Pharmacodynamic separation of gemcitabine and erlotinib in locally advanced or metastatic pancreatic cancer: therapeutic and biomarker results

Abstract

Purpose Erlotinib marginally improves survival when administered continuously with gemcitabine to patients with advanced pancreatic cancer; however, preclinical data suggest that there is antagonism between chemotherapy and Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors when these are delivered concurrently. We tested a pharmacodynamic separation approach for erlotinib plus gemcitabine and interrogated EGFR signaling intermediates as potential surrogates for the efficacy of this strategy. Methods Patients with measurable, previously untreated locally advanced unresectable or metastatic pancreatic cancer were treated with gemcitabine 1000 mg/m2 as an intravenous infusion over 30-minutes on days 1, 8, 15 and erlotinib 150 mg/day on days 2–5, 9–12, 16–26 of each 28-day cycle. The primary endpoint was progression free survival (PFS); secondary endpoints included RECIST objective response rate (ORR) and safety. The study was terminated after thirty patients due to funding considerations. Results The median PFS was 2.07 months (95% CI; 1.87 – 5.50 months) and the ORR was 11%. No unexpected safety signals were seen: the most common grade 3 or higher adverse events were neutropenia (23%), lymphopenia (23%), and fatigue (13%). Patients with mutant plasma KRAS had significantly lower median PFS (1.8 vs. 4.6 months, p=0.014) and overall survival (3.0 vs. 10.5 months, p=0.003) than those without detected plasma KRAS mutations. Conclusions Although pharmacodynamically separated erlotinib and gemcitabine were feasible and tolerable in patients with advanced pancreatic cancer, no signal for increased efficacy was seen in this molecularly unselected cohort. Detection of a KRAS mutation in circulating cell-free DNA was a strong predictor of survival.

Efficacy and safety of gemcitabine plus erlotinib for locally advanced or metastatic pancreatic cancer: a systematic review and meta-analysis

“…The detailed description of the selected studies is listed in Table 1 . Within the selected studies, there were five retrospective studies, 21 , 25 , 30 , 34 , 37 nine single-arm Phase II trials, 18 , 19 , 22 , 23 , 27 – 29 , 32 , 38 six Phase II RCTs, 26 , 31 , 33 , 35 , 36 , 39 three Phase III RCTs, 16 , 20 , 24 and one Phase Ib trial. 17 Among the studies, one RCT 16 and a retrospective study 34 investigated the difference between the GemErlo-treated arm and the gemcitabine monotherapy arm directly.…”

“…18 , 19 , 27 , 28 The first and second most common patterns of administration interval were “weekly for the first 3 weeks in a 4-week cycle” 23 , 27 – 30 , 33 , 35 , 36 , 39 and “weekly for the first 7 weeks in the first 8-week cycle then weekly for the first 3 weeks in a 4-week cycle”. 16 , 20 , 24 , 31 , 37 Erlotinib was administered at the dose of 100 mg/d in 17 studies, 19 , 20 , 23 , 25 – 36 , 38 , 39 100 or 150 mg/d in three studies, 16 , 17 , 21 and 150 mg/d in the remaining three studies. 18 , 22 , 24 …”

The prognostic value of KRAS mutation by cell-free DNA in cancer patients: A systematic review and meta-analysis

“…Several studies found that cfDNA and the presence of mutant KRAS in plasma or serum cfDNA was significantly associated with the metastasis in patients with cancer [ 28 , 33 , 38 , 48 ]. In recent years, many studies found that KRAS mutation was associated with the recurrence [ 49 – 51 ] and with survival prognosis in various types of cancer [ 32 , 35 ][ 38 ], but several studies suggested that KRAS mutation in cfDNA was not associated with survival outcome of patients with pancreatic, lung or colon cancer [ 14 , 25 , 33 ]. The prognostic values of KRAS mutations in cfDNA as a biomarker remain to confirm.…”

Current Status of Circulating Tumor DNA Liquid Biopsy in Pancreatic Cancer

“…CA19-9 has traditionally been used as a surveillance tool, but has its limitations, namely low sensitivity and the fact that 5–10% of the population are incapable of producing CA19-9, rendering it useless in these patients [ 93 , 94 ]. ctDNA can be used for monitoring throughout treatments including surgery and chemotherapy [ 95 , 96 , 97 , 98 , 99 ].…”