FDA News - April 2016

VBCC - April 2016, Vol 7, No 3 - FDA Approvals, News & Updates

In This Article




Xalkori Receives New Indication for Metastatic Non–Small-Cell Lung Cancer with the ROS-1 Mutation

On March 11, 2016, the FDA approved a new indication for crizotinib (Xalkori; Pfizer) for the treatment of patients with metastatic non–small-cell lung cancer (NSCLC) that is associated with the ROS-1 genetic mutation. Crizotinib is the first and only FDA-approved treatment for patients with ROS-1–positive NSCLC. Oral crizotinib blocks the activity of the ROS-1 protein in tumors that harbor the ROS-1 mutation. This effect on ROS-1 may prevent NSCLC from growing and spreading.

“Lung cancer is difficult to treat, in part, because patients have different mutations, some of which are rare,” said Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products. “The expanded use of Xalkori will provide a valuable treatment option for patients with the rare and difficult to treat ROS-1 gene mutation by giving health care practitioners a more personalized way of targeting ROS-1–positive NSCLC.”

The ROS-1 mutation has been identified in different types of cancers, including NSCLC. Approximately 1% of patients with NSCLC have this mutation. The characteristics of NSCLC that involve the ROS-1 mutation are similar to the characteristics of NSCLC that harbors the anaplastic lymphoma kinase (ALK) mutation, which is the original indication for which crizotinib was approved for by the FDA in 2011.

The safety and efficacy of crizotinib for the treatment of patients with ROS-1–positive NSCLC were evaluated in a multicenter, single-arm study of 50 patients with ROS-1–positive metastatic NSCLC. The patients received crizotinib twice daily to evaluate the overall response rate. Overall, 66% of the patients had a complete or partial tumor reduction lasting a median of 18.3 months. The safety profile of crizotinib in patients with NSCLC and the ROS-1 mutation was generally consistent with the safety profile of crizotinib that had been reported in 1669 patients with ALK-positive metastatic NSCLC.

The most common adverse events associated with crizotinib are vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminase levels, fatigue, decreased appetite, upper respiratory infection, dizziness, and neuropathy. Serious side effects include liver problems, life-threatening or fatal inflammation of the lungs, abnormal heartbeats, and partial or complete loss of vision.

The FDA granted crizotinib an expanded-use application breakthrough therapy designation, and priority review status, as well as an orphan drug designation, because it is designated to treat a rare disease.

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Afinitor Granted New Indication for Unresectable, Locally Advanced or Metastatic Neuroendocrine Tumors

On February 26, 2016, the FDA approved a new indication for everoli­mus (Afinitor; Novartis) for the treatment of adults with progressive, well-differentiated, nonfunctional neuroendocrine tumors (NETs) of gastrointestinal or lung origin with unresectable, locally advanced or metastatic disease.

The FDA approval was based on a multicenter, placebo-controlled, randomized clinical trial of 302 patients with unresectable, locally advanced or metastatic, well-differentiated, nonfunctional (ie, no current or a history of carcinoid symptoms) NETs of gastrointestinal or lung origin. The patients were randomized (2:1 ratio) to oral everolimus 10 mg once daily plus best supportive care or to placebo plus best supportive care. The patients in the everolimus 10-mg arm had an improvement in progression-free survival (PFS) compared with those in the placebo arm.

The median PFS was 11 months in the everolimus arm and 3.9 months in the placebo arm (hazard ratio, 0.48; 95% confidence interval, 0.35-0.67; P <.001). Furthermore, the overall response rate was 2% in the everolimus arm versus 1% in the placebo arm.

At the planned interim analysis, no significant difference in overall survival was reported between the 2 arms.

The safety data were based on 300 patients who received at least 1 dose of everolimus, with a median exposure of 9.3 months: 64% of the patients received the drug for ≥6 months, and 39% received it for ≥12 months. Everolimus was discontinued in 29% of patients because of adverse reactions, and dose reduction or delay was required in 70% of the patients. Serious adverse reactions occurred in 42% of those receiving everolimus and included 3 fatal events (cardiac failure, respiratory failure, and septic shock).

The most common adverse reactions (≥30%) were stomatitis, infections, diarrhea, peripheral edema, fatigue, and rash. The most common laboratory abnormalities (≥50%) were anemia, hypercholesterolemia, lymphopenia, elevated aspartate transaminase, and fasting hyperglycemia. The recommended dose and schedule for everolimus is 10 mg orally once daily.

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FDA Designates Iomab-B as Orphan Drug in the Treatment of Relapsed and/or Refractory Acute Myeloid Leukemia in Older Patients

On March 30, 2016, the FDA granted an orphan drug designation to Iomab-B (BC8-I-131 construct; Actinium Pharmaceuticals), a radio-immunotherapeutic agent that conditions patients with relapsed and/or refractory acute myeloid leukemia (AML) for a hematopoietic stem-cell transplant (HSCT). BC8-I-131 construct is a radio-immunoconjugate consisting of BC8, a novel murine monoclonal antibody, and iodine-131 radioisotope. BC8 has been developed to target CD45, a pan-leukocytic antigen that is widely expressed on white blood cells. This antigen makes BC8 potentially useful in targeting white blood cells in preparation for HSCT in several blood cancers, including AML.

BC8-I-131 construct will soon begin a pivotal phase 3 multicenter clinical trial that will include 150 patients with relapsed and/or refractory AML who are aged >55 years. The trial has been approved by the FDA.

According to the manufacturer, BC8-I-131 construct has been successfully used as a myeloconditioning or myeloablative agent in more than 250 patients with relapsed or refractory blood cancers who were candidates for HSCT. In phase 1 and phase 2 clinical trials, BC8-I-131 construct has led to cures in patients who had no other options beyond HSCT, the only potentially curative treatment option for those patients.

The majority of patients aged >50 years are either ineligible for HSCT because of concomitant conditions or have a high disease burden and/or resistant disease that makes reduced-dose conditioning futile. BC8-I-131 construct has demonstrated its ability to prepare patients for HSCT successfully when no other treatment is available for them.

Sandesh Seth, Executive Chairman of Actinium, stated, “We are pleased to have been granted orphan drug status by the FDA for Iomab-B, particularly ahead of its pivotal phase 3 clinical trial. There has not been a new drug approved for relapsed and refractory AML patients over the age of 55 in decades, and with Iomab-B being the only therapy of its kind, we are pleased to have achieved this important milestone.”

The FDA grants orphan drug designation to drugs and biologics that are intended for use in rare conditions that affect <200,000 persons in the United States.

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