The FDA on July 26, 2021 approved KEYTRUDA® for high-risk, early-stage, Triple-Negative Breast Cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. KEYTRUDA® is a product of Merck & Co.
Author: RR
KEYTRUDA® (Pembrolizumab) in combination with LENVIMA® (Lenvatinib)
The FDA on July 21, 2021 approved KEYTRUDA® in combination with LENVIMA® for patients with advanced Endometrial carcinoma that is not MicroSatellite Instability-High (MSI-H) or MisMatch Repair deficient (dMMR), who have disease progression following prior systemic therapy in any setting, and are not candidates for curative surgery or radiation. KEYTRUDA® is a product of Merck & Co. and LENVIMA® is a product of Eisai Co., Ltd.
REZUROCK® (Belumosudil)
The FDA on July 16, 2021 approved REZUROCK®, a kinase inhibitor, for adult and pediatric patients 12 years and older with chronic Graft-Versus-Host Disease (chronic GVHD), after failure of at least two prior lines of systemic therapy. REZUROCK® is a product of Kadmon Pharmaceuticals, LLC.
DARZALEX FASPRO® (Daratumumab and Hyaluronidase-fihj)
The FDA on July 9, 2021 approved DARZALEX FASPRO® in combination with Pomalidomide and Dexamethasone for adult patients with Multiple Myeloma, who have received at least one prior line of therapy including Lenalidomide and a Proteasome Inhibitor. DARZALEX FASPRO® is a product of Janssen Biotech, Inc.
PADCEV® (Enfortumab Vedotin-ejfv)
The FDA on July 9, 2021 approved PADCEV®, a Nectin-4-directed antibody and microtubule inhibitor conjugate, for adult patients with locally advanced or metastatic urothelial cancer who
- have previously received a Programmed Death receptor-1 (PD-1) or Programmed Death-Ligand (PD-L1) inhibitor and Platinum-containing chemotherapy, or
- are ineligible for Cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.
PADCEV® is a product of Astellas Pharma US, Inc.
RYLAZE® (Asparaginase Erwinia Chrysanthemi (recombinant)-rywn)
The FDA on July 1, 2021 approved RYLAZE® as a component of a multi-agent chemotherapeutic regimen for the treatment of Acute Lymphoblastic Leukemia (ALL) and Lymphoblastic Lymphoma, in adult and pediatric patients 1 month or older who have developed hypersensitivity to E. coli-derived asparaginase. RYLAZE® is a product of Jazz Pharmaceuticals.
Immune Checkpoint Inhibitor Therapy and Risk of Venous Thromboembolism
SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis (DVT)/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. Ambulatory cancer patients initiating chemotherapy are at varying risk for Venous Thromboembolism (VTE), which in turn can have a substantial effect on health care costs, with negative impact on quality of life.
Approximately 20% of cancer patients develop VTE and about 20% of all VTE cases occur in patients with cancer. Cancer patients have a 4-7 fold increased risk of thrombosis, compared with those without cancer, and patients with cancer and VTE are at a markedly increased risk for morbidity and mortality. The etiology of thrombosis in cancer is multifactorial, and the vascular system is an important interface between the malignant cells and their systemic and external environments. Genetic alterations in malignant cells, as they respond to their microenvironment, can result in inflammation, angiogenesis, and tissue repair. This in turn leads to the local and systemic activation of the coagulation system. It has been postulated that the procoagulant effect of malignant cells may be related to the release of soluble mediators such as G-CSF into the circulation or by the shedding of procoagulant Extracellular Vesicles (EVs) harboring Tissue Factor. Previously published studies had entertained the notion that certain oncogenic mutations may deregulate hemostatic genes (coagulome) in cancer cells.
Immune Checkpoint Inhibitors (ICIs) have revolutionized cancer management. They bind to either PD-1 receptor or its ligand PD-L1 and block their interaction, thereby reversing the PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. This can however be accompanied by various off-target manifestations of autoimmunity induced by immune checkpoint inhibitors with resulting systemic inflammation on the hemostatic system. The risk of Venous ThromboEmbolism (VTE) and Arterial ThromboEmbolism (ATE) associated with ICIs is currently unclear. The goal of this study was to quantify the risk of VTE/ATE in patients with cancer, treated with ICIs, explore clinical impact, and investigate potential clinical risk factors.
The authors conducted a single-center, retrospective cohort study at the Medical University of Vienna, Austria, and included 672 patients with histologically confirmed cancer, who were treated with one or more doses of an Immune Checkpoint Inhibitor (Nivolumab, Pembrolizumab, Ipilimumab, Atezolizumab, or Avelumab), between 2015 and 2018. Patients received a median of 7 cycles of therapy. About a third of patients (30.4%) had Malignant Melanoma, whereas 24% had Non Small Cell Lung Cancer, 11% had Renal Cell Carcinoma, 10.4% had Head and Neck Squamous Cell Carcinoma and 5% had Urothelial cancer. Majority of patients (86%) had advanced disease at the time of ICI initiation. The median patient age was 64 years, 39% were female and most patients had an ECOG Performance Status of 0 or 1. Approximately 13% of patients had a history of VTE prior to the initiation of ICI therapy. Approximately 9% of patients had a history of ATE, and was associated with the current cancer diagnosis in 2.2% of the total cohort. At the time of ICI therapy initiation, 16.5% received continuous anticoagulation and 20% received antiplatelet therapy. The Primary outcomes of the study were cumulative incidence rates of VTE and ATE. Secondary outcomes included the association of VTE/ATE with Overall Survival (OS), Progression Free Survival (PFS), and radiological Disease Control Rate (DCR). The median follow up was 8.5 months.
It was noted that the cumulative incidences of VTE and ATE during ICI therapy were 12.9% and 1.8% respectively. The occurrence of VTE was associated with increased mortality with shorter OS. The median OS after the occurrence of VTE was 11.6 months compared with 25.5 months in those without VTE (P<0.001). The researchers noted that the number of fatal Pulmonary Embolisms were not high (N=2) in this study, suggesting that the impact of VTE goes beyond direct VTE-related mortality. The diagnosis of VTE was further associated with shorter PFS. Median PFS after VTE was 1.7 months compared with 6.7 months in those without VTE (P<0.001). The occurrence of ATE was not associated with risk of mortality or early progression of disease. However, this could have been due to relatively low number of ATE events and potential lack of statistical power. Therefore, definite conclusions cannot be drawn. Prior history of VTE predicted VTE occurrence. Distant metastasis was associated with VTE risk, although this was not statistically significant. The researchers did not find association of VTE with ECOG Performance Status or Khorana score, and the rates of VTE were comparable between tumor types and different immune Checkpoint Inhibitors. No association with VTE risk was observed for patients undergoing continuous anticoagulation or anti-platelet therapy at baseline.
It was concluded that despite the limitations of this study, patients with cancer undergoing treatment with Immune Checkpoint inhibitors are at a high risk of developing thromboembolic complications, especially VTE, and VTE occurrence was associated with increased mortality. The authors added that further studies are needed to better understand the risk of VTE and ATE associated with ICIs, and thus improve patient care by preventing thromboembolic complications.
Incidence, risk factors, and outcomes of venous and arterial thromboembolism in immune checkpoint inhibitor therapy. Moik F, Chan WE, Wiedemann S, et al. Blood.2021;137:1669-1678.
FDA Approves LENVIMA® Plus KEYTRUDA® for Advanced Renal Cell Carcinoma
SUMMARY: The FDA on August 10, 2021, approved the combination of LENVIMA® (Lenvatinib) plus KEYTRUDA® (Pembrolizumab) for first line treatment of adult patients with advanced Renal Cell Carcinoma (RCC). The American Cancer Society estimates that 76,080 new cases of kidney cancers will be diagnosed in the United States in 2021 and about 13,780 people will die from the disease. Renal Cell Carcinoma (RCC) is by far the most common type of kidney cancer and is about twice as common in men as in women. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. The five year survival of patients with advanced RCC is less than 10% and there is a significant unmet need for improved therapies for this disease.
SUTENT® (Sunitinib) is a MultiKinase Inhibitor (MKI) which simultaneously targets the tumor cell wall, vascular endothelial cell wall as well as the pericyte/fibroblast/vascular/smooth vessel cell wall, and is capable of specifically binding to tyrosine kinases inhibiting the earlier signaling events and thereby inhibits phosphorylation of VEGF receptor, PDGF receptor, FLT-3 and c-KIT. SUTENT® has been the standard first line intervention for treatment naïve patients with advanced RCC. In a large, multi-center, randomized, Phase III study, the median Progression Free Survival (PFS) with SUTENT® was 9.5 months, the Objective Response Rate (ORR) was 25%, and the median Overall Survival (OS) was 29.3 months, when compared with Interferon Alfa, in patients with treatment-naïve Renal Cell Carcinoma. This was however associated with a high rate of hematological toxicities.
KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells.
LENVIMA® (Lenvatinib) is an oral multitargeted TKI which targets Vascular Endothelial Growth Factor Receptor (VEGFR) 1-3, Fibroblast Growth Factor Receptor (FGFR) 1-4, Rearranged during Transfection tyrosine kinase receptor (RET), c-KIT, and Platelet Derived Growth Factor Receptor (PDGFR). LENVIMA® differs from other TKIs with antiangiogenesis properties by its ability to inhibit FGFR-1, thereby blocking the mechanisms of resistance to VEGF/VEGFR inhibitors. In addition, it controls tumor cell growth by inhibiting RET, c-KIT, and PDGFR beta and influences tumor microenvironment by inhibiting FGFR and PDGFR beta.
AFINITOR® (Everolimus) does not inhibit tyrosine kinases, but is a specific inhibitor of mTOR (Mammalian Target of Rapamycin), which is a serine/threonine kinase, normally activated further downstream in the signaling cascade. With the inhibition of mTOR, protein synthesis is inhibited resulting in decreased angiogenesis, cell proliferation and survival as well as decreased levels of HIF-1 alpha.
A combination of LENVIMA® plus AFINITOR® was shown to be associated with longer Progression Free Survival than AFINITOR® alone as second line treatment in advanced RCC (Lancet Oncol 2015;16:1473-1482). LENVIMA® plus KEYTRUDA® was shown to have promising antitumor activity in previously treated patients with RCC in a Phase IB-II trial (J Clin Oncol 2020;38:1154-1163). Based on this data, the authors conducted a multicenter, randomized, open-label, Phase III trial to compare the efficacy and safety of LENVIMA® in combination with KEYTRUDA® or AFINITOR® versus SUTENT® alone, in first line treatment of patients with advanced RCC.
The researchers randomly assigned 1069 patients with advanced RCC and no previous systemic therapy in a 1:1:1 ratio to receive LENVIMA® 20 mg orally once daily plus KEYTRUDA® 200 mg IV once every 3 weeks (N=355), LENVIMA® 18 mg orally once daily plus AFINITOR® 5 mg orally once daily (N=357) or SUTENT® 50 mg orally once daily, alternating 4 weeks on and 2 weeks off (N=357). The Primary end point was Progression Free Survival (PFS) and Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR) and Safety. The median follow up for OS was 26.6 months.
The median PFS was significantly longer with LENVIMA® plus KEYTRUDA® combination, compared to single agent SUTENT® (23.9 months versus 9.2 months, HR=0.39; P<0.001). The median PFS with the LENVIMA® plus AFINITOR® combination was also significantly longer, compared to single agent SUTENT® (14.7 months versus 9.2 months, HR=0.65; P<0.001). The PFS benefit favored the two LENVIMA® combination regimens over single agent SUTENT® across all evaluated subgroups, including those based on MSKCC prognostic risk group and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group. At interim analysis, the OS was significantly longer with LENVIMA® plus KEYTRUDA® than with SUTENT® (HR for death=0.66; P=0.005). This benefit was noted in most subgroups, including patients with PD-L1 positive or negative tumors, with an exception of patients with favorable risk disease as defined by IMDC criteria. Overall Survival with LENVIMA® plus AFINITOR® was however not significantly longer compared with SUTENT® (HR=1.15; P=0.30).
The confirmed ORR was 71% with LENVIMA® plus KEYTRUDA®, 53.5% with LENVIMA® plus AFINITOR®, and 36.1% with single agent SUTENT®. The Complete Response rate was 16.1% in the LENVIMA® plus KEYTRUDA® group, 9.8% in the LENVIMA® plus AFINITOR® group, and 4.2% in the SUTENT® group. The median Duration of Response in patients who had a confirmed response was 25.8 months in the LENVIMA® plus KEYTRUDA® group, 16.6 months in the LENVIMA® plus AFINITOR® group, and 14.6 months in the SUTENT® group. Grade 3 or higher Adverse Events occurred in 82.4% of the patients who received LENVIMA® plus KEYTRUDA® group, in 83.1% of the patients who received LENVIMA® plus AFINITOR®, and in 71.8% of the patients who received SUTENT®.
It was concluded that a combination of LENVIMA® plus KEYTRUDA® provided superior Progression Free Survival and Overall Survival compared to SUTENT®, in the first line treatment of patients with advanced Renal Cell Carcinoma.
Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. Motzer R, Alekseev B, Rha S-Y, et al. for the CLEAR Trial Investigators. N Engl J Med 2021; 384:1289-1300
AYVAKIT® (Avapritinib)
The FDA on June 16, 2021, approved AYVAKIT® for adult patients with advanced Systemic Mastocytosis, including patients with aggressive Systemic Mastocytosis, Systemic Mastocytosis with an associated hematological neoplasm, and Mast Cell Leukemia. AYVAKIT® is a product of Blueprint Medicines Corp.
TRUSELTIQ® (Infigratinib)
The FDA on May 28, 2021, granted accelerated approval to TRUSELTIQ®, a kinase inhibitor, for adults with previously treated, unresectable locally advanced or metastatic Cholangiocarcinoma with a Fibroblast Growth Factor Receptor 2 (FGFR2) fusion or other rearrangement, as detected by an FDA-approved test. TRUSELTIQ® is a product of QED Therapeutics, Inc.
The FDA also approved FoundationOne® CDx (Foundation Medicine, Inc.) for selection of patients with FGFR2 fusion or other rearrangement as a companion diagnostic device for treatment with TRUSELTIQ®.