Month: September 2018

KEYTRUDA® (Pembrolizumab) and TECENTRIQ® (Atezolizumab)

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The FDA on August 16, 2018 updated the prescribing information for these two agents, to require the use of an FDA-approved companion diagnostic test to determine PD-L1 levels in tumor tissue from patients with locally advanced or metastatic urothelial cancer who are Cisplatin-ineligible. FDA approved two different companion diagnostic tests, the Dako PD-L1 IHC 22C3 PharmDx Assay (Dako North America, Inc.) as a companion diagnostic for treatment with KEYTRUDA® and Ventana PD-L1 (SP142) Assay® (Ventana Medical Systems, Inc.) as a companion diagnostic test for treatment with TECENTRIQ®.

OPDIVO® (Nivolumab)

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The FDA on August 16, 2018 granted accelerated approval to OPDIVO® for patients with metastatic Small Cell Lung Cancer (SCLC) with progression after platinum-based chemotherapy and at least one other line of therapy. OPDIVO® is a product of Bristol-Myers Squibb Company Inc.

AZEDRA® (Iobenguane I131)

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The FDA on July 30, 2018 approved AZEDRA® for adult and pediatric patients (12 years and older) with Iobenguane scan-positive, unresectable, locally advanced or metastatic Pheochromocytoma or Paraganglioma (PPGL) who require systemic anticancer therapy. AZEDRA® is a product of Progenics Pharmaceuticals, Inc.

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.

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.

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

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