Ruxolitinib + capecitabine in advanced/metastatic pancreatic cancer after disease progression/intolerance to first-line therapy: JANUS 1 and 2 randomized phase III studies

Abstract

Background Ruxolitinib, a Janus kinase 1 (JAK1)/JAK2 inhibitor, plus capecitabine improved overall survival (OS) vs capecitabine in a subgroup analysis of patients with metastatic pancreatic cancer and systemic inflammation (C-reactive protein [CRP] >13 mg/dL) in the randomized phase II RECAP study. We report results from two randomized phase III studies, JANUS 1 (NCT02117479) and JANUS 2 (NCT02119663). Patients and Methods Adults with advanced/metastatic pancreatic cancer, one prior chemotherapy regimen and CRP >10 mg/L were randomized 1:1 (stratified by modified Glasgow Prognostic Score [1 vs 2] and Eastern Cooperative Oncology Group performance status [0/1 vs 2]) to 21-day cycles of ruxolitinib 15 mg twice daily plus capecitabine 2000 mg/m2/day (Days 1-14) or placebo plus capecitabine. The primary endpoint was OS. Results Both studies were terminated following a planned interim futility/efficacy analysis of JANUS 1. Overall, 321 and 86 patients were randomized in JANUS 1 (ruxolitinib: n = 161; placebo: n = 160) and JANUS 2 (ruxolitinib: n = 43; placebo: n = 43). There was no significant difference in OS or progression-free survival (PFS) between treatments in JANUS 1 (OS: hazard ratio [HR], 0.969, 95% confidence interval [CI], 0.747-1.256; PFS: HR, 1.056; 95% CI, 0.827-1.348) or JANUS 2 (OS: HR, 1.584; 95% CI, 0.886-2.830; PFS: HR, 1.166; 95% CI, 0.687-1.978). The most common hematologic adverse event was anemia. No new safety signals with ruxolitinib or capecitabine were identified. Conclusions Ruxolitinib plus capecitabine was well tolerated in refractory pancreatic cancer patients; this combination did not improve survival.

Keywords: Clinical trial; JAK1 protein tyrosine kinase; JAK2 protein tyrosine kinase; Pancreatic neoplasms.

Conflict of interest statement

Conflicts of interest Hurwitz: Honoraria – Genentech/Roche, Lilly/ImClone; Consulting or advisory role – Acceleron Pharma, Bristol-Myers Squibb, Genentech/Roche, GlaxoSmithKline, Incyte, Lilly, Novartis, OncoMed, TRACON Pharma; Research funding – Bristol-Myers Squibb (Inst), Genentech/Roche (Inst), GlaxoSmithKline (Inst), Lilly (Inst), Macrogenics (Inst), NCI (Inst), Novartis (Inst), Regeneron (Inst), TRACON Pharma (Inst); Employment – Genentech/Roche as of 23 October 2017. Van Cutsem: Research funding – Amgen (Inst), Bayer (Inst), Boehringer Ingelheim (Inst), Celgene (Inst), Ipsen (Inst), Lilly (Inst), Merck Serono (Inst), Novartis (Inst), Roche (Inst), Sanofi (Inst). Bendell: Research funding – Incyte. Sahai: Consulting – Celgene, Halozyme, NewLink; Research funding – Agios (Inst), Bristol-Myers Squibb (Inst), Celgene (Inst), Incyte (Inst). Sama: Honoraria – OncoPlex Diagnostics; Research funding – Bristol-Myers Squibb (Inst), Incyte (Inst), MedImmune (Inst), OncoMed (Inst), Precision Biologics (Inst); Employment – Bristol-Myers Squibb (Inst) as of March 20, 2017. Yu: Consulting or advisory role – Celgene, Merck Serono, Merrimack. Dawkins, Walker, Clark: Employment – Incyte; Stock and other ownership interests – Incyte. O’Reilly: Consulting or advisory role – Aduro Biotech, Astellas Pharma (Inst), Celgene, Celsion (Inst), Cipla, Exelixis (Inst), Gilead Sciences, Hexal (Inst), IntegraGen (Inst), Jennerex (Inst), Lilly (Inst), MedImmune, Merrimack, Novartis (Inst), Pharmacyclics, Sanofi, Silenseed, Vicus Therapeutics; Research funding – AstraZeneca/MedImmune (Inst), Bristol-Myers Squibb (Inst), Celgene (Inst), Immunomedics (Inst), Incyte (Inst), Momenta Pharmaceuticals (Inst), Myriad Genetics (Inst), OncoMed (Inst), Polaris (Inst), Sanofi (Inst). Hidalgo, Li, Garrido, Macarulla, Greeno, Verslype: Nothing to disclose.

Figures

Fig. 1

Study design of JANUS 1 and JANUS 2. aTreatment continued until disease progression, withdrawal due to toxicity, or withdrawal of consent; bAfter the final primary analysis, follow-up was to be reduced to every 12 weeks. BID twice daily; ECOG PS Eastern Cooperative Oncology Group performance status; mGPS modified Glasgow Prognostic Score; OS overall survival

Fig. 2

Patient disposition (intent-to-treat population). aAt the time of study termination (date of study termination: February 11, 2016); bOn or before study termination

Fig. 3

OS and PFS Kaplan-Meier of JANUS 1 and JANUS 2 (intent-to-treat population). aCalculated using the method of Brookmeyer and Crowley (1982) [34]; bEstimated using a Cox regression model with Efron’s method used for ties, stratified by mGPS score and ECOG PS; cOne-sided p-value calculated from log-rank test stratified by mGPS score and ECOG PS. CI confidence interval; ECOG PS Eastern Cooperative Oncology Group performance status; HR hazard ratio; mGPS modified Glasgow Prognostic Score; OS overall survival; PFS progression-free survival