robust signature of NF-κB signaling not seen in cases of PD-1 antibody response. Among paired samples between blood and tumor, several of the newly cycling clonotypes matched activated T-cell clonotypes observed in the tumor. Conclusions: Cytotoxic T cells in the blood of patients with PDAC remain sensitive to reinvigoration by PD-1 blockade, and some have tumor-recognizing potential. Although these T cells proliferate and have a signature of IFN exposure, they also upregulate NF-κB signaling, which potentially counteracts the beneficial effects of anti–PD-1 reinvigoration and marks these T cells as non-productive contributors to antitumor immunity. See related commentary by Lander and DeNardo, p. 474