Recent FDA Actions Include New Drug Approvals in Leukemia, Expanded Approvals in Colorectal Cancer and Graft-vs-Host Disease


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The U.S. Food and Drug Administration (FDA) recently granted approval, expanded approval, and breakthrough therapy designation to numerous treatments across a range of tumor types and malignancies.

New Drug Approvals

Daunorubicin-Cytarabine Combination (Vyxeos): On August 3, the FDA granted regular approval to a liposome-encapsulated combination of daunorubicin and cytarabine (Vyxeos) for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes, two types of AML associated with a poor prognosis. This is the first FDA-approved treatment specifically for patients with therapy-related AML or AML with myelodysplasia-related changes.

Approval was based on data from Study CLTR0310-301, a randomized (1:1), multicenter, open-label, active-controlled trial comparing the liposome-encapsulated daunorubicin-cytarabine to a standard combination of daunorubicin and cytarabine (7+3) in 309 patients aged 60 to 75 years with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. The liposome-encapsulated daunorubicin-cytarabine combination demonstrated an estimated median overall survival of 9.6 months compared with 5.9 months for the 7+3 control (hazard ratio = 0.69; 95% confidence interval [CI] = 0.52–0.90; P = .005).

The most common adverse reactions occurring in greater than 25% of patients treated with the liposome-encapsulated daunorubicin-cytarabine combination were hemorrhage events, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting.

Enasidenib (Idhifa): On August 1, the FDA approved enasidenib -(Idhifa) for the treatment of adult patients with relapsed or refractory AML who have a specific genetic mutation. The drug is approved for use with a companion diagnostic, the RealTime IDH2 Assay, which is used to detect specific mutations in the IDH2 gene in patients with AML.

Enasidenib is an isocitrate dehydrogenase-2 inhibitor that works by blocking several enzymes that promote cell growth. If the IDH2 mutation is detected in blood or bone marrow samples using the assay, the patient may be eligible for enasidenib.

The efficacy of enasidenib was studied in a single-arm trial of 199 patients with relapsed or refractory AML who had IDH2 mutations as detected by the assay. With a minimum of 6 months of treatment, 19% of patients experienced complete remission for a median of 8.2 months, and 4% of patients experienced complete remission with partial hematologic recovery for a median of 9.6 months. Of the 157 patients who required transfusions of blood or platelets due to AML at the start of the study, 34% no longer required transfusions after treatment with enasidenib.

Common side effects of enasidenib included nausea, vomiting, diarrhea, increased levels of bilirubin, and decreased appetite.

Expanded Approvals

Nivolumab (Opdivo): On July 31, the FDA approved nivolumab (Opdivo) injection for intravenous use for the treatment of adult and pediatric (12 years and older) patients with microsatellite instability–high or mismatch repair–deficient metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Approval for this -indication has been granted under accelerated approval based on the overall response rate and duration of response seen in the CheckMate 142 trial. 

Checkmate 142 was a multicenter, open-label, single arm study conducted in 53 patients with locally determined microsatellite instability–high or mismatch repair–deficient metastatic colorectal cancer who had disease progression during, after, or were intolerant to prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. This was a subset of the 74 patients who received at least one prior regimen for treatment of metastatic disease containing a fluoropyrimidine with oxaliplatin or irinotecan. All patients received nivolumab 3 mg/kg by intravenous infusion every 2 weeks until unacceptable toxicity or radiographic progression.

The objective response rate as assessed by independent radiographic review committee using RECIST 1.1 was 28% (n = 15) (95% confidence interval, range 17%–42%) in the 53 patients who received prior fluoropyrimidine, oxaliplatin, and irinotecan. Responses lasted 6 or more months for 67% of patients. There was 1 complete response and 14 partial responses. 

The most common adverse reactions (≥ 20%) in patients who received nivolumab as a single agent were fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, and pyrexia.

The recommended nivolumab dose for this indication is 240 mg every 2 weeks.

Ibrutinib (Imbruvica): On August 2, the FDA approved ibrutinib (Imbruvica) for the treatment of adult patients with chronic graft-vs-host disease after failure of one or more lines of systemic therapy. This is the first FDA-approved therapy for the treatment of chronic graft-vs-host disease. 

Approval was based on Study PCYC-1129-CA, an open-label, multicenter, single-arm clinical trial enrolling 42 patients with chronic graft-vs-host disease after failure of first-line corticosteroid therapy and requiring additional therapy. Responses were seen in all organs involved with graft-vs-host disease (skin, mouth, gastrointestinal tract, and liver). Responses lasting 5 months or longer were observed in 48% of the patients (n = 20).

The most common adverse reactions (≥ 20%) were fatigue, bruising, diarrhea, thrombocytopenia, stomatitis, muscle spasms, nausea, hemorrhage, anemia, and pneumonia. Treatment was discontinued due to adverse reactions in 24% of the patients. 

Breakthrough Therapy Designations

Acalabrutinib: On August 1, the FDA granted Breakthrough Therapy designation for acalabrutinib in the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Acalabrutinib is a highly selective, potent Bruton tyrosine kinase inhibitor in development for the treatment of multiple B-cell cancers. The Breakthrough Therapy designation was based on the totality of clinical data from the acalabrutinib development program, including data from the phase II ACE-LY-004 clinical trial in patients with relapsed or refractory MCL.

Durvalumab (Imfinzi): On July 31, the FDA granted Breakthrough Therapy designation for durvalu-mab (Imfinzi) for the treatment of patients with locally advanced, unresectable non–small cell lung cancer (NSCLC) whose disease has not progressed following platinum-based chemoradiation therapy. The Breakthrough Therapy designation for durvalumab was granted on the basis of interim results from the phase III PACIFIC trial.

Venetoclax (Venclexta): On July 28, the FDA granted Breakthrough Therapy designation for venetoclax (Venclexta) in combination with low-dose cytarabine for elderly patients with previously untreated AML who are ineligible for intensive chemotherapy. Breakthrough Therapy designation was granted based on data from an ongoing open-label phase Ib study of venetoclax in combination with low-dose cytarabine in previously untreated elderly patients (> 65 years) with AML who were ineligible for intensive chemotherapy. 

For additional information about these drugs visit www.fda.gov. ■



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