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Bosansko-hercegovačka kooperativna grupa za hematološke bolesti

Idelalisib, a Novel PI3Kδ Inhibitor, Improves ORR and PFS in Double-Refractory Indolent NHL

 

Idelalisib, a Novel PI3Kδ Inhibitor, Improves ORR and PFS in Double-Refractory Indolent NHL



• Study 101-09: phase II single-arm clinical trial [1]
Summary of Key Conclusions
• High response rate to idelalisib in patients with double-refractory indolent non-Hodgkin’s lymphoma (iNHL): 57%
    o Efficacy independent of previous treatment history, histologic subtype, or degree of refractory disease
    o Median duration of response: 12.5 months
• Safety profile manageable
• Results suggest idelalisib promising for individuals with double-refractory iNHL
Background
• Current standard of care for iNHL: rituximab plus an alkylating agent
    o Double-refractory iNHL: resistance to rituximab and the coadministered alkylating agent
• Few effective therapies for double-refractory iNHL
• Inhibition of PI3Kδ signaling in iNHL inhibits cell proliferation, homing, and retention, and enhances apoptosis, reducing survival of malignant B cells
• Recent phase I data suggest that idelalisib, an oral, selective inhibitor of PI3Kδ, has efficacy against relapsed/refractory iNHL[2]
• Current study evaluated efficacy of idelalisib in patients with double-refractory iNHL
Summary of Study Design
• 125 individuals enrolled from April 2011 - October 2012
• Treatment: Idelalisib 150 mg twice daily until disease progression
Baseline Characteristics
• Double-refractory iNHL
    o Documented radiographically
    o Established as < PR on therapy or progression within 6 months of completion of therapy
• Previous iNHL treatment (follicular lymphoma [FL], small lymphocytic lymphoma [SLL], marginal zone lymphoma [MZL], lymphoplasmacytic lymphoma [LPL]/Waldenström’s macroglobulinemia [WM])
• Minimum node diameter: >= 2 cm
• ECOG performance status 0-2
• Karnofsky performance status score >= 60
• Organ function
    o Serum transaminases <= 2.5 x ULN
    o Neutrophils >= 1000 cells/µL
    o Hemoglobin >= 8 g/dL
    o Platelets >= 50K/µL
    o Serum creatinine < 1.5 x ULN


• All patients received rituximab and alkylating agent; many received bendamustine and anthracycline as well


• Heavily refractory population


Description of Current Analysis
• Disease evaluated by an independent review committee
• Disease assessment (Cheson and WM criteria) at Weeks 0, 8, 16, 24, and every 12 months for duration of study
• Assessment by 2-3 independent radiologists with adjudication, clinical review by a hematologist/oncologist
• Primary endpoint: ORR
• Secondary endpoints
    o Safety
    o PFS
    o OS
    o Duration of response
    o Quality of life
Main Findings
• ORR: 57% (95% CI: 0.48% to 0.66%)
• Improvement in lymphadenopathy: 90%
    o >= 50% decrease from baseline: 57%
• Median PFS: 11 months
• Median OS: 20.4 months
• Median DOR: 12.5 months


• Most common adverse events: diarrhea, fatigue, nausea, cough, pyrexia


Other Outcomes
• Average duration of treatment with idelalisib: 8.1 months (median: 6.6; range: 0.6-23.9)
• Patients remaining on treatment: 32%
• Discontinuations (68%) due to
    o Disease progression: 32%
    o Adverse event: 20%
    o Death: 6.4%
    o Investigator request (3 referred for transplantation): 5.6%
    o Withdrew consent: 3.2%
• Elevations in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST): grade 1/2 in 35%, grade 3 in 10%, and grade 4 in 2%
    o Continued idelalisib resolved grade 1/2 elevations
    o Drug interruption resolved grade ? 3 elevations
• 14/16 patients with grade >= 3 ALT/AST elevations rechallenged
    o No recurrence: 71%
    o Recurrence of grade >= 3 elevation: 29%
• Decreased neutrophils observed in more than half of patients


References
1. Gopal A, Kahl BS, de Vos S, et al. Mature response data from a phase 2 study of PI3K-delta inhibitor idelalisib in patients with double (rituximab and alkylating agent)-refractory indolent b-cell non-Hodgkin lymphoma (iNHL). Program and abstracts of the 55th American Society of Hematology Annual Meeting of and Exposition; December 7-10, 2013; New Orleans, Louisiana. Abstract 85.
2. Benson DM, Kahl BS, Furman RR, et al. Final results of a phase I study of idelalisib, a selective inhibitor of PI3K?, in patients with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL). Program and abstracts of the 2013 Annual Meeting of the American Society of Clinical Oncology; May 31 - June 4, 2013; Chicago, Illinois. Abstract 8526.

 


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