SUMMARY: Obinutuzumab or GAZYVA® (GA101) is glycoengineered, fully humanized, third generation, type II anti-CD20 antibody (IgG1 monoclonal antibody) that selectivity binds to the extracellular domain of the CD20 antigen on malignant human B cells. It has enhanced antibody-dependent cellular cytotoxicity (ADCC) and strong apoptosis-inducing activity. In contrast, RITUXAN® (Rituximab) is a first generation chimeric anti-CD20 targeted monoclonal antibody. In this phase III trial, LEUKERAN® (Chlorambucil – Clb)) was compared with a combination of GAZYVA® plus LEUKERAN® (GClb) and a combination of RITUXAN® plus LEUKERAN® (RClb). Five Hundred and eighty nine (589) treatment naïve CLL patients over 70 years of age with comorbidities were enrolled of whom 118 patients received Clb, 238 received GClb and 233 received RClb. The primary endpoint was Progression-Free Survival (PFS). Chemoimmunotherapy with both GClb and RClb significantly prolonged PFS compared to Clb alone. The median PFS was 10.8 months with Clb alone compared to 23 months for GClb (HR=0.14, P<0.0001) and 15.7 months for RClb (HR=0.32, P<0.0001). There were no Complete Responses (CR) with Clb alone whereas the CR rates with GClb and RClb were 22% and 8% respectively. This study gives new life to LEUKERAN® when given in combination with CD20 targeted monoclonal antibodies and may be of value when treating elderly patients with comorbid conditions. Goede V, Fischer K, Humphrey K, et al. J Clin Oncol 31, 2013 (suppl; abstr 7004)
Category: Meeting Updates
Safety and Tumor Responses with Lambrolizumab (Anti–PD-1) in Melanoma
SUMMARY:Lambrolizumab (MK-3475) is a humanized anti–PD-1 monoclonal antibody. The programmed death 1 (PD-1) receptor is an inhibitory receptor expressed on activated T-cells in the tumor micro environment. The anti–PD-1 antibody by blocking the PD-1 receptor essentially unleashes the immune system to fight off cancer cells. One hundred and thirty five patients with advanced melanoma regardless of their prior therapy with YERVOY® (Ipilimumab) received IV Lambrolizumab every 2-3 weeks. There was no difference in the response rates between patients who had prior therapy with YERVOY® and those who did not (38%). Majority of these patients had a rapid and durable response. The median progression-free survival was more than 7 months. The most common adverse events, mostly low grade were, fatigue, rash, pruritus, and diarrhea. The authors concluded that Lambrolizumab can significantly benefit patients with advanced Malignant Melanoma, regardless of their prior therapy with anti-CTLA 4 antibody, YERVOY® and with minimal toxicity. Hamid O, Robert C, Daud A, et al. N Engl J Med 2013; 369:134-144
Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT)
SUMMARY: The FDA recently approved ABRAXANE® ((Paclitaxel albumin-bound particles) for use in combination with GEMZAR® (Gemcitabine) for the first line treatment of patients with metastatic adenocarcinoma of the pancreas. This approval was based on the demonstration of improved overall survival (OS) in a multi-center, international, open-label, randomized trial. Eight hundred and sixty one (861) patients with metastatic pancreatic cancer were randomized to receive either the combination of ABRAXANE® and GEMZAR® (n=431) or GEMZAR® alone (n=430). Patients were stratified based on geographic region, performance status, and presence of liver metastasis. The median age was 63 years. The primary end point was OS and secondary endpoints included progression-free survival (PFS) and overall response rate (ORR. There was a statistically significant prolongation of OS for patients in the combination group with a 28% reduction in the risk of death [HR= 0.72; P < 0.0001]. The median OS was 8.5 months in the combination group and 6.7 months in the single agent GEMZAR® group. There was in addition a significant improvement in the PFS in the combination arm vs the single agent arm (5.5 months vs 3.7 months, respectively.HR= 0.69; P < 0.0001). Objective response rates were 23% in the combination group and 7% in the single agent GEMZAR® group (P<0.0001). Serious adverse reactions in patients receiving combination therapy included fever, vomiting, dehydration and pneumonia. This is clearly a major development in the management of advanced pancreatic cancer patients. Von Hoff DD, Ervin TJ, Arena FP, et al. J Clin Oncol 30: 2012 (suppl 34; abstr LBA148)
Final Results of a Phase 2 Open-Label, Monotherapy Efficacy and Safety Study of Quizartinib (AC220) in Patients with FLT3-ITD Positive or Negative Relapsed/Refractory Acute Myeloid Leukemia After Second-Line Chemotherapy or Hematopoietic Stem Cell Transplantation
SUMMARY: FLT3-ITD (FMS-like tyrosine kinase 3 – Internal Tandem Duplications) mutations are seen in approximately a third of the patients with AML and are associated with early relapse and poor survival. Quizartinib is an oral tyrosine kinase inhibitor, which has demonstrated activity in patients with both wild type FLT3 as well as those with FLT3 mutations. In this phase II trial, 333 patients were enrolled and divided into 2 cohorts – patients older than 60 years and those between 18 and 60 years of age. The data presented here relates to cohort 2 (younger cohort) which included 137 patients with AML, who either relapsed or were refractory to second line chemotherapy or relapsed after hematopoietic stem cell transplantation (HSCT). Of these patients, 99 were FLT3 -ITD mutation positive and 38 were FLT3 wild type. The dose of Quizartinib was 90 mg/day for women and 135 mg/day for men and was given continuously in 28-day cycles. This dosing schedule was chosen because of the risk for QT interval prolongation, based on gender. The primary end point was a composite complete remission rate (CRc), which included complete remission, complete remission with incomplete platelet recovery (CRp) and complete remission with incomplete hematologic recovery (CRi). Patients with FLT3 mutations had a CRc of 44% with 4% CR and 40% CRi. The median duration of response was 11.3 weeks and the median overall survival was 23.1 weeks. This compared to a CRc of 34% for those with wild type FLT3. Thirty four percent (34%) of the patients were able to undergo HSCT following response to Quizartinib. The most common side effects included nausea, vomiting, QT prolongation, cytopenia, diarrhea and fatigue. The authors concluded that Quizartinib has significant activity in patients with resistant and refractory AML and can facilitate HCST in about a third of the treated patients. Levis MJ, Perl AE, Dombret H, et al. 54th ASH Annual Meeting and Exposition 2012, Abstract 673
Pomalidomide in Combination with Low-Dose Dexamethasone Demonstrates a Significant Progression Free Survival and Overall Survival Advantage, in Relapsed/Refractory MM A Phase 3, Multicenter, Randomized, Open-Label Study
SUMMARY: Pomalidomide (POM) is a novel, oral, immunomodulatory drug which is far more potent than Thalidomide (THALOMID® and Lenalidomide (REVLIMID®) and has been shown to be active in REVLIMID® and Bortezomib (VELCADE®) refractory patients. In this phase III trial, the efficacy and safety of POM given along with low-dose dexamethasone (LoDEX) (n=302) was compared with high-dose dexamethasone (HiDEX) (n=153) in patients who were refractory to both REVLIMID® and VELCADE®. The primary endpoint was Progression Free Survival (PFS). The Overall Survival (OS) was only evaluated if PFS was statistically significant. With a median follow up of 18 weeks, the PFS was significantly longer in the POM + LoDEX group compared to the HiDEX group (15.7 vs 8.0 weeks; hazard ratio [HR], 0.45; P < .001). Following interim analysis, the OS was significantly longer in the POM + LoDEX group compared to HiDEX group (median not reached vs 34 weeks; HR, 0.53; P< .001). The authors concluded that this oral treatment regimen should be the new standard of care for patients who have disease refractory to REVLIMID® and VELCADE®. Carfilzomib (KYPROLIS®), a new parenteral proteasome inhibitor is another option for patients with resistant and refractory multiple myeloma. Dimopoulos MA, Lacy MQ, Moreau P, et al. 54th ASH Annual Meeting and Exposition 2012, LBA-6
A Phase 1/2 Study of Weekly MLN9708, an Investigational Oral Proteasome Inhibitor, in Combination with Lenalidomide and Dexamethasone in Patients with Previously Untreated Multiple Myeloma (MM)
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
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
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.