FDA Drug Approvals - November 2015

In This Article

Gefitinib Approved for First-Line Treatment of Metastatic Lung Cancer Associated with EGFR Mutations
Sonidegib Approved for Locally Advanced Basal-Cell Carcinoma
Brentuximab Vedotin Gets New Indication for Patients with Hodgkin Lymphoma
Emend Gets Expanded Indication for CINV Prevention in Pediatric Patients
Rolapitant a New Antiemetic Option for CINV Prevention
Lonsurf a New Oral Combination for Patients with Metastatic Colorectal Cancer
First Combination of 2 Immunotherapies Approved for Advanced Melanoma
Keytruda, plus a Companion Diagnostic, Approved for Metastatic Lung Cancer

Gefitinib Approved for First-Line Treatment of Metastatic Lung Cancer Associated with EGFR Mutations

The FDA approved the oral therapy gefitinib (Iressa; AstraZeneca) for the first-line treatment of patients with metastatic non–small-cell lung cancer (NSCLC) and EGFR mutations exon 19 deletions or exon 21 L858R substitution (July 13, 2015).

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 as a companion diagnostic test to identify patients with NSCLC plus EGFR mutations to ensure appropriate use of this drug.

“Companion diagnostics provide information that is essential for the safe and effective use of important medications,” said Alberto Gutierrez, PhD, Director of the FDA’s Office of In Vitro Diagnostics and Radiological Health.

Gefitinib was originally approved by the FDA in 2003 for the treatment of patients with advanced NSCLC after the disease progressed with platinum-based chemotherapy and docetaxel. This medication was voluntarily withdrawn from the market when confirmatory trials did not verify clinical benefit. However, this new FDA approval is for patients with metastatic NSCLC and EGFR mutations who have not received any previous therapy, based on new trial data showing 50% response rate among 106 patients with treatment-naïve, metastatic NSCLC plus EGFR mutations.

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Sonidegib Approved for Locally Advanced Basal-Cell Carcinoma

Sonidegib (Odomzo Capsules, Novartis Pharmaceuticals) received FDA approval for use in patients with locally advanced basal-cell carcinoma (BCC) after surgery or radiation therapy, or those who are not candidates for either (July 24, 2015).

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 the durable overall response rate 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 800 mg, but the side effects were more common at this dose.

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 prescribing this medication.

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Brentuximab Vedotin Gets New Indication for Patients with Hodgkin Lymphoma

Brentuximab vedotin (Adcetris; Seattle Genetics) received a new indication from the FDA for the postautologous hematopoietic stem-cell transplantation (auto-HSCT) consolidation treatment of patients with Hodgkin lymphoma at high risk for disease relapse or progression (August 17, 2015).

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 relapse or progression. After an auto-HSCT, patients were randomized to brentuximab vedotin or to placebo once every 3 weeks for a maximum of 16 cycles. Significant improvement in progression-free survival was seen with brentuximab vedotin compared with placebo—42.9 months versus 24.1 months, respectively. So far, no difference was seen in overall survival between the 2 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.

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Emend Gets Expanded Indication for CINV Prevention in Pediatric Patients

The FDA approved a new indication for the NK1 receptor antagonist aprepitant capsules (Emend; Merck & Co) in combination with other antiemetic agents for the prevention of acute or delayed chemotherapy-induced nausea and vomiting (CINV) in young patients aged 12 to 17 years, and for children and adolescents aged <12 years who weigh ?30 kg and are receiving highly emetogenic chemotherapy or moderately emetogenic chemotherapy (August 28, 2015). Activation of NK1 receptors plays a central role in nausea and vomiting induced by chemotherapy.

The new indication is based on phase 3 clinical trial results that compared the combination of aprepitant plus ondansetron (Zofran) versus ondansetron plus placebo. Overall, 49.2% of patients receiving the aprepitant combination achieved complete response in the delayed phase, defined as 25 to 120 hours after the initiation of chemotherapy, compared with 18.8% of those receiving ondansetron monotherapy. In the acute CINV phase, 55.6% of patients had a complete response with the combination versus 37.7% with ondansetron alone.

The most common grade 3 or 4 adverse events with aprepitant plus ondansetron were febrile neutropenia, anemia, and reduced neutrophils. Febrile neutropenia was the most common serious adverse event in each group. Aprepitant dosing is not yet available for patients younger than age 12 years who weigh less than 30 kg. An application for an investigational powder for suspension formulation for that patient population is pending.

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Rolapitant a New Antiemetic Option for CINV Prevention

The FDA approved rolapitant (Varubi; Tesaro), an NK1 receptor antagonist, for the prevention of delayed-phase CINV in adults (September 2, 2015). Rolapitant is intended to be used in combination with other antiemetic agents that prevent CINV in the initial and repeated courses of vomit-inducing highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC) 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 approval of rolapitant was based on 3 phase 3 clinical trials comparing rolapitant in combination with granisetron and dexamethasone and a control group.

Rolapitant was associated with a significant reduction in CINV episodes or in the use of rescue medication in the 25 to 120 hours after MEC or HEC. 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.

Rolapitant is contraindicated for use with thioridazine, which is metabolized by the CYP2D6 enzyme. The most common side effects in patients treated with rolapitant included neutropenia, hiccups, decreased appetite, and dizziness.

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Lonsurf a New Oral Combination for Patients with Metastatic Colorectal Cancer

The oral combination of tipiracil plus trifluridine (Lonsurf; Taiho Oncology Inc) was approved for use in patients with metastatic colorectal cancer who are no longer responding to other therapies (September 22, 2015).

“There are many patients who still need additional options, and today’s approval is a testament to the FDA’s commitment to work with companies to develop new drugs in disease areas where unmet needs remain,” said Dr Pazdur.

The efficacy and safety of the new combination drug were evaluated in a randomized, double-blind study that included 800 patients with metastatic disease who had received previous therapy. The patients received the oral combination plus best supportive care or placebo plus best supportive care until disease progression or until the side effects became intolerable. The overall survival was 7.1 months with the tipiracil plus triflur­idine compared with 5.3 months with placebo. The average time to disease progression was 2 months versus 1.7 months, respectively.

The most common side effects of tipiracil plus trifluridine were anemia, neutropenia, thrombocytopenia, physical weakness, fatigue, nausea, decreased appetite, diarrhea, vomiting, abdominal pain, and fever. The patient’s complete blood count should be evaluated before prescribing this oral combination, because this new therapy may cause myelosuppression.

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First Combination of 2 Immunotherapies Approved for Advanced Melanoma

The FDA approved the use of the first combination regimen of 2 immunotherapies for the treatment of patients with wild-type BRAF V600 unresectable or metastatic melanoma (October 1, 2015). The new combination includes 2 therapies currently approved as monotherapies for patients with melanoma—nivolumab (Opdivo), a PD-1 checkpoint inhibitor, and ipilimumab (Yervoy), a CTLA-4 checkpoint inhibitor; both drugs are manufactured by Bristol-Myers Squibb.

The FDA used its accelerated review process to approve this new regimen based on the results from the pivotal CheckMate-69 clinical trial, a phase 2, double-blind, randomized study of 140 patients with treatment-naïve unresectable or metastatic melanoma; of these, 109 patients had BRAF wild-type melanoma. The primary end point was objective response rate.

The objective response rate was significantly higher in the patients without the BRAF mutation (ie, BRAF wild-type melanoma) who received the combination regimen compared with ipilimumab alone. The combination regimen showed a 60% reduction in disease progression risk compared with ipilimumab alone. Overall, 79% of patients had ongoing responses lasting at least 6 months at the time of data analysis, with 20 patients showing response duration of ?9 months. The side effects were similar to those seen with each monotherapy. Melanoma experts responded to the FDA news with excitement.

“Historically, metastatic melanoma has been a difficult disease to treat,” said Jedd D. Wolchok, MD, PhD, Chief, Melanoma and Immunotherapeutics Service, Department of Medicine and Ludwig Center at Memorial Sloan Kettering Cancer Center. “Today’s approval represents a step forward for the melanoma community, providing hope for patients with metastatic melanoma.”

The Society for Immunotherapy of Cancer (SITC) issued a press release applauding the approval and its implications. “The approval of this combination therapy is a major turning point, offering patients a new treatment option, and opens the door for many other synergistic therapies to emerge.” SITC President, Howard L. Kaufman, MD, FACS, Rutgers Cancer Institute of New Jersey, added, “Today’s approval also illustrates the potential advantage of combining immunotherapy agents offering previously unavailable options to cancer patients.”

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Keytruda, plus a Companion Diagnostic, Approved for Metastatic Lung Cancer

The FDA granted accelerated approval for pembrolizumab (Keytruda; Merck & Co) for the treatment of patients with metastatic NSCLC that has progressed after other treatments and with tumors that express the PD-1 ligand 1 (PD-L1) protein (October 2, 2015). Pembrolizumab is the second PD-1/PD-L1 approved for NSCLC. Earlier in 2015, the PD-1/PD-L1 nivolumab was approved for the treatment of squamous NSCLC.

Pembrolizumab was approved with an immunohistochemistry (IHC) companion diagnostic test called PD-L1 IHC 22C3 pharmDx (Dako North America Inc), the first test designed to detect PD-L1 expression in NSCLC.

“Our growing understanding of underlying molecular pathways and how our immune system interacts with cancer is leading to important advances in medicine,” said Dr Pazdur. “Today’s approval of Keytruda gives physicians the ability to target specific patients who may be most likely to benefit from this drug.”

The efficacy of pembrolizumab in NSCLC was studied in a subgroup of 61 patients who participated in a large clinical trial and had advanced NSCLC. PD-L1 overexpression in patients in this subgroup was determined with the PD-L1 IHC 22C3 pharmDx diagnostic test. The overall response rate with pembrolizumab was 41%.

Quest Diagnostics announced it will provide laboratory testing using the PD-L1 IHC 22C3 pharmDx companion diagnostic test.

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