Author: RR

Role of Bone-Modifying Agents in Multiple Myeloma American Society of Clinical Oncology Clinical Practice Guideline Update

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 30,770 new cases will be diagnosed in 2018 and 12,770 patients are expected to die of the disease. Multiple Myeloma in 2018 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). ASCO recently issued a clinical practice guideline update on the role of Bone-Modifying Agents (BMA) in Multiple Myeloma following a systematic literature review of 35 relevant studies by an expert panel. In the updated guidelines, ASCO has recommended expanding the use of bisphosphonates to include all patients being treated for active Multiple Myeloma. The previous guidelines recommended BMAs only for patients with lytic disease. The new recommendation was based on results from the phase III MRC Myeloma IX Trial, which demonstrated the benefit of bisphosphonate therapy in patients with newly diagnosed multiple myeloma who did not have lytic bone disease.

Indications to initiate a BMA – Key Recommendations

Patients with lytic disease on plain radiographs or other imaging studies

For patients with Multiple Myeloma who, on plain radiograph(s) or other imaging studies (MRI or CT scan), have lytic destruction of the bone or compression fracture of the spine from osteopenia, AREDIA® (Pamidronate) 90 mg IV over at least 2 hours or ZOMETA® (Zoledronic acid) 4 mg IV over at least 15 minutes every 3 to 4 weeks is recommended. Alternative treatment includes the use of XGEVA® (Denosumab), a monoclonal antibody that targets Receptor Activator of Nuclear factor Kappa-B Ligand (RANKL).

Patients with solitary plasmacytoma or smoldering (asymptomatic) or indolent myeloma

Starting bisphosphonates in patients with Solitary Plasmacytoma or Smoldering (asymptomatic) or indolent Myeloma is not recommended.

Adjunct to pain control in patients with pain as a result of osteolytic disease and those receiving other interventions for fractures or impending fractures

AREDIA® or ZOMETA® IV is recommended for patients with pain as a result of osteolytic disease and as an adjunctive treatment of patients receiving radiation therapy, analgesics, or surgical intervention to stabilize fractures or impending fractures. XGEVA® is an additional option.

Patients with myeloma with normal plain radiograph or osteopenia in bone mineral density measurements

The Expert Panel supports starting intravenous bisphosphonates in patients with Multiple Myeloma with osteopenia (osteoporosis), but no radiographic evidence of lytic bone disease.

Patients with monoclonal gammopathy of undetermined significance

Starting bisphosphonates in patients with Monoclonal Gammopathy of Undetermined Significance is not recommended, unless osteopenia/osteoporosis exists.

Dosing and selection of BMAs

As a result of increased concerns over renal adverse events, Guidelines recommend that patients with preexisting mild to moderate renal impairment (estimated Creatinine Clearance, 30-60 mL/min) should receive a reduced dosage of ZOMETA®. No changes in infusion time or interval are required. ZOMETA® has not been studied in patients with severe renal impairment and is not recommended for use in these patients. Recent data that compare XGEVA® with ZOMETA® has demonstrated fewer adverse events related to renal toxicity with XGEVA®, and this may be preferred in patients with compromised renal function. AREDIA® 90 mg administered over 4-6 hours is recommended for patients with extensive bone disease and existing severe renal impairment (serum creatinine level more than 3.0 mg/dL (265 µmol/L or an estimated Creatinine Clearance of less than 30 mL/min. Although no dosing guidelines are available for patients with preexisting renal impairment, the Expert Panel recommends that clinicians consider reducing the initial AREDIA® dose in that setting. Infusion times less than 2 hours with AREDIA® or less than 15 minutes with ZOMETA® should be avoided.

Duration of therapy

The Expert Panel suggests that bone-targeting treatment continue for a period of up to 2 years. Less frequent dosing has been evaluated and should be considered in patients with responsive or stable disease. In patients who do not have active Myeloma and are on maintenance therapy, the physician may consider a 3-month interval of bisphosphonate administration. There are no data to support a more precise recommendation for the duration of bisphosphonate therapy in this group of patients. For those patients for whom bisphosphonates were withdrawn after 2 years, the drug should be resumed upon relapse with new-onset Skeletal Related Events. XGEVA® should not be stopped abruptly, given its reversible mechanism of action.

Monitoring

The Expert Panel recommends that serum creatinine should be monitored before each dose of AREDIA® or ZOMETA®, in accordance with FDA-approved labeling. XGEVA® does not require monitoring of renal function. In patients who develop renal deterioration without an apparent cause during bisphosphonate therapy, ZOMETA® or AREDIA® should be withheld. Bisphosphonate therapy can be resumed at the same dosage as that before treatment interruption, when serum creatinine returns to within 10% of the baseline level. XGEVA® requires no dose modification. Serum Calcium should be monitored regularly, and serum Vitamin D levels should be evaluated intermittently. Hypocalcemia is an adverse effect of all bone resorptive agents and is more pronounced with XGEVA®. Patients should be Calcium and Vitamin D repleted. The Expert Panel also recommends intermittent evaluation (every 3-6 months) of all patients receiving AREDIA® or ZOMETA® therapy for the presence of albuminuria, on a spot urine sample. In patients who experience unexplained albuminuria, a 24-hour urine collection should be obtained to assess for more than 500 mg/24 hours of urinary albumin, and discontinuation of the drug is advised until renal problems are resolved. These patients should be reassessed every 3-4 weeks with a 24-hour urine collection for total protein and Urine Protein ElectroPhoresis, and AREDIA® should be reinstituted over a longer infusion time (4 hours or more) and at doses not to exceed 90 mg every 4 weeks, when renal function returns to baseline. The Expert Panel supports the use of screening urinalysis for proteinuria, but underscores that a 24-hour urine collection for the determination of total protein and electrophoresis is required if the test is positive. Although no similar guidelines are available for ZOMETA®, some Expert Panel members recommend that ZOMETA® be reinstituted over a longer infusion time (30 minutes or more).

Biochemical markers

Use of the biochemical markers of bone metabolism to monitor bone-modifying therapy use, is not suggested for routine care.

Osteonecrosis of the jaw

OsteoNecrosis of the Jaw (ONJ) is an uncommon but potentially serious complication of IV bisphosphonates and XGEVA®. The Expert Panel agrees with the recommendations described in the revised FDA label for ZOMETA® and AREDIA®, Dear Doctor letters, a white paper, and various position papers or statements. All patients should receive a comprehensive dental examination and appropriate preventive dentistry before bone-modifying therapy. Active oral infections should be treated, and sites that are at high risk for infection should be eliminated. While on therapy, patients should maintain excellent oral hygiene and avoid invasive dental procedures, if possible. Continuation of a bone-targeting agent in the setting of ONJ has to be individualized and dependent on a risk-benefit ratio and the severity of bone disease.

Role of bone-modifying agents in multiple myeloma: American Society of Clinical Oncology clinical practice guideline update. Anderson K, Ismaila N, Flynn PJ, et al. J Clin Oncol. 2018;36:812-818.

HER2 Testing in Breast Cancer American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update

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SUMMARY: 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 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and about 40,920 women will die of the disease. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2, and adjuvant and neoadjuvant chemotherapy given along with HERCEPTIN® reduces the risk of disease recurrence and death, among patients with HER2-positive, early stage as well as advanced metastatic breast cancer. Since the approval of HERCEPTIN®, several other HER2-targeted therapies have become available. Accurate determination of HER2 status of the tumor is therefore essential for patients with invasive breast cancer, to ensure that those most likely to benefit are offered a HER2-targeted therapy and those who are unlikely to benefit can avoid toxicities as well as financial burden associated with those drugs.

Laboratory testing for HER2 status in patients with breast cancer in the US is performed according to guidelines developed by an Expert panel of members of the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP). The ASCO/CAP guidelines were first published in 2007 and were updated in 2013. The Expert panel in 2018 developed and issued a focused update of the clinical practice guideline on HER2 testing in breast cancer. This new information made available since the previous update in 2013 addresses uncommon clinical scenarios and improves clarity, particularly for infrequent HER2 test results that are of uncertain biologic or clinical significance. There are currently two approved methods for determining HER2 status in breast cancer: ImmunoHistoChemistry (IHC) and In Situ Hybridization (ISH). This new guideline enables the Health Care Provider, how to best evaluate some of the less common patterns in HER2 results emerging from ISH.

Guideline Questions

1) What is the most appropriate definition for ImmunoHistoChemistry (IHC) 2+ (IHC equivocal)?

2) Must Human Epidermal growth factor Receptor 2 (HER2) testing be repeated on a surgical specimen if the initially tested core biopsy is negative?

3) What is the optimal algorithm for less common patterns observed when performing dual-probe In Situ Hybridization (ISH) HER2 testing in breast cancer?

Updated Recommendations

1) Immunohistochemistry (IHC) 2+ is defined as invasive breast cancer with weak to moderate complete membrane staining observed in more than 10% of tumor cells.

2) If the initial HER2 test result in a core needle biopsy specimen of a primary breast cancer is negative, a new HER2 test may (not “must”) be ordered on the excision specimen based on some criteria (such as tumor grade 3).

3)The HER2 testing algorithm now includes more rigorous interpretation criteria of the less common patterns that can be seen in about 5% of all cases when HER2 status in breast cancer is evaluated using a dual-probe ISH assay. These scenarios are described as ISH group 2 (HER2/Chromosome Enumeration Probe 17 [CEP17] ratio of 2.0 or more; average HER2 copy number less than 4.0 signals per cell), ISH group 3 (HER2/CEP17 ratio less than 2.0; average HER2 copy number 6.0 or more signals per cell), and ISH group 4 (HER2/CEP17 ratio less than 2.0; average HER2 copy number 4.0 or more and less than 6.0 signals per cell). These cases, described as ISH groups 2-4, should now be assessed using a diagnostic approach that includes a concomitant review of the IHC (ImmunoHistoChemistry) test, which will help the pathologist make a final determination of the tumor specimen as HER2 positive or negative.

4)The Expert Panel also preferentially recommends the use of dual-probe instead of single-probe ISH assays, but it recognizes that several single-probe ISH assays have regulatory approval in many parts of the world. 

Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. Wolff AC, Hammond EH, Allison KH, et al. J Clin Oncol 2018; 36:2105-2122.

Chronic Diseases Associated with Increased Cancer Risk

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SUMMARY: Cancer along with Cardiovascular disease, Diabetes, Chronic Kidney Disease and Respiratory disease, account for over 80% of all chronic disease deaths. Gouty arthritis is the most common inflammatory arthritis worldwide. Chronic inflammation may be the common denominator for chronic diseases and cancer, although other mechanisms may come into play. Patients with chronic diseases have associated lifestyle risk factors as well, which can reduce life span and increased cancer risk.

The purpose of this Prospective cohort study was to assess the independent as well as joint associations of several common chronic diseases and disease markers with cancer risk, and to explore the benefit of physical activity in reducing the cancer risk associated with chronic diseases and disease markers.

This study cohort consisted of 405,878 participants and the authors selected five common chronic diseases for evaluation, which account for most of the disease burden worldwide. They included Cardiovascular disease and associated markers such as diastolic blood pressure and systolic blood pressure, total cholesterol level, and heart rate, Diabetes and fasting blood glucose level using WHO criteria, Chronic Kidney Disease markers such as dipstick proteinuria and estimated Glomerular Filtration Rate using National Kidney Foundation criteria, Pulmonary disease markers such as Forced Expiratory Volume in one second and Forced Vital Capacity using Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria and Gouty arthritis marker such as uric acid. In this study, 48% were men and 52% were women. These participants were followed for an average of 8.7 years and the main outcome measures were cancer incidence and cancer mortality overall, as well as cancer specific incidence and mortality. The eight chronic diseases or markers included Blood Pressure, Total Cholesterol, Heart Rate, Diabetes, Proteinuria, Glomerular Filtration Rate, Pulmonary disease and Gouty arthritis marker Uric acid.

The authors observed a statistically significantly increased risk of incident cancer for the eight diseases and markers individually with the exception of Blood Pressure and Pulmonary disease. All eight diseases and markers were statistically significantly associated with risk of cancer death. Population Attributable Fraction (PAF) is the proportional reduction in population disease or mortality that would occur if exposure to a risk factor were reduced to an alternative ideal exposure scenario (eg. no tobacco use). The PAFs of cancer incidence or cancer mortality from the eight chronic diseases and markers together were comparable to those from five major lifestyle factors – ever smoking, insufficient physical activity, insufficient fruit and vegetable intake, ever alcohol consumption, and non-ideal BMI, combined (cancer incidence: 20.5% versus 24.8%; cancer mortality: 38.9% versus 39.7%). Among physically active (versus inactive) participants, the increased cancer risk associated with chronic diseases and markers was decreased by 48% for cancer incidence and 27% for cancer mortality.

It was concluded that chronic diseases contribute to more than 20% of the risk for incident cancer and more than one third of the risk for cancer death and is as important as five major lifestyle factors combined. Physical activity is associated with significant reduction in the cancer risk associated with chronic diseases. Cancer risk associated with chronic diseases and disease markers: prospective cohort study. Tu H, Wen CP, Tsai SP, et al. BMJ 2018;360:k134

A Completely Oral Chemotherapy-Free Regimen for Acute Promyelocytic Leukemia

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SUMMARY: Acute Promyelocytic Leukemia (APL) is a subtype (M3) of Acute Myeloid Leukemia (AML) accounting for 5-10% of AMLs in adults. The diagnostic hallmark of this subtype of AML is the balanced reciprocal translocation involving the long arms of chromosomes 15 and 17 – t(15;17)(q22;q11-12), leading to the fusion of ProMyeLocytic (PML) gene with the Retinoic Acid Receptor Alpha (RARA) gene. This hybrid PML-RARA hybrid oncoprotein blocks the differentiation of promyelocytes resulting in APL. The median age for patients diagnosed with APL is around 40 years.

Patients with APL often present with life-threatening bleeding secondary to consumptive coagulopathy and more rarely thrombosis. Therefore, rapid diagnosis of APL and institution of anti-leukemic and supportive therapy is of paramount importance, to prevent bleeding related mortality. Given the early mortality rate of 17-29%, immediate institution of anti-leukemic therapy without delay is strongly recommended upon clinical suspicion of APL following morphologic evaluation of the bone marrow, pending cytogenetics. Invasive procedures, routinely done at initial presentation of AML, should be avoided. APL is a curable disease and approximately 80% of the all APL patients present with non-high risk disease (WBC 10,000 or less per microliter).

The FDA in early 2018 approved the use of TRISENOX® (Arsenic Trioxide) injection, in combination with VESANOID® (All-Trans Retinoic Acid (ATRA), Tretinoin), for the treatment of adults with newly diagnosed low-risk APL, whose APL is characterized by the presence of the t(15;17) translocation or PML/RARA gene expression. This approval was based on the superiority of Arsenic Trioxide plus ATRA which resulted in a to a 2-year Event-Free Survival (EFS) rate of 97%, compared with 86% for chemotherapy plus ATRA. The combination of chemotherapy-free ATRA and Intravenous Arsenic Trioxide is therefore considered the standard of care for non-high risk APL patients. TRISENOX® (Arsenic Trioxide) was initially approved by the FDA in 2000 for the treatment of patients with APL who are refractory or have relapsed on Retinoid and Anthracycline chemotherapy.

First published from China in the 1980’s, ATRA induces terminal differentiation of leukemic promyelocytes and leads to an immediate improvement in bleeding symptoms and almost complete resolution of the associated coagulopathy within 1-2 weeks of treatment. Arsenic Trioxide is probably the most effective single agent used in the treatment of APL. It directly binds to the PML‐RARA oncoprotein inducing its proteosomal degradation and leads to apoptosis of leukemic cells.

Arsenic Trioxide infusion requires hospitalization. There is however an oral tetra-arsenic tetra-sulfide (As4S4) -containing formulation, Realgar-Indigo naturalis Formula (RIF). In a previously published study, a more convenient oral RIF plus ATRA was found not to be inferior to intravenous Arsenic Trioxide plus ATRA, as first-line treatment in patients with APL (J Clin Oncol. 2013 ;31:4215-4221).

The authors in this study compared oral RIF plus ATRA treatment regimen with the standard intravenous Arsenic Trioxide plus ATRA treatment regimen in patients with non-high-risk APL. In this multicentre, non-inferiority, open-label, randomized, controlled phase III trial, patients with newly diagnosed (within 7 days) non-high-risk APL (N=109), were randomly assigned 2:1 to receive treatment with RIF-ATRA (N=72) or Arsenic Trioxide-ATRA (N=37) as the induction and consolidation therapy. Patients received RIF 60 mg/kg orally daily in divided doses or Arsenic Trioxide 0.15 mg/kg IV daily and ATRA 25 mg/m2 orally daily in divided doses. Treatment was continued until complete remission was achieved. The home-based consolidation therapy consisted of RIF 60 mg/kg orally daily in divided doses or Arsenic Trioxide 0.15 mg/kg IV daily, 4 weeks on and 4 weeks off for four cycles and ATRA 25 mg/m2 orally daily in divided doses, 2 weeks on and 2 weeks off for seven cycles. The median patient age was 35 years. The Primary outcome was Event-Free Survival at 2 years.

After a median follow up of 32 months, 97% of patients in the RIF-ATRA group and 94% in the Arsenic Trioxide-ATRA group had achieved 2-year Event-Free Survival confirming non-inferiority of RIF-ATRA compared with Arsenic Trioxide and ATRA (P=0.0017 for non-inferiority). The 2 year Overall Survival was 100% in the RIF-ATRA group and 94% in the Arsenic Trioxide-ATRA group (P=0.049). Toxicities during induction treatment included grade 3-4 hepatotoxity (elevated AST or ALT) in 9% of patients in the RIF-ATRA group versus 14% in the Arsenic Trioxide-ATRA group. Grade 3-4 infections were reported in 23% versus 42% in the two groups respectively. Two patients in the Arsenic Trioxide-ATRA group died during induction therapy (one from hemorrhage and one from thrombocytopenia).

It was concluded that oral RIF plus ATRA was not inferior to intravenous Arsenic Trioxide plus ATRA, for the treatment of patients with non-high-risk Acute Promyelocytic Leukemia. The authors suggested that this completely oral, chemotherapy-free therapy might be an alternative to the standard intravenous treatment for patients with non-high-risk APL. Oral arsenic plus retinoic acid versus intravenous arsenic plus retinoic acid for non-high-risk acute promyelocytic leukaemia: a non-inferiority, randomised phase 3 trial. Zhu HH, Wu DP, Du X, et al. Lancet Oncol. 2018;19:871-879

FDA Approves DOPTELET® for Thrombocytopenia in Chronic Liver Disease

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SUMMARY: The FDA on May 21, 2018, approved DOPTELET® (Avatrombopag) for thrombocytopenia in adults with Chronic Liver Disease (CLD) scheduled to undergo a procedure. Thrombocytopenia is the most common hematological abnormality encountered in patients with Chronic Liver Disease (CLD), occurring in 65-85% of patients. Thrombocytopenia is an indicator of advanced disease and is associated with a poorer prognosis, and can impact routine care of patients with CLD, interfering with diagnostic and therapeutic interventions. Therefore treatment options that can safely and effectively raise platelet levels could have a significant impact on care of these patients.

The cause of thrombocytopenia in CLD is multifactorial and can be due to decreased production, splenic sequestration, and increased destruction. Thrombopoietin (TPO) regulates platelet production and maturation, and CLD is associated with depressed Thrombopoietin levels . Bone marrow suppression can be also be caused by alcohol, viruses, medications and iron overload. Hypersplenism causes splenic platelet sequestration. Increased platelet destruction in cirrhosis can be due to increased shear stress, increased fibrinolysis, increased platelet aggregation related to infections, or immune mediated platelet destruction secondary to antiplatelet antibodies.

DOPTELET® (Avatrombopag), a second generation orally administered Thrombopoietin Receptor Agonist (TPO-RA), designed to mimic the effects of TPO, the primary regulator of normal platelet production. DOPTELET® stimulates the proliferation and differentiation of megakaryocytes from bone marrow progenitor cells and results in increased production of platelets.

The approval of DOPTELET® by the FDA was based on two identically designed, international, randomized, double-blind, placebo-controlled phase III trials, ADAPT-1 (N=231) and ADAPT-2 (N=204). In these two studies totaling 430 patients with Chronic Liver Disease and thrombocytopenia (N=430), patients were randomized 2:1 to DOPTELET® (N=274) or placebo (N=156) daily for 5 days prior to a scheduled procedure, and had at least 1 post-dose safety assessment. Patients randomized to DOPTELET® received differential dosing based on mean platelet count at entry. Patients with a baseline platelet count less than 40,000/uL (low baseline platelet cohort) received DOPTELET® 60 mg orally once daily for 5 consecutive days. Those with a baseline platelet count of 40,000 to less than 50,000/uL (high baseline platelet cohort) received DOPTELET® 40 mg orally once daily for 5 consecutive days. Eligible patients were scheduled to undergo their procedure 5 to 8 days after the last dose of study drug. Patients were stratified according to HepatoCellular Cancer status and bleeding risk associated with the elective procedure (low, moderate, or high). The Primary efficacy endpoint was the proportion of patients, or responders, who did not require a platelet transfusion or any rescue procedure for bleeding after randomization, and for up to 7 days following an elective procedure.

In both trials, DOPTELET® exhibited superiority compared to placebo, in increasing the proportion of patients not requiring platelet transfusions or rescue procedures for bleeding up to 7 days, following a scheduled procedure. In the low baseline platelet cohort, 66% and 69% of patients treated with DOPTELET® responded in the ADAPT-1 and ADAPT-2 trials, respectively. For those receiving placebo, 23% (treatment difference 43%, P<0.0001) and 35% (treatment difference 34%, P=0.0006) responded in the ADAPT-1 and ADAPT-2 trials, respectively. In the high baseline platelet cohort, 88% of DOPTELET®-treated patients in both trials responded compared to 38% and 33% of placebo-treated patients. Treatment difference was 50% (P<0.0001) in the ADAPT-1 trial and 55% (P<0.0001) in the ADAPT-2 trial. Additionally, DOPTELET® was statistically superior to placebo at the two Secondary efficacy endpoints in each trial which included proportion of patients with platelet count of 50,000/uL or more by procedure day, and mean change in the platelet count from baseline to procedure day. The most common adverse reactions reported in at least 3% of patients were pyrexia, abdominal pain, nausea, headache, fatigue, and peripheral edema.

It was concluded that DOPTELET® is the first orally administered treatment option approved by the FDA for patients with Chronic Liver Disease who routinely undergo multiple, invasive procedures. The availability of this new oral agent can lead to a measured increase in platelets and minimize the risk of bleeding and need for platelet transfusions. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm608323.htm

KISQALI® plus FASLODEX® Improve Progression Free Survival in Advanced Breast Cancer

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SUMMARY: 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 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and about 40,920 women will die of the disease. Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients.

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. RetinoBlastoma protein has antiproliferative and tumor-suppressor activity and phosphorylation of RB protein nullifies its beneficial activities. 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. The understanding of the role of Cyclin Dependent Kinases in the cell cycle, has paved the way for the development of CDK inhibitors.Cell-Cycle-Inhibition-by-RIBOCICLIB-A-CDK4-and-CDK6-Inhibitor

KISQALI® (Ribociclib) is an orally bioavailable, selective, small-molecule inhibitor of CDK4/6 that blocks the phosphorylation of RetinoBlastoma protein, thereby preventing cell-cycle progression and inducing G1 phase arrest. KISQALI® in combination with an Aromatase Inhibitor has been approved by the FDA for pre and perimenopausal women with HR (Hormone Receptor)-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine-based therapy. The efficacy of KISQALI® was evaluated in two prior randomized phase III studies. In the MONALEESA-2 trial which evaluated KISQALI® in combination with FEMARA® (Letrozole) compared to FEMARA® alone, in postmenopausal women with HR-positive, HER2-negative advanced breast cancer who received no prior therapy for their advanced breast cancer, the addition of KISQALI® to FEMARA® significantly prolonged Progression Free Survival (PFS) compared to FEMARA® alone. In the MONALEESA-7 study, KISQALI® in combination with Tamoxifen or a Non-Steroidal Aromatase Inhibitor plus ZOLADEX® (Goserelin) was compared with Tamoxifen or an Aromatase Inhibitor plus ZOLADEX®, in premenopausal or perimenopausal women with HR-positive, HER2- negative advanced breast cancer, who had not previously received endocrine therapy for advanced disease. In this study of premenopausal women, KISQALI® plus endocrine therapy significantly improved PFS compared with placebo plus endocrine therapy

MONALEESA-3 is a randomized, double-blind, placebo-controlled Phase III study which compared the efficacy of KISQALI® in combination with FASLODEX® with FASLODEX® alone, among postmenopausal women with HR-positive, HER2-negative advanced breast cancer who received no prior or only one line of prior endocrine therapy for advanced disease. In this trial, 726 women were randomized, of whom 367 were treatment-naïve and 345 patients had received up to one line of prior endocrine therapy for advanced disease. . Patients were randomized 2:1 to receive KISQALI® plus FASLODEX® (N=484) or placebo plus FASLODEX® (N=242). Treatment consisted of KISQALI® 600 mg orally daily 3 weeks on and 1 week off and FASLODEX® 500 mg IM on day 1 of each 28-day cycle, with an additional dose given on day 15 of cycle 1. Patients were stratified by the presence or absence of lung or liver metastases and prior endocrine therapy (first-line versus second-line). The median age in both groups was 63 years. The Primary endpoint was Progression Free Survival. Secondary end points included Overall Survival, Overall Response Rate, and Safety. The median time from randomization to data cutoff was 20.4 months.

Among all randomized patients, the median PFS in the KISQALI® plus FASLODEX® group was 20.5 months compared to 12.8 months in the FASLODEX® plus placebo group (HR= 0.59; P<0.001). This represented a 41% reduction in the risk of disease progression. The PFS benefit was consistent among the 367 patients who were treatment-naïve (HR=0.57) and 345 patients had received up to one line of prior endocrine therapy for advanced disease (HR=0.56). In the subgroup of patients taking KISQALI® plus FASLODEX® as first-line treatment, the median PFS was not reached and 70% were estimated to remain Progression Free at median follow up of 16.5 months. Among those patients with measurable disease at baseline, the Overall Response Rate was 40.9% for the KISQALI® plus FASLODEX® arm versus 28.7% for FASLODEX® plus placebo group (P=0.003). At first interim analysis, the Overall Survival data were immature. The most common grade 3/4 Adverse Events in patients receiving KISQALI® plus FASLODEX® compared to FASLODEX® alone were neutropenia (53.4% versus 0%) and leukopenia (14.1% versus 0%).

It was concluded that KISQALI® plus FASLODEX® might represent a new, first or second-line treatment option for patients with Hormone Receptor-positive, Human Epidermal growth factor Receptor 2-negative advanced breast cancer. MONALEESA-3 is the only randomized Phase III trial to study a CDK4/6 inhibitor plus FASLODEX® in the first-line setting, with demonstrable efficacy in patients with de novo advanced breast cancer and those who had not received adjuvant therapy in more than a year. Ribociclib (RIB) + fulvestrant (FUL) in postmenopausal women with hormone receptor-positive (HR+), HER2-negative (HER2 –) advanced breast cancer (ABC): Results from MONALEESA-3. Slamon DJ, Neven P, Chia SKL, et al. J Clin Oncol. 2018: 36, (suppl; abstr 1000).

FDA Approves LENVIMA® for Unresectable Hepatocellular Carcinoma

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SUMMARY: The FDA on August 16, 2018, approved LENVIMA® (Lenvatinib) for first-line treatment of patients with unresectable HepatoCellular Carcinoma (HCC). The American Cancer Society estimates that for 2018, about 42,220 new cases of primary liver cancer will be diagnosed in the US and 30,200 patients will die of their disease. Liver cancer is seen more often in men than in women and the incidence has more than tripled since 1980. This increase has been attributed to the higher rate of Hepatitis C virus (HCV) infection among baby boomers (born between 1945 through 1965). Obesity and type II diabetes have also likely contributed to the trend. Other risk factors include alcohol, which increases liver cancer risk by about 10% per drink per day, and tobacco use which increases liver cancer risk by approximately 50%. HepatoCellular Carcinoma (HCC) is the second most common cause of cancer-related deaths worldwide.

NEXAVAR® (Sorafenib) was approved by the FDA in 2007 for the treatment of unresectable HepatoCellular Carcinoma (HCC) and is the only approved agent for the first line treatment of unresectable HCC. LENVIMA® is an oral multitargeted TKI which targets Vascular Endothelial Growth Factor Receptor (VEGFR) 1-3, Fibroblast Growth Factor Receptor (FGFR) 1-4, Rearranged during Transfection tyrosine kinase receptor (RET), c-KIT, and Platelet Derived Growth Factor Receptor (PDGFR). LENVIMA® differs from other TKIs with antiangiogenesis properties by its ability to inhibit FGFR-1, thereby blocking the mechanisms of resistance to VEGF/VEGFR inhibitors. In addition, it controls tumor cell growth by inhibiting RET, c-KIT, and PDGFR beta and influences tumor microenvironment by inhibiting FGFR and PDGFR beta. Based on the activity of LENVIMA® in unresectable HCC in a phase II trial, the efficacy of LENVIMA® was evaluated comparing this agent with NEXAVAR® in treatment naïve patients with unresectable HCC.Multikinase-Inhibition-by-Lenvatinib

This present approval by the FDA was based on an international, multicenter, randomized, open-label, noninferiority trial (REFLECT study) in which 954 patients with previously untreated, metastatic or unresectable HCC were randomized in a 1:1 ratio to receive LENVIMA® 12 mg orally once daily for patients with a baseline body weight of 60 kg or more and 8 mg orally once daily for patients with a baseline body weight of less than 60 kg (N=478) or NEXAVAR® 400 mg orally twice daily (N=476). Treatment was continued until radiological disease progression or unacceptable toxicity. Patients had one or more measurable target lesions, Barcelona Clinic Liver Cancer (BCLC) Stage B or C, Child-Pugh Class A, ECOG PS of 1 or less, and no prior systemic therapy. Baseline characteristics were similar in both treatment groups. The median age was 62 years, the most common Child-Pugh class was A (99%) and 79% of patients had BCLC stage C disease. Twenty percent (20%) of patients had 3 or more sites of disease involvement, and 50% of patients had underlying Hepatitis B infection. The median baseline AFP level was 133 ng/mL in the LENVIMA® group and 71 ng/mL in the NEXAVAR® group. The Primary endpoint of this study was noninferiority for Overall Survival (OS). Secondary efficacy endpoints included Progression Free Survival (PFS), Time to Progression (TTP) and Objective Response Rate (ORR).

In this study, LENVIMA® was noninferior, but not statistically superior to NEXAVAR® for Overall Survival (HR=0.92). The median OS in the LENVIMA® arm was 13.6 months and 12.3 months in the NEXAVAR® arm. There was however a statistically significant improvement in Progression Free Survival with LENVIMA® when compared to NEXAVAR®, with a median PFS of 7.3 months in the LENVIMA® group 3.6 months in the NEXAVAR® arm (HR=0.64; P<0.0001). The Objective Response Rate was higher for the LENVIMA® group as compared to NEXAVAR® group – 40.6% versus 12.4% per modified RECIST assessment (P<0.0001). The median TTP in this review was 8.9 months with LENVIMA® versus 3.7 months for NEXAVAR® (HR=0.60; P<0.0001). More patients in the LENVIMA® group experienced hypertension, decreased weight, proteinuria and decreased platelet count, whereas Palmar Plantar Erythrodysesthesia and diarrhea were more common in the NEXAVAR® group.

It was concluded that LENVIMA® is noninferior to NEXAVAR® in OS, and achieves statistically significant and clinically meaningful improvements in PFS, TTP, and ORR as first line therapy, for patients with HepatoCellular Carcinoma. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Kudo M, Finn RS, Qin S, et al. The Lancet 2018;391:1163-1173

FDA Approves OPDIVO® for Metastatic Small Cell Lung Cancer

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SUMMARY: The FDA on August 16, 2018, granted accelerated approval to OPDIVO® (Nivolumab), for patients with metastatic Small Cell Lung Cancer (SCLC) with progression after platinum-based chemotherapy and at least one other line of therapy. Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Small cell lung cancer (SCLC) accounts for approximately 13-15% of all lung cancers and is aggressive. Patients with SCLC are often treated with platinum based chemotherapy as first-line treatment and the tumor response rates are as high as 60-80%. However, only 20% of patients with Limited Stage SCLC are cured and majority of the patients relapse within months of completing initial therapy. The only FDA-approved agent for recurrent or progressive SCLC (second-line treatment) is HYCAMTIN® (Topotecan) and there is presently no standard therapy, after failure on second-line therapy. The 5 year survival rate for Extensive Stage SCLC is less than 5%, with a median survival of 9 to 10 months from the time of diagnosis.Unleashing-T-Cell-Function-with-PD-1-and-PD-L1-Antibodies

OPDIVO® is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor (Checkpoint proteins) and blocks its interaction with PD-L1 and PD-L2. Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response.

The present FDA approval for OPDIVO® was based on the results of phase I/II CheckMate-032 trial, which is a multicenter, open-label, ongoing study. This study included 245 patients with SCLC who experienced disease progression after platinum-based chemotherapy. Efficacy data was submitted by the investigators to the FDA from 109 patients who received OPDIVO® after disease progression on platinum-based chemotherapy and at least one other prior line of therapy, to support this present indication. Patients received OPDIVO® 3 mg/kg IV every 2 weeks until disease progression or unacceptable toxicity. The first tumor assessments were conducted 6 weeks after the first dose and were continued every 6 weeks for the first 24 weeks and every 12 weeks thereafter. The Primary endpoint of the study was Objective Response Rate (ORR). Secondary outcome measures included Overall Survival (OS), Progression Free Survival (PFS), Duration of Response (DOR), and the occurrence of treatment-related Adverse Events (AEs) leading to treatment discontinuation.

The results from a blinded, independent central review showed that the ORR was 12% and among the responders, the median Duration of Response was 17.9 months. The responses were durable for 6 months or longer in 77%, 12 months or longer in 62%, and 18 months or longer in 39% of the responding patients. These treatment responses were noted regardless of PD-L1 expression. OPDIVO® was granted accelerated approval for this indication on the basis of Overall Response Rate and Duration of Response, and further proof of benefit in confirmatory trials may be required for full approval.

It was concluded that OPDIVO® is the first new agent approved in nearly 20 years for Small Cell Lung Cancer, and is the first checkpoint inhibitor approved for this patient group. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm617370.htm

American Cancer Society Updates Colorectal Cancer Screening Guideline for Average Risk Adults

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SUMMARY: The American Cancer Society estimates that approximately 140,250 new cases of ColoRectal Cancer will be diagnosed in the United States in 2018 and about 50,630 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 21 (4.7%). ColoRectal cancer (CRC) is the fourth most common cancer diagnosed among adults in the US and the second leading cause of death from cancer.

The ACS recently updated Colorectal Cancer Screening Guideline using prevailing evidence as well as microsimulation modeling analyses, and included a new evaluation of the age, to begin screening by race and sex and additional modeling that incorporates changes in United States CRC incidence. The ACS Guideline Development Group applied the Grades of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria in developing and rating the recommendations. The new guideline does not prioritize among screening test options. This is because test preferences vary among individuals and the guidelines development committee emphasized that screening rates could be improved by endorsing the full range of tests without preference.

Even though the incidence of Colorectal cancer (CRC) in the United States has been rapidly declining overall in people 55 and over primarily driven by screening, among adults younger than 55 years there was a 51% increase in the incidence of colorectal cancer (CRC) from 1994 to 2014 and a 11% increase in deaths from 2005 to 2015. Adults born around 1990 have twice the risk of colon cancer and four times the risk of rectal cancer compared with adults born around 1950, who have the lowest risk. Studies suggest that the younger individuals will continue to be at a higher risk as they age. The increase in the incidence of CRC in young adults has been attributed to western life style including high carbohydrate, high fat, low fiber diet which can initiate inflammation and proliferation in the colonic mucosa within two weeks. Other lifestyle factors associated with CRC include obesity, high consumption of processed meat and alcohol, low levels of physical activity and cigarette smoking. Further, young patients are 58% more likely than older patients to be diagnosed with advanced versus localized stage CRC, due to delayed follow up of symptoms, sometimes for years, and these young adults are less likely to be screened for colon cancer, despite their symptoms.

The current ACS recommendations are as follows:

1) Adults aged 45 and older with an average risk of colorectal cancer should undergo regular screening with either a high-sensitivity stool-based test or a structural (visual) exam, depending on patient preference and test availability.

2) As a part of the screening process, all positive results on non-colonoscopy screening tests should be followed up with timely colonoscopy.

3) The recommendation to begin screening at age 45 years is a “qualified recommendation”. The change in starting age is designated as a “qualified recommendation” because there is less direct evidence of the balance of benefits and harms, or patients’ values and preferences, related to colorectal cancer screening in adults aged 45 to 49, since most studies have only included adults aged 50 and older.

4) The recommendation for regular screening in adults aged 50 years and older is designated as a “strong recommendation,” on the basis of the greater strength of the evidence and the judgment of the overall benefit.

5) Average-risk adults in good health with a life expectancy of greater than 10 years should continue colorectal cancer screening through age 75 years.

6) Clinicians should individualize colorectal cancer screening decisions for individuals aged 76 through 85 years, based on patient preferences, life expectancy, health status, and prior screening history.

7) Clinicians should discourage individuals over age 85 years from continuing colorectal cancer screening.

Test options for CRC screening include the following:

Stool-based tests

1) Highly sensitive Fecal Immunochemical Test (FIT) annually

2) Highly sensitive guaiac-based Fecal Occult Blood Test (gFOBT) annually

3) Multi-targeted stool DNA test every 3 years

Visual exams

1) Colonoscopy every 10 years

2) CT colonography (virtual colonoscopy) every 5 years

3) Flexible sigmoidoscopy every 5 years

Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. Wolf AM, Fontham ET, Church TR, et al. CA Cancer J Clin 2018;68:250-281.

Tumor Mutation Burden is a Predictive Biomarker for Response to Immune Checkpoint Inhibitors

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Patients with advanced NSCLC (Non-Small Cell Lung Cancer) often receive either platinum-doublet chemotherapy combination as first line therapy or KEYTRUDA® (Pembrolizumab) if the tumor PD-L1 expression is 50% or more. About 20-25% of patients benefit from immunotherapy. Other biomarkers besides PD-L1 are needed, to select appropriate patients for immunotherapy.

Tumor Mutational Burden (TMB) has recently emerged as a potential biomarker for immunotherapy with anti PD-1 antibodies. TMB can be measured using Next-Generation Sequencing (NGS) and is defined as the number of somatic, coding base substitutions and short insertions and deletions (indels) per megabase of genome examined. In a previously published trial (CheckMate 568), patients most likely to have a response to a combination of OPDIVO® (Nivolumab) plus YERVOY® (Ipilimumab), irrespective of tumor PD-L1 expression level in NSCLC, had a TMB of at least 10 mutations per megabase. This was the basis for CheckMate 227, which evaluated the efficacy of OPDIVO® and OPDIVO®-based regimens, as first line treatment in biomarker-selected groups of patients with advanced NSCLC.Unleashing-T-Cell-Function-with-Combination-Immunotherapy

OPDIVO® is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, whereas YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4(Cytotoxic T-Lymphocyte Antigen 4, also known as CD152). Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response. The complementary mechanisms of action of OPDIVO® and YERVOY® combination resulted in greater efficacy in phase I trials, compared with OPDIVO® monotherapy.

CheckMate 227 is a three part, open-label, randomized, phase III trial, designed to compare different OPDIVO® -based regimens with chemotherapy in distinct patient populations. This study enrolled 1,739 patients with previously untreated Stage IV or recurrent NSCLC with no known sensitizing EGFR or ALK mutations and patients were randomized in a 1:1:1 ratio and the comparison was between either OPDIVO®, OPDIVO® plus YERVOY® or OPDIVO® plus platinum-doublet chemotherapy and platinum-doublet chemotherapy alone. Patients were stratified according to tumor histology and PD-L1 expression of 1% or more (positive) or less than 1% (negative). The study incorporated Tumor Mutational Burden (TMB) as a biomarker. This was determined by the FoundationOne CDx assay, an FDA approved test for molecular profiling, using the validated cutoff of TMB of 10 or more mutations/megabase as High, and less than 10 mutations/megabase as Low.

The authors in this publication reported data from part 1 of this study, which was a comparison between OPDIVO® plus YERVOY® versus chemotherapy, in patients with previously untreated Stage IV or recurrent NSCLC. In this comparison, 139 TMB-High patients were treated with OPDIVO® 3 mg/kg IV every 2 weeks plus YERVOY® 1 mg/kg IV every 6 weeks, whereas 160 TMB-High patients received chemotherapy, based on tumor histology. All treatments were continued until disease progression or unacceptable toxicity. Part 1 of the study had two Coprimary end points. One Coprimary end point was Progression Free Survival (PFS) with OPDIVO® plus YERVOY® versus chemotherapy in a patient population selected on the basis of TMB. The other Coprimary end point was Overall Survival (OS) with OPDIVO® plus YERVOY® versus chemotherapy in a patient population selected on the basis of the PD-L1 expression level.

It was noted that the PFS among patients with High TMB was significantly longer with OPDIVO® plus YERVOY®, compared with chemotherapy. The median PFS with the immunotherapy combination was 7.2 months compared to 5.5 months with chemotherapy (HR=0.58; P<0.001). This represented a 42% reduction in the risk of disease progression or death. The 1 year PFS more than tripled with combination immunotherapy at 42.6% versus 13.2% with chemotherapy. The Objective Response Rate (ORR) was 45.3% with immunotherapy combination and 26.9% with chemotherapy. The improved outcomes with OPDIVO® plus YERVOY® over chemotherapy was broadly consistent within all subgroups and was independent of tumor histology and PD-L1 expression. There was a clear trend toward improved survival with the immunotherapy combination although this data is immature. Grade 3 or 4 treatment related adverse events were 31.2% with immunotherapy combination and 36.1% with chemotherapy.

The authors concluded that this is the first phase III study to evaluate Tumor Mutational Burden as a predictive biomarker for immunotherapy as a coprimary endpoint. They added that these results highlight that Tumor Mutational Burden and PD-L1 are independent biomarkers and TMB is predictive of benefit with OPDIVO® plus YERVOY® irrespective of PD-L1 expression. TMB-High therefore is a new biomarker and represents a distinct subgroup of NSCLC. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. N Engl J Med 2018; 378:2093-2104