Randomized, double‐blind, phase two study of ruxolitinib plus regorafenib in patients with relapsed/refractory metastatic colorectal cancer

Abstract

BackgroundThe Janus kinase/signal transducer and activator of transcription (JAK‐STAT) signaling pathway plays a key role in the systemic inflammatory response in many cancers, including colorectal cancer (CRC). This study evaluated the addition of ruxolitinib, a potent JAK1/2 inhibitor, to regorafenib in patients with relapsed/refractory metastatic CRC.MethodsIn this two‐part, multicenter, phase 2 study, eligible adult patients had metastatic adenocarcinoma of the colon or rectum; an Eastern Cooperative Oncology Group performance status of 0‐2; received fluoropyrimidine, oxaliplatin, and irinotecan‐based chemotherapy, an anti‐vascular endothelial growth factor therapy (if no contraindication); and if KRAS wild‐type (and no contraindication), an anti‐epidermal growth factor receptor therapy; and progressed following the last administration of approved therapy. Patients who received previous treatment with regorafenib, had an established cardiac or gastrointestinal disease, or had an active infection requiring treatment were excluded. The study was conducted in 95 sites in North America, European Union, Asia Pacific, and Israel. After an open‐label, safety run‐in phase (part 1; ruxolitinib 20 mg twice daily [BID] plus regorafenib 160 mg once daily [QD]), the double‐blind, randomized phase (part 2) was conducted wherein patients were randomized 1:1 to receive ruxolitinib 15 mg BID plus regorafenib 160 mg QD [ruxolitinib group] or placebo plus regorafenib 160 mg QD [placebo group]. Part 2 included substudy 1 (patients with high systemic inflammation, ie, C‐reactive protein [CRP] >10 mg/L) and substudy 2 (patients with low systemic inflammation, ie, CRP ≤10 mg/L); the primary endpoint was overall survival (OS).ResultsThe study was terminated early; substudy 1 was terminated for futility at interim analysis and substudy 2 was terminated per sponsor decision. Ruxolitinib 20 mg BID was well tolerated in the safety run‐in (n = 11). Overall, 396 patients were randomized (substudy 1: n = 175 [ruxolitinib group, n = 87; placebo group, n = 88]; substudy 2: n = 221 [ruxolitinib group, n = 110; placebo group, n = 111]). There was no significant difference in OS or progression‐free survival (PFS) between treatments in substudy 1 (OS: hazard ratio [HR] = 1.040 [95% confidence interval: 0.725‐1.492]; PFS: HR = 1.004 [0.724‐1.391]) and substudy 2 (OS: HR = 0.767 [0.478‐1.231]; PFS: HR = 0.787 [0.576‐1.074]). The most common hematologic adverse event was anemia. No new safety signals with ruxolitinib were identified.ConclusionsAlthough addition of ruxolitinib to regorafenib did not show increased safety concerns in patients with relapsed/refractory metastatic CRC, this combination did not improve OS/PFS vs. regorafenib plus placebo.

<p>Progress in Understanding the IL-6/STAT3 Pathway in Colorectal Cancer</p>

“… 83 Incyte Corporation performed a clinical trial to test the combination of ruxolitinib, a selective inhibitor of JAK1/JAK2, with regorafenib for the treatment of refractory mCRC. 84 Although the combination did not lead to more adverse effects, it did not improve efficacy over regorafenib alone. The 396 patients included in the trial were randomized into two subgroups.…”

Further Therapeutic Options in Heavily Pretreated Colorectal Cancer Patients

“…An objective response rate to regorafenib combined with modified FOLFOX (mFOLFOX6) as the first-line treatment was no better than that observed in historical controls, with 85.4% DCR and median PFS of 8.5 months [18]. Negative results, specifically the lack of either OS or PFS benefit, were obtained in a study investigating the efficacy and toxicity of regorafenib plus ruxolitinib, a Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling pathway [19].…”

Signal transducer and activator of transcription 6 as a target in colon cancer therapy (Review)

“…Ruxolitinib, an oral selective inhibitor of JAK1/2, is approved by the FDA for use in myelofibrosis (65). Ruxolitinib was tested in a phase 2 study in combination with regorafenib, an oral multi-targeted kinase inhibitor, in patients with advanced and metastatic adenocarcinoma of the colon or rectum (66). However, there was no significant difference in the overall survival rate or progression-free survival rate between the regorafenib + placebo vs. regorafenib + ruxolitinib groups (66).…”

“…Ruxolitinib was tested in a phase 2 study in combination with regorafenib, an oral multi-targeted kinase inhibitor, in patients with advanced and metastatic adenocarcinoma of the colon or rectum (66). However, there was no significant difference in the overall survival rate or progression-free survival rate between the regorafenib + placebo vs. regorafenib + ruxolitinib groups (66). Nevertheless, the treatment was administered in the advanced stages of tumor development, and the trial was terminated early per sponsor decision; therefore, further investigation is required, particularly during early stages of CRC.…”