The US Food and Drug Administration (FDA) has approved the PI3K delta inhibitor idelalisib (Zydelig) for the treatment of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and follicular lymphoma (FL).
The drug was granted traditional approval for use in combination with rituximab to treat patients with relapsed CLL who cannot receive rituximab alone.
Idelalisib has also received accelerated approval to treat patients with relapsed FL or SLL who have received at least 2 prior systemic therapies.
The FDA’s accelerated approval program allows for 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 that is reasonably likely to predict a clinical benefit to patients.
This program provides earlier patient access to a drug while the developer—in this case, Gilead Sciences—conducts trials confirming the drug’s benefit.
Idelalisib in CLL: Results of a phase 3 study
The approval of idelalisib in CLL is based on results of a phase 3 trial (Study 116), which was stopped early because idelalisib had a significant impact on progression-free survival.
The study included 220 CLL patients who could not receive chemotherapy. Half were randomized to receive idelalisib plus rituximab, and the other half were randomized to rituximab plus placebo.
Patients in the idelalisib arm had a much higher overall response rate than patients in the placebo arm—81% and 13%, respectively (P<0.001). But all responses were partial responses.
At 24 weeks, the rate of progression-free survival was 93% in the idelalisib arm and 46% in the placebo arm (P<0.001). The median progression-free survival was 5.5 months in the placebo arm and not reached in the idelalisib arm (P<0.001).
At 12 months, the overall survival rate was 92% in the idelalisib arm and 80% in the placebo arm (P=0.02).
Most adverse events, in either treatment group, were grade 2 or lower. The most common events in the idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the placebo arm, the most common events were infusion-related reactions, fatigue, cough, nausea, and dyspnea.
There were more serious adverse events in the idelalisib arm than in the placebo arm—40% and 35%, respectively. The most frequent serious events were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).
Idelalisib in FL and SLL: Results of a phase 2 study
Idelalisib’s accelerated approval in FL and SLL is supported by data from a single-arm, phase 2 trial (Study 101-09).
The drug was given as a single agent to patients who were refractory to rituximab and alkylating-agent-containing chemotherapy. Seventy-two patients had FL, and 26 had SLL.
The overall response rate was 54% in FL and 58% in SLL. Eight percent of FL responses were complete, and all responses in SLL patients were partial.
The median duration of response was 11.9 months in SLL patients (range, 0-14.7 months) but was not reached in FL patients (range, 0-14.8 months).
Improvements in patient survival or disease-related symptoms have not been established.
In all patients, the most common grade 3 or higher adverse events were neutropenia (27%), elevations in aminotransferase levels (13%), diarrhea (13%), and pneumonia (7%).
About idelalisib: Dosing, boxed warning and REMS
Idelalisib is an oral inhibitor of PI3K delta, a protein that plays a role in the activation, proliferation, and viability of B cells. PI3K delta signaling is active in many B-cell leukemias and lymphomas, and, by inhibiting the protein, idelalisib blocks several cellular signaling pathways that drive B-cell viability.
The drug is available as 150 mg and 100 mg tablets, administered orally twice-daily, but 150 mg is the recommended starting dose.
Idelalisib has a boxed warning on its label communicating the risks of fatal and serious toxicities, which include hepatic toxicity, severe diarrhea, colitis, pneumonitis, and intestinal perforation.
The drug is being approved with a risk evaluation and mitigation strategy (REMS) comprised of a communication plan to ensure healthcare providers are fully informed about these risks. For more information on this program, visit www.ZydeligREMS.com.
