The FDA has scheduled an Oncologic Drugs Advisory Committee hearing for May 14, 2019, to discuss a new drug application for pexidartinib for the treatment of adult patients with symptomatic tenosynovial giant cell tumor.
The FDA has scheduled an Oncologic Drugs Advisory Committee (ODAC) hearing for May 14, 2019, to discuss a new drug application (NDA) for pexidartinib for the treatment of adult patients with symptomatic tenosynovial giant cell tumor.1
The agency also scheduled a meeting for the same date to discuss the NDA for quizartinib tablets for the treatment of adult patients with relapsed/refractory FLT3-ITD—positive acute myeloid leukemia (AML). Both therapies are developed by Daiichi Sankyo, Inc.
The FDA will consider the recommendations of the ODAC panel following each hearing. Under the Prescription Drug User Fee Date, the FDA must make a decision on the approval for pexidartinib by August 3, 2019. The deadline for the approval of quizartinib is May 25, 2019.
The FDA granted a priority review designation to the application for pexidartinib, an investigational, small molecule, CSF1R inhibitor, in February 2019. The decision was based on findings from the phase III ENLIVEN study, which showed a superior overall response rate (ORR) with pexidartinib at 39.3% compared with 0% at placebo, after 24 weeks of treatment based on central review of magnetic resonance imaging (MRI) scans.2
In the first part of the international, multicenter, double-blind, phase III ENLIVEN study, which was the double-blind phase, 120 patients with symptomatic advanced TGCT—in whom surgical removal of the tumor would lead to potentially worsening functional limitation or severe morbidity—were randomized 1:1 to receive either pexidartinib or placebo at 1000 mg daily for 2 weeks followed by 800 mg daily for 22 weeks.
The primary endpoint of the study was the percentage of patients achieving a complete or partial response (PR), assessed with centrally read MRI scans using RECIST 1.1 criteria, after 24 weeks of treatment. Secondary endpoints included range of motion, response by tumor volume score, Patient-Reported Outcomes Measurement Information System physical function, stiffness, and measures of pain reduction.
Patients had histologically confirmed, advanced, symptomatic TGCT with measurable disease ≥2 cm by RECIST v1.1 criteria. Stratification factors included US versus non-US sites, and upper versus lower extremity.
The findings, which were presented at the 2018 ASCO Annual Meeting, showed that the ORR was 39.3% (95% CI, 28.1-51.9) with pexidartinib versus 0% (95% CI, 0-6.1) in the placebo arm (P <.0001) at the end of part 1. At a median 6 months of follow-up, no responders in the trial progressed. Tumor response was assessed by tumor volume score (TVS), which was 56% (95% CI, 43.3-67.5) with pexidartinib and 0% (95% CI, 0-6.1) with placebo (P <.0001). Responses also correlated with improved patient symptoms and function.
In patients who crossed over to pexidartinib at an initial dose of 800 mg daily (n = 30), the RECIST v1.1 ORR and TVS ORR were 30% and 57% at week 25, respectively.
Regarding safety, all-grade adverse events (AEs) were reported in 98% (n = 60) of patients on pexidartinib and 93% (n = 55) of the placebo arm. Moreover, grade 3/4 AEs were higher with pexidartinib (44%; n = 27) versus placebo (12%; n = 7), and serious AEs were reported in 13% (n = 8) of those on the pexidartinib arm compared with 2% (n = 1) of patients on the placebo arm.
Hepatic toxicities were more frequent with pexidartinib versus placebo (aspartate aminotransferase or alanine aminotransferase ≥3 x upper limit of normal [ULN], 33% vs 0% and total bilirubin ≥2 x ULN, 5% vs 0%). Additionally, 8 patients discontinued pexidartinib treatment because of hepatic AEs. Additionally, 4 patients experienced serious nonfatal AEs with increased bilirubin, one of which lasted about 7 months.
In non-TGCT development trials of pexidartinib, there were 2 severe liver toxicity cases observed. One case required liver transplant and the other was associated with death.
For patients who completed part 1, they may continue onto part 2 of the ENLIVEN trial, which will be an open-label extension portion.
Pexidartinib was also mentioned in ASCO’s January 2019 announcement of selecting progress in treating rare cancers as its Advance of the Year.3 ASCO made the announcement as part of Clinical Cancer Advances 2019: ASCO’s Annual Report on Progress Against Cancer, an annual update that highlights the most impactful clinical research milestones and policy developments that have been achieved over the past year in oncology.
TGCT, which is also referred to as pigmented villonodular synovitis or giant cell tumor of the tendon sheath, is a nonmalignant tumor of the joint or tendon sheath. TGCT is said to be locally aggressive and debilitating in some patients, and is associated with severe morbidity or function limitations. There are currently no FDA-approved systemic therapies for TGCT, and surgery is the primary therapy.
The FDA granted a priority review to the NDA for quizartinib for the treatment of adult patients with relapsed/refractory FLT3-ITD—positive AML in November 2018, with an original action date of May 25, 2019. In April 2019, the agency added 3 months to the review period for the application, allowing the agency to review additional data provided by Daiichi Sankyo.
The application is based on results from the phase III QuANTUM-R study, which demonstrated that the small molecule receptor tyrosine kinase inhibitor targeting FLT3 led to a 24% reduction in the risk of death versus salvage chemotherapy in patients with FLT3-ITD—positive relapsed/refractory AML after frontline treatment with or without hematopoietic stem cell transplantation (HSCT).
In QuANTUM-R, patients were randomized 2:1 to quizartinib at 60 mg once daily, with a 30-mg lead-in (n = 245) or to receive investigators’ choice of salvage chemotherapy that was selected prior to randomization. Chemotherapy regimens included low-dose cytarabine (n = 29); the combination of mitoxantrone, etoposide, and cytarabine, (MEC; n = 40); or the combination of fludarabine, cytarabine and GCSF with idarubicin (FLAG-IDA; n = 53).
Baseline patient characteristics were well balanced between the two arms. The median age in the quizartinib arm was 55 years (range, 19-81) and 89% had an ECOG performance status of 0 to 1. Moreover, 33% of patients were refractory to prior therapy, 23% had relapsed following remission with HSCT, and 45% had relapsed after remission without HSCT.
Additionally, among those who received quizartinib, the FLT3-ITD variant allele frequency ranges included <3% (1%); ≥3% to ≤25% (27%); >25% to ≤50% (35%), and >50% (37%). Cytogenetic risk status included favorable (5%), intermediate (78%), unfavorable (9%), and unknown (8%).
Results showed that the median OS was 6.2 months (95% CI, 5.3-7.2) with quizartinib compared with 4.7 months (95% CI, 4.0-5.5) with salvage chemotherapy (HR, 0.76; 95% CI, 0.58-0.98; stratified log-rank test, 1-sided P = .0177) at a median follow-up of 23.5 months.
The OS benefit with quizartinib in QuANTUM-R was upheld across 3 prespecified sensitivity analyses. In the first, which censored for the effect of transplant, the median OS with quizartinib versus salvage chemotherapy was 5.7 versus 4.6 months (HR, 0.79; 95% CI, 0.59-1.05; P = 0.519). An analysis that censored for the use of other FLT3 inhibitors showed a median OS of 6.6 months versus 5.0 months, respectively (HR, 0.74; 95% CI, 0.55-0.99; P = .0203).
In the third sensitivity analysis that examined the per-protocol set (patients who were randomized and treated without significant protocol deviations), the median OS was 6.2 months and 4.6 months with quizartinib and salvage chemotherapy, respectively (HR, 0.75; 95% CI, 0.57-1.00; P = .0246).
Furthermore, the survival improvement was upheld across several patient subgroups. Among those who underwent prior allogeneic HSCT, the median OS was 5.3 months with quizartinib compared with 4.0 months with salvage chemotherapy; the median OS was 6.9 versus 5.2 months in those without prior allogeneic HSCT. Across subgroups defined by AML risk scores, the OS benefit was also observed; this included intermediate (6.2 vs 4.6 months) and unfavorable risk scores (9.4 vs 5.8 months).
In subgroups defined by response to prior therapy, the median OS was 6.5 vs 4.7 months in patients who relapsed, with no HSCT; 7.9 vs 5.4 months in refractory patients; and 5.1 versus 4.0 months in patients who relapsed following HSCT.
The benefit with quizartinib versus salvage chemotherapy was also observed across subgroups defined by varying allelic ratio, age, sex, and AML history.
The ORR was 69% with quizartinib versus 30% with salvage chemotherapy. Additionally, the composite complete remission (CRc) rate was 48% versus 27% and the PR rate was 21% versus 3%, respectively, and the median duration of CRc was 12.1 weeks versus 5.0 weeks, respectively.
The median event-free survival was 1.4 months (95% CI, 0.0-1.9) with quizartinib compared with 0.9 months (95% CI, 0.4-1.3) with salvage chemotherapy (HR, 0.90; 95% CI, 0.70-1.16; 1-sided, stratified log-rank P = .1071).
Regarding safety, quizartinib was found to be well tolerated; grade 3 QT prolongation was uncommon and there were no grade 4 cases. The most common grade ≥3 hematologic adverse events (AEs) in the quizartinib arm included thrombocytopenia (35% vs 34% in the salvage chemotherapy arm), anemia (30% vs 29%, respectively), neutropenia (32% vs 25%), febrile neutropenia (31% vs 21%), and leukopenia (17% vs 16%).
The most common grade ≥3 nonhematologic AEs in the quizartinib arm were nausea (3% vs 1% in the salvage chemotherapy arm), fatigue (8% vs 1%, respectively), pyrexia (3% vs 4%), musculoskeletal pain (4% in each arm), vomiting (3% vs 1%), hypokalemia (12% vs 9%), and diarrhea (2% vs 3%).