SUMMARY: PI3K delta signaling is hyperactive in B-cell malignancies and is important for the activation, proliferation, homing of malignant B cells in the lymphoid tissues and their survival. The delta isoform of PI3K enzyme is predominantly expressed in leukocytes. Idelalisib is a highly selective oral inhibitor of the enzyme phosphoinositide 3-kinase (PI3K) and specifically blocks the delta isoform of PI3K enzyme and its signaling pathway. Following promising data from Phase I trials, a Phase III study was conducted in which 220 previously treated patients with recurrent CLL, measurable lymphadenopathy and ineligible to receive chemotherapy due to comorbidities, were enrolled. Patients received first dose of RITUXAN® (Rituximab) at 375 mg/m2 and then 500 mg/m2 q2 weeks x 4, followed by RITUXAN® q4 wks x 3 for a total of 8 doses along with Idelalisib 150 mg PO BID continuously until disease progression (N=110) or along with placebo. The median age was 71 years and patients had received a median of three prior therapies. Poor prognosis patients included 44% with 17p deletion/p53 mutation and 84% who had unmutated immunoglobulin variable region heavy chain (IgVH) gene. Primary endpoint was progression-free survival (PFS). Following a recommendation by an Independent Data Monitoring Committee after an interim analysis that showed superiority of RITUXAN®/Idelalisib combination, this trial was stopped early. The PFS at 24 weeks was 93% for the RITUXAN® plus Idelalisib group compared to 46% for those treated with RITUXAN® and placebo. The median PFS for the RITUXAN®/Idelalisib combination group has not yet been reached, whereas the the median PFS for the RITUXAN®/placebo arm was 5.5 months (Hazard Ratio [HR] = 0.15; P < .0001). Further, the PFS was favorable in the poor prognosis patients with either a 17p deletion or p53 mutation, when Idelalisib was combined with RITUXAN® (HR = 0.12). An improvement in the Overall Survival (OS) was also noted in the Idelalisib group compared with patients in the RITUXAN® alone group (HR = 0.28; P = 0.018). The combination of Idelalisib and RITUXAN® had an overall response rate of 81% compared with 13% in the RITUXAN®alone group (P <0 .0001). Patients treated with a combination of Idelalisib and RITUXAN® also had a higher decrease in lymphadenopathy (93%) compared with 4% in the RITUXAN® alone group (P < 0.0001). The most common adverse events which included pyrexia, fatigue, nausea and chills were similar in both treatment groups. The authors concluded that Idelalisib plus RITUXAN® may be a new treatment option for patients with previously treated CLL, who are not eligible for chemotherapy, as well as those with unfavorable cytogenetics. Furman RR, Sharman JP, Coutre SE, et al. Blood 2013;122:LBA-6
Category: Meeting Updates
PROSE: Randomized proteomic stratified phase III study of second line erlotinib versus chemotherapy in patients with inoperable non–small cell lung cancer (NSCLC)
SUMMARY: VeriStrat ® is a clinically validated serum/plasma-based assay, for patients with advanced Non Small Cell Lung Cancer (NSCLC). VeriStrat® is a serum test of prognostic and predictive value that classifies patients as VeriStrat-Good (VS-G) or VeriStrat-Poor (VS-P) based on eight mass spectral peaks or proteomic patterns of the patients serum. Proteomics is the large-scale study of protein structure and functions. VeriStrat® testing is protein based and therefore has no correlation with known genomic biomarkers. It is well established that EGFR-TKIs (Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors) are more effective in NSCLC patients with EGFR activating mutations. PROSE is a multicenter, double blind, randomized, VeriStrat® stratified, phase III study. In this trial, over 90% of the patients had no EGFR mutations (EGFR-Wild Type). Two hundred and eighty five (285) patients with advanced NSCLC who had first line treatment regimen with platinum-based therapy were randomly assigned to receive second line chemotherapy (CT) with single agent ALIMTA® (Pemetrexed) or TAXOTERE® (Docetaxel), at standard doses (N=129) or TARCEVA® (Erlotinib) 150 mg po qd (N=134). Patients and study investigators were blinded to the patients VeriStrat® status. Patients were classified as VeriStrat-Good or VeriStrat-Poor based on the VeriStrat® results. Patients in the treatment groups were stratified by age, gender, tumor histology, ECOG-PS and smoking history. Crossover was permitted upon disease progression. The primary objective of the study was to demonstrate differential treatment benefit between TARCEVA® and CT with regards to Overall Survival (OS). Median overall survival (OS) was 9 months for the patients in the CT group and 7.7 months for TARCEVA® group and this was not statistically significant (P=0.3). However when evaluated by VeriStrat® status, CT was beneficial for the VeriStrat-Poor patients compared to TARCEVA®, with significantly better median OS (6.3 vs 3 months, P=0.02). Age, gender, histology (squamous vs non-squamous) and smoking history had no impact on the overall survival. The authors concluded that patients classified as VeriStrat-Poor have better survival with CT than TARCEVA®, whereas patients classified as VeriStrat-Good have similar survival with TARCEVA® and CT. VeriStrat® testing therefore, can help physicians choose between TARCEVA® and CT, for their patients with advanced NSCLC. This test helps physicians identify patients who are likely to have good or poor outcomes after treatment with EGFR inhibitors and thereby can provide valuable insight into whether CT or targeted therapy with TARCEVA®, a EGFR-TKI, is appropriate for their patients with advanced NSCLC, in the second line setting. This information is especially important for patients without an EGFR mutation or for those, whose EGFR mutation status is unknown. Sorlini C, Barni S, Petrelli F, et al. J Clin Oncol 29: 2011 (suppl; abstr TPS214)
PROSE Randomized proteomic stratified phase III study of second line erlotinib versus chemotherapy in patients with inoperable non–small cell lung cancer (NSCLC)
SUMMARY: VeriStrat ® is a clinically validated serum/plasma-based assay, for patients with advanced Non Small Cell Lung Cancer (NSCLC). VeriStrat® is a serum test of prognostic and predictive value that classifies patients as VeriStrat-Good (VS-G) or VeriStrat-Poor (VS-P) based on eight mass spectral peaks or proteomic patterns of the patients serum. Proteomics is the large-scale study of protein structure and functions. VeriStrat® testing is protein based and therefore has no correlation with known genomic biomarkers. It is well established that EGFR-TKIs (Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors) are more effective in NSCLC patients with EGFR activating mutations. PROSE is a multicenter, double blind, randomized, VeriStrat® stratified, phase III study. In this trial, over 90% of the patients had no EGFR mutations (EGFR-Wild Type). Two hundred and eighty five (285) patients with advanced NSCLC who had first line treatment regimen with platinum-based therapy were randomly assigned to receive second line chemotherapy (CT) with single agent ALIMTA® (Pemetrexed) or TAXOTERE® (Docetaxel), at standard doses (N=129) or TARCEVA® (Erlotinib) 150 mg po qd (N=134). Patients and study investigators were blinded to the patients VeriStrat® status. Patients were classified as VeriStrat-Good or VeriStrat-Poor based on the VeriStrat® results. Patients in the treatment groups were stratified by age, gender, tumor histology, ECOG-PS and smoking history. Crossover was permitted upon disease progression. The primary objective of the study was to demonstrate differential treatment benefit between TARCEVA® and CT with regards to Overall Survival (OS). Median overall survival (OS) was 9 months for the patients in the CT group and 7.7 months for TARCEVA® group and this was not statistically significant (P=0.3). However when evaluated by VeriStrat® status, CT was beneficial for the VeriStrat-Poor patients compared to TARCEVA®, with significantly better median OS (6.3 vs 3 months, P=0.02). Age, gender, histology (squamous vs non-squamous) and smoking history had no impact on the overall survival. The authors concluded that patients classified as VeriStrat-Poor have better survival with CT than TARCEVA®, whereas patients classified as VeriStrat-Good have similar survival with TARCEVA® and CT. VeriStrat® testing therefore, can help physicians choose between TARCEVA® and CT, for their patients with advanced NSCLC. This test helps physicians identify patients who are likely to have good or poor outcomes after treatment with EGFR inhibitors and thereby can provide valuable insight into whether CT or targeted therapy with TARCEVA®, a EGFR-TKI, is appropriate for their patients with advanced NSCLC, in the second line setting. This information is especially important for patients without an EGFR mutation or for those, whose EGFR mutation status is unknown. Sorlini C, Barni S, Petrelli F, et al. J Clin Oncol 29: 2011 (suppl; abstr TPS214)
Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS wild-type metastatic colorectal cancer German AIO study KRK-0306 (FIRE-3)
SUMMARY: It is common practice to combine anti-EGFR agent ERBITUX® (Cetuximab) or anti-VEGF agent AVASTIN® (Bevacizumab) with chemotherapy, in the initial management of patients with metastatic colorectal cancer. There is however a higher likelihood for patients with tumors expressing wild type KRAS (non-mutated KRAS), to respond to ERBITUX®. In this randomized multicenter study, a CAMPTOSAR® (Irinotecan) based backbone, FOLFIRI (folinic acid, fluorouracil and Irinotecan) given along with ERBITUX® (Group A) was compared with FOLFIRI plus AVASTIN® (Group B), in treatment naïve patients with metastatic ColoRectal Cancer (mCRC). Of the 592 patients with wild type KRAS mCRC, 297 patients were randomized to Group A and 295 patients to Group B. The median age was 64 years. The median duration of treatment was 4.7 months and 5.3 months in Group A and Group B respectively. The primary endpoint was Objective Response Rate (ORR). Even though the ORR was comparable in Groups A and B (62% vs 57%), there was a significant improvement in the overall survival (OS) favoring Group A (28.8 vs 25.0 months, HR= 0.77, P=0.0164). The comparable response rates and surprising improvement in OS in the ERBITUX® group suggests that either ERBITUX® or AVASTIN® can be added to FOLFIRI, in the first-line treatment of wild type KRAS mCRC patients. It is however clear that in wild type KRAS mCRC patients, it may be harmful to combine ERBITUX® with FOLFOX chemotherapy regimen, as was seen in the EPOCH trial and based on MRC COIN trial, NORDIC-VII trial and N0147 trial, ERBITUX® should not be combined with FOLFOX chemotherapy regimen as there is no added benefit. It is now well established that mCRC that harbors KRAS mutations in exon 2 (about 40% of the patients) do not benefit from anti-EGFR therapies. The PRIME study has given us aditional insight and it appears that other activating RAS mutations may also predict lack of response to anti-EGFR therapies. With regards to BRAF mutations, they portend a poor prognosis, regardless of treatment. Heinemann V, Weikersthal LF, Decker T, et al. J Clin Oncol 31, 2013 (suppl; abstr LBA3506)
Obinutuzumab (GA101) plus chlorambucil (Clb) or rituximab (R) plus Clb versus Clb alone in patients with chronic lymphocytic leukemia (CLL) and preexisting medical conditions (comorbidities) Final stage 1 results of the CLL11 (BO21004) phase III trial
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)
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