Latest advances in the treatment of mesothelioma Assoc Prof Thomas John Medical Oncologist, NHMRC Fellow Olivia Newton-John Cancer Research Institute 28 th March 2015 Disclosures Nil relevant Honoraria: Astra Zeneca, BMS, Roche, Merck Travel Grants: Boehringer Ingelheim, Roche, Astra Zeneca Advisory Boards: Pfizer, Astra Zeneca 1
1990 1992 2000 2008 2010 2016 04 1014 2024 3034 4044 5054 6064 7074 8084 Number 573 117 690 538 100 638 Crude rate 5.2 1.0 3.1 4.8 0.9 2.8 ASR 5.1 0.9 2.8 4.6 0.7 2.5 Risk to age 75 1 in 302 1 in 1,505 1 in 507 1 in 382 1 in 2,057 1 in 650 Risk to age 85 1 in 130 1 in 842 1 in 238 1 in 140 1 in 970 1 in 259 Mean age 73.3 73.3 73.3 74.4 74.0 74.3 Estimated number for 2014, 2015 and 2016 (c) 2014 640 145 780 575 125 700 The statistics 2015 655 150 805 595 130 725 2016 675 155 830 620 135 755 Rate (per 100,000) Rate (per 100,000) 6 5 4 3 2 1 60 50 40 30 20 10 0 1988 1984 1986 1982 0 1998 1996 1994 Incidence males Mortality males 2006 2002 2004 2014 2012 Incidence females Mortality females Incidence males Mortality males Incidence females Mortality females Figure B18(a): Incidence and mortality ASRs (b,c) of mesothelioma, 19822016 Figure B18(b): Incidence (2011) and mortality (2012) rates of mesothelioma, by age group (a) Based on IARC (2014) and WCRF & AICR (2007) (see Chapter 2). (b) The 2011 incidence data include estimates for NSW and the ACT. Mean age for 2011 incidence was calculated excluding NSW and the ACT (see Appendix F). Deaths registered in 2010 and earlier are based on the final version of cause of death data; deaths registered in 2011 and 2012 are based on revised and preliminary versions, respectively, and are subject to further revision by the ABS. ASRs were directly standardised to the Australian population as at 30 June 2001. Rates are expressed per 100,000 population. Cancer in Australia 2014 (c) The 20122016 estimates for incidence are based on 20022011 incidence data. The 20132016 estimates for mortality are based on 20022012 mortality data (see Appendix G). They are rounded to the nearest 10. Estimates less than 1,000 are rounded to the nearest 5. The estimates for males and females may not add to estimates for persons due to rounding. Sources: AIHW ACD 2011; AIHW NMD. 120 Cancer in Australia: an overview 2014 Progress is slow NSCLC 2004: EGFR mutations discovered 2012: Immunotherapy 2000: 2 nd line chemo NSCLC 1995: 1 st line chemo NSCLC 2003 2007: ALK rearrangements 2009: Maintenance chemo 1993 Mesothelioma 2015 Multiple negative Phase II studies 2003: 1 st line chemotherapy Mesothelioma 2
Carbone et al. CCR 2011 Robinson et al NEJM, 2005 Important Trials for 2015 Phase II/III Pemetrexed/Platinum +/-Bevacizumab as first line therapy in MPM Preliminary data presented from Phase II portion met criteria for continuing DCR at 6 months was 73.5% in the Bev arm compared to 43.2% in the control arm Likely to be presented at ASCO 2015 Phase I/II study of Pembrolizumab in MPM (Keynote- 028) Data presented at ESMO 2014 showed the target PDL-1 was expressed in 20% MPM Patients with strong PDL-1 expression had the poorest outcomes (i.e it is a predictive marker but also poor prognostic marker) This study will be presented at AACR next month 3
Immunotherapy Ribas NEJM, 2012 Immunotherapy predictive marker PD-L1 + PD-L1-4
Response to PD-1 inhibitors by PD- L1 expression in tumour Note bw 9-20% PD-L1 negative respond PD-1 inhibitors Do they work? Week 1 Week 6 Week 12 5
Progression-Free Survival (%) Kaplan-Meier Estimate of Progression-Free Survival by RECIST 1.1 (Central Review) a with Clinical Trial Assay 110 100 90 80 70 Median, wks Rate, 12 wks Rate, 24 wks PS0 (n=49) 9.3 36% 13% PS1-49 (n=53) 9.3 43% 20% PS 50 (n=44) 14.0 54% 41% 60 50 40 30 20 10 0 0 8 16 24 32 40 48 56 64 72 80 88 96 N at risk: PS0: 49 30 15 5 0 Time in Weeks 0 0 0 0 0 0 0 0 PS1-49: 53 43 17 8 1 0 0 0 0 0 0 0 0 PS 50: 44 30 19 13 6 3 3 3 3 2 1 0 0 PFS was significantly longer in patients with strongly (PS 50) PD-L1+ staining tumors compared to weakly positive (PS1-49) and negative (PS0) HR=0.53 95% CI: 0.33,0.83 P=0.004 Data cut-off was December 31, 2013. a Evaluable patients were those patients in the training set with evaluable tumor PD-L1 expression. 6
PD-L1 in Mesothelioma Cedres et al. PLOS One 2015 Is there progress? Other trials Trial Pem/Cis +/- Cedirinib SS1P and Pentostatin + Cyclophos CAR T Cell Receptor Immunotherapy Adjuvant Iscomatrix/Tumor Lysate Vax adc1 Vax+Chemokine Mod Regimen Pemetrexed second line Erlotinib in MPM Mithramycin in chest cancers Allogeneic Tumor Cell Vaccine Intrapleural Gene Therapy for MPM Intrapleural measles Virus Therapy Proton beam RT Phase II I/II I/II I/II I/II II II II I I I Mesothelioma Trials on Cancer.Gov 7
Novel agents targeting mesothelioma 8
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Novel solution for mir-15/16 construct delivery: Minicells or EngeneIC Delivery Vesicles (EDVs) 10
Targetable mutations.. Lynch et al. NEJM 2004 11
Targetable mutations in mesothelioma Iacono et al JTO 2015 Guo et al Can Res 2015 12
Targeting the NF2/Merlin pathway Shapiro et al. Sci Trans Med 2014 Where is the research heading? Globally individual centres have small patient numbers Number of new cases still rising, but still small Mesothelioma is not a priority for Pharma! Need for collaborative group trials 13
Clinical Development of Inhibitors of PD-1 in NSCLC Target Agent Molecule Company Development PD-1 Nivolumab- BMS-936558 Pidilizumab CT-011 Pembrolizumab MK-3475 Fully human IgG4 mab Humanized IgG1 mab Humanized IgG4 mab Bristol-Myers Squibb CureTech Merck Phase II, III multiple tumors Phase II multiple tumors Phase I-II,III AMP-224 Recombinant PD-L2- Fc fusion protein PD-L1 BMS-936559 Fully human IgG4 mab MedI-4736 MPDL-3280A Engineered human IgG1 mab Engineered human IgG1 mab GlaxoSmithKline Bristol-Myers Squibb MedImmune/AZ Roche-Genentech Phase I Phase I Phase I-II Phase II-III Adapted from J. Brahmer ASCO 2013, Leighl ASCO 2013 REVIEWS Antigen-presenting cell PDL1 or PDL2 PDL1 or PDL2 CD80 or CD86 CD80 or CD86 B7RP1 B7-H3 B7-H4 HVEM MHC class I or II CD137L OX40L CD70 + CD40 GAL9 Adenosine Peptide Cytokines (TGFβ, IL-1, IL-6, IL-10, IL-12, IL-18) T cell? PD1 CD28 CTLA4 ICOS?? BTLA KIR TCR LAG3 CD137 OX40 CD27 CD40L TIM3 A2aR + + + Signal 1 + + + Figure 1 Multiple co-stimulatory and inhibitory interactions regulate T cell responses. Depicted are various ligandreceptor interactions between T cells and antigen-presenting cells (APCs) that regulate the T cell response to antigen (which is mediated by peptide major histocompatibility complex (MHC) molecule complexes that are recognized by the T cell receptor (TCR)). These responses can occur at the initiation of T cell responses in lymph nodes (where the major APCs are dendritic cells) or in peripheral tissues or tumours (where effector responses are regulated). In general, T cells do not respond to these ligandreceptor interactions unless they first recognize their cognate antigen through the TCR. Many of the ligands bind to multiple receptors, some of which deliver co-stimulatory signals and others deliver inhibitory signals. In general, pairs of co-stimulatoryinhibitory receptors that bind the same ligand or ligands such as CD28 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) display distinct kinetics of expression with the co-stimulatory receptor expressed on naive and resting T cells, but the inhibitory receptor is commonly upregulated after T cell activation. One important family of membrane-bound ligands that bind both co-stimulatory and inhibitory receptors is the B7 family. All of the B7 family members and their known ligands belong to the immunoglobulin superfamily. Many of the receptors for more recently identified B7 family members have not yet been identified. Tumour necrosis factor (TNF) family members that bind to cognate TNF receptor family molecules represent a second family of regulatory ligandreceptor pairs. These receptors predominantly deliver co-stimulatory signals when engaged by their cognate ligands. Another major category of signals that regulate the activation of T cells comes from soluble cytokines in the microenvironment. Communication between T cells and APCs is bidirectional. In some cases, this occurs when ligands themselves signal to the APC. In other cases, activated T cells upregulate ligands, such as CD40L, that engage cognate receptors on APCs. A2aR, adenosine A2a receptor; B7RP1, B7-related protein 1; BTLA, B and T lymphocyte attenuator; GAL9, galectin 9; HVEM, herpesvirus entry mediator; ICOS, inducible T cell co-stimulator; IL, interleukin; KIR, killer cell immunoglobulinlike receptor; LAG3, lymphocyte activation gene 3; PD1, programmed cell death protein 1; PDL, PD1 ligand; TGFβ, transforming growth factor-β; TIM3, T cell membrane protein 3. Immunotherapy In Phase III trials In Phase I trials Pardoll. Nat Rev Cancer 2012 CD4 + helper T cells T cells that are characterized by the expression of CD4. They recognize antigenic peptides presented by MHC class II molecules. This type of T cell produces a vast range of cytokines that mediate inflammatory and effector Nature Reviews Cancer the expression of which determines the T Reg cell lineage expression of the CTLA4 ligands (other than for some 34,35, and T Reg cells therefore express CTLA4 constitutively. myeloid and lymphoid tumours) and because the dra- Although the mechanism by which CTLA4 matic lethal autoimmune and hyperimmune pheno- enhances the immunosuppressive function of T Reg type of Ctla4-knockout mice predicted a high degree of cells is not known, T Reg cell-specific CTLA4 knockout immune toxicity associated with blockade of this receptor. or blockade significantly inhibits their ability to regulate However, Allison and colleagues 36 used preclinical both autoimmunity and antitumour immunity 30,31. models to demonstrate that a therapeutic window was Thus, in considering the mechanism of action for indeed achieved when CTLA4 was partially blocked with CTLA4 blockade, both enhancement of effector CD4 + antibodies. The initial studies demonstrated significant T cell activity and inhibition of T Reg cell-dependent antitumour responses without overt immune toxicities immunosuppression are probably important factors. when mice bearing partially immunogenic tumours were treated with CTLA4 antibodies as single agents. Poorly Clinical application of CTLA4-blocking antibodies immunogenic tumours did not respond to anti-ctla4 as 14
Conclusion 2015 is likely to see some practice changing studies in mesothelioma Targeting downstream pathways of mutations in mesothelioma may enable personalisation of treatment Immune therapies have shown considerable promise in mesothelioma and are likely to alter treatment paradigms in the near future as single agents or in combination Questions? Tom.john@onjcri.org.au 15