The FDA on December 20, 2017 granted regular approval to the anti-PD1 monoclonal antibody OPDIVO® for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or in patients with metastatic disease who have undergone complete resection. OPDIVO® was previously approved for the treatment of patients with unresectable or metastatic melanoma. OPDIVO® is a product of Bristol-Myers Squibb Company.
Author: RR
OGIVRI® (Trastuzumab-dkst)
The FDA on December 1, 2017 approved OGIVRI® as a Biosimilar to HERCEPTIN® (Trastuzumab, Genentech, Inc.) for the treatment of patients with HER2-overexpressing breast or metastatic stomach cancer (Gastric or GastroEsophageal junction adenocarcinoma). OGIVRI® is a product of Mylan N.V.
CABOMETYX® (Cabozantinib)
The FDA on December 19, 2017 granted regular approval to CABOMETYX® for treatment of patients with advanced Renal Cell Carcinoma (RCC). CABOMETYX® is a product of Exelixis, Inc.
BOSULIF® (Bosutinib)
The FDA on December 19, 2017 granted accelerated approval to BOSULIF® for treatment of patients with newly-diagnosed Chronic Phase (CP) Philadelphia chromosome positive (Ph+) Chronic Myelogenous Leukemia (CML). BOSULIF® is a product of Pfizer Inc.
Direct Oral Anticoagulant SAVAYSA® Noninferior to Subcutaneous FRAGMIN® for Cancer-Associated Venous Thromboembolism
SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke.
Approximately 20% of cancer patients develop VTE and the current recommendations are treatment with parenteral Low Molecular Weight Heparin (LMWH) preparations, based on efficacy data. This however can be inconvenient and expensive, leading to premature discontinuation of treatment. Direct Oral Anticoagulant agents have been proven to be as effective as Warfarin, a Vitamin K antagonist, for the treatment of VTE, and are associated with less frequent and less severe bleeding and fewer drug interactions. However, the efficacy and safety of Direct Oral Anticoagulants for the treatment of cancer-associated VTE have not been established.
SAVAYSA® (Edoxaban) an oral Factor Xa inhibitor was compared with subcutaneous Low Molecular Weight Heparin FRAGMIN® (Dalteparin), for the treatment of patients with cancer-associated VTE in the Hokusai VTE Cancer trial. This open-label, noninferiority trial randomized 1050 patients in a 1:1 ratio to receive either SAVAYSA® or FRAGMIN®. SAVAYSA® was given after an initial course of physician’s choice of Low Molecular Weight Heparin, given subcutaneously in therapeutic doses, for at least 5 days. SAVAYSA® was administered orally at a fixed dose of 60 mg once daily. FRAGMIN® was given subcutaneously at a dose of 200 IU/kg once daily for 30 days and at a dose of 150 IU/kg once daily thereafter. This treatment was continued for up to 12 months. The median age was 64 years and 90% of the patients had solid tumors and were on various chemotherapy regimens. The primary endpoint was a composite of recurrent VTE or major bleeding during the 12 months after randomization, regardless of treatment duration.
It was noted that SAVAYSA® was noninferior to FRAGMIN® with regards to composite rates of recurrent VTE and bleeding, which occurred in 12.8% of those receiving SAVAYSA® and 13.5% of those receiving FRAGMIN®. The similarity between the two treatment groups met statistical criteria for demonstrating noninferiority for SAVAYSA® (P=0.006). The rate of recurrent VTE was numerically lower with SAVAYSA® compared with FRAGMIN® (7.9% vs 11.3%, HR=0.71; P=0.09). The rate of major bleeding was however significantly higher with SAVAYSA® compared with FRAGMIN® (6.9% vs 4.0%, HR=1.77; P=0.04). This difference was mainly due to higher rate of upper gastrointestinal bleeding with SAVAYSA® in patients with gastrointestinal cancers. The frequency of severe major bleeding (category 3 or 4) however was similar in both treatment groups.
It was concluded that Direct Oral Anticoagulant, SAVAYSA® was noninferior to subcutaneous Low Molecular Weight Heparin, FRAGMIN® with respect to the composite outcome of recurrent Venous ThromboEmbolism or major bleeding. The lower rate of recurrent VTE observed with SAVAYSA® was offset by a similar increase in the risk of major bleeding. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. Raskob GE, Van Es N, Verhamme P, et al. for the Hokusai VTE Cancer Investigators. December 12, 2017DOI: 10.1056/NEJMoa1711948
Consolidation with IMFINZI® after Chemoradiotherapy Improves Outcomes in Patients with Unresectable Stage III Non-Small Cell Lung Cancer
SUMMARY: 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. The American Cancer Society estimates that for 2017 about 222,500 new cases of lung cancer will be diagnosed and over 155,000 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Approximately one third of all patients with NSCLC have stage III, locally advanced disease at the time of initial presentation. Worldwide, about 500,000 patients are diagnosed with unresectable, stage III NSCLC, each year. These patients include those with locally advanced primary tumors with tumor invading the vital mediastinal organs, as well as those with involvement of locoregional mediastinal lymph nodes. These patients are often treated with platinum-based doublet chemotherapy with concurrent radiation and have a median Progression Free Survival (PFS) of approximately 8 months and 5 year survival of only 15%. There is hence a significant unmet need for this patient group, with no major treatment advances thus far.
Preclinical evidence had suggested that chemotherapy and radiotherapy may upregulate PD-L1 expression in tumor cells. IMFINZI® (Durvalumab) is a selective, high-affinity, human IgG1 monoclonal antibody, that blocks the binding of Programmed Death Ligand 1 (PD-L1) to Programmed Death 1 (PD-1) and CD80, thereby unleashing the T cells to recognize and kill tumor cells. IMFINZI® showed encouraging antitumor activity in an early phase clinical study involving multiple advanced solid tumors, including stage IIIB or IV NSCLC. IMFINZI® was recently approved by the FDA for the treatment of patients with locally advanced or metastatic urothelial carcinoma, who had received prior platinum-based chemotherapy.
The authors in this publication evaluated the role of immune checkpoint blockade in locally advanced, unresectable, stage III NSCLC. PACIFIC trial is a randomized, double-blind, international, phase III study in which IMFINZI® as consolidation therapy was compared with placebo, in patients with stage III, locally advanced, unresectable NSCLC, that had not progressed following platinum-based chemoradiotherapy. Eligible patients received two or more cycles of platinum-based doublet chemotherapy concurrently with definitive radiation therapy (54-66 Gy). Following completion of concurrent chemoradiation treatment, 713 patients were randomized, of whom 709 patients in a 2:1 ratio received consolidation treatment, within 6 weeks after completion of chemoradiation with IMFINZI® 10 mg/kg every 2 weeks (N=473) or placebo (N=236), for up to 12 months. The median age was 64 years, and the majority of patients were men (70%) and 46% had a squamous histology. The coprimary end points were Progression Free Survival (PFS) and Overall Survival (OS). Secondary end points included 12-month and 18-month PFS rates, Objective Response Rate (ORR), Duration of Response, time to death or distant metastasis, and safety. The authors reported the results of a preplanned interim analysis after a median follow up of 14.5 months.
The median PFS from randomization to consolidation treatment was 16.8 months with IMFINZI® versus 5.6 months with placebo (HR=0.52; P<0.001). This meant a 48% decrease in the probability of disease progression with IMFINZI® and this improvement was consistent across all patient subgroups that were analyzed. The 12-month PFS was 55.9% vs 35.3%, and the 18-month PFS rate was 44.2% vs 27.0%, in favor of IMFINZI®. The ORR was higher with IMFINZI® compared to placebo (28.4% vs 16.0%; P<0.001), and the median Duration of Response was longer as well, with 73% of the patients in the IMFINZI® group having an ongoing response at 18 months versus 47% of the patients in the placebo group. Patients in the IMFINZI® group also had a lower incidence of new brain metastases. The median time to death or distant metastasis was longer with IMFINZI® compared with placebo (23.2 months vs 14.6 months; P<0.001). Adverse events of any grade occurred in 68% of patients in the IMFINZI® group compared to 53% in the placebo group and majority of the toxicities were grade 1 or 2, and grade 3 or higher toxicities were infrequent (less than10%), in both treatment groups. Treatment had to be discontinued due to pneumonitis in 6.3% of patients on IMFINZI® and 4.3% on placebo.
It was concluded that IMFINZI® significantly prolonged PFS in all prespecified groups of patients with locally advanced stage III NSCLC, and toxicity profile was acceptable. Biomarkers, such as mutational load or immunosignature, may be of value, as PD-L1 expression had little or no impact on outcomes. The National Comprehensive Cancer Network (NCCN) Guidelines have been updated to include one year of consolidation therapy with IMFINZI®, after curative-intent chemoradiation, for inoperable stage III lung cancer. Durvalumab after Chemoradiotherapy in Stage III Non-Small Cell Lung Cancer. Antonia SJ, Villegas A, Daniel D, et al. for the PACIFIC Investigators. N Engl J Med 2017; 377:1919-1929
FoundationOne CDx (F1CDx)
The FDA on November 30, 2017, granted marketing approval to the FoundationOne CDx, a Next Generation Sequencing (NGS) based in vitro diagnostic (IVD) 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. This test is offered by Foundation Medicine, Inc.
Platelet Transfusion for Patients with Cancer American Society of Clinical Oncology Clinical Practice Guideline Update
SUMMARY: The ASCO convened an Expert Panel and updated evidence-based guidance on the use of platelet transfusion in patients with cancer. This guideline updates is based on a systematic review of the medical literature published from September 1, 2014, through October 26, 2016 and this review builds on two 2015 systematic reviews that were conducted by the AABB and the International Collaboration for Transfusion Medicine Guidelines. This ASCO guideline replaces the previous ASCO platelet transfusion guideline published initially in 2001. The updated ASCO review included 24 more recent publications which included 3 clinical practice guidelines, 8 systematic reviews, and 13 observational studies.
Target Population: Adults and children (4 months of age or older) with hematologic malignancies, solid tumors, or hypoproliferative thrombocytopenia.
Target Audience: Clinician’s administering intensive therapies to patients with cancer.
Clinical Questions and Recommendations:
(1) How should platelets for transfusion be prepared?
Platelets can be prepared either by separation of units of platelet concentrates from whole blood using either the buffy coat or the platelet-rich plasma method, which can then be pooled before administration, or by apheresis from single donors. Studies have shown that the post-transfusion increments, hemostatic benefit, and adverse effects are similar with any of these platelet products and they can be used interchangeably. However, single-donor platelets from selected donors are necessary when histocompatible platelet transfusions are needed.
(2) In what circumstances should providers take steps to prevent Rh alloimmunization resulting from platelet transfusion?
Prevention of RhD alloimmunization resulting from platelet transfusions to RhD-negative recipients can be achieved either through the exclusive use of platelet products collected from RhD-negative donors or via anti-D immunoprophylaxis. These approaches may be used for female children and female adults of child-bearing potential being treated with curative intent. However, because of the low rate of RhD alloimmunization in patients with cancer, these approaches need not be applied universally.
(3) In what circumstances should providers use leukoreduced blood products to prevent alloimmunization?
Providing leukoreduced blood products to patients with Acute Myeloid Leukemia from the time of diagnosis is appropriate, as the incidence of alloantibody-mediated refractoriness to platelet transfusion can be decreased in patients receiving induction chemotherapy, when both platelet and RBC products are leukoreduced before transfusion. It is likely that alloimmunization can also be decreased in patients with other types of leukemia and in other patients with cancer who are receiving chemotherapy. The same holds true for patients with Aplastic Anemia, and Myelodysplasia not receiving chemotherapy, in the same time periods that the transfusions are being administered. In the United States and in several other countries, majority of blood products are leukoreduced at the time of blood collection and component preparation. Prestorage leukoreduction can result in a substantial reduction in transfusion reactions and in transmission of cytomegalovirus (CMV) infection
(4) Should platelet transfusions be given prophylactically or therapeutically?
Prophylactic platelet transfusion should be administered to patients with thrombocytopenia resulting from impaired bone marrow function to reduce the risk of hemorrhage, when the platelet count falls below a predefined threshold level. This threshold level for transfusion varies according to the patient’s diagnosis, clinical condition, and treatment modality.
(5) What is the appropriate threshold for prophylactic platelet transfusion in patients with hematologic malignancies?
The Panel recommends a threshold of less than 10×109/L for prophylactic platelet transfusion in patients receiving therapy for hematologic malignancies. Transfusion at higher levels may be advisable in patients with signs of hemorrhage, high fever, hyperleukocytosis, rapid fall of platelet count, or coagulation abnormalities (eg, acute promyelocytic leukemia) and in those undergoing invasive procedures or in circumstances in which platelet transfusions may not be readily available in case of emergencies, as might be the case for outpatients who live at a distance from the treatment center.
(6) What is the appropriate threshold for prophylactic platelet transfusion in the setting of Hematopoietic Stem Cell Transplantation (HSCT)?
The Panel recommends a threshold of less than 10×109/L for prophylactic platelet transfusion in adult and pediatric patients undergoing allogeneic HSCT. Prophylactic platelet transfusion may be administered at higher counts based on clinician judgment. In adult recipients of autologous HSCT, randomized trials have demonstrated similar rates of bleeding with decreased platelet usage when patients are transfused at the first sign of bleeding rather than prophylactically, and this approach may be used in experienced centers. This recommendation is not generalizable to pediatric patients.
(7) Is there a role for prophylactic platelet transfusion in patients with chronic, stable, severe thrombocytopenia who are not receiving active treatment?
Patients with chronic, stable, severe thrombocytopenia, such as individuals with Myelodysplasia or Aplastic Anemia, who are not receiving active treatment may be observed without prophylactic transfusion, reserving platelet transfusions for episodes of hemorrhage or during times of active treatment.
(8) What is the appropriate threshold for prophylactic platelet transfusion in patients with solid tumors?
The risk of bleeding in patients with solid tumors during chemotherapy-induced thrombocytopenia is related to the depth and duration of the platelet nadir, although other factors contribute as well. The Panel recommends a threshold of less than 10×109/L for prophylactic platelet transfusion. Platelet transfusion at higher levels is appropriate in patients with active localized bleeding, which can sometimes be seen in patients with necrotic tumors.
(9) At what platelet count can surgical or invasive procedures be performed?
The Panel recommends a threshold of 40×109/L to 50×109/L for performing major invasive procedures in the absence of associated coagulation abnormalities. Certain procedures, such as bone marrow aspirations and biopsies, and insertion or removal of central venous catheters, can be performed safely at counts 20×109/L or more. If platelet transfusions are administered before a procedure, it is critical that a post-transfusion platelet count be obtained to prove that the desired platelet count level has been reached. Platelet transfusions should also be available on short notice, in case intraoperative or postoperative bleeding occurs. For alloimmunized patients, histocompatible platelets must be available in these circumstances.
(10) When and how should patients be monitored for refractoriness to platelet transfusion?
The Panel recommends that when refractoriness is suspected, platelet counts should be performed 10-60 minutes after transfusion. Because patients may have a poor increment to a single transfusion and yet have excellent platelet increments with subsequent transfusions, a diagnosis of refractoriness to platelet transfusion should only be made when at least two transfusions of ABO-compatible units, stored for less than 72 hours, result in poor increments (less than 5000/microliter).
(11) How should refractoriness to platelet transfusion be managed?
Alloimmunization is usually due to antibody against HLA antigens and only rarely to platelet-specific antigens. Patients with alloimmune-refractory thrombocytopenia, as defined previously, are best managed with platelet transfusions from histocompatible donors matched for HLA-A and HLA-B antigens. For patients( 1) whose HLA type cannot be determined, (2) who have uncommon HLA types for whom suitable donors cannot be identified, or (3) who do not respond to HLA-matched platelets, histocompatible platelet donors can often be identified using platelet cross-matching techniques. In many patients, these two techniques are complementary.
Platelet Transfusion for Patients With Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. Schiffer CA, Bohlke K, Delaney M, et al. J Clin Oncol. 2017 Nov 28:JCO2017761734. doi: 10.1200/JCO.2017.76.1734. [Epub ahead of print]
FDA Approves OGIVRI® as a Biosimilar to HERCEPTIN®
SUMMARY: The FDA on December 1, 2017 approved OGIVRI® (Trastuzumab-dkst) as a biosimilar to HERCEPTIN® (Trastuzumab), for the treatment of patients with HER2-overexpressing breast or metastatic stomach cancer (gastric or gastroesophageal junction adenocarcinoma). It is estimated that 252,710 new cases of invasive breast cancer and 63,410 new cases of non-invasive breast cancer will be diagnosed in women in 2017 and 28,000 new cases of stomach cancer will be diagnosed during this same period. Approximately 20-25% of primary breast cancers are HER2-positive. The frequency of HER2 overexpression in gastric and gastroesophageal cancer is about 18% with the frequency ranging from 4% to 53%.
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-licensed (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’s standards.
The approval of OGIVRI® was based on comparisons of extensive structural and functional product characterization, animal data, human pharmacokinetic and pharmacodynamic data, and clinical studies including clinical immunogenicity between OGIVRI® and HERCEPTIN®. Heritage is a double-blind, randomized phase III trial in which the efficacy and safety of OGIVRI® , a Biosimilar, was compared with HERCEPTIN®. The randomization included 500 patients treated at 95 sites worldwide, with centrally confirmed, measurable HER2 positive metastatic breast cancer, who had not received prior chemotherapy or HERCEPTIN® for their metastatic disease. Patients received either OGIVRI® or HERCEPTIN® along with TAXOTERE® (Docetaxel) or TAXOL® (Paclitaxel) administered every 3 weeks for a minimum of 8 cycles (24 weeks), with the antibody therapy continued, until disease progression. Both antibodies were administered with a loading dose of 8 mg/kg and a maintenance dose of 6 mg/kg every 3 weeks. Approximately 44% of the enrolled patients had hormone receptor positive disease and 84% received TAXOTERE®. The final analysis included 458 patients of whom 230 were in the OGIVRI® group and 228 were in the HERCEPTIN® group. The Primary endpoint was Overall Response Rate (ORR) at 24 weeks and Secondary endpoints include Progression Free Survival (PFS), Overall Survival (OS) and Safety.
The ORR after 24 weeks of treatment was 69.6% for the OGIVRI® group and 64% for the HERCEPTIN® group and this was not statistically significant. The median PFS had not yet been reached. Safety data in both treatment groups were comparable and there was no significant change in cardiac function from baseline to Week 24 in either group. Safety data were also comparable. The dose-normalized maximum concentration, and Area Under the Curve (AUC), were similar for both antibodies.
The authors concluded that OGIVRI® is equivalent to HERCEPTIN®, when given in combination with a Taxane, as first line therapy, for patients with HER2 positive metastatic breast cancer. Heritage: A phase III safety and efficacy trial of the proposed trastuzumab biosimilar Myl-1401O versus Herceptin. Rugo HS, Barve A, Waller CF, et al. J Clin Oncol 34, 2016 (suppl; abstr LBA503)
FDA Approves FoundationOne CDx Next Generation Sequencing Based Assay to Tailor Cancer Therapies
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