FIRST PI3K INHIBITOR FOR CLL

Clinical results with the investigational agent idelalisib (under development by Gilead) in both relapsed chronic lymphocytic leukemia (CLL) and refractory indolent lymphoma caused quite a stir when they were presented last month at the American Society of Hematology (ASH) annual meeting. Now, details from the 2 trials have been published online January 22 in the New England Journal of Medicine.

Idelalisib, an oral first-in-class kinase inhibitor, is currently awaiting approval for these 2 indications in both the United States and Europe.

The US Food and Drug Administration (FDA) has awarded the drug "breakthrough status" for the CLL indication, after a pivotal trial was stopped early due to benefit. This trial showed that idelalisib used in combination with rituximab (Rituxan, Genentech/Roche) offered an option for patients with relapsed CLL who were unable to tolerate chemotherapy. The company filed these data with the FDA on December 6, 2013, and the agency has not yet announced whether the data would undergo accelerated review (within 6 months) or standard review (12 months).

The company has also filed the data from the other trial, which show activity for idelalisib as monotherapy in refractory indolent non-Hodgkin's lymphoma. The FDA announced recently that this indication would undergo standard review, which means that the decision on the lymphoma indication is due by September 11.

In Europe, the company filed for approval for both indications with the European Medicines Agency on October 28, 2013.

CLL Trial Stopped Early Due to Benefit

The pivotal trial in CLL (known as Study 116) was stopped early due to benefit in October 2013.

As previously reported by Medscape Medical News, the study was conducted in 220 patients with previously treated recurrent CLL who were unable to undergo standard cytotoxic chemotherapy because of decreased renal function, previous therapy-induced myelosuppression, or major coexisting illness.

All patients received rituximab, which principal investigator Richard Furman, MD, from the Weill Cornell Medical College in New York City, described as a standard of care for this patient population during his presentation. They were also randomized to receive either idelalisib 150 mg twice daily or placebo.

"At the first specified interim analysis, the study was stopped early on the recommendation of the data and safety monitoring board owing to overwhelming efficacy," the authors comment in their published study.

The primary end point of median progression-free survival was 5.5 months in the placebo group, and was not reached in the idelalisib group (hazard ratio [HR] for progression or death in the idelalisib group, 0.15;P < .001).

There were also significant improvements in overall survival at 12 months (92% with idelalisib vs 80% for placebo; HR for death, 0.28; P = .2) and in the overall response rate (81% vs 13%; odds ratio, 29.92; P < .001).

Serious adverse events occurred in 40% of patients taking idelalisib plus rituximab and in 35% of patients taking placebo and rituximab. At the meeting, Dr. Furman noted that the most commonly reported events were pyrexia, fatigue, nausea, chills, and infusion-related reactions.

The addition of idelalisib to rituximab "provided effective durable disease control and improved overall survival for patients with relapsed CLL who were not suitable for cytotoxic chemotherapy, including high-risk patients," he concluded at the meeting.

Now in a statement, Dr. Furman commented that some of the responses seen with idelalisib were "incredible" and were seen within a week. "It is remarkable how quickly idelalisib worked in this heavily treated group of patients, many of whom were resistant to chemotherapy.... Their cancer quickly melted away."

"The treatment today for CLL can be worse than the disease, leading to a great deal of side effects and death. This study, along with others we have conducted on idelalisib, demonstrates that we may no longer need to use chemotherapy in CLL," Dr. Furman commented.

Monotherapy in Refractory Lymphoma

The results from the lymphoma trial were described as some of the most exciting data to be presented at the ASH meeting by Gilles Salles, MD, PhD, professor of medicine, Department of Hematology, Université Claude Bernard, Hospices Civils de Lyon, France, in a Medscape Cheson on Oncology video.