Unmet Need Mucosal and Uveal Melanoma Matteo Carlino Crown Princess Mary Cancer Centre Westmead and Blacktown Hospitals Melanoma Institute Australia The University of Sydney.
Cutaneous Overall Survival Metastatic Melanoma ^ 1-year OS Phase 3 Studies 25 35% 46% 47% 56% 70% 71% 71% Pembro b 74% Dab + Tram c 75% Vem + Cobi 73% Nivo+Ipi (Ph II) 1990 2010 2011 2012 2013 2014 2015 2016 15% 24% 29% Ipi 45% Dab 58% Nivo a 53% Dab + Tram c 48% Vem + Cobi 2-year OS 64% Nivo + Ipi (Ph II) 55% Pembro 3-year OS 22% Ipi 42% Nivo (Ph I) 44% Dab + Tram 40/45% Pembro (Ph I) 5-year OS 18% Ipi 34% Nivo (Ph I) Slide Courtesy Georgina V Long a BRAF wt only; b Pooled pembrolizumab Q2W and Q3W 10mg/kg; c Pooled Dab + Tram data; Cobi=cobimetinib; Dab=dabrafenib; Ipi=ipilimumab; Nivo=nivolumab; Pembro=pembrolizumab; Tram=trametinib; Vem=vemurafenib.
Mucosal Melanoma Melanomas arising from the Oral/nasal cavity Genitourinary tract Anorectum Pathogenesis not linked to Sun exposure 1 Account for 3% of all melanoma cases in Caucasians 1 20% in Asian populations 2 More likely to present at a later stage 3 More likely node +ve worse survival than cutaneous melanoma 1: Postow et.al Curr Oncol Rep (2012) 2: Chi et.al BMC Cancer (2011) 3: Chang et.al Cancer (1998) 3
Melanoma Genetics Lower rate of BRAF mutations < 10% 1 C-kit mutations more commonly seen 10-20% of cases 2 1: Curtin et.al NEJM (2005) 2: Lyle &Long JCO (2013) 3: Carlino et.al Oncosicence (2014)
Mucosal Genetics Thanks to Graham Mann and the Australian Melanoma Genome Project (under review 2016)
Treatment strategies Immunotherapy Targeted therapy Chemo
Immunotherapy
Overview We conducted a pooled analysis of data from patients with metastatic mucosal melanoma who had received NIVO monotherapy (3 mg/kg), NIVO (1 mg/kg) plus IPI (3 mg/kg), or IPI monotherapy (3 mg/kg) in one of six trials: Phase I: CA209-003 and CA209-038 Phase II: CheckMate 069 Phase III: CheckMate 037, CheckMate 066, and CheckMate 067 NIVO Monotherapy NIVO+IPI IPI Monotherapy Studies 003/037/038/066/067 067/069 067/069 Total patients, N 889 407 357 Mucosal mel, n (%) 86 (10%) 35 (9%) 36 (10%) Cutaneous mel, n (%) 665 (75%) 326 (80%) 269 (75%) Acral/Ocular/Other 138 (15%) 46 (11%) 52 (15%) 8
Baseline Patient Characteristics NIVO (N=86) Mucosal NIVO+IPI (N=35) IPI (N=36) Cutaneous NIVO (N=665) Age, years Median (range) 61 (22 89) 65 (35 86) 61 (31 80) 60 (18 90) Age category, No. (%) <65 years 49 (57) 17 (49) 24 (67) 412 (62) 65 and <75 years 23 (27) 8 (23) 9 (25) 167 (25) 75 years 14 (16) 10 (29) 3 (8) 86 (13) Sex, No. (%) Female 44 (51) 19 (54) 19 (53) 233 (35) ECOG performance status, No. (%) 1 27 (31) 10 (29) 11 (31) 209 (31) M stage, No. (%)* M1c 57 (66) 22 (63) 19 (53) 409 (62) LDH, No. (%) >ULN 41 (48) 17 (49) 16 (44) 253 (38) >2x ULN 15 (17) 7 (20) 4 (11) 76 (11) BRAF status, No. (%) Mutant 4 (5) 2 (6) 4 (11) 151 (23) PD-L1 status, No. (%) ** Positive ( 5%) 15 (17) 10 (29) 7 (19) 228 (34) LDH, lactate dehydrogenase; ULN, upper limit of normal. *Based on cutaneous melanoma criteria. **PD-L1 positivity was defined as 5% of tumor cells exhibiting cell-surface PD-L1 staining of any intensity in a section containing at least 100 evaluable tumor cells. 9
Response to Treatment ORR, % (95% CI) * Mucosal (N=86) 23.3 (14.8 33.6) NIVO NIVO+IPI IPI Cutaneous (N=665) 40.9 (37.1 44.7) Mucosal (N=35) 37.1 (21.5 55.1) Cutaneous (N=326) 60.4 (54.9 65.8) Mucosal (N=36) 8.3 (1.8 22.5) Cutaneous (N=269) 21.2 (16.5 26.6) P value vs IPI 0.075 <0.0001 0.005 <0.0001 -- -- Best overall response, n (%) Complete response 5 (5.8) 46 (6.9) 1 (2.9) 44 (13.5) 0 7 (2.6) Partial response 15 (17.4) 226 (34.0) 12 (34.3) 153 (46.9) 3 (8.3) 50 (18.6) Stable disease 19 (22.1) 112 (16.8) 7 (20.0) 41 (12.6) 3 (8.3) 67 (24.9) Progressive disease 40 (46.5) 245 (36.8) 11 (31.4) 66 (20.2) 27 (75.0) 120 (44.6) Duration of response (mos) Median (95% CI) NR 22.0 (22.0 NR) NR (7.6 NR) NR (13.1 NR) 2.4 (1.8 3.0) NR (8.8 NR) CI, confidence interval; NR, not reached; ORR, objective response rate. *By RECIST v1.1 in all studies except CA209-003 in which RECIST v1.0 was used. 10
Tumor Burden Change Mucosal Melanoma 150 NIVO+IPI (N=28) Change from baseline in target lesions (%) 100 50 0-50 Median change: -34.2% 30% reduction in tumor burden by RECIST v1.1-100 Patients 150 NIVO (N=75) 150 IPI (N=32) Change from baseline in target lesions (%) 100 50 0-50 Median change: -1.4% Change from baseline in target lesions (%) 100 50 0-50 Median change: +28.6% -100 Patients -100 Patients 11
PFS Mucosal Melanoma Probability of Progression-Free Survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 NIVO 0.2 NIVO+IPI 0.1 IPI 0.0 0 Number of Patients at Risk 3 6 9 Months 12 NIVO (N=86) 15 NIVO+IPI (N=35) 18 IPI (N=36) Median, mos (95% CI) 3.0 (2.2 5.4) 5.9 (2.8 NR) 2.7 (2.6 2.8) HR (95% CI) vs IPI 0.61 (0.39 0.96) 0.42 (0.23 0.75) -- P value vs IPI* 0.12 0.003 -- Median follow-up, mos (range) 6.2 (0.5 17.4) 8.1 (0.5 16.9) 8.6 (1.9 17.1) *Unstratified log-rank test. NIVO 86 40 29 22 7 1 0 NIVO+IPI 35 19 12 11 2 0 -- IPI 36 8 2 0 0 0 -- 12
Targeting mutant Kit Multiple Ph2 studies Imatinib, Nilotinib, Sunitinib Studies often included pts with Kit amplification (no responses) RR upto 50% (in those with Kit mutations) No RCT Nilotinib study closed because of slow accrual.
Targeting mutant Kit Responses usually transient 1: Hodi et.al JCO(2013)
Adjuvant Chemotherapy Randomized Ph II study Observation vs IFN vs temozolomide +Cisplatin Single centre 189 pts stage II and III Multicentre study ongoing 1: Lian et.al CCR(2014)
Conclusions: Mucosal Melanoma Immunotherapy less active than in cutaneous melanoma? Indication for Ipi/anti-PD1 over anti-pd1 Consider Kit inhibition for palliative benefit after immunotherapy failure Adjuvant data awaited Chemo Excluded from EORTC adj study
Uveal Melanoma <3% of melanoma Arising from the choroid, iris or ciliary body Upto 50% of pts develop metastatic disease 1 Predilection for liver metastasis 1: Kujala et.al IOVS(2003) Chattopadhyay C et al. Cancer 2016
Uveal Genetics BRAF/NRAS mutations not seen GNAQ/GNA11 mutations seen>90% cases 1 BAP 1 mutations and Ch 3 monosomy associated with metastatic risk 2 1: Moore et.al Nat Genetics (2016) 2: Carvajal et.al BJ Opthal (2016)
Liver targeted treatment Numerous case series Surgery SIR speres RCT of hepatic intraarterial fotemustine vs IV Improvement in RR/PFS 10.5 vs 2.4% No improvement in OS 1: Leyvraz et.al Annals Onc (2014)
Uveal-Immunotherapy
Baseline characteristics Characteristic Total (N=56) Characteristic Total (N=56) Age at PD-1 start, median yrs (range) 62.4 (38.2-88.6) Male n (%) 32 (57.1) ECOG PS n (%) 0 1 25 (44.6) 22 (39.3) LDH > ULN n (%) 40 (71.4) Metastatic site n (%) Liver Lung Bone Lymph nodes CNS 50 (89.3) 23 (41.1) 14 (25) 11 (19.6) 7 (12.5) # lines of prior systemic therapy n (%) 0 1 2 3 8 (14.3) 28 (50) 17 (30.4) 3 (5.4) Prior immunotherapy n (%) 36 (64) Prior liver-directed therapy n (%) Bland/chemo/immuno/ radioembolization External beam RT Radiofrequency ablation 13 (23.2) 2 (3.6) 1 (1.8) Presented by: Katy K. Tsai, MD
Treatment responses (RECIST v1.1) Best overall response n (%) N=56 Complete response 0 Partial response 2 (3.6) Stable disease >= 6 months 5 (8.9)* Progressive disease 48 (85.7) * 1 patient lost to follow-up with stable disease at 5 months Presented by: Katy K. Tsai, MD
Best overall response Change in sum of lesion diameters (RECIST v1.1) 30% Response in liver (41.7% reduction in sum of tumor diameters) on pembrolizumab Presented by: Katy K. Tsai, MD
Survival estimates Progression-free survival, % PFS Median (95% CI): 2.6 months (2.4-2.8) Overall survival, % OS Median (95% CI): 7.7 months (0.7-14.6) Months Months Presented by: Katy K. Tsai, MD
Is Uveal melanoma an immune target? Low mutation burden of UM 1 Predominance of CD4+ve T cells 2 1: Furney SJ et al. Cancer Discov 2013 1: Rothermal et al. CCR 2016
Targeted therapy Uveal melanoma a better targeted therapy candidate than cutaneous melanoma? 1: Carvajal et.al BJO (2016)
Targeted therapy-mek inhibitors Promising PhII data with Selumetinib 1: Carvajal et.al ASCO (2016)
Targeted therapy-mek inhibitors 1: Carvajal et.al ASCO (2016)
Preclinical activity of selumetinib + TMZ Selumetinib potentiated the effects of TMZ in a human colorectal cancer tumor xenograft 1 TMZ has the same active metabolite as DTIC 2 Mean tumor volume (cm 3 ) ± SEM 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 Control Sel 25 mg/kg qd TMZ 6.25 mg/kg qd Sel + TMZ TGI vs control at Day 30 52%* 89%* 103%* 0 0 4 8 12 16 20 24 28 32 Days post selection TMZ-dosing period Sel-dosing period Adapted from 1 *p<0.0005 DTIC, dacarbazine; PFS, progression-free survival; qd, once daily; Sel, selumetinib; SEM, standard error of the mean; TGI, tumor growth inhibition; TMZ, temozolomide 1. Holt et al. Br J Cancer 2012;106:858 866; 2. Tsang et al. Cancer Chemother Pharmacol 1991;27:342 346
SUMIT: a Phase III, randomized, placebo-controlled, double-blind trial (NCT01974752) Patients with mum, with no prior systemic therapy Randomized 3:1, stratified by the presence/absence of liver metastases Selumetinib 75 mg bid PO + DTIC 1000 mg/m 2 IV on Day 1 of every 21-day cycle Pbo bid PO + DTIC 1000 mg/m 2 IV on Day 1 of every 21-day cycle Administered until objective disease progression (BICR), intolerable toxicity, or another discontinuation criteria; scanning schedule q6wk Optional open-label treatment: selumetinib +/- DTIC (data not shown) Primary endpoint PFS by central review (RECIST 1.1) Secondary endpoints include ORR, OS, DoR, safety and tolerability Exploratory endpoint MEK pathway mutations in GNAQ/GNA11 Key inclusion criteria mum (histologically or cytologically confirmed) 1 lesion measurable at baseline ECOG PS 0 1 Life expectancy >12 weeks Key exclusion criteria Previous systemic anticancer therapy (may have prior surgery, or intra-hepatic or non-systemic therapy) Protocol amended to ensure all randomized patients had the opportunity to complete 14-week minimum follow-up (two post-baseline tumor assessments) BICR, blinded independent central review; bid, twice daily; DoR, duration of response; DTIC, dacarbazine; ECOG PS, Eastern Cooperative Oncology Group performance status; IV, intravenously; mum, metastatic uveal melanoma; ORR, objective response rate; OS, overall survival; Pbo, placebo; PFS, progression-free survival; Pbo, placebo; PO, orally; q6wk, every 6 weeks; RECIST 1.1, Response Evaluation Criteria In Solid Tumors version 1.1
Progression-free survival (primary endpoint) Median PFS by central review was not statistically significantly improved with Sel + DTIC compared with Pbo + DTIC There was a numerical improvement in median PFS with Sel + DTIC compared with Pbo + DTIC by site-based review Probability of progression-free survival 1.0 0.8 0.6 0.4 0.2 Central review (primary analysis) HR 0.78 (95% CI 0.48, 1.27) 2-sided p=0.3195 Sel + DTIC Pbo + DTIC Probability of progression-free survival 1.0 0.8 0.6 0.4 0.2 Site-based review HR 0.49 (95% CI 0.28, 0.84) 2-sided p=0.0102 Sel + DTIC Pbo + DTIC 0 0 1 2 3 4 5 6 7 8 9 10 11 12 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Patients at risk: Time from randomization (months) Time from randomization (months) Sel + DTIC Pbo + DTIC 97 95 60 31 27 12 7 4 4 0 0 0 0 32 29 15 7 6 3 1 1 1 1 1 1 0 97 95 68 45 38 16 11 6 4 1 0 0 0 32 29 15 7 6 3 1 1 1 1 1 1 0 Sel + DTIC (n=97) Pbo + DTIC (n=32) Events, n (%) 82 (85) 24 (75) Median, mo 2.8 1.8 Progression free at 3/6 mo 38%/10% 26%/18% Sel + DTIC (n=97) Pbo + DTIC (n=32) Events, n (%) 77 (79) 26 (81) Median, mo 3.8 2.1 Progression free at 3/6 mo 56%/16% 26%/14% Population: full analysis set, data cut-off May 15, 2015. Analysis performed using stratified log-rank test with factors for treatment and liver metastases; crosses denote censored data CI, confidence interval; DTIC, dacarbazine; HR, hazard ratio; mo, months; Pbo, placebo; PFS, progression-free survival; Sel, selumetinib
Best change in tumor size (%) 100 80 60 40 20 0-20 -40-60 -80 200 180 100 80 60 40 20 0-20 -40-60 -80 Best tumor response by central review* GNA11 positive Population: full analysis set, data cut-off May 15, 2015 *Assessed by blinded independent central review using Response Evaluation Criteria In Solid Tumors version 1.1 DTIC, dacarbazine; Pbo, placebo Selumetinib + DTIC Partial response recorded for three patients GNAQ positive Pbo + DTIC No responses recorded GNAQ/GNA11 negative Unknow n Missing
Targeted therapy-pkc inhibitors Preclinical models showing PKC inhibitors active in uveal melanoma 1 Synergy with MEKi 2 1: Piperno-Neumannet.al ASCO (2014) 2: Chen et.al Oncogene (2013)
AEB071-PKC inhibitor 1: Piperno-Neumannet.al ASCO (2014)
Conclusions: Uveal Melanoma No current standard of care Current immunotherapy minimally active Novel strategies in early phase trials Liver directed therapy can be considered in selected cases.
Moving Forward More translational science More Trials