Abstract P4-22-04: A randomized, double-blind, phase 2 study of ruxolitinib (RUX) or placebo (PBO) in combination with capecitabine (CAPE) in patients (pts) with advanced HER2-negative breast cancer (ABC) and elevated C-reactive protein (CRP), a marker of systemic inflammation
Authors: O'Shaughnessy J , DeMichele A , Ma C , Richards P , Yardley DA , Wright G , Kalinsky K , Steis R , Diab S , Kennealey G , Geschwindt R , Jiang W , Rugo H 
Published: March 2017

Abstract
Background: Systemic inflammation is associated with poor prognosis in pts with ABC. The JAK/STAT pathway is a key regulator of inflammatory signaling, associated with tumorigenesis, cell survival, and progression. We evaluated the efficacy and safety of RUX, a JAK1/JAK2 inhibitor, plus CAPE in pts with HER2-negative ABC and high systemic inflammation defined by the modified Glasgow Prognostic Score (mGPS). Methods: In this double-blind phase 2 trial, pts were randomized 1:1 to 21 day cycles of RUX+CAPE or PBO+CAPE: RUX 15 mg or PBO PO BID for 21 d; CAPE 1000 mg/m2 PO BID for 14 d. Key inclusion criteria were systemic inflammation by mGPS of 1 or 2 (ie, CRP &gt;10 mg/L), ECOG performance status ≤2, ≤2 prior chemotherapy regimens, and no prior CAPE. The primary endpoint was overall survival (OS); key secondary endpoints were progression-free survival (PFS), objective response rate (ORR; complete [CR] + partial response [PR]) per RECIST v1.1, clinical benefit rate (CBR; CR + PR + stable disease for ≥6 mo), duration of response, and safety. Treatment differences in OS and PFS were analyzed by the log-rank test; HRs and CIs were analyzed by the Cox proportional hazards model. Results: Baseline characteristics were similar between pts randomized to RUX+CAPE (n=76) vs PBO+CAPE (n=73): mGPS status (1, 82.9% vs 83.6%), hormone receptor (HR) status (positive, 67.1% vs 63.0%), and number of prior chemotherapy regimens for ABC (0, 50.0% vs 50.7%; 1, 38.2% vs 34.2%; 2, 9.2% vs 13.7%). Median treatment durations were 85 d with RUX in the RUX+CAPE group and 65 d with PBO in the PBO+CAPE group. Median OS was 11.2 mo with RUX+CAPE vs 10.9 mo with PBO+CAPE (HR, 0.932; 95% CI, 0.59–1.46; P=0.762). Median OS was 6.1 mo with RUX+CAPE vs 5.5 mo with PBO+CAPE in HR-negative pts and 11.7 mo and 12.2 mo in HR-positive pts. Median PFS was 4.5 mo with RUX+CAPE and 2.5 mo with PBO+CAPE (HR, 0.737; 95% CI, 0.49–1.12; P=0.151). Median PFS was 2.1 mo with RUX+CAPE vs 2.2 mo with PBO+CAPE in HR-negative pts and 6.1 mo and 4.1 mo in HR-positive pts. ORRs were 28.9% and 13.7% (P=0.024) in the RUX+CAPE and PBO+CAPE arms, respectively. The CBRs were 13.2% and 6.8%, respectively (P=0.278). Worsening of hematologic toxicity was higher and rates of grade 3/4 palmar-plantar erythrodysethesia (PPE) were lower (1.4% vs 12.7%, respectively) with RUX+CAPE (Table).
Safety RUX+CAPE (n=71)PBO+CAPE (n=71)%All-GradeGrade 3/4All-GradeGrade 3/4Nonhematologic Adverse Event*Fatigue56.35.643.74.2Nausea54.98.549.35.6Diarrhea47.98.526.82.8PPE46.51.438.012.7Vomiting38.05.629.64.2Hypokalemia15.58.57.02.8Worsening of Hematologic Toxicity†Anemia80.323.956.37.0Lymphopenia40.815.545.112.7Neutropenia39.411.322.52.8Thrombocytopenia39.411.315.51.4*Most common all-grade (≥35%) or grade 3/4 (≥5%) events in the RUX+CAPE arm (safety group). †Laboratory abnormalities.
Conclusion: These data support the prognostic capabilities of the mGPS. The addition of RUX to CAPE for pts with ABC and high systemic inflammation was associated with an improved ORR compared with PBO+CAPE, but did not improve OS or PFS.
Citation Format: O'Shaughnessy J, DeMichele A, Ma C, Richards P, Yardley DA, Wright G, Kalinsky K, Steis R, Diab S, Kennealey G, Geschwindt R, Jiang W, Rugo H. A randomized, double-blind, phase 2 study of ruxolitinib (RUX) or placebo (PBO) in combination with capecitabine (CAPE) in patients (pts) with advanced HER2-negative breast cancer (ABC) and elevated C-reactive protein (CRP), a marker of systemic inflammation [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-04.