Cutaneous melanoma: new developments for 2018

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1 Cutaneous melanoma: new developments for 2018 and beyond KIM MARGOLIN, M.D., FASCO CITY OF HOPE MEDICAL ONCOLOGY CORONADO, CALIFORNIA SEPTEMBER 20, 2018

2 DISCLOSURE Consultant for ImaginAb, Nektar Therapeutics, Iovance Biotherapeutics and Amgen Will be discussing the off-label or investigational use of NKTR 214, a novel investigational form of interleukin-2

3 Melanoma has been the poster child for immuno-oncology and a role model for targeted combinations Toni Ribas renamed the NEJM the New England Journal of MELANOMA

4 Challenges remain Why does a disease conceived in the skin kill in the brain? How is resistance to immunotherapy mediated, and what are the biomarkers of success, failure, short- and longterm toxicity?) Why is it so difficult to drug additional pathways besides MAPK? In first-line therapy At failure of first-line therapy

5 Melanoma incidence and death by gender Melanoma still < 2% of all U.S. cancer deaths

6 Young women (tanning?), older men (sun? neglect?) account for most of increase in incidence

7 Some shared alterations between germline mutations or polymorphisms and somatic or acquired mutations Familial melanomas (<2% of cutaneous melanoma) Chromosome 9 alterations: CDKN2A (P16INK4A) or P14ARF or CDK4 single-gene effect Others at lower penetrance even if more frequent, or multi-genic Relationship to tanning/pigmentation polymorphisms complex but critical BRAFmu common in moles; melanoma often arises from non-nevus skin Relationship to DNS is unclear, not yet amenable to intervention Impact on prognosis and immune control/rx is complex, not well-understood

8 AJCC 8 th edition: yellow=new *Clinically occult LNs are microscopically diagnosed after sentinel lymph node biopsy. Clinically detected LNs are defined as clinically evident nodal metastases confirmed on FNA and/or therapeutic lymphadenectomy. Intralymphatic metastasis is defined by the presence of in-transit, satellite, and/or microscopic metastasis.

9 Additional N3 designations N3a N3b N3c 4 positive clinically occult nodes, NO intralymphatic mets 4 metastatic nodes (> one clinically detected), or matted nodes (any number), without intralymphatic mets 2 clinically-occult or -detected nodes and/or matted nodes (any number), WITH intralymphatic mets *Clinically occult LNs are microscopically diagnosed after sentinel lymph node biopsy. Clinically detected LNs are defined as clinically evident nodal metastases confirmed on FNA and/or therapeutic lymphadenectomy. Intralymphatic metastasis is defined by the presence of in-transit, satellite, and/or microscopic metastasis.

10 MSLT-2 study Patients with + sentinel node randomized to completion lymph node dissection vs observation w/ q 4 month nodal-bed ultrasound 1 o endpoint was survival 2 o endpoints were RFS, QoL, impact of tyrosinase gene pcr +/-

11 RFS (%) Adjuvant nivolumab vs ipilimumab at 24 months, stage IIIb++ Primary = RFS, with HR.66!!! [Note plateaux vs medians] NIVO IPI Events/patients 171/ /453 Median (95% CI) 30.8 (30.8, NR) a 24.1 (16.6, NR) HR (95% CI) 0.66 (0.54, 0.81) Log-rank P value < % 66% a Median estimate not reliable or stable due to few patients at risk. 63% % 53% 50% NIVO IPI Number of patients at risk NIVO IPI Months Weber, ASCO 2018

12 RFS: Prespecified Subgroups Subgroup No. of events/no. of patients NIVO 3 mg/kg IPI 10 mg/kg Unstratified HR (95% CI) Overall Overall 171/ / (0.56, 0.83) Age <65 years 117/ / (0.53, 0.85) 65 years 54/120 63/ (0.49, 1.01) Sex Male 106/ / (0.53, 0.88) Female 65/195 80/ (0.49, 0.94) Stage (CRF) Stage IIIb 48/165 60/ (0.47, 1.00) Stage IIIc 87/ / (0.52, 0.91) Stage IV M1a-M1b 27/62 37/ (0.40, 1.08) Stage IV M1c 8/20 10/ (0.31, 1.99) Not reported 1/1 0/0 Stage III: Ulceration Absent 64/ / (0.44, 0.83) Stage III: Lymph node involvement Present 68/154 68/ (0.55, 1.08) Not reported 3/15 6/ (0.11, 1.70) Microscopic 46/126 59/ (0.51, 1.10) Macroscopic 82/ / (0.49, 0.88) Not reported 7/25 8/ (0.19, 1.48) PD-L1 status <5%/indeterminate 132/ / (0.58, 0.91) 5% 39/152 64/ (0.36, 0.81) BRAF mutation status Mutant 73/187 95/ (0.54, 0.99) Wild-type 73/ / (0.45, 0.82) Not reported 25/69 19/ (0.47, 1.55) Unstratified HR (95% CI) NIVO IPI

13 Adjuvant dabrafenib and trametinib for stage IIIa (>1 mm) and higher RFS While not obvious from these curves, significant OS difference There remains skepticism NCCN panel members and other experts favor adjuvant immunotherapy OS

14 Illegal cross-trial (and mechanism) comparisons Comparison Stage Median f/u (yrs) RFS (HR) OS (HR) Grade 3-4 Toxicity Rx-related deaths COMBI- AD DT vs Placebo III a,b,c % 0 Checkmat e 238 Nivolumab vs Ipilimumab III b,c IV _ 14.4% 0 EORTC Pembro vs Placebo III a,b,c _ 14.7% 1 Ragini R. Kudchadkar, M.D.

15 Key efficacy landmarks in the adjuvant Rx of melanoma EORTC Ipilimumab 10 mg/kg vs placebo, Stage IIIA-C; RFS HR 0.76, OS HR Checkmate O N Number of patients at risk Placebo Ipilimumab 10 mg/kg vs nivolumab, Stage IIIB-C + IV; RFS HR 0.65, OS HR NA Ipi > Pbo Years Years Ipilimumab EORTC 1325 Pembrolizumab vs placebo, Stage IIIA-C; RFS HR 0.57, OS HR NA Pembro > Pbo Months COMBI-AD Dabrafenib + trametinib vs placebo Stage IIIA-C; RFS HR 0.47, OS HR RFS (%) % 61% 66% 53% Nivo > Ipi D+T > Pbo NIVO IPI Number of patients at risk NIVO IPI Months Months Months Current adjuvant options shown in orange Olivier Michielin, MD-PhD (note the initial shape of the curves we saw this in advanced melanoma starting in 2011)

16 Neoadjuvant therapy for melanoma? Let s try to cure melanoma before and after surgery so we don t have to cure metastatic disease and brain metastases Preliminary data suggest high OR rate for neo-adjuvant therapy of melanoma with regimens used for advanced disease Ongoing trials will test value of neo-adjuvant Rx added to standard surgery plus postoperative adjuvant Rx Standardization of pathology reporting as well as the detailed immunologic and molecular correlates ongoing

17 Proportion Alive Ipilimumab in advanced melanoma: pooled OS data, N = Median OS, months (95% CI): 9.5 ( ) not very meaningful to pts/docs 3-year OS rate, % (95% CI): 21 (20 22) Ipilimumab CENSORED Months Patients at Risk Ipilimumab Schadendorf et al. JCO 2015

18 5 yr survival update on pembro in adv melanoma Hamid, oral presentation ASCO 2018

19 Pembrolizumab progression-free survival by irrc

20 Response rates Median follow-up: 55 months (range, months) % (95% CI) Total N = 655 Treatment Naive n = 151 ORR DCR Best response Complete response Partial response Stable disease Progressive disease No assessment 41 (37-45) 52 (43-60) 65 (61-68) 72 (64-79) 16 (13-19) 25 (19-33) 25 (22-28) 27 (20-34) 24 (21-27) 20 (14-27) 25 (22-29) 21 (15-29) 10 (8-13) 7 (4-13)

21 Duration of response a Assessed per irrc by investigator review. Analysis is based on patients with a best overall response as confirmed complete or partial response. b + indicates non-pd at the last assessment (censored) for the patient with the minimum and maximum response duration within the treatment group. c Derived by the Kaplan-Meier method of censored data. Data cutoff: Sep 1, 2017.

22 New combination: Encorafenib + Binimetinib Reinhard Dummer 3. Long GV, et al. Lancet. 2015;386(9992): Ascierto PA, et al. Lancet Oncol. 2016;17: Chapman PB, et al. N Engl J Med. 2011;364(26): Robert C, et al. N Engl J Med. 2015;372(1): Delord JP, et al. Clin Cancer Res. 2017;23: Data on File. Array BioPharma Inc. 7. Sullivan RJ, et al. J Clin Oncol. 2015;33:9007. BINI=binimetinib; BRAFi=BRAF inhibitor; ENCO=encorafenib; MEKi=MEK inhibitor; OS=overall survival; PFS=progression-free survival

23 Overall Survival, % Landmark OS: COMBO-450 vs Vemurafenib COMBO450: 76% VEM: 63% COMBO450 VEM 10 Censored patients Patients at risk Time (months) COMBO VEM COMBO450=encorafenib 450 mg QD + binimetinib 45 mg BID; VEM=vemurafenib 960 mg BID. *3-year rates are not fully mature. COMBO450: 58% VEM: 43% COMBO450: 47%* VEM: 32% Median OS in months (95% CI) COMBO450 VEM 33.6 ( ) 16.9 ( ) HR (95% CI), 0.61 ( ) Nominal 2-sided P< Reinhard Dummer

24 Confirmed response rates Confirmed Response ORR (95% CI)* Central Review 64% (57 70) COMBO450 n=192 Local Review Central Review 76% (69 81) 52% (44 59) ENCO300 n=194 Local Review 58% (50 65) Central Review 41% (34 48) VEM n=191 Local Review 49% (42 57) CR 11% 19% 7% 10% 8% 8% PR 52% 56% 44% 48% 32% 41% Median DOR (95% CI), mo 18.6 ( ) 16.2 ( ) 15.2 ( ) 14.8 ( ) 12.3 ( ) 7.7 ( ) SD 29% 17% 32% 29% 40% 35% PD 8% 7% 16% 13% 19% 16% DCR (95% CI) 92% (87 96) 93% (88 96) 84% (78 89) 87% (81 91) 81% (75 86) 84% (78 89) COMBO450=encorafenib 450 mg QD + binimetinib 45 mg BID; CR=complete response; DCR=disease control rate; DOR=duration of response; ENCO300=encorafenib 300 mg QD; ORR=overall response rate; PD=progressive disease; PR=partial response; SD=stable disease; VEM=vemurafenib 960 mg BID. *ORR = CR + PR. Includes patients with only non-target lesions with best response of non-cr/non-pd. Includes patients with best response of unknown or no assessment. DCR = CR + PR + SD.

25 Overall Survival, % Overall survival: ENCO300 vs Vemurafenib ENCO300 VEM 10 Censored patients Patients at risk Time (months) ENCO VEM ENCO300=encorafenib 300 mg QD; HR=hazard ratio; OS=overall survival; VEM=vemurafenib 960 mg BID. Median OS in months (95% CI) ENCO300 VEM 23.5 ( ) 16.9 ( ) HR (95% CI), 0.76 ( ) Nominal 2-sided P=0.033 Reinhard Dummer

26 MAPKi resistance

27 What about (HD-) IL-2? Gone, forgotten, or coming back? adjunctive to other Rxs now Combination with CTLA4 disappointing and toxic Combination with PD-1 blockade ongoing, but slowly Engineered IL-2 molecules failed in 90s but have resurfaced IL-2 agonist with selective βγ receptor binding avoids Treg stimulation PEGylated IL-2 with measured hydrolysis from 5 to 1-2 PEG residues per IL-2 preferentially stimulates CD8, NK>>Treg and has promise with PD-1 blockade

28 NKTR214 plus + Nivolumab for untreated advanced melanoma Best ORR by RECIST: ORR=12/23 (52%); DCR=18/23 (78%) Best ORR by irrecist: ORR=14/23 (61%); DCR=19/23 (83%) N=23 in dose escalation + expansion ^ + + Best overall response is PR (non-target lesions still present) # Best overall Response is SD per RECIST 1.1 and PR per irrecist. Patient had PD per new lesion on confirmatory scan. ^ Best overall response is PD per RECIST 1.1 and unconfirmed PR per irrecist. Patient achieved PR at 2 nd scan after PD at 1 st scan due to new lesion (enlarged lymph node).

29 Mechanism and activity of T-VEC Talimogene laherparepvec Single-agent response rate 25% Durable response rate (>6 mo) 15% GM-CSF alone is inactive Combinations of TVEC with PD-1 blockade very promising Ph III placebo-controlled trial with pembro completed Frederick J. Kohlhapp, and Howard L. Kaufman Clin Cancer Res 2016;22:

30 MANAGEMENT OF MELANOMA WITH BRAIN METASTASES Whole brain radiotherapy ineffective, SRT standard Neurosurgery for selected urgent indications like bleed, mass effect SRT is very active, risks radionecrosis, leaves untreated micromets Systemic Rx has been assumed inactive in brain, poorly penetrant Pts excluded from trials due to dismal prognosis and above considerations capture, cross, crawl concept circulating effector T cells get into brain Ipilimumab activity in brain comparable to extracranial N=51 in CWG study N=20 in Italian study. (both reported in Lancet O 2012)

31 BMS S (NO NICKNAME ALTHOUGH COULD CALL IT BRAIN METS SUPER-STUDY! ) 94 ASx pts with small lesions/minimal or no edema/no steroid requirement or need for urgent SRT Rx standard ipi x 4 plus nivo x 4, every 3 weeks, the nivo every 2 weeks until 2 yrs/progression/intolerance Toxicity: same as for pts without brain mets Outcome similar in brain and extracranial sites ORR ~55% in all sites/globally Durability looks promising

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33 OVERALL SURVIVAL, KAPLAN-MEIER WITH LANDMARKS

34 PFS BY COMPARTMENT AND GLOBAL PFS

35 SWIMMER PLOT FOR RESPONDERS

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37 Combi-MB, Dabrafenib+Trametinib in melanoma metastatic to brain, favorable pts Clinical benefit and tolerability with dabrafenib + trametinib in patients with BRAF V600 mutant melanoma metastatic to brain OR rate of 58% (95% CI, 46%-69%); primary endpoint was met Median duration of OR (6.5 months) was generally shorter than that observed in patients without melanoma brain metastases (12-14 months) 1-3 No unexpected safety issues were observed with the combination These results support: Dabrafenib + Trametinib option for patients with brain metastases/brafmu Need for continued research to improve outcomes in these patients 1. Long GV, et al. Lancet. 2015;386: ; 2. Long GV, et al. Ann Oncol May 5. [Epub ahead of print]; 3. Robert C, et al. Ann Oncol. 2016;27(suppl 6) [abstract LBA40]. Presented by: Michael A. Davies

38 TRIALS TO ANSWER MOST IMPORTANT QUESTIONS MAPKi resistance add or switch to PI3K or AKT inhibitor, CDK4/6 inhibitor, demethylating agent, others PD-1 blockade resistance Combine with LAG3 blockade promising, in Phase III Switch to or add CTLA4 blockade SWOG phase III, others Add lesional therapy e.g. oncolytic virus or immune adjuvant such as TLR agonist Add small molecular inhibitor of suppressive indoleamine dioxygenase ineffective in melanoma Combine with co-stimulatory agonists like 4-1BB agonistic Ab early investigation Immunomodulation on both sides of the immune synapse e.g. adenosine deaminase and adenosine receptor blockade

39 THANK YOU! ANY QUESTIONS?