Author: RR

FDA Approves ALECENSA® for Metastatic ALK-Positive Non Small Cell Lung Cancer

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SUMMARY: The FDA on December 11, 2015 granted accelerated approval to Alectinib (ALECENSA®) for the treatment of patients with Anaplastic Lymphoma Kinase (ALK)-positive metastatic Non Small Cell Lung Cancer (NSCLC), who have progressed on or are intolerant to XALKORI® (Crizotinib). Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 27% of all cancer deaths. It is the leading cause of cancer death among both men and women. The American Cancer Society estimates that over 221,200 new cases of lung cancer will be diagnosed in the United States in 2015 and over 158,000 patients will die of the disease. 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. The discovery of rearrangements of the Anaplastic Lymphoma Kinase (ALK) gene in some patients with advanced NSCLC and adenocarcinoma histology, led to the development of agents such as XALKORI® (Crizotinib) and ZYKADIA® (Ceritinib), with promising results. It has become clear that appropriate, molecularly targeted therapy for tumors with a molecular abnormality, results in the best outcomes. According to the US Lung Cancer Mutation Consortium (LCMC), two thirds of patients with advanced adenocarcinoma of the lung, have a molecular driver abnormality. The most common oncogenic drivers in patients with advanced adenocarcinoma of the lung are, KRAS in 25%, EGFR in 21% and ALK in 8% as well as other mutations in BRAF, HER2, AKT1 and fusions involving RET and ROS oncogenes. These mutations are mutually exclusive and the presence of two simultaneous mutations, are rare.

The approval of ALECENSA®) was based on two multicenter, single arm, open label, clinical trials (Study 1 and 2) in which enrolled patients received ALECENSA® 600 mg twice daily. The primary end point was Objective Response Rate (ORR). Secondary end points included Duration of Response (DoR), Objective Response Rate in the Central Nervous System (CNS) in those with measurable lesions in the CNS, and CNS Duration of Response. In Study 1 (N=87), the ORR was 38% and the Duration of Response was 7.5 months. In Study 2 (N=138), the ORR was 44% and the Duration of Response was 11.2 months. In a pooled analysis of patients from both Study 1 and Study 2 with measurable CNS lesions, the CNS Objective Response Rate was 61% and the median CNS Duration of Response was 9.1 months. The most common grade 1-2 adverse events were fatigue, constipation, edema, myalgia, anemia and elevation in liver function tests. The most common but rare grade 3-4 adverse reaction was dyspnea. It should be noted that ZYKADIA® (Ceritinib) is already approved for a similar patient population. A global phase III trial comparing ALECENSA® with XALKORI® as first line treatment, is presently underway.

A phase II, open-label, multicenter study of the ALK inhibitor alectinib in an ALK+ non-small-cell lung cancer (NSCLC) U.S./Canadian population who had progressed on crizotinib (NP28761). Gandhi L, Shaw A, Gadgeel SM, et al. J Clin Oncol 33, 2015 (suppl; abstr 8019)

Alectinib in Crizotinib-Refractory ALK-Rearranged Non–Small-Cell Lung Cancer: A Phase II Global Study. Ou SI, Ahn JS, Petris LD, et al. Published online before print November 23, 2015, doi: 10.1200/JCO.2015.63.9443

FDA Approves Antidote PRAXBIND® to Reverse the Anticoagulant Effects of PRADAXA®

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SUMMARY: The FDA on October 16, 2015, granted accelerated approval to Idarucizumab (PRAXBIND®) for the treatment of patients treated with Dabigatran (PRADAXA®), when reversal of the anticoagulant effects of PRADAXA® is needed for emergency surgery/urgent procedures, or in life-threatening or uncontrolled bleeding. There are presently four New Oral Anticoagulants approved in the United States for the treatment of Venous ThromboEmbolism. They include PRADAXA® (Dabigatran), which is a direct thrombin inhibitor and XARELTO® (Rivaroxaban), ELIQUIS® (Apixaban), SAVAYSA® (Endoxaban), which are Factor Xa inhibitors. Compared to COUMADIN® (Warfarin), the New Oral Anticoagulants have a rapid onset of action, wider therapeutic window, shorter half-lives (7-14 hours in healthy individuals), no laboratory monitoring and fixed dosing schedule. The half life of these agents can however be prolonged in those with renal insufficiency. In several clinical studies, these New Oral Anticoagulants have been shown to reduce the rate of major bleeding by 28% and the rates of intracranial and fatal hemorrhage by 50%, when compared to COUMADIN®. Unlike bleeding caused by COUMADIN®, which can be reversed using Vitamin K or Fresh Frozen Plasma, there are no specific agents presently available, for reversing bleeding caused by the New Oral Anticoagulants or for stopping the anticoagulant effects of these drugs, in patients who need urgent surgical intervention.

To address this concern, the RE-VERSE AD study was conducted to evaluate the efficacy and safety of Idarucizumab, to reverse the anticoagulant effects of PRADAXA®, in patients who had serious bleeding (Group A) or required an urgent surgical procedure (Group B). PRAXBIND® (Idarucizumab) is a humanized monoclonal antibody fragment with high affinity for both free and thrombin-bound PRADAXA® and neutralizes the anticoagulant activity of PRADAXA®. In this prospective cohort study, results from the first 90 patients enrolled in the study were presented (Interim analysis). Group A included 51 patients and Group B included 39 patients and PRAXBIND® 5 grams IV was administered, to reverse the anticoagulant effects of PRADAXA®. The median age was 76 years and the median creatinine clearance was 58 ml/minute. The primary end point was the maximum percentage reversal of the anticoagulant effect of PRADAXA® within 4 hours after the administration of PRADAXA®, based on the dilute thrombin time or ecarin clotting time. An important secondary end point was the restoration of hemostasis. Among the patients with an elevated dilute thrombin time and ecarin clotting time at baseline, the median maximum percentage reversal was 100% and this benefit was seen within minutes after the first infusion with PRAXBIND®. The median time to restoration of hemostasis in Group A was 11.4 hours. In Group B, normal intraoperative hemostasis was reported in more than 90% of the patients who underwent procedures after the administration of PRAXBIND®.

The authors concluded that PRAXBIND® was, within minutes, able to completely reverse the anticoagulant effect of PRADAXA®. This reversal agent will fulfill an unmet need and with the availability soon of Factor Xa inhibitor antidotes, it is anticipated that Health Care Providers will be more willing to replace COUMADIN® with the Newer Oral Anticoagulants. Idarucizumab for Dabigatran Reversal. Pollack CV, Reilly PA, Eikelboom J, et al. N Engl J Med 2015; 373:511-520

FDA Approves COTELLIC® in Combination with ZELBORAF® for Advanced Melanoma

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SUMMARY: The U.S. FDA on November 10, 2015, approved COTELLIC® (Cobimetinib) for the treatment of patients with unresectable or metastatic melanoma, with a BRAF V600E or V600K mutation, in combination with ZELBORAF® (Vemurafenib). The American Cancer Society estimates that for 2015, approximately 74,000 new melanomas will be diagnosed in the United States and about 10,000 people are expected to die of the disease. 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. The most common BRAF mutation in melanoma is at the V600E/K site and is detected in approximately 50% of melanomas. In the BRIM 3 randomized, phase III study, ZELBORAF® (Vemurafenib), a selective oral inhibitor of mutated BRAF demonstrated significant improvement in Progression Free Survival and Overall Survival compared to Dacarbazine. Squamous cell carcinoma’s were seen in about 6% of the patients treated with BRAF inhibitors. Paradoxical activation of the MAPK pathway in cells without a BRAF mutation has been implicated in the emergence of drug resistance and increased incidence of BRAF-inhibitor induced skin tumors. MEK gene is downstream from RAF in the MAPK pathway. The addition of a selective inhibitor of MEK gene such as COTELLIC® (Cobimetinib) to a BRAF inhibitor such as ZELBORAF®, has addressed some of these limitations, in previously published studies, with improvement in Objective Response rates and decrease in the incidence of cutaneous secondary cancers.

coBRIM is an international, multicenter, randomized, phase III study in which the efficacy and safety of COTELLIC® combined with ZELBORAF®, was evaluated in previously untreated patients, with advanced BRAF-mutated melanoma. Four hundred and ninety five (N=495) patients were randomly assigned in a 1:1 ratio to receive ZELBORAF® 960 mg orally twice daily along with either COTELLIC® 60 mg orally once daily on days 1-21 (N=247) or matching placebo (N=248), of a 28 day cycle. BRAF V600 mutation-positive status was detected using the cobas 4800 BRAF V600 mutation test. The median age of the study group was 55 years and patient demographics in both treatment groups were well balanced. About 60% of the patients, had stage IV disease. The primary endpoint for the study was Progression Free Survival (PFS) and secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR), and duration of response.

The primary analysis published in NEJM demonstrated a significant improvement in the median PFS (9.9 months vs 6.2 months) as well as ORR (68% vs 45%) with the combination of ZELBORAF® and COTELLIC® compared to ZELBORAF® and placebo respectively. In this updated analysis submitted to the FDA, the median PFS with the combination of ZELBORAF® and COTELLIC® was 12.3 versus 7.2 months for ZELBORAF® alone (HR= 0.56; P <0.001). There was also a statistically significant improvement in OS based on an interim analysis, with the median OS not reached (NR) in the combination group versus 17 months in the single agent ZELBORAF® group (HR=0.63; P=0.0019). The ORR were 70% and 50% in the ZELBORAF® and COTELLIC® and single agent ZELBORAF® groups, respectively (P<0.001).

The most common adverse reactions were diarrhea, photosensitivity reaction, nausea, pyrexia and vomiting. Treatment-related discontinuation rates in the combination and single agent groups were similar at 13% and 12%, respectively. It was concluded that in patients with unresectable or metastatic melanoma, with a BRAF V600E or V600K mutation, a combination of COTELLIC® and ZELBORAF® delays disease progression and improves survival compared to single agent ZELBORAF®. Update of progression-free survival (PFS) and correlative biomarker analysis from coBRIM: Phase III study of cobimetinib (cobi) plus vemurafenib (vem) in advanced BRAF-mutated melanoma. Larkin JMG, Yan Y, McArthur GA, et al. J Clin Oncol. 2015;33 (suppl; abstr 9006).

The 2015 ASH CHOOSING WISELY® Campaign Five Hematologic Tests and Treatments to Question

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SUMMARY: CHOOSING WISELY® is a quality improvement initiative led by the American Board of Internal Medicine Foundation in collaboration with leading medical societies in the United States such as the American Society of Hematology (ASH). This organization was established to improve quality of medical care, after it was noted that about 25% of the tests ordered at the time of hospital admission and 65% of the tests ordered on subsequent days were avoidable. Further, there is ample evidence to suggest that, reducing unneeded investigations can decrease costs, increase patient satisfaction and quality of care. CHOOSING WISELY® has challenged 70 medical societies to identify 5 tests, procedures or treatments, within each specialty’s clinical domain, that are offered to patients, despite the lack of evidence demonstrating its benefit. The goal is to make positive changes in the actual delivery of patient care without harming the patient. The ASH CHOOSING WISELY® Task Force comprised of 13 individuals, represents a broad spectrum of hematologic expertise including malignant, benign, adult, and pediatric specialists. The five final recommendations of the 2015 ASH Choosing Wisely Campaign is an addition to the 10 prior recommendations made by ASH over the past 2 years. These top 5 recommendations were presented on December 7, 2015, at the 57th annual meeting of ASH, in Orlando, Florida. Practicing hematologists should give due consideration to these recommendations which are evidence based and cost effective.

Don’t image for suspected Pulmonary Embolism (PE) without moderate or high pre-test probability of PE

The American College of Radiology has recommended that assessment of the risk-benefit ratio is important especially with pulmonary embolism and imaging can be avoided for suspected PE, without moderate to high pre-test probability.

Don’t routinely order thrombophilia testing on patients undergoing a routine infertility evaluation

With Nearly 15% couples of patients receiving an infertility evaluation, the American Society for Reproductive Medicine has recommended that even though several population-based studies have found association of infertility or failure of assisted reproduction with thrombophilia, 2 large cohort studies have shown no association between thrombophilias such as Factor V Leiden or Prothrombin gene mutations and assisted reproduction failure or infertility. Further, thrombophilia is not a predictor of who will benefit from Low Molecular Weight Heparin (LMWH) treatment with respect to assisted reproduction and LMWH can be associated with adverse events.

Don’t perform repetitive Complete Blood Count (CBC) and chemistry testing in the face of clinical and lab stability

The Society for Hospital Medicine and Adult Hospital Medicine noted that ordering routine complete blood counts (CBCs) during hospitalization is common practice and is unnecessary. Critically ill patients do not have the bone marrow reserve or erythropoietin stimulus to compensate for iatrogenic blood loss. Reducing the frequency of CBC’s does not result in inferior outcomes and several studies have shown that there is no difference in readmission rates, length of hospital stay and rates of adverse events. In addition to the risks of phlebotomy, this practice is economically disadvantageous, as they may not be reimbursable and will be an additional avoidable cost to dispose the biohazard waste of the blood samples.

Don’t transfuse red blood cells for iron deficiency without hemodynamic instability

The American Association of Blood Banks has recommended against PRBC transfusions for patients with hemodynamically stable iron deficiency anemia. These patients when evaluated in the Emergency Department (ED) can be prescribed oral or IV iron with similar responses noted at 6-8 weeks. The compliance rate in those receiving oral iron may only be 50% due to GI side effects. Therefore parenteral iron may be a better treatment option for certain groups of patients seen in the ED.

Avoid using positron emission tomography (PET) or PET-CT scanning as part of routine follow-up care to monitor for a cancer recurrence in asymptomatic patients who have finished initial treatment to eliminate the cancer unless there is high-level evidence that such imaging will change the outcome

Professional organizations like ASCO, ESMO and NCCN do not include surveillance PET in disease-specific guidelines because, routine use of intensive surveillance does not improve survival or enhance quality of life. Besides cost implications, CT scans may in fact expose patients to small doses of radiation.

The ASH Choosing Wisely® Campaign: Top 5 Non-ASH Choosing Wisely® Recommendations of Relevance to Hematology. Presented on December 7, 2015, at the 57th annual meeting of ASH, in Orlando, Florida.

Addition of Radiation Therapy to Androgen-Deprivation Therapy Also Benefits Elderly Patients with Locally Advanced Prostate Cancer

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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 220,800 new cases of prostate cancer will be diagnosed in 2015 and over 27,000 men will die of the disease. The development and progression of prostate cancer is driven by Androgens. 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. Prostate cancer in general is a disease of the elderly and is a leading cause of cancer mortality in men, second only to lung cancer. Elderly patients however are often under-represented in clinical trials. This is in spite of data published in previous studies showing that an average 75 yr old male in the United States has an additional life expectancy of 11 years. Further in clinical practice, elderly patients are less likely to receive either Surgery or Radiation Therapy (RT) and this is also true in men with high risk prostate cancer. This mind set has been further reinforced by recent recommendations against PSA screening and role of close surveillance for patients with low risk prostate cancer.

It is generally perceived that clinically localized prostate cancer is an indolent tumor. Patients with clinically localized prostate cancer can present with either locally advanced prostate cancer or prostate cancer detected by PSA screening. Patients with locally advanced disease have clinical stage T3 disease with tumor extending beyond the confines of the prostate gland. The 10 yr mortality in this patient group is as high as 25%. Patients with PSA screening-detected prostate cancer may have earlier stage disease with a much better prognosis. However, in this subgroup, those with poorly differentiated or undifferentiated clinical stage T1c tumors, with a Gleason score of 8-10, have a significantly higher mortality rate. It is now well established that the addition of Radiation Therapy (RT) to Androgen Deprivation Therapy (ADT) improves Overall Survival compared to ADT alone, in patients with locally advanced prostate cancer. However, these studies did not include patients over 75 years of age or those with PSA screen detected high risk prostate cancer.

With this age-biased background, the authors conducted a non-randomized observational study to assess, whether the survival advantage of ADT plus RT over ADT alone, reported in clinical trials, could be replicated in real world clinical practice, to two subgroups of patients poorly represented in the clinical trials such as, men older than 75 years, with locally advanced prostate cancer and men age 65 years or older, with PSA screen detected high risk prostate cancer. Utilizing the SEER-Medicare data set, the authors reviewed the effectiveness of ADT plus RT compared to ADT alone in three groups of patients diagnosed with localized prostate cancer between 1995 and 2007 and observed through 2009. These three groups included 1) The Randomized Clinical Trial (RCT) cohort, which included men age 65 to 75 years, a profile consistent with participants in the randomized trials 2) The elderly cohort, which included men over 75 years of age, with locally advanced prostate cancer 3) PSA screen-detected cohort, which included men 65 years or older with PSA screen-detected high risk prostate cancer. The cause-specific and all-cause mortality was determined in these patient groups.

It was noted that in the RCT cohort, ADT plus RT was associated with reduced cause-specific and all-cause mortality compared to ADT alone and these finding were not significantly different from published randomized trials data. Interestingly, similar Overall Survival benefit was noted in the elderly and PSA screen-detected cohorts, with ADT plus RT. The authors in this thought provoking study concluded that older men with locally advanced or PSA screen-detected high-risk prostate cancer should also be offered ADT plus Radiation Therapy, as this therapeutic modality can improve Overall Survival. Effectiveness of Androgen-Deprivation Therapy and Radiotherapy for Older Men with Locally Advanced Prostate Cancer. Bekelman JE, Mitra N, Handorf EA, et al. J Clin Oncol 2015;33:716-722

FDA Approves PORTRAZZA® for Metastatic Squamous Non-Small Cell Lung Cancer

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SUMMARY: The FDA on November 24, 2015, granted approval to Necitumumab (PORTRAZZA®) in combination with GEMZAR® (Gemcitabine) and Cisplatin for the first line treatment of patients with metastatic Squamous Non Small Cell Lung Cancer (NSCLC). Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 27% of all cancer deaths. It is the leading cause of cancer death among both men and women. The American Cancer Society estimates that over 221,200 new cases of lung cancer will be diagnosed in the United States in 2015 and over 158,000 patients will die of the disease. 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), 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large cell carcinomas.

Epidermal Growth Factor Receptor (EGFR) a Receptor Tyrosine Kinase (RTK) has been long known to control malignant cell proliferation, growth, survival, metabolism and migration. Therefore targeting EGFR with monoclonal antibodies has proven to be an effective strategy for the treatment of cancer. The two EGFR targeted monoclonal antibodies that have been available in the US include ERBITUX® (Cetuximab-chimeric IgG1) and VECTIBIX® (Panitumumab-human IgG2). PORTRAZZA® is a human IgG1 monoclonal antibody which also binds to the human Epidermal Growth Factor Receptor and blocks the binding of EGFR to its ligands.

The approval of PORTRAZZA® was based on the results of an open label, multicenter, multinational, phase III trial in which treatment naïve patients with metastatic Squamous NSCLC (N=1093) were randomized to receive PORTRAZZA® in combination with GEMZAR® (Gemcitabine) and Cisplatin (N=545) or GEMZAR® and Cisplatin alone (N=548). Treatment consisted of either PORTRAZZA® 800 mg IV days 1 and 8, GEMZAR® 1250 mg /m2 IV on days 1 and 8 along with Cisplatin 75mg/m2 IV on day 1 of each of a 21 day cycle or GEMZAR® and Cisplatin alone. Both treatment groups were well balanced and median age of patients was 62 years. The primary endpoint was Overall Survival and secondary endpoints included Progression Free Survival (PFS) and Overall Response Rate (ORR).

At a median follow up of 25 months, the median OS was 11.5 months in the PORTRAZZA® group and 9.9 months in the chemotherapy alone control group (HR = 0.84; P=0.01). The median PFS was 5.7 months in the PORTRAZZA® group and 5.5 months in the control group (HR=0.85; P=0.02). There was no difference in ORR noted in the two treatment groups (31% vs 29%). More patients in the PORTRAZZA® group experienced skin rash and hypomagnesemia and patients will therefore require close monitoring of serum electrolytes.

The authors concluded that the addition of PORTRAZZA® to GEMZAR® and Cisplatin chemotherapy significantly improves Overall Survival in patients with advanced Squamous NSCLC and represents a new first line treatment option for this malignancy. Because of the lack of benefit, PORTRAZZA® is not indicated for the treatment of non-Squamous NSCLC. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Thatcher N, Hirsch FR, Luft AV, et al. Lancet Oncol. 2015;16:763-774

YERVOY® (Ipilimumab)

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The FDA on October 28, 2015 approved YERVOY® injection for the additional indication of adjuvant treatment of patients with Cutaneous Melanoma, with pathologic involvement of regional lymph nodes of more than 1 mm, who have undergone complete resection, including total lymphadenectomy. YERVOY® is a product of Bristol-Myers Squibb Company.

YONDELIS® (Trabectedin)

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The FDA on October 23, 2015 approved YONDELIS®) for the treatment of patients with unresectable or metastatic Liposarcoma or Leiomyosarcoma who have received a prior Anthracycline-containing regimen. YONDELIS® injection is a product of Janssen Biotech, Inc.

ONIVYDE® (Irinotecan liposome injection)

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The FDA on October 22, 2015 approved ONIVYDE® injection, administered in combination with Fluorouracil (5-FU) and Leucovorin, for the treatment of patients with metastatic Adenocarcinoma of the Pancreas, whose disease has progressed following Gemcitabine-based therapy. ONIVYDE® injection is a product of Merrimack Pharmaceuticals, Inc

PRAXBIND® (Idarucizumab)

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The FDA on October 16, 2015 granted accelerated approval to PRAXBIND® for the treatment of patients treated with PRADAXA® (Dabigatran), when reversal of the anticoagulant effects of PRADAXA® is needed for emergency surgery/urgent procedures, or in life-threatening or uncontrolled bleeding. PRAXBIND® injection is a product of Boehringer Ingelheim Pharmaceuticals, Inc.