Circulating cytokines and angiogenic factors (CAF) as markers of clinical response in the study of trametinib (T) plus gemcitabine (G) versus placebo (P) plus gemcitabine for patients (pts) with untreated metastatic adenocarcinoma of the pancreas (MEK113487).

Abstract

4042 Background: T is a reversible and highly selective allosteric inhibitor of MEK1/MEK2. The addition of T to G did not improve overall survival (OS) as first-line treatment for pts with metastatic adenocarcinoma of the pancreas (ASCO GI 2013 #291). CAF profiles have shown potential for identification of prognostic and predictive markers in cancer pts (Tran, Lancet, 2012). Methods: Plasma samples (n = 144 baseline [BL]; n = 112 day 15) from pts who consented to participate in MEK113487 study were analyzed for 30 CAFs (ANG2, IGFBP3, IL2R, IP10, MMP2, MMP9, OPN, PDGFBB, SCF, TIMP1, IL6, MIP1B, SDF1, TRAIL, VEGF, MIP3A, MCP2, FGFB, IL8, VEGFR1, IL10, IL1A, IL12P40, PIGF, EGF, IL1B, TNFA, IL4, MIP1A, MCP3) using SearchLight multiplex assays in a CLIA-certified laboratory. Change from BL was assessed using either paired t tests or Wilcoxon tests. BL and change from BL CAF levels were tested for association with clinical outcome using proportional hazards regression within arm (P < .01 for significance) and between arms (treatment arm by CAF level interaction, P < .05 for significance). Results: Lower levels (< median) of BL ANG2, IL6, TIMP1, and IL8 were associated with an average of 5 mo longer OS in both the T+G and G arms. Lower BL levels (less than first quartile) of IGFBP3 and PDGFBB were associated with 6 mo longer OS in the T+G arm, while higher levels (greater than third quartile) of IGFBP3 and PDGFBB were associated with 4.8 mo longer OS in the G arm. A combined model of low IGFBP3 and/or PDGFBB showed improved survival for T+G vs G (median OS, 10.3 vs 5.6 mo). Decreases of ANG2 and IL2R levels at day 15 from BL were observed in the T+G arm only; additional results will be presented. Conclusions: This study suggests that plasma CAF profiling may aid in the prognostic evaluation of pts, assessing therapeutic response, and identifying pathways modulated by treatment in pancreatic cancer pts. Low IGFBP3 and PDGFBB may identify patients who receive greater benefit from T+G compared with G in this population and merit further investigation as predictive markers. Clinical trial information: NCT01231581.