Melanoma Clinical Trials and Real World Experience

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1 Melanoma Clinical Trials and Real World Experience Paul Lorigan University of Manchester Manchester, UK Melanoma Bridge, Naples 214

2 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

3 Negative Studies 25-1 Combinations with new agents Sorafenib Bevacizumab Oblimersen Elesclomol New agents Tasisulam nab-paclitaxel Melanoma Bridge, Naples 214

4 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

5 Melanoma Treatment Paradigm Immunotherapy Target host Targeted Therapy Target tumour Vaccines Checkpoint inhibitors Cytokines Small molecule inhibitors Melanoma Bridge, Naples 214

6 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

Activation signals B7 CD28 Negative regulation PD1 PD-L1 Inhibitory signals B7

7 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

8 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.

9 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 Dermatologic GI Endocrine Hepatic *Across entire study duration Hodi et al. NEJM 21 Melanoma Bridge, Naples 214

10 Pooled Analysis of Phase I-III Studies of Ipilimumab in 28 Stage IV Melanoma Patients Melanoma Bridge, Naples 214

11 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, % 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

12 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

13 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 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

14 Nivolumab Phase 1- Overall Survival 1 9 Died/Treated, n/n Median OS, mo (95% CI) Patients Surviving (%) yr OS 63% 1-yr OS 65% 2-yr OS 47% 2-yr OS 48% 3-yr OS 42% All cohorts 67/ (12.5, 37.8) 3. mg/kg 11/ (7.2, NE) 3-yr OS 41% 4-yr OS 35% 4-yr OS 32% 3 mg/kg (N=17) All cohorts (N=17) Time Since Treatment Initiation (months) Patients at Risk Total 3. mg/kg September 214 data analysis Hodi et al SMR 214 Melanoma Bridge, Naples 214

Study Design Eligible patients with advanced

Open Label Investigator s choice of chemotherapy

AUC 6 IV and paclitaxel 175 mg/m 2 Q3W Treat

Patients receiving nivolumab may be treated

investigator to be experiencing clinical benefit

vs. BRAF V6 mutant Best overall response (BOR) to

15 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

16 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 ICC 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

17 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

18 Patients Surviving (%) Patients at Risk Nivolumab Dacarbazine Primary Endpoint: Overall Survival HR.42 (99.79% CI,.25.73; P <.1) (Boundary for statistical significance.21) Patients who died, n/n Median OS mo (95% CI) Nivolumab (n=21) 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 ( ) *NR=not reached. Based on 5 Aug 214 database lock Months Melanoma Bridge, Naples 214

19 Secondary Endpoint: PFS Patients without Progression (%) Patients at Risk Nivolumab Dacarbazine Death or disease progression, n/n Median PFS mo (95% CI) Nivolumab 18/ ( ) Dacarbazine 163/ ( ) 6-mo PFS 48% 6-mo PFS 19% HR.43 (95% CI,.34.56; P <.1) 12 Dacarbazine (n=28) 1 Nivolumab (n=21) Based on 5 August 214 database lock Months Melanoma Bridge, Naples 214

20 Phase I Combination Study: Dose Cohorts Dose (mg/kg) Treatment Schedule Regimen Cohort No. N Nivolumab Ipilimumab Induction Maintenance Concurrent 1 2 2a * Sequenced 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

21 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 [Cohort 8] c d Sequenced 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

22 Characteristics of Response Median duration of response in Cohorts 1-3 and cohort 8 not reached 18/22 responses ongoing Melanoma Bridge, Naples 214

23 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 Select AEs Gastrointestinal Hepatic Skin Endocrine Renal Other Uveitis Pneumonitis Lipase increased Amylase increased Gr 3/4 22/94 (23%) patients discontinued treatment due to treatment-related adverse events 1/94 drug-related death Melanoma Bridge, Naples 214

24 Overall Survival for Concurrent Therapy by Dose Cohort Yr OS 94% 2 Yr OS 88% 7 1 Yr OS 85% 2 Yr OS 79% Survival (%) 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 Months Melanoma Bridge, Naples

25 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

26 Results Toxicity similar except gastrointestinal significantly reduced % vs 26.7% Hodi et al. JAMA 214 Melanoma Bridge, Naples 214

27 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

28 Combination Targeted Therapy COMBI-V Study Overall Survival Robert et al NEJM 214 Melanoma Bridge, Naples 214

29 Efficacy: Baseline Characteristics BREAK-3 Dabra BRIM-3 Vem COMBI-d COMBI-v CoBRIM D+T D D+T V V+C V ORR % CR % Median PFS, mths HR for PFS DoR Median OS, mths nr nr nr 17.2 nr nr HR for OS yr OS rate % @ 6mth 85@ 6mth @ 9mth 73@ 9mth Melanoma Bridge, Naples 214

30 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

31 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 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.

32 EORTC 1871: Recurrence-free Survival (IRC) Patients Alive Without Relapse (%) Median: 17.1 mo Ipilimumab 1 mg/kg Placebo Median: 26.1 mo Ipilimumab Placebo Events/patients 234/ /476 HR (95% CI)*.75 (.64.9) Log-rank P value*.13 2-Year RFS rate (%) Year RFS rate (%)** *Stratified by stage. **Data are not yet mature Patients at Risk O Ipilimumab 234 Placebo 294 N Months

33 Correlation RFS and OS Succi ESMO 214 The Christie NHS

34 EORTC RFS vs OS Predicted HR for OS.76 The Christie NHS

35 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 A (D1/3-MAGE-3-His fusion protein) Vs. Placebo GSK A 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 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

36 Progress 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

37 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

38 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

39 Predicting Response To CTLA-4 Melanoma Bridge, Naples 214 Snyder NEJM 214

40 Patients Surviving (%) Patients at Risk Dacarbazine PD-L1-74 Nivolumab PD-L1-128 Dacarbazine PD-L1+ 74 Nivolumab PD-L OS by PD-L1 Status* 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 L ) PD-L1+ Nivolumab PD- 37/128 NR 67.8 (58.3 L1-75.7) Dacarbazine 12.4 (9.2 29/ (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/ (26.4 NR=not reached. Based on 5 Aug PD-L1-11.8) 48.3) 214 database lock. 3 6 Months Melanoma Bridge, Naples 214 Improved OS irrespective of PD-L1 status

41 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

benefit Died October 21 www.challengeforlife.

chemotheapy and radiotherapy Died May 28 www.factor5.org.

42 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 Jonathan Herron 32 Aeronautical Engineer Metastatic disease May 27 Standard chemotheapy and radiotherapy Died May 28 Richard Jackson 38 Head Teacher Metastatic disease December 26 Clinical trial Education, prevention, fundraising. NICE Melanoma Bridge, Naples 214

43 THANK YOU Melanoma Bridge, Naples 214

Manchester s global recruitment drive 2 new senior

packages Priority areas: - Screening and

Radiotherapy - Lung cancer - Melanoma (immunology)

State-of-the-art new laboratories www.mcrc.

44 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 Contact Louise Crow for further information: - lcrow@mcrc.man.ac.uk - Tel: +44 () Melanoma Bridge, Naples 214 Outstanding research services

Melanoma: From Chemotherapy to Targeted Therapy and Immunotherapy. What every patient needs to know. James Larkin

Melanoma: From Chemotherapy to Targeted Therapy and Immunotherapy What every patient needs to know James Larkin Melanoma Therapy 1846-2017 Surgery 1846 Cytotoxic Chemotherapy 1946 Checkpoint Inhibitors