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FDA Actions & Updates

The latest approvals, designations, and new indications from the U.S. Food and Drug Administration for oncology drugs.

Monday, December 22, 2014

The Food and Drug Administration has granted accelerated approval to nivolumab (Opdivo, made by Bristol-Myers Squibb) for use in patients with unresectable or metastatic melanoma who no longer respond to other drugs.


Opdivo works by inhibiting the PD-1 protein on cells, which blocks the immune system from attacking melanoma cells. The drug is intended for patients who have been previously treated with ipilimumab and, for melanoma patients whose tumors express the BRAF V600 gene mutation, for use after treatment with ipilimumab and a BRAF inhibitor.


“Opdivo is the seventh new melanoma drug approved by the FDA since 2011,” said Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products. “The continued development and approval of novel therapies based on our increasing understanding of tumor immunology and molecular pathways are changing the treatment paradigm for serious and life-threatening diseases.”


Other FDA-approved treatments for melanoma include ipilimumab (approved in 2011), peginterferon alfa-2b (2011), vemurafenib (2011), dabrafenib (2013), trametinib (2013), and pembrolizumab (2014). Opdivo is being approved more than three months ahead of the prescription drug user fee goal date of March 30, 2015, the date when the agency was scheduled to complete its review of the application.


Opdivo, which had been given both Breakthrough Therapy and Orphan Product designation, was approved under the FDA’s accelerated approval program, which allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients. This program provides earlier patient access to promising new drugs while the company conducts additional clinical trials to confirm the drug’s benefit.


Opdivo’s efficacy was demonstrated in a trial of 120 patients with unresectable or metastatic melanoma, and 32 percent had an objective response. The effect lasted for more than six months in approximately one-third of the participants who had tumor shrinkage.  


Safety was evaluated in the overall trial population of 268 participants treated with Opdivo and 102 treated with chemotherapy. The most common side effects of Opdivo were rash, itching, cough, upper respiratory tract infections, and edema. The most serious side effects were severe immune-mediated side effects involving healthy organs, including the lung, colon, liver, kidneys, and hormone-producing glands.

Saturday, December 20, 2014

The Food and Drug Administration has granted accelerated approval to olaparib (Lynparza, made by AstraZeneca) to treat women with advanced ovarian cancer associated with defective BRCA genes, as detected by an FDA-approved test—i.e., in this case, Myriad’s BRACAnalysis CDx, which was approved at the same time.


Lynparza is a poly ADP-ribose polymerase (PARP) inhibitor that blocks enzymes involved in repairing damaged DNA. It is intended for women with heavily pretreated ovarian cancer that is associated with defective BRCA genes.


“The approval constitutes the first of a new class of drugs for treating ovarian cancer,” said Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products. “Lynparza is approved for patients with specific abnormalities in the BRCA gene and is an example of how a greater understanding of the underlying mechanisms of disease can lead to targeted, more personalized treatment."


The approval was accompanied by approval of the companion BRACAnalysis CDx diagnostic to detect the presence of mutations in BRCA genes in blood samples from patients with ovarian cancer. The BRCA genes are involved with repairing damaged DNA and normally work to suppress tumor growth. Women with mutations resulting in defective BRCA genes are more likely to get ovarian cancer, and an estimated 10 to 15 percent of all ovarian cancer is thought to be associated with hereditary BRCA mutations.


As explained in an FDA news release, the agency evaluated BRACAnalysis CDx’s safety and efficacy under the premarket approval pathway used for high-risk medical devices. Until now, the manufacturer, a clinical laboratory, had been marketing the test--although not specifically as a companion diagnostic--without FDA approval as a laboratory-developed test (LDT)—i.e., a test designed, manufactured, and used in a single laboratory.


“The approval of safe and effective companion diagnostic tests and drugs continue to be important developments in oncology,” said Alberto Gutierrez, PhD, Director of the FDA’s Office of In Vitro Diagnostics and Radiological Health. “We are very excited that the BRACAnalysis CDx is the FDA’s first approval of an LDT under a premarket approval application and is the first approval of an LDT companion diagnostic. The use of companion diagnostics helps bring to market safe and effective treatments specific to a patient’s needs.”


Common side effects of Lynparza included nausea, fatigue, vomiting, diarrhea, distorted taste (dysgeusia), indigestion, headache, decreased appetite, common cold-like symptoms, cough, arthralgia, musculoskeletal pain, myalgia, back pain, dermatitis, and abdominal pain. Serious side effects included the development of myelodysplastic syndrome, acute myeloid leukemia, and lung inflammation.


The most common laboratory abnormalities were increased creatinine, increased average volume of red blood cells, decreased red blood cell count, decreased white blood cell count, and decreased platelet levels.


In June, Lynparza was reviewed by the FDA’s Oncologic Drugs Advisory Committee for potential use as maintenance therapy, but the vote was 11 to 2 that the data did not support accelerated approval for this use. After the meeting, the company submitted additional information supporting Lynparza’s use for a different use: in patients with mutated BRCA genes (gBRCAm)-associated ovarian cancer who have received three or more chemotherapy treatments.

Wednesday, December 17, 2014

The U.S. Food and Drug Administration has approved Somatuline Depot (lanreotide) Injection for the treatment of adult patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs), which are unresectable, well- or moderately differentiated, locally advanced, or metastatic. The drug is being approved after being granted priority review earlier this year (OT 10/10/14 issue).


The FDA's priority review designation shortens the time to complete a drug's review and aims to deliver a decision on marketing approval designation for drugs that may offer major advances in treatment or provide a treatment where no adequate therapy exists within six months under the Prescription Drug User Fee Act (PDUFA).


Somatuline—which contains lanreotide acetate, a somatostatin analogue that inhibits the secretion of several endocrine, exocrine, and paracrine amines and peptides—will be delivered via a newly approved, ready-to-use, prefilled syringe that includes a retractable needle guard to help avoid needle sticks, and it is manufactured without latex or natural dry rubber, according to a news release from the manufacturer, Ispen Biopharmaceuticals, Inc. The new delivery device does not require reconstitution and is a low volume (0.5 mL) deep subcutaneous injection offering a streamlined process that supports full dose delivery.


The approval is based on data from a Phase III, double-blind study of 204 patients with advanced gastrointestinal and pancreatic neuroendocrine tumors who received treatment with Somatuline or placebo. Median progression-free survival for the patients receiving Somatuline was not reached (and will be greater than 22 months), and 65.1 percent of those patients had no disease progression and had not died at 96 weeks; whereas median progression-free survival for patients treated with the placebo was 16.6 months, and at 96 weeks 33 percent of those patients had no disease progression and had not died.


The most common adverse events reported in the trial for Somatuline were abdominal pain, musculoskeletal pain, vomiting, headache, injection site reaction, hyperglycemia, hypertension, and cholelithiasis. Five percent of patients receiving Somatuline discontinued treatment due to an adverse event, compared with three percent of patients who received the placebo.

Friday, December 12, 2014

The U.S. Food and Drug Administration has expanded the approved use of Cyramza (ramucirumab) for the treatment of patients with metastatic non-small cell lung cancer. Cyramza, an angiogenesis inhibitor that blocks the blood supply to tumors, is intended for patients whose tumor has progressed during or following treatment with platinum-based chemotherapy. Cyramza is to be used in combination with docetaxel.


Cyramza was also approved earlier this year as a single agent to treat patients with advanced stomach cancer or gastroesophageal junction adenocarcinoma (OT 5/25/14 issue). That indication was expanded in November to include the chemotherapy paclitaxel with that use for Cyramza (OT 12/10/14 issue).


“Today’s approval is the third indication that Cyramza has received in 2014,” Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a news release. “The commitment to study Cyramza in a variety of malignancies provides important treatment options to patients.”


Cyramza’s latest approval is based on a clinical study of 1,253 patients with previously treated and progressive lung cancer who were randomly assigned to receive Cyramza plus docetaxel or a placebo plus docetaxel. Median overall survival for patients treated with Cyramza plus docetaxel was 10.5, compared with 9.1 months for the patients who received placebo plus docetaxel. Treatment was stopped for the other patients in the trial due to disease progression or intolerable side effects.


“By adding ramucirumab [Cyramza] to docetaxel, patients were able to live longer than those who were treated with the standard approach," the study’s principal investigator, Edward Garon, MD, a researcher at UCLA's Jonsson Comprehensive Cancer Center, said in a news release from UCLA. "We are pleased to have access to a drug that lengthens survival time in a population of lung cancer patients who often have few treatment options."


The most common side effects associated with Cyramza plus docetaxel from the study were neutropenia, fatigue, and stomatitis. Cyramza can also cause severe bleeding, blood clots, elevation in blood pressure, and may impair wound healing.


The FDA reviewed Cyramza’s application for this new use under the agency’s priority review program, which provides for an expedited review of drugs that are intended to treat a serious disease or condition and, if approved, would offer significant improvement compared to marketed products.


Cyramza is marketed by Eli Lilly.

Wednesday, December 10, 2014

The U.S. Food and Drug Administration has today approved Gardasil 9 (Human Papillomavirus 9-valent Vaccine, Recombinant) for the prevention of certain diseases caused by nine types of Human Papillomavirus—five additional types of HPV than were covered by Gardasil, which was approved by the FDA in 2006 (OT 8/10/06 issue). Gardasil 9 has the potential to prevent approximately 90 percent of cervical, vulvar, vaginal, and anal cancers.


“Vaccination is a critical public health measure for lowering the risk of most cervical, genital and anal cancers caused by HPV,” Karen Midthun, MD, Director of the FDA’s Center for Biologics Evaluation and Research, said in a news release. “The approval of Gardasil 9 provides broader protection against HPV-related cancers.”


The Gardasil 9 vaccine is approved for use in females ages nine through 26 and males ages nine through 15. It is approved for the prevention of cervical, vulvar, vaginal, and anal cancers caused by HPV types 16, 18, 31, 33, 45, 52, and 58, and for the prevention of genital warts caused by HPV types 6 or 11. The new vaccine adds protection against HPV types 31, 33, 45, 52, and 58, which cause approximately 20 percent of cervical cancers and are not covered by previously FDA-approved vaccines.


Gardasil 9 was evaluated in a randomized, controlled, clinical study (conducted in the U.S. and internationally) of approximately 14,000 females 16 through 26, all of whom tested negative for vaccine HPV types at the start of the study. The females received either Gardasil or Gardasil 9. Gardasil 9 was found to be 97 percent effective in preventing cervical, vulvar, and vaginal cancers caused by the five additional HPV types (31, 33, 45, 52, and 58) that Gardasil does not protect against. Additionally, Gardasil 9 was found to be as effective as Gardasil for the prevention of diseases caused by the four shared HPV subtypes (6, 11, 16, and 18) based on similar antibody responses in participants in clinical studies.


Due to the low incidence of anal cancer caused by the five additional HPV types, the prevention of anal cancer is based on Gardasil’s demonstrated effectiveness of 78 percent and additional data on antibodies in males and females who received Gardasil 9.


The effectiveness of Gardasil 9 in females and males ages nine through 15 was determined in studies that measured antibody response to the vaccine in approximately 1,200 males and 2,800 females in this age group. Antibody responses for these individuals were similar to those in females 16 through 26. And based on these results, the vaccine is expected to have similar effectiveness when used in this younger age group, the FDA news release notes.


The safety of Gardasil 9 was evaluated in approximately 13,000 males and females; the most commonly reported adverse reactions were injection site pain, swelling, redness, and headaches.


Gardasil 9 is administered as three separate shots, with the initial dose followed by additional shots given two and six months later. For all of the indications for use approved by the FDA, Gardasil 9’s full potential for benefit is obtained by those who are vaccinated prior to becoming infected with the HPV strains covered by the vaccine.


Gardasil 9 is manufactured by Merck Sharp & Dohme Corp.

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