資料來源：https://www.multivu.com/players/English/8001251-novartis-rydapt-aml-fda-approval/?c=y

Novartis announced the US Food and Drug Administration (FDA) has approved Rydapt® (midostaurin, formerly PKC412) for two indications. The first indication is for the treatment of acute myeloid leukemia (AML) in newly diagnosed patients who are FMS-like tyrosine kinase 3 mutation-positive (FLT3+), as detected by an FDA-approved test, in combination with chemotherapy. Rydapt is also approved to treat adults with advanced systemic mastocytosis (SM), which includes aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN) and mast cell leukemia. This approval follows a prior Breakthrough Therapy designation in FLT3-mutated AML, as well as Orphan Drug designation and Priority Review in both indications by the FDA. Worldwide filings for Rydapt are currently underway.

“Rydapt represents a remarkable advance as the first and only targeted therapy approved for patients who had limited options for many years,” said Bruno Strigini, CEO, Novartis Oncology. “We are proud to continue our leadership in hematology as we work diligently to bring innovative medicines to patients worldwide.”

Rydapt is the only approved targeted therapy for newly diagnosed FLT3-mutated AML

AML is a rare and aggressive cancer of the blood and bone marrow. In the US, about 21,000 people are estimated to be diagnosed with AML in 2017. Approximately one-third of these AML patients, or 7,000, will have a FLT3 gene mutation. FLT3 is a type of cell-surface receptor which plays a role in increasing the number of certain blood cells. The FLT3 gene mutation can result in faster disease progression, higher relapse rates and lower rates of survival than other forms of AML. Prior to the approval of Rydapt, the AML therapeutic strategy had remained relatively unchanged for more than 25 years.

“The overall survival advantage for midostaurin plus chemotherapy seen in the RATIFY trial was a significant advancement for newly diagnosed AML patients with the FLT3 mutation,” said Dr. Richard Stone, Chief of Staff and Director of the Adult Leukemia program at Dana-Farber Cancer Institute, and Alliance for Clinical Trials in Oncology study chair for the RATIFY trial. “The availability of midostaurin now helps to establish a new standard of care in this high-risk patient population.”

Rydapt is indicated for use in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy, for the treatment of adult patients with newly diagnosed AML who are FLT3 mutation-positive, as detected by an FDA-approved test. Rydapt is not indicated as a single-agent induction therapy for the treatment of patients with AML.

The FDA approval is based on the Phase III RATIFY (CALGB 10603 [Alliance]) clinical trial, which was conducted in collaboration with the Alliance for Clinical Trials in Oncology and its 13 contributing international cooperative groups. In the trial, newly diagnosed FLT3+ patients who received Rydapt plus chemotherapy experienced significant improvement in overall survival with a 23% reduction in the risk of death compared with chemotherapy alone (hazard ratio [HR] = 0.77, 95% confidence interval [CI], 0.63, 0.95; 2 sided p=0.016).

Event-free survival (EFS; event defined as no complete remission within 60 days of the start of induction therapy, relapse or death) was significantly higher for Rydapt plus chemotherapy versus chemotherapy alone (median of 8.2 months compared to 3.0 months, HR = 0.78, 95% CI 0.66, 0.93 and 2 sided p=0.004). RATIFY is the largest worldwide clinical trial in newly diagnosed FLT3-mutated AML to date, as 3,279 AML patients were screened for the FLT3 mutation and 717 patients were enrolled. All FLT3+ patients enrolled in the trial were treated regardless of whether or not cytogenetic status was normal or abnormal.

The most frequent adverse reactions (incidence greater than or equal to 20%) in the Rydapt plus chemotherapy arm were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae (small red skin spots), device-related infection, epistaxis, hyperglycemia and upper respiratory tract infections. The most frequent Grade 3/4 adverse reactions (incidence greater than or equal to 10%) were febrile neutropenia, device-related infection and mucositis.

In order to identify FLT3+ AML patients who may benefit from Rydapt, Novartis collaborated with Invivoscribe Technologies, Inc. on the development of LeukoStrat® CDx FLT3 Mutation Assay, a companion molecular diagnostic test, which was also approved by the FDA today. LeukoStrat® CDx FLT3 Mutation Assay is the first molecular companion diagnostic in AML and identifies both FLT3 internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations and is performed by The Laboratory for Personalized Molecular Medicine, a subsidiary of Invivoscribe Technologies, Inc.

Rydapt provides an innovative treatment option for advanced SM

Advanced SM is a rare blood disorder characterized by uncontrolled growth and accumulation of mast cells – or mediators of allergic responses – in one or more organs. In advanced SM, mast cells accumulate in such high quantities that they begin to cause organ damage. Median overall survival is currently less than six months for mast cell leukemi, two years for SM-AHN and 3.5 years for ASM.

Rydapt is approved in the US for the treatment of adult patients with ASM, SM-AHN, or mast cell leukemia. The approval of Rydapt was based on two single-arm open-label multicenter trials, including the Phase II study (CPKC412D2201), which was the largest and longest-running prospective trial ever conducted in this ultra-rare disorder. The efficacy of Rydapt was established on the basis of confirmed complete remission (CR) plus incomplete remission (ICR) by six cycles of treatment per the modified Valent criteria (n=89), in which CR and ICR are the two most rigorous subcategories of a major response. This analysis demonstrated an overall response rate of 21% (95% CI, 13, 31). Efficacy was also assessed in a post-hoc analysis using the 2013 International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis (IWG-MRT-ECNM) consensus criteria (n=115). This assessment estimated complete remission or partial remission rate of 17% (95% CI, 10, 25).

The most frequent adverse reactions (incidence greater than or equal to 20%), excluding laboratory terms, were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache and dyspnea. The most frequent Grade 3 or greater adverse reactions (incidence greater than or equal to 5%), excluding laboratory terms, were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain and renal insufficiency.

Rydapt patient support

Novartis is committed to providing patients with access to medicines, as well as resources and support to address a range of needs. The Rydapt patient support program is available to help guide eligible patients through the various aspects of their treatment journey, from providing educational information to helping them understand their insurance coverage and identify potential financial assistance options.

Advanced SM-specific rebate program

Novartis is offering an innovative indication-based rebate offer to payers related to advanced SM utilization, which will require a patient cost-savings provision. Payers interested in the advanced SM rebate program can call 800-310-6644.

About AML

AML is the most common acute leukemia in adults; it accounts for approximately 25% of all adult leukemias worldwide, with the highest incidence rates occurring in the US, Europe and Australia. It also has the lowest survival rate of all adult leukemias.

AML prevents white blood cells from maturing, causing an accumulation of “blasts,” which do not allow room for the normal blood cells. Mutations in specific genes are found in many cases of AML, and genetic testing for mutations in newly diagnosed AML patients can help to determine prognosis and potential treatment strategies.

About advanced SM

In advanced SM, the uncontrolled growth of neoplastic mast cells causes organ damage (e.g., liver dysfunction), low blood counts and weight loss. Patients also suffer from debilitating systemic symptoms such as pruritus (severe itching of the skin) caused by mast cells releasing inflammatory mediators, such as histamine, into the blood.

The uncontrolled proliferation of mast cells is caused in many people by a KIT gene mutation – the most common mutation, encoding the D816V substitution, occurs in approximately 90% of patients. The KIT gene mutation results in activation of the KIT enzyme, which triggers the abnormal proliferation and survival of mast cells.