Obinutuzumab plus Chlorambucil in Patients with CLL and Coexisting Conditions

SUMMARY: Chronic Lymphocytic leukemia (CLL) is a disease of the elderly with a median age at diagnosis of 72 years. Given the age at diagnosis, it is not uncommon for these patients to have multiple comorbidities. The authors in this trial attempted to study a new agent, Obinutuzumab or GAZYVA® (GA101) specifically in this patient population. GAZYVA® 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. By virtue of binding affinity of the glycoengineered Fc portion of GAZYVA® to Fcγ receptor III on innate immune effector cells such as natural killer cells, macrophages and neutrophils, antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis is significantly enhanced, whereas it induces very little complement-dependent cytotoxicity. This is in contrast to RITUXAN® (Rituximab), which is a first generation type I, chimeric anti-CD20 targeted monoclonal antibody that kills CLL cells primarily by complement-dependent cytotoxicity and also ADCC. In this phase III trial, LEUKERAN® (Chlorambucil) was compared with a combination of GAZYVA® plus LEUKERAN® and a combination of RITUXAN® plus LEUKERAN®. Five Hundred and eighty nine (589) treatment naïve CLL patients over 70 years of age with comorbidities were enrolled of whom 118 patients received LEUKERAN® alone, 238 received GAZYVA® plus LEUKERAN® and 233 received RITUXAN® plus LEUKERAN®. The primary endpoint was Progression-Free Survival (PFS). Chemoimmunotherapy with both GAZYVA® plus LEUKERAN® and RITUXAN® plus LEUKERAN® significantly prolonged PFS compared to LEUKERAN® alone. The median PFS was 11.1 months with LEUKERAN® alone compared to 26.7 months for GAZYVA® plus LEUKERAN® (HR=0.18, P<0.001) and 16.3 months for RITUXAN® plus LEUKERAN® (HR=0.44, P<0.001). This benefit was seen in all subgroups except those with del(17) and quality of life in those who received antibody along with LEUKERAN® was not compromised. The combination of GAZYVA® and LEUKERAN®, also prolonged overall survival when compared to LEUKERAN® alone (HR=0.41; P=0.002). This benefit however was not noted with the RITUXAN® plus LEUKERAN® combination. Treatment with GAZYVA® plus LEUKERAN® when compared with RITUXAN® plus LEUKERAN®, resulted in a longer PFS (26.7 vs15.2 months; HR=0.39; P<0.001), higher complete response rates (20.7% vs. 7.0%) and deeper molecular responses. Infusion related reactions were more common in the GAZYVA® plus LEUKERAN® group without increase in the risk for infections. The authors concluded that a combination of GAZYVA® and LEUKERAN® when given to elderly patients with comorbid conditions improved overall survival compared to LEUKERAN® alone and resulted in higher response rates and longer PFS than RITUXAN® plus LEUKERAN®. Goede V, Fischer K, Busch R, et al. N Engl J Med 2014; 370:1101-1110

Ceritinib in ALK-Rearranged Non–Small-Cell Lung Cancer

SUMMARY: EML4-ALK (Echinoderm Microtubule associated protein Like 4) – (Anaplastic Lymphoma Kinase) is an aberrant fusion-type oncoprotein and is a tyrosine kinase. This oncoprotein/tyrosine kinase is found in 2-7% of all Non Small Cell Lung Cancers (NSCLC) and is generated due to an inversion in the short arm of chromosome 2. This oncoprotein is more prevalent in patients with adenocarcinoma, who have little or no exposure to tobacco. Tyrosine kinases normally play an important role in cellular proliferation and differentiation. However with point mutations, translocation/rearrangement and amplification of the respective genes, the associated tyrosine kinases can potentially cause malignancy. Such is the case with mutations or translocations of the Anaplastic Lymphoma Kinase gene (ALK). XALKORI® (Crizotinib) is a small molecule Tyrosine Kinase Inhibitor that targets ALK, MET and ROS1 tyrosine kinases. In an open label phase III trial involving 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum based regimen, treatment with XALKORI® significantly improved Progression Free Survival (PFS) and Response Rates (RR). In spite of this initial benefit, patients will however relapse within 12 months, with the average response duration of about 8 months. This has been attributed to acquired mutation within the ALK tyrosine kinase domain, amplification of the ALK fusion gene, subtherapeutic inhibition of ALK tyrosine kinase or activation of other pathways that can cause abnormal cell proliferation. Ceritinib (LDK378) is an oral, small molecule, second generation tyrosine kinase inhibitor of ALK and is 20 times as potent as XALKORI® against ALK. Unlike XALKORI®, Ceritinib does not inhibit MET kinase activity. Based on preclinical data supporting the efficacy of Ceritinib in both XALKORI® sensitive and resistant NSCLC tumors, the authors conducted a study to evaluate the antitumor activity of Ceritinib in patients with advanced NSCLC and other cancers harboring genetic alterations in ALK, in addition to determining the safety, MTD (maximum tolerated dose) and pharmacokinetics of Ceritinib. In this trial, patients who had received prior therapy with one or more ALK inhibitors as well as those with asymptomatic treated or untreated CNS metastases, were eligible to be enrolled. This study had 2 components – a dose escalation phase and an expansion phase. In the dose escalation phase, 59 patients were enrolled and the MTD of Ceritinib was determined to be 750 mg PO daily. In the expansion phase, 71 additional patients were treated for a total of 130 patients (N=59+71). Majority of these patients (94%) had advanced NSCLC. Patients with NSCLC who received at least 400mg of Ceritinib daily (N=114) had an overall response rate (RR) of 58% and median PFS was 7 months. Patients with advanced NSCLC who had received XALKORI® prior to enrollment (N=80) had a RR of 56%. The responses were noted both in patients with tumors harboring resistance mutations in the ALK tyrosine kinase domain as well as those in whom there was no new genetic alterations of ALK. Further, responses were seen in the untreated CNS lesions both in patients who had prior therapy with XALKORI® as well as those who did not. Adverse events were grade 1or 2 and GI related. These included vomiting, diarrhea, elevated aminotransferase levels and hypophosphatemia. The authors concluded that Cerifinib has marked antitumor activity in patients with advanced ALK rearranged NSCLC and in those who had progressed during XALKORI® treatment, regardless of the presence of resistance mutations in the ALK tyrosine kinase domain. Whether Cerifinib should be considered for the first line treatment of advanced ALK rearranged NSCLC, remains to be seen. Shaw AT, Kim D, Mehra R, et al. N Engl J Med 2014; 370:1189-1197