Disclosures. Disclosures. Grand Unification: The rationale for combining immunotherapy and molecular targeted therapy 25/02/2014

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1 Grand Unification: The rationale for combining immunotherapy and molecular targeted therapy Ryan J. Sullivan, M.D. Massachusetts General Hospital / Harvard University Canadian Melanoma Conference February 23, 2014 Disclosures Unfortunately, I have no relevant disclosures to declare. Disclosures I have one irrelevant disclosure. 1

2 Disclosures I have one irrelevant disclosure. Beware of agreeing to hike with Michael Smylie Objectives (Nov 2013) Review preclinical data justifying the combo of BRAF directed therapy and immunotherapy Describe the clinical data of BRAFi/immunotherapy combinations Review ongoing and future trials of BRAFi/immunotherapy combinations Revised Objectives Briefly review BRAF/immunotherapy sequencing data Review preclinical data justifying the combo of targeted therapy and immunotherapy Describe the clinical data of BRAFi/immunotherapy combinations Review ongoing and future trials of targeted therapy/immunotherapy combinations 2

3 An Era of Futility: Dacarbazine High dose Interleukin We ve learned that melanoma is driven by genetic changes TCGA 2012 Oncogenes in melanoma Year Target Prevalence Drug 1984 NRAS 20% tramentinib, MEK BRAF 50% vemurafenib, LGX 818 dabrafenib; trametinib, MEK CKIT 1% imatinib, dasatinib, nilotinib 2008 GNAQ/11 1% * selumetinib,?pkci 2012 NF1 loss 10% unknown *(80-90% of uveal) 3

4 X X X X X Immune (T cell) activation is not as simple as 4

5 Immune (T cell) activation is not as simple as Immune (T cell) activation is amazingly much more complex Pardoll. Nat Rev Cancer 2012 yet druggable! Pardoll. Nat Rev Cancer

6 An Era of Futility: Dacarbazine High dose Interleukin An Era of Futility: An Era of Hope: 2006 Nivolumab, MK 3475 Dabafenib, trametinib Dacarbazine High dose Interleukin 2 Ipilimumab vemurafenib Immunotherapy: Ipilimumab BRAF mutant: Vemurafenib An Era of Hope: By subclass

7 An Era of Hope: By subclass Immunotherapy: Ipilimumab BRAF mutant: Vemurafenib Dabafenib, trametinib An Era of Hope: By subclass Immunotherapy: Ipilimumab BRAF mutant: Vemurafenib Dabafenib, trametinib MK 3475, Nivolumab An Era of Hope: By subclass Immunotherapy: Ipilimumab BRAF mutant: Vemurafenib Dabafenib, trametinib MK 3475, Nivolumab MEK162, LGX818, cobimetinib

8 An Era of Hope: By subclass Immunotherapy: Ipilimumab BRAF mutant: Vemurafenib NRAS mutant: Other mutants: Dabafenib, trametinib MK 3475, Nivolumab, other anti PD1/PDL1/checkpoint inhibitors. MEK162, LGX818, cobimetinib, ERKi MEK162, trametinib, CDKi, ERKi MEKi, PKCi, AKTi, KITi Is there an ideal sequence of immunotherapy and molecularly targeted therapy? BRAF-directed therapy is as effective before or after immunotherapy Response No Response Total ITfirst MAPKi first Ackerman et al. Cancer In Press 8

9 Ipilimumab does not appear to be as effective following progression on BRAF-directed therapy Ackerman et al. Cancer In Press Outcome is better with iplimumab first sequence Ascierto et al. ASCO 2013 Outcome is better with BRAFi than ipilimumab sequence Ascierto et al. ASCO 2013 though selection bias must be considered Ackerman et al. Cancer In Press 9

10 Intergroup Study (formerly E4613) ECOG PS 0 1 Stage IIIC (unres) or M1a/b M1c Prior therapy No Yes R A N D O M I Z E Arm 1: Ipi q3wks x 4 Arm 2: Vem 960 BID PD Vem Ipi PI: Mike Atkins Intergroup Study (formerly E4613) Dabrafenib plus trametinib Nivolumab plus ipilimumab Wolchok et al. NEJM 2012 Flaherty et al. NEJM 2012 PI: Mike Atkins Intergroup Study (formerly E4613) ECOG PS 0 1 Stage IIIC (unres) or M1a/b M1c Prior therapy No Yes R A N D O M I Z E Arm 1: Ipi/Nivo q 3wks x 4 then nivo q2wks x 42wks Arm 2: Dab 150 BID, Tram 2 qd PD Dab/Trem Ipi/Nivo PI: Mike Atkins 10

11 New Paradigm? New Paradigm? Ribas, Society for Melanoma Research 2012 New Paradigm? Ribas, Society for Melanoma Research

12 New Paradigm? Ribas, Society for Melanoma Research 2012 Is there any reason to combine immunotherapy with molecularly targeted therapy? BRAF inhibitor therapy plus immunotherapy in BRAF mutant melanoma 12

13 Are BRAF inhibitors immunosuppressive? Treatment with BRAFi does not impair overall immune competance; MEKi does. BRAF inhibition does NOT affect T cell function, however MEK inhibition impairs proliferation & function Boni et al. Cancer Res 2010; Hong et al. Clin Cancer Res BRAF/MAPK Inhibition Increases Recognition of Melanoma Cells by Antigen Specific T Cells MEK Inhibitor U0126 * * BRAF Inhibitor PLX4720 * * P<0.05 Boni et al. Cancer Res

14 What are the effects of BRAF inhibitors on tumors? Treatment with BRAFi increases MDI expression in tumors of patients with melanoma Frederick et al. Clin Cancer Res 2013 Treatment with BRAFi increases CD8+ T Cell infiltrate in tumors of patients with melanoma Frederick et al. Clin Cancer Res

15 Treatment with BRAFi reduce immunosuppressive cytokines but increases immuno exhaustion Frederick et al. Clin Cancer Res 2013 Preclinical data predicts synergy of BRAF inhibitor plus anti PDL1/PD1 combinations Cooper et al SMR 2012 Clinical trials of BRAF/MEK inhibitors and immunotherapy IFN a IL2 ACT Ipilimumab nivolumab MK3475 MPDL 3280A MEDI 4736 BRAF inhibitors Vemurafenib (V) Dabrafenib (D) * 0 0 1** 0 MEK inhibitors Cobimetinib (C) Trametinib (T) Combined T +/ D; D +/ T Ribas et al. NEJM 2013*; Hamid et al. ASCO 2013** 15

16 The combination of vemurafenib and ipilimumab leads to significant hepatotoxicity 6/10 patients enrolled who received the combination had Grade 3 ALT/AST elevation Ribas et al. NEJM 2013 MPDL3280A + Vemurafenib Preliminary Safety MPDL3280A 20 mg/kg Q3W mg vemurafenib BID Treatment Start Cycle (Q3W) /3 Patients: Rash (Gr 3) AST/ALT elevation (Gr 1-3) Flu-like symptoms (Gr 1-2) 1 Resolved with vemurafenib hold/reduction 2/2 Active Patients 2 : AST/ALT elevation (Gr 3) Resolved with vemurafenib hold/reduction Rash and flu-like symptoms did not recur 2/2 Active Patients: AST elevation Gr 1 Patient status: 1 patient D/C due to PD Cycle 8 1 patient active (Cycle 12+; CR) 1 Included fever, headache, sore throat, arthralgia, chills, fatigue 2 One patient with PD at 8 weeks 1 PR, 1 CR Hamid et al. ASCO 2013 Summary of BRAF inhibition and immunotherapy BRAFi lead to: Increase melanocyte derived antigen expression Reduced immunosuppressive cytokine production Flooding of CD8+, T lymphocytes Increased PDL1 expression Combined BRAFi/immunotherapy In vivo synergy in murine models Higher than predicted toxicity in two phase I trials of vemurafenib plus immune checkpoint inhibitors Many ongoing studies with more planned 16

17 NRAS mutations, MITF, and immunotherapy MAPK suppresses MITF and MDA expression Haq, Johnson et al. SMR 2013 MAPK suppresses MITF and MDA expression Haq, Johnson et al. SMR

18 MAPK suppresses MITF and MDA expression Haq, Johnson et al. SMR 2013 MAPK suppresses MITF and MDA expression Haq, Johnson et al. SMR 2013 Differential patterns of MITF amplification in BRAF and NRAS mutations and NF1 loss TCGA

19 MITF amplification is commonly seen in BRAF mutant melanoma TCGA 2012 MITF amplification is never seen in NRAS mutant or NF1 loss melanoma Melanocyte gene expression from BRAF mutant, MITF amplified cells is more similar to NRAS mutant cells than BRAF mutant, MITF non amplified Haq, Johnson et al. SMR

20 Mutational Status and HD IL-2 Joseph, Sullivan et al. JIT 2012 NRAS mutation is associated with higher response rate and improved outcome compared to WT/WT Johnson et al. ASCO 2013 Survival in the setting of immunotherapy: BRAF vs NRAS mutant 20

21 Next Steps 1. Determine the mechanism Next Steps 1. Determine the mechanism 2. Clinical trials MEDI trametinib MPDL3280A + cobimetinib Acknowledgments MGH Center for Melanoma Keith Flaherty Donald Lawrence Rizwan Haq Fisher Lab David Fisher Rizwan Haq Sullivan Lab Dennie Frederick MDACC Jen Wargo Zachary Cooper Mike Davies Vanderbilt Ingram Cancer Center Jeff Sosman Doug Johnson Christine Lovly MSKCC Rich Carvajal MIA Oliver Klein Georgina Long BIDMC David McDermott Alison Ackerman 21