FDA News: April 1, 2022, and May 25, 2022

TON - June 2022 Vol 15, No 3

Tibsovo Receives a New Indication, in Combination with Onureg, for Newly Diagnosed Patients with AML and IDH1 Mutation

On May 25, 2022, the FDA accelerated the approval of ivosidenib tablets (Tibsovo; Servier Pharmaceuticals), in combination with azacitidine tablets (Onureg; Celgene) for newly diagnosed acute myeloid leukemia (AML) and a susceptible IDH1 mutation, as detected by an FDA-approved test, in patients aged ≥75 years, or patients with comorbidities that preclude the use of intensive induction chemotherapy.

The FDA granted this indication a breakthrough therapy designation. Ivosidenib was previously approved for the treatment of adults with relapsed or refractory AML and for locally advanced or metastatic cholangiocarcinoma. Oral azacitidine was previously approved for adults with AML who achieved first complete remission (CR) or CR with incomplete blood count recovery following intensive induction chemotherapy and who are not able to complete intensive curative therapy.

This new indication was approved based on a randomized, multicenter, double-blind, placebo-controlled clinical trial of 146 patients with newly diagnosed AML and IDH1 mutation who met ≥1 of the following criteria: age ≥75 years, or having comorbidities that preclude intensive induction chemotherapy, baseline Eastern Cooperative Oncology Group performance status 2, severe cardiac or pulmonary disease, hepatic impairment with bilirubin >1.5 times the upper limit of normal, creatinine clearance <45 mL/min, or another comorbidity.

The patients were randomized in a 1:1 ratio to oral ivosidenib once daily (N = 72) or to matched oral placebo once daily (N = 74), on days 1 to 28, in combination with oral azacitidine once daily on days 1 to 7 or days 1 to 5, 8, and 9 of each 28-day cycle, until disease progression, unacceptable adverse events, or hematopoietic stem-cell transplantation.

The primary end point of the trial was event-free survival (EFS), defined as time from randomization until treatment failure (failure to achieve CR by week 24), relapse from remission, or death from any cause, whichever occurred first. Key secondary end points included overall survival (OS) and the rate and duration of CR.

Results showed a statistically significant improvement in EFS (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.17-0.72; P = .0038) and OS (HR, 0.44; 95% CI, 0.27-0.73; P = .0010) with ivosidenib plus azacitidine compared with placebo plus azacitidine. EFS events occurred in 65% of patients in the ivosidenib arm and 84% of patients in the placebo arm.

Median OS was 24.0 months (95% CI, 11.3-34.1) and 7.9 months (95% CI, 4.1-11.3) in the ivosidenib plus azacitidine and placebo plus azacitidine arms, respectively (HR, 0.44; 95% CI, 0.27-0.73; P = .0010).

By week 24, the CR rate was 47% (95% CI, 35-59) versus 15% (95% CI, 8-25), respectively. The median duration of CR was not estimable (NE) in the ivosidenib plus azacitidine arm (95% CI, 13.0-NE) and was 11.2 months (95% CI, 3.2-NE) in the placebo plus azacitidine arm.

The most common (≥25%) adverse reactions reported with ivosidenib plus azacitidine or as monotherapy were diarrhea, fatigue, edema, nausea, vomiting, decreased appetite, leukocytosis, arthralgia, dyspnea, abdominal pain, mucositis, rash, electrocardiogram prolonged QT, differentiation syndrome (which may be life-threatening), and myalgia.

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Vidaza Now Approved for Patients with Newly Diagnosed Juvenile Myelomonocytic Leukemia

On May 20, 2022, the FDA accelerated the approval of a new indication for azacitidine injection (Vidaza; Celgene) for the treatment of pediatric patients with newly diagnosed juvenile myelomonocytic leukemia (JMML).

The FDA granted this indication a breakthrough therapy designation. Azacitidine injection was previously approved for the treatment of adult patients with myelodysplastic syndromes.

This new indication was approved based on a multicenter, open-label clinical trial that included 18 pediatric patients with JMML. Researchers assessed the pharmacokinetics, pharmacodynamics, safety, and activity of azacitidine prior to hematopoietic stem-cell transplantation (HSCT).

The patients received intravenous (IV) azacitidine once daily on days 1 to 7 of a 28-day cycle, for a minimum of 3 cycles and a maximum of 6 cycles. Patients were included in the study if they did not have disease progression or were not ready for HSCT between cycles 4 and 6.

The main efficacy outcome measures were clinical complete remission or clinical partial remission according to the International Juvenile Myelomonocytic Leukemia Working Group response criteria at 3 months (cycle 3, day 28). The responses must have been sustained for at least 4 weeks in the 4-week period preceding or succeeding cycle 3.

Nine of the 18 patients (50%) had confirmed clinical responses, with 3 having a clinical complete response and 6 having a clinical partial response. The median time to response was 1.2 months (range, 0.95-1.87 months).

Most (94%) patients underwent HSCT, with a median time to HSCT of 4.6 months (range, 2.8-19 months).

The most common (>30%) adverse reactions reported with IV azacitidine in pediatric patients with JMML were pyrexia, rash, upper respiratory tract infection, and anemia.

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FDA Grants Enhertu Regular Approval for Patients with Unresectable or Metastatic Breast Cancer

On May 4, 2022, the FDA granted a regular full approval for fam-trastuzumab deruxtecan-nxki (Enhertu; Daiichi Sankyo), an HER2-directed antibody and topoisomerase inhibitor conjugate, for the treatment of adults with unresectable or metastatic HER2-positive breast cancer who had received a prior anti–HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and who had developed disease recurrence during or within 6 months of completing therapy.

The FDA granted this approval a priority review, breakthrough designation, and orphan drug designation. In December 2019, fam-trastuzumab deruxtecan-nxki received accelerated approval for the treatment of adults with unresectable or metastatic HER2-positive breast cancer after ≥2 previous anti–HER2-based regimens in the metastatic setting. This accelerated approval was based on a multicenter, open-label, randomized clinical trial of 524 patients with HER2-positive, unresectable, and/or metastatic breast cancer who had received previous trastuzumab and taxane therapy for metastatic disease or developed disease recurrence during or within 6 months of completing neoadjuvant or adjuvant therapy.

Patients were randomized in a 1:1 ratio to receive either intravenous (IV) fam-trastuzumab deruxtecan-nxki or IV ado-trastuzumab emtansine (Kadcyla; Genentech, Inc) every 3 weeks until unacceptable toxicity or disease progression. Randomization was stratified by hormone receptor status, previous treatment with pertuzumab (Perjeta; Genentech, Inc), and history of visceral disease.

The main efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review based on RECIST version 1.1. Key secondary outcomes included overall survival (OS) and confirmed objective response rate (ORR). Median PFS was not reached (95% confidence interval [CI], 18.5-not estimable) in the fam-trastuzumab deruxtecan-nxki arm and was 6.8 months (95% CI, 5.6-8.2) in the ado-trastuzumab emtansine arm. The hazard ratio was 0.28 (95% CI, 0.22-0.37; P <.0001). At the time of the PFS analysis, 16% of patients had died and OS was immature. The ORR based on the patients with measurable disease assessed by blinded independent central review at baseline was 82.7% (95% CI, 77.4-87.2) in the fam-trastuzumab deruxtecan-nxki arm and 36.1% (95% CI, 30.0-42.5) in the ado-trastuzumab emtansine arm.

The most common (>30%) adverse reactions with fam-trastuzumab deruxtecan-nxki were nausea, fatigue, vomiting, alopecia, constipation, anemia, and musculoskeletal pain.

Fam-trastuzumab deruxtecan-nxki is associated with a risk for interstitial lung disease and embryo-fetal toxicity. Pregnant women should not take this medication.

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Yescarta First CAR T-Cell Therapy FDA Approved for Patients with Large B-Cell Lymphoma

On April 1, 2022, the FDA accelerated the approval of a new indication for the CAR T-cell therapy axicabtagene ciloleucel (Yescarta; Kite Pharma) for adults with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or relapses within 12 months of first-line chemoimmunotherapy.

The FDA granted this new indication breakthrough therapy and orphan drug designations.

This new indication was based on a randomized, open-label, multicenter clinical trial of adults with primary refractory large B-cell lymphoma or large B-cell lymphoma that relapses within 12 months after completion of first-line therapy. The patients had not received treatment for relapsed or refractory lymphoma and were candidates for autologous hematopoietic stem-cell transplantation (HSCT).

The study included 359 patients who were randomized in a 1:1 ratio to a single infusion of the CAR T-cell therapy after lymphodepleting chemotherapy or to second-line standard therapy consisting of 2 or 3 cycles of chemoimmunotherapy, followed by high-dose therapy and autologous HSCT in patients achieving complete or partial remission.

The primary efficacy measure was event-free survival (EFS). The EFS was significantly longer in the axicabtagene ciloleucel arm, with a hazard ratio of 0.40 (95% confidence interval [CI], 0.31-0.51; P <.0001). The estimated 18-month EFS rate was 41.5% (95% CI, 34.2-48.6) in the axicabtagene ciloleucel arm and 17% (95% CI, 11.8-23.0) in the standard-therapy arm. The estimated median EFS was 8.3 months and 2.0 months, respectively.

Among patients who received standard therapy, 35% underwent autologous HSCT; lack of response to chemotherapy was the most common reason for not receiving HSCT. The objective response rate was 83% with axicabtagene ciloleucel and 50% with standard therapy, a significant difference.

The most common (≥30%) nonlaboratory adverse reactions reported with axicabtagene ciloleucel were cytokine-release syndrome, fever, hypotension, encephalopathy, fatigue, tachycardia, headache, nausea, febrile neutropenia, diarrhea, musculoskeletal pain, infections with pathogen unspecified, chills, and decreased appetite.

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