Recent approvals announced by the U.S. Food and Drug Administration (FDA) have led to increased treatment options for managing several difficult-to-treat hematologic B-cell cancers. The newly approved drugs and/or their indications include the oral PI3K delta inhibitor idelalisib (Zydelig) for the treatment of patients with relapsed chronic lymphocytic leukemia, relapsed follicular B-cell non-Hodgkin lymphoma, and relapsed small lymphocytic lymphoma, and the oral Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) for the treatment patients with chronic lymphocytic leukemia who carry deletions of the short arm of chromosome 17.
Difficult-to-Treat Patient Populations
“[Idelalisib] is a much needed new treatment option for appropriate patients with [chronic lymphocytic leukemia] and these indolent lymphomas who have experienced relapses and have limited, if any, treatment options,” said Bruce Cheson, MD, Professor of Medicine, Head of Hematology and Director of Hematology Research at Lombardi Comprehensive Cancer Center at Georgetown University, and a Principal Investigator on the pivotal phase III trial of idelalisib in chronic lymphocytic leukemia.1
“In clinical studies among patients with relapsed chronic lymphocytic leukemia, follicular lymphoma, and small lymphocytic lymphoma, [idelalisib] produced strong responses, including a significant improvement in progression-free survival in chronic lymphocytic leukemia. I believe it helps fill a significant unmet need for these patients,” he said.1,2
Idelalisib in Chronic Lymphocytic Leukemia
Idelalisib is being granted traditional approval to treat patients with relapsed chronic lymphocytic leukemia. Used in combination with rituximab (Rituxan), idelalisib is to be used in patients for whom rituximab alone would be considered appropriate therapy due to other existing comorbidities. Idelalisib is the fifth new drug with Breakthrough Therapy designation to be approved by the FDA and the third drug with this designation approved to treat chronic lymphocytic leukemia.
Idelalisib’s safety and effectiveness to treat relapsed chronic lymphocytic leukemia were established in a clinical trial of 220 participants who were randomly assigned to receive idelalisib and rituximab or placebo and rituximab. The trial was stopped for efficacy following the first prespecified interim analysis point, which showed participants treated with idelalisib and rituximab had a median progression-free survival of 10.7 months compared to about 5.5 months for participants treated with placebo and rituximab. Results from a second interim analysis continued to show a statistically significant improvement for idelalisib and rituximab over placebo and rituximab.
Idelalisib in Non-Hodgkin B-Cell Lymphomas
The FDA is also granting idelalisib accelerated approval to treat patients with relapsed follicular B-cell non-Hodgkin lymphoma and relapsed small lymphocytic lymphoma. Idelalisib is intended for use in patients who have received at least two prior systemic therapies.
Idelalisib’s safety and effectiveness to treat relapsed follicular lymphoma and relapsed small lymphocytic lymphoma were established in a clinical trial with 123 participants who had indolent non-Hodgkin lymphomas. All participants were treated with idelalisib and were evaluated for objective response rate. Results showed 54% of participants with relapsed follicular lymphoma and 58% of participants with small lymphocytic lymphoma experienced complete or partial disappearance of their cancer.
The FDA is approving idelalisib to treat follicular lymphoma and small lymphocytic lymphoma under the agency’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 confirmatory clinical trials.
Idelalisib Boxed Warning
Idelalisib carries a Boxed Warning alerting patients and health-care professionals of fatal and serious toxicities including liver toxicity, diarrhea, colitis, pneumonitis, and intestinal perforation that can occur in idelalisib-treated patients. The drug is also being approved with a Risk Evaluation and Mitigation Strategy (REMS) comprising a communication plan to ensure health-care providers who are likely to prescribe idelalisib are fully informed about these risks.
Common side effects include diarrhea, pyrexia, fatigue, nausea, cough, pneumonia, abdominal pain, chills, and rash. Common laboratory abnormalities include neutropenia, hypertriglyceridemia, hyperglycemia, and elevated levels of liver enzymes.
Ibrutinib in Chronic Lymphocytic Leukemia
The FDA also expanded the approved use of ibrutinib (Imbruvica) to treat patients with chronic lymphocytic leukemia who carry deletions of the short arm of chromosome 17, which are associated with poor responses to standard treatment for the disease. Ibrutinib received a Breakthrough Therapy designation for this use.
The FDA is also approving new labeling to reflect that ibrutinib’s clinical benefit in treating chronic lymphocytic leukemia has been verified. In February 2014, ibrutinib received accelerated approval for the treatment of patients with chronic lymphocytic leukemia who have received at least one prior therapy based on its effect on overall response rate. New clinical trial results examining progression-free survival and overall survival have confirmed the drug’s clinical benefit.
RESONATE Trial
The recent approvals for ibrutinib are based on data from the phase III RESONATE trial of 391 patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma, 127 of whom had chronic lymphocytic leukemia with 17p deletion.3 Participants were randomly assigned to receive ibrutinib or ofatumumab (Arzerra) until disease progression or side effects became intolerable.
The trial was stopped early for efficacy after a preplanned interim analysis showed ibrutinib-treated participants experienced a 78% reduction in risk of disease progression or death. Results also showed a 57% reduction in risk of death in participants treated with ibrutinib. Of the 127 participants who had chronic lymphocytic leukemia with 17p deletion, those treated with ibrutinib experienced a 75% reduction in risk of disease progression or death.
The most common side effects associated with ibrutinib included thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper respiratory tract infection, rash, nausea, and pyrexia.
The FDA reviewed ibrutinib’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. Ibrutinib’s new use is being approved more than 2 months ahead of the product’s prescription drug user fee goal date of Oct. 7, 2014.
Breakthrough Therapy Designation
“In less than a year, we have seen considerable progress in the availability of treatments for chronic lymphocytic leukemia,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “We continue to see advances in the availability of therapies to treat chronic lymphocytic leukemia, especially for difficult-to-treat patients populations.”
The FDA approved obinutuzumab (Gazyva) in November 2013, ibrutinib (Imbruvica) in February 2014, and a new use for ofatumumab (Arzerra) in April 2014 to treat chronic lymphocytic leukemia. Both obinutuzumab and ofatumumab also received Breakthrough Therapy designation for this indication. Like the other two drugs, idelalisib was also granted Orphan Drug designation because it is intended to treat a rare disease.
Dr. Pazdur noted that the recent approvals of drugs previously given Breakthrough Therapy designation “[reflects] the promise of the Breakthrough Therapy designation program and the FDA’s commitment to working cooperatively with companies to expedite the development, review, and approval of these important new drugs.” ■
Disclosure: Dr. Cheson was Principal Investigator for the pivotal trial of idelalisib and has received honoraria from Gilead Sciences. Dr. Pazdur reported no potential conflicts of interest.
References
1. Furman RR, Sharman JP, Coutre SE, et al: Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 370:997-1007, 2014.
2. Gopal AK, Kahl BS, deVos S, et al: PI3Kdelta inhibition by idelalisib in patients with indolent lymphoma. N Engl J Med 370:1008-1018, 2014.
3. Byrd JC, Brown JR, O’Brien S, et al: Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 371:213-223, 2014.
