Idelalisib (Zydelig) Approved in Europe

Zosia Chustecka


September 19, 2014

A much anticipated product, the first-in-class oral drug idelalisib (Zydelig, Gilead Sciences, Inc), has now been granted marketing authorization by the European Commission for use in the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma.

The indications are similar, but not identical, to those in the United States, where the drug was approved in July 2014.

For the treatment of CLL, the EU approval covers use of idelalisib in combination with rituximab for patients who have received at least one prior therapy (same as the US indication).

This approval was based mainly on a placebo-controlled trial in 220 patients that was stopped early for benefit, after it showed a significantly longer progression-free survival in patients receiving idelalisib plus rituximab (10.7 months) compared with those on placebo plus rituximab (5.5 months) (hazard ratio = 0.18, P < .0001). The results were published earlier this year in the New England Journal of Medicine, as reported at the time by Medscape Medical News. Lead author Richard Furman, MD, from the Weill Cornell Medical College in New York City, concluded that 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."

Some of the responses seen with idelalisib were "incredible" and were seen within a week, Dr. Furman said. "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 at the time.

Another CLL Indication

In Europe, idelalisib is also approved for use as first-line treatment in patients with CLL who are considered to be unsuitable for chemoimmunotherapy and who also carry a chromosome 17p deletion or TP53 mutation. These defects in CLL cells have been linked to poor prognosis and a more rapid disease progression, and these patients respond poorly to chemotherapy and have limited treatment options, Gilead noted in a press release.

Peter Hillmen, PhD, professor of experimental hematology and honorary consultant hematologist at Leeds Teaching Hospitals NHS Trust in the United Kingdom, commented in the release: "CLL patients with the 17p deletion or TP53 mutation are not suitable for chemo-immunotherapy, requiring alternative first-line treatment options. Thus, idelalisib is a welcomed treatment option that offers a new approach in the management of these cancers."

Also Approved for Follicular Lymphoma

For the treatment of follicular lymphoma, the EU approval covers use of idelalisib as monotherapy in patients who are refractory to two prior lines of treatment.

This approval is supported by data from a single-arm phase 2 study of idelalisib monotherapy in 125 patients with indolent non–Hodgkin's lymphoma who were refractory to rituximab and alkylating-agent-containing chemotherapy; these data were published earlier this year in the New England Journal of Medicine, as reported at the time by Medscape Medical News. These patients had previously taken a median of 4 therapies (range, 2 to 12), which most commonly included rituximab plus bendamustine; rituximab plus cyclophosphamide, doxorubicin, and prednisone (R-CHOP); rituximab alone; and rituximab with cyclophosphamide, and prednisone (R-CVP).

In a subgroup of 72 patients with follicular lymphoma, idelalisib achieved an overall response rate of 54%, and the median duration of response was not reached (range: 0.0 -14.8+ months).

The researchers concluded that idelalisib "appears to provide effective oral monotherapy in patients with previously treated indolent non–Hodgkin's lymphoma," and these data were described as "eyebrow raising" when they were first presented at the 2103 American Society of Hematology meeting.

Novel Mechanism of Action

The drug has a novel mechanism of action, inhibition of phosphoinositide 3-kinase delta (PI3K delta), a protein that is overexpressed in many B-cell malignancies. 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 manufacturer explains.

In the clinical trials submitted for approval, idelalisib was used at a dose of 150 mg twice daily, but it is available as both150-mg and 100-mg tablets.

Adverse drug reactions reported in the clinical trials included infections, neutropenia, pneumonitis, diarrhea/colitis, increased transaminase levels, rash, and pyrexia.

There is a potential for drug/drug interactions with several other products. The primary metabolite of idelalisib is a strong inhibitor of the cytochrome enzyme CYP3A4, so the drug may interact with products that are metabolized by this enzyme (eg, alfuzosin, amiodarone, cisapride, pimozide, quinidine, ergotamine, dihydroergotamine, quetiapine, lovastatin, simvastatin, sildenafil, midazolam, and triazolam). This interaction may be serious and even life-threatening, and so such products should be avoided if possible, the manufacturer cautions.

Idelalisib may also interact by this same mechanism with drugs that induce the CYP3A enzyme, such as rifampicin, phenytoin, St. John's wort (Hypericum perforatum), or carbamazepine. These products may result in a lowering of idelalisib plasma concentrations and lead to decreased efficacy, and so coadministration should be avoided.

Both studies were funded by the manufacturer, Gilead.


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