Summary Basis of Decision for Rydapt

Clinical Pharmacology

The medicinal ingredient of Rydapt, midostaurin, inhibits multiple receptor tyrosine kinases, including FLT3 and KIT kinase. Midostaurin inhibits FLT3 receptor signalling and induces cell cycle arrest and apoptosis in leukemic cells expressing internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutant receptors or overexpressing wild-type receptors. Midostaurin inhibits both the wild-type and D816V mutant KIT, leading to interference with the aberrant signaling of KIT and inhibits mast cell proliferation and survival, and histamine release.

Midostaurin is primarily eliminated by hepatic metabolism. A dedicated hepatic impairment study and population pharmacokinetic analyses indicated that mild to moderate hepatic impairment had no clinically relevant effects on the pharmacokinetics of midostaurin or its active metabolites. The pharmacokinetics of midostaurin has not been assessed in patients with severe hepatic impairment (Child-Pugh Class C).

No dedicated renal impairment study has been conducted. Population pharmacokinetic analyses indicated that mild and moderate renal impairment had no impact on the pharmacokinetics of midostaurin or its active metabolites. There is limited clinical data for patients with severe renal impairment.

Midostaurin is primarily metabolized by the cytochrome P450 (CYP) enzyme 3A4. Drug interactions were observed when Rydapt was coadministered with a strong CYP3A4 inhibitor, and a strong CYP3A4 inducer. Exposure of midostaurin also increased when midostaurin was administered with food.

Overall, the clinical pharmacological data support the use of Rydapt for the specified indication. Adequate warnings and precautions for the identified safety concerns are in place within the Rydapt Product Monograph.

For further details, please refer to the Rydapt Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy and safety of Rydapt, in combination with standard chemotherapy versus (vs.) placebo plus standard chemotherapy, and as single agent maintenance therapy was investigated in 717 patients (18 to 60 years of age) in a randomized, double-blind, pivotal, Phase III study. Patients with newly diagnosed FLT3-mutated acute myeloid leukemia (AML) as determined by a clinical trial assay were randomized (1:1) to receive Rydapt 50 mg twice daily (number of patients [n] = 360) or placebo (n = 357) sequentially (Days 8 to 21) in combination with standard daunorubicin (60 mg/m² daily on Days 1 to 3) / cytarabine (200 mg/m2 daily on Days 1 to 7) for up to two cycles of induction and high dose cytarabine (3 g/m² every 12 hours on Days 1, 3, 5) for up to four cycles of consolidation. The dosing regimen was followed by continuous Rydapt or placebo treatment according to initial assignment for up to 12 additional 28-day cycles as maintenance. There was no re-randomization at the start of maintenance therapy. Patients who proceeded to hematopoietic stem cell transplant (SCT) stopped receiving study treatment before the SCT conditioning regimen.

Patients with acute promyelocytic leukemia (M3) or therapy-related AML were excluded. Patients were stratified by FLT3 mutation status: TKD, ITD with allelic ratio <0.7, and ITD with allelic ratio ≥0.7.

The two treatment groups were generally balanced with respect to the baseline demographics and disease characteristics, except that the placebo plus standard chemotherapy group had a higher percentage of females than in the Rydapt plus standard chemotherapy group.

Of the 717 patients, 25% had a second course of induction, 62% initiated at least one cycle of consolidation, 29% initiated maintenance, and 17% completed all 12 planned cycles of maintenance. The overall rate of SCT was 59.4% (214/360) of patients in the Rydapt plus standard chemotherapy group vs. 55.2% (197/357) in the placebo plus standard chemotherapy group. Twenty-one percent of all the patients in the study underwent SCT in the first complete remission. All patients were followed for survival.

The primary endpoint of the study was overall survival (OS), measured from the date of randomization until death by any cause. The primary analysis was conducted after a minimum follow-up of approximately 3.5 years after the randomization of the last patient. The key secondary endpoint was event-free survival (EFS; defined as a failure to obtain a complete remission [CR] within 60 days of initiation of protocol therapy, or relapse, or death from any cause). Another secondary endpoint was disease-free survival (DFS) which was measured from the date of the first CR to the date of relapse or death from any cause, whichever occurred first.

A statistically significant improvement in OS was observed with a 23% risk reduction of death for Rydapt plus standard chemotherapy over placebo plus standard chemotherapy (hazard ratio [HR] of 0.77 [95% confidence interval [CI]: 0.629, 0.953; one-sided p value = 0.0078]). Median OS could not be reliably estimated.

The key secondary efficacy endpoint EFS non-censored at the time of SCT, also demonstrated the benefits of Rydapt plus standard chemotherapy over placebo plus standard chemotherapy. The median EFS was 8.2 months (95% CI: 5.4, 10.7) vs. 3.0 months (95% CI: 1.9, 5.9) respectively, with a HR of 0.78 (95% CI: 0.66, 0.93, p = 0.0024, one-sided).

Other secondary efficacy endpoints also supported the benefit of adding Rydapt to chemotherapy. Rates of CR by Day 60 were also numerically higher in patients treated with Rydapt (58.9% vs. 53.5%) although the difference was not statistically significant. Median DFS (not censored at the time of SCT) was 26.7 months in the Rydapt group and 15.5 months in the placebo group (HR = 0.71; 95% CI: 0.55, 0.92; p = 0.0051, one-sided).

The impact of SCT on the efficacy endpoints were analyzed by censoring at the time of SCT for OS, EFS and DFS analyses, and the results were supportive of the primary OS analysis.

Subgroup analyses showed a consistent OS benefit across most investigated subgroups, except for the analysis by gender which showed no apparent OS advantage in female patients treated with Rydapt where the HR was 1.01 (95% CI: 0.76, 1.34). The HR for male patients was 0.53 (95% CI: 0.39, 0.72). This gender effect was not observed with the secondary efficacy endpoints (EFS, DFS and CR rate). Collectively, the available data are not sufficient to conclude that there is a difference in treatment benefit for males and females, especially when the subgroup analyses are not powered to demonstrate statistically significant differences between treatment groups. The observed difference in OS by gender has been communicated in the Clinical Trial section of the Rydapt Product Monograph.

The submission also included eight supportive studies. Two supportive studies (A2106 and ADE02T) evaluated the use of Rydapt in combination with standard chemotherapy in patients with FLT3-mutated AML. In the other six supportive studies (A2104, A2104E1, A2104E2, A2114, D2201, and A2213), Rydapt was administered as a single agent in patients with AML or other types of hematological malignancies (myelodyplastic syndrome, aggressive systemic mastocytosis, and mast cell leukemia).

Indication

The New Drug Submission for Rydapt was filed by the sponsor with the following indication:

• Rydapt is indicated in combination with standard induction and consolidation chemotherapy followed by single agent maintenance therapy for adult patients with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive.

The indication proposed by the sponsor included a maintenance phase with Rydapt monotherapy following the consolidation therapy. Health Canada did not approve this indication because the sponsor failed to provide convincing evidence of the benefit of maintenance therapy. Although maintenance therapy was an integral part of the pivotal study, the patients were not re-randomized prior to the start of the maintenance phase. When the small number of patients who entered this phase was considered, it was difficult to assess the contribution of this phase to the OS benefit.

To ensure safe and effective use of the product, Health Canada approved the following indication:

• Rydapt is indicated in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy for the treatment of adult patients with newly diagnosed FLT3-mutated acute myeloid leukemia (AML).
• A validated test is required to confirm the FLT3 mutation status of AML.

Overall Analysis of Efficacy

Based on the data reviewed, the combination of Rydapt with standard cytarabine and daunorubicin induction and cytarabine consolidation is an effective treatment for adult patients with newly diagnosed FLT3-mutated AML.

For more information, refer to the Rydapt Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety evaluation of Rydapt (50 mg twice daily) in patients with newly diagnosed FLT3-mutated AML was based on the pivotal Phase III, randomized, double-blind, placebo-controlled study described in the Clinical Efficacy section.

All patients in the pivotal study experienced at least one adverse event of any grade and all but one patient in the Rydapt group experienced at least one Grade 3/4 adverse event.

The most frequent adverse drug reactions (ADRs, incidence ≥20% and ≥2% more in the Rydapt group) were febrile neutropenia, lymphopenia, device- related infection, and exfoliative dermatitis.

Serious ADRs occurred in 32.3% of patients in the Rydapt group vs. 30.1% in the placebo group. The most frequent serious ADR in the Rydapt group was febrile neutropenia (16.2%) and this occurred at a similar rate in the placebo group (15.9%); less frequent serious ADRs (>2%) included pyrexia (3.1% vs. 4.0%), device-related infection (7.4% vs. 4.4%), exfoliative dermatitis (2.6% vs. 1.8%), and hypotension (2.6% vs. 1.3%), respectively.

There were fewer patients who died during treatment in the Rydapt group than in the placebo group, 15 patients (4.3%) vs. 21 patients (6.3%), respectively.

Of the laboratory abnormalities, the following parameters were observed at a higher frequency in the Rydapt group compared to the placebo group: aspartate aminotransferase (AST) (73.9% vs. 65.4%), Grade 3/4 alanine aminotransferase (ALT) (19.4% vs. 14.9%), hypercalcemia (6.7% vs. 3.6%), and hypernatremia (20% vs. 14.9%), respectively.

QT prolongation, cardiac toxicity (cardiac failure), neutropenia and infection, and pulmonary toxicity (interstitial lung disease and pneumonitis) were observed in patients treated with Rydapt. Appropriate warnings are included in the Rydapt Product Monograph. Inclusion of these adverse events within a Serious Warnings and Precautions box was not required as causality could not be established given the available data. The recommendations to monitor for these adverse events and the actions to take upon their occurrence are included in the Rydapt Product Monograph.

The clinical studies with Rydapt did not include sufficient numbers of patients aged 60 years and over to determine whether they respond differently from younger patients. Therefore, it is stated under the Warning and Precautions section of the Rydapt Product Monograph that there is limited experience with the indicated use of Rydapt in AML patients aged 60-70 years and no experience in AML patients above 70 years. That section also indicates that, in patients aged ≥60 years, Rydapt should be used only in patients eligible to receive intensive induction chemotherapy with adequate performance status and without significant comorbidities.

Overall, the safety data show that while there is toxicity associated with the treatment combinations used in the pivotal study, the addition of Rydapt to the standard chemotherapy regimen did not appear to considerably increase the toxicity of the treatment combination (compared to the addition of placebo in the comparator arm). The safety profile of Rydapt and risk mitigation recommendations for the specified indication and clinical use are appropriately captured in the Rydapt Product Monograph.

For more information, refer to the Rydapt Product Monograph, approved by Health Canada and available through the Drug Product Database.