FDA News – September 2015

September 2015, Vol 6, No 8 - FDA Approvals, News & Updates


In This Article




FDA Approved Gefitinib with a Companion Diagnostic Test for First-Line Treatment of Patients with Metastatic Lung Cancer and EGFR Mutations

The FDA approved gefitinib (Iressa; AstraZeneca) for the first-line treatment of patients with metastatic non–small-cell lung cancer (NSCLC) and the epidermal growth factor receptor (EGFR) genetic mutations exon 19 deletions or exon 21 L858R substitution.

Gefitinib is an oral kinase inhibitor that blocks proteins that promote the development of cancer cells that harbor the EGFR exon 19 deletions or exon 21 L858R substitution mutations. The recommended dose of gefitinib is 250 mg, orally, once daily, with no regard to food.

“Iressa offers another effective first-line therapy option for selected lung cancer patients. This approval provides further support for a highly targeted approach to treating cancer,” said Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products. The FDA also granted gefitinib orphan drug designation for this specific indication.

Simultaneously, the FDA approved therascreen EGFR RGQ PCR Kit, to be used as a companion diagnostic test for the identification of patients with tumors that contain these specific EGFR mutations to ensure accurate and appropriate use of gefitinib.

“The approval of the therascreen EGFR RGQ PCR Kit will allow physicians to identify non-small cell lung cancer patients who are candidates for receiving Iressa as first-line therapy,” said Alberto Gutierrez, PhD, Director of the FDA’s Office of In Vitro Diagnostics and Radiological Health. “Companion diagnostics provide information that is essential for the safe and effective use of important medications.”

Gefitinib was approved based on efficacy and safety data from a multicenter, single-arm clinical trial of 106 patients with treatment-naïve, EGFR mutation–positive metastatic NSCLC. The primary end point was the percentage of patients with complete and partial tumor shrinkage or disappearance. Overall, 50% of the patients had their tumor shrink, which lasted for an average of 6 months.

The response rates to therapy were similar in patients with EGFR exon 19 deletions or with exon 21 L858R substitution mutations.

The most common side effects reported with gefitinib were diarrhea and skin reactions, including rash, acne, dry skin, and pruritus. Furthermore, gefitinib may cause serious adverse reactions, including interstitial lung disease, fatal hepatotoxicity, gastrointestinal perforation, severe diarrhea, and grade 3 ocular disorders.

Gefitinib was originally approved by the FDA in 2003 (using its accelerated review process) for the treatment of patients with advanced NSCLC after disease progression with platinum doublet chemotherapy and docetaxel. This medication was voluntarily withdrawn from the market by its manufacturer after confirmatory trials did not verify clinical benefit. However, the current FDA approval is for a different patient population with metastatic NSCLC that is associated with treatment-naïve EGFR mutations, based on new trial data showing clinical benefits in this specific population. (July 13, 2015)

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Sonidegib Approved for Locally Advanced Basal-Cell Carcinoma

The FDA approved sonidegib (Odomzo Capsules, Novartis Pharmaceuticals) for the treatment of patients with locally advanced basal-cell carcinoma (BCC) after surgery or radiation therapy, or patients with BCC who are not candidates for surgery or radiation therapy. The recommended dose for sonidegib is 200 mg orally once daily, taken at least 1 hour before or 2 hours after a meal.

The approval was based on an international, multicenter, double-blind, randomized, 2-arm, noncomparative trial in patients with locally advanced BCC who are not eligible for local therapy or for patients with metastatic BCC. Sonidegib demonstrated improvement in durable objective response rate (ORR) in patients with locally advanced BCC.

Among the 79 patients with locally advanced BCC who received sonidegib 200 mg daily, 76% received previous therapy for BCC and 56% had aggressive disease.

The FDA approval was based on the durable ORR in 58% of patients with locally advanced BCC, among the 66 patients who received sonidegib 200 mg, including 5% complete responses and 53% partial responses. A prespecified sensitivity analysis yielded a complete response rate of 20%. The response rates were similar with the 800 mg, but the side effects were more common at this dose.

Adverse events reported in >10% of patients receiving sonidegib 200 mg included muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, and pruritus. The most common grade 3 or 4 laboratory abnormalities in ?5% of patients were serum lipase and creatine kinase elevations. The most serious adverse events with sonidegib are rhabdomyolysis and embryofetal toxicity.

Sonidegib was approved with a boxed warning about the risk for death or severe birth defects in a developing fetus. Pregnancy status should be verified before using this medication. (July 24, 2015)

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Brentuximab Vedotin Receives New Indication for Patients with Hodgkin Lymphoma

The FDA approved brentuximab vedotin (Adcetris; Seattle Genetics) for the postautologous hematopoietic stem-cell transplantation (auto-­HSCT) consolidation treatment of patients with Hodgkin lymphoma who are at high risk for disease relapse or progression.

The approval was based on a randomized, double-blind, placebo-controlled clinical trial in 329 patients with Hodgkin lymphoma who were at high risk for disease relapse or progression based on pretransplant factors. After an auto-HSCT, patients were randomized to brentuximab vedotin or placebo once every 3 weeks for a maximum of 16 cycles.

The results showed a significant improvement in progression-free survival (PFS) in the arm receiving brentuximab vedotin compared with the placebo arm—42.9 months versus 24.1 months, respectively. At the time of the PFS analysis, an interim analysis of overall survival demonstrated no difference between the groups.

The most common adverse reactions seen with brentuximab vedotin were neutropenia, peripheral sensory neuropathy, thrombocytopenia, anemia, upper respiratory tract infection, fatigue, peripheral motor neuropathy, nausea, cough, and diarrhea. Overall, 24% of the patients had serious adverse reactions, which included pneumonia, pyrexia, vomiting, nausea, hepatotoxicity, and peripheral sensory neuropathy.

The recommended dose and schedule for brentuximab vedotin as post–auto-­HSCT consolidation is 1.8 mg/kg, administered intravenously over 30 minutes every 3 weeks. Treatment should be initiated within 4 to 6 weeks after auto-HSCT or upon recovery from transplantation. Patients should continue treatment until a maximum of 16 cycles, disease progression, or unacceptable toxicity. (August 17, 2015)

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Rolapitant a New Antiemetic Agent Approved for CINV Prevention

The FDA approved rolapitant (Varubi; Tesaro), a selective and competitive antagonist of human substance P/neurokinin 1 (NK-1) receptor antagonist, for the prevention of delayed-phase chemotherapy-induced nausea and vomiting (CINV) in adults. Activation of NK-1 receptors plays a central role in nausea and vomiting induced by certain cancer chemotherapies, particularly in the delayed phase.

Rolapitant was approved for use in combination with other antiemetic agents that prevent CINV in the initial and repeated courses of vomit-­inducing highly emetogenic chemotherapy or moderately emetogenic chemo­therapy regimens.

“Chemotherapy-induced nausea and vomiting remains a major issue that can disrupt patients’ lives and sometimes their therapy,” said Amy Egan, MD, MPH, Deputy Director of the FDA’s Office of Drug Evaluation III. “Today’s approval provides cancer patients with another treatment option for the prevention of the delayed phase of nausea and vomiting caused by chemotherapy.”

The FDA approval of rolapitant was based on results from 3 phase 3 clinical trials comparing rolapitant in combination with granisetron and dexamethasone with a control group (placebo, granisetron, and dexamethasone), showing a significant reduction in episodes of vomiting or in the use of rescue medication during the 25 to 120 hours after the administration of highly emetogenic or moderately emetogenic chemotherapy.

Patients who received rolapitant also reported fewer CINV events during multiple cycles of chemotherapy. The 180-mg dose of rolapitant is to be administered approximately 1 to 2 hours before chemotherapy administration, in combination with a 5-HT3 receptor antagonist and dexamethasone. No dose adjustment is required for dexamethasone, a CYP3A4 substrate, when administering rolapitant.

“While important strides in preventing nausea and vomiting associated with chemotherapy have been made, still up to half of patients receiving emetogenic cancer chemotherapy can experience delayed CINV,” said Richard J. Gralla, MD, Professor of Medicine, Albert Einstein College of Medicine, New York City. “Because NK-1 receptors are key drivers of CINV, especially in the delayed phase, NK-1 receptor antagonists such as VARUBI, when combined with a 5-HT3 receptor antagonist and a corticosteroid, provide enhanced protection from CINV, and do so in the delayed timeframe where the most help is needed.”

Rolapitant is contraindicated for use with thioridazine. The most common side effects in patients treated with rolapitant included neutropenia, hiccups, decreased appetite, and dizziness. (September 2, 2015)

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