SUMMARY: Bortezomib (VELCADE®) is a parenteral proteosome inhibitor with remarkable activity in multiple myeloma. This agent however, can be associated with neuropathy in about 30- 40% of the patients, when given intravenously twice a week, and in about 10-15% of patients when given subcutaneously. MLN9708 is an oral, reversible proteasome inhibitor with favorable toxicity profile and lower incidence of peripheral neuropathy (PN). In the phase I component of this trial, 15 patients were enrolled and a maximum tolerated dose of 4 mg of MLN9708, taken orally once a week, was established. For the phase II component of this study, 50 treatment naïve patients with multiple myeloma were enrolled and MLN9708 was given at a dose of 4 mg orally on days 1, 8, and 15, in combination with lenalidomide (REVLIMID®) (25 mg once daily on days 1 to 21) and dexamethasone (40 mg on days 1, 8, 15, and 22) every 28 days for up to 12 cycles. Patients subsequently went on to receive maintenance therapy with MLN9708 once a week until progression. In this regimen, MLN9708 was essentially substituted for VELCADE®. The overall response rate was 96%, with Very Good Partial Response seen in more than 44% of patients and 26% Complete Response rate. More importantly grade 1 neuropathy was only seen in 8% and grade 3 neuropathy developed in 3% of the patients. The authors concluded that the responses with this new combination is similar to the VRD (VELCADE®, REVLIMID®, and Dexamethasone) regimen but with significantly less neuropathy and more importantly, all three drugs can be given orally. Kumar SK, Berdeja JG, Niesvizky R, et al. 54th ASH Annual Meeting and Exposition 2012, Abstract 332
Author: RR
Cardiovascular Events and Intensity of Treatment in Polycythemia Vera
SUMMARY: The significance of maintaining a hematocrit less than 45% to prevent cardiovascular events, was evaluated in this randomized clinical study. Patients with JAK2-positive polycythemia vera (n=365) treated with phlebotomy, hydroxyurea, or both were randomized to receive either a more intensive treatment to maintain a target hematocrit of less than 45% (low-hematocrit group, n=182) or less intensive treatment to a target hematocrit of 45 to 50% (high-hematocrit group, n= 183). The primary end point was the time until death from cardiovascular events or major thrombotic episodes. The secondary end points included cardiovascular events, cardiovascular hospitalizations, incidence of cancer, progression to myelofibrosis, myelodysplasia or leukemia and hemorrhage. At a median follow-up of 31 months, the primary end point was recorded in 5 of 182 patients (2.7%) in the low-hematocrit group and 18 of 183 patients (9.8%) in the high-hematocrit group ( P=0.007). There were no significant differences in the secondary end points. The authors concluded that maintaining a lower hematocrit can lower the risk of cardiovascular death and major thrombosis. Marchioli R, Finazzi G, Specchia G, et al. N Engl J Med 2013; 368:22-33
The Bruton’s Tyrosine Kinase (BTK) Inhibitor Ibrutinib (PCI-32765) Promotes High Response Rate, Durable Remissions, and Is Tolerable in Treatment Naïve (TN) and Relapsed or Refractory (RR) Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) Patients Including Patients with High-Risk (HR) Disease New and Updated Results of 116 Patients in a Phase Ib/II Study
SUMMARY: BTK is predominantly expressed in B-cells and is a mediator of B-cell receptor signaling in normal and transformed B-cells. BTK is necessary for the proliferation and survival of B-cell tumors. Ibrutinib (PCI-32765) is an oral, irreversible inhibitor of BTK and thereby inhibits cell proliferation and promotes programmed cell death (Apoptosis). In this phase Ib/II trial, 116 patients with CLL were enrolled who were either treatment naïve or had relapsed/ refractory CLL or Small Lymphocytic Lymphoma. Patients with high risk cytogenetic features were included as well and patients were divided into 5 groups and received Ibrutinib at fixed doses of 420mg or 840mg daily, until disease progression. The primary objective of this study was to determine the safety of the two dosing regimens. Secondary objectives were to assess efficacy, pharmacokinetics and long-term safety. In the treatment naïve group, the Complete Response (CR) was seen in 10% of the patients, PR (Partial Response) in 61% and the estimated 22 month PFS (Progression Free Survival) and OS (Overall Survival) was 96%. In the relapsed/refractory group, the CR was 3% and PR was 64%, whereas in the high risk cytogenetics group, there were no CR’s and PR was 50%. Estimated 22 month PFS and OS for the relapsed/refractory as well as high risk groups were 76% and 85% respectively. This benefit was achieved with minimal toxicity which included diarrhea, fatigue, skin rash and arthralgias. The authors concluded that treatment with Ibrutinib resulted in significant disease control extending beyond 12 months with minimal adverse events in this difficult-to-treat CLL patients. Byrd JC, Furman RR, Coutre S, et al. 54th ASH Annual Meeting and Exposition 2012, Abstract 189
Phase II Multicenter Study of Single-Agent Lenalidomide in Subjects with Mantle Cell Lymphoma Who Relapsed or Progressed After or Were Refractory to Bortezomib The MCL-001 “EMERGE” Study
SUMMARY: Mantle cell lymphomas constitute approximately 5% of all Non Hodgkins lymphomas and have a high relapse rate following dose-intensive therapies. Bortezomib (VELCADE®) is approved for the treatment of relapsed mantle cell myeloma (MCL) and has a response rate of 30%. This open label, phase II trial, evaluated the safety and efficacy of Lenalidomide (REVLIMID®) in 134 patients with MCL who have had prior therapy with Rituximab (RITUXAN®), Cyclophosphamide, Anthracycline and had relapsed or progressed in less than 12 months or were refractory to VELCADE®. Patients had a median of 4 prior treatments. Treatment consisted of single agent REVLIMID® 25 mg/day given on days 1 thru 21 of a 28-day cycle, given until disease progression or unacceptable toxicity. The primary endpoints were overall response rate (ORR) and duration of response. The secondary endpoints included complete response (CR), Progression Free Survival (PFS), time to progression, overall survival (OS) and safety. In this heavily pretreated patient population the ORR was 28% and the median duration of response of 16.6 months. The CR was 8%, PFS was 4.0 months, and OS was 19.0 months. The most common grade 3/4 adverse events were cytopenias. The authors concluded that REVLIMID® resulted in rapid and durable responses in patients with relapsed/refractory MCL. Goy A, Sinha R, Williams ME, et al. 54th ASH Annual Meeting and Exposition 2012, Abstract 905
ICLUSIG® (Ponatinib)
ICLUSIG® (Ponatinib): The FDA on December 17, 2012 granted accelerated approval to ICLUSIG® for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy. ICLUSIG® is available as oral tablets and is a product of ARIAD Pharmaceuticals, Inc.
ZYTIGA® (Abiraterone)
The FDA on December 10, 2012 approved an expanded indication for ZYTIGA® in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer. ZYTIGA® tablets are a product of Janssen Biotech, Inc.
COMETRIQ® (Cabozantinib)
The FDA on November 29, 2012 approved COMETRIQ® for the treatment of patients with progressive metastatic medullary thyroid cancer (MTC). COMETRIQ® is a small molecule that inhibits the activity of multiple tyrosine kinases, including RET, MET, and VEGF receptor 2. COMETRIQ® is available in capsule form and is a product of Exelixis, Inc.
Results of a randomized phase 2 study of PD 0332991, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (BC)
SUMMARY: PD 0332991 is an oral, selective inhibitor of CDK4/6 kinases. This agent interrupts cellular DNA synthesis by inhibiting the progression of the cell cycle from G1 to S phase and thus prevents tumor cell growth. The results presented, includes the pooled data from the study of 2 cohorts of patients. Both groups included postmenopausal women with advanced breast cancer and ER positive, HER2 negative tumors. Patients were randomized 1:1 to receive either letrozole (FEMARA®) along with PD 0332991 or FEMARA® alone. Group 1 enrolled 66 patients and Group 2 enrolled 99 patients. Group 2 patient tumors were also evaluated for the biomarkers cyclinD1 amplification and/or loss of p16, by FISH analysis. For both these study groups, the primary endpoint was Progression Free Survival (PFS). Secondary endpoints included response rates, overall survival, safety, and biomarker correlates. Data from the pooled analysis which included 165 women from both the groups demonstrated a median PFS of 26.1 months for the combination compared to 7.5 months with FEMARA® alone. This represented a 63% reduction in risk of progression (hazard ratio =0.37; P < 001). The most common adverse events noted in the combination group included uncomplicated neutropenia, anemia, and fatigue. Biomarkers expression (cyclinD1 amplification and/or loss of p16) had no impact on outcomes suggesting that the biomarker for PD0332991 may be the estrogen receptor itself rather than CDK4/6 kinases. Finn RS, Crown JP, Lang I, et al. CTRC-AACR San Antonio Breast Cancer Symposium 2012; Abstract S1-6.
Prospective study of treatment pattern, effectiveness, and safety of zoledronic acid (ZOL) therapy beyond 24 months subgroup analysis of patients (pts) with metastatic bone disease (MBD) from breast cancer (BC)
SUMMARY:There is not much data on the effectiveness and safety of Zoledronic acid (ZOMETA®) beyond 2 years. Two studies one from Belgium and the other from Japan shed some light on this issue. In the prospective multicenter Belgian trial, 108 women with breast cancer prior to enrollment had received at least 24 months of therapy with ZOMETA® infusions given every 3 to 4 weeks and 21% had received at least 48 months of therapy. They were followed for 18 months and monitored for Skeletal Related Events (SRE’s), Osteo Necrosis of the Jaw bone (ONJ), renal failure and hypocalcemia. During this follow up period, SRE’s were low and 83% of the women were free of SRE’s. ONJ was seen in 7 patients (4.5%). The rate of ONJ however rose to 11% after any invasive dental procedure. The risk of renal failure was low but increased to 12%when the dose of ZOMETA® was not adjusted for renal function. The Japanese study was a retrospective analysis of 83 patients who had been treated with ZOMETA® for at least 24 months (median 33 months). SRE’s were low and the frequency of ONJ was 3.6% compared to 2.4% for those patients who had been ZOMETA® for shorter periods. Both these studies demonstrated that longer duration of therapy with ZOMETA® resulted in increased rate of ONJ. Therefore, particular attention should be paid to prevent this complication by adhering to proper dental hygiene and avoiding dental trauma and extractions. Van den Wyngaert T, Delforge M, Doyen C, et al. and Suzuki Y, Saito Y, Ogiya R, et al. CTRC-AACR San Antonio Breast Cancer Symposium 2012; Poster P3-13-01 and P3-13-02.
Final analysis of overall survival for the phase III CONFIRM trial fulvestrant 500 mg versus 250 mg
SUMMARY: Fulvestrant (FASOLODEX®) is an Estrogen Receptor (ER) antagonist and downregulates the cellular levels of ER in a dose-dependent manner. The CONFIRM trial is a phase III study in which postmenopausal women with estrogen receptor (ER) positive advanced breast cancer, who had progressed after prior endocrine therapy, were randomized to be treated with either FASLODEX® 500 mg (n=362) or FASLODEX® 250 mg (n=374) every 28 days. The primary end point for this study was Progression Free Survival (PFS). In the primary analysis, FASLODEX® 500 mg was associated with a statistically significant increase in PFS compared with FASLODEX® 250 mg. Even though there was a trend towards improved overall survival (OS) with the higher dose, this was not statistically significant. In the updated second survival analysis presented at this symposium, the median OS trend prevailed with FASLODEX® 500mg compared with FASLODEX® 250mg, given every 28 days (26.4 months vs 22.3 months, P=0.16). This translated into a 4 month increase in median overall survival and a 19% reduction in the risk of death. The authors concluded that the higher dose of FASLODEX® may indeed confer some survival benefit to this patient subsets. Di Leo A, Jerusalem G, Petruzelka L, et al. CTRC-AACR San Antonio Breast Cancer Symposium; 2012; Abstract S1-4.