Tag: General Medical Oncology & Hematology

SUMMARY: The FDA on November 30, 2017, granted marketing approval to FoundationOne CDx (F1CDx), a Next Generation Sequencing (NGS) based, in vitro diagnostic (IVD) assay, to detect genetic mutations in 324 genes and two genomic signatures, in any solid tumor type. The test can also identify which patients with Non Small Cell Lung Cancer (NSCLC), Melanoma, Breast cancer, ColoRectal cancer, or Ovarian cancer may benefit from 15 different FDA-approved targeted treatment options.

The basic premise of cancer genomics is that cancer is caused by somatically acquired mutations, and is therefore a disease of the genome. Tumor genomic profiling enables the identification of specific genomic alterations and thereby can provide personalized treatment options with targeted therapies that are specific for those molecular targets. A genomic test can be performed on a tumor specimen or on cell-free DNA in plasma (“liquid biopsy”) or an ImmunoHistoChemistry (IHC) test can be performed on tumor tissue for protein expression that demonstrates a genomic variant known to be a drug target, or to predict sensitivity to a chemotherapeutic drug.

Next-Generation Sequencing (NGS) platforms or second-generation sequencing, unlike the first-generation sequencing, known as Sanger sequencing, perform massively parallel sequencing, which allows sequencing of millions of fragments of DNA from a single sample. With this high-throughput sequencing, the entire genome can be sequenced in less than 24 hours. This is in contrast to Sanger sequencing technology which has required over a decade to decipher the human genome. There are a number of different NGS platforms using different sequencing technologies and NGS can be used to sequence and systematically study the cancer genomes in their entirety or specific areas of interest in the genome or small numbers of individual genes. Recently reported genomic profiling studies, performed in patients with advanced cancer suggest that actionable mutations are found in 20-40% of patients’ tumors.

The application for F1CDx , was reviewed by the FDA using a coordinated, cross-agency approach and clinical performance of the test was established by comparing F1CDx to previously FDA-approved companion diagnostic tests, that are currently used to determine patient eligibility for certain treatments. It was noted that F1CDx assay’s ability to detect select mutation types (substitutions and short insertions and deletions) representative of the entire 324 gene panel was accurate approximately 94.6% of the time. This 324 gene panel included EGFR, KRAS, BRAF, BRCA1/2, ALK, and several other genes with emerging therapies, such as NTRK1/2/3. This assay can additionally detect MicroSatellite Instability (MSI) and Tumor Mutational Burden, which can predict response to immunotherapy.

The FDA noted that this is the first device with the FDA’s “Breakthrough Device” designation to complete the PreMarket Approval (PMA) process, and it is the second IVD authorized under the FDA and Centers for Medicare & Medicaid Services’ (CMS) Parallel Review program. Under this program, the CMS issued a proposed national coverage determination of the F1CDx for Medicare beneficiaries with recurrent, metastatic, or advanced Stage IV cancer, who have not been previously tested using NGS technology, and who continue to remain candidates for further therapy. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm587387.htm

Alcohol consumption is an established risk factor for several malignancies, and is a potentially modifiable risk factor for cancer. The International Agency for Research on Cancer (IARC), a branch of WHO, classified alcohol as a group 1 carcinogen. The American Heart Association, American Cancer Society, and US Department of Health and Human Services all recommend that men limit intake to one to two drinks per day and women to one drink per day. People who do not currently drink alcohol should not start for any reason. There is a clear association between alcohol and upper aerodigestive tract cancers (larynx, esophagus, and oral cavity/pharynx). A recent meta-analysis of cohort studies among 209,597 cancer survivors showed an 8% increase in overall mortality and a 17% increased risk for recurrence in the highest versus lowest alcohol consumers. The benefit of alcohol consumption on cardiovascular health likely has been overstated and the net effect of alcohol is harmful. Alcohol consumption should therefore not be recommended to prevent cardiovascular disease or all-cause mortality.

SUMMARY: It has been estimated that in the United States, 3-4% of all cancer deaths are attributable to drinking alcohol. According to the Centers for Disease Control and Prevention, approximately 88,000 deaths were attributed to excessive alcohol use in the United States between 2006 and 2010. Alcohol consumption is an established risk factor for several malignancies, and is a potentially modifiable risk factor for cancer. The International Agency for Research on Cancer (IARC), a branch of WHO, classified alcohol as a group 1 carcinogen. The Cancer Prevention Committee of the American Society of Clinical Oncology has now provided an overview of the evidence of the links between alcohol drinking and cancer risk and cancer outcomes.

DRINKING GUIDELINES AND DEFINITIONS

The American Heart Association, American Cancer Society, and US Department of Health and Human Services all recommend that men limit intake to one to two drinks per day and women to one drink per day. People who do not currently drink alcohol should not start for any reason. A standard drink is defined as one that contains roughly 14 g of pure alcohol, which is the equivalent of 1.5 ounces of distilled spirits, 5 ounces of wine or 12 ounces of regular beer. Moderate drinking is defined at up to one drink per day for women and up to 2 drinks per day for men whereas heavy drinking is defined as 8 or more drinks per week or 3 or more drinks per day for women, and as many as 15 or more drinks per week or 4 or more drinks per day for men. Hispanics and blacks have a higher risk than whites, for developing alcohol-related liver disease. Use of alcohol during childhood and adolescence is a predictor of increased risk of alcohol related disorders later in life.

ROLE OF ALCOHOL IN CARCINOGENESIS

Alcohol is predominantly metabolized in the liver to acetaldehyde, which is a carcinogen and is responsible for many “hangover” symptoms. Acetaldehyde is then converted into harmless acetic acid radicals also known as acetyl radicals, and eliminated from the body. There is strong evidence to suggest that acetaldehyde damages DNA. Acetaldehyde generated during alcohol metabolism in the human body is eliminated by Aldehyde Dehydrogenase-2 (ALDH2). However, a genetic variant of ALDH2, which is an inactive form, exists and individuals with the inactive form of ALDH2 who consume alcohol, accumulate excessive amounts of acetaldehyde, which in turn can lead to greater susceptibility to alcohol-induced cancer. It has been noted that this high-risk genotype in prevalent in about 50% of North East Asian population and in 5–10% of blond-haired blue-eyed people of Northern European descent. Alcohol consumption in this group is more strongly associated with cancers of the upper aerodigestive tract. Breast tissue is also more susceptible to alcohol than other sites. Even moderate alcohol intake has been associated with increased levels of circulating sex hormones, which in turn can activate cellular proliferation. Alcohol consumption is associated with lower serum folate concentrations and this may play a role in the etiology of colon cancer.

ALCOHOL AND CANCER

There is a clear association between alcohol and upper aerodigestive tract cancers (larynx, esophagus, and oral cavity/pharynx), as a result of direct contact of ingested alcohol with the involved tissues.

Continued alcohol use among survivors of upper aerodigestive tract cancers is associated with a 3 fold increase in the risk of a second primary tumor in the upper aerodigestive tract. Additionally, there is a synergistic interaction between alcohol consumption and cigarette smoking. Smoking and alcohol use during and after radiation therapy have been associated with an increased risk of osteoradionecrosis of the jaw, in patients with oral and oropharyngeal cancers.

Among women with Estrogen Receptor-positive breast cancer, those consuming 7 or more drinks per week have a 90% increased risk of asynchronous contralateral breast cancer, versus those who do not consume alcohol. It is estimated that there is a 5% increase in premenopausal breast cancer per 10 grams of ethanol consumed per day and the risk is even greater at 9%, for postmenopausal breast cancer.

A recent meta-analysis of cohort studies among 209,597 cancer survivors showed an 8% increase in overall mortality and a 17% increased risk for recurrence in the highest versus lowest alcohol consumers and these numbers were statistically significant.

The benefit of alcohol consumption on cardiovascular health likely has been overstated and nondrinkers have lower rates of coronary heart disease and stroke than even light drinkers. Given the increase in the risk of cancer even with low levels of alcohol consumption, the net effect of alcohol is harmful. Alcohol consumption should therefore not be recommended to prevent cardiovascular disease or all-cause mortality.

In conclusion, alcohol is a well-established risk factor for the development of certain cancers and further research is needed to understand the effects of alcohol exposure on the efficacy of chemotherapy, immunotherapy and radiation treatment. Alcohol and Cancer: A Statement of the American Society of Clinical Oncology. LoConte NK, Brewster AM, Kaur JS, et al. DOI: 10.1200/JCO.2017.76.1155 Journal of Clinical Oncology – published online before print November 7, 2017

SUMMARY: The FDA on Sept. 14, 2017 approved MVASI® (Bevacizumab-awwb) as a Biosimilar to AVASTIN® (Bevacizumab). Bevacizumab is a recombinant immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that binds to Vascular Endothelial Growth Factor (VEGF) and inhibits the interaction of VEGF with its receptors, VEGF receptor-1 and VEGF receptor-2. This in turn inhibits establishment of new blood vessels that are essential for the maintenance and growth of solid tumors. MVASI® is the first Biosimilar approved in the U.S. for the treatment of cancer. A Biosimilar product is a biological product that is approved based on its high similarity to an already approved biological product (also known as reference product). Biological products are made from living organisms including humans, animals and microorganisms such as bacteria or yeast, and are manufactured through biotechnology, derived from natural sources or produced synthetically. Biological products have larger molecules with a complex structure, than conventional drugs (also known as small molecule drugs).

Unlike biological products, conventional drugs are made of pure chemical substances and their structures can be identified. A generic drug is a copy of brand name drug and has the same active ingredient and is the same as brand name drug in dosage form, safety and strength, route of administration, quality, performance characteristics and intended use. Therefore, brand name and the generic drugs are bioequivalent. The Affordable Care Act in 2010 created an abbreviated licensure pathway for biological products that are demonstrated to be “Biosimilar” to, or “interchangeable” with an FDA approved biological product (reference product). The Biosimilar must show that it has no clinically meaningful differences in terms of safety and effectiveness from the reference product. A Biosimilar product can only be approved by the FDA if it has the same mechanism of action, route of administration, dosage form and strength as the reference product, and only for the indications and conditions of use that have been approved for the reference product. Biosimilars are not as easy to manufacture as generics (copies of brand name drugs), because of the complexity of the structure of the biologic product and the process used to make a biologic product. The facilities where Biosimilars are manufactured must also meet the FDA standards.

MVASI® is approved for the treatment of patients with the following cancers:

• Metastatic Colorectal cancer, in combination with intravenous 5-Fluorouracil-based chemotherapy for first or second line treatment. MVASI® is not indicated for the adjuvant treatment of surgically resected Colorectal cancer.

• Metastatic Colorectal cancer, in combination with Fluoropyrimidine-Irinotecan or Fluoropyrmidine-Oxaliplatin-based chemotherapy for the second line treatment of patients who have progressed on a first-line Bevacizumab containing regimen.

• Non-squamous Non Small Cell Lung Cancer, in combination with Carboplatin and Paclitaxel for first line treatment of unresectable, locally advanced, recurrent or metastatic disease.

• Glioblastoma with progressive disease following prior therapy, based on improvement in Objective Response Rate. No data is available demonstrating improvement in disease-related symptoms or survival with Bevacizumab.

• Metastatic Renal cell carcinoma, in combination with Interferon alfa.

• Cervical cancer that is persistent, recurrent, or metastatic disease, in combination with Paclitaxel and Cisplatin or Paclitaxel and Topotecan.

The approval of MVASI® was based on two studies. In the first study, PharmacoKinetics (PK) of biosimilar MVASI® was compared with Bevacizumab, following a single infusion of 3 mg/kg. It was concluded that the PK data was similar between the Biosimilar, MVASI® and Bevacizumab. The second study is a randomized, double-blind, phase III trial, that evaluated the efficacy and safety of MVASI®, compared with Bevacizumab, in patients with non-squamous Non Small Cell Lung Cancer (NSCLC). Patients with non-squamous NSCLC, on first line chemotherapy with Carboplatin and TAXOL® (Paclitaxel), were randomized in a 1:1 ratio to receive either MVASI® (N=328) or Bevacizumab 15 mg/kg (N=314), as an IV infusion, every 3 weeks, for 6 cycles. The Objective Response Rate (ORR) was similar between the two treatment groups (39.0% for MVASI® and 41.7% for Bevacizumab) and these results were not statistically different. The Duration of Response was similar. Adverse events were comparable in the two treatment groups. This study demonstrated that MVASI® was clinically similar to Bevacizumab.

The FDA concluded that the approval of MVASI® was based on comparisons of extensive structural and functional product characterization, animal data, human PharmacoKinetic and pharmacodynamic data, clinical immunogenicity, between MVASI® and AVASTIN® (Bevacizumab), and it was noted that MVASI® is highly similar to AVASTIN® and that there are no clinically meaningful differences between the two products. Randomized, double-blind, phase 3 study evaluating efficacy and safety of ABP 215 compared with bevacizumab in patients with non-squamous NSCLC. Thatcher N, Thomas M, Paz-Ares L, et al. DOI: 10.1200/JCO.2016.34.15_suppl.9095 Journal of Clinical Oncology 34, no. 15_suppl (May 2016) 9095-9095.

SUMMARY: Chemotherapy Induced Nausea and Vomiting (CINV) is quite common and occurs in about 80% of patients receiving chemotherapy. The following (Part II) is a continuation of the ASCO Antiemetics Clinical Practice Guideline Update.

KEY RECOMMENDATIONS (ctd) – PART II

Adult Patients

Breakthrough nausea and vomiting

• (No change) For patients with breakthrough nausea or vomiting, clinicians should re-evaluate emetic risk, disease status, concurrent illnesses, and medications, and ascertain that the best regimen is being administered for the emetic risk.

• (Updated) Adult patients who experience nausea or vomiting despite optimal prophylaxis, and who did not receive Olanzapine prophylactically, should be offered Olanzapine in addition to continuing the standard antiemetic regimen.

• (Updated) Adult patients who experience nausea or vomiting despite optimal prophylaxis, and who have already received Olanzapine, may be offered a drug of a different class—for example, an NK1 receptor antagonist, Lorazepam or Alprazolam, a dopamine receptor antagonist, Dronabinol, or Nabilone—in addition to continuing the standard antiemetic regimen.

Anticipatory nausea and vomiting

• (Reworded for clarity) All patients should receive the most active antiemetic regimen that is appropriate for the antineoplastic agents being administered. Clinicians should use such regimens with initial antineoplastic treatment, rather than assessing the patient’s emetic response with less effective antiemetic treatment. If a patient experiences anticipatory emesis, clinicians may offer behavioral therapy with systematic desensitization.

KEY RECOMMENDATIONS

High emetic risk Radiation Therapy

• (Updated) Adult patients who are treated with high-emetic-risk radiation therapy should be offered a two-drug combination of a 5-HT3 receptor antagonist and Dexamethasone before each fraction and on the day after each fraction if Radiation Therapy is not planned for that day.

Moderate-emetic-risk radiation therapy

• (Reworded for clarity) Adult patients who are treated with moderate-emetic-risk Radiation Therapy should be offered a 5-HT3 receptor antagonist before each fraction, with or without Dexamethasone before the first five fractions. Low-emetic-risk radiation therapy

• (Updated) Adult patients who are treated with Radiation Therapy to the brain should be offered rescue Dexamethasone therapy. Patients who are treated with Radiation Therapy to the head and neck, thorax, or pelvis should be offered rescue therapy with a 5-HT3 receptor antagonist, Dexamethasone, or a Dopamine receptor antagonist.

Minimal-emetic-risk radiation therapy

• (Updated) Adult patients who are treated with minimal-emetic-risk radiation therapy should be offered rescue therapy with a 5-HT3 receptor antagonist, Dexamethasone, or a Dopamine receptor antagonist.

Concurrent radiation and antineoplastic agent therapy

• (Updated) Adult patients who are treated with concurrent radiation and antineoplastic agents should receive antiemetic therapy that is appropriate for the emetic risk level of antineoplastic agents, unless the risk level of the radiation therapy is higher. During periods when prophylactic antiemetic therapy for antineoplastic agents has ended and ongoing radiation therapy would normally be managed with its own prophylactic therapy, patients should receive prophylactic therapy that is appropriate for the emetic risk of the radiation therapy until the next period of antineoplastic therapy, rather than receiving rescue therapy for antineoplastic agents as needed.

Pediatric Patients

High-emetic-risk antineoplastic agents

• (Updated) Pediatric patients who are treated with high-emetic-risk antineoplastic agents should be offered a three-drug combination of a 5-HT3receptor antagonist, Dexamethasone, and Aprepitant.

• (New) Pediatric patients who are treated with high-emetic-risk antineoplastic agents who are unable to receive Aprepitant should be offered a two-drug combination of a 5-HT3 receptor antagonist and Dexamethasone.

• (New) Pediatric patients who are treated with high-emetic-risk antineoplastic agents who are unable to receive Dexamethasone should be offered a two-drug combination of Palonosetron and Aprepitant.

Moderate-emetic-risk antineoplastic agents

• (Reworded for clarity) Pediatric patients who are treated with moderate-emetic-risk antineoplastic agents should be offered a two-drug combination of a 5-HT3receptor antagonist and Dexamethasone.

• (New) Pediatric patients who are treated with moderate-emetic-risk antineoplastic agents who are unable to receive Dexamethasone should be offered a two-drug combination of a 5-HT3 receptor antagonist and Aprepitant.

Low-emetic-risk antineoplastic agents

• (New) Pediatric patients who are treated with low-emetic-risk antineoplastic agents should be offered Ondansetron or Granisetron.

Minimal emetic risk antineoplastic agents

• (New) Pediatric patients who are treated with minimal-emetic-risk antineoplastic agents should not be offered routine antiemetic prophylaxis.

Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. Hesketh PJ, Kris MG, Basch E, et al. DOI: 10.1200/JCO.2017.74.4789 Journal of Clinical Oncology – published online before print July 31, 2017