Herbert I. Hurwitz, MD
Adding ruxolitinib (Jakafi) to capecitabine as a second-line treatment for patients with metastatic pancreatic cancer significantly improved survival for a subgroup with a high degree of local and systemic inflammation compared with capecitabine plus placebo, according to phase II trial results presented at the ESMO 16th World Congress on Gastrointestinal Cancer.
The results from the RECAP trial confirm the role of inflammation in promoting cancer and the importance of the JAK-STAT pathway, which ruxolitinib inhibits, as a therapeutic target in metastatic pancreatic cancer, said lead author Herbert I. Hurwitz, MD, in presenting the findings at the conference, held June 25-28 in Barcelona, Spain.
Ruxolitinib, which is supplied in tablet form, inhibits JAK1/JAK2 kinases and blocks signaling mediated by many proinflammatory cytokines. Initially approved by the FDA in 2011, ruxolitinib is indicated for treatment of patients with intermediate or high-risk myelofibrosis.
Two phase III clinical trials, JANUS 1 and JANUS 2, are evaluating ruxolitinib among patients with pancreatic cancer with inflammation scores of 1 or 2 as measured by the modified Glasgow Prognostic Score (mGPS), according to Hurwitz, a professor of Medicine at Duke University School of Medicine in Durham, North Carolina. He said mGPS also is being used as a selection criterion in trials evaluating ruxolitinib in colorectal, non-small cell lung, and breast cancers.
RECAP Trial Results
The RECAP trial enrolled 127 patients who progressed after treatment with gemcitabine; all patients were treated with 1000 mg/m2
capecitabine twice daily on days 1 through 14 of a 21-day cycle. A cohort of 64 patients also received 15-mg doses of ruxolitinib twice daily on days 1-21 and 63 patients received placebo.
The primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS) and objective response rate (ORR). Reported P
values are 2-sided.
In the overall patient population, a trend toward improved OS at 12 months favoring the ruxolitinib combination over capecitabine/placebo that did not reach statistical significance was seen (hazard ratio [HR] = 0.79; 95% CI 0.53–1.18), and PFS (HR = 0.75; 95% CI, 0.51-1.10; P
= .14). The confirmed ORR was 7.8% in the ruxolitinib arm compared with 0% in the placebo arm.
However, preplanned subgroup analysis of data from patients with high serum C-reactive protein (CRP) and albumin levels told a stronger story. Subgroup analysis of a cohort of 60 patients with CRP levels greater than the group median of 13 mg/L showed statistically significant OS improvement (HR = 0.47; 95% CI, 0.26-0.85; P
= .01) and a trend toward improved PFS (HR = 0.62; 95% CI, 0.35-1.10; P
= .10) among the 31 patients receiving ruxolitinib. Patients with CRP ≤13 mg/L who received ruxolitinib also showed improved OS (HR = 0.89) and PFS (HR = 0.82), but the differences between arms did not reach statistical significance.
The subgroup analysis also revealed improved survival rates at 3 months and 6 months of 48% and 42%, respectively, in the ruxolitinib arm, compared with 29% and 11%, respectively, in the placebo arm.
Outcome evaluated by mGPS showed patients with higher inflammation scores achieved improved survival with ruxolitinib. Significantly improved OS was achieved by patients with a score of 2 with ruxolitinib (HR = 0.49). OS decreased as the mGPS score decreased; patients with a score of 1 demonstrated slight improvements (HR = 0.71), but almost no benefit was observed in patients with a score of 0 (HR = 0.91).
The greatest gains in OS were seen in analyses of inflammation measures were combined. OS was prolonged in 70 patients with mGPS of 1 or 2 plus CRP >10 mg/L (HR = 0.60; P
= .063) and in 36 patients with mGPS 2, CRP >10 mg/L, and albumin <35 g/L (HR = 0.49; P
Hurwitz noted that mGPS has been well characterized as a clinical measure in cancer. “Importantly, more than 50 clinical studies across multiple tumor types in over 25,000 patients support the prognostic value of the GPS,” said Hurwitz.
Adverse events of grade 3 or grade 4 severity were reported by 75% of patients in the ruxolitinib arm compared with 82% of patients in the placebo arm. Grade 3/4 anemia was observed more often with ruxolitinib than with placebo (15.3% vs 1.7%), respectively, and grade 3/4 neutropenia and thrombocytopenia occurred in 1.7% of ruxolitinib treated patients versus 0% of patients receiving placebo.
“Ruxolitinib demonstrated clinical utility—something we can really do for our patients,” commented Discussant Jordan D. Berlin, MD, clinical director of the GI Oncology Program at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. “If we reduce inflammation and cancer cachexia, it could prolong the patient’s life and give us a chance to treat the cancer itself.”