Cutaneous melanoma: new

developments for 2018

KIM MARGOLIN, M.D., FASCO

CITY OF HOPE MEDICAL ONCOLOGY

CORONADO, CALIFORNIA

SEPTEMBER 20, 2018

and beyond

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

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

• 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 long-

term toxicity?)

• Why is it so difficult to drug additional pathways besides

MAPK?

– In first-line therapy

– At failure of first-line therapy

Challenges remain

Melanoma incidence and death by gender

Melanoma still < 2% of all U.S. cancer deaths

Young women (tanning?), older men (sun?

neglect?) account for most of increase in incidence

• 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

Some shared alterations between germline mutations or

polymorphisms and somatic or acquired mutations

AJCC 8th 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.

Additional N3 designations

• N3a

– ≥4 positive clinically occult nodes, NO intralymphatic

mets

• N3b

– ≥4 metastatic nodes (> one clinically detected), or

matted nodes (any number), without intralymphatic

mets

• N3c

– ≥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.

MSLT-2 study

• Patients with + sentinel node

randomized to completion lymph

node dissection vs observation

w/ q 4 month nodal-bed

ultrasound

• 1o endpoint was survival

• 2o endpoints were RFS, QoL,

impact of tyrosinase gene pcr +/-

Primary = RFS, with HR .66!!!

[Note plateaux vs medians]

RF

S (

%)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 273 9 15 21 30 33

NIVO

IPI

Number of patients at risk

NIVO

IPI

NIVO IPI

Events/patients 171/453 221/453

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 <0.0001

63%

50%

70%

60%

453 353 311 280 205 28394 331 291 264 7 0

453 314 251 216 149 23363 270 230 204 5 0

66%

53%

aMedian estimate not reliable or stable due to few patients at risk.

Adjuvant nivolumab vs ipilimumab

at 24 months, stage IIIb++

Weber, ASCO 2018

RFS: Prespecified Subgroups

NIVO IPI

0 1 2

Subgroup

No. of events/no. of patientsUnstratified

HR (95% CI)

Unstratified HR

(95% CI)NIVO 3 mg/kg IPI 10 mg/kg

Overall Overall 171/453 221/453 0.68 (0.56, 0.83)

Age <65 years 117/333 158/339 0.67 (0.53, 0.85)

≥65 years 54/120 63/114 0.70 (0.49, 1.01)

Sex Male 106/258 141/269 0.69 (0.53, 0.88)

Female 65/195 80/184 0.68 (0.49, 0.94)

Stage (CRF) Stage IIIb 48/165 60/148 0.68 (0.47, 1.00)

Stage IIIc 87/203 114/218 0.68 (0.52, 0.91)

Stage IV M1a-M1b 27/62 37/66 0.66 (0.40, 1.08)

Stage IV M1c 8/20 10/21 0.78 (0.31, 1.99)

Not reported 1/1 0/0

Stage III: Ulceration Absent 64/201 100/216 0.61 (0.44, 0.83)

Present 68/154 68/135 0.77 (0.55, 1.08)

Not reported 3/15 6/15 0.42 (0.11, 1.70)

Stage III: Lymph node involvement

Microscopic 46/126 59/134 0.75 (0.51, 1.10)

Macroscopic 82/219 107/214 0.66 (0.49, 0.88)

Not reported 7/25 8/18 0.53 (0.19, 1.48)

PD-L1 status <5%/indeterminate 132/300 157/299 0.73 (0.58, 0.91)

≥5% 39/152 64/154 0.54 (0.36, 0.81)

BRAF mutation status Mutant 73/187 95/194 0.73 (0.54, 0.99)

Wild-type 73/197 107/212 0.61 (0.45, 0.82)

Not reported 25/69 19/47 0.85 (0.47, 1.55)

Adjuvant dabrafenib

and trametinib for stage

IIIa (>1 mm) and higher

While not obvious from

these curves, significant

OS difference

There remains

skepticism—NCCN panel

members and other

experts favor adjuvant

immunotherapy

RFS

OS

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

2.8 0.47 0.57 41% 0

Checkmat

e 238

Nivolumab vs

Ipilimumab

III b,c

IV

2 0.66 _ 14.4% 0

EORTC Pembro vs

Placebo

III

a,b,c

1.3 0.57 _ 14.7% 1

Ragini R. Kudchadkar, M.D.

Olivier Michielin, MD-PhD

EORTC 1325 • Pembrolizumab vs placebo, • Stage IIIA-C; RFS HR 0.57, OS HR NA

RF

S (

%)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 273 9 15 21

453 353 311 249 5 0399 332 291 71NIVO

453 314 252 184 2 0364 269 225 56IPI

Number of patients at risk

NIVO

IPI

66%

53%

71%

61%

Checkmate 238

• Ipilimumab 10 mg/kg vs nivolumab, • Stage IIIB-C + IV; RFS HR 0.65,

OS HR NA

Months

Nivo > Ipi

Months

Pembro > Pbo

COMBI-AD • Dabrafenib + trametinib vs placebo• Stage IIIA-C; RFS HR 0.47, OS HR 0.57

Months

D+T > Pbo

EORTC 18071 • Ipilimumab 10 mg/kg vs placebo, • Stage IIIA-C; RFS HR 0.76, OS HR 0.72

Years0 1 2 3 4 5 6 7 8

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk

264 475 283 217 184 161 77 13 1

323 476 261 199 154 133 65 17 0

Ipilimumab

Placebo

Ipi > Pbo

Years

Current adjuvant options shown in orange

Key efficacy landmarks in the adjuvant Rx of melanoma

(note the initial shape of the curves—we saw

this in advanced melanoma starting in 2011)

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

Patients at Risk

Ipilimumab 4846 1786 612 392 200 170 120 26 15 5 0

0.0

0.1

0.4

0.3

0.2

0.5

0.8

0.7

0.6

0.9

1.0

0 12 24 36 48 60

Months

72 84 96 108 120

Ipilimumab

CENSORED

Ipilimumab in advanced melanoma: pooled

OS data, N = 4846

Median OS, months (95% CI): 9.5 (9.0–

10.0)—not very meaningful to pts/docs

3-year OS rate, % (95% CI): 21 (20–22)

Pro

po

rtio

nA

live

Schadendorf et al. JCO 2015

5 yr survival update on pembro in adv melanoma

Hamid, oral presentation ASCO 2018

Pembrolizumab—progression-free survival by irRC

Response rates

• Median follow-up: 55 months (range, 48-69 months)

% (95% CI)Total

N = 655

Treatment Naive

n = 151

ORR41 (37-45) 52 (43-60)

DCR65 (61-68) 72 (64-79)

Best response

Complete response16 (13-19) 25 (19-33)

Partial response25 (22-28) 27 (20-34)

Stable disease24 (21-27) 20 (14-27)

Progressive disease25 (22-29) 21 (15-29)

No assessment10 (8-13) 7 (4-13)

Duration of response

aAssessed 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. cDerived by the Kaplan-Meier method of censored data. Data cutoff: Sep 1, 2017.

New combination: Encorafenib + Binimetinib

1. Chapman PB, et al. N Engl J Med.

2011;364(26):2507-2516.

2. Robert C, et al. N Engl J Med.

2015;372(1):30-39.

BINI=binimetinib; BRAFi=BRAF inhibitor; ENCO=encorafenib; MEKi=MEK inhibitor; OS=overall survival; PFS=progression-free survival

5. Delord JP, et al. Clin Cancer Res.

2017;23:5339-5548.

6. Data on File. Array BioPharma Inc.

7. Sullivan RJ, et al. J Clin Oncol.

2015;33:9007.

Reinhard Dummer

3. Long GV, et al. Lancet.

2015;386(9992):444-451.

4. Ascierto PA, et al. Lancet Oncol.

2016;17:1248-1260.

COMBO450=encorafenib 450 mg QD + binimetinib 45 mg BID; VEM=vemurafenib 960 mg BID.

*3-year rates are not fully mature.

Landmark OS: COMBO-450 vs Vemurafenib

0

10

20

30

40

50

60

70

80

90

100

Ove

rall S

urv

iva

l, %

COMBO450

VEM

Patients at risk Time (months)

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

192 188 182 166 144 132 124 115 108 102 95 82 57 30 9 1 0

191 184 166 140 115 100 89 83 77 71 62 56 30 19 8 1 0

COMBO450

VEM

Censored patients

COMBO450:

76%

VEM: 63%

COMBO450:

58%

VEM: 43%

COMBO450: 47%*

VEM: 32%

Reinhard Dummer

Median OS in months (95% CI)

COMBO450 VEM

33.6 (24.4–39.2) 16.9 (14.0–24.5)

HR (95% CI), 0.61 (0.47–0.79)

Nominal 2-sided P<0.0001

Confirmed response rates

Confirmed Response

COMBO450

n=192

ENCO300

n=194

VEM

n=191

Central

ReviewLocal Review

Central

Review

Local

Review

Central

Review

Local

Review

ORR (95% CI)*64%

(57–70)

76%

(69–81)

52%

(44–59)

58%

(50–65)

41%

(34–48)

49%

(42–57)

CR 11% 19% 7% 10% 8% 8%

PR 52% 56% 44% 48% 32% 41%

Median DOR (95% CI),

mo

18.6

(12.7–24.1)

16.2

(11.1–24.1)

15.2

(11.1–27.6)

14.8

(11.0–16.6)

12.3

(6.9–14.5)

7.7

(5.8–11.0)

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.

Ove

rall S

urv

iva

l, %

Time (months)

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 21 24 27 36 39 42 4815 18 30 33 45

ENCO300

VEM

Censored patients

194 181 168 147 133 117 109 94 86 83 79 59

191 184 166 140 115 100 89 83 77 71 62 56

ENCO300

VEM

Patients at risk40 24 5 0 0

30 19 8 1 0

Overall survival: ENCO300 vs Vemurafenib

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 (19.6–33.6) 16.9 (14.0–24.5)

HR (95% CI), 0.76 (0.58–0.98)

Nominal 2-sided P=0.033

Reinhard Dummer

MAPKi resistance

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

NKTR214 plus + Nivolumab for untreated

advanced melanoma

+ 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 2nd scan after PD at 1st scan due

to new lesion (enlarged lymph node).

+

^

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

Mechanism and activity of T-VEC

Frederick J. Kohlhapp, and Howard L. Kaufman Clin Cancer Res 2016;22:1048-1054

• 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

Talimogene laherparepvec

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)

BMS’S 209-204 (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

OVERALL SURVIVAL, KAPLAN-MEIERWITH LANDMARKS

PFS BY COMPARTMENT AND GLOBAL PFS

SWIMMER PLOT FOR RESPONDERS

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

Presented by: Michael A. Davies

1. Long GV, et al. Lancet. 2015;386:444-451; 2. Long GV, et al. Ann Oncol. 2017 May 5. [Epub ahead of print]; 3. Robert C, et al. Ann Oncol. 2016;27(suppl 6) [abstract LBA40].

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

THANK YOU!

ANY QUESTIONS?