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FDA Update - May 2015

TOP - May 2015, Vol 8, No 2 - FDA Approvals

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Dinutuximab FDA-Approved for Pediatric Patients with High-Risk Neuroblastoma

The US Food and Drug Admin­istration (FDA) has recently approved dinutuximab (Unituxin; United Therapeutics Corporation), an antibody that binds to the surface of neuroblastoma cells, for the treatment of pediatric patients with high-risk neuroblastoma. It is approved for use as part of a multimodal regimen, including surgery, chemotherapy, and radiation therapy in patients who achieved at least partial response to previous first-line, multiagent, multimodality therapy. Dinutuximab received priority review and orphan product designation. It also received a rare pediatric disease priority review voucher.

Dinutuximab was approved based on the safety and efficacy data from a clinical trial of 226 pediatric patients with high-risk neuroblastoma with tumors that shrunk or disappeared after treatment with multidrug chemotherapy and surgery, followed by intensive chemotherapy, bone marrow transplantation support, and radiation therapy. As part of the trial, participants were randomly assigned to receive isotretinoin, an oral retinoid drug, or dinutuximab in combination with interleukin-2 and granulocyte-macrophage colony-stimulating factor. Sixty-three percent of patients who received combination therapy with dinutuximab were alive and free of tumor growth or recurrence after 3 years, compared with 46% of patients who received isotretinoin alone. Updated survival data demonstrated that 73% of patients who received the combination therapy were alive, compared with 58% of patients who were treated with isotretinoin.

The FDA announcement notes that dinutuximab comes with a boxed warning. It is associated with irritation of nerve cells leading to severe pain requiring treatment with intravenous narcotics. Dinutuximab has also been shown to cause nerve damage and life-threatening infusion reactions (eg, upper airway swelling, difficulty breathing, and low blood pressure), during or shortly following completion of the infusion.

Serious side effects associated with dinutuximab include infections, eye problems, electrolyte abnormalities, and bone marrow suppression. The most common side effects of the drug were pain, fever, low platelet counts, infusion reactions, low blood pressure, hyponatremia, elevated liver enzymes, anemia, vomiting, diarrhea, low potassium levels, capillary leak syndrome, neutropenia, lymphopenia, hives, and low calcium levels.

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First HDAC Inhibitor, Panobinostat, Approved for Patients with Multiple Myeloma

The FDA approved panobinostat (Farydak; Novartis Pharmaceuticals) for the treatment of patients with multiple myeloma. Panobinostat works by inhibiting the histone deacetylase (HDAC) enzymes, which slow and/or kill the excess production of plasma cells in the bone marrow that leads to the development of multiple myeloma. Panobinostat was approved under the FDA’s priority review and accelerated approval programs and carries an orphan drug designation.

Panobinostat is the first HDAC inhibitor approved by the FDA. Panobinostat is approved for the treatment of myeloma in patients who have received at least 2 previous standard myeloma therapies, including bortezomib and an immunomodulatory agent (eg, lenalidomide). Panobinostat should be used in combination with bortezomib and dexamethasone.

“Farydak has a new mechanism of action that distinguishes it from prior drugs approved to treat multiple myeloma, making it a potentially attractive candidate agent for the treatment of multiple myeloma,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Farydak’s approval is particularly important, because it has been shown to slow the progression of multiple myeloma.”

The safety and efficacy of panobin­ostat were based on a clinical trial with 193 patients with myeloma who received at least 2 previous treatments, including bortezomib and an immunomodulatory agent. The patients were randomized to a combination of panobinostat, bortezomib, and dexamethasone, or to bortezomib and dexamethasone alone. The 3-drug combination of panobino­stat, bortezomib, and dexamethasone extended the progression-free survival (PFS) by 4.10 months; it was approximately 10.6 months with the 3-drug combination compared with only 5.8 months with bortezomib and dexamethasone alone. In addition, the response rate was 59% among the patients receiving the 3-drug combination versus 41% among those receiving bortezomib and dexamethasone without panobinostat.

The most common side effects seen with panobinostat were diarrhea, tiredness, nausea, swelling in the arms or legs, decreased appetite, fever, vomiting, and weakness. The most common laboratory abnormalities were hypophosphatemia, hypokalemia, hyponatremia, increased creatinine, thrombocytopenia, leukopenia, and anemia.

Panobinostat carries a boxed warning about the risk for severe diarrhea and fatal cardiac events. The FDA requires a Risk Evaluation and Mitigation Strategy program to inform providers of these risks.

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Palbociclib Approved for Metastatic Breast Cancer in Postmenopausal Women

The FDA granted approval to palbociclib (Ibrance; Pfizer) for the treatment of postmenopausal women with metastatic breast cancer. Palbociclib works by blocking the activity of the cyclin-dependent kinases 4 and 6, which promotes cancer cell growth. Palbociclib is indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, HER2-negative cancer who have not received any endocrine-based therapy.

According to Dr Pazdur, “The addition of palbociclib to letrozole provides a novel treatment option to women diagnosed with metastatic breast cancer. The FDA is committed to expediting marketing approval of cancer drugs through our accelerated approval regulations.”

The FDA expedited the approval of palbociclib under its accelerated and priority review programs, and designated it as a breakthrough therapy based on the strength of the preliminary clinical evidence, which shows that the drug may offer an improvement for patients compared with current therapies.

Palbociclib’s efficacy was demonstrated in a clinical trial of 165 postmenopausal women with ER-positive, HER2-negative metastatic breast cancer who had not received treatment for metastatic disease. Patients were randomized to palbociclib plus letrozole or to letrozole alone. PFS was 20.2 months with the combination of palbociclib and letrozole compared with approximately 10.2 months in patients receiving letrozole alone. Overall survival (OS) data are not yet available.

The most common side effects were neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, hair loss, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, and nose bleeding.

The recommended dose is 125 mg for the first 21 days, followed by 7 days without treatment. Patients’ complete blood count should be monitored before the start of therapy, at the beginning of each treatment cycle, and on day 14 of the first 2 cycles.

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FDA Expedites Approval of Lenvatinib for Refractory Differentiated Thyroid Cancer

The FDA approved lenvatinib (Lenvima; Eisai), a multitargeted tyrosine kinase inhibitor (TKI), for the treatment of patients with progressive, differentiated thyroid cancer that is refractory to therapy with radioactive iodine (also known as 131I), a common treatment used for patients with advanced thyroid cancer. The FDA expedited its review of lenvatinib under its priority review program, based on data suggesting that lenvatinib provides significant improvement in safety or efficacy in terms of the treatment of differentiated thyroid cancer, the most common type of thyroid cancer.

The National Cancer Institute estimates that 62,980 Americans were diagnosed with thyroid cancer in 2014, and more than 1800 patients died from the disease. Lenvatinib is the fourth TKI approved by the FDA in the past decade for the treatment of patients with refractory thyroid cancer.

“The development of new therapies to assist patients with refractory disease is of high importance to the FDA,” said Dr Pazdur. “Today’s approval gives patients and healthcare professionals a new therapy to help slow the progression of DTC [differentiated thyroid cancer].”

Lenvatinib also received orphan drug designation, because thyroid cancer is considered a relatively rare disease.

The FDA’s approval of lenvatinib was based on a phase 3 clinical trial with 392 patients with progressive, radioactive iodine therapy–refractory differentiated thyroid cancer who were randomized to lenvatinib or to placebo. The median PFS was 18.3 months in the lenvatinib arm compared with a median PFS of 3.6 months in the placebo arm. In addition, 65% of patients receiving lenvatinib had a reduction in their tumor size compared with only 2% in patients in the placebo arm. The majority of the patients in the placebo arm were switched to lenvatinib therapy upon disease progression.

The most common side effects of lenvatinib were hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, decreased weight, nausea, stomatitis, headache, vomiting, proteinuria, swelling and pain in the palms, palmar-plantar erythrodysesthesia syndrome, and dysphonia.

Lenvatinib is associated with serious side effects, including cardiac failure, arterial thromboembolic events, hepatotoxicity, renal failure and impairment, gastrointestinal perforation or fistula formation, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhage, and risks to an unborn child.

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Nivolumab First Immunotherapy to Get FDA Approval for Metastatic Lung Cancer

The FDA approved a new indication for the immunotherapy nivolumab (Opdivo; Bristol-Myers Squibb) for the treatment of patients with metastatic squamous non–small-cell lung cancer (NSCLC) whose disease progressed during or after platinum-based chemotherapy. Nivolumab is the first immunotherapy to receive FDA approval for patients with lung cancer. It was initially approved late last year for the treatment of patients with unresectable or metastatic melanoma.

Nivolumab is a monoclonal antibody that binds to the PD-1 receptor; it blocks the interaction of PD-1 with its ligands 1 and 2, which inhibits an antitumor immune response.

This new indication is based on results from an open-label, multicenter, multinational randomized trial in patients with metastatic squamous NSCLC with disease progression during or after chemotherapy with a platinum-based regimen. Patients were randomized to nivolumab (N = 135) 3 mg/kg intravenously every 2 weeks or to docetaxel (N = 137) 75 mg/m2 intravenously every 3 weeks. The major efficacy outcome was OS.

The OS was 9.2 months with nivolumab compared with 7.3 months with docetaxel, a significant improvement (P = .002).

Additional efficacy support was provided from a single-arm, multinational, multicenter trial in 117 patients with metastatic squamous NSCLC whose ­disease progressed after platinum-based chemotherapy and ≥1 additional systemic regimens. Objective response rate, the major efficacy outcome, was 15%. At the time of analysis, the response duration was ≥6 months in 59% of the responding patients.

Adverse events were similar to previous trials with nivolumab. Immunemediated adverse reactions included pneumonitis, colitis, hepatitis, nephritis/renal dysfunction, hypothyroidism, and hyperthyroidism.

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Lenalidomide Combined with Dexamethasone Receives Expanded Indication for Patients with Newly Diagnosed Myeloma

The FDA approved an expanded indication for lenalidomide (Revlimid; Celgene Corporation) in combination with dexamethasone for the treatment of patients with newly diagnosed multiple myeloma. This combination was previously approved for the treatment of patients with multiple myeloma who had received ≥1 therapies before.

“The approval of Revlimid as an option for use in all patients with multiple myeloma represents a new paradigm in the management of this disease,” said Kenneth Anderson, MD, Director, Jerome Lipper Multiple Myeloma Center, Dana-Farber/Brigham and Women’s Cancer Center. “We now have clinical evidence demonstrating that starting and keeping newly diagnosed multiple myeloma patients on Revlimid significantly improves progression-free survival.”

The approval was based on the results of several phase 3 clinical trials, including the FIRST trial. This trial evaluated the continuous use of a regimen of lenalidomide plus dexamethasone (Rd) until disease progression compared with the regimen of melphalan, prednisone, and thalidomide (MPT) for 18 months as the primary analysis; a secondary analysis evaluated the use of Rd at a fixed duration of 18 cycles in 1623 patients with newly diagnosed myeloma who were not candidates for stem-cell transplant.

The primary end point in this randomized, open-label, 3-arm trial was median PFS. The PFS was significantly longer among patients who received the continuous Rd regimen (25.5 months) than among patients who received the MPT regimen (21.2 months; hazard ratio [HR], 0.72; P = .001).

Based on an interim OS analysis, the median OS was 58.9 months with continuous Rd and 48.5 months with the MPT regimen (HR, 0.75; 95% confidence interval, 0.62-0.90). Furthermore, patients in the continuous Rd arm had a 25% reduction in mortality risk compared with patients in the MPT arm.

The most common grade 3 or 4 events reported in the continuous Rd arm (until disease progression) included neutropenia (27.8%), anemia (18.2%), thrombocytopenia (8.3%), pneumonia (11.3%), asthenia (7.7%), fatigue (7.3%), back pain (7%), hypokalemia (6.6%), rash (7.3%), cataract (5.8%), dyspnea (5.6%), deep-vein thrombosis (5.6%), and hyperglycemia (5.3%).

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Last modified: September 9, 2019