XTANDI® Superior to CASODEX® in Advanced Prostate Cancer

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer and 1 in 7 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 180,890 new cases of prostate cancer will be diagnosed in 2016 and over 26,000 men will die of the disease. The development and progression of prostate cancer is driven by androgens (primarily testosterone) and androgen signaling pathways. Androgen Deprivation Therapy (ADT) has therefore been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention for hormone sensitive prostate cancer. This is accomplished by either surgical castration (bilateral orchiectomy) or medical castration using LHRH (GnRH- Gonadotropin-Releasing Hormone) agonists, given along with 2 weeks of first generation anti-androgen agents such as CASODEX® (Bicalutamide), with the anti-androgen agents given to prevent testosterone flare. There is evidence to suggest that prostate cancer cells continue to depend on androgen receptor (AR) signaling even in an androgen-deprived environment. Therefore, targeting AR and AR signaling pathways remains a rational approach in the treatment of Castration Resistant Prostate Cancer (CRPC).

The first generation anti-androgen agents such as EULEXIN® (Flutamide), CASODEX® (Bicalutamide) and NILANDRON® (Nilutamide) act by binding to the Androgen Receptor (AR) and prevent the activation of the AR and subsequent up-regulation of androgen responsive genes. They may also accelerate the degradation of the AR. These agents have a range of pharmacologic activity from being pure anti-androgens to androgen agonists. CASODEX® is a nonsteroidal oral anti-androgen, that is often prescribed along with LHRH (GnRH- Gonadotropin-Releasing Hormone) agonists for metastatic disease or as a single agent second line hormonal therapy for those who had progressed on LHRH agonists. XTANDI® (Enzalutamide) is a second-generation anti-androgen with no reported agonistic effects. It competitively inhibits androgens and AR binding to androgens as well as AR nuclear translocation and interaction with DNA. It thus inhibits several steps in the AR signaling pathway.

TERRAIN is a double-blind, randomized phase II trial, in which 375 asymptomatic or minimally symptomatic prostate cancer patients, who had progressed following treatment with an LHRH agonists or following surgical castration, were enrolled. The objective of the TERRAIN study was to compare the efficacy and safety of XTANDI® with CASODEX®, in patients with metastatic Castration Resistant Prostate Cancer. Patients were randomly assigned in a 1:1 ratio to receive XTANDI® 160 mg daily (N=184) or CASODEX® 50 mg daily (N=191), both taken orally, in addition to Androgen Deprivation Therapy, until disease progression. Bone targeted agents, ie. Bisphosphonates and RANKL inhibitors were allowed. The primary endpoint was Progression Free Survival and secondary endpoints included PSA response and time to PSA progression. Median time on treatment for the XTANDI® group was 11.7 months and 5.8 months for the CASODEX® group.

It was noted that patients in the XTANDI® group had a significantly improved median Progression Free Survival (15.7 months) compared with 5.8 months in the CASODEX® group (HR=0.44; P<0.0001). Adverse events in the two treatment groups were different as anticipated. The most common adverse events with XTANDI® were fatigue, back pain and hot flashes whereas CASODEX® was more often associated nausea, constipation and arthralgia. Serious adverse events were experienced by 31% of the patients in the XTANDI® group and 23% of the patients in the CASODEX® group.

The authors concluded that XTANDI® increased Progression Free Survival (PFS) by nearly 10 months compared with CASODEX®, in patients with metastatic Castration Resistant Prostate Cancer (CRPC). In the PREVAIL study, XTANDI® significantly improved Overall Survival and radiographic PFS, in patients with chemotherapy-naive mCRPC and demonstrated that it can significantly delay the need for chemotherapeutic intervention. With this abundant data in favor of XTANDI®, CASODEX® may not have a significant role to play in patients with mCRPC. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 study. Shore ND, Chowdhury S, Villers A, et al. The Lancet Oncology 2016; 17:153-163

IntraVenous Immunoglobulin and ThromboEmbolic Events

SUMMARY: Secondary hypogammaglobulinemia is a common immune defect in malignancies such as Chronic Lymphocytic Leukemia, Multiple Myeloma and Non-Hodgkin B cell lymphomas. Approximately 20-70% of these patients may experience hypogammaglobulinemia during the course of their illness. Secondary hypogammaglobulinemia generally correlates with duration and stage of the disease and there is a direct relationship between the frequency/severity of infections and low IgG levels. The infection risk may be further exacerbated by treatment induced hypogammaglobulinemia.

IntraVenous Immune globulin (IVIg) is a purified plasma fraction and contains more than 95% unmodified Immunoglobulin G (IgG). It is derived from large donor pools and is often recommended for patients with hypogammaglobulinemia, to reduce the risk of serious infection. With the recognition of serious IVIg-associated ThromboEmbolic Events (TEEs) dating back to the 1980’s, the FDA in 2013 mandated boxed warning for IVIg products. The TEE risk has been attributed to increased blood viscosity secondary to erythrocyte aggregation following administration of IVIg, resulting in stasis and thrombosis, platelet activation by exogenous IgG, arterial vasospasm and other plasma components such as coagulation factor XIa, that is not completely removed in some IVIg manufacturing processes. However, it is not clear if the TEEs are directly attributable to the IVIg itself or whether other risk factors such as patient’s age, disease state or other factors play a role.

The authors in this study conducted a retrospective review of data from the Surveillance, Epidemiology and End Results (SEER) cancer registries for Chronic Lymphocytic Leukemia (CLL) and Multiple Myeloma (MM) patients, linked to Medicare claims and enrollment data. This study included CLL and Myeloma patients (N=2724), 66 years or older, who were new users of IVIg and this group was propensity matched to non recipients of IVIg (N=8035). Propensity matching allowed comparison of groups across measured demographic and clinical characteristics and other variables. The primary endpoint was the occurrence of serious arterial ThromboEmbolic Event (TEE), defined as hospitalization for Acute Myocardial Infarction or Ischemic Stroke. Secondary endpoints included venous TEE (hospitalization for Deep Vein Thrombosis (DVT) or Pulmonary Embolism (PE). Based on previously published studies, the authors hypothesized that the prothrombotic effects of IVIg would most likely be acute but could last for as long as 1 month after an IVIg infusion.

It was noted that patients receiving IVIg were significantly more likely to develop a TEE such as Acute Myocardial Infarction or Stroke within the first 24 hours compared to IVIg nonrecipients (HR=3.40). This arterial thrombotic risk declined during the following 30 days. There was however, no significant increase in venous thrombotic events during the first 30 days after IVIg infusion. The risk for any ThromboEmbolic Events (TEEs) increased with age during the first 30 days following IVIg therapy (P=0.03), but was not associated with the type or duration of malignancy, history cardiovascular disease, history of venous thromboembolism or IVIg brand.

It was concluded that based on this study, arterial thrombotic events (Myocardial Infarction and Stroke) are likely to occur within the first 24 hours following IVIg administration, in patients with immunodeficiency, secondary to Chronic Lymphocytic Leukemia or Multiple Myeloma and this thrombotic risk is more common with increasing patient age. Clinicians should therefore weigh the risk/benefits with IVIg use and elderly patients should be well hydrated and closely monitored for the first 24 hours following IVIg infusion. Intravenous immune globulin and thromboembolic adverse events in patients with hematologic malignancy. Eric M. Ammann EM, Jones MP, Link BK, et al. Blood 2016; 127:200-207

FDA Approves XALKORI® for ROS1-Rearranged Non Small Cell Lung Cancer

SUMMARY: The FDA on March 11, 2016, approved XALKORI® (Crizotinib) for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC), whose tumors are ROS1-positive. XALKORI® was first approved in 2011 for the treatment of patients with NSCLC, whose tumors are Anaplastic Lymphoma Kinase (ALK) positive. Lung cancer is the second most common cancer in both men and women and the American Cancer Society estimates that for 2016, about 224,390 new cases of lung cancer will be diagnosed and over 158,000 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of Non Small Cell Lung Cancer (NSCLC), 25% are Squamous cell carcinomas, 40% are Adenocarcinomas and 10% are Large cell carcinomas. There is now growing body of evidence suggesting superior outcomes when advanced NSCLC patients with specific genomic alterations receive targeted therapies. Approximately 1-2% of lung adenocarcinomas harbor ROS1 gene rearrangements. ROS1 gene is located on chromosome 6q22 (long arm of chromosome 6) and plays an important role in cell growth and development. ROS1 gene fusion with another gene results in a mutated DNA sequence which then produces an abnormal protein responsible for unregulated cell growth and cancer. ROS1 gene rearrangement has been identified as a driver mutation in Non Small Cell Lung Cancer with adenocarcinoma histology. This is more common in nonsmokers or in light smokers (<10 pack years), who are relatively young (average age of 50 years) and thus share similar characteristics with ALK-positive patients. The ROS protein and the ALK protein have similar structure and function and are sensitive to Tyrosine Kinase Inhibitors such as XALKORI® (Crizotinib) and ZYKADIA® (Ceritinib). ROS1 mutations have been also been associated with Cholangiocarcinoma (Bile duct cancer) and Glioblastoma multiforme. ROS1 rearrangements are mutually exclusive with other oncogenic mutations found in NSCLC such as EGFR mutations, KRAS mutations and ALK rearrangement. The presence of a ROS1 rearrangement can be detected by Fluorescence In Situ Hybridization (FISH), ImmunoHistoChemistry (IHC), Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) and Next Generation-Sequencing. XALKORI® is a small molecule Tyrosine Kinase Inhibitor that targets ALK, MET and ROS1 tyrosine kinases.

The latest FDA approval was based on the results of a multicenter, single-arm, expansion cohort of the phase I study of XALKORI®, in which 50 patients with advanced NSCLC, who tested positive for ROS1 rearrangement, were enrolled. The median age was 53 years, 98% had adenocarcinoma histology and majority of patients (86%) had received previous treatment for advanced disease, with 44% having received more than 1 prior therapy. XALKORI® was administered orally at 250 mg twice daily in continuous 28-day cycles. Treatment was continued until disease progression or unacceptable toxicities. The primary end point was Objective Response Rate, and Duration of Response (DoR) was an additional outcome measure.

The Objective Response Rate by investigator assessment was 72%, with 3 Complete Responses and 33 Partial Responses. The median Duration of Response was 17.6 months. The median Progression Free Survival was 19.2 months and Overall Survival rate at 12 months was 85%. The most common adverse reactions associated with XALKORI® were vision disorders, nausea, diarrhea, vomiting, edema, elevated transaminases, fatigue, upper respiratory infection and neuropathy.

The authors concluded that XALKORI® has significant antitumor activity in patients with advanced ROS1-rearranged NSCLC. The significantly superior median Duration of Response (17.6 vs 11.4 months) and median Progression Free Survival (19.2 vs 9.7 months) in the ROS1-rearranged NSCLC compared to ALK- rearranged NSCLC, may be due to more potent inhibition of ROS1 than ALK, by XALKORI®, resulting in more effective target inhibition and more durable responses. Crizotinib in ROS1-Rearranged Non–Small-Cell Lung Cancer. Shaw AT, Ou S-HI, Bang Y-J, et al. N Engl J Med 2014; 371:1963-1971

COMETRIQ® Benefits All Patient Subgroups with Advanced Renal Cell Carcinoma

SUMMARY: The American Cancer Society estimates that about 62,700 new cases of kidney cancer will be diagnosed in the United States in 2016 and over 14,000 patients will die from this disease. The VHL (Von Hippel-Lindau) protein is a tumor suppressor gene which is frequently mutated and inactivated in approximately 90% of clear cell Renal Cell Carcinomas (ccRCC). The VHL gene under normal conditions binds to Hypoxia-Inducible Factor (HIF-1 alpha) and facilitates degradation of this factor. Under hypoxic conditions and in patients having biallelic loss of function and mutation of VHL genes, HIF-1alpha is not degraded. Build up of HIF-1 alpha results in increased angiogenesis, increased tumor cell proliferation and survival, as well as metastasis. COMETRIQ® (Cabozantinib) is an oral, small-molecule Tyrosine Kinase Inhibitor (TKI) and inhibits tyrosine kinases including MET, VEGF receptors (VEGFRs), and AXL. Both MET and AXL are up-regulated in Renal Cell Carcinoma as a consequence of VHL inactivation and increased expression of MET and AXL is associated with poor prognosis and development of resistance to VEGFR inhibitors. COMETRIQ® in previous studies has shown objective responses and prolonged disease control in patients with Renal Cell Carcinoma, resistant to VEGFR and mTOR inhibitors. The FDA initially approved COMETRIQ® in 2012, for treatment of patients with metastatic Medullary Thyroid Cancer. AFINITOR® (Everolimus) is a specific inhibitor of mTOR (Mammalian Target of Rapamycin), which is a serine/threonine kinase, and is a standard treatment for patients who progress on a VEGFR-targeted therapy.

The METEOR is a phase III trial in which 658 patients were randomized 1:1 to receive COMETRIQ® 60 mg PO daily or AFINITOR® 10 mg PO daily. Treatment was continued until disease progression or unacceptable toxicities. Enrolled patients had advanced clear cell Renal Cell Carcinoma and were stratified by MSKCC (Memorial Sloan Kettering Cancer Center) prognostic criteria and number of prior therapies with VEGFR TKIs. Of the enrolled patients in the COMETRIQ® group, 43% of the patients were considered favorable, 43% intermediate and 14% poor risk, by MSKCC criteria. Seventy three percent (73%) of the patients had one prior therapy with VEGFR TKIs and 27% of the patients had 2 or more prior therapies with VEGFR TKIs. To be eligible, patients must have progressed during treatment or within 6 months of the last dose of their most recent VEGFR TKI. Prior therapies included cytokines, chemotherapy, and monoclonal antibodies, including those targeting VEGF, the Programmed Death 1 (PD-1) receptor or its ligand PD-L1. The primary endpoint was Progression Free Survival (PFS) and secondary endpoints included Overall Survival (OS) and Objective Response Rate (ORR). At the time of preplanned interim analysis which included the first 375 patient who underwent randomization, the primary end point of PFS was met, with a significant improvement in PFS with COMETRIQ® compared to AFINITOR® (7.4 months vs 3.8 months; HR=0.58; P< 0.001). In addition, there was a significant improvement in ORR with COMETRIQ® (21% vs 5%; P<0.001) and a trend for improved OS. (N Engl J Med 2015; 373:1814-1823).

In this updated analysis, the authors provided a detailed analysis of the clinical activity of COMETRIQ compared to AFINITOR® across the various patient subgroups. For all 658 patients enrolled, the PFS data was comparable to the interim analysis data, favoring COMETRIQ® (7.4 months versus 3.9 months (HR=0.52; P<0.001). When subgroup analysis was performed in patients with 3 or more metastases sites, the median PFS was 7.3 months versus 3.7 months for COMETRIQ® vs AFINITOR® respectively (HR=0.38). The risk of disease progression was reduced with COMETRIQ® by 74% in patients with visceral and bone metastases compared to AFINITOR® (5.6 vs 1.9 months; HR=0.26). The PFS benefit with COMETRIQ® was not impacted by prior therapy with VEGFR TKIs. However, patients who received prior VEGFR TKI therapy with SUTENT® (Sunitinib) benefited the most with COMETRIQ® (median PFS 9.1 vs 3.7 months (HR=0.43), whereas the PFS benefit with COMETRIQ® for those who received prior VOTRIENT® (Pazopanib) was 7.4 vs 5.1 months (HR=0.67). The PFS benefit was also significantly better in the COMETRIQ® group, for patients previously treated with an anti–PD-1/PD-L1 agents, compared to AFINITOR® (HR=0.22). In the MSKCC poor risk group, the benefit with COMETRIQ® was 5.4 versus 3.5 months with AFINITOR® (HR=0.70). The most common serious toxicities AEs in the COMETRIQ® group were abdominal pain, pleural effusion and diarrhea, whereas in the AFINITOR® arm, the most common serious toxicities were anemia, dyspnea and pneumonia.

The authors concluded that COMETRIQ® is associated with longer Progression Free Survival compared with AFINITOR®, in patients with Renal Cell Carcinoma, following progression on prior VEGFR inhibitor therapy. COMETRIQ® may help overcome treatment resistance and benefits all subgroups of patients with advanced Renal Cell Carcinoma. Studies are underway combining COMETRIQ® with Immune checkpoint inhibitors. Subgroup analyses of METEOR, a randomized phase 3 trial of cabozantinib versus everolimus in patients (pts) with advanced renal cell carcinoma (RCC). Escudier BJ, Motzer RJ, Powles T, et al. J Clin Oncol 34, 2016 (suppl 2S; abstr 499)

Cancer Death Rate Declines in the US

SUMMARY: The American Cancer Society released the Cancer Statistics 2016 report, which includes the most recent data on cancer incidence, mortality, and survival in the US. It is estimated that in 2016, 1,685,210 new cancer cases will be diagnosed in the US and 595,690 cancer deaths are projected.

With a considerable decline in mortality from heart disease, cancer is now the leading cause of death in 21 states. In males, prostate cancer will be the leading cancer diagnosis in 2016 (21%) and Breast Cancer will be the leading cancer diagnosis in women (29%).

Lung Cancer remains the leading cause of cancer death both in men and women (27%). With major therapeutic advances against leukemia, brain cancer is now the leading cause of cancer death among children and adolescents (birth-19 years).

The overall cancer incidence rate in women has remained stable since 1998. However in men, cancer incidence has decreased by 3.1% per year since 2009 and this has been attributed to decline in routine screening with the PSA test. Routine screening with the PSA test is no longer recommended because of high rates of overdiagnosis, estimated at 23% to 42% for screen-detected cancers, which may not result in bad outcomes.

The cancer death rate in the US has dropped by 23% since 1991 which translates to more than 1.7 million deaths averted through 2012. There has been a continued decrease in death rates for the four major cancer sites – lung, breast, prostate, and colon/rectum. This overall decline in cancer deaths may be the result of reduction in smoking prevalence, improved screening modalities for breast, colon and prostate cancers and improvements in treatment.

Despite the overall reduction in cancer mortality, death rates are increasing for cancers of the liver, pancreas, and uterine corpus. Obesity has been shown to increase endometrial cancer risk by 50% for every 5 body mass index (BMI) units. Chronic infection with Helicobacter pylori and Hepatitis B virus has increased the incidence and death rates of stomach and liver cancer, respectively.

The authors concluded that “Advancing the fight against cancer will require continued clinical and basic research, which is dependent on funding, as well as the application of existing cancer control knowledge across all segments of the population, with an emphasis on disadvantaged groups.” With progress being made in cancer prevention using improved screening techniques and behavioral interventions, as well as rapid advances in cancer treatment with the understanding of cancer biology, it is expected that cancer death rate will continue to decline in the years to come. Cancer statistics, 2016. Siegel RL, Miller KD and Jemal A. CA Cancer J Clin 2016;66:7-30.

FDA Approves AFINITOR® for Advanced NeuroEndocrine Tumors of GI or Lung Origin

SUMMARY: The FDA on February 26, 2016 approved AFINITOR® (Everolimus) for the treatment of adult patients with progressive, well-differentiated non-functional, NeuroEndocrine Tumors (NET) of GastroIntestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease. NeuroEndocrine Tumors (NETs) arise from cells of the endocrine and nervous systems and produce biogenic amines and polypeptide hormones. NETs can be clinically symptomatic (functioning) or silent (nonfunctioning). The incidence is higher in African-Americans and is most frequently diagnosed in the small intestine, appendix, rectum, lungs and bronchi. NETs may be sporadic or may be a component of inherited genetic syndromes such as Multiple Endocrine Neoplasia (MEN) types 1 and 2.

Majority of the NETs are nonfunctioning and are diagnosed incidentally but are clinically symptomatic following spread to the liver. Most NETs are classified based on tumor differentiation into 1) Well-differentiated, Low-grade (G1) 2) Well-differentiated, Intermediate-grade (G2) and 3) Poorly differentiated, High-grade (G3). Tumor differentiation and tumor grade often correlate with mitotic count and Ki-67 proliferation index. Even though surgery is curative when the tumor is detected early, this is often not the case, as most patients present with metastatic disease at the time of diagnosis. Somatostatin analogues, such as long acting SANDOSTATIN® LAR Depot (Octreotide), has been shown in the PROMID study to control tumor growth, as well as improve symptoms, in patients with newly diagnosed, well-differentiated metastatic midgut NETs. Following progression on SANDOSTATIN®, these patients have limited treatment options. Everolimus (AFINITOR®), is a mTOR (mammalian Target Of Rapamycin) inhibitor, which has shown activity in advanced NETs, in phase II trials.

The FDA approved AFINITOR® in 2011, for the treatment for patients with progressive, metastatic pancreatic NETs. This approval was based on the phase III RADIANT-3 study, in which the primary end point of Progression Free Survival (PFS) was met, with a PFS of 11 months in the AFINITOR® group and 4.6 months in the placebo group (HR=0.35; P<0.001).

RADIANT-4 is a randomized, double blind phase III trial, in which 302 patients with unresectable, locally advanced or metastatic, well differentiated (low or intermediate grade), non-functional (no current or prior history of carcinoid symptoms), NeuroEndocrine Tumors (NETs) of gastrointestinal or lung origin, were randomly assigned in a 2:1 ratio, to receive AFINITOR® (Everolimus) 10 mg orally once daily plus best supportive care (N=205) or placebo plus BSC (N=97). Tumor locations were, GI tract (N=175), Lung (N=90) and Unknown origin (N=36). The median age was 63 years. The primary endpoint was Progression Free Survival (PFS) and secondary endpoints included Overall Survival (OS), response, and safety.

The median PFS were 11 months and 3.9 months in the AFINITOR® and placebo groups, respectively (HR=0.48; P<0.001), with a 52% reduction in the risk of progression in the AFINITOR® group. In a subgroup analysis which specifically looked at GI NETs, the median PFS was 13.1 months with AFINITOR® versus 5.4 months with placebo (HR=0.56), with a 44% risk reduction in favor of AFINITOR®. In patients with NETs of unknown primary, the median PFS was 13.6 months with AFINITOR® versus 7.5 months with placebo. (HR=0.60), with a 40% risk reduction in favor of AFINITOR®. The most common adverse reactions (incidence greater than or equal to 30%) were stomatitis, infections, diarrhea, peripheral edema, fatigue and rash.

The authors following this subgroup analysis concluded that, there was a 40-44% risk-reduction in favor of AFINITOR®, compared to placebo, for patients with metastatic GI NeuroEndocrine Tumors, as well as NeuroEndocrine Tumors from an unknown primary, thus providing a new treatment option for this patient group. Efficacy and safety of everolimus in advanced, progressive, nonfunctional neuroendocrine tumors (NET) of the gastrointestinal (GI) tract and unknown primary: A subgroup analysis of the phase III RADIANT-4 trial. Singh S, Carnaghi C, Buzzoni R, et al. J Clin Oncol 34, 2016 (suppl 4S; abstr 315)

FDA Approves IBRANCE® in Combination with FASLODEX® for Advanced Breast Cancer

SUMMARY: The FDA on February 19, 2016, approved IBRANCE® (Palbociclib) in combination with FASLODEX® (Fulvestrant), for the treatment of women with Hormone Receptor (HR)-positive, Human Epidermal growth factor Receptor 2 (HER2)-negative advanced or metastatic breast cancer, with disease progression following endocrine therapy. Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and over 40,450 women will die of the disease. Estrogen Receptor (ER) positive breast cancer cells are driven by estrogens. NOLVADEX® (Tamoxifen) is a nonsteroidal Selective Estrogen Receptor Modulator (SERM) and works mainly by binding to the Estrogen Receptor and thus blocks the proliferative actions of estrogen on the mammary tissue. ARIMIDEX® (Anastrozole) and FEMARA® (Letrozole) are nonsteroidal Aromatase Inhibitors that binds reversibly to the aromatase enzyme and inhibit the conversion of androgens to estrogens in the extra-gonadal tissues. Approximately 80% of breast tumors express Estrogen Receptors and/or Progesterone Receptors and these patients are often treated with anti-estrogen therapy as first line treatment.

Cyclin Dependent Kinases (CDK) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. Cyclin Dependent Kinases 4 and 6 (CDK4 and CDK6), phosphorylate RetinoBlastoma protein (RB), and initiate transition from the G1 phase to the S phase of the cell cycle. CDK4 and CDK6 are activated in hormone receptor positive breast cancer, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation. IBRANCE® (Palbociclib) is a reversible, oral, selective, small molecule inhibitor of Cyclin Dependent Kinases, CDK4 and CDK6, and prevents RB1 phosphorylation. IBRANCE® is the first CDK inhibitor approved by the FDA. It exhibits synergy when combined with endocrine therapies. In an open-label, randomized, phase II study, which included treatment naïve postmenopausal women with ER-positive, HER2-negative, advanced breast cancer, IBRANCE® given along with Aromatase Inhibitor FEMARA® (Letrozole), significantly prolonged Progression Free Survival, Overall Response rate and median duration of response, compared to FEMARA® alone. Based on this data, the U. S. Food and Drug Administration in February 2015, granted accelerated approval to IBRANCE® (Palbociclib), for use in combination with FEMARA®, in this patient population. FASLODEX® (Fulvestrant) is a selective estrogen receptor down-regulator presently indicated for the treatment of hormone receptor positive metastatic breast cancer patients, with disease progression following antiestrogen therapy.

The PALOMA3 is double-blind, phase 3 study in which the efficacy and safety of the combination of IBRANCE® and FASLODEX® was evaluated, in premenopausal or postmenopausal women, with hormone receptor positive, HER-2 negative, advanced breast cancer, who had disease progression during prior endocrine therapy. Five hundred and twenty one (N=521) patients were randomly assigned in a 2:1 ratio to receive either FASLODEX® 500 mg IM on days 1 and 15 during cycle 1, of a 28 day cycle, and then on day 1 of each cycle thereafter, along with IBRANCE® 125 mg PO daily for 3 weeks, followed by 1 week off (N=347) or FASLODEX® and placebo (N=174). ZOLADEX® (Goserelin) was administered to premenopausal or perimenopausal patients for the duration of study treatment, starting at least 4 weeks before randomization and continuing every 28 days. The median age was 57 years. One previous line of chemotherapy for metastatic disease was allowed and 79% were post-menopausal, 60% had visceral disease and 75% of the patients had received a previous chemotherapy regimen.

The primary endpoint was Progression Free Survival (PFS) and secondary endpoints included Overall Survival (OS), Response Rates, safety and tolerability. At the time of the preplanned interim analysis, the median Progression Free Survival was 9.2 months in the FASLODEX® / IBRANCE® group and 3.8 months in the FASLODEX® /placebo group (HR=0.42; P<0.001). This PFS benefit was observed across all prespecified patient subgroups, regardless of menopausal status. The most common grade 3 or 4 adverse events in the FASLODEX® / IBRANCE® group were neutropenia (62.0%, vs. 0.6%) and fatigue (2.0% vs. 1.2%). The incidence of febrile neutropenia was very rare (0.6%) and similar in both treatment groups. Treatment discontinuation rate due to adverse events was 2.6% in the IBRANCE® group and 1.7% in the placebo group.

The authors concluded that IBRANCE® in combination with FASLODEX® more than doubled the Progression Free Survival in advanced breast cancer patients, with hormone receptor positive and HER-2 negative disease, who had progressed on prior endocrine therapy. This study has reinforced the importance of CDK4 and CDK6, as key targets for hormone receptor positive breast cancer. Palbociclib in Hormone-Receptor–Positive Advanced Breast Cancer. Turner NC, Ro J, Andre F, et al. N Engl J Med 2015; 373:209-219

FDA Approves GAZYVA® in Combination with TREANDA® for Follicular Lymphoma

SUMMARY: The FDA on February 26, 2016, approved GAZYVA® (Obinutuzumab) for use in combination with TREANDA® (Bendamustine) followed by GAZYVA® monotherapy for the treatment of patients with Follicular Lymphoma (FL) who relapsed after, or are refractory to, a RITUXAN® (Rituximab) containing regimen. GAZYVA® was previously approved for use in combination with Chlorambucil for the treatment of patients with previously untreated Chronic Lymphocytic Leukemia. The American Cancer Society estimates that in 2016, about 72,580 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,150 individuals will die of this disease. Indolent Non Hodgkin Lymphomas are mature B cell lymphoproliferative disorders and include Follicular Lymphoma, Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT) lymphoma, Splenic Marginal Zone Lymphoma (SMZL), LymphoPlasmacytic Lymphoma (LPL) and Small Lymphocytic Lymphoma (SLL). Follicular Lymphoma is the most indolent form and second most common form of all NHLs and they are a heterogeneous group of lymphoproliferative malignancies. Approximately 20% of all NHLs are Follicular Lymphomas. Advanced stage indolent NHL are not curable and as such, prolonging Progression Free Survival (PFS) and Overall Survival (OS), while maintaining quality of life (QoL), has been the goals of treatment intervention. Asymptomatic patients with indolent NHL are generally considered candidates for “watch and wait” approach, whereas those with B symptoms (fever, night sweats, and weight loss), painful lymphadenopathy/splenomegaly, organ compromise and cytopenias are generally considered candidates for therapy.

GAZYVA® (Obinutuzumab) 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 lymphoma cells primarily by Complement-Dependent Cytotoxicity and also ADCC.

GADOLIN is a pivotal multicenter, open-label phase III, study in which TREANDA® (Bendamustine) alone was compared with TREANDA® plus GAZYVA® followed by GAZYVA® maintenance, in patients with indolent NHL (iNHL), refractory to RITUXAN®. Four hundred and thirteen (N=413) RITUXAN® refractory iNHL were randomized and patients in the control arm received TREANDA® 120 mg/m2 IV on days 1 and 2 every 28 days for a total of 6 cycles. Patients in the experimental arm received TREANDA® 90 mg/m2 IV on days 1 and 2 every 28 days for 6 cycles and GAZYVA® 1000mg IV days 1,8 and 15 every 28 days of cycle 1 and on day 1 of cycles 2-6. In patients with non-progressive disease in the experimental arm, GAZYVA® was continued (maintenance) every 2 months for up to 2 years. Both treatment groups were well balanced and the median age was 63 years, with a median of two prior lines of therapy. More than 90% of patients in each treatment group were refractory to their previous therapy and between 76% and 81% were double-refractory to both RITUXAN® and an alkylating agent. The Primary end point was Progression Free Survival (PFS) and Secondary end points included Overall Survival and Response Rate.

The study was unblinded at the time of planned interim analysis and had to be halted early, upon recommendations from the Independent Data Monitoring Committee, as the primary end point was reached. The median Progression Free Survival was 29 months with GAZYVA®/ TREANDA® plus maintenance GAZYVA® versus 14 months with TREANDA® monotherapy and no maintenance (HR=0.52; P<0.001). This meant a 45% reduction in the rate of disease progression. There was however no difference in the Response Rates between the treatment groups and the best Overall Response Rate up to 12 months from start of treatment was, 76.6% in the TREANDA® alone group and 78.6% in the TREANDA® plus GAZYVA® group. Median Overall Survival has not yet been reached in either arm and longer follow up is needed. The combination experimental group experienced more grade 3 adverse events such as infusion related reactions and neutropenia whereas the TREANDA® alone group experienced more thrombocytopenia, anemia and pneumonia.

The authors concluded that GAZYVA® in combination with TREANDA® is superior to TREANDA® alone, in patients with RITUXAN® refractory indolent Non Hodgkin Lymphoma, with a significant improvement in Progression Free survival. The lack of difference in the Response Rate begs the question, if the improvement in PFS was predominantly contributed by the continuous maintenance treatment with GAZYVA®. GADOLIN: Primary results from a phase III study of obinutuzumab plus bendamustine compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma. Sehn LH, Chua NS, Mayer J, et al. J Clin Oncol 33, 2015 (suppl; abstr LBA8502)