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Managing relapsed and refractory DLBCL Andy Davies [email protected] Oxford Lymphoma Course June 2018 DLBCL is a curable disease Overall survival: All randomised 83.0% 82.0% HR=0.907 p=0.549 Real World Data Haematological Malignancies research Network 2017 Events occur early… Overall survival from Overall survival from diagnosis 2 years event free Maurer M J et al. JCO 2014;32:1066-1073 Outcomes of R-CHOP population 100% 90% 15-25% refractory 80% 5% PR patients 70% 20-30% relapses 60% 50% 40% 50-60% cured 30% 20% 10% 0% Coiffier and Sarkozy et al 2016 How can we identify those patients that may not respond well…? IPI Age greater than 60 years Stage III or IV disease Elevated serum LDH ECOG > 2 More than 1 extranodal site Age adjusted IPI Stage LDH Performance status Ziepert at al. J Clin Oncol 28:2373-2380. Primary Refractory Early relapse Late relapse Not eligible for HDT • Age Eligible for HDT • Co-morbidity consolidation • No response to reinduction • No stem cells at harvest Reinduction regimen Reinduction regimen (I hate ‘salvage’) Followed by HDT+PBSCT Primary Refractory Early relapse Late relapse Not eligible for HDT • Age Eligible for HDT • Co-morbidity consolidation • No response to reinduction • No stem cells at harvest Reinduction regimen Reinduction regimen (I hate ‘salvage’) Followed by HDT+PBSCT PARMA Trail (Phillip NEJM 1995) • PARMA study (n=215 aggressive relapsed disease) • 109 demonstrated chemosenstivity after DHAP x2: randomised DHAP x4 more or BEAC + ABMT • OS 53 vs 32% at 5 years (P=0.038) • Time to relapse (< or > 12 months most important prognostic factor, along with second line aaIPI and response to salvage PR vs CR Guglielmi et al, JCO 1998 PARMA TRIAL: ABMT vs DHAP (A) Actuarial PFS curves in responding early relapses (less than 12 months from initial diagnosis) according to treatment arm (ABMT versus DHAP). (B) Actuarial PFS curves in responding late relapses (more than 12 months from initial diagnosis) according to treatment arm (ABMT versus DHAP) Evolving Standards of Care in Non-Hodgkin’s Lymphoma clinicaloptions.com/oncology Guideline Recommendations for Treatment of Relapsed DLBCL . Second-line therapy in . Second-line therapy for candidates for high-dose patients who are not therapy + ASCT candidates for high-dose therapy – DHAP ± rituximab – Clinical trial – ESHAP ± rituximab – Rituximab – GDP ± rituximab – CEPP ± rituximab – GemOx ± rituximab – Lenalidomide – ICE ± rituximab – EPOCH ± rituximab – MINE ± rituximab NCCN practice guidelines in oncology: non-Hodgkin’s lymphomas V.1.2010. Available at: http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf. High Dose Chemotherapy plus ASCT: CORAL trial experience Gisselbrecht C et al, JCO 2010 Which Reinduction Strategy? • DHAP, ESHAP, ICE, IVE , MIME etc ? • Similar response rates • CORAL study: n=396, median age 55 years. Similar response rates R-ICE 64% R-DHAP 63% Factors affecting response rates: refractory disease relapse less than 12 months after diagnosis International Prognostic Index (IPI) >1 than 1 Prior rituximab treatment versus no (51% v 83%) Gisselbrecht C et al. JCO 2010;28:4184-4190 ©2010 by American Society of Clinical Oncology The limited value of HDT+PBCT in relapsed DLBCL Friedberg 2011 R-DHAP R-ICE Thieblemont C et al. JCO 2011;29:4079-4087 ©2011 by American Society of Clinical Oncology Differential outcome by COO R-DHAP R-ICE N=232; 50% split GCB and non GCB Thieblemont C et al. J Clin Oncol 2011;29:4079-4087 SCHOLAR-1 Crump et al. 2017 Crump et al. 2017 Crump et al. 2017 GDP…outpatient regimen Crump et al. JCO 2014 Toxicity…. Crump et al. 2014 Better QoL Crump et al. JCO 2014 ORCHARRD Van Imhoff et al JCO 2016 Value of pre-auto PET Van Imhoff et al JCO 2016 Allogeneic transplantation provides durable remission in a subset of DLBCL patients relapsing after autologous transplantation.. Fenske et al. BJH 2016 n=503 Median age 51 Primary Refractory Early relapse Late relapse Not eligible for HDT • Age Eligible for HDT • Co-morbidity consolidation • No response to reinduction • No stem cells at harvest Reinduction regimen Reinduction regimen (I hate ‘salvage’) Followed by HDT+PBSCT LYSA Study: GemOx Mournier et al. R-GemOX in R/R DLBCL Mournier er al. PFS by cell of origin model Mournier et al. Pixantone Phase III open label Pixantrone 85mg/m2 1, 8 and 15 28 days Aggressive Lymphoma* Relapsed >2 therapies (inc 1 anthracycline with R response >24 weeks) LVEF>50% Vinorelbine 30 mg/m2 1, 8, 15, and 22 4 weeks Oxaliplatin 100 mg/m2 1 3 weeks 1o Endpoint: CR/CRu Ifosfamide 3000 mg/m2 1 and 2 4 weeks 2o Endpoints: ORR, PFS, OS Etoposide 100 mg/m2 1, 2, 3, 4, and 5 4 weeks Etoposide 50 mg/m2 Daily for 21 days 4 weeks Mitoxantrone 14 mg/m2 1 3 weeks Gemcitabine 1250 mg/m2 1, 8, and 15 4 weeks * Exclusion of Burkitt’s, 1, 8, and 15 of lmyphoblastic, Mantle, CNS, Rituximab 375 mg/m2 cycle 1 and day 1 3 weeks HIV related of cycle 2 Pixantrone…. Median PFS IIT 5.3 vs 2.6 months Pettengell et al. Lancet Oncol 2012 Pixantrone..real world experience (Eyre et al 2016) 92 R/R DLBCL 85% refractory disease 72% had an international prognostic index (IPI) 3–5 Median PFS 2·0 months (95% confidence interval (CI) 1·5–2·4 Median OS was 3·4 months (95% CI 2·7–4·5). ORR 24% (complete response 10%; partial response 14%). Lenalidomide ► Immunomodulatory properties ► Modulation of both cellular and cytokine tumour cell microenvironment ► Activates T cell and NK response to tumour cell ► Down regulates pro-survival cytokines ► Approval in myeloma Chanan-Khan, A. A. et al. J Clin Oncol; 26:1544-1552 2008 Differential response according to cell of origin in DLBCL (n=40). Retrospective review. Response rates Progression-free survival Hernandez-Ilizaliturri et al. Cancer 2011 DLC-001: Lenalidomide in R/R DLBCL Subtypes Progression-free Survival (IHC versus GEP) Czuczman et al ASH 2014 GCB (IHC) GCB (GEP) Non-GCB (IHC) ABC (GEP) Abbreviations: ABC, activated B-cell; CR, complete response; DLBCL, diffuse large B-cell lymphoma; GCB, germinal center B-cell; GEP, gene expression profiling; IC, investigator’s 38 choice; IHC, immunohistochemistry; L, lenalidomide; OS, overall survival; PFS, progression-free survival; PR, partial response; R/R, relapsed/refractory; wk, weeks. What about the GCB Phenotype? ► Enhancer of Zeste 2 (EZH2) is the enzyme component of the Polycomb Repressive Complex 2 (PRC2) that methylates histone H3 on lysine 27 (H3K27) ► Somatic activating mutations in EZH2 have been identified in follicular and GCB-DLBCL [Morin, 2010; Morin, 2011; Pasqualucci, 2011]; ► The frequency of the most prevalent mutation, Y641, 22% in DLBCL. ► Inhibitors in early phase investigation McCabe M T et al. Proc Nat Acad Sci USA 2012;109:2989-2994 Activity in EZH2 mutated DLBCL (Ribrag et al ASH 2015) Microenvironment Surface markers EXAMPLE HEADER UPPERCASE TEXT…CD22 Anti CD20 moAb Lenalidomide Ofatumumab CD20 CD80 GA-101 • HeaderT-cell exhaustion • Anti CD40 moAb First level bold bullet: text… Dacetuzumab Actionable• mutations First level bold old bullet Anti CD22 - SecondCD79a/b level bullet Epratuzumab EZH2 Inotuzumab Ozogamicin AEB071 E7438- Third level bullet Pathways polatuzumab - Third level bullet mTOR inhibitors Proteosome inhibitors Everolimus HDAC inhibitors - SecondBortezomib level bullet Temsirolimus Vorinostat Panobinostat - PI3K inhibitors • HeaderBcl-2 family Idelalisib PKC inhibitors inhibitors Copanlisib Enzastaurin Duvelisib • First levelABT bullet:-263 text… TGR-1202 Aurora kinase Survivin inhibitors Btk inhibitors inhibitors YM155 Ibrutinib ONO/GS-4059 Nedd8-activating ACP-196 References… Syk inhibitors enzyme inhibitors…Footnote Fostamatinib Hsp 90 inhibitors MLN4924 entosplentib KW 2478 Exhausted T-Cells and Checkpoint blockade therapy ► Important interplay between malignant cells and microenvironment. ► …eventually ineffective. Immune escape or immune checkpoints ► Blocking immune checkpoints may promote endogenous antitumour activity ► PD1: Inhibitory receptor on activated T-cells, B-cells, NK and myeloid cells. Inhibition of T-cell activation when engaged by ligands (PDL1/2) ► PD1 expressed on T-cells when exposed to tumour, and associated with exhaustion. Blocking can restore Ribas A. N Engl J Med 2012;366:2517-2519. function PD1/PD-L1 in DLBCL ► Investigation of nivolumab (anti PD-1), pembrolizumab (anti PD-1), avelumab (PD-1), durvalumab (anti PD-L1) and atezoluimumab (PD-L1), in DLBCL ► PD-L1 expressed on about 30% of patients with DLBCL (more frequent in PMBL) ► High is EBV +ve DLBCL and TCRLCL (Chen et al. Clin Canc Res 2013) ► Nivoulumab ORR DLBCL 36% (n=11) median duration of response 22 weeks (Lesokhin et al. ASH 2014) ► Is PD-L1 expression a biomarker of activity (Chen et al. Clin Canc Res 2013) Microenvironment Surface markers EXAMPLE HEADER UPPERCASE TEXT…CD22 Anti CD20 moAb Lenalidomide Ofatumumab CD20 CD80 GA-101 • HeaderT-cell exhaustion • Anti CD40 moAb First level bold bullet: text… Dacetuzumab Actionable• mutations First level bold old bullet Anti CD22 - SecondCD79a/b level bullet Epratuzumab EZH2 Inotuzumab Ozogamicin AEB071 E7438- Third level bullet Pathways polatuzumab - Third level bullet mTOR inhibitors HDAC inhibitors Proteosome inhibitors Everolimus - Vorinostat SecondBortezomib level bullet Temsirolimus Panobinostat - PI3K inhibitors Bcl-2 family Idelalisib PKC inhibitors • Header Copanlisib Enzastaurin inhibitors Duvelisib • First levelABT bullet:-263 text… TGR-1202 Aurora kinase Survivin inhibitors Btk inhibitors inhibitors YM155 Ibrutinib ONO/GS-4059 Nedd8-activating ACP-196 References… Syk inhibitors
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    NEXT-GENERATION RADIOIMMUNOTHERAPIES FOR NON-HODGKIN’S LYMPHOMA PATIENTS SEPTEMBER 2019 Nordic Nanovector ASA Kjelsåsveien 168 B, 0884 Oslo, Norway www.nordicnanovector.com IR contact: [email protected] Forward-looking statements This slide presentation contains certain forward-looking statements. These statements are based on management's current expectations and are subject to uncertainty and changes in circumstances, since they relate to events and depend on circumstances that will occur in the future and which, by their nature, will have an impact on Nordic Nanovector's business, financial condition and results of operations. The terms "anticipates", "assumes", "believes", "can", "could", "estimates", "expects", "forecasts", "intends", "may", "might", "plans", "should", "projects", "targets", "will", "would" or, in each case, their negative, or other variations or comparable terminology are used to identify forward looking statements. These forward-looking statements are not historic facts. There are a number of factors that could cause actual results and developments to differ materially from those expressed or implied in the forward-looking statements. Factors that could cause these differences include, but are not limited to, risks associated with implementation of Nordic Nanovector's strategy, risks and uncertainties associated with the development and/or approval of Nordic Nanovector's product candidates, ongoing and future clinical trials and expected trial results, the ability to commercialise Betalutin®, technology changes and new products in Nordic Nanovector's potential market and industry, Nordic Nanovector's freedom to operate (competitors patents) in respect of the products it develops, the ability to develop new products and enhance existing products, the impact of competition, changes in general economy and industry conditions, and legislative, regulatory and political factors.