Date: 2015-12-05
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the 57th American Society of Hematology Meeting (ASH) in Orlando, Florida
Company: Novartis (Switzerland)
Product: Jakafi® - INC424 (ruxolitinib)
Action
mechanism: enzyme inhibitor/tyrosine kinase inhibitor. Jakafi®/Jakavi® (INC424, ruxolitinib) is an oral inhibitor of the JAK 1 and JAK 2 tyrosine kinases that are involved in regulating blood and immunological functioning. Myelofibrosis is associated with the deregulation of JAK 1 and 2. The product was approved by the European Commission in August 2012for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis.
Novartis licensed INC424 (ruxolitinib) from Incyte for development and commercialization outside the United States. Both the European Commission and the FDA granted INC424 (ruxolitinib) orphan drug status for myelofibrosis. Jakavi® is marketed in the United States by Incyte Corporation under the name Jakafi®for the treatment of patients with intermediate or high-risk myelofibrosis.
Disease: myelofibrosis
Therapeutic area: Cancer - Oncology - Blood diseases - Hematological diseases
Country:
Trial
details: The COMFORT-II (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy) study randomized 219 patients to receive Jakavi (15 or 20 mg BID) or BAT (2:1 randomization for Jakavi vs. BAT). A total of 73.3% (107/146) of patients in the Jakavi arm entered the extension phase vs. 61.6% (45/73) in the BAT arm, and 55.5% (81/146) of those originally randomized to Jakavi remained on treatment at the time of this analysis. Overall survival was estimated using the Kaplan-Meier method. In the analysis of COMFORT-II data examining JAK2V617 allele burden reduction, allele burden was measured from blood samples using allele-specific quantitative real-time polymerase chain reaction (qPCR). No specific long-term safety signals emerged during the two-year follow-up period. In the primary analysis of the COMFORT-II study published in The New England Journal of Medicine in February 2012 (median treatment duration of 50.1 weeks; Jakavi®, 51.4 weeks; BAT, 45.1 weeks), the most common grade 3/4 hematologic adverse events (AEs) in either arm (Jakavi®, BAT) were anemia (42.4%; 31.4%) and thrombocytopenia (8.3%; 7.2%), and were manageable with either dose reduction or occasional interruption[4]. In the Jakavi arm, mean hemoglobin levels decreased over the first 12 weeks of treatment and then recovered to levels similar to the BAT from week 24 onward. One patient in each arm discontinued for thrombocytopenia, and no patients discontinued for anemia. One week after discontinuing Jakavi, these patients experienced a return of myelofibrosis symptoms that were present before initiating therapy. Since the core study has completed, all patients either entered the extension phase or discontinued from the study. A total of 107 of the 146 patients on Jakavi® entered the extension phase in addition to 45 of the 73 patients previously treated with BAT (median treatment duration of 83.3 weeks; Jakavi, 111.4 weeks [randomized and extension phases]; BAT, 45.1 weeks [randomized treatment only per primary analysis]. Grade 3/4 hematologic abnormalities in the extension phase for Jakavi® were consistent with the primary analysis: anemia (40.4%); lymphopenia (22.6%) and thrombocytopenia (9.6%). The COMFORT-I study randomized 309 patients to Jakavi® or placebo. The primary analysis occurred when all patients completed 24 weeks of therapy, and all patients receiving placebo were eligible to cross over to Jakavi® after the primary analysis. Quality of life was evaluated beyond week 24 using the European Organization for Research and Treatment of Cancer QoL Questionnaire-Core 30, and overall survival was assessed according to original randomized treatment.
Latest
news: * On December 5, 2015, Novartis announced that five-year treatment with Jakavi® (ruxolitinib) suggested an overall survival advantage for patients with myelofibrosis, despite crossover to Jakavi® from the best available therapy arm after the primary analysis at 48 weeks (intent-to-treat analysis: 33% reduction in risk of death, hazard ratio=0.67 [95% confidence interval (CI), 0.44-1.02], crossover-corrected hazard ratio=0.44 [95% CI, 0.18-1.04]). In the COMFORT-II (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy) Phase III study, more than half of the patients with MF (53.4%) also experienced significant reductions (>=35%) in spleen size with Jakavi therapy, and sustained this benefit over prolonged periods of time (median duration of 3.2 years). Findings from this study were presented at the 57th American Society of Hematology Meeting (ASH) in Orlando, Florida. * On December 9, 2013, Novartis has announced that patients with myelofibrosis initially randomized to treatment with Jakavi® (ruxolitinib) lived longer than those randomized to treatment with placebo or conventional therapy, as described in several analyses from the Phase III COMFORT-I and COMFORT-II studies. Results are being presented at the 55th American Society of Hematology (ASH) Annual Meeting and Exposition in New Orleans, LA. Study investigators presented the following analyses from the COMFORT clinical program demonstrating an overall survival benefit for patients with myelofibrosis treated with Jakavi®: * Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK Inhibition with Ruxolitinib versus Best Available Therapy for Myelofibrosis. New Eng J Med. 2012: March 1;366:787-98. **Verstovsek S, Mesa RA, Gotlib J, et al. A Double-Blind, Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis.New Eng J Med. 2012: March 1;366:799-807.
- Impact of Prognostically Detrimental Mutations in COMFORT-II (abstract #107)
Patients with certain disease mutations are considered to be at high molecular risk (HMR+) and tend to have shorter overall survival and greater risk of leukemia compared to those without these mutations, classified as low molecular risk (LMR). Investigators analyzed the impact of disease mutations on spleen size reduction, anemia development and overall survival in patients with myelofibrosis initially randomized to treatment with Jakavi in the COMFORT-II trial. Researchers found that Jakavi had a similar effect in patients with and without these mutations. The presence of mutations did not impact achievement of >=35% spleen volume reduction at 24 (34.8% vs 35.0% in HMR+ vs LMR respectively) and 48 weeks (26.1% vs 35.0% in HMR+ vs LMR respectively) in patients initially randomized to treatment with Jakavi. There was also a survival benefit in both groups in the Jakavi treatment arm (survival estimate of 0.79 vs 0.85 in HMR+ vs LMR respectively).
- Three-Year Update From COMFORT-I Study (abstract #396)
In COMFORT-I, risk of death at three years was reduced by 31% in patients initially randomized to treatment with Jakavi compared to those randomized to the placebo group (HR=0.69; 95% CI: 0.46, 1.03; P = 0.067). The trial design allowed patients who were receiving placebo to cross over to be treated with Jakavi. At the time of analysis, placebo patients had received Jakavi therapy for a median of 104 weeks and the suggested risk of death for those patients had decreased to approach that for patients originally randomized to Jakavi. Consistent with observations at the two year follow-up, grade 3 or 4 anemia and thrombocytopenia typically only occurred early (<=6 months) in Jakavi treatment and decreased with long-term therapy.
- A Pooled Overall Survival Analysis of the COMFORT Studies (abstract #2820)
In the COMFORT-I and -II studies, risk of death at three years was reduced by 35% in patients initially randomized to treatment with Jakavi compared to patients randomized to the control group (HR = 0.65; 95% CI, 0.46-0.90; P = 0.01). Patients with high risk myelofibrosis who were initially randomized to treatment with Jakavi had an estimated survival similar to patients with intermediate-2-risk myelofibrosis in the control group. Additionally, among all patients in the study, bigger spleen size before treatment was associated with higher risk of death (HR = 1.09; 95% CI, 1.03-1.15; P = 0.003).
- A Retrospective Comparison of the DIPSS and COMFORT-II Study (abstract #4066)An analysis of survival from diagnosis showed a better prognosis for patients initially randomized to treatment with Jakavi in the COMFORT-II study compared to patients from the multicenter Dynamic International Prognostic Scoring System (DIPSS) database. The probability of survival at 10 years from initial diagnosis was 28.6% in the COMFORT-II trial and 11.2% in the DIPSS (95% CI: 12.5-47.1 vs 4.8-20.6, HR = 0.51 95% CI: 0.30-0.88). This suggests that the risk of death is halved by introducing Jakavi in the treatment of patients with primary myelofibrosis.
* On June 16, 2013, Novartis has announced results from a Phase III three-year follow-up study that showed Jakavi® (ruxolitinib) demonstrated improved overall survival and sustained reductions in spleen size compared to conventional therapy. In a separate long-term exploratory analysis, Jakavi® slowed or stabilized the advancement of bone marrow fibrosis, one of the underlying disease mechanisms and consequences of myelofibrosis, an effect that has not been observed with conventional therapy in advanced myelofibrosis patients. Findings are being presented at the 18th Congress of European Hematology Association (EHA) in Stockholm, Sweden. In a three-year follow-up analysis of the COMFORT-II study, patients treated with Jakavi® demonstrated an overall survival advantage compared to patients receiving conventional therapy. A 52% reduction in risk of death was observed in the Jakavi® arm compared with conventional therapy (HR=0.48; 95% CI, 0.28-0.85; p=0.009), and the estimated probability of overall survival was significantly greater with Jakavi® compared to conventional therapy (81% compared to 61%, respectively) at 144 weeks. Additionally, 51.4% of patients treated with Jakavi® achieved a >=35% reduction from baseline in spleen size. Patients continue to maintain their spleen response, with the median spleen reduction not yet reached in the study. The results are consistent with previous COMFORT-II and COMFORT-I study analyses, which demonstrate that Jakavi® provides significant clinical benefits over conventional therapy and placebo for patients suffering from myelofibrosis, a rare blood cancer.
Data were also presented from an exploratory analysis of bone marrow morphology from a separate Phase I/II trial of Jakavi®, compared with historical controls from patients treated with conventional therapy. After four years of Jakavi® therapy, bone marrow fibrosis improved in 22% and stabilized in 56% of patients with myelofibrosis. A comparable effect was not seen with long-term conventional therapy.
In the three-year analysis of COMFORT-II (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy), a total of 45.2% of patients remained on the Jakavi® treatment arm, while all patients randomized to conventional therapy discontinued treatment. For patients on conventional therapy, 61.6% crossed over to the Jakavi treatment arm, with 48.9% of these patients ongoing in the extension phase of the study. The median duration of Jakavi exposure (randomized and extension phases) was 136 weeks and conventional therapy exposure (randomized treatment only) was 45 weeks. Overall survival was estimated using the Kaplan-Meier method.
All AEs were consistent with previous analyses of treatment with Jakavi. The most common hematologic AEs in either arm (Jakavi®, conventional therapy) were anemia (50.0%; 16.4%) and thrombocytopenia (50.7%; 13.7%). The most common non-hematologic abnormalities for each arm (Jakavi®, conventional therapy) include peripheral edema (swelling of extremities) (36.3%; 28.8%), diarrhea (32.2%; 17.8%) and asthenia (weakness) (24.0%; 12.3%).
A total of 191 patients were exposed to Jakavi® by the data cut-off date, 146 patients initially randomized to Jakavi treatment and 45 patients that eventually crossed over from the conventional therapy arm. Treatment discontinuations in the Jakavi arm were primarily due to adverse events (AEs) (16.4%) and disease progression (15.1%), while discontinuations in the conventional therapy arm were primarily due to consent withdrawal and other reasons (12.3% each). Only two patients discontinued due to anemia (1%) and seven patients due to thrombocytopenia (3.6%).
Long-Term Bone Marrow Morphology Analysis Background. The data from this separate exploratory analysis assessed the effect of long-term Jakavi® treatment on bone marrow morphology in patients with myelofibrosis. An analysis of trephine biopsies were obtained from the cohort of myelofibrosis patients treated at MD Anderson Cancer Center who participated in Study 251, a Phase I/II trial of ruxolitinib.
Biopsies of myelofibrosis patients treated with Jakavi® were obtained at baseline, 24 months (68 patients) and 48 months (18 patients). Samples were also collected from a multicenter observational database from three European Union countries (160 biopsies in a cohort of 139 patients) in patients treated with conventional therapy at 24 months (97 patients) and 48 months (63 patients).
Bone marrow fibrosis grade (G) changes vs. baseline were categorized as improvement, stabilization, and worsening according to the World Health Organization (WHO) grading scale (0-3) and reviewers were blinded to patient characteristics and outcomes. Additional analyses were performed on biopsies from patients in the Jakavi-treated cohort: changes over time in the degree of collagen deposition, amount of osteosclerosis (abnormal bone density) and bone marrow cellularity. Bone marrow biopsies of Jakavi® treated patients who were evaluated at baseline presented with 21% G1 fibrosis, 53% G2 fibrosis and 26% G3 fibrosis. Distribution of baseline WHO fibrosis grades between Jakavi- and conventionally- treated groups showed no noticeable difference (p=0.441 by Cochran Mantel-Haenszel test).
* On December 11, 2012, Novartis has announced that presentation of long-term follow-up data from the COMFORT-I and COMFORT-II Phase III studies in myelofibrosis at the 54th American Society of Hematology (ASH) Annual Meeting. In these studies, Jakavi® (INC424, ruxolitinib) treatment resulted in sustained reductions in spleen size, a hallmark of myelofibrosis, while also improving quality of life and extending overall survival compared to placebo or the best available therapy (BAT).
A two-year follow-up analysis of COMFORT-II showed Jakavi® was associated with sustained reductions in splenomegaly (enlarged spleen). Overall, 48.3% of patients treated with Jakavi® achieved a >=35% reduction in spleen volume, and the majority of reductions were sustained with continued treatment over two years. In a rigorous intent-to-treat analysis, Jakavi®-treated patients showed an overall survival advantage compared to patients receiving BAT (HR=0.51; 95% CI, 0.26-0.99; p=0.041)[1], which was defined by protocol as any commercially available agent (monotherapy or in combination) or no therapy at all. A total of 61.6% of BAT patients switched to Jakavi treatment, but remained categorized as BAT patients during the follow-up analyses.
In COMFORT-I, which compared the use of Jakavi® versus placebo, researchers presented long-term follow-up data evaluating the efficacy and safety of Jakavi®. Similar to COMFORT-II, Jakavi® was associated with sustained reductions in spleen volume. Mean spleen volume reduction in the Jakavi® arm was 31.6% at week 24, and maintained through week 96 (34.9%)[2]. Among patients with a >=35% reduction in spleen volume, response was maintained with a median duration of 108 weeks. The study demonstrated a continued overall survival benefit in favor of Jakavi®, as 83% of patients on Jakavi survived at the 102 week follow-up period, compared to 73% of patients on placebo (HR=0.58; 95% CI, 0.36-0.95; p=0.028)[2]. Overall survival favored Jakavi® across subgroups, including starting dose as well as baseline risk status and hemoglobin.
While Jakavi® has proven to provide patient benefits regardless of mutational status, an analysis of patients with the JAK2V617F mutation within the COMFORT-II study was also presented at ASH. Findings demonstrate the disease-modifying effects of Jakavi®. Patients bearing the JAK2V617F mutation who received Jakavi had greater reductions in the presence of cancerous cells with the mutated JAK2V617F allele (allele burden) compared with BAT[5]. Allele burden reductions among Jakavi®-treated patients were gradual and sustained over the duration of the study, whereas BAT-treated patients demonstrated zero reductions. Among patients with >=20% allele burden reduction, sustained spleen volume reductions were observed to week 72.
* On February 29, 2012, Novartis has announced that The New England Journal of Medicine (NEJM) has published the results of the two Phase III trials that found treatment with the investigational Janus kinase (JAK) inhibitor INC424 (ruxolitinib) significantly reduced disease burden in patients with myelofibrosis (* and **).The results of COMFORT-I and COMFORT-II (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy) were first presented at the 47th American Society of Clinical Oncology (ASCO) annual meeting in June 2011.
In the COMFORT-II trial, INC424 produced a volumetric spleen size reduction of 35% or greater (roughly equivalent to a reduction in palpable spleen size by 50%) in 28% of patients compared to 0% of patients in the best available therapy (BAT) group at 48 weeks (p<0.001). At week 24, 32% of patients treated with INC424 demonstrated a 35% or greater volumetric spleen size reduction compared to 0% of patients treated with the BAT (p<0.001) for the key secondary endpoint[1]. Additionally, INC424 was associated with improvements in myelofibrosis symptoms at each evaluation as compared to the BAT.
Continuous INC424 therapy also provided a marked and durable improvement in overall quality of life measures, functioning and symptoms, including appetite loss, dyspnea (shortness of breath), fatigue, insomnia and pain, at week 48, compared to a worsening of symptoms in BAT-treated patients. INC424 showed modest toxicity as compared with the BAT, with increased frequency of anemia and thrombocytopenia. The most frequently reported serious adverse event (SAE) was anemia for both groups (INC424, 5%; BAT, 4%). Pneumonia was the only SAE reported in >=5% of patients in either group (INC424, 1%; BAT, 5%). These findings are consistent with previous investigation of INC424.
The COMFORT-I trial, conducted by Incyte Corporation, demonstrated that 41.9% of INC424 treated patients achieved at least a 35% reduction in spleen volume at 24 weeks from baseline compared to 0.7% of patients in the placebo group (p<0.0001). Additionally, an early analysis of COMFORT-I data shows INC424 treatment resulted in an overall survival benefit as compared to placebo (hazard ratio=0.50 [95% confidence interval: 0.25, 0.98]). For patients taking INC424, the most frequently reported grade 3 or higher adverse events were hematologic. Only one patient in each group discontinued for thrombocytopenia and for anemia, respectively. The most common non-hematologic adverse events of any grade reported for patients receiving INC424 or placebo respectively were fatigue (25% vs 34%), diarrhea (23% vs 21%), peripheral edema (19% vs 22%) and ecchymosis (19% vs 9%).
Novartis and Incyte Corporation have a worldwide collaboration and license agreement for INC424. Incyte received US Food and Drug Administration (FDA) approval for INC424 in November 2011 under the name Jakafi®forthe treatment of patients with intermediate or high-risk myelofibrosis. INC424 will be marketed by Incyte in the US. These data provided the basis for worldwide regulatory filings with first actions expected in the second half of 2012.
