“These new findings add to the role of idelalisib-containing regimens for the treatment of relapsed CLL,” said Andrew D. Zelenetz, MD, PhD, Medical Oncologist and Vice Chair, Medical Informatics, Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center. “In this Phase 3 study, adding idelalisib to BR provided not only statistically significant but clinically meaningful improvements in progression-free and overall survival compared to BR, a current standard of care in relapsed/refractory CLL. Further, idelalisib treatment also benefitted patients with genetic factors associated with a poorer prognosis.”
Zydelig is approved in the United States in combination with rituximab for patients with relapsed CLL for whom rituximab alone would be considered appropriate therapy due to comorbidities. Based on the Study 115 results, Gilead plans to submit supplemental regulatory filings in the U.S. and Europe early next year.
Study 115 enrolled 416 adult patients with previously treated CLL whose disease had progressed less than 36 months following completion of prior therapy, and was not refractory to bendamustine. Eligible patients were randomized (1:1) to receive six cycles of BR over 24 weeks with either Zydelig 150 mg or placebo taken orally twice daily until disease progression or unacceptable toxicity. In November, the trial was unblinded following the recommendation of an independent Data Monitoring Committee.
The primary endpoint was PFS, defined as the time from randomization to definitive disease progression or death, as assessed by an independent review committee. Median PFS for patients receiving Zydelig plus BR was 23.1 months compared to 11.1 months for patients receiving placebo plus BR. Among patients with a 17p deletion or TP53 mutation (Zydelig plus BR: n=69; placebo plus BR: n=68), genetic abnormalities that have been linked to poor prognosis, there was a 50 percent reduction in the risk of disease progression or death (HR=0.50, 95 percent CI: 0.32, 0.77).
The study also found a statistically significant benefit in OS, with a 45 percent reduction in the risk of death among patients receiving Zydelig plus BR compared to those receiving BR alone (HR=0.55; 95 percent CI: 0.36, 0.86; p=0.008). Median OS has not been reached in either arm. The overall response rate (ORR) was 68 percent in the Zydelig arm and 45 percent for the control arm.
Grade ≥3 adverse events for the Zydelig plus BR and placebo plus BR arms, respectively, included neutropenia (60 versus 46 percent), febrile neutropenia (20 versus 6 percent) and diarrhea (7 versus 2 percent). Grade ≥3 elevations in ALT and AST occurred in 21 and 16 percent, respectively, of patients receiving Zydelig plus BR compared to 3 percent and 3 percent in patients receiving BR alone; see below for Important Safety Information, including BOXED WARNING.
Zydelig in combination with bendamustine and rituximab is an investigational regimen and its safety and efficacy have not been established.
About Zydelig (idelalisib)
Zydelig is an oral inhibitor of phosphoinositide 3-kinase (PI3K) delta, a protein that plays a role in the activation, proliferation and viability of B cells, a critical component of the immune system. PI3K delta signaling is active in many B-cell leukemias and lymphomas, and by inhibiting the protein, Zydelig blocks several cellular signaling pathways that drive B-cell viability.
Important U.S. Safety Information
BOXED WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, AND INTESTINAL PERFORATION
- Fatal and/or serious hepatotoxicity occurred in 14 percent of Zydelig-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Zydelig as recommended.
- Fatal and/or serious and severe diarrhea or colitis occurred in 14 percent of Zydelig-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Zydelig as recommended.
- Fatal and serious pneumonitis can occur. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Zydelig as recommended.
- Fatal and serious intestinal perforation can occur in Zydelig-treated patients. Discontinue Zydelig for intestinal perforation.
- History of serious allergic reactions, including anaphylaxis and toxic epidermal necrolysis (TEN).
Warnings and Precautions
- Hepatotoxicity: Findings were generally observed within the first 12 weeks of treatment and reversed with dose interruption. Upon rechallenge at a lower dose, ALT/AST elevations recurred in 26 percent of patients. In all patients, monitor ALT/AST every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, and every 1 to 3 months thereafter. If ALT/AST is >3x upper limit of normal (ULN), monitor for liver toxicity weekly. If ALT/AST is >5x ULN, withhold Zydelig and monitor ALT/AST and total bilirubin weekly until resolved. Discontinue Zydelig for recurrent hepatotoxicity. Avoid concurrent use with other hepatotoxic drugs.
- Severe diarrhea or colitis: Grade 3+ diarrhea can occur at any time and responds poorly to antimotility agents. Avoid concurrent use with other drugs that cause diarrhea.
- Pneumonitis: Evaluate for pneumonitis in patients presenting with pulmonary symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on radiologic exam, or oxygen saturation decline by ≥5 percent.
- Intestinal perforation: Advise patients to promptly report any new or worsening abdominal pain, chills, fever, nausea, or vomiting.
- Severe cutaneous reactions: One case of TEN occurred in a study of Zydelig in combination with rituximab and bendamustine. Other severe or life-threatening (Grade ≥3) cutaneous reactions have been reported. Monitor patients for the development of severe cutaneous reactions and discontinue Zydelig if a reaction occurs.
- Anaphylaxis: Serious allergic reactions including anaphylaxis have been reported. Discontinue Zydelig permanently and institute appropriate supportive measures if a reaction occurs.
- Neutropenia: Treatment-emergent Grade 3-4 neutropenia occurred in 31 percent of Zydelig-treated patients in clinical trials. In all patients, monitor blood counts ≥every 2 weeks for the first 3 months. In patients with neutrophil counts <1.0 Gi/L, monitor weekly.
- Embryo-fetal toxicity: Zydelig may cause fetal harm. Women who are or become pregnant while taking Zydelig should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Zydelig and to use effective contraception during and at least 1 month after treatment with Zydelig.
- Most common adverse reactions (incidence ≥20 percent; all grades) in clinical studies, when used alone or in combination with rituximab, were diarrhea, pyrexia, fatigue, nausea, cough, pneumonia, abdominal pain, chills, and rash.
- Most frequent serious adverse reactions (SAR) in clinical studies in combination with rituximab were pneumonia (17 percent), pyrexia (9 percent), sepsis (8 percent), febrile neutropenia (5 percent), and diarrhea (5 percent); SAR were reported in 49 percent of patients and 10 percent of patients discontinued due to adverse reactions. Most frequent SAR in clinical studies when used alone were pneumonia (15 percent), diarrhea (11 percent) and pyrexia (9 percent); SAR were reported in 50 percent of patients and 53 percent of patients discontinued or interrupted therapy due to adverse reactions.
- Most common lab abnormalities (incidence ≥30 percent; all grades) in clinical studies were neutropenia, hypertriglyceridemia, hyperglycemia, and ALT/AST elevations.
- CYP3A inducers: Avoid coadministration with strong CYP3A inducers.
- CYP3A inhibitors: When coadministered with strong CYP3A inhibitors, monitor closely for Zydelig toxicity.
- CYP3A substrates: Avoid coadministration with CYP3A substrates.
Dosage and Administration
- Adult starting dose: One 150 mg tablet twice daily, swallowed whole with or without food. Continue treatment until disease progression or unacceptable toxicity. The safe dosing regimen for patients who require treatment longer than several months is unknown.
- Dose modification: Consult the Zydelig full Prescribing Information for dose modification and monitoring recommendations for the following specific toxicities: pneumonitis, ALT/AST elevations, bilirubin elevations, diarrhea, neutropenia, and thrombocytopenia. For other severe or life-threatening toxicities, withhold Zydelig until toxicity is resolved and reduce the dose to 100 mg, twice daily, upon resuming treatment. If severe or life-threatening toxicities recur upon rechallenge, Zydelig should be permanently discontinued.
About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Gilead has operations in more than 30 countries worldwide, with headquarters in Foster City, California.
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the risk that Gilead may be unable to submit supplemental filings for the use of Zydelig in combination with bendamustine and rituximab in the U.S. and Europe in the currently anticipated timelines. In addition, the regulatory filings may not be approved by regulatory agencies and marketing approvals, if granted, may have significant limitations on their use. As a result, Zydelig in combination with bendamustine and rituximab may never be successfully commercialized. Further, there is the possibility of unfavorable results from other clinical trials involving Zydelig. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2015, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.
U.S. full prescribing information, including BOXED WARNING for Zydelig is available at www.gilead.com.
Zydelig is a registered trademark of Gilead Sciences, Inc.
For more information on Gilead Sciences, please visit the company’s website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.
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Nathan Kaiser, 650-522-1853 (Media)