Advances in the biology and treatment of malignant melanoma 2018

Transcription

1 Advances in the biology and treatment of malignant melanoma 2018

2 GF Y-P RTK Y-P Ras GTP P BRAF V600 MEK BRAFi P ERK Cyclin D Cell cycle (Ki67) Baseline Day 15

3 Toxicity Dabrafenib Dabrafenib + trametinib 150/1 Dabrafenib + trametinib 150/2 Hyperkerat osis 30% 6% 9% cuscc 19% 2% 7% Papillomas 15% 7% 4% Pyrexia 26% 69% 71% Higher efficacy, lower toxicity related to paradoxical MAPK activation

4 Overview of acquired resistance mechanisms Core pathways MAPK pathway Acquired resistance according to Roger Lo Nazarian, Lo. Nature 2010 Shi Lo. Nature Communications 2012 Poulikakos, Solit. Nature 2011 Shi, Hugo Lo. Cancer Discovery 2013

5 Branched evolution underlying acquired BRAF inhibitor resistance Shi et al. Cancer Discovery 2013

6 Ribas, NEJM 2012; Jun 28; 366 (26):

7 Pembrolizumab 27% ORR 28% ORR ORR: 38% 18% ORR Nivolumab Pembrolizumab

8

9 NEJM 2017

10 Adjuvant BRAF Directed Therapy in Melanoma

11 Adjuvant Immunotherapy in Melanoma

12 Adjuvant Immunotherapy in Melanoma

13 Desmoplastic melanoma: Defined by a dense collagenous fibrous tissue Trichrome S100 DM 1 DM 2 DM3 Non-DM 1 Non-DM 2 Baseline 2-3 months after anti-pd1 therapy Bartosz Chmielowski, MD, PhD, UCLA Suthee Rapisuwon, MD Georgetown-Lombardi Top panel: S100 stains (brown) Lower panel: Masson s trichrome stain (blue collagenous stroma, red cytoplasm and brown nucleus) Wen-Jen Hwu, MD MD Anderson A rare subtype of melanoma (less than 4%) A dense fibrous reaction A known relationship to UV light damage High NF1 mutation rate but no other actionable genes for targeted therapies Zeynep Eroglu, Jesse Zaretsky, Siwen Hu-Lieskovan, et al. Nature 2018

14 High response rate and high mutational load in Desmoplastic melanoma 70% overall response rate 32% complete response rate % Overall survival (OS), median not reached Estimated 2 year OS 73% (CI 62-88). Time (months) n=60 (out of 1058 cases reviewed*) 2 siiic 3 M1a 20 M1b 35 M1c *Retrospective Review Nature 2018

15 TVEC: HSV-1 Modified by Attenuation and Insertion of GM-CSF Gene

16 Intra-tumoral T-VEC (oncolytic virus) plus systemic pembrolizumab induces high response rates by increases in tumor CD8 infiltration T-VEC Intralesional Pembrolizumab Wk: Percentage Change from Baseline N = 21 Stage IIIB (N = 1) Stage IIIC (N = 6) Stage IV M1a (N = 2) Stage IV M1b (N = 4) Stage IV M1c (N = 8) 62% objective response rate 33% complete response rate T-VEC T-VEC+ pembro Ribas et al. Cell 2017 Sep 7; 170 (6): e10.

17 The Anti-PD-1/L1 Field is Crowding in an Unprecedented Way (Need for Flexible Combinatorial Strategies) Annals of Oncology 29: 84 91, 2018

18 The IO Field is Complex and Crowded Number of IO Agents Already High and Likely to More Than Double Annals of Oncology 29: 84 91, 2018

19 Immuno-Oncology Clinical Trial Landscape 2018 A Growing Number of Targets and Strategies Annals of Oncology 29: 84 91, 2018

20 Immuno-Oncology Clinical Trial Landscape 2018 Anti-PD Combination Types Annals of Oncology 29: 84 91, 2018

21 Immuno-Oncology Clinical Trial Landscape 2018 Number and Planned Size of Combination Trials Over Time Size Decreasing Multiple Histologies Increasing Annals of Oncology 29: 84 91, 2018

22 Immuno-Oncology Clinical Trial Landscape 2018 Lots of Combination Trials More Numerous Are Least Interesting Biologically Annals of Oncology 29: 84 91, 2018

23 EA 6134 SWOG Sequencing Trial STRAT FACTORS ECOG PS 0 1 Serum LDH Normal 2 Elevated 2 R A N D O M I Z A T I O N Step 1: Arm A Initial Treatment Immunotherapy Induction Nivolumab 1mg/kg IV infusion day 1 and 22 of cycles 1 and 2 Ipilimumab 3mg/kg IV infusion day 1 and 22 of cycles 1 and 2 Immunotherapy Maintenance Nivolumab 3mg/kg IV infusion day 1, 15, and 29 of cycles 3-14 (max 84 weeks) Arm B Dabrafenib 150mg PO BID days 1-42 of each 6 week cycle Trametinib 2mg PO QD days 1-42 of each 6 week cycle PD 1 PD 1 C R O S S O V E R Step 2: 3 Arm C Dabrafenib 150mg PO BID days 1-42 of each 6 week cycle Trametinib 2mg PO QD days 1-42 of each 6 week cycle Arm D Initial Treatment Immunotherapy Induction Nivolumab 1mg/kg IV infusion day 1 and 22 of cycles 1 and 2 Ipilimumab 3mg/kg IV infusion day 1 and 22 of cycles 1 and 2 Immunotherapy Maintenance Nivolumab 3mg/kg IV infusion day 1, 15, and 29 of cycles 3-14 (max 84 weeks) PD 1 PD 1 L O N G - T E R M F O L L O W - U P Cycle = 42 days Accrual Goal = Progressive disease will be determined by RECIST criteria for all arms, found in Section 6. Crossover should proceed no sooner than 2 weeks following RECIST defined PD on either arm. 2. Elevated Serum LDH is defined as above ULN for institution. 3. Must meet eligibility criteria found in Section 3.2.

24 Management of cancer in the anti-pd-1/l1 era Anti-PD-1/anti-PD-L1 Bring T cells into tumors: + anti-ctla4 + immune activating antibodies or cytokines + TLR agonists or oncolytic viruses + IDO or macrophage inhibitors + targeted therapies Generate T cells: Vaccines TCR engineered ACT CAR engineered ACT Modified from Ribas, Cancer Discovery 2016

25 Study Schema SWOG 1616 Patients with advanced melanoma with disease progression on PD-1 antibody without prior response Randomize 1:3 Biopsy Ipilimumab 3mg/kg q3wk x4 doses Ipilimumab 3mg/kg q3wk x4 doses + Nivolumab 1mg/kg q3wk x4 doses then Nivolumab 240mg q2wk Biopsy at Day Tumor assessment following completion of ipilimumab then every 12 weeks x 12 months Continue treatment while clinical benefit persists per investigator- OS Follow-up for 2 years Blood for correlative studies will be collected prior to each on-study biopsy.

26 Tesaro Anti-TIM-3 +/- Nivo

27 Reversing T cell exclusion with intra-tumoral therapies Anti-PD-1/anti-PD-L1 IT injection oncolytic virus TLR agonist, MDA5 agonist STING agonist + Anti-PD-1/anti-PD-L1 May bring rare antitumor T cells into tumors and improve responds to anti- PD-1/L1 therapy

28 SD-101 (TLR9-agonist) SD-101 is a synthetic Class C CpG-ODN (Toll-like Receptor 9 Agonist) that stimulates plasmacytoid dendritic cells to release interferon-alpha and mature into efficient antigen presenting cells. Pre-clinically, in a CT26 mouse model, SD- 101 in combination with an anti-pd-1 induced T cell infiltration and durable complete responses in all treated animals (Campos et al, AACR 2016).

29 Intra-tumoral SD101 (TLR9 agonist) plus systemic pembrolizumab induces responses in patients anti-pd-1 treated Patients with prior anti-pd-1/l1 therapy i.v. anti-pd-1 i.t. TLR9 agonist + i.v. anti-pd-1 Percent Change From Baseline, % Days Ribas et al. Cancer Discovery 2018 (epub)

30 CMP-001: CpG-A DNA in a Virus-Like Particle CpG-A DNA ( G10 ) 30-mer native DNA oligonucleotide Virus-like Particle (VLP) Purified coat protein from bacteriophage Qβ Non-replicating; no viral genes Protects the CpG-A DNA from degradation The Qβ protein selfassembles around G10 into highly-ordered icosahedral VLPs (~30 nm) Mechanism of Action TLR9 agonist, leading to activation of plasmacytoid dendritic cells (pdc) Originally developed by Dr. Martin F. Bachmann, University in Bern

31 CMP Pembrolizumab in PD-1 Resistant Melanoma Baseline Scans 12 Week Scans Percent Change from Baseline in SLD of Target Lesions [ 24 0 ] ORR = 22% [95% CI 13%-33%] CR=2; PR=13 Injection Site Injection Site Baseline Noninjected (spleen) 12 weeks Injection Site 24 weeks Abscopal response

32 Adding BRAF Targeted Therapies to Anti-PD-1/L1 Anti-PD-1/anti-PD-L1 BRAFi+MEKi Wilmott et al. CCR Frederick DT, et al. BRAFi+MEKi + anti-pd-1/l1 Wilmott et al. Clin Cancer Res 2012, doi: / CCR Frederick DT, et al. Clin Cancer Res. 2013;19:

33 Clinical trials combining BRAFi+MEKi+anti-PD-1/L1 dabrafenib+trametinib +durvalumab dabrafenib+trametinib +pembrolizumab vemurafenib+cobimetinib +atezolizumab dabrafenib+trametinib +spartalizumab 100 N = 9 Change from Baseline, % * * * * * Time, months * * Ribas et al. ASCO 2015 Ribas et al. ASCO 2016 and ESMO, 2017 * Time, months Hwu et al. ESMO 2016 Dummer et al. ASCO-SITC 2017

34 Desmoplastic Melanoma S1512 (Chmielowski) Pembro Neoadjuvant/ Adjuvant/ Metastatic Melanoma Targeted Therapy Frontline, BRAF mutant Sequence with Immunotherapy SWOG EA6134 (Chmielowski) Debra+Trame vs Ipi+Nivo, crossover at progression Targeted Therapy Only SWOG S1320 (Chmielowski) Dabrafenib+ Trametinib Intermittent vs Continuous Uveal Melanoma Immunocore IMCgp (Chmielowski) IMCp100 vs investigator s choice HLA A2.1+ only

35 Melanoma/Solid Tumors Immunotherapy Checkpoint Inhibitor Naïve Only Frontline or Salvage Prior Checkpoint Inhibitor OK Multi-histology Melanoma Only BRAF Mutant SWOG EA6134 (Chmielowski) Debra+Trame vs Ipi+Nivo, crossover at progression BRAF Wild Type MK022 (Ribas) Pembro vs placebo +Dabrafenib +Trametinib Injectable Lesion S1607 (Hu-Lieskovan) TVEC + Pembro After anti- PD1/L1 Idera (Chmielowski) Ipilimumab +/- IMO-2125 After anti- PD1/L1 Checkmate 001/002 (Ribas) CMP001+Pembro Dynavax (Ribas) SD101 +Pembro Hu-Lieskovan IST VINO VX Ipi or Nivo After anti-pd1/l1 S1616 (Ribas) Ipi +/- Nivo After anti- PD1/L1 Immunocore (Ribas) IMCgp100 (HLA A2.1+ pts) +/-MDI4736 +/- Tremelimumab Adoptive Cell Transfer Therapy NYSCT (Ribas) NYESO TCR PBSC+PBMC NYN (Hu-Lieskovan) NYESO TCR PBMC + Nivo Astellas (Hu-Lieskovan) Anti-TIGIT +/- pembro (now all histologies) BMS 627 (Glaspy) Nivolumab Basket Trial Tesaro 3000 (Konecny) Anti-PD1 (Endometrial, NSCLC MacroGenics (Chmielowski) Bispecific (anti- LAG3 + anti-pd-1) Infinity (Chmielowski) IPI549 (PI3Kr inh) +/- Nivo Aeglea (Chmielowski) AEB1102 (Co-Argl-PEG) Rgenix (Chmielowski) RGX-104 (LXR agonist) Solid Tumors Tesaro 4020 (Ribas) Anti-TIM3 +/-Nivo Solid Tumors Biothera (Chmielowski) Imprime PGG + Pembro Pfizer B (Hu-Lieskovan) Anti-OX40 +/- anti-cd137 Melanoma, HCC F Star (Hu-Lieskovan) Bispecific (anti- LAG3 + anti- PDL1) (all histologies) After anti-pd1/l1 only Nektar (Hu-Lieskovan) NKTR Nivo Pfizer B (Ribas) Avelumab + anti-cd137 +anti-ox40