P2.03a-014 A Dose-Finding and Phase 2 Study of Ruxolitinib plus Pemetrexed/Cisplatin for Nonsquamous Non–Small Cell Lung Cancer (NSCLC)

Abstract

Dysregulation of the JAK/STAT pathway contributes to abnormal inflammatory responses, oncogenesis, treatment resistance, and poor prognosis in NSCLC. This phase 2 clinical trial evaluated the JAK1/JAK2 inhibitor ruxolitinib+pemetrexed/cisplatin as first-line treatment for patients with stage IIIB/IV or recurrent nonsquamous NSCLC and systemic inflammation (per modified Glasgow Prognostic Score [mGPS]). Key inclusion criteria were mGPS of 1/2 and ECOG performance status ≤1. Part 1, an open-label, 21-day safety run-in, assessed ruxolitinib (15 mg BID [chosen dose for Part 2]) plus pemetrexed (500 mg/m2 IV on Day 1) and cisplatin (75 mg/m2 IV on Day 1). Ruxolitinib dose selection for Part 2 required <3 dose-limiting toxicities (DLTs) for 9 evaluable patients. Part 2 randomized patients to ruxolitinib+pemetrexed/cisplatin or placebo+pemetrexed/cisplatin. The trial was terminated early for lack of efficacy in other solid tumor programs in patients with high systemic inflammation. All 15 patients enrolled in Part 1 received ruxolitinib 15 mg BID plus pemetrexed/cisplatin. Median age was 64 years; male, 80%; mGPS 1, 80%. Median treatment duration was 140 days. The Table reports Part 1 safety data. Four patients were inevaluable for DLTs (<80% compliance, n=2; disease progression, n=2). No DLTs occurred in 11 evaluable patients. The Part 1 overall response rate (ORR) was 53% (8/15; all partial responses). At study termination, 39 and 37 patients were randomized in Part 2 to ruxolitinib and placebo, respectively. Median treatment duration was 43 days. ORR was 31% (12/39) with ruxolitinib+pemetrexed/cisplatin versus 35% (13/37) with placebo+pemetrexed/cisplatin (all partial responses). The short follow-up duration may limit interpretation of Part 2 efficacy. The Part 2 safety profile was consistent with Part 1 (data to be presented).TableThe Most Common Treatment-Emergent Adverse Events in Part 1Event, n (%)Ruxolitinib+Pemetrexed/Cisplatin (N=15)All-GradeGrade 3/4Nonhematologic*Nausea11(73)1(7)Fatigue8(53)3(20)Vomiting8(53)1(7)Constipation7(47)0Diarrhea7(47)0Dizziness7(47)0Peripheral edema7(47)0Decreased appetite6(40)0Pyrexia6(40)0Dyspnea5(33)1(7)Pneumonia4(27)3(20)Pulmonary embolism2(13)2(13)Sepsis2(13)2(13)New/worsening hematologic laboratory abnormalitiesAnemia13(87)5(33)Lymphopenia11(73)2(13)Leukopenia9(60)1(7)Neutropenia9(60)5(33)Thrombocytopenia9(60)1(7)*Common all-grade (≥30%) or grade 3/4 (≥10%) events. Open table in a new tab *Common all-grade (≥30%) or grade 3/4 (≥10%) events. Ruxolitinib 15 mg BID had an acceptable safety profile in combination with pemetrexed/cisplatin as first-line treatment of patients with stage IIIB/IV or recurrent nonsquamous NSCLC.