Author: RR

Caplacizumab, a Novel Anti-vWF targeted Nanobody, for Acquired TTP

RR

SUMMARY: Thrombotic Thrombocytopenic Purpura (TTP), Hemolytic Uremic Syndrome (HUS) and Atypical Hemolytic Uremic Syndrome (aHUS) are life-threatening Thrombotic MicroAngiopathies (TMAs) associated with systemic microvascular thrombosis, MicroAngiopathic Hemolytic Anemia (MAHA), thrombocytopenia and organ failure. Even though their clinical presentation has some similarities, they are distinct entities with different pathophysiology and hence managed differently. Patients with TTP have either severe deficiency of ADAMTS13 (A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13) secondary to anti-ADAMTS13 autoantibodies or rarely due to ADAMTS13 gene mutations. The physiological role of ADAMTS13 is to prevent intravascular platelet thrombosis. ADAMTS13 accomplishes this by cleaving ultralarge von Willebrand Factor multimers (which bind to platelets and induce aggregation), thereby mitigating the tendency of von Willebrand Factor (vWF) and platelets to form aggregates in normal microcirculation. Deficiency of ADAMTS13 causes vWF-platelet aggregation in the arterioles and capillaries, characteristic of TTP, resulting in tissue ischemia from microthrombi and end organ damage. Thus the microthrombi in TTP are platelets bound to vWF and not to fibrinogen. Rapid initiation of Plasma Exchange, the frontline therapy in patients with TTP, removes the anti-ADAMTS13 autoantibodies and ultra large vWF multimers and replenishes ADAMTS13. Immunosuppressive therapy with glucocorticoids and RITUXAN® (Rituximab) inhibits anti-ADAMTS13 autoantibody formation, by targeting the B lymphocytes. These interventions have significantly improved the survival rate among patients with TTP. Despite these advances with the use of Plasma Exchange, approximately 10-20% of the patients with TTP will succumb to their disease.

Caplacizumab is an anti-von Willebrand Factor, humanized, single-variable-domain immunoglobulin (Nanobody), directed against the A1 domain of von Willebrand Factor and prevents the interaction of vWF with the platelet glycoprotein Ib-IX receptor. TITAN is an international, multicenter, phase II, randomized, placebo-controlled study, designed to assess the efficacy and safety of Caplacizumab given as an adjunct to Plasma Exchange, in patients with acquired TTP. Seventy five patients (N=75) were randomized in a 1:1 ratio to receive Plasma Exchange plus either Caplacizumab 10 mg subcutaneous or placebo, daily. The mean age was 42 years and the mean platelet count was 24,600 per cubic millimeter. Majority of the patients in both groups received concomitant glucocorticoids and 23% of the patients in the placebo group received RITUXAN® during daily Plasma Exchange compared 6% in the Caplacizumab group. The primary end point was the time to response, defined as normalization of the platelet count (150,000 per cubic millimeter or higher) and a Lactate DeHydrogenase (LDH) level that was no more than twice the upper limit of the normal range. Secondary end points included TTP exacerbations and relapses.

It was noted that the median time to a response was significantly reduced with Caplacizumab as compared with placebo (39% reduction in median time, P=0.005). The mean number of Plasma Exchange days was lower with Caplacizumab (5.9 versus 7.9 days), the mean volume of Plasma administered was lower with Caplacizumab (19.9L versus 28.3L), normalization of LDH and creatinine occurred more rapidly with Caplacizumab and Complete Remissions after initial course of Plasma Exchange was more common in the Caplacizumab group (81% versus 46%), when compared to the placebo group. Mild to moderate bleeding was more common with Caplacizumab than with placebo (54% versus 38%).

The authors concluded that the addition of Caplacizumab to Plasma Exchange induces a faster resolution of acute TTP compared with placebo and Caplacizumab maintained a platelet-protective effect during the treatment period. Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura. Peyvandi F, Scully M, Hovinga JK, et al. for the TITAN Investigators. N Engl J Med 2016; 374:511-522

EGFR Inhibition may not be Effective Immediately after VEGF blockade in Metastatic ColoRectal Cancer

RR

SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 135,000 new cases of ColoRectal Cancer will be diagnosed in the United States in 2016 and over 49,000 patients are expected to die of the disease. Even though colon cancer localized to the bowel is potentially curable with surgery and adjuvant chemotherapy, advanced colon cancer is often incurable. Standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as VECTIBIX® (Panitumumab) and ERBITUX® (Cetuximab) as well as anti VEGF agent AVASTIN® (Bevacizumab), have demonstrated improvement in Progression Free Survival (PFS) and Overall Survival (OS). The benefit with anti EGFR agents however is only demonstrable in patients with metastatic CRC, whose tumors do not harbor KRAS mutations in codons 12 and 13 of exon 2 (KRAS Wild Type). It is now becoming clear that even among the KRAS Wild Type patients, about 15% to 20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents. Therefore, pan RAS (expanded RAS) testing is now recommended.

The CALGB/SWOG 80405 study reported that either ERBITUX® or AVASTIN® in combination with chemotherapy have equivalent Overall Survival benefit, when given as first line therapy, for patients with metastatic ColoRectal Cancer (mCRC), whose tumors are KRAS Wild Type. Consequently, the optimal first-line therapy for patients with KRAS Wild Type metastatic CRC still remains unclear. ERBITUX® has a similar activity across all treatment lines whereas AVASTIN® appears to lose its efficacy along the course of treatment lines. Although FOLFOX and FOLFIRI are equally effective as first line treatment for patients with metastatic CRC, FOLFOX might be more effective as second line treatment. Preclinical studies have suggested that a prior anti VEGF therapy, may lower sensitivity to a subsequent anti EGFR treatment.

The authors in a phase III randomized multicenter trial addressed these issues by comparing two different sequences of ERBITUX® and FOLFOX chemotherapy in KRAS Wild Type metastatic CRC patients, refractory to first line FOLFIRI chemotherapy and AVASTIN®. Patients with mCRC (N=110) were randomly assigned in a 1:1 ratio to receive CAMPTOSAR® (Irinotecan)/ERBITUX® as second line followed by FOLFOX-4 chemotherapy as third line (Arm A) or the reverse sequence (FOLFOX-4 chemotherapy second line followed by CAMPTOSAR®/ERBITUX® as third line – Arm B). The primary endpoint was Progression Free Survival (PFS) and secondary endpoints included Overall Survival (OS) and toxicity. It was noted that the median PFS in Arm A was 9.9 months compared to 11.3 months in Arm B (HR=0.85; P=0.42) and the median OS was 12.3 months in Arm A and 18.6 months in Arm B (HR=0.79; P=0.28). The Objective Response Rate in Arm A was 37% and in Arm B was 57% (P=0.05). Treatment was well tolerated with a low incidence of serious adverse events.

It was concluded that EGFR inhibition is not active immediately after VEGF blockade and therefore ERBITUX® is less effective immediately after AVASTIN®. The sequence of biological agents appears to be more important than the first-line chemotherapy choice. In RAS Wild Type metastatic CRC patients progressing after a first line AVASTIN® based therapy, ERBITUX® should be given in the third line setting or should be considered in first line treatment regimen. Efficacy of cetuximab immediately after bevacizumab: A phase III multicenter trial comparing two different sequences of cetuximab and FOLFOX in K-Ras WT metastatic colorectal cancer patients refractory FOLFIRI/bevacizumab. Cascinu S, Zaniboni A, Lonardi S, et al. J Clin Oncol 34, 2016 (suppl 4S; abstr 632)

IMBRUVICA® in Combination with BR Regimen Shows Significant Benefit in Relapsed CLL patients

RR

SUMMARY: The American Cancer Society estimates that approximately 18,960 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in 2016 and approximately 4660 patients will die from the disease. CLL is a disease of the elderly and the average age at the time of diagnosis is 72 years. There are two main types of lymphocytes, B and T lymphocytes/cells. B-cell CLL is the most common type of leukemia in adults. Normal B-cell activation and proliferation is dependent on B-cell receptor (BCR) signaling. This signaling is also important for initiation and progression of B-cell lymphoproliferative disorders. Bruton's Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Following binding of antigen to the B-Cell Receptor, kinases such as Syk (Spleen Tyrosine Kinase), Lyn (member of the Src family of protein tyrosine kinases) and BTK (Bruton's Tyrosine Kinase) are activated, with subsequent propagation through PI3K/Akt, MAPK, and NF-κB pathways. This results in B-cell activation and proliferation. IMBRUVICA® (Ibrutinib) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. The FDA initially granted accelerated approval to IMBRUVICA® in February 2014 for previously treated patients with CLL and this was followed by full FDA approval and a new treatment indication for high-risk CLL patients with 17p deletions, in July 2014. Previously published studies had shown significant Response Rates and and Event-Free Survival with BR (Bendamustine-TREANDA® and Rituximab-RITUXAN®) in FLUDARA® (Fludarabine) refractory patients, with Chronic Lymphocytic Leukemia.

The HELIOS study is a double-blind, randomized, phase III trial which evaluated the benefit of combining IMBRUVICA® with BR compared to placebo plus BR, in patients with previously treated, relapsed/refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. In this study, of the 578 randomized patients, 289 patients received a maximum of six cycles of BR with IMBRUVICA® 420 mg PO daily and 289 patients received BR with placebo. The median patient age was 64 years, patients had received a median of two prior therapies and 38% of the patients had Rai Stage III/IV disease. Patients with 17p deletions in more than >20% of cells, were excluded. The planned six cycles of BR were completed by 83% in the IMBRUVICA® group and 78% in the placebo group. The primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS) and Overall Response Rate (ORR).

Following an interim analysis, this study was unblinded as there was a significant PFS benefit with IMBRUVICA® and patients receiving placebo, were allowed to cross over to the IMBRUVICA® group, per study protocol,. Thirty one percent (31%) of the patients in the BR plus placebo group with confirmed progressive disease crossed over to receive BR plus IMBRUVICA®. At a median follow up of 17.2 months, the PFS in the IMBRUVICA® plus BR group was not yet reached whereas the PFS was 13.3 months for patients receiving placebo plus BR (HR=0.203; P<0.0001). This PFS benefit was seen across subgroups of high-risk patients as well. The ORR was 82.7% in the IMBRUVICA® plus BR group compared to 67.8% in the placebo plus BR group (P <0.0001). Complete Response (CR) rates which included CR with incomplete blood count recovery were 10.4% versus 2.8% with IMBRUVICA® and placebo, respectively. The median OS was not reached. The incidence of most adverse events were comparable between the two treatment groups and the most frequent side effects were neutropenia affecting about 55% of the patients and nausea experienced by about 35% of the patients.

The authors concluded that IMBRUVICA® plus BR resulted in an 80% reduction in the risk of disease progression, as well as improved Overall Response Rates, compared to placebo plus BR. This triplet combination of IMBRUVICA®, TREANDA® and RITUXAN® should therefore be considered an important treatment option for patients with previously treated Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Chanan-Khan A, Cramer P, Demirkan F, et al. The Lancet Oncology 2016;17:200-211

BRAF Inhibitors versus Immunotherapy in Patients with BRAF V600-Mutant Metastatic Melanoma

RR

SUMMARY: It is estimated that in the US, approximately 76,380 new cases of melanoma will be diagnosed in 2016 and approximately 10,130 patients will die of the disease. The incidence of melanoma has been on the rise for the past three decades. The approval of the combination of MEKINIST® (Trametinib) and TAFINLAR® (Dabrafenib), to treat patients with advanced melanoma, was based on the understanding of the biological pathways of this malignancy. The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been demonstrated in 6%-8% of all malignancies. The most common BRAF mutation in melanoma is at the V600E/K site and is detected in approximately 50% of melanomas. In the BREAK-3 randomized phase III trial, TAFINLAR® (Dabrafenib), a selective oral BRAF inhibitor demonstrated a statistically significant improvement in Progression Free Survival (PFS) and Response Rate (RR) compared to Dacarbazine (DTIC), in patients with advanced BRAF V600E/K mutated melanoma. However, Squamous Cell carcinomas were seen in about 6% of the patients treated with BRAF inhibitors. Paradoxical activation of the MAPK pathway in cells without a BRAF mutation (BRAF wild-type cells) has been implicated in the emergence of drug resistance and increased incidence of BRAF-inhibitor induced skin tumors. The addition of a MEK inhibitor such as MEKINIST® (Trametinib) to a BRAF inhibitor such as TAFINLAR®, has addressed some of these limitations, in previously published studies, with improvement in PFS. MEKINIST® is a potent and selective inhibitor of MEK gene, which is downstream from RAF in the MAPK pathway and has been shown to significantly improve PFS, RR and Overall Survival (OS), when compared to chemotherapy, in advanced melanoma patients with BRAF V600E/K mutations. A combination of BRAF inhibitor TAFINLAR® and MEK inhibitor MEKINIST®, significantly improved OS, as compared with monotherapy with BRAF inhibitor, with a 31% relative reduction in the risk of death, in previously untreated patients with metastatic melanoma, with BRAF V600E or V600K mutations. This benefit was accomplished without increased overall toxicity. However, approximately 50% of patients progress after 12 months, although a significant number of patients experience long-term benefit without progression.

The purpose of this study was to identify the clinical predictors and analyze the clinical correlates of those who had prolonged survival. The authors in this manuscript report the updated OS results of a previously published study, in which BRAF inhibitor-naive patients were treated with a combination of TAFINLAR® and MEKINIST®. Additionally, the authors in this study also report the clinical factors associated with long term survival. The original open-label phase I and II study of combination therapy with TAFINLAR® and MEKINIST® (N Engl J Med. 2012;367:1694-1703) had four parts (parts A, B, C, and D). The present analysis evaluated the outcomes of a total of 78 BRAF inhibitor-naive patients, enrolled in part B (N= 24) and part C (N= 54), who received the phase III dose (optimal dose) of oral TAFINLAR® 150 mg twice daily combined with oral MEKINIST® 2 mg once daily. The remaining cohorts in parts B and C and all cohorts in parts A and D did not receive the phase III dose of the combination therapy and therefore are not described here.

It was noted that among patients in part B of the study, the 1 year Progression Free Survival (PFS) was 44%, 2 year PFS was 22% and 3 year PFS was 18%. Among patients in part C, the 1 year PFS was 41%, 2 year PFS was 25% and 3 year PFS was 21%. The median Overall Survival (OS) was 27.4 months in part B and 25 months in part C with an OS at 1, 2, and 3 years of 72%, 60%, and 47%, respectively, for part B and 80%, 51%, and 38%, respectively, for part C. Prolonged survival was associated with good prognostic factors such as metastases in fewer than three organ sites and lower baseline LDH (Lactate Dehydrogenase) levels. The 3 year OS was 62% in patients with normal baseline LDH levels and 63% in those who had a complete response.

The authors concluded that a combination of TAFINLAR® and MEKINIST® results in a median OS of more than 2 years in BRAF V600 mutation-positive metastatic melanoma, with approximately 20% of the patients remaining progression free at 3 years. Good prognostic features at baseline, were predictive of durable responses. With dilemma facing clinicians, whether to choose MAP Kinase inhibitors versus Immunotherapy, as first line therapy for this patient group, the longest follow up data presented, demonstrating durable benefit with a combination TAFINLAR® and MEKINIST®, should be very reassuring. Overall Survival and Durable Responses in Patients With BRAF V600-Mutant Metastatic Melanoma Receiving Dabrafenib Combined With Trametinib. Long GV, Weber JS, Infante JR, et al. JCO JCO629345; published online on January 25, 2016

BCR-ABL Transcript Type May Predict Outcomes in Patients with Chronic Phase CML Treated with Tyrosine Kinase Inhibitors

RR

SUMMARY: Chronic Myeloid Leukemia (CML) constitutes a little over 10% of all new cases of leukemia. The American Cancer Society estimates that about 8,220 new CML cases will be diagnosed in the United States in 2016 and about 1,070 patients will die of the disease. The hallmark of CML, the Philadelphia Chromosome (Chromosome 22), is a result of a reciprocal translocation-t(9;22), between chromosomes 9 and 22, wherein the ABL gene from chromosome 9, fuses with the BCR gene on chromosome 22. As a result, the auto inhibitory function of the ABL gene is lost and the BCR-ABL fusion gene is activated resulting in cell proliferation and leukemic transformation of hematopoietic stem cells. Even though the reciprocal translocation resulting in the formation of Philadelphia chromosome involves a fairly constant breakpoint in the ABL gene on chromosome 9, the breakpoint in the BCR gene on chromosome 22 can vary, resulting in different BCR-ABL transcript types. There has been ongoing debate whether the type of transcript, has prognostic significance, for patients with newly diagnosed chronic phase CML. Over 95% of patients with CML have expression of e13a2 (b2a2), e14a2 (b3a2), or both transcripts, coding for p210 BCR-ABL tyrosine kinase, whereas a small minority of patients express rare variants such as e1a2 transcripts, which code for p190 BCR-ABL, which is associated with aggressive disease. Previously published studies have shown that expression of certain type of transcripts may predict response to therapy, as well as outcomes.

The purpose of this study was to evaluate the prognostic relevance of the commonly expressed BCR-ABL transcripts in patients with chronic phase CML and the influence of the transcript type, on molecular and cytogenetic responses, across chronic phase CML patients, treated with different Tyrosine Kinase Inhibitors (TKI). This analysis included 481 treatment naïve patients with chronic phase CML treated with different TKI modalities, expressing e13a2 (42%), e14a2 (41%), or coexpression of both e13a2 with e14a2 (18%) transcripts. These patients were treated with 4 different frontline TKIs which included, GLEEVEC® (Imatinib) 400 mg daily (N=69), GLEEVEC® 800 mg daily (N=199), SPRYCEL® (Dasatinib) 50 mg twice daily or 100 mg daily (N=105) and TASIGNA® (Nilotinib) 400 mg twice daily (N=108).

It was noted that patients with e13a2 transcripts who received GLEEVEC® 400 mg had an inferior Complete Cytogenetic Response (77%) compared with other TKI modalities (90-95%). Unlike these patients, patients with e14a2 transcripts or those expressing both e13a2 and e14a2 transcripts treated with GLEEVEC® 400 mg, had a Complete Cytogenetic Response rate of 93%, which was similar to treatment with other TKI modalities (93-96%). Even though the time to Complete Cytogenetic Response was 3 months and similar in all treatment groups, the trend for lower rates of Complete Cytogenetic Response and Major Cytogenetic Response for the e13a2 transcript cohort compared with the e14a2 cohort, persisted even at 60 months. Patients with e13a2 treated with GLEEVEC® 400 mg similarly had an inferior Major Molecular Response (MMR) at all time points than individuals with e14a2 and inferior MR4.5, compared with those treated with other TKI modalities. In patients with e14a2 transcripts, the MMR and MR4.5 rates were generally similar with all TKI modalities. In a multivariate analysis, patients with e14a2 alone or those with coexpressed e13a2, achieved an earlier and deeper response, compared to those with e13a2 transcripts, and predicted for longer event-free and transformation-free survival.

The authors concluded that the type of BCR-ABL transcript may determine outcomes in patients with chronic phase CML. Patients with e13a2 transcripts have lower platelet count and inferior outcomes with GLEEVEC® 400 mg, whereas patients with e14a2 have favorable outcomes regardless of TKI treatment modality. Further, expression of e14a2 or both e14a2 and e13a2 predicts optimal responses and longer Event Free Survival and Transformation Free Survival. Thus BCR-ABL transcript type may help in selecting the appropriate treatment and may predict outcomes in patients with chronic phase CML. Impact of BCR-ABL transcript type on outcome in patients with chronic-phase CML treated with tyrosine kinase inhibitors. Jain P, Kantarjian H, Patel KP, et al. Blood 2016;127:1269-1275

XTANDI® Superior to CASODEX® in Advanced Prostate Cancer

RR

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

RR

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

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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

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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

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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.