Abstract 3157: Serial droplet digital PCR (ddPCR) of plasma cell-free DNA (cfDNA) as pharmacodynamic (PD) biomarker in Phase 1 clinical trials for patients (pts) with KRAS mutant non-small cell lung cancer (NSCLC)
Authors: Paweletz Cloud P. , Oxnard Geoffrey R. , Feeney Nora , Hilton John F. , Gandhi Leena , Do Khanh T. , Anderson Adrienne , Wolanski Andrew , Tejeda Alexander , English Jessie M. , Kirschmeier Paul T. , Jänne Pasi A. , Shapiro Geoffrey I. 
Published: July 2016

Abstract
Introduction: Phase 1 clinical trials of novel therapeutics have historically focused on toxicity, but increasingly are doubling as efficacy studies in biomarker-enriched populations. Given the small sample sizes (∼3-6 patients per dose), response on imaging may be a coarse marker of therapeutic effect. Here we piloted serial ddPCR of plasma cfDNA as a PD marker in a phase I combination study of a MEK inhibitor and a CDK 4/6 inhibitor in patients with RAS mutated cancers.
Methods / Results: Twenty-five pts with RAS-mutated cancer (incl. 17 patients with KRAS-mutant NSCLC) have been enrolled to date in a phase I dose escalation trial of the MEK inhibitor PD-0325901 with the CDK4/6 inhibitor palbociclib (NCT02022982). Plasma for cfDNA genotyping was collected at baseline prior to therapy and at the beginning of cycle 2. Plasma genotyping for KRAS G12X mutations was performed using a validated and highly quantitative droplet digital PCR assay.
Pts were enrolled in 5 dose level cohorts ranging from 75 mg palbociclib daily (3 weeks on, 1 week off) with 2 mg PD-0325901 BID (3 weeks on 1week off) to 125 mg palbociclib daily with 8 mg PD-0325901 BID (Table). KRAS mutations were detected in 14/24 pts at baseline (59%, median 1402 copies/mL plasma, range: 11-93000), consistent with the previously reported sensitivity of 64%. A second blood draw at cycle 2 was obtained for all 14 pts. A positive plasma response, defined as decrease of KRAS G12X mutants from first to second dose, was observed in 6 pts (range -6% - -100%) with the most plasma responders (n = 4 pts) at the maximum administered dose. At lower administered doses, there was a median increase in plasma KRAS mutant levels.
Conclusions: Increasing dose levels resulted in more consistent decreases in KRAS mutation in cfDNA, consistent with a dose-dependent pharmacodynamic effect.These results highlight the potential value of serial plasma ddPCR as a PD marker in early phase clinical trials. Dose LevelPalbociclib (QD, 3 wks on 1 wk off) mgPD-0325901 (BID, 3 wks on 1 wk off) mgN Enrolled (N analyzed)Median Plasma change KRAS mut(%)17523 (1)+2427543 (3)+60 (range +31 - +150)310048 (4)+150 (range -6 - +341)412544 (2)+9 (range -45 - +61)512587 (4)-27 (range -7 - -43)
Citation Format: Cloud P. Paweletz, Geoffrey R. Oxnard, Nora Feeney, John F. Hilton, Leena Gandhi, Khanh T. Do, Adrienne Anderson, Andrew Wolanski, Alexander Tejeda, Jessie M. English, Paul T. Kirschmeier, Pasi A. Jänne, Geoffrey I. Shapiro. Serial droplet digital PCR (ddPCR) of plasma cell-free DNA (cfDNA) as pharmacodynamic (PD) biomarker in Phase 1 clinical trials for patients (pts) with KRAS mutant non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3157.