VENCLEXTA® (Venetoclax)

The FDA on October 16, 2020, granted regular approval to VENCLEXTA® (Venetoclax) in combination with Azacitidine, Decitabine, or Low-Dose Cytarabine (LDAC), for newly diagnosed Acute Myeloid Leukemia (AML) in adults, 75 years or older, or who have comorbidities precluding intensive induction chemotherapy. VENCLEXTA® was initially granted accelerated approval for this indication in November 2018. VENCLEXTA® is a product of AbbVie Inc. and Genentech Inc.

ONUREG® (Azacitidine tablets)

The FDA on September 1, 2020, approved ONUREG® for continued treatment of patients with Acute Myeloid Leukemia who achieved first Complete Remission (CR) or Complete Remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy, and are not able to complete intensive curative therapy. ONUREG® is a product of Celgene Corporation.

VIDAZA® plus VENCLEXTA® for Elderly patients with AML

SUMMARY: The American Cancer Society estimates that in 2020, 19,940 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 11,180 patients will die of the disease. AML is one of the most common types of leukemia in adults and can be considered as a group of molecularly heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy or have disease that is refractory to standard chemotherapy. Even with the best available therapies, the 5 year Overall Survival in patients 65 years of age or older is less than 5%. Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients, based on risk and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high risk features such as unfavorable cytogenetics, molecular abnormalities, prior myelodysplasia and advanced age, have poor outcomes with conventional chemotherapy alone. More importantly, with the understanding of molecular pathology of AML, personalized and targeted therapies are becoming an important part of the AML treatment armamentarium.

The pro-survival (anti-apoptotic) protein BCL2 is over expressed by AML cells and regulates clonal selection and cell survival. A new class of anticancer agents known as BH3-mimetic drugs mimic the activity of the physiologic antagonists of BCL2 and related proteins and promote apoptosis (programmed cell death). VENCLEXTA® is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. VIDAZA® (Azacitidine) is a hypomethylating agent that promotes DNA hypomethylation by inhibiting DNA methyltransferases. VIDAZA® has been shown to significantly improve Overall Survival (OS), when compared to conventional care regimens, in elderly unfit patients with newly diagnosed AML, who are not candidates for intensive chemotherapy. The combination of VIDAZA® and VENCLEXTA® in a previously published Phase Ib study was highly efficacious, with significant responses, duration of response and Overall Survival benefit.VENCLEXTA_MOA

VIALE-A is a Phase III, multicenter, randomized, double-blind, placebo-controlled confirmatory trial, conducted to evaluate the efficacy and safety of a combination of VIDAZA® and VENCLEXTA®, as compared with VIDAZA® plus placebo (the control regimen), in previously untreated patients with AML, who were ineligible for intensive induction therapy. In this study, 431 patients (N=431) with previously untreated AML were randomly assigned in a 2:1 ratio to receive either VIDAZA® plus VENCLEXTA® (N=286), or VIDAZA® plus placebo (N=145). Enrolled patients were ineligible for standard induction chemotherapy because of coexisting conditions, 75 years of age or older, or both.

All patients received VIDAZA® 75 mg/m2 subcutaneously or IV on days 1 through 7 of every 28-day cycle. Patients in the study group also received VENCLEXTA® 100 mg orally on day 1 and 200 mg on day 2 and target dose of 400 mg on day 3, and continued daily until day 28 during cycle 1, to mitigate Tumor Lysis Syndrome. The dose of VENCLEXTA® was initiated at 400 mg daily in all subsequent 28-day cycles. In the control group, a matching placebo was administered orally, once daily, in 28-day cycles. The median patient age was 76 years. Secondary AML was reported in 25% of the patients in the VIDAZA® plus VENCLEXTA® group and in 24% of the patients in the control group, and poor cytogenetic risk was reported in 36% and 39%, respectively. All the patients were hospitalized on or before day 1 of cycle 1 and for at least 24 hours after receiving the final dose of VENCLEXTA®, in order to receive prophylaxis against the Tumor Lysis Syndrome and for monitoring. The Primary endpoint was Overall Survival (OS). The Secondary end points included Complete Remission (CR) rates, composite Complete Remission (Complete Remission or Complete Remission with incomplete hematologic recovery), RBC and platelet transfusion independence, and Quality of Life according to Patient-Reported Outcomes.

At a median follow up of 20.5 months, the median OS was 14.7 months in the VIDAZA® plus VENCLEXTA® group versus 9.6 months in the VIDAZA® plus placebo group (HR=0.66; P<0.001). VIDAZA® plus VENCLEXTA® combination resulted in a CR rate of 36.7% versus 17.9%; P<0.001 and composite CR of 66.4% versus 28.3%; P<0.001, when compared to the control regimen. Most responses were seen after the first 28-day cycle. The median time to first response was 1.3 versus and 2.8 months respectively, duration of CR was 17.5 months versus 13.3 months and median duration of composite CR was 17.5 months in the VIDAZA® plus VENCLEXTA® group and 13.4 months in the control group. RBC transfusion independence occurred in 59.8% of the patients in the VIDAZA® plus VENCLEXTA® group and in 35.2% of those in the control group (P<0.001), and platelet transfusion independence occurred in 68.5% and 49.7% (P<0.001), respectively. The benefits with VIDAZA® plus VENCLEXTA® were noted in almost all molecular subgroups compared to the control regimen. The response rates were highest among patients with FLT3 mutations (72.4% versus 36.4%, P=0.02) and those with IDH1 or IDH2 mutations (75.4 % versus 10.7%, P<0.001), respectively. The incidence of febrile neutropenia was higher in the VIDAZA® plus VENCLEXTA® group than in the control group. Infections of any grade occurred in 85% of the patients in the VIDAZA® plus VENCLEXTA® group and in 67% of those in the control group, and serious Adverse Events occurred in 83% and 73%, respectively.

It was concluded that among previously untreated patients with AML who were ineligible for intensive chemotherapy, those who received VIDAZA® plus VENCLEXTA® had significantly longer Overall Survival and higher remission rates, compared to those who received VIDAZA® alone. Whether VIDAZA® plus VENCLEXTA® will replace conventional induction chemotherapy for AML, remains to be seen.

Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. DiNardo CD, Jonas BA, Pullarkat V, et al. N Engl J Med 2020; 383:617-629

IDHIFA® plus VIDAZA® Significantly Improves Complete Remission and Overall Response in Newly Diagnosed IDH2-Mutated AML

SUMMARY: The American Cancer Society estimates that in 2019, 21,450 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 10,920 patients will die of the disease. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy. Even with the best available therapies, the 5 year Overall Survival in patients 65 years of age or older is less than 5%. Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients, based on risk and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high risk features such as unfavorable cytogenetics, molecular abnormalities, prior myelodysplasia and advanced age, have poor outcomes with conventional chemotherapy alone. More importantly, with the understanding of molecular pathology of AML, personalized and targeted therapies are becoming an important part of the AML treatment armamentarium.

Isocitrate DeHydrogenase (IDH) is a metabolic enzyme that helps generate energy from glucose and other metabolites, by catalyzing the conversion of Isocitrate to Alpha-Ketoglutarate. Alpha-ketoglutarate is required to properly regulate DNA and histone methylation, which in turn is important for gene expression and cellular differentiation. IDH mutations lead to aberrant DNA methylation and altered gene expression thereby preventing cellular differentiation, with resulting immature undifferentiated cells. IDH mutations can thus promote leukemogenesis in Acute Myeloid Leukemia and tumorigenesis in solid tumors and can result in inferior outcomes. There are three isoforms of IDH. IDH1 is mainly found in the cytoplasm, as well as in peroxisomes, whereas IDH2 and IDH3 are found in the mitochondria, and are a part of the Krebs cycle. Approximately 20% of patients with AML, 70% of patients with Low-grade Glioma and secondary Glioblastoma, 50% of patients with Chondrosarcoma, 20% of patients with Intrahepatic cholangiocarcinoma, 30% of patients with Angioimmunoblastic T-cell lymphoma and 8% of patients with Myelodysplastic syndromes/Myeloproliferative neoplasms, are associated with IDH mutations.

IDHIFA® (Enasidenib) is a selective, oral, small molecule inhibitor of mutated IDH2 protein that promotes myeloid cell differentiation. IDHIFA® indirectly reduces DNA methylation by suppressing the oncometabolite, 2-HydroxyGlutarate, thereby restoring function to Alpha-Ketoglutarate-dependent TET family enzymes. IDHIFA® was approved in the US in 2017 for the treatment of adult patients with relapsed or refractory Acute Myeloid Leukemia (AML), with an IDH2 mutation. Further, treatment with single agent IDHIFA® resulted in an Overall Response Rate (ORR) of 31% and a Completer Response (CR) rate of 18% in patients with newly diagnosed AML. VIDAZA® (Azacitidine) is a hypomethylating agent that promotes DNA hypomethylation by inhibiting DNA methyltransferases. VIDAZA® has been shown to significantly improve Overall Survival (OS) when compared to conventional care regimens in elderly unfit patients with newly diagnosed AML, who are not candidates for intensive chemotherapy. In vitro studies demonstrated that a combination of IDHIFA® and VIDAZA® enhance cell differentiation and apoptosis.

Based on this preclinical data and early clinical trials, an open label, Phase I/II study was conducted comparing a combination of IDHIFA® and VIDAZA® with single agent VIDAZA® in patients with newly diagnosed IDH2 mutated AML, who are not candidates for intensive chemotherapy. The authors reported the first interim outcomes from the randomized, Phase II portion of this ongoing study. The Phase II portion of the trial enrolled 101 patients with newly diagnosed IDH2-mutant AML who were ineligible to receive intensive chemotherapy. Patients had an ECOG PS score of 2 or less and were randomized in a 2:1 ratio to receive IDHIFA® plus VIDAZA® or VIDAZA® alone in repeated 28-day cycles. All patients received VIDAZA® 75 mg/m2/day SC for the first 7 days of each treatment cycle, whereas patients randomized to IDHIFA® plus VIDAZA® also received IDHIFA® 100 mg orally QD continuously. The median patient age was 75 years, and 78% in the combination group and 90% in the VIDAZA® only group had intermediate-risk cytogenetics respectively, and 18% and 10% had poor-risk cytogenetics. The median number of treatment cycles was 8. The Primary endpoint was Overall Response Rate (ORR), which included Complete Remission (CR), CR with incomplete blood or platelet count recovery (CRi/CRp), Partial Remission (PR), and Morphologic Leukemia-Free State (MLFS), per modified IWG 2003 AML response criteria. Mutant IDH2 Variant Allele Frequencies (VAF) in bone marrow mononuclear cells was assessed by digital PCR.

It was noted that the ORR were significantly higher with combination treatment vs VIDAZA® alone (71% versus 42% respectively, P=0.0064) and the CR rates were 53% versus 12% (P=0.0001). The time to first response was about 2 months in each treatment group and the median Duration of Response was 24.1 months with the combination treatment and 12.1 months with VIDAZA® alone. Responses were observed in patients with RAS pathway co-mutations, which have been usually associated with resistance to IDHIFA® monotherapy. The maximal mutant IDH2 VAF suppression from baseline was significantly greater with the combination treatment versus single agent VIDAZA® (median –69.3% versus –14.1% respectively, P=0.0004). Treatment related Grade 3-4 Adverse Events occurring in 10% or more of patients in the combination group were neutropenia, thrombocytopenia, anemia, febrile neutropenia and IDH differentiation syndrome.

It was concluded that a combination of IDHIFA® plus VIDAZA® was associated with significantly improved Complete Remission and Overall Response Rates, with significant mutant IDH2 Variant Allele Frequencies reductions, compared with VIDAZA® alone, in patients with newly diagnosed IDH2-mutant AML. Further the combination treatment was generally well tolerated, with a safety profile similar to that reported for monotherapy with either of these two agents. Enasidenib Plus Azacitidine Significantly Improves Complete Remission and Overall Response Compared with Azacitidine Alone in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) with Isocitrate dehydrogenase 2 (IDH2) Mutations: Interim Phase II Results from an Ongoing, Randomized Study. DiNardo CD, Schuh AC, Stein EM, et al. Presented at 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 643.

Single Agent XOSPATA® for FLT3 Mutated AML

SUMMARY: The American Cancer Society estimates that in 2019, 21,450 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 10,920 patients will die of the disease. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy. Even with the best available therapies, the 5 year Overall Survival in patients 65 years of age or older is less than 5%.

Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients, based on risk and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high risk features such as unfavorable cytogenetics, molecular abnormalities, prior myelodysplasia and advanced age, have poor outcomes with conventional chemotherapy alone. More importantly, with the understanding of molecular pathology of AML, personalized and targeted therapies are becoming an important part of the AML treatment armamentarium.MUTATED-FLT3-INDUCES-LIGAND-INDEPENDENT-PATHWAY-ACTIVATION

The Fms-Like Tyrosine kinase 3 (FLT3) is a cytokine receptor tyrosine kinase in the PDGF family of growth factor receptors. It is located on the cell surface (transmembrane) of early hematopoietic stem and progenitor cells and regulates their proliferation and differentiation. It plays an important role in both normal and malignant hematopoiesis by activating key signaling pathways. Activating mutations in the FLT3 receptor is the most common genetic abnormality in AML and is detected in approximately 30% of the patients. FLT3 mutations occur most often as Internal Tandem Duplications (FLT3-ITD) or point mutations at codon D835 (FLT3-Tyrosine Kinase Domain or TKD). Approximately 80% of AML patients with a FLT3 mutation will have the FLT3-ITD, and about 15% will have both FLT3-ITD and FLT3-TKD, and about 5% will have FLT3-TKD alone. The presence of FLT3-ITD mutations can negate the benefit of any other favorable molecular and cytogenetic features. Patients with FLT3-ITD mutations are predicted to have poor outcomes with shorter remission duration and significantly decreased leukemia-free and Overall Survival. FLT3-TKD can confer resistance to other Tyrosine Kinase Inhibitors and frequently do not respond to salvage chemotherapy.

XOSPATA® (Gilteritinib) is a highly selective oral FLT3/AXL Tyrosine Kinase Inhibitor with activity against both FLT3-ITD and FLT3-TKD mutations. Tyrosine Kinase AXL has been implicated in FLT3 inhibitor resistance. Another FLT3 inhibitor, RYDAPT® (Midostaurin), is also approved, but in combination with standard Cytarabine and Daunorubicin-based chemotherapy for patients with newly diagnosed FLT3-mutated AML. However, for patients with relapsed or refractory AML, RYDAPT® has not conferred durable clinical benefit as a single agent. Unlike XOSPATA®, RYDAPT® is a not selective and is a multikinase inhibitor and inhibits FLT3, PDGFR, c-KIT (CD 117), VEGFR, and protein kinase C. Single-agent XOSPATA®, in a phase 1-2 study, resulted in a 41% composite Complete Remission rate (Complete Remission with or without normal hematologic recovery), among patients with relapsed or refractory FLT3-mutated AML. Based on this information, the authors conducted a multicenter, randomized trial comparing XOSPATA® with conventional salvage chemotherapy regimens in patients with relapsed or refractory FLT3-mutated AML.

The ADMIRAL trial is an international, multicenter, randomized, Phase III study in which 371 patients with relapsed or refractory FLT3 mutated AML were randomly assigned in a 2:1 ratio to receive either XOSPATA® 120 mg orally once daily or salvage chemotherapy, in 28-day cycles. The median age was 62 years, approximately 60% of the patients had relapsed AML and 39% had primary refractory disease. Over 85% of patients had received previous induction therapy with Anthracyclines but not FLT3 inhibitors. The two Primary end points were Overall Survival and the percentage of patients who had Complete Remission with full or partial hematologic recovery. Secondary end points included Event-Free Survival (freedom from treatment failure – relapse or lack of remission or death) and the percentage of patients who had Complete Remission. The median duration of follow up for Overall Survival was 17.8 months.

The median Overall Survival in the XOSPATA® group was significantly longer than that in the chemotherapy group (9.3 months versus 5.6 months) with a 36% reduction in the risk of death, compared to salvage chemotherapy (HR for death=0.64; P<0.001). The median Event-Free survival was 2.8 months in the XOSPATA® group and 0.7 months in the chemotherapy group (HR for treatment failure or death=0.79). The percentage of patients who had Complete Remission with full or partial hematologic recovery was 34.0% in the XOSPATA® group and 15.3% in the chemotherapy group and the Complete Remission rates were 21.1% and 10.5%, respectively. The median Overall Survival as well as Complete Remission rates were similar among those with FLT3 ITD mutations alone and those with FLT3 TKD mutations, when treated with XOSPATA®. Further, longer survival was observed with XOSPATA® than with chemotherapy across all cohorts of patients with co-mutations, particularly in those patients with double mutation (DNMT3A and NPM1), and baseline levels of AXL expression did not influence survival with XOSPATA®. Serious adverse events occurred less frequently in the XOSPATA® group than in the chemotherapy group and the most common adverse events of Grade 3 or higher were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%).

It was concluded that treatment with single agent XOSPATA® resulted in significantly longer Overall Survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. Perl AE, Martinelli G, Cortes JE, et al. N Engl J Med 2019; 381:1728-1740

XOSPATA® (Gilteritinib)

The FDA on May 29, 2019 approved the addition of overall survival data in labeling for XOSPATA®, indicated for adult patients who have relapsed or refractory Acute Myeloid Leukemia (AML) with a FLT3 mutation, as detected by an FDA-approved test. XOSPATA® is a product of Astellas Pharma US, Inc.

FDA Approves TIBSOVO® for Newly Diagnosed AML Patients Ineligible for Intensive Chemotherapy

SUMMARY: The FDA on May 2, 2019, approved TIBSOVO® (Ivosidenib) for newly-diagnosed acute myeloid leukemia (AML) with a susceptible IDH1 (Isocitrate DeHydrogenase-1) mutation, as detected by an FDA-approved test, in patients who are at least 75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy. The American Cancer Society estimates that for 2019, 21,450 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 10,920 patients will die of the disease. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients, based on risk and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high risk features such as unfavorable cytogenetics, molecular abnormalities, prior Myelodysplasia and advanced age, have poor outcomes with conventional chemotherapy alone.MOA-of-Ivosidenib

Isocitrate DeHydrogenase (IDH) is a metabolic enzyme that helps generate energy from glucose and other metabolites, by catalyzing the conversion of Isocitrate to Alpha-Ketoglutarate. Alpha-ketoglutarate is required to properly regulate DNA and histone methylation, which in turn is important for gene expression and cellular differentiation. IDH mutations lead to aberrant DNA methylation and altered gene expression thereby preventing cellular differentiation, with resulting immature undifferentiated cells. IDH mutations can thus promote leukemogenesis in Acute Myeloid Leukemia and tumorigenesis in solid tumors and can result in inferior outcomes. There are three isoforms of IDH. IDH1 is mainly found in the cytoplasm, as well as in peroxisomes, whereas IDH2 and IDH3 are found in the mitochondria, and are a part of the Krebs cycle. Approximately 20% of patients with AML, 70% of patients with Low-grade Glioma and secondary Glioblastoma, 50% of patients with Chondrosarcoma, 20% of patients with Intrahepatic cholangiocarcinoma, 30% of patients with Angioimmunoblastic T-cell lymphoma and 8% of patients with Myelodysplastic syndromes/Myeloproliferative neoplasms, are associated with IDH mutations. TIBSOVO® is an oral, targeted, small-molecule inhibitor of mutant IDH1. The FDA in July, 2018, approved TIBSOVO® for adult patients with relapsed or refractory AML with a susceptible IDH1 mutation.

The present first line approval by the FDA was based on an open-label, single-arm, multicenter clinical trial (Study AG120-C-001, NCT02074839)of single-agent TIBSOVO®, for newly-diagnosed AML patients, with an IDH1 mutation detected by an FDA-approved IDH1 Assay. In this study, 28 patients were included and these patients were at least 75 years old, or had comorbidities that precluded the use of intensive induction chemotherapy. For comorbidities, enrolled patients met at least one of the following criteria – baseline ECOG PS of 2 or more, severe cardiac or pulmonary disease, hepatic impairment with Bilirubin more than 1.5 times the upper limit of normal, or Creatinine Clearance less than 45 mL/min. The median age was 77 years and 79% had therapy-related AML or AML with Myelodysplasia-related changes. Patients received TIBSOVO® 500 mg orally daily until disease progression, development of unacceptable toxicity, or hematopoietic stem cell transplantation. Efficacy was based on the rate of Complete Remission (CR) or Complete Remission with partial hematologic improvement (CRh) rate, the duration of CR+CRh, and the conversion rate from transfusion dependence to transfusion independence. CRh was defined as less than 5% of blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets more than 50,000/microliter and ANC more than 500/microliter).

In this trial, TIBSOVO® demonstrated a CR+CRh rate of 42.9%, with a CR rate of 28.6% and a CRh rate was 14.3%. The median durations of CR and CR+CRh could not be estimated, with 41.7% of those who achieved CR or CRh remaining on TIBSOVO® treatment as of the data cutoff (treatment duration ranged from 20.3 to 40.9 months). At 12 months after receiving treatment, 58.3% of patients who achieved CR or CRh, remained in remission. For those who achieved a CR or CRh, the median time to best response of CR or CRh was 2.8 months. Among those patients who were dependent on RBC and/or platelet transfusions at baseline, 41.2% achieved transfusion independence lasting at least 8 weeks.

The most common adverse reactions were fatigue, nausea, diarrhea, rash, pyrexia, arthralgia, leukocytosis and QT prolongation. One important side effect of the IDH inhibitors is the induction of differentiation of the malignant cells, and in 10-20% of patients, a clinical syndrome known as the IDH differentiation syndrome can occur. The IDH differentiation syndrome should be promptly managed by dose interruption and treatment with glucocorticoids, oral hydroxyurea, or both.

It was concluded that TIBSOVO® can induce durable responses among newly diagnosed poor risk AML patients with an IDH1 mutation, who are ineligible for intensive chemotherapy, fulfilling an unmet need. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ivosidenib-first-line-treatment-aml-idh1-mutation

TIBSOVO® (Ivosidenib)

The FDA on May 2, 2019 approved TIBSOVO® for newly diagnosed Acute Myeloid Leukemia (AML), with a susceptible IDH1 mutation, as detected by an FDA-approved test, in patients who are at least 75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy. TIBSOVO® was approved in July 2018 for adult patients with relapsed or refractory AML with a susceptible IDH1 mutation. TIBSOVO® is a product of Agios Pharmaceuticals, Inc.

FDA Approves Single Agent XOSPATA® for FLT3 Positive Acute Myeloid Leukemia

SUMMARY: The FDA in November 2018 approved XOSPATA® (Gilteritinib) for treatment of adult patients who have relapsed or refractory Acute Myeloid Leukemia (AML) with a FLT3 mutation as detected by an FDA-approved test. The FDA also approved an expanded indication for a companion diagnostic, to include use with XOSPATA®. The LeukoStrat CDx FLT3 Mutation Assay, developed by Invivoscribe Technologies, Inc., is used to detect the FLT3 mutation in patients with AML. The American Cancer Society estimates that in 2019, 21,450 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 10,920 patients will die of the disease. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy. Even with the best available therapies, the 5 year Overall Survival in patients 65 years of age or older is less than 5%.

Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients, based on risk and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high risk features such as unfavorable cytogenetics, molecular abnormalities, prior myelodysplasia and advanced age, have poor outcomes with conventional chemotherapy alone. More importantly, with the understanding of molecular pathology of AML, personalized and targeted therapies are becoming an important part of the AML treatment armamentarium.

The Fms-Like Tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase in the PDGF family of growth factor receptors located on the cell surface (transmembrane) and plays an important role in both normal and malignant hematopoiesis by activating key signaling pathways. Activating mutations in the FLT3 receptor is the most common genetic abnormality in AML and is detected in approximately 30% of the patients. FLT3 mutations occur most often as Internal Tandem Duplications (FLT3-ITD) or point mutations at codon D835 (FLT3-Tyrosine Kinase Domain or TKD). Approximately 80% of AML patients with a FLT3 mutation will have the FLT3-ITD, and about 15% will have both FLT3-ITD and FLT3-TKD, and about 5% will have FLT3-TKD alone. The presence of FLT3-ITD mutations can negate the benefit of any other favorable molecular and cytogenetic features. Patients with FLT3-ITD mutations are predicted to have poor outcomes with shorter remission duration and significantly decreased leukemia free and Overall Survival. FLT3-TKD can confer resistance to other Tyrosine Kinase Inhibitors.MUTATED-FLT3-INDUCES-LIGAND-INDEPENDENT-PATHWAY-ACTIVATION

XOSPATA® (Gilteritinib) is a highly selective FLT3/AXL Tyrosine Kinase Inhibitor with activity against both FLT3-ITD and FLT3-TKD mutations. This unlike RYDAPT® (Midostaurin), which is a not selective and is a multikinase inhibitor and inhibits FLT3, PDGFR, c-KIT (CD 117), VEGFR, and protein kinase C. The approval of XOSPATA® was based on an interim analysis of the ADMIRAL trial, which included 138 adult patients with relapsed or refractory AML having a FLT3 ITD, D835, or I836 mutation as detected by the LeukoStrat CDx FLT3 Mutation Assay. XOSPATA® was given orally at a dose of 120 mg daily until unacceptable toxicity or lack of clinical benefit. The median patient age was 60 years and 59% of patients had untreated relapsed AML, 41% had primary refractory AML and 20% of patients had prior Stem Cell transplantation. With regards to FLT3 mutation status, 121 patients had ITD alone, 12 patients had TKD alone, and 5 patients had ITD and TKD.

At the time of interim analysis, the complete remission (CR)/Complete Remission with partial hematologic recovery (CRh) rate was 21%. The median duration of CR/CRh was 4.6 months. The rate of conversion from transfusion dependence to transfusion independence was 31.1% for any 56 day post-baseline period. For those patients who were independent of both RBC and platelet transfusions at baseline, 53.1% remained transfusion-independent during any 56-day post-baseline period. . For patients who achieved a CR/CRh, the median time to first response was 3.6 months. The CR/CRh rate was 29 of 126 in patients with FLT3-ITD or FLT3-ITD/TKD and 0 of 12 in patients with FLT3-TKD only. The most common adverse reactions included skin rash, fatigue, diarrhea, elevated AST and ALT. Approximately 10% of patients required dose reductions, most commonly for diarrhea or fatigue.

It was concluded that XOSPATA® is the first and only FLT3-targeting therapy approved by the FDA, that can be used as a single agent for the treatment of adult patients who have relapsed or refractory Acute Myeloid Leukemia with a FLT3 mutation. Studies are underway evaluating XOSPATA® as maintenance therapy after allogeneic hematopoietic stem cell transplant in patients with FLT3-ITD positive AML. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm627045.htm

FDA Approves VENCLEXTA® for Elderly Patients with AML

SUMMARY: The FDA on November 21, 2018 granted accelerated approval to VENCLEXTA® (Venetoclax) in combination with Azacitidine or Decitabine or low-dose Cytarabine for the treatment of newly diagnosed Acute Myeloid Leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. The American Cancer Society estimates that in 2018, 19,520 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 10,670 patients will die of the disease. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy. Even with the best available therapies, the 5 year Overall Survival in patients 65 years of age or older is less than 5%.

The pro-survival (anti-apoptotic) protein BCL2 is over expressed by AML cells and regulates clonal selection and cell survival. A new class of anticancer agents known as BH3-mimetic drugs mimic the activity of the physiologic antagonists of BCL2 and related proteins and promote apoptosis (programmed cell death). VENCLEXTA® is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells.

The present FDA approval was based on two open-label non-randomized clinical trials in patients with newly diagnosed AML who were 75 years of age or older or had comorbidities that precluded the use of intensive induction chemotherapy. Efficacy was established based on the rate of Complete Remission (CR) and CR duration.

The M14-358 study is an open-label, phase Ib dose escalation and expansion study which evaluated the safety and efficacy of VENCLEXTA® in combination with HypoMethylating Agents, Azacitidine or Decitabine. This study included a subpopulation of 80 patients who received VENCLEXTA® (daily ramp-up to a final dose of 400 mg once daily) in combination with a hypomethylating agent, either Azacitidine (N=67) or Decitabine (N=13). Patients were hospitalized for monitoring during the ramp-up and received prophylaxis for Tumor Lysis Syndrome. Azacitidine was administered at 75 mg/m2 SC or IV on days 1-7 of each 28-day cycle and Decitabine was administered at 20 mg/m2 IV on days 1-5 of each 28-day cycle. Treatment was continued until disease progression or unacceptable toxicity. Majority of patients in each treatment group had an ECOG performance status of 0 or 1. In the Azacitidine group, 64% of patients had intermediate cytogenetic risk and 34% had poor cytogenetic risk whereas this was 38% and 62%, respectively in the Decitabine group.

The median follow up was 7.9 months for the Azacitidine group and 11 months for the Decitabine group. The Complete Response rate was 37% in the Azacitidine group with a median observed time in remission of 5.5 months. The rates of CR with partial hematologic recovery were 24%. In combination with Decitabine, the CR rate was 54%, with a median observed time in remission of 4.7 months. The CR with partial hematologic recovery was 7.7%.

The M14-387 study is an open-label, phase Ib/II dose escalation and expansion study which evaluated the safety and efficacy of VENCLEXTA® in combination with Low Dose Ara-C (Cytarabine). This study included a subpopulation of 61 AML patients who received VENCLEXTA® plus low-dose Cytarabine. Included patients had newly diagnosed AML, and some patients had previous exposure to a HypoMethylating Agent for an antecedent hematologic disorder. Patients received VENCLEXTA® (daily ramp-up to a final dose of 600 mg orally once daily). Patients were hospitalized for monitoring during the ramp-up and received prophylaxis for Tumor Lysis Syndrome. Cytarabine was given at 20 mg/m2 SC on days 1-10 of each 28-day cycle. Treatment was continued until disease progression or unacceptable toxicity.

At a median follow-up of 6.5 months, the CR rate was 21%, with a median observed time in remission of 6 months. The rate of CR with partial hematologic recovery was 21%. The most common adverse reactions to VENCLEXTA® in combination with Azacitidine, Decitabine or low-dose Cytarabine were fever, nausea, vomiting, diarrhea, fatigue, cytopenias, myalgias, dyspnea, peripheral edema and hypotension.

This FDA approval marks a significant advance for patients with Acute Myeloid Leukemia, who are unable to tolerate standard intensive induction chemotherapy. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm626499.htm