Clinical and molecular determinants of treatment benefit with phase I trials in patients (pts) with advanced pancreatic cancer (PC).

Abstract

409 Background: PC is the 4th leading cause of cancer-related death, with limited efficacy of systemic treatment (tx) beyond first-line chemotherapy (chemo). We aimed to assess the potential benefit of phase 1 trials in this setting. Methods: From 2011 to 2016, 49 pts were enrolled in 54 phase 1 trials at our institution. Clinical and molecular data were retrospectively extracted from medical records. Time to progression (TTP) was calculated from time of tx start to discontinuation due to progressive disease, and clinical benefit rate (CBr) was defined as partial response or stable disease > 4 months. Results: Median age was 58 (41-75), 69% were male, 60% had metastases in liver. Most pts received gemcitabine-based regimens (47%) or Folforinox (32%) as first-line tx (median TTP of 5.63 months [CI 95% 4.0-8.1]). Median tx line of Phase 1 trial was 3 (range 2-5). Regimens included chemo or immunotherapies (chemo-imm group) in 16 cases (12 and 4, respectively), small molecule inhibitor (SMI) as single-agent in 19 cases (SMI.1 group), and SMI in combinations in 19 cases (SMI.2 group). In 17 cases, tx was matched to genomic profile; most frequent matches were PI3K + MEK SMI or RAF SMI ( KRAS mut in 7 pts), PI3K SMI ( PTEN loss/ PIK3CA mut in 3 pts) and PD1 blockade (PDL1 high in 4 pts). There were 3 (6%) partial responses (PI3K SMI unmatched, RAF SMI matched and anti-PD1 agent matched) and 12 (24%) disease stabilizations. Median TTP in phase 1 trial was 1.9 months [CI 95% 1.6-2.5], without significant differences if matched/unmatched agent (p = 0.5) or tx given as second-line/later regimen (p = 0.5). Median TTP was 2.7 months [CI95% 1.6-10.7] with chemo-imm (control arm), 2.0 months [CI95% 1.8-5.6] with SMI.2 (HR = 1.8, p = 0.13) and 1.4 months [CI95% 1.3-2.8] with SMI.1 (HR = 3.0, p = 0.004). This difference was maintained in a multivariable model (HR = 2.9, p = 0.005). CBr with chemo-imm (38%) or SMI.2 (21%) was higher as compared with SMI.1 (5%; p = 0.06). Conclusions: Selected PC pts are eligible to phase 1 trials and up to one-third derive substantial benefit from the intervention. In our experience, chemo-imm agents or targeted SMI given as combination regimens associate with longer TTP and CBr when compared with single-agent SMI.