Idelalisib With Rituximab Boosts Survival in Relapsed CLL

Roxanne Nelson

December 11, 2013

NEW ORLEANS — A new first-in-class agent oral kinase inhibitor might soon be added to the growing cache of treatments for chronic lymphocytic leukemia (CLL).

In a phase 3 trial, known as Study 116, the investigational agent idelalisib (under development by Gilead), when added to rituximab (Rituxan), improved outcomes in patients with relapsed CLL. "Idelalisib is a targeted, highly selective, orally administered inhibitor of PI3K-delta," said lead author Richard R. Furman, MD, assistant professor of clinical medicine and Richard A. Stratton Assistant Professor in Hematology and Oncology at Weill Cornell Medical College in New York City. "It 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."

Dr. Furman presented results comparing the combination of idelalisib and rituximab with rituximab alone during a late-breaker session here at the American Society of Hematology 55th Annual Meeting.

Patients receiving the idelalisib combination also had a better overall response rate, lymph node response rate, and profession-free survival than those who received rituximab alone.

Approval of idelalisib is pending in both the United States and Europe. However, the US Food and Drug Administration granted breakthrough therapy designation for CLL in relapsed patients on the basis of results from Study 116, according to media reports.

Best Control Agent?

These data are very compelling in terms of efficacy for this new agent.

"These data are very compelling in terms of efficacy for this new agent," said Wendy Stock, MD, professor of medicine at the University of Chicago. "We will have to see how it gets incorporated with other novel agents, and maybe into the front-line setting."

However, there has been concern about whether the use of rituximab as a control is appropriate in a population that has already been heavily pretreated with that agent, she told Medscape Medical News.

She pointed out that it can be difficult to find an appropriate control agent for patients with relapsed or refractory disease, and noted that Dr. Furman "did say that rituximab is the standard of care in the community for this patient population." There are a number of new agents being studied for CLL, she added. "That we are seeing nonchemotherapy agents becoming the standard of care is very exciting."

Study Details

A total of 220 adults from approximately 70 study sites in the United States and Europe were enrolled in Study 116. Eligible patients had previously treated recurrent CLL, with measurable lymphadenopathy that had progressed in the 24 months after the completion of previous therapy. Participants were considered unfit to receive cytotoxic therapy because of comorbidities (defined as a Cumulative Illness Rating Score [CIRS] above 6), renal dysfunction, or cytopenias related to poor marrow reserve.

The median age of the patients was 71 years. Overall, 85% had a median creatinine clearance of 63.6 mL/min, 73% had anemia, 61% had thrombocytopenia, and 34% had neutropenia.

Median time since diagnosis was 8.5 years, and the median number of previous therapies was 3 (range, 1 - 12). In addition, 44% of participants had del(17p)/TP53 mutations, and 84% had unmutated IgVH.

All patients received 8 doses of rituximab: an original dose of 375 mg/m², followed by 500 mg/m² every 2 weeks for 4 cycles, and then every 4 weeks for 3 cycles. They were also randomized to receive idelalisib 150 mg twice daily continuously (n = 110) or placebo (n = 110).

The primary study end point was progression-free survival.

The results presented were from a prespecified interim analysis after 50% of the 119 planned events of CLL progression or death from any cause had occurred, explained Dr. Furman.

Outcomes Improved

At 24 weeks, progression-free survival was better in the idelalisib group than in the placebo group (93% vs 46%; hazard ratio [HR], 0.15; P = 3.0 × 10–11). "Progression-free survival was also favored in all subgroups analyzed," reported Dr. Furman. He noted that the median progression-free survival in the idelalisib group has not yet been reached.

There was also a significant improvement in overall survival in the idelalisib group (HR, 0.28; P = .018).

The overall response rate was also significantly better in the idelalisib group than in the placebo group (81% vs 13%; odds ratio [OR], 29.9; P = 3.0 × 10–19). The lymph node response rate was also higher (93% vs 4%; OR, 264.5; P = 1.3 × 10–30).

Adverse events were common, and occurred in most patients. The rate of events grade 3 or higher was higher in the idelalisib group than in the placebo group (56.4% vs 47.7%), and the rate of serious adverse events was similar in the 2 groups (44% vs 37%). The most commonly reported events were pyrexia, fatigue, nausea, chills, and infusion-related reactions.

Dr. Furman and several of his coauthors report financial relationships with Gilead, the manufacturer of idelalisib.

American Society of Hematology (ASH) 55th Annual Meeting: Abstract LBA-6. Presented December 10, 2013.


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