Melanoma Clinical Trials and Real World Experience Paul Lorigan University of Manchester Manchester, UK www.christie.nhs.uk/melanoma Melanoma Bridge, Naples 214
New Benchmarks for Phase II Trials OS at 1 year 25% PFS at 6 mths 15% 1 year OS 6 mths PFS Numbers of patients Numbers of patients META-ANALYSIS OF 7 PHASE II TRIALS IN 21 PATIENTS OVER PAST 35 YEARS Melanoma Bridge, Naples 214 Korn et al JCO 28
Negative Studies 25-1 Combinations with new agents Sorafenib Bevacizumab Oblimersen Elesclomol New agents Tasisulam nab-paclitaxel Melanoma Bridge, Naples 214
Tasisulam vs Paclitaxel as Second Line Treatment Mechanism of action poorly understood PK poorly understood Evidence of activity in Phase 2 study Study stopped after 336 patients randomised Imbalance in treatment related deaths. 13 vs Median OS 6.77 months vs 9.36 months Melanoma Bridge, Naples 214 Hamid Cancer 214
Melanoma Treatment Paradigm Immunotherapy Target host Targeted Therapy Target tumour Vaccines Checkpoint inhibitors Cytokines Small molecule inhibitors Melanoma Bridge, Naples 214
The Role Of The Immune System In Cancer Advantages Responds to tumour specific antigens Adapts to new mutations Provides memory Disadvantages Many controls are inhibitory, allowing tolerance Inhibitory controls subverted by cancer Melanoma Bridge, Naples 214
Targeting The Immune Checkpoints Priming phase Effector phase Dendritic cell T-cell T-cell Cancer cell Lymph node Peripheral tissue MHC TCR TCR MHC Activation signals B7 CD28 Negative regulation PD1 PD-L1 Inhibitory signals B7 Antibody CTLA-4 Antibody Antibody Melanoma Bridge, Naples 214 Ribas A, et al. NEJM 212
Importance Of Checkpoint Blockade TGN1412 Melanoma Bridge, Naples 214
Most Common Immune-Related Adverse irae Events* (All Grades) % of Patients Ipi + gp1 N=38 All grades Ipi + pbo N=131 gp1 + pbo N=132 Any 58.2 61.1 31.8 Dermatologic 4. 43.5 16.7 GI 32.1 29. 14.4 Endocrine 3.9 7.6 1.5 Hepatic 2.1 3.8 4.5 *Across entire study duration Hodi et al. NEJM 21 Melanoma Bridge, Naples 214
Pooled Analysis of Phase I-III Studies of Ipilimumab in 28 Stage IV Melanoma Patients Melanoma Bridge, Naples 214
Keynote-1: Maximum % Change from Baseline Tumour Size a (Central Review, RECIST v1.1) 1 8 Change From Baseline in Sum of Longest Diameter of Target Lesion, % 6 4 2-2 -4-6 -8-1 IPI-T IPI-N 72% Individual Patients Treated With Pembrolizumab a In patients with measurable disease at baseline by RECIST v1.1 by central review and 1 postbaseline assessment (n = 317). Percentage changes >1% were truncated at 1%. Analysis cut-off date: October 18, 213. Melanoma Bridge, Naples 214 Ribas ASCO 214
Immune-Mediated AEs Adverse Event, n (%) Any Grade Grade 3-4 Hypothyroidism 32 (8) 1 (<1) Hyperthyroidism 4 (1) 1 (<1) Pneumonitis a 11 (3) 1 (<1) Colitis 3 (<1) 2 (<1) Hepatitis b 2 (<1) 1 (<1) Some reported skin rashes may have been immune-mediated Other potentially immune-mediated AEs reported in <1% of patients: nephritis, hypophysitis, and uveitis a 1 additional patient experienced interstitial lung disease of grade 1-2. b Includes autoimmune hepatitis. Analysis cut-off date: October 18, 213. Melanoma Bridge, Naples 214 Ribas ASCO 214
Response Characteristics in Patients with Melanoma Receiving Nivolumab Responses ongoing in 19/34 (56%) responders at time of analysis 52% (11/21) of responding pts who discontinued therapy for reasons other than PD responded for 24 wks 64% (7/11) remained in response from 24-56 wks 44% (15/34) of responding patients showed a response at first tumour assessment (8 wks) Median DOR 22.9 months Melanoma Bridge, Naples 214
Nivolumab Phase 1- Overall Survival 1 9 Died/Treated, n/n Median OS, mo (95% CI) Patients Surviving (%) 8 7 6 5 4 3 2 1-yr OS 63% 1-yr OS 65% 2-yr OS 47% 2-yr OS 48% 3-yr OS 42% All cohorts 67/17 17.3 (12.5, 37.8) 3. mg/kg 11/17 2.3 (7.2, NE) 3-yr OS 41% 4-yr OS 35% 4-yr OS 32% 3 mg/kg (N=17) All cohorts (N=17) 1 3 6 9 12 15 18 21 24 27 3 33 36 39 42 45 48 51 54 57 6 63 66 69 Time Since Treatment Initiation (months) Patients at Risk Total 3. mg/kg 17 17 97 17 86 15 71 11 64 11 55 1 51 9 5 8 49 8 47 8 43 7 39 7 35 7 23 6 19 6 16 6 16 6 15 6 13 4 5 2 2 1 1 1 September 214 data analysis Hodi et al SMR 214 Melanoma Bridge, Naples 214
Study Design Eligible patients with advanced melanoma (n=45) R 2:1 Nivolumab 3 mg/kg IV Q2W Open Label Investigator s choice of chemotherapy (ICC): Dacarbazine 1 mg/m 2 Q3W OR Carboplatin AUC 6 IV and paclitaxel 175 mg/m 2 Q3W Treat until Progression or Unacceptable toxicity Patients receiving nivolumab may be treated beyond initial progression if considered by the investigator to be experiencing clinical benefit and tolerating study drug Stratified by: PD-L1 expression: PD-L1 positive vs. PD-L1 negative/indeterminate (positive: 5% tumour cell surface staining cutoff by immunohistochemistry) BRAF status: BRAF wild-type vs. BRAF V6 mutant Best overall response (BOR) to prior anti-ctla-4: Clinical benefit (BOR=CR/PR/SD) vs. no clinical benefit (BOR=PD) Melanoma Bridge, Naples 214
Co-Primary Endpoint: ORR By Central Review per RECIST 1.1 Treatment N ORR a, % Best Overall Response a, % CR PR SD PD UNK Central review b Nivolumab 12 32 3 28 23 35 1 ICC 47 11 11 34 32 23 a Confirmed response; b Independent radiology review committee (IRRC) based on RECIST 1.1 CR=complete response; PR=partial response; SD=stable disease; PD=progressive disease; UNK=unknown Melanoma Bridge, Naples 214
Nivolumab vs DTIC in BRAF WT patients Eligible patients with unresectable stage III or IV melanoma (n=418) BRAF wild-type Treatment-naïve Stratified by: PD-L1 status M-stage Doubleblind R 1:1 Nivolumab 3 mg/kg IV Q2W + Placebo IV Q3W n=21 (26 treated) Placebo IV Q2W + Dacarbazine 1 mg/m 2 IV Q3W n=28 (25 treated) Treat until progression * or unacceptable toxicity Primary endpoint: OS Secondary endpoints: PFS ORR PD-L1 correlates PD-L1 positive: 5% tumour cell surface staining. * Patients may be treated beyond initial RECIST v1.1-defined progression if considered by the investigator to be experiencing clinical benefit and tolerating study drug. Melanoma Bridge, Naples 214
Patients Surviving (%) Patients at Risk Nivolumab Dacarbazine Primary Endpoint: Overall Survival 1 9 8 7 6 5 4 3 2 1 21 28 HR.42 (99.79% CI,.25.73; P <.1) (Boundary for statistical significance.21) 185 177 Patients who died, n/n 15 123 Median OS mo (95% CI) 15 82 Nivolumab (n=21) 45 22 1-yr OS 73% 1-yr OS 42% 8 3 Dacarbazine (n=28) ORR, % (95% CI) 4% (33 47%) 14% (1 19%) Nivolumab (n=21) Dacarbazine (n=28) Nivolumab Dacarbazine 5/21 96/28 NR* 1.8 (9.3 12.1) *NR=not reached. Based on 5 Aug 214 database lock 3 6 9 Months 12 15 18 Melanoma Bridge, Naples 214
Secondary Endpoint: PFS Patients without Progression (%) Patients at Risk Nivolumab Dacarbazine 1 9 8 7 6 5 4 3 2 1 21 28 116 74 82 28 Death or disease progression, n/n Median PFS mo (95% CI) Nivolumab 18/21 5.1 (3.5 1.8) Dacarbazine 163/28 2.2 (2.1 2.4) 6-mo PFS 48% 6-mo PFS 19% 57 12 HR.43 (95% CI,.34.56; P <.1) 12 Dacarbazine (n=28) 1 Nivolumab (n=21) Based on 5 August 214 database lock 3 6 9 12 15 18 Months Melanoma Bridge, Naples 214
Phase I Combination Study: Dose Cohorts Dose (mg/kg) Treatment Schedule Regimen Cohort No. N Nivolumab Ipilimumab Induction Maintenance Concurrent 1 2 2a 3 14 17 16 6.3 1 3 3 8* 41 1 3 Sequenced 6 7 17 16 1 3 3 3 1 3 Prior Prior Nivo Q3W x 8 + IPI Q3W x 4 Nivo Q3W x 8 + IPI Q3W x 4 Nivo + IPI Q12W x 8 Nivo 3 mg/kg Q2W (Max. 48 doses) Nivo Q2W (Max of 48 doses) *Insufficient follow-up at this data collection to report survival endpoints Melanoma Bridge, Naples 214
Activity Summary: Concurrent and Sequenced Cohorts from 4 Nivolumab (mg/kg) + IPI (mg/kg) n ORR a % CR % Aggregate Clinical Activity Rate 8% tumour burden reduction at 36 wks b, % Concurrent Cohorts 1-3 53 42 17 7 42.3 + 3 14 21 14 57 36 1 + 3 17 53 18 65 53 3 + 1 16 44 25 81 31 3 + 3 6 5 83 5 1 + 3 [Cohort 8] c 4 43 1 d 53 28 Sequenced 33 31 3 44 31 a per RECIST, [CR+PR]/N x 1; b Best OR c Cohort 8: Phase 2/3 trial; last patient, 1st dose Nov 213. d 2 confirmed and 2 unconfirmed responses n: no. response-evaluable pts. Melanoma Bridge, Naples 214
Characteristics of Response Median duration of response in Cohorts 1-3 and cohort 8 not reached 18/22 responses ongoing Melanoma Bridge, Naples 214
Safety Overview AE, % Concurrent Cohorts 1-3 n=53 Any Gr Gr 3/4 Cohort 8 n = 41 Any Gr Gr 3/4 All Concurrent n=94 Any Gr All Related AEs 96 62 95 61 96 62 Select AEs Gastrointestinal 43 9 34 2 39 14 Hepatic 3 15 12 12 22 14 Skin 79 4 73 15 77 9 Endocrine 17 4 22 2 19 3 Renal 6 6 3 3 Other Uveitis 6 4 2 2 4 3 Pneumonitis 6 2 2 2 4 2 Lipase increased 26 19 15 1 21 15 Amylase increased 21 6 12 7 17 6 Gr 3/4 22/94 (23%) patients discontinued treatment due to treatment-related adverse events 1/94 drug-related death Melanoma Bridge, Naples 214
Overall Survival for Concurrent Therapy by Dose Cohort 1 9 8 1 Yr OS 94% 2 Yr OS 88% 7 1 Yr OS 85% 2 Yr OS 79% Survival (%) 6 5 4 3 2 1 Censored 1 Yr OS 57% Nivo.3 mg/kg + IPI 3 mg/kg (n=14) Nivo 1 mg/kg + IPI 3 mg/kg (n=17) Nivo 3 mg/kg + IPI 1 mg/kg (n=16) Nivo 3 mg/kg + IPI 3 mg/kg (n=6) Concurrent Cohorts 1-3 (n=53) 2 Yr OS 5% Pts at Risk Nivo.3_IPI 3 Nivo 1 _IPI 3 Nivo 3_IPI 1 Nivo 3_IPI 3 Concurrent 3 6 9 12 15 18 21 24 27 3 33 36 39 42 45 48 Months 14 17 16 6 53 13 17 16 6 52 11 16 15 6 48 1 15 15 6 46 8 15 15 6 44 7 14 13 6 4 7 14 4 6 31 7 13 2 6 28 7 9 3 19 7 4 11 5 3 8 Melanoma Bridge, Naples 214 2 3 5 2 3 5 2 2 4 1 1 1 1
GMCSF + Ipilimumab Ipilimumab 1mg/kg every 3 wks x 4 doses, then every 12 wks maintenance Sagramostim 25µg day 1-14 of 3 wk cycle No limit in number of treatments, Treatment allowed through disease progression n = 245 Melanoma Bridge, Naples 214
Results Toxicity similar except gastrointestinal significantly reduced - 16.1% vs 26.7% Hodi et al. JAMA 214 Melanoma Bridge, Naples 214
Targeted Anti-BRAF Therapy RTK RAS 4-6% of melanomas ATP ATP BRAF V6E MEK Vemurafenib/dabrafenib Trametinib/cobimetanib ERK Cellular Proliferation Melanoma Bridge, Naples 214
Combination Targeted Therapy COMBI-V Study Overall Survival Robert et al NEJM 214 Melanoma Bridge, Naples 214
Efficacy: Baseline Characteristics BREAK-3 Dabra BRIM-3 Vem COMBI-d COMBI-v CoBRIM D+T D D+T V V+C V ORR % 59 57 67 51 64 51 68 45 CR % 9 5.6 1 9 13 8 1 4 Median PFS, mths 6.9 6.9 9.3 8.8 11.4 7.4 9.9 6.2 HR for PFS.37.38.75.56.51 DoR 8. 9.2 1.2 13.8 7.5 7.3 Median OS, mths 2. 13.6 nr nr nr 17.2 nr nr HR for OS.77.7.63.69.65 1yr OS rate % 7 56 93@ 6mth 85@ 6mth 72 65 81@ 9mth 73@ 9mth Melanoma Bridge, Naples 214
Distribution of Melanoma Burden by Stage Advanced unresectable Stage III, IV Intermediate and high-risk resectable stage IIB, IIIA, IIIB Systemic Therapy Adjuvant Therapy Low risk resectable MIS, stage IA, IB, IIA Prevention The burden of high risk disease dwarfs the problem of advanced melanoma Melanoma Bridge, Naples 214
Adjuvant Trials Results 214 Trial No. pts Experimental arm vs obs HR for disease recurrence HR for OS IFN meta-analysis 7,84 IFN (all doses).85 (2p<.1).91 (2p=.6) AVAST-M 1,343 Bevacizumab.83 (p=.3).97 (p=.76) EORTC 1871 951 Ipilimumab.75 (p=.13) NR DERMA 1,388 MAGE A3 ASCI NS* NR * All patients NS = not significant NR = not reported Melanoma Bridge, Naples 214
EORTC 1871: Recurrence-free Survival (IRC) Patients Alive Without Relapse (%) 1 9 8 7 6 5 4 3 2 1 Median: 17.1 mo Ipilimumab 1 mg/kg Placebo Median: 26.1 mo Ipilimumab Placebo Events/patients 234/475 294/476 HR (95% CI)*.75 (.64.9) Log-rank P value*.13 2-Year RFS rate (%) 51.5 43.8 3-Year RFS rate (%)** 46.5 34.8 *Stratified by stage. **Data are not yet mature. 12 24 36 48 6 Patients at Risk O Ipilimumab 234 Placebo 294 N 475 476 276 26 25 193 Months 67 62 5 4 32
Correlation RFS and OS Succi ESMO 214 The Christie NHS
EORTC 18971 RFS vs OS Predicted HR for OS.76 The Christie NHS
Ongoing Adjuvant Trials Study No of Patients TNM Stage Therapy Dose and Schedule Treatment Arm Primary Endpoint DERMA 1349 IIIB or IIIC (tumour expression of MAGE-A3 gene) GSK 2132231A (D1/3-MAGE-3-His fusion protein) Vs. Placebo GSK 2132231A IM solution, 13 injections over 27 mths DFS Intergroup E169 ~15 III ( IIIB, IIIC), IV (M1a, M1b) Ipilimumab at 1 mg/kg or 3 mg/kg Vs. HDI IV, 1 mg/kg (A) or 3 mg/kg (C), 4x every 21 days, then starting from wk 24 every 12 wks, 4x Vs. IV 2MU/m 2 5 days/wk for 4 wks, then SC 1MU/m 2 3 days a wk for 48 wks RFS and OS COMBI-AD 852 III (BRAF V6E/K) Dabrafenib + Trametinib Vs. Placebo Dabrafenib (15 mg BD) and trametinib (2 mg OD) PO for 12 mths RFS BRIM 8 725 IIC, III (BRAF V6; Cobas) S144 ~ 12 IIIA (N2), IIIB, IIIC, M Vemurafenib Vs. Placebo Vemurafenib 96 mg PO BD for 52 wks Anti-PD1 Pembrolizumab 2mg/kg q 3 wks vs HDIFN OS DFS Melanoma Bridge, Naples 214
Progress 213-214 Three Phase III studies show combination BRAFi + MEKi superior to BRAFi Nivolumab superior to DTIC as 1st line therapy BRAFwt patients Nivolumab superior to chemotherapy in patients progressing on/after ipilimumab Ipilimumab increased RFS in Stage 3 resected disease Melanoma Bridge, Naples 214
Targeted therapy Where To Next? Resistance, tumour heterogeneity and microenvironment New targets and drugs Immunotherapy Predicting response Tumour microenvironment New molecules Sequencing treatments Personalised therapy Melanoma Bridge, Naples 214
Predicting Response To CTLA-4 64 patients responding or not to ipilimumab WES of tumours Somatic mutations and candidate neoantigens characterised Neoantigen peptides tested for ability to activate T cells in ipi treated patients Discovery and validation set Mutational load assoc with but not predictive of response Identified neoantigen panel predictive of response Melanoma Bridge, Naples 214
Predicting Response To CTLA-4 Melanoma Bridge, Naples 214 Snyder NEJM 214
Patients Surviving (%) 1 9 8 7 6 5 4 3 2 1 Patients at Risk Dacarbazine PD-L1-74 Nivolumab PD-L1-128 Dacarbazine PD-L1+ 74 Nivolumab PD-L1+ 126 OS by PD-L1 Status* 69 18 64 17 56 88 44 78 39 63 3 52 18 26 11 11 Nivolumab PD-L1+ Pts who Median OS Nivolumab PD-L1- Died, n/n mths (95% CI) 1-Yr OS % (95% CI) Nivolumab PD- 11/74 NR 82.1 (69.6 Dacarbazine L1+ 89.8) PD-L1+ Nivolumab PD- 37/128 NR 67.8 (58.3 L1-75.7) Dacarbazine 12.4 (9.2 29/74 52.7 (37.7 *PD-L1 positive: 5% tumour cell PD-L1+ NR) 65.7) surface staining. PD-L1 negative: Dacarbazine < 5% tumour cell surface staining. Dacarbazine 1.2 (7.6 PD-L1-64/126 37.4 (26.4 NR=not reached. Based on 5 Aug PD-L1-11.8) 48.3) 214 database lock. 3 6 Months 9 12 15 18 Melanoma Bridge, Naples 214 Improved OS irrespective of PD-L1 status 1 7 1 2
Where Do We Go From Here? Academic studies to address key clinical questions Biomarker identification Trial design and endpoints Rapid access for all patients to effective drugs Melanoma Bridge, Naples 214
Three Remarkable Patients And Their Families Elise Astle 34 Business Development Manager Metastatic disease Jan 21 2 separate clinical trials no benefit Died October 21 www.challengeforlife.org Jonathan Herron 32 Aeronautical Engineer Metastatic disease May 27 Standard chemotheapy and radiotherapy Died May 28 www.factor5.org.uk Richard Jackson 38 Head Teacher Metastatic disease December 26 Clinical trial Education, prevention, fundraising. NICE Melanoma Bridge, Naples 214
THANK YOU www.christie.nhs.uk/melanoma Melanoma Bridge, Naples 214
Manchester s global recruitment drive 2 new senior academic positions available Generous start up packages Priority areas: - Screening and prevention - Personalised cancer therapy - Radiotherapy - Lung cancer - Melanoma (immunology) - Women s cancers Ambitious plans for expansion State-of-the-art new laboratories www.mcrc.manchester.ac.uk/jobs Contact Louise Crow for further information: - Email: lcrow@mcrc.man.ac.uk - Tel: +44 ()161 446 335 Melanoma Bridge, Naples 214 Outstanding research services