Inhibitor PI3K delta

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Liliana Kowalczyk
7 lat temu
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1 CENTRUM ONKOLOGII INSTYTUT IM. MARII SKŁODOWSKIEJ-CURIE Klinika Nowotworów Układu Chłonnego Inhibitor PI3K delta w leczeniu chorych na nawrotowego chłoniaka grudkowego wykład sponsorowany przez Gilead Sciences Poland Jan Walewski, Warszawa,

2 Struktura zachorowań na nowotwory układu limfoidalnego, Polska dostęp

3 FLIPI2: a new prognostic index for FL developed by the International FL Prognostic Factor Project LoDLIN longest diameter of the largest involved node Federico M et al. J Clin Oncol 2009; 27: 4555

4 Charakterystyka produktu leczniczego Zydelig (idelalizyb) Niniejszy produkt leczniczy będzie dodatkowo monitorowany. Umożliwi to szybkie zidentyfikowanie nowych informacji o bezpieczeństwie. Osoby należące do fachowego personelu medycznego powinny zgłaszać wszelkie podejrzewane działania niepożądane. Aby dowiedzieć się, jak zgłaszać działania niepożądane - patrz punkt NAZWA PRODUKTU LECZNICZEGO Zydelig 100 mg tabletki powlekane 2. SKŁAD JAKOŚCIOWY I ILOŚCIOWY Każda tabletka powlekana zawiera 100 mg idelalizybu 4.1 Wskazania do stosowania Produkt Zydelig jest wskazany do stosowania w terapii skojarzonej z rytuksymabem w leczeniu dorosłych pacjentów z przewlekłą białaczką limfocytową (PBL): którzy uprzednio otrzymywali co najmniej jedną terapię, lub jako leczenie pierwszego rzutu w przypadku delecji 17p lub mutacji TP53 u pacjentów, u których nie można stosować chemioimmunoterapii. Produkt Zydelig jest wskazany w monoterapii u dorosłych pacjentów z chłoniakiem grudkowym (ang. Follicular Lymphoma, FL), który jest oporny na dwie wcześniej zastosowane linie leczenia. EU/1/14/938/002 EMA 18/09/2014

5 The phosphoinositol-3-kinase family group gene protein aliases class 1 catalytic class 1 regulatory class 2 PIK3CA PI3K, catalytic, alpha polypeptide p110-α PIK3CB PI3K, catalytic, beta polypeptide p110-β PIK3CG PI3K, catalytic, gamma polypeptide p110-γ PIK3CD PI3K, catalytic, delta polypeptide p110-δ PIK3R1 PI3K, regulatory subunit 1 (alpha) p85-α PIK3R2 PI3K, regulatory subunit 2 (beta) p85-β PIK3R3 PI3K, regulatory subunit 3 (gamma) p55-γ PIK3R4 PI3K, regulatory subunit 4 p150 PIK3R5 PI3K, regulatory subunit 5 p101 PIK3R6 PI3K, regulatory subunit 6 p87 PIK3C2A PI3K, class 2, alpha polypeptide PI3K-C2α PIK3C2B PI3K, class 2, beta polypeptide PI3K-C2β PIK3C2G PI3K, class 2, gamma polypeptide PI3K-C2γ class 3 PIK3C3 PI3K, class 3 Vps /04/2015

6 PI3Kd-dependent Signaling Pathways in B-cell Malignancies Signaling pathways that are critical for survival, proliferation, and homing in many B-cell malignancies are dependent upon PI3Kd.

The evolution of a selective PI3Kδ inhibitor

Idelalisib is a propeller-shaped p110δ-selective inhibitor that induces the formation of

potency toward p110δ, which is reflected in its greatly lowered halfmaximal inhibitory

7 The evolution of a selective PI3Kδ inhibitor quinazoline-(s)-2-{1-[(9h-purin-6-yl)amino]propyl}-5-fluoro-3-phenylquinazolin-4(3h)-1 Idelalisib is a propeller-shaped p110δ-selective inhibitor that induces the formation of the specificity pocket This interaction leads to a substantial increase in inhibitor potency toward p110δ, which is reflected in its greatly lowered halfmaximal inhibitory concentration (IC50) values (2.5 nm in vitro) Fruman DA, Rommel C: Cancer Discovery 2011; 1: Berndt A, et al. Nat Chem Biol. 2010; 6:

8 Inhibiting PI3Kδ targets both malignant B cells and the tumor microenvironment Fruman DA, Rommel C: Cancer Discovery 2011; 1(7):

9 The tumor microenvironment in FL Rimsza LM, Jaramillo MC: Hematology 2014; 163

10 Idelalisib in B-cell Malignancies: Summary Idelalisib inhibits key signaling pathways in B-cell malignancies that are important for growth, proliferation, survival and homing in lymph nodes 1-4 Targeting PI3Kδ does not inhibit antibody-dependent cellular cytotoxicity mediated by anti-cd20 antibodies 2 Combination strategies (e.g., chemoimmunotherapy) targeting additional survival signaling pathways or orthogonal mechanisms may provide a deeper and greater breadth of response across B-cell malignancies In clinical trials, idelalisib has demonstrated efficacy and an acceptable safety profile EMA approved for use in combination in CLL and as monotherapy in FL Okkenhaug K.. Nat Rev Immunol. 2003;3: ; 2. Herman SE, et al. Blood. 2010; 116: Vanhaesebroeck B. et al. Trends Biochem Sci. 2005;30: ; 4. Bernal A, et al, Blood. 2001;98: Zydelig (idelalisib) SmPC September

11 Mature Follow-up 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 Ajay K. Gopal, Brad S. Kahl, Sven de Vos, Nina D. Wagner-Johnston, Stephen J. Schuster, Wojciech J. Jurczak, Ian W. Flinn, Christopher R. Flowers, Peter Martin, Andreas Viardot, Kristie A. Blum, Andre H. Goy, Andrew Davies, Pier L. Zinzani, Martin H. Dreyling, Leanne M. Holes, Bess Sorensen, Wayne R. Godfrey, and Gilles A. Salles Gopal AK et al.: Blood :1708

Study 101-09 (Phase 2) Study Design and Patient

12 Study (Phase 2) Study Design and Patient Characteristics Study Long-term Follow-up Week 0 48 N=125 Continuous therapy Idelalisib 150 mg BID Therapy maintained until progression

13 Study (Phase 2) Overall Response Rate and By Disease Subgroups June 2013 June 2014 Complete Response Partial Response Minor Response Stable Disease Progressive Disease Not evaluable 2% n=2 8% n=10 6% n=7 57% 2% n=2 8% n=10 10% n=12 58% 34% n=42 50% n=63 Overall Response n=71/125 (95% CI: ) 33% n=41 47% n=59 Overall Response n=72/125 (95% CI: ) 1% n=1* 1% n=1* Overall Response Rate By Disease Subgroups: 2014 FL n=72 Complete Response 14% n=10 Partial Response 42% n=30 Minor Response Stable Disease Progressive Disease 32% n=23 Not evaluable 8% n=11 1% n=1 ORR, % (95% CI) 56% (43 67) SLL n=28 4% n=1 57% n=16 36% n=10 4% n=1 61% (41 79) MZL n=15 7% n=1 40% n=6 47% n=7 7% n=1 47% (21 73) LPL/WM n=10 70% n=7 10% n=1 10% n=1 10% n=1 80% (44 98) 0% 20% 40% 60% 80% 100% *LPL/WM patient.

Study 101-09 (Phase 2) Lymph Node Response by Disease Group 3 patients had no postbaseline computed

node biopsy. Criterion for lymphadenopathy response. 1 *Criterion for lymphadenopathy response.

14 Study (Phase 2) Lymph Node Response by Disease Group 3 patients had no postbaseline computed tomographic scan evaluation; *2 of these patients were not evaluable; 1 had progressive disease by lymph node biopsy. Criterion for lymphadenopathy response. 1 *Criterion for lymphadenopathy response. 1 Response in LPL/WM group predominantly determined by IgM response. 1. Cheson BD, et al. J Clin Oncol 2007;25:

Study 101-09 (Phase 2) Duration of Response All

3 2 1 1 1 7 1 *Includes patients who achieved a CR

15 Study (Phase 2) Duration of Response All Patients* By Disease Group Patients at risk, n *Includes patients who achieved a CR or PR (or MR for LPL/WM) according to IRC assessments. Patients at risk, n *Includes patients who achieved a CR or PR (or MR for LPL/WM) according to IRC assessments.

16 Study (Phase 2) Progression-Free Survival PFS 2014* By Disease Group Patients at risk, n On Study vs Last Prior Therapy Patients at risk, n Patients at risk, n * Gopal AK, et al. N Engl J Med. 2014; 370:

17 Study (Phase 2) Adverse Events

Study 101-09 (Phase 2) Adverse events (cont d) Adverse Events

18 Study (Phase 2) Adverse events (cont d) Adverse Events Occurring >1 year Idelalisib Exposure, n=43 *5 new AEs and 2 recurrences

Study 101-09 (Phase 2) Adverse events (cont d)

19 Study (Phase 2) Adverse events (cont d) Serious Adverse Events Occurring in >2 patients

Study 101-09 (Phase 2) Adverse events (cont d) Hematologic Lab Abnormalities Patients with Grades 1-2 ALT/AST elevations could continue idelalisib treatment

20 Study (Phase 2) Adverse events (cont d) Hematologic Lab Abnormalities Patients with Grades 1-2 ALT/AST elevations could continue idelalisib treatment (resolve/accommodation) Grade 3 was reversible with drug interruption 15 of 18 patients with Grade 3 were rechallenged 11 (73%) did not have recurrence of Grade 3 4 (27% had recurrence

22 Study (Phase 2) Author Conclusions The selective oral PI3Kδ inhibitor idelalisib demonstrated high response rates (ORR 58%) in patients with R/R inhl Response durations were prolonged (median 12.5 months) The safety profile of idelalisib in these patients on continuous therapy was manageable

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