RESUMEN
INTRODUCTION: Tazemetostat is an enhancer of zeste homolog 2 (EZH2) inhibitor recommended for patients with relapsed/refractory (R/R) follicular lymphoma (FL) after demonstrating single-agent, antitumor activity in patients with wild-type or mutant EZH2. The phosphoinositide 3-kinase (PI3K) inhibitors idelalisib, copanlisib, umbralisib and (formerly) duvelisib are indicated for third-line, fourth-line, and later (3L/4L+) treatment of R/R FL. The objective of this analysis was to provide an indirect treatment comparison of tazemetostat with each PI3K inhibitor for 3L/4L+ R/R FL treatment. METHODS: A systematic literature review was conducted to identify trials for idelalisib (DELTA), duvelisib (DYNAMO), copanlisib (CHRONOS-1 Part B), and umbralisib (UNITY-NHL) in 3L+ R/R FL. Matching-adjusted indirect comparisons were conducted by weighting tazemetostat individual patient data with available baseline characteristics from each comparator trial: age, Eastern Cooperative Oncology Group performance status, disease stage, histology, prior treatment lines, prior stem cell therapy, progression within 24 months, and refractory status to last therapy. Only the tazemetostat trial included patients with grade 3b or transformed FL, or recorded EZH2 mutation status. Primary safety outcomes included risk of grade ≥ 3 treatment-emergent adverse events (TEAEs); primary efficacy outcomes included objective response rate (ORR). RESULTS: Matched patients treated with tazemetostat had lower relative risk (RR) for all grouped safety outcomes, including any grade ≥ 3 TEAEs, compared with idelalisib (RR = 0.45), duvelisib (RR = 0.35), copanlisib (RR = 0.37), and umbralisib (RR = 0.65; all, p < 0.01), any serious TEAE, and any TEAE leading to dose reduction, drug discontinuation, or interruption. The ORR was not significantly different for tazemetostat versus other treatments (idelalisib 43% vs 56%, p = 0.16; duvelisib 48% vs 47%, p = 0.91; copanlisib 49% vs 61%, p = 0.11; and umbralisib 57% vs 47%, p = 0.10). CONCLUSIONS: In this statistically adjusted comparison, tazemetostat was associated with lower RR for safety outcomes versus idelalisib, duvelisib, copanlisib, and umbralisib, while achieving similar efficacy outcomes.
Asunto(s)
Linfoma Folicular , Fosfatidilinositol 3-Quinasas , Benzamidas , Compuestos de Bifenilo , Preescolar , Compuestos Heterocíclicos de 4 o más Anillos , Humanos , Isoquinolinas , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/genética , Linfoma Folicular/patología , Morfolinas , Recurrencia Local de Neoplasia/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/uso terapéutico , Purinas , Piridonas , Pirimidinas , Quinazolinas , Quinazolinonas , RiesgoAsunto(s)
Antineoplásicos/administración & dosificación , Linfoma Folicular/tratamiento farmacológico , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas/administración & dosificación , Quinazolinas/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/economía , Costos de los Medicamentos , Interacciones Farmacológicas , Humanos , Linfoma Folicular/patología , Fosfatidilinositol 3-Quinasa/metabolismo , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/economía , Pirimidinas/efectos adversos , Pirimidinas/economía , Quinazolinas/efectos adversos , Quinazolinas/economía , Recurrencia , Transducción de Señal/efectos de los fármacos , Resultado del TratamientoRESUMEN
Idelalisib (also known as GS-1101, CAL-101, IC489666, and Zydelig) is a PI3Kδ inhibitor that has recently been approved for the treatment of several hematological malignancies. Given its use in human diseases, we needed a clear picture of how idelalisib binds to and inhibits PI3Kδ. Our data show that idelalisib is a potent and selective inhibitor of the kinase activity of PI3Kδ. A kinetic characterization clearly demonstrated ATP-competitive inhibition, and several additional biochemical and biophysical assays showed that the compound binds reversibly and noncovalently to the kinase. A crystal structure of idelalisib bound to the p110δ subunit of PI3Kδ furthers our understanding of the binding interactions that confer the potency and selectivity of idelalisib.