Abstract
A phase II trial found that the drug ruxolitinib extends the lives of some patients with metastatic pancreatic cancer who no longer responded to first-line therapy. Ruxolitinib, approved for treating myelofibrosis, blocks the JAK/STAT pathway, which promotes inflammation. Ruxolitinib increased median survival from 1.8 to 2.7 months in patients with pancreatic cancer who had high levels of the inflammation marker C-reactive protein in their blood.
A drug that disrupts a proinflammatory pathway may increase survival for patients with metastatic pancreatic cancer, according to a recent study (J Clin Oncol 2015 Sep 8 [Epub ahead of print]).
Metastatic pancreatic cancer is extremely difficult to treat. First-line therapy typically consists of the four-drug regimen FOLFIRINOX, gemcitabine (Gemzar; Eli Lilly) alone, or gemcitabine with nab-paclitaxel (Abraxane; Celgene). These options can be toxic, and the disease eventually progresses.
Doctors haven't reached a consensus on the best second-line therapy for metastatic pancreatic cancer. One possible approach involves targeting inflammation. Researchers suspect that inflammation promotes the growth of many cancers, and some of the strongest evidence linking it to survival comes from studies of pancreatic cancer, notes Herbert Hurwitz, MD, of Duke University Medical Center in Durham, NC. Patients with pancreatic cancer typically die sooner if they show signs of systemic inflammation, for example. Besides spurring tumor growth, inflammation might also drive some of the cancer's symptoms, such as weight loss.
To curb tumor-related inflammation, Hurwitz and colleagues turned to ruxolitinib (Jakavi; Novartis), a drug approved for treating myelofibrosis. Ruxolitinib inhibits the JAK1 and JAK2 kinases in the JAK/STAT pathway, which helps orchestrate inflammation. To measure ruxolitinib's effectiveness against metastatic pancreatic cancer, the researchers performed a phase II trial that included 127 patients who had previously been treated with gemcitabine. Sixty-four patients received ruxolitinib and capecitabine (Xeloda; Roche), a drug often used to treat refractory pancreatic cancer. The 63 patients in the control group received a placebo and capecitabine.
Overall survival was 4.5 months in the ruxolitinib group and 4.3 months in the control group'not a significant difference. However, the researchers did detect a significant difference in the 60 patients with high blood levels of C-reactive protein (CRP), a marker of inflammation. The median survival for patients in this subgroup who received ruxolitinib was 2.7 months, and the objective response rate was 6.5%, versus 1.8 months and 3.4% for patients who received a placebo.
The most common side effect for patients treated with ruxolitinib was anemia, followed by fatigue and abdominal pain. “The drug is well tolerated,” says Hurwitz. “The fact that it appears to work in patients who are the sickest [those with high CRP] is particularly encouraging.”
“It's an important proof of principle,” says Andrew Ko, MD, of the University of California, San Francisco, who wasn't connected to the study. “I wouldn't necessarily say the result is a home run,” but “it's enough of a positive signal to go forward with larger trials.”
However, NCI's Tim Greten, MD, describes the results as “quite disappointing” because the treatment helps only a fraction of patients.
Researchers now need to determine whether ruxolitinib works in a larger group of patients with metastatic pancreatic cancer and high CRP levels. Two phase III trials designed to do just that began in 2014, and Hurwitz says that the results should be available within a year.
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