Melanoom behandeling in 2017

Size: px

Start display at page:

Download "Melanoom behandeling in 2017"

Sabrina Waters
6 years ago
Views:

1 Melanoom behandeling in 2017 Prof Winald R. Gerritsen Radboud University Medical Center Department of Medical Oncology Nijmegen, the Netherlands Adjunct Professor Johns Hopkins Sidney Kimmel Cancer Center Baltimore, USA Rutger Koornstra, Niven Mehra, Koos vd Hoeven, Kalijn Bol, Steve Boudewijns, Martine Bloemendal, Jolanda de Vries, Carl Figdor, Gerty Schreibelt

2 Melanoom behandeling in 2017

3 Melanoom behandeling in 2017 Target host Target tumor Immunotherapie Doelgerichte Therapie

4 Melanoom behandeling Stadium III Eggermont AM et al. N Engl J Med 2016;375:

5 Melanoom behandeling Stadium III Eggermont AM et al. N Engl J Med 2016;375:

6 Melanoma patients Immunized with Natural DenDritic Cells (MIND-DC) A randomized, double-blind, placebo-controlled phase III study to evaluate active immunization in adjuvant therapy of patients with stage IIIB and IIIC melanoma with natural dendritic cells pulsed with synthetic peptides. NL

7 Rationale dendritische celvaccinatie

8 Rationale dendritische celvaccinatie

s Nachts: Kweken met GM-CSF, IL-3, KLH Beladen

gp100 tyrosinase MAGE-C2 MAGE-A3 NY-ESO-1

(3,5-4 weken) Cryopreservatie (tot 24 maanden)

9 s Nachts: Kweken met GM-CSF, IL-3, KLH Beladen met Peptivator : MAGE-A3 NY-ESO-1 Geactiveerde en beladen ndc s Dag 2: Activatie met protamine/mrna (6u) Beladen met peptiden: gp100 tyrosinase MAGE-C2 MAGE-A3 NY-ESO-1 Natural Dendritische cellen Dag 1: 1. Depletie van B cellen en monocyten 2. Selectie van mydc s en pdc s Steriliteitstest (3,5-4 weken) Cryopreservatie (tot 24 maanden) 9 echogeleide intranodale injecties Dag 1: Leukaferese (12 liter) Immunomonitoring

11 Behandelschema Patiënten worden gerandomiseerd: ndc (arm A) of placebo (arm B) in verhouding 2:1

13 Stadium IV melanoom: combinatie therapie

14 melanoomcellen T-lymfocyten

15 Immuuntherapie kan zeer effectief zijn voor het uitgezaaide melanoom: TIL behandeling Tumor-infiltrerende lymfocyten (TIL) worden uit een uitzaaiing opgegroeid Rapid Expansion

16 Immuuntherapie kan zeer effectief zijn voor het uitgezaaide melanoom: TIL behandeling Tumor-infiltrerende lymfocyten (TIL) worden uit een uitzaaiing opgegroeid Rapid Expansion Infusie van TIL + IL-2-50% response rate in trials in multiple centers (US, Israel, DK, NL)

17 Patient N10TIL003: voortgaande CR > 4 jaar Voor TIL 3 wkn na TIL 8 wkn na TIL 12 wkn na TIL Patiënt had al 3 behandelingen voor uitgezaaid melanoom gehad Kreeg bijna afweercellen toegediend

18 Improved 1 year OS of stage IV melanoma patients thanks to targeted and and immunotherapy 79% 74% 74% 68%? 41% 50%? 53% 24% DTIC Ipilimumab * no phase 3 data TIL* Vemurafenib Young TIL* Dabrafenib + Trametinib Nivolumab/ Pembrolizumab Ipi+ +Nivo* McArthur et al. Lancet Oncol 2014; Hodi et al. NEJM 2010; based on Rosenberg and Dudley Curr Opin Immunol 2009; McArthur et al. Lancet Oncol 2014; based on Dudley et al. JCO 2013; Long et al. Lancet 2015; based on Robert et al. NEJM 2015; prediction based on Larkin et al. NEJM 2015 and Sznol et al. ASCO 2014, Postow et al. AACR 2016 Courtesy CU Blank et al al

19 Ipilimumab + Nivolumab induces high overall survival rates (phase 2 study data, BRAFwt pat) Postow et al., AACR 2016

20 PFS (%) PFS (%) CheckMate 067: Nivo + Ipi Provides Most Benefit for PD-L1lo, Similar to Nivo for PD-L1hi PD-L1 5%* PD-L1 < 5%* Nivo + Ipi Nivo alone Ipi alone Median PFS, Mos HR Median PFS, Mos Nivo + Ipi 11.2 Nivo alone 5.3 Ipi alone 2.8 HR Mos Mos 21 *Per validated PD-L1 IHC assay based on PD-L1 staining of tumor cells in a section of at least 100 evaluable tumor cells. Larkin J, et al. N Engl J Med. 2015;373:23-34.

21 OS Probability Pooled Overall Survival: Dabrafenib + Trametinib (N = 617) yr 74% Median (95% CI), mo 25.6 (23.1,34.3) yr 53% Months PRESENTED BY GV LONG AT SMR

22 Before we start to combine everything with each other. Melero, Haanen, et al., Nature Reviews Cancer 2015

23 How to personalize Immunotherapy The Cancer Immunogram Tumor foreignness Mutational load Tumor sensitivity to immune effectors MHC expression IFN-g sensitivity General immune status Lymphocyte count Absence of inhibitory tumor metabolism LDH, glucose utilization.let s focus! Immune cell infiltration Intratumoral T cells Absence of soluble inhibitors IL6->CRP/ESR Absence of Checkpoints PD-L1 Blank, Schumacher, et al., Science 2016

24 General immune status lymphocyte count ipilimumab pembrolizumab Martens et al., CCR 2016 Weide et al., CCR 2016 Courtesy CU Blank et al al

25 melanoomcellen T-lymfocyten

26 Immune cell-associated biomarkers ALC, eosinophils, and intratumoral CD8 (pembrolizumab) Tumeh et al., Nature 2014

27 LDH and CRP are independent baseline predictors (ipilimumab, anti-ctla-4) RR according to LDH (NKI cohort) LDH < ULN: 26,3% LDH > ULN < 2x ULN: 6,3% LDH > 2x ULN: 2,5% 2 ESR baseline P = ULN 1 LDH baseline P < > ULN ULN > ULN N = Node 32 (27%) 3 (n = 32) Node N = 12 4 (n(7%) = 12) Node N = 73 5 (n (62%) = 73) CR: N = 6 PR: N = CR: N = 0 PR: N = CR: N = 1 PR: N = Time (months) Time (months) Time (months) Supplementary Figure 1 Stratification by baseline LDH and ESR values Kelderman, Blank, Larkin et al. CII 2014

Case 1: a patient with PD-L1 positive tumor, normal LDH solution: anti-pd-1 (+ anti-ctla-4) Tumor foreignness Mutational load Tumor sensitivity to immune effectors MHC expression IFN-g sensitivity

28 Case 1: a patient with PD-L1 positive tumor, normal LDH solution: anti-pd-1 (+ anti-ctla-4) Tumor foreignness Mutational load Tumor sensitivity to immune effectors MHC expression IFN-g sensitivity General immune status Lymphocyte count Absence of inhibitory tumor metabolism LDH, glucose utilization Immune cell infiltration Intratumoral T cells Absence of soluble inhibitors IL6->CRP/ESR Absence of Checkpoints PD-L1 Blank, Schumacher, et al., Science 2016

29 LDH high, ESR/CRP high, ALC low, CD8 intratumor low is associated with disastrous outcome upon ipilimumab Geukes, Blank, et al. manuscript in preparation

30 Phase 2 Study testing the COmbination of Vemurafenib With Cobimetinib in BRAF V600E/K mutated Melanoma Patients to Normalize LDH and Optimize immunotherapy with Nivolumab and Ipilimumab (COWBOY) Rutger Koornstra Christiaan Blank Jan Willem de Groot

31 Optimise response immunooncology LDH decrease/ normalisation Sufficient effective T-cells present in a tumor/ tumor milieu Low number of Tregs in a tumor. Improved tumorantigen presentation Inhibit immunecheckpoints

32 Own data: LDH BRAFi/ MEKi Elevated LDH (median LDH 391 U/l (range U/l)) Start BRAFi + MEKi: normalized serum LDH within 8 week: 74% patients Median duration till LDH normalisation: 25 days (range 7-56 days) >> maximum effect can be expected within 6 weeks treatment

33 Tumor Response to Vemurafenib Baseline, C4 D1,

34 Frequency TILs increased after combined MAPK and PI3K pathway inhibition Deken, MA et al.; Oncoimmunology (12):e

35 General Scientific Rationale Elevated LDH has been repeatedly identified as a prognosticator for impaired response and long-term outcome in metastasized melanoma. We postulate that induction therapy with combined BRAF+MEK inhibition, and subsequent rapid LDH normalization, can improve response rates to the rates seen in LDH normal patients. We hypothesize that we can turn a poor-prognosis (LDH high) tumor into a high response tumor upon treatment with ipilimumab + nivolumab by induction therapy with vemurafenib + cobimetinib However the underlying mechanisms are still to be dissected.

36 Follow-up CR: stop PR: additional 6x nivolumab, then stop Irresect. Stage IIIc or IV BRAFV600 Melanoma LDH>ULN, Stratified according LDH (>ULN; >2xULN) PBMC, CT Tumor biopsy Randomisation ratio 1:1 induction therapy : ipilimumab + nivolumab Vemurafenib+ Cobimetinib PBMC, CT tumor biopsy Ipilimumab + Nivolumab, 4 cycles Ipilimumab + Nivolumab, 4 cycles PBMC CT PBMC, CT tumor biopsy 3x Nivolumab maintenance flat dose SD: additional 12x nivolumab, then stop PD during FU: 2 additional cycles ipilimumab + nivolumab Late response PD: off protocol // In case of suspected pseudo-progression: additional 3x nivolumab weeks

37 Follow-up CR: stop PR: additional 6x nivolumab, then stop Irresect. Stage IIIc or IV BRAFV600 Melanoma LDH>ULN, Stratified according LDH (>ULN; >2xULN) PBMC, CT Tumor biopsy Randomisation ratio 1:1 induction therapy : ipilimumab + nivolumab Vemurafenib+ Cobimetinib PBMC, CT tumor biopsy Ipilimumab + Nivolumab, 4 cycles Ipilimumab + Nivolumab, 4 cycles PBMC CT PBMC, CT tumor biopsy 3x Nivolumab maintenance flat dose SD: additional 12x nivolumab, then stop PD during FU: 2 additional cycles ipilimumab + nivolumab Late response PD: off protocol // In case of suspected pseudo-progression: additional 3x nivolumab weeks

38 Conclusies B-RAF inhibitors combinatie therapie Immuun checkpoint inhibitors combinatie therapie Veel orgineel Nederlands onderzoek in melanoma centra

History of Cancer Immunotherapy: Key Milestones Discovery of dendritic cell Tumor-specific monoclonal Abs Adoptive T-cell immunotherapy IFN-α as adjuvant therapy for melanoma BCG approved for bladder

39 History of Cancer Immunotherapy: Key Milestones Discovery of dendritic cell Tumor-specific monoclonal Abs Adoptive T-cell immunotherapy IFN-α as adjuvant therapy for melanoma BCG approved for bladder cancer Discovery of checkpoint inhibitors First immunotherapy approved for prostate cancer (sipuleucel-t) Pembrolizumab and nivolumab approved for advanced melanoma Atezolizumab approved for advanced UC and metastatic NSCLC Nivolumab approved for RCC Nivolumab approved for HL 1970s 1980s 1990s 2000s Immune component to spontaneous regressions in melanoma IL-2 approved for RCC and melanoma (US) First tumor-associated antigen cloned (MAGE-1) First checkpoint inhibitor (ipilimumab) approved for advanced melanoma Nivolumab approved for NSCLC Pembrolizumab approved for PD-L1+ NSCLC Pembrolizumab approved for HNSCC

Immunotherapy for the Treatment of Melanoma. Marlana Orloff, MD Thomas Jefferson University Hospital

Immunotherapy for the Treatment of Melanoma Marlana Orloff, MD Thomas Jefferson University Hospital Disclosures Immunocore and Castle Biosciences, Consulting Fees I will be discussing non-fda approved