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significantly inhibited tumor growth. Ruxolitinib treatment was associated with an increase in CD8+ T
cells in pancreatic cancer xenograft models and a decrease in myeloid-derived suppressor cells in KRAS-
mutated lung adenocarcinoma models, indicating an impact on immune activity [52,80] .

Ruxolitinib has also been shown to overcome drug resistance and increase sensitivity to several
chemotherapeutic or targeted agents. In preclinical in vitro and in vivo models of cisplatin-resistant
NSCLC, with increased JAK2 and STAT3 activation levels, the addition of ruxolitinib to cisplatin
[81]
decreased STAT3 activation and cell growth, enhanced apoptosis, and inhibited tumor growth . In
myxoid liposarcoma cancer stem cells, which can be resistant to chemotherapy due to upregulated JAK/
STAT signaling, ruxolitinib treatment inhibited phosphorylation of STAT3 and cell viability, overcoming
[82]
chemotherapy resistance . Ruxolitinib in combination with antibodies against cytokines such as IL-6
(tocilizumab) improved survival in mice bearing ovarian cancer tumors. Ruxolitinib in combination with
paclitaxel reduced cell proliferation and colony formation in ovarian cancer cell lines and inhibited tumor
growth in in vivo models [83,84] . Ruxolitinib has been shown to improve sensitivity to oncolytic viral therapy
[86]
[88]
[87]
[85]
in HNC , pancreatic cancer , glioblastoma multiforme (GBM) , and NSCLC . Collectively, the safety
profile of ruxolitinib in conjunction with promising preclinical findings in a variety of tumor models make
ruxolitinib an attractive therapeutic agent against solid tumors.
Several clinical trials have studied the impact of ruxolitinib in patients with solid tumors. In a Phase
II study of ruxolitinib and capecitabine in patients with pancreatic cancer who failed to respond to
gemcitabine, known as the RECAP trial, there was improved survival among a subgroup of patients
with inflammation, defined by a C-reactive protein (CRP) greater than the population median of 13 mg/
[89]
L (NCT01423604) . Given these initial promising results, ruxolitinib was administered to patients
with pancreatic cancer and an elevated CRP in two Phase III trials, JANUS 1 (NCT02117479) and
JANUS 2 (NCT02119663). In both trials, patients were randomized to be treated with either ruxolitinib
and capecitabine or placebo and capecitabine. However, these studies were terminated as there was no
increase in overall or progression-free survival observed in the group receiving ruxolitinib compared with
placebo . The combination of ruxolitinib and capecitabine in breast cancer patients with elevated CRP
[90]
was also investigated in a Phase II clinical trial (NCT02120417). While patients receiving ruxolitinib and
capecitabine had a more favorable health-related quality of life outcome, this study was terminated because
[91]
there was no improvement in overall survival compared to the group receiving placebo and capecitabine .
A Phase II trial of ruxolitinib in triple-negative breast cancer confirmed inhibition of STAT3 activation in
patient tumor samples; however, no clinical response was observed, as evaluated by the RECIST criteria,
and the study was terminated (NCT01562873) [92,93] . The most recently completed clinical trial (results
not reported or published) included a Phase II study testing ruxolitinib in combination with exemestane
in patients with estrogen receptor-positive breast cancer (NCT01594216). The addition of ruxolitinib to
regorafenib in a Phase II trial in patients with colorectal cancer did not show a difference in overall survival
or progression-free survival as compared to placebo and regorafenib; therefore, this study was terminated
[94]
early (NCT02119676) . Ruxolitinib was also tested in patients with lung cancers. A Phase II trial of
ruxolitinib (or placebo), pemetrexed, and cisplatin in patients with stage IIIb/IV or recurrent NSCLC
demonstrated that this combination was well-tolerated; the study was terminated without achieving
[95]
an efficacy endpoint (NCT02119650) . Partial responses were seen in 31% of patients who received
ruxolitinib and in 35% of patients who received placebo. A Phase Ib study of ruxolitinib combined with
afatinib, an inhibitor of mutant EGFR, in patients with NSCLC showed that this regimen was both well-
tolerated and displayed activity against this malignancy, as 23.3% displayed a partial response and 80%
had stable disease (NCT02145637) . In a Phase I/II study, ruxolitinib combined with the EGFR inhibitor
[96]
[97]
erlotinib in lung adenocarcinoma was shown to be well-tolerated but ineffective (NCT02155465) . A Phase
Ib study of ruxolitinib with gemcitabine or nab-paclitaxel in solid tumors showed that this combination
was well-tolerated (NCT01822756). However, efficacy could not be evaluated due to early termination of