(Neo)Adjuvant Treatment of Melanoma

Jeffrey S Weber, MD, PhD Deputy Director

Laura and Isaac Perlmutter Cancer CenterProfessor of Medicine

NYU Langone Medical CenterNew York, New York

Disclosures: Possibly, Probably or Definitely Related

• I consult for and have received less than $10,000 dollars per annum from Merck, Genentech, Astra Zeneca, GSK, Novartis, Nektar, Medivation, Celldex, Incyte and EMD Serono and $10-25,000 dollars from BMS for membership on Advisory Boards

• I hold equity in CytoMx, Biond and Altor• I am on scientific advisory boards for Celldex, CytoMx, Incyte,

Biond, Protean, CV6 and Sellas• I am not a member of any speaker’s bureau• NYU, but not me personally received research support from

BMS, Merck, GSK, Novartis and Astra Zeneca• Moffitt Cancer Center filed a patent on an IPILIMUMAB

biomarker that I am named on, and I was named on a PD-1 biomarker patent by Biodesix

Adjuvant Ipilimumab in Stage III Melanoma

Eggermont et al. N Engl J Med. 2016;375:1845-1855.Pa

tient

s al

ive

(%)

YearYear

HR for recurrence or death= 0.76 (95% CI, 0.64–0.89)P<0.001

Ipilimumab

Ipilimumab

Placebo

Placebo

HR for death = 0.72(95% CI, 0.58–0.88)P=0.001

Recurrence-Free SurvivalNo. of

Events/Total No.

Median RFS(95% CI)

mos

5-Yr Rate(95% CI)

%

Ipilimumab 264/475 27.6 (19.3–37.2) 40.8 (36.0–45.6)

Placebo 323/476 17.1 (13.6–21.6) 30.3 (26.0–34.6)

Overall SurvivalNo. of

Events/Total No.

5-Yr Rate(95% CI)

%

Ipilimumab 162/475 65.4 (60.8–69.6)

Placebo 214/476 54.4 (49.7–58.9)

Patie

nts

aliv

e an

d w

ithou

t rec

urre

nce

(%)

No. at riskIPI

Placebo

100908070605040302010

00 1 2 3 4 5 6 7 8

476 261 199 154 133 65 17 0 0475

No. at riskIPI

Placebo

100908070605040302010

00 1 2 3 4 5 6 7 8

413 348 297 273 178 58 8 0431 369 325 290 199 62 4 0

476475283 217 184 161 77 13 1 0

CheckMate 238: Study Design

Primary endpoint: RFS

Patients with:• High-risk,

completely resected stage IIIB/IIIC or stage IVa melanoma

• No prior systemic therapy

• ECOG PS 0/1

Follow-up

Maximum treatment

duration of 1 year

NIVO 3 mg/kg IV Q2W and

IPI placebo IV Q3W for 4 doses,

then Q12W from week 24

IPI 10 mg/kg IV Q3W for 4 doses,

then Q12W from week 24 and

NIVO placebo IV Q2W

1:1

n = 453

n = 453

Stratified by: 1) Disease stage: IIIB/IIIC vs IV M1a or M1b vs IV M1c2) Tumor PD-L1 status at a 5% cutoff

NCT02388906.aPer American Joint Committee on Cancer (AJCC) Cancer Staging Manual, seventh edition.

Database lock: January 31, 2019; minimum follow-up of 36 months for all patients

Weber, J et al ESMO 2019

Primary Endpoint CheckMate 238: RFS in All PatientsNIVO (n = 453) IPI (n = 453)

Events, n 188 239Median, mo (95% CI) NR (38.7‒NR) 24.9 (16.6‒35.1)HR (95% CI)a 0.68 (0.56–0.82)Pb < 0.0001

aStratified; bLog-rank test. NR, not yet reached.

58%

70%62%

45%

61%51%R

FS (%

)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 273 9 15 21 30 45

NIVOIPI

No. at risk

36 3933 42

453 316 254 221 203 193365 272 235 209 185 170 122 37 12 0453 353 311 280 261 249394 331 290 270 243 234 178 50 13 0

NIVOIPI

Weber, J et al ESMO 2019

Exploratory Endpoint for CheckMate 238: DMFS in Stage III Disease

NIVO(n = 370) IPI (n = 366)

Events, n 126 144Median, mo (95% CI) NR NR (41.8‒NR)HR (95% CI)a 0.78 (0.62–0.99)Pb 0.044

aStratified; bLog-rank test.

66%

80%70%

58%

73%64%

DM

FS (%

)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 273 9 15 21 30 45

NIVOIPI

No. at risk

36 3933 42

366 287 244 220 200 195314 258 232 208 181 168 118 40 12 0370 312 284 253 231 221334 295 270 240 215 208 157 41 11 0

NIVOIPI

Weber, J et al ESMO 2019

KEYNOTE-54 (EORTC 1325): RFSITT Population

Eggermont AMM, et al. N Eng J Med. 2018;378:1789-1801.

RFS rates were longer for PEMBRO (71.4%) vs. PBO (53.2%) at 18 months, with distant metastasis incidence of 16.7% vs 29.7% respectively.

Total No. No. with Event

Hazard Ratio

(98,4% CI)

Pembro 514 135 0.57 (0.43-0.74)

Placebo 505 216 1.00

P<0.001 by stratified log-rank test

Overall Intention-to-Treat Population

Perc

ent o

f Pat

ient

s Aliv

e an

d Re

curr

ence

-free

Months

Pembrolizumab

Placebo

PembrolizumabPlacebo

No. at Risk

100

80

60

40

20

90

70

50

30

10

0 3 6 9 12 15 18 21 24

514 438 413 392 313 182 73 15 0505 415 363 323 264 157 60 15 0

0

KEYNOTE-054 (EORTC 1325): RFSITT Population

Total No. No. with Event

Hazard Ratio (98.4% CI)

Pembro 514 135 0.57(0.43-0.74)

Placebo 505 216 1.00

COMBI-AD: Study Design — AND Extended Follow-up Analysis in 2018

Long GV, et al. N Engl J Med. 2017;377:1813-1823 and Long, G et al ESMO 2018

BID, twice daily; DMFS, distant metastasis–free survival; D+T, dabrafenib + trametinib; ECOG, Eastern Cooperative Oncology Group; FFR, freedom from relapse; FU, follow-up; QD, once daily.

Key eligibility criteria• Completely resected stage IIIA (lymph node

metastasis > 1 mm), IIIB, or IIIC cutaneous melanoma

• BRAF V600E/K mutation• ECOG performance status 0 or 1• No prior radiotherapy or systemic therapy• Tissue collection was mandatory at baseline

and optional upon recurrence

RANDOMIZATION

Stratification•BRAF mutation status (V600E, V600K)

•Disease stage (IIIA, IIIB, IIIC)

1:1

•Primary endpoint: RFS•Secondary endpoints: OS, DMFS, FFR, safetyN = 870

Treatment duration: 12 months

Primary analysisD+T median FU,

33 months

Updated analysisD+T median FU,

44 months

PRESENTED BY GV LONG AT ESMO 2018

Dabrafenib 150 mg BID + trametinib 2 mg

QD(n = 438)

2 matched placebos (n = 432)

Adjuvant Dabrafenib + Trametinib:COMBI-AD: Relapse-Free survival

Dabrafenib + trametinibNo. at risk

Placebo

10090807060504030201000 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64

Months Since Randomization

Rel

apse

-Fre

e Su

rviv

al, %

438 405 381 354 324 281 262 249 236 227 183 148 92 47 13 2 0432 322 263 219 198 178 168 164 157 147 128 107 63 27 4 1 0

1-year, 88% (95% CI, 85%-91%)

1-year, 56% (95% CI, 51%-61%)

2-year, 67% (95% CI, 62%-72%) 3-year, 59%

(95% CI, 55%-64%)

3-year, 40% (95% CI, 35%-45%)

4-year, 54% (95% CI, 49%-59%)

4-year, 38% (95% CI, 34%-44%)

2-year, 44% (95% CI, 40%-49%)

HR 0.49 (95% CI, 0.40-0.59)

21% drop-off year 1>2

For stage IIIB/C only in COMBI-AD, RFS at 3 years was 54%; for the same population in CheckMate 238, it was 60%!

Long, G et al ESMO 2018

Long, G et al ESMO 2018

AE, adverse event; SAE, serious adverse event.a Most common AEs leading to treatment discontinuation in the dabrafenib plus trametinib arm were pyrexia (9%) and chills (4%).

COMBI-AD: Safety summary

AE Category, n (%)Dabrafenib Plus Trametinib

(n = 435)Placebo (n = 432)

Any AE 422 (97) 380 (88)

AEs related to study treatment 398 (91) 272 (63)

Any grade 3/4 AE 180 (41) 61 (14)

Any SAE 155 (36) 44 (10)

SAEs related to study treatment 117 (27) 17 (4)

Fatal AEs related to study drug 0 0

AEs leading to dose interruption 289 (66) 65 (15)

AEs leading to dose reduction 167 (38) 11 (3)

AEs leading to treatment discontinuationa

114 (26) 12 (3)

COMBI-AD: Common adverse eventsDabrafenib Plus Trametinib

(n = 435) Placebo (n = 432)AEs, n (%) All Grades Grade 3/4 All Grades Grade 3/4Any AE (> 20% with dabrafenib plus trametinib)a

422 (97) 180 (41) 380 (88) 61 (14)

Pyrexia 273 (63) 23 (5) 47 (11) 2 (< 1)Fatigue 204 (47) 19 (4) 122 (28) 1 (< 1)Nausea 172 (40) 4 (1) 88 (20) 0Headache 170 (39) 6 (1) 102 (24) 0Chills 161 (37) 6 (1) 19 (4) 0Diarrhoea 144 (33) 4 (1) 65 (15) 1 (< 1)Vomiting 122 (28) 4 (1) 43 (10) 0Arthralgia 120 (28) 4 (1) 61 (14) 0Rash 106 (24) 0 47 (11) 1 (< 1)

a Eleven patients (3%) in the treatment arm and 10 patients (2%) in the placebo arm had new primary melanomas; 8 (2%) and 7 (2%), respectively, had cutaneous squamous cell carcinoma/keratoacanthoma; 19 (4%) and 14 (3%), respectively, had basal cell carcinoma; and 10 (2%) and 4 (1%), respectively, had noncutaneous malignancies.

The IMMUNED Adjuvant Study: RFS

NIVO (n=59)NIVO+IPI

(n=56)Placebo (n=52)

Median RFS, mo (95% CI) 12.4 (5.30, 33.26) NR1 6.4(3.26, 9.61)

HR (95% CI) vs placebo 0.56 (0.36, 0.88) 0.23 (0.13, 0.41) -HR (95% CI) vs NIVO - 0.40 (0.22, 0.73) -

Data cut-off date July 2nd, 2019Median follow-up time: 28.4 months (n=167)

0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 80

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

m o n th s

RF

S (

%)

Patients at risk:

Placebo 2652

3459NIVONIVO + IPI 4056

15

2934

11

2226

6

1921

6

1614

2

1110

-

31

52%

75%

32%

42%

70%

14%

61%

84%

53%

-

--

46%

70%

26%

1NR: not reached

Schadendorf, D et al ESMO 2019

CheckMate 915 Study Schema

NCT03068455.

N = 1950

RA

ND

OM

IZE

D

• Primary endpoint: RFS (up to 30 months). • Secondary endpoints: OS (up to 5 years), PD-L1 expression (approximately 3 years).

NIVO + IPI combination therapy

NIVO monotherapy

Randomized, phase 3 study of adjuvant NIVO ± IPI in resected high-risk stage III/IV melanoma

• ≥ 12 year old with melanoma• Stage IIIb/c/d or IV before

complete resection• Complete surgical resection• No prior medical therapy for

melanoma treatment

• No previous CTLA4 treatment

• No uveal melanoma

Trial dates: 4/2017 – 2/2020 (estimated)

1:1

11-20-19 Press Release: A statistically significant benefit was not reached for the co-primary endpoint of recurrence-free survival (RFS) in patients whose tumors expressed PD-L1 <1%. The Data Monitoring Committee recommended that the study continue unchanged. The study remains double-blinded and will continue to assess the other co-primary endpoint of RFS in the all-comers (intent-to-treat) population.

Conclusions• Adjuvant BRAF + MEK inhibition with dabrafenib and trametinib results in prolonged

RFS and OS with the longest follow-up of any adjuvant trial in resected stage III disease

• Adjuvant nivolumab has the best long term record for immunotherapy in patients with resected stage IIIB/IIIC/IV melanoma with improved RFS versus the active ipilimumab comparator

• Adjuvant IPI + NIVO ???? better than NIVO alone

• Neoadjuvant IPI + NIVO may define pCR patients requiring no further treatment

• New strategies require non-resistant mechanisms, new agents against specific resistance mechanisms to checkpoint inhibition

OpACIN-neo Study Schema

NCT02977052; Blank, C et al ESMO 2018 (#LBA39)

N = 110

NO

TR

AN

DO

MIZ

ED

• Primary endpoint: RFS (24 months), grade 3/4 immune-related adverse events (irAEs). • Secondary endpoints: RFS (3 years), late AEs, DMFS, OS.

Phase 2 study of neoadjuvant NIVO ± IPI in resectable stage III melanoma

• ≥ 18 year old with melanoma• Stage III before complete

resection• Complete surgical resection• No prior radiation therapy for

melanoma treatment

• No previous CTLA4 or PD-L1 treatment

• No distant metastases

Trial dates: 4/2017 – 2/2020 (estimated)

1:1:1

IPI 3 mg/kg + NIVO 1 mg/kgQ3 week x 2 courses –

prior to surgery at week 6

IPI 3 mg/kg followed by NIVO 3 mg/kg (> 2 hours and < 24 hours after IPI) Q3 week x 2 courses –

prior to surgery at week 6

IPI 1 mg/kg + NIVO 3 mg/kgQ3 week x 2 courses –

prior to surgery at week 6

irAEs = immune-related adverse events.

Neoadjuvant IPI+NIVO yields a high pCR rate and long-term RFS with tolerable toxicity

Rozeman L et al Lancet Oncology 2019

At 32 months of f-u, pRR is 47% arm A, 57% arm B, and 23% arm C. No pRRpts have relapsed vs relapse in 9 of 21 with no pathol. response;A 20% grade 3-4 irAE rate seen in arm B

Neoadjuvant IPI+NIVO yields a high pCR rate and long-term RFS with tolerable toxicity

Rozeman L et al Lancet Oncology 2019

At 32 months of f-u, pRR is 47% arm A, 57% arm B, and 23% arm C. No pRRpts have relapsed vs relapse in 9 of 21 with no pathol. response;A 20% grade 3-4 irAE rate seen in arm B

One dose of neoadjuvant PEMBRO, then adjuvant PEMBRO: association with relapse-free survival

“major” ORR was 27% or 8/27: 5 with pCR, 3 with >90% pPR, and

none have relapsed with 25 mos. of follow-up;1 year RFS was 63%

Huang, A et al Nat Med 2018

Alexander M Menzies, MIA ASCO 2019

Neoadjuvant Therapy: Relapse by Pathological Complete Response and Targeted Versus Immunotherapy

Menzies, A et al ESMO 2019

Immunotherapy Targeted Therapy

Med f/u 10 mo Med f/u 22 mo

100%

72%

pCR*

non-pCRpCR

non-pCR

* 1 pt died from toxicity without recurrence, censored at time of death

100%

72%

88%

43%

78%

8%