E-Learning Metastatic Melanoma Treatment

METASTATIC MELANOMA TREATMENT

Paolo A. Ascierto, MD

Unit Melanoma, Cancer Immunotherapy and Innovative Therapies

Istituto Nazionale Tumori – Fondazione “G. Pascale”, Napoli, Italy

US FDA APPROVAL OF MELANOMA THERAPIES

Michielin O.. J Immunother Cancer 2020;8:e000948. Reproduced under the terms of the Creative Commons Attribution Non Commercial (CC BY-NC 4.0). Available at: http://creativecommons.org/licenses/by-nc/4.0/;

accessed March 2021.

http://creativecommons.org/licenses/by-nc/4.0/

FIRST-LINE THERAPY: OVERALL SURVIVAL

Mean survival curves created by weighted averaging of digitised Kaplan-Meier survival curves of metastatic melanoma patients treated in selected clinical trials.

Reprinted from Eur J Cancer, 83, Ugurel S, et al. Survival of patients with advanced metastatic melanoma: the impact of novel therapies–update 2017, 247–57. Copyright 2017, with permission from Elsevier.

Korn meta analysis

LONG-TERM OS IN CLINICAL TRIALS WITH IMMUNO-

ONCOLOGY AGENTS AND TARGETED THERAPIES

In patients with advanced melanoma

Michielin O.. J Immunother Cancer 2020;8:e000948. Reproduced under the terms of the Creative Commons Attribution Non Commercial (CC BY-NC 4.0). Available at: http://creativecommons.org/licenses/by-nc/4.0/;

accessed March 2021.

http://creativecommons.org/licenses/by-nc/4.0/

Diagnosis of

cutaneous melanoma

pT2bN0M0

Metastatic

melanoma to liver

(multiple lesions)

Start Vemurafenib

in COLUMBUS

study

B-RAF mutation detected (V600E)

First tumour

assessment

PR PD Liver

Start

Ipilimumab

PD Liver

Start

Nivolumab

ECOG = 1

Stop

Nivolumab

For fast PD

ECOG = 2

LDH level

(204-480)1030760 390 2130860

CLINICAL CASE

39-year-old Male

Images courtesy of Prof PA Ascierto

July

2014

October

2014

December

2013

August

2014

April

2015

October

2015

December

2015

LDH level

(204-480)

Dabrafenib +

Trametinib

Re-challange

January

2016

Still on treatment

mFU (30 mos)

220

November

2019

Stop

Nivolumab

For fast PD

ECOG = 2

2130

December

2015

CT Scan

PR

187

March

2016

Brain progression

disease

780

January

2020

Death for

progression disease

1500

March

2020

CLINICAL CASE

39-year-old-Male

Image courtesy of Prof PA Ascierto

TARGET THERAPY

THE ROLE OF BRAF V600 MUTATION IN MELANOMA

Ascierto PA, et al. J Transl Med 10(1):85. This article is published under license to BioMed Central Ltd. Reproduced under the terms of the Creative Commons Attribution License, available atL

(http://creativecommons.org/licenses/by/2.0); accessed March 2021.

http://creativecommons.org/licenses/by/2.0

ANTI-BRAF + ANTI-MEK COMBINATION

Decreases the risk of death of 30 to 37% vs. anti-BRAF monotherapy

1. From N Engl J Med, Long GV, et al. Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma, 371 (20), 1877–88. Copyright © 2014 Massachusetts Medical Society. Reprinted with permission from

Massachusetts Medical Society; 2. From N Engl J Med, Robert C, et al. Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib, 372(1), 30–9. Copyright © 2015 Massachusetts Medical Society.

Reprinted with permission from Massachusetts Medical Society; 3. Reprinted from The Lancet, 17(9), Ascierto P, et al. Cobimetinib combined with vemurafenib in advanced BRAF V600-mutant melanoma (coBRIM): updated

efficacy results from a randomised, double-blind, phase 3 trial, 1248–60. Copyright 2016 with permission from Elsevier; 4. Ascierto PA, et al. Eur J Cancer 2020;126:33–44. Reproduced under the terms of the Creative

Commons CC-BY-NC-ND license, available at https://creativecommons.org/licenses/by-nc-nd/3.0/; accessed March 2021.

OVERVIEW OF STUDY DESIGNS OF PHASE 3 TRIALS

Study Treatment Arms Primary Endpoint Secondary Endpoint

CoBrim◆ Cobimetinib 60 mg QD* + vemurafenib 960 mg BID (n=247)

◆ Vemurafenib 960 mg BID + placebo (n=248)PFS ◆ OS

Combi-D◆ Dabrafenib 150 mg BID + trametinib 2 mg QD (n=211)

◆ Dabrafenib 150 mg BID + placebo (n=212)PFS

◆ OS

◆ ORR

◆ DOR

◆ Safety

◆ PK

Combi-V◆ Dabrafenib 150 mg BID + trametinib 2 mg QD (n=352)

◆ Vemurafenib 960 mg BID (n=352)OS

◆ PFS

◆ ORR

◆ DOR

◆ Safety

COLUMBUS

Part 1

◆ COMBO450 (N=192)

◆ Encorafenib 450 mg QD + binimetinib 45 mg BID

◆ Vemurafenib 960 mg BID (n=191)

◆ Encorafenib 300 mg QD (n=194)

PFS ◆ OS

Citation of data without the intention of direct or indirect comparison in the absence of head-to-head clinical trials

ORR FROM PHASE 3 PIVOTAL TRIALS WITH

BRAF/MEK INHIBITORS

1. Dummer R, et al. ASCO 2018; 2. Robert C, et al. ESMO 2016; Abstract LBA40. 3. Ascierto PA, et al. Lancet Oncol 201619(10);1315–27.

©PA Ascierto. By permission of Prof PA Ascierto.


100

80

60

40

20

0

0 9 18 27 36 48

Time, Months

3 12 21 30 396 15 24 33 42 5145

NA

NA

NR

1-yr rate 2-yr rate 3-yr rate 4-yr rate

56%

50%

50%

37%

30%

NR%

28%

24%

NR

Columbus1

Combi-v2

CoBRIM3,4

Pro

gre

ssio

n-f

ree

Su

rviv

al (

%)

mPFS14.9 months

12.1 months

12.3 months

HR (95% CI)0.51 (0.39–0.67)

0.61 (0.51–0.73)

0.58 (0·46–0·72)

Elevated LDH29%

34%

46%

mFU32.1 months

23.0 months

14.2 months

PFS CURVES FROM PHASE 3 PIVOTAL TRIALS WITH

BRAF/MEK INHIBITORS

1. Dummer R, et al. ASCO 2018; 2. Robert C, et al .ESMO 2016; 3. Ascierto PA, et al. Lancet Oncol 2016;19(10);1315–27; 4. Dreno B, et al. ASCO 2018.

© PA Ascierto. By permission of Prof PA Ascierto


100

80

60

40

20

0

0 9 18 27 36 48

Time, Months

3 12 21 30 396 15 24 33 42 5145

NA

NA

34.7%


76%

74%

74,5%

58%

53%

49%

47%

45%

38,5%

Ove

rall

Su

rviv

al (

%)

mOS33.6 months

26.1 months

22.5 months

HR (95% CI)0.61 (0.47–0.79)

0.68 (0.56–0.83)

0.78 (0.62–0.97)

Elevated LDH29%

34%

46%

mFU36.8 months

23.0 months

21.2 months

OS CURVES FROM PHASE 3 PIVOTAL TRIALS WITH

BRAF/MEK INHIBITORS

1. Dummer R, et al ASCO 2018; 2. Robert C, et al. ESMO 2016; 3. Dreno B, et al. ASCO 2018. ©PA Ascierto. By permission of Prof PA Ascierto


Columbus1

Combi-v2

CoBRIM3

ENCORAFENIB/BINIMETINIB COMBO RESULT LOOKS SIMILAR TO THE RESULTS FROM THE OTHER BRAF/MEK INHIBITORS COMBOS

PFS CURVES FROM PHASE 3 PIVOTAL TRIALS WITH

BRAF INHIBITORS MONOTHERAPY

1. Dummer R, et al. ASCO 2018; 2. Robert C, et al. ESMO 2016; 3. Dreno B, et al .ASCO 2018; 4. Long G, et al. Ann Oncol 2017. ©PA Ascierto. By permission of Prof PA Ascierto


Elevated LDH27%

32%

43%

33%

24%

mFU32.1 months

15.0 months

16.8 months

16.0 months

32.1 months

100

80

60

40

20

0

0 9 18 27 36 48

Time, Months

3 12 21 30 396 15 24 33 42 5145

NA

NA

NR%

NA

NA


33%

27%

31%

35%

50%

20%

16%

16%

16%

32%

13%

10%

NR%

12%

27%

Pro

gre

ssio

n-f

ree

Su

rviv

al (

%)

mPFS7.3 months

7.3 months

7.2 months

8.8 months

9.6 months

Columbus (vemurafenib)1

Combi-v (vemurefenib)2

CoBRIM (vemurafenib)3

Combi-d (dabrafenib)4

Columbus (encorafenib)1

100

80

60

40

20

0

0 9 18 27 36 48

Time, Months

3 12 21 30 396 15 24 33 42 5145

NA

NA

29.2%

NA

NA


63%

62%

63,8%

63%

74.6%

43%

39%

39%

43%

49.1%

32%

31%

31.1%

32%

39%

Ove

rall

Su

rviv

al (

%)

mOS16.9 months

17.8 months

17.4 months

18.7 months

23.5 months

Elevated LDH27%

32%

43%

33%

24%

mFU36.8 months

15.0 months

16.8 months

16.0 months

36.8 months

OS CURVES FROM PHASE 3 PIVOTAL TRIALS WITH

BRAF INHIBITORS MONOTHERAPY

1. Dummer R, et al. ASCO 2018; 2. Robert C, et al. ESMO 2016; 3. Dreno B, et al .ASCO 2018; 4. Long G, et al. Ann Oncol 2017. ©PA Ascierto. By permission of Prof PA Ascierto

Columbus (vemurafenib)1

Combi-v (vemurefenib)2

CoBRIM (vemurafenib)3

Combi-d (dabrafenib)4

Columbus (encorafenib)1


SAFETY PROFILE OF BRAF/MEK INHIBITORS FROM

PHASE 3 PIVOTAL TRIALS

Dummer R, et al. ASCO 2018; Robert C, et al. ESMO 2016. Abstract LBA40; Dreno B, et al. ASCO 2018.

Event, %

COMBO450

encorafenib/binimetinib

Median duration of exposure:

51 weeks

Combi-v

dabrafenib/trametinib


12.2 months

CoBRIM

vemurafenib/cobimetinib


9 months

Adverse events 98 99 99

Grade 3/4 adverse events 64 58 74,6

Adverse events leading to

discontinuation15 16 20.6

AESI OF BRAF/MEK INHIBITORS FROM PHASE 3

PIVOTAL TRIALS

Dummer R, et al. ASCO 2018; Robert C, et al. ESMO 2016. Abstract LBA40; Dreno B, et al. ASCO 2018.

COMBO450

encorafenib/binimetinib[a]

Combi-V

dabrafenib/trametinib[b]

CoBrim

vemurafenib/cobimetinib[c]

Event, %

All Grades

%

Grade ≥3

%

All Grades

%

Grade ≥3

%

All Grades

%

Grade ≥3

%

Pyrexia 15 4 57 5 29 1

Photosensitivity 4 1 4 <1 34 3

LFT increase 6 5 NR NR 26 11

SCC 2 - 2 - 8 -

Ocular 16 3 1 0 27 3

Cardio-toxicity 8 2 8 4 17 3


IMMUNOTHERAPY

CHECKMATE 066: 5-YEAR OVERALL SURVIVAL AND

PROGRESSION-FREE SURVIVAL

Robert C, et al. Five-Year Outcomes With Nivolumab in Patients With Wild-Type BRAF Advanced Melanoma. J Clin Oncol, 38(33), 3937–46. Reproduced under the terms of the Creative Commons Attribution Non-

Commercial No Derivatives 4.0 License (available at: hhttps://creativecommons.org/licenses/by-nc-nd/4.0/; accessed April 2021). © 2020 by American Society of Clinical Oncology.

38.7%

KEYNOTE 006: 5-YEAR OVERALL SURVIVAL AND


Reprinted from The Lancet, 20(9), Robert C, et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study,

1239–51. Copyright 2019, with permission from Elsevier.

CHECKMATE 067: 5-YEAR OVERALL SURVIVAL

Improved OS with NIVO+IPI and NIVO vs. IPI over 5 years

Larkin J, et al. Presented at ESMO 2019. By permission of Prof J. Larkin;

From N Engl J Med, Larkin J, et al. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma, 381(16), 1535–46. Copyright © 2019 Massachusetts Medical Society. Reprinted with permission from

Massachusetts Medical Society

NIVO+IPI (n=314) NIVO (n=316) IPI (n=315)

Median OS, mo (95% CI) NR (38.2‒NR) 36.9 (28.2‒58.7) 19.9 (16.8‒24.6)

HR (95% CI) vs IPI 0.52 (0.42‒0.64) 0.63 (0.52‒0.76) –

HR (95% CI) vs NIVOa 0.83 (0.67‒1.03) – –

0 9 12 18 36 693 6 15 33 3921 2724 30 42 48 66636057545145

OS

(%

)

100

90

70

50

30

0

80

60

40

20

10

Months

NIVO+IPI

NIVO

IPI

316 292 266 245 231 214 201 191 181 175 171 164 158 150 145 142 141 139 137 135 130 78 14 0

315 285 253 227 203 181 163 148 135 128 113 107 100 95 94 91 87 84 81 77 73 36 12 0

314 292 265 248 227 222 210 201 199 193 187 181 179 172 169 164 163 159 157 155 150 92 14 0

52%

44%

26%NIVO+IPI

NIVO

IPI

53%

46%

30%

64%

59%

45%

58%

52%

34%

No. at risk

HR = 0.83

(95% CI, 0.67–1.03)


Larkin J, et al. Presented at ESMO 2019. By permission of Prof J. Larkin;

From N Engl J Med, Larkin J, et al. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma, 381(16), 1535–46. Copyright © 2019 Massachusetts Medical Society. Reprinted with permission from

Massachusetts Medical Society.

SAFETY SUMMARY

No new safety signals were observed with the additional follow-up

No additional deaths due to study drug toxicity were reported since the prior analysisa

aPreviously reported treatment-related deaths were cardiomyopathy and liver necrosis for NIVO+IPI (n=1 each; both occurred >100 days after last treatment), neutropenia for NIVO

(n=1), and colonic perforation for IPI (n=1); bPost-hoc analysis. TRAE, treatment-related adverse event.

Larkin J, et al. N Engl J Med 2019;381(16):535–46.

Survival outcomes were not impacted by discontinuing NIVO+IPI early due to a TRAEb

◆ Patients who discontinued NIVO+IPI during induction due to a TRAE had 5-year PFS (35%) and OS rates (51%)

similar to patients in the overall population (36% and 52%, respectively)

PATIENT CHARACTERISTICS AFFECTING

IMMUNE SURVEILLANCE

LDH, lactate dehydrogenase1. Immunological effects of BRAF+MEK inhibition, Ascierto P, Dummer R. Oncoimmunology, Jul 23, 2018; reprinted by permission of the publisher (Taylor & Francis Ltd, http://www.tandfonline.com ); 2. Ascierto P.

Educational Session ASCO 2018. Courtesy of Prof P Ascierto.

Active immune

surveillance

Long-term benefit patients

• ≤3 brain metastases (size <2 cm)

• Low tumour burden (<3 organ

involved?)

• Normal LDH

Inactive immune

surveillance

No long-term benefit patients

• Multiple (>3) brain metastases

• High tumour burden (>3 organ involved?)

• High LDH

LDH level

Brain metastases

tumour burden

IS THERE A PATIENT SUBGROUP WHERE COMBINATION

THERAPY MAY HAVE GREATER CLINICAL BENEFIT?

Patient history

(e.g., autoimmune disease)

Performance status

Organ system function,

especially cardiac function

Patient’s wishes and

lifestyle factors Mutational status

Disease tempo



Patient history

(eg, autoimmune disease)

Performance status

tumour burden




lifestyle factors

LDH level

Mutational status

Brain metastases

Disease tempo

NR (NR-NR)

19.5 (14.7-NR)

5.3 (4.0-9.5)

NR (20.8-NR)

8.0 (5.8-10.9)

3.9 (1.8-6.9)

Median (95% CI), mo

Pembro ≤1ULN

Pembro >1–≤2ULN

Pembro >2ULN

Ipi ≤1ULN

Ipi >1–≤2ULN

Ipi >2ULN

0 4 8 12 16 20 24 280

10

20

30

40

50

60

70

80

90

100

Time, months

OS

, %

KEYNOTE 006: OVERALL SURVIVAL ACCORDING TO

LDH LEVEL

Data cutoff date: Dec 3, 2015.

Long GV, et al. Presented at ECCO 2017. By permission of Dr GV Long.

369 355 324 288 262 237 64 0134 111 89 82 75 63 18 0

45 28 17 10 9 8 4 0178 152 133 118 100 91 23 0

66 46 29 19 15 12 4 025 10 4 4 4 4 1 0

≤1ULN>1–≤2ULN>2ULN≤1ULN>1–≤2ULN>2ULN

No. at risk

CHECKMATE 066: 5-YEAR OVERALL SURVIVAL AND


Robert C, et al. Five-Year Outcomes With Nivolumab in Patients With Wild-Type BRAF Advanced Melanoma. J Clin Oncol, 38(33), 3937–46. Reproduced under the terms of the Creative Commons Attribution Non-

Commercial No Derivatives 4.0 License (available at: hhttps://creativecommons.org/licenses/by-nc-nd/4.0/; accessed April 2021). © 2020 by American Society of Clinical Oncology.

LDH ≤ULN LDH >ULN

LDH ≤ULN LDH >ULN

DABRAFENIB PLUS TRAMETINIB:

PFS ACCORDING TO LDH

From N Engl J Med 2019; Robert C, et al. Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma, 381(7), :626-636. Copyright © (2019) Massachusetts Medical Society. Reprinted with permission from


DABRAFENIB PLUS TRAMETINIB:

OS ACCORDING TO LDH

From N Engl J Med 2019; Robert C, et al. Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma, 381(7), :626-636. Copyright © (2019) Massachusetts Medical Society. Reprinted with permission from


PFS OUTCOMES WITH COBIMETINIB

PLUS VEMURAFENIB

Better in patients with normal vs. elevated LDH at baseline

McArthur GA, et al. Presented at 2019 International Congress of the Society for Melanoma Research. By permission of Dr Grant A. McArthur.

Normal LDHn = 131

Elevated LDHn = 112

PFS, median months(95% CI)

15.0 (12.9 – 22.0)

8.6(7.3 – 10.0)

No. of patients at risk

LDH Normal (N=131)

LDH Elevated (N=112)

131

112

100

71

74

39

54

27

46

19

29

12

35

16

20

7

100

80

60

40

20

0

Months0 12 24 36 48 72

11

6

6

3

60

1

1

15

7

25

8

LDH Normal

LDH Elevated

Censored ++19%

40%

28%

14%

23%

8% 7%

18%

Pro

gre

ssio

n-f

ree

Su

rviv

al, %

No. of patients at risk

LDH Normal (N=131)

LDH Elevated (N=112)

131

112

117

89

104

61

99

45

75

30

56

23

62

25

49

18

100

80

60

40

20

0

Ove

rall

Su

rviv

al, %

Months0 12 24 36 48 72

44

13

25

6

60

2

1

46

17

54

18

LDH Normal

LDH Elevated

Censored ++

29%

65%

50%

23%

46%

19% 16%

43%

OS OUTCOMES WITH COBIMETINIB

PLUS VEMURAFENIB

Better in patients with normal vs. elevated LDH at baseline

McArthur GA, et al. Presented at 2019 International Congress of the Society for Melanoma Research. By permission of Dr Grant A. McArthur.

Normal LDHn = 131

Elevated LDHn = 112

OS, median months(95% CI)

38.5(28.0 – NE)

14.8(11.3–18.6)

CKM 067: PFS AND OS BY LDH LEVELImproved with NIVO+IPI and NIVO vs. IPI regardless of LDH

aDescriptive analysis.

LDH, lactate dehydrogenase; ULN, upper limit of normal. Long GV, et al. Presented at 2019 International Congress of the Society for Melanoma Research;

From N Engl J Med 2019; Larkin J, et al., Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma, 381(16), 1535–46. Copyright © 2019 Massachusetts Medical Society. Reprinted with

permission from Massachusetts Medical Society.

LDH > ULN (n=341)LDH ≤ ULN (n=590)

0 9 12 18 36 693 6 15 33 3921 2724 30 42 48 66636057545145

PF

S (

%)

Months

100

90

70

50

30

0

80

60

40

20

10

41%

34%

10%

45%

37%

14%

47%

44%

16%

HR (95% CI)

NIVO+IPI vs IPI: 0.38 (0.30‒0.49)

NIVO vs IPI: 0.50 (0.39‒0.63)

NIVO+IPI vs NIVOa: 0.76 (0.59‒0.99)

0 9 12 18 36 693 6 15 33 3921 2724 30 42 48 66636057545145

OS

(%

)

Months

100

90

70

50

30

0

80

60

40

20

10

60%

53%

34%

66%

61%

42%

74%

69%

55%

HR (95% CI)

NIVO+IPI vs IPI: 0.48 (0.37‒0.64)

NIVO vs IPI: 0.58 (0.44‒0.76)


0 9 12 18 36 693 6 15 33 3921 2724 30 42 48 66636057545145

OS

(%

)

Months

100

90

70

50

30

0

80

60

40

20

10

38%

28%

15%

44%

33%

20%

46%

40%

28%

HR (95% CI)

NIVO+IPI vs IPI: 0.58 (0.43‒0.79)

NIVO vs IPI: 0.71 (0.53‒0.96)


Months

0 9 12 18 36 693 6 15 33 3921 2724 30 42 48 66636057545145

PF

S (

%)

100

90

70

50

30

0

80

60

40

20

10

28%

18%3%

29%

3%

31%

4%

HR (95% CI)

NIVO+IPI vs IPI: 0.46 (0.34‒0.62)

NIVO vs IPI: 0.60 (0.44‒0.80)


21%22%

NIVO+IPI NIVO IPI

HR

0.76 HR

0.77

HR

0.83

HR

0.82



Patient history


Performance status

tumour burden




lifestyle factors

LDH level

Mutational status

Brain metastases

Disease tempo

DABRAFENIB PLUS TRAMETINIB: PFS IN PATIENTS

WITH NORMAL LDH AND <3 ORGAN SITES

From N Engl J Med 2019; Robert C, et al. Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma, 381(7), 626–36. Copyright © 2019 Massachusetts Medical Society. Reprinted with permission from


PFS AND OS BY LDH AND 3 SITES WITH ≥1 TARGET

OR NON-TARGET LESION

aDescriptive analysis. Long GV, et al. Presented at 2019 International Congress of the Society for Melanoma Research. By permission of Dr GV Long;

Larkin J, et al. N Engl J Med 2019:381:1535–46.

LDH > ULN; ≥3 sites (n=191) LDH ≤ ULN; <3 sites (n=399)

0 9 12 18 36 693 6 15 33 3921 2724 30 42 48 66636057545145

PF

S (

%)

Months

100

90

70

50

30

0

80

60

40

20

10

45%

35%

12%

48%

39%

17%

50%

48%

18%

HR (95% CI)

NIVO+IPI vs IPI: 0.37 (0.27‒0.50)

NIVO vs IPI: 0.48 (0.36‒0.65)


Months

0 9 12 18 36 693 6 15 33 3921 2724 30 42 48 66636057545145

PF

S (

%)

100

90

70

50

30

0

80

60

40

20

10

30%

13%

4%

32%

4%

32%

4%

HR (95% CI)

NIVO+IPI vs IPI: 0.41 (0.27‒0.63)

NIVO vs IPI: 0.56 (0.38‒0.84)


15%17%

0 9 12 18 36 693 6 15 33 3921 2724 30 42 48 66636057545145

OS

(%

)

Months

100

90

70

50

30

0

80

60

40

20

10

64%

58%

35%

69%

64%

44%

75%

73%

59%

HR (95% CI)

NIVO+IPI vs IPI: 0.46 (0.33‒0.65)

NIVO vs IPI: 0.53 (0.38‒0.74)


0 9 12 18 36 693 6 15 33 3921 2724 30 42 48 66636057545145

OS

(%

)

Months

100

90

70

50

30

0

80

60

40

20

10

32%

19%

12%

36%24%

14%

37%

32%

19%

HR (95% CI)

NIVO+IPI vs IPI: 0.59 (0.39‒0.89)

NIVO vs IPI: 0.67 (0.46‒0.99)


NIVO+IPI NIVO IPI

HR

0.76 HR

0.74

HR

0.87

HR

0.87

Recommendation 2.2

In metastatic melanoma, there is no clear definition for tumour burden. As such, there is no

consensus regarding how this should be used to select treatment

Level of evidence: IV

Strength of recommendation: E

Level of consensus: 93% (26) yes, 4% (1) no, 4% (1) abstain (28 voters)

ESMO CONSENSUS CONFERENCE

RECOMMENDATIONS

On the management of metastatic melanoma: Under the auspices of

the ESMO Guidelines Committee

Keilholz U, et al. Ann Oncol 2020:31(11):1435–48.



Patient history


Performance status

tumour burden




lifestyle factors

LDH level

Mutational status

Brain metastases

Disease tempo

Single

Few (≤3)

Multiple

Without visceral involvement With visceral involvement

Symptomatic

or

Asymptomatic

Better to say: who requires

steroid or not

BRAIN METASTASES:

Ascierto PA. ESMO 2016. By permission of Prof PA Ascierto

Few (≤3)

CHECKMATE 204 PFS AND OS

(ASYMPTOMATIC PATIENTS)

Tawbi W, et al. ASCO 2019. By permission of Prof W. Tawbi

MultipleCohort B:

• Symptomatic patients

• ECOG PS 0−2

• ≤4 mg dexamethasone or

equivalent/day allowed

CHECKMATE 204 PFS AND OS

(SYMPTOMATIC PATIENTS)

aOne patient did not have extracranial disease

Tawbi W, et al. ASCO 2019. By permission of Prof W Tawbi.

Overall survival – Symptomatic patientsProgression-free survival – Symptomatic patients

Demographic and patient characteristics – Symptomatic patients

ESMO CONSENSUS CONFERENCE

RECOMMENDATIONS

On the management of metastatic melanoma: Under the auspices of

the ESMO Guidelines Committee

Recommendation 14.1

For patients with multiple asymptomatic BMs, combination treatment with ipilimumab and

nivolumab is recommended due to its more durable disease control compared with targeted

therapy

Level of evidence: V

Strength of recommendation: B

Level of consensus: 100% (32) yes (32 voters)

Keilholz U, et al. Ann Oncol 2020:31(11):1435–48.

WHAT ABOUT THE RIGHT SEQUENCE… ?

FIRST REPORT OF EFFICACY AND SAFETY FROM THE

PHASE II STUDY SECOMBIT

(SEquential COMBo Immuno and Targeted therapy study)

Ascierto PA,1 Mandalà M,2 Ferrucci PF,3 Rutkowski P,4 Guidoboni M,5 Arance AM,6 Ferraresi V7, Maiello E,8 Guida M,9 Del Vecchio M,10 Fierro MT,11

Queirolo P,3-12 Lebbè C,13 Helgadottir H,14 Melero I,15 Palmieri G,16 Giannarelli D,17 Grimaldi AM,1 Dummer R,18* Chiarion Sileni V,19*.

1-Department of Melanoma, Cancer Immunotherapy and Development Therapeutics. I.N.T. IRCCS Fondazione “G. Pascale” Napoli; 2-Department of Oncology and

Haematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy; 3- Unit of Oncology of Melanoma, European Institute of Oncology, 20141 - Milan/IT;

4-Department of Soft Tissue/Bone Sarcoma, Maria Sklodowska Curie National Research Institute of Oncology, 02-781 - Warsaw/PL; 5-Immunotherapy and Cell

Therapy Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy; 6-Department of Medical Oncology, Hospital Clínic

Barcelona, 08036 - Barcelona/ES; 7-Department of Medical Oncology 1; 7-IRCCS Regina Elena National Cancer Institute, Rome, Italy; 8-Department of Oncology,

Fondazione IRCCS Casa Sollievo della Sofferenza, Foggia, Italy; 9-Medical Oncology Department, National Cancer Research Centre "Giovanni Paolo II", Bari, Italy;

10-Unit of Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 11-Department of Medical Sciences, Dermatologic Clinic, University of Turin, Turin,

Italy; 12-IRCCS Ospedale Policlinico San Martino, Skin Cancer Unit, Genova, Italy; 13-Institut de Recherche Saint Louis (IRSL), Université de Paris, F-75010 Paris,

France; 14-Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden; 15-Department of Immunology and

Immunotherapy, Clínica Universidad de Navarra, Pamplona, Spain; 16-Unit of Cancer Genetics, CNR, Sassari, Italy; 17-Regina Elena National Cancer Institute,

IRCCS - Biostatistical Unit, Rome, Italy; 18-Department of Dermatology, University and University Hospital Zurich, Zurich, Switzerland; 19-Melanoma Oncology Unit,

Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.

*contributed equally to this study

Ascierto PA, et al. Presented at ESMO 2020 Abstract Number LBA#2621

SEQUENTIAL COMBO IMMUNO AND TARGET THERAPY

(SECOMBIT): STUDY DESIGN

DOR, duration of response; ECOG-PS, Eastern Cooperative Oncology Group performance status; LGX, encorafenib (BRAFi); MEK162, binimetinib (MEKi);

ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PD, progressive disease.

Clinicaltrials.gov: NCT02631447.Ascierto PA, et al. Presented at ESMO 2020 Abstract Number LBA#2621. By permission of Prof PA Ascierto.

Primary endpoint:

• OS

• Patients affected by

metastatic melanoma

BRAF V600 mutated

• Sample size 230 pts

RA

ND

OM

ISA

TIO

NSecondary endpoints:

• PFS

• Total PFS

• Time to second progression

• % patients alive at 2–3 years

• Best ORR

• DOR

ARM B

Combo I

Ipilimumab 3 mg/kg

Nivolumab 1 mg/kg

ARM A

Combo T

Encorafenib 450 mg

Binimetinib 45 mg

• ECOG PS: 0 or 1

• Treatment-naïveARM C

Sandwich

Encorafenib 450 mg

Binimetinib 45 mg for 8 weeks

PD

PD

ipi/nivo

until PD

enco/bini

until PD

ipi/nivo

until PD

enco/bini

until PD

Stratification Factors:

◆ IIIb/c – M1a – M1b

◆ M1c with normal LDH (≤2ULN)

◆ M1c with elevated LDH (>2 ULN)

BASELINE CHARACTERISTICS OF ITT POPULATIONS

Ascierto PA, et al. Presented at ESMO 2020 Abstract Number LBA#2621. By perrmission of Prof PA Ascierto.

Arm A (n. 69) Arm B (n. 71) Arm C (n. 69)

Median age, years (range) 55.0 (19-77) 55.0 (18-81) 51.0 (28-80)

Sex - Male no (%) 42 (60.9%) 34 (47.9%) 42 (60.9%)

ECOG-PS 0 no. (%) 57 (82.6%) 62 (87.3%) 62 (89.9%)

Lactate Dehydrogenase (LDH) levels

<=1.00 x ULN 41 (59.4%) 37 (52.1%) 44 (63.8%)

>1.00 x ULN 28 (40.6%) 34 (47.9%) 25 (36.2%)

>2.00 x ULN 7 (10.1%) 9 (12.7%) 7 (10.1%)

Stage n (%)

M0-M1a- M1b 29 (42%) 28 (39.4 %) 29 (42%)

M1c 40 (58.0%) 42 (59.1%) 39 (56.5%)

Not reported 0 1 (1.5 %) 1 (1.5%)

History of brain metastases n. (%) 0 1 (1.4%) 1 (1.5%)

Number of lesion sites, n (%)

<3

>3

NE

43 (62.3%)

25 (36.2%)

1 (1.5%)

41 (57.7%)

29 (40.9%)

1 (1.4%)

43 (62.3%)

25 (36.2%)

1 (1.5%)

ARM A: Enco/Bini

ARM B: Ipi/Nivo

ARM C: Enco/Bini (8 weeks) Ipi/Nivo

60%

43%

46%

35%

38% 39%

Arm A Arm B Arm C

N of events (%) 39 (56.5) 41 (57.7) 41 (59.4)

mPFS, months

(95% CI)

15.8

(9.5-22.2)

7.2

(3.2-11.3)

11.4

(7.2-15.5)

1y PFS %

(95% CI)

60

(48-72)

43

(31-55)

46

(34-58)

2y PFS %

(95% CI)

35

(21-49)

38

(26-50)

39

(27-51)

ARM A: 69 54 37 21 11 8 3

ARM B: 71 32 23 16 11 7 2

ARM C: 69 45 28 18 8 5 3

(median follow-up: 17.5 months; IQR: 10.2-23.4)

SECOMBIT: PROGRESSION-FREE SURVIVAL

Ascierto PA, et al. Presented at ESMO 2020 Abstract Number LBA#2621. By permission of Prof PA Ascierto.

Arm A

(n. 69)

Arm B

(n. 71)

Arm C

(n. 69)

BORR. %*(95% CI) 82.6 (73.7-91.6) 45.1 (33.5-53.6) 78.3 (68.5-88.0)

DCR. % (95% CI) 89.8 (82.7-97.0) 55.0 (43.3-66.5) 92.8 (86.6-98.9)

Best overall response N (%)

Complete response 15 (21.7) 11 (15.5) 20 (29.0)

Partial response 42 (60.9) 21 (29.6) 34 (49.3)

Stable disease 5 (7.2) 7 (9.9) 10 (14.5)

Progressive disease 3 (4.3) 27 (38.0) 3 (4.3)


(SECOMBIT): BORR


ARM A: 57 40 27 15 6

ARM B: 32 21 17 11 7

ARM C: 52 34 19 8 3

ARM A ARM B ARM C

mDoR, months (95%CI)17.8

(10.5-25.1)NR

9.8

(0.8-18.8)

12-months DR rate (%)

(95% CI)

56.5

(43.4-69.6)

69.9

(52.2-87.5)

48.5

(34.2-62.8)

24-months DR rate (%)

(95% CI)

34.2

(18.7-49.7)

69.9

(52.2-87.5)

33.7

(14.7-52.7)

ARM A: Enco/Bini

ARM B: Ipi/Nivo

ARM C: Enco/Bini (8 weeks) Ipi/Nivo

SECOMBIT: DOR

NR= not reached; DR= durable responsesAscierto PA, et al. Presented at ESMO 2020 Abstract Number LBA#2621. By permission of Prof PA Ascierto.


(SECOMBIT): SAFETY OVERVIEW


ARM A(n = 69)

ARM B(n = 71)

ARM C(n = 69)

Patients reporting event Any grade Grade 3/4 Any grade Grade 3/4 Any grade Grade 3/4

Any Adverse Event n, (%) 63 (91) 34 (49) 68 (96) 52 (73) 58 (84) 35 (51)

Treatment-related AE, n, (%) 53 (77) 19 (28) 59 (83) 38 (54) 56 (81) 22 (32)

Treatment-related AE leading to discontinuation, n, (%)

7 (10) 8 (11) 3 (4)

◆ No new safety signals were observed as compared with the data from clinical trials with IPI+NIVO and ENCO+BINI

◆ No treatment-related deaths

A

C

B

Arm A Arm B Arm C

N of events (%) 29 (42.0) 28 (39.4) 25 (35.2)

1y tot PFS (95% CI) 76 (66-86) 65 (53-77) 73 (62-84)

2y tot PFS (95% CI) 48 (33-63) 58 (45-71) 62 (50-74)

ARM A: Enco/Bini PD Ipi/Nivo

ARM B: Ipi/Nivo PD Enco/Bini

ARM C: Enco/Bini (8 weeks) Ipi/Nivo PD Enco/Bini

ARM A: 69 50 13 5

ARM B: 71 38 17 5

ARM C: 69 50 14 6

SECOMBIT: TOTAL PROGRESSION-FREE SURVIVAL

Preliminary report

Total Progression-free Survival = time from randomisation until the date of the second progression.Ascierto PA, et al. Presented at ESMO 2020 Abstract Number LBA#2621. By permission of Prof PA Ascierto.

ONGOING CLINICAL STUDIES

ONGOING CLINICAL STUDIES (CONT’D)

EORTC EBIN: Study design

ClinicalTrials.gov. NCT03235245. Available at: https://clinicaltrials.gov/ct2/show/NCT03235245; accessed April 2021.

DESPITE THE DURABLE RESPONSES OBSERVED,

MANY PATIENTS DO NOT BENEFIT FROM THE TREATMENT

Ascierto PA. Presented at ESMO Annual Congress 2019. By permission of Prof PA Ascierto.

30%10-year survival rates

are still poor in 50% of

melanoma patients

Anti-CTLA-4

Anti-PD-1

Anti-CTLA-4 + anti-PD-1

Time (years)

Ove

rall

surv

ival

(%

)

No biomarkers can

predict long-term

benefit

How can we make the tumour more responsive?

(overcoming primary resistance)

How can we reduce the risk of relapse?

(overcoming acquired resistance)

THE TUMOUR MICROENVIRONMENT IS A KEY DRIVER

OF RESPONSE OR RESISTANCE TO TREATMENT

APC = antigen-presenting cell; IDO = indoleamine 2,3 dioxygenase; LN = lymph node; MHC = major histocompatibility complex; TAP = transporter associated with antigen processing;

TCR = T-cell receptor; TDO = tryptophan 2,3-dioxygenase; TGF = tumour growth factor; VEGF = vascular endothelial growth factor.Extracted from Chen DS, Mellman I. Nature 2017;541:321–30.

Adapted by permission from Springer Nature, Nature, Elements of cancer immunity and the cancer–immune set point, Chen DS, et al., Copyright 2017.

B cellsCytokines

PD-L1

Regulatory

T cells

Cytokines

PD-L1

Exhausted

or hyper-

exhausted

T cells

Apoptosis Other

PD-1high

Chronic

TCR

stimulation

Myeloid

suppressors

Poliovirus

receptor

PD-L1

Amino-acid

catabolism

Glutaminase

TDO

IDO

Arginase 1

Cytokines

Cancer-

associated

fibroblasts

PD-L1

Amino-acid

catabolism

TGF-β

IDOTDO

Tumour

cellsCytokines

Poliovirus

receptor

Amino-acid

catabolismPD-L1

Adenosine

A2A receptor IDO

TDO

IMMUNE-DESERT TUMOUR IMMUNE-EXCLUDED TUMOUR INFLAMED TUMOUR

Stromal

interactions

CXCL12

Chemokine proteases

Dipeptidyl

peptidase 4

Chemokines

Vascular

Fas ligand

VEGF

Collagen Fibronectin

Extracellular

matrix

Tolerance

No

priming

Suppressive

cytokines

Regulatory

T cells

No

danger

signals

Non-

inflammatory

conditions

Immuno-

logic

ignorance

No

presentation

No

antigens

Tapasin

MHC class I

TAP-1

TAP-2 Other

Loss

of B2M

No

neoantigens

No

viral

antigens

No

cancer-

associated

antigens

No

T-cell

help

No

co-

stimulation

No

APC

to LN

No B7.1

B7.2

No other

co-stimulatory

ligands

No

danger

signals

Immunotherapy plus

immunotherapy

Immunotherapy plus

chemotherapy

Immunotherapy plus

targeted therapy

Immunotherapy plus

loco-regional treatment

Potential

combinations

POTENTIAL COMBINATION STRATEGIES FOR THE

TREATMENT OF CANCER

Immunotherapy plus

immunotherapy

Immunotherapy plus

chemotherapy

Immunotherapy plus

targeted therapy

Immunotherapy plus


Potential

combinations


TREATMENT OF CANCER

BRAF/MEK INHIBITORS AS

IMMUNOMODULATING AGENTS

ADE, adensosine; IFNAR, interferon-α/β receptor; MHC, major histocompatibility complex; TAA, tumour-associated antigen; Treg, regulatory T cellAscierto PA, Dummer R. Immunological effects of BRAF MEK inhibition. Oncoimmunology 2018;7(9):e1468955. reprinted by permission of the publisher (Taylor & Francis Ltd, http://www.tandfonline.com).

Tumour microenvironment before

BRAFi and MEKi

Tumour microenvironment after

BRAFi and MEKi:

↓ Adenosine

↓ Treg and myeloid-derived suppressor cells

↑ Activity of CD4-CD8+ lymphocytes

BRAFi/MEKi induce profound changes in:

Antigen display ↑

Expression of MHC ↑

IFNAR ↑ and CD73 ↓

Melanoma cell

MEK

ERK

NRAS

BRAF

MEKi

BRAFi

MHC ↑

IFNAR ↑

TAA ↑

CD73 ↓

T reg

CD4-CD8+ lymphocytes

Myeloid-derived suppressor cells

TARGETED THERAPY WITH IMMUNOTHERAPY

A rational combination for advanced BRAFV600 mutant melanoma

Dummer R, et al.. Reproduced with permission from JAMA Oncol 2020;6(12) :1957–66. Copyright©2020 American Medical Association. All rights reserved.

Dabrafenib + trametinib

+ nivolumab

DIFFERENT TRIPLE COMBINATION BRAF/MEK +

ANTI-PD-1/PD-L1

BID, twice daily; CR, complete response; PD, progressive disease; PR, partial response; QD, once daily; SD, stable disease. a Patients with CR and < 100% change in sum of diameters (SOD)

have (a) 100% change for non-nodal target lesions and all nodal target lesions are < 10 mm and (b) CR for nontarget lesions. b Patients with PR and 100% change in SOD have (a) 100%

change for all target lesions and (b) non-CR/non-PD response for nontarget lesions.1. Ribas A, et al. J Clin Oncol 2015;33(suppl) [abstract 3003]; by permission of Prof P Ascierto; 2. Ribas A, et al. J Clin Oncol 2016; 34(suppl) [abstract 3014]; by permission of Dr A Ribas; 3. Ribas A, et al. Ann Oncol 2017; 28(suppl 5)

[abstract 1216O]; by permission of Dr A Ribas; 4. Hwu P, Sullivan RJ, et al. Ann Oncol. 2016; 27(suppl 6) [abstract 1109PD], by permission of Dr RJ Sullivan; 5. Dummer, R, et al. J Clin Oncol 2018;36(suppl 5S) [abstract 189]; by

permission of Prof Drummer; 6. Burton E. et al. ESMO 2019; Abstract 5704, by permission of Prof E. Burton.


+ spatalizumab

Vemurafenib + cobimetinib

+ atezolizumab


+ pembrolizumab


+ durvalumab

WHAT DO WE KNOW ABOUT THE TRIPLET TT+IO FROM RANDOMISED STUDIES… ?

NEGATIVE! NEGATIVE!

POSITIVE!

aBased on Kaplan-Meier estimate of PFS, per investigator assessment.bBased on Cox regression model with treatment as a covariate stratified by ECOG PS (0 vs 1) and LDH (LDH >1.1 × ULN vs =1.1 × ULN); owing to the small number of patients

enrolled in the ECOG PS 1 and LDH ≤1.1 × ULN strata, these strata were combined.cOne-sided p-value based on stratified log-rank test.

Data cutoff: Feb 15, 2018. Ascierto P, et al. ESMO 2018; Ascierto P, et al. Nat Med 2019; 25:941–6. Reproduced by permission of Prof P Ascierto.

0 2 4 6 8 10 12

Time, monthsNo. at risk

14 16 18 20 22 24 26

Pembro + D + T 60 55 49 39 36 34 27 21 17 12 5 4 1 0

Placebo + D + T 60 59 52 38 35 29 23 20 16 9 4 3 0 0

100

90

80

70

60

50

40

30

20

10

0

PF

S %

Events, n

Median,a mo (95% CI)

HRb

(95% CI)bp-valuec

Pembro + D + T 31 16.0 (8.6-21.5)0.66 (0.40-1.07) 0.04287

Placebo + D + T 41 10.3 (7.0-15.6)

KEYNOTE-022 PROGRESSION-FREE SURVIVAL

59%

45%

PFS did not reach statistical

significance threshold per

study design

(required HR for

significance ≤0.62; p≤0.025)

KEYNOTE-022 OVERALL SURVIVAL

aBased on Kaplan-Meier estimate of overall survival.bBased on Cox regression model with treatment as a covariate stratified by ECOG PS (0 vs 1) and LDH (>1.1 × ULN vs ≤1.1 × ULN; owing to the small number of patients enrolled in

the ECOG PS 1 and LDH ≤1.1 × ULN strata, these strata were combined. cP values are provided for descriptive purposes only, no multiplicity adjustment is made. One-sided P value based on stratified log-rank test.

Data cutoff: Feb 15, 2018. Ascierto P, et al. ESMO 2018; Ascierto P, et al. Nat Med 2019; 25:941–6. Reproduced by permission of Prof P Ascierto.

Events, n

Mediana

(95% CI), moHRb

(95% CI)bp-valuec

Pembro + D + T 19 NR (19.6-NR)0.76 (0.41-1.39) 0.18467

Placebo + D + T 24 23.4 (17.8-NR)

Pembro + D + T 60 60 59 56 53 50 43 35 29 23 18 9 4 1

Placebo + D + T 60 60 59 55 51 47 39 36 31 25 18 7 2 0

0

0

No. at risk0 2 4 6 8 10 12

Month

14 16 18 20 22 24 26

100

90

80

70

60

50

40

30

20

10

0

Ove

rall

Su

rviv

al, %

28

79%

73%

KEYNOTE-022: ONCOLOGIC THERAPIES AFTER

DISCONTINUING STUDY TREATMENT

aIncludes BRAF inhibitors or MEK inhibitors.bCarboplatin, paclitaxel, and 1 unspecified chemotherapy.Ascierto P, et al. ESMO 2018; Ascierto P, et al. Nat Med 2019; 25:941–6.

n (%)Pembro + D + T

N = 60

Placebo + D + T

N = 60

≥1 New systemic therapy 21 (35.0) 34 (56.7)

BRAF/MEK inhibitora 14 (23.3) 7 (11.7)

Dabrafenib 8 (13.3) 8 (13.3)

Vemurafenib 8 (13.3) 1 (1.7)

Trametinib 7 (11.7) 5 (8.3)

Cobimetinib 8 (13.3) 1 (1.7)

Chemotherapyb 1 (1.7) 2 (3.3)

n (%)Pembro + D + T

N = 60

Placebo + D + T

N = 60

Immunotherapy 9 (15.0) 29 (48.3)

Pembro 7 (11.7) 21 (35.0)

Nivolumab 0 (0) 10 (16.7)

Ipilimumab 2 (3.3) 8 (13.3)

Other

Exemestane 0 (0) 1 (1.7)

Tamoxifen 0 (0) 1 (1.7)

OVERALL SURVIVAL

aBased on Kaplan-Meier estimate of overall survival.bBased on Cox regression model with treatment as a covariate stratified by ECOG PS (0 vs 1) and LDH (>1.1 × ULN vs ≤1.1 × ULN; owing to the small number of patients enrolled in

the ECOG PS 1 and LDH ≤1.1 × ULN strata, these strata were combined.

Data cutoff: Jun 26, 2019.Ferrucci P, et al. SMR 2019. By permission of Dr P. Ferrucci.

Events, n (%)

Mediana

(95% CI), moHRb

(95% CI)b

Pembro + D + T 26 (43.3) NR (23.9-NR) 0.64 (0.38-1.06)Placebo + D + T 36 (60.0) 26.3 (18.2-NR)

No. at risk

Pembro + D + T

Placebo + D + T

60

60

59

59

60

60

100

90

80

70

60

50

40

30

20

10

0

Ove

rall

Su

rviv

al (

%)

Time in Months

0 4

53

51

8

48

44

12

43

41

16

40

35

20

37

31

24

32

25

28

25

20

32

18

11

362

56

55

6

50

47

10

46

44

14

41

39

18

39

35

22

37

30

26

28

24

30

23

18

34

6

4

40

9

6

38

24-mo OS

63%

52%

1

0

42 44

0

0

KN022 first report

Ascierto et al ESMO 2018

mFU = 9.6 months

KN022 second report

Ferrucci et al SMR 2019

mFU = 29.6 months

COMBI-I STUDY DESIGN (PART 3)

BID, twice daily; DCR, disease control rate; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase;

ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; Q4W, every 4 weeks; QD, once daily;

RECIST, Response Evaluation Criteria in Solid Tumours. Nathan P, et al. ESMO 2020

Randomization stratification

• ECOG PS

• LDH level

Spartalizumab 400 mg Q4W +

dabrafenib 150 mg BID +

trametinib 2 mg QD

Placebo Q4W +

dabrafenib 150 mg BID +

trametinib 2 mg QD

Primary endpoint: Investigator-assessed PFS using RECIST 1.1

Secondary endpoints: OS, ORR, DOR, DCR, safety, PRO, PK

N = 532 R

A

N

D

O

M

I

S

A

T

I

O

N

Key eligibility criteria

• BRAF V600 mutation–positive unresectable or

metastatic melanoma

• Previously untreated

• No active brain metastases

• ECOG PS ≤ 2

STUDY ANALYSIS AND ENDPOINTS

The primary endpoint was investigator-assessed progression-free survival using RECIST 1.1

◆ The study design assumed a 5-month delay in the treatment effect of Sparta-DabTram

◆ A target number of 352 events was set to ensure 80% power. Note: The prespecified final analysis could occur at 24

months after the last patient was randomised if this occurred before the target number was reached

◆ A prespecified interim analysis was conducted after 276 events were observed, at which time the data monitoring

committee recommended not to unblind the study

◆ This primary analysis is based on a minimum follow-up of 24 months, with 312 events

(statistical threshold, P=0.02497 [1-sided])

Overall survival was a key secondary endpoint

◆ Overall survival could be statistically tested only after the primary endpoint was determined to be statistically significant

All efficacy analyses were performed using the full analysis set, which comprised all patients randomised to receive study

treatment; safety analyses included all patients who received ≥1 dose of at least 1 drug in each treatment regimen

Nathan P, et al. ESMO 2020

Sparta-DabTram

Placebo-DabTram

INVESTIGATOR-ASSESSED


HR, hazard ratio.Nathan P, et al. ESMO 2020. By permission of Prof P Nathan.

Event, n

(%)

Median

(95% Cl), mo

HR

(95% CI)

Sparta-DabTram 147 (55.1)16.2

(12.7-23.9)0.820

(0.655-1.027)

P = .042 (1-sided)

Not significantPlacebo-DabTram 165 (62.3)12.0

(10.2-15.4)

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32

Months

Pro

gre

ssio

n-F

ree

Su

rviv

al, %

267

265

256

252

229

228

204

202

180

162

159

148

142

127

130

115

121

105

115

100

111

95

108

93

90

76

40

36

13

11

5

8

0

0

No. at risk

Sparta-DabTram

Placebo-DabTram

58%

50%

44%

36%

IMSPIRE150: PRIMARY ENDPOINT: INVESTIGATOR-

ASSESSED PFS

Reprinted from The Lancet, 395 Gutzmer R, et al. Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAF V600 mutation-positive melanoma (IMspire150): primary analysis of the

randomised, double-blind, placebo-controlled, phase 3 trial, 1835–44 Copyright 2020, with permission from Elsevier.

PFS FROM KEYNOTE-022, IMSPIRE 150 AND COMBI-I

(TRIPLET ARMS)

Ascierto P. ESMO Educational Session 2020. By permission of Prof P Ascierto.

Ferrucci P, et al. SMR 2019; McArthur et al. AACR 2020; Nathan P, et al. ESMO 2020.

0 9 12 18 36 693 6 15 33 3921 2724 30 42 48 66636057545145

OS

(%

)

100

90

70

50

30

0

80

60

40

20

10

1-yr PFS

62%

58%

54%2-yr PFS

41%

44%

43,6% (18mos)

Dabrafenib + trametinib + spartalizumab

Dabrafenib + trametinib + pembrolizumab

Vemurafenib + cobimetinib + atezolizumab

HR (95% CI)

0.51 (0.39–0.67)

0.82 (0.655-1.027)

0.78 (0,63–0,97)

Elevated LDH

45%

39,3%

33%

mFollow-up

29,6 mos

27,2 mos

18,9 mos


PFS FROM KEYNOTE-022, IMSPIRE 150 AND COMBI-I

(CONTROL ARMS)

0 9 12 18 36 693 6 15 33 3921 2724 30 42 48 66636057545145

OS

(%

)

100

90

70

50

30

0

80

60

40

20

10

Dabrafenib + trametinib +placebo (KN022)

Vemurafenib + cobimetinib + placebo

Dabrafenib + trametinib +placebo (COMBI-I)

1-yr PFS

50%

47%

45,1%

2-yr PFS

45,1%

(18mos)

36%

16%

Elevated LDH

43%

39,2%

33%

HR (95% CI)

0.51 (0.39–0.67)

0.82 (0.655-1.027)

0.78 (0,63–0,97)


Ferrucci P, et al. SMR 2019; McArthur et al. AACR 2020; Nathan P, et al. ESMO 2020


OS FROM KEYNOTE-022, IMSPIRE 150 AND COMBI-I

(TRIPLET ARMS)

0 9 12 18 36 693 6 15 33 3921 2724 30 42 48 66636057545145

OS

(%

)

100

90

70

50

30

0

80

60

40

20

10

DABRAFENIB + TRAMETINIB + PEMBROLIZUMAB

VEMURAFENIB + COBIMETINIB + ATEZOLIZUMAB

DABRAFENIB + TRAMETINIB + SPARTALIZUMAB

2-yr OS

68%

63%

60,4%

HR (95% CI)

0.64 (0.38–1.06)

0.785 (0.589-1.047)

0.85 (0.64–1.11)

mFollow-up

29,6 mos

27,2 mos

18,9 mos





(CONTROL ARMS)



0 9 12 18 36 693 6 15 33 3921 2724 30 42 48 66636057545145

OS

(%

)

100

90

70

50

30

0

80

60

40

20

10

DABRAFENIB + TRAMETINIB + PLACEBO (KN022)

VEMURAFENIB + COBIMETINIB + PLACEBO

DABRAFENIB + TRAMETINIB + PLACEBO (COMBI-i)

2-yr OS

62%

52%

53,1%

HR (95% CI)

0.64 (0.38–1.06)

0.785 (0.589-1.047)

0.85 (0.64–1.11)

Elevated LDH

43%

39,2%

33%



(CONTROL ARMS)



0 9 12 18 36 693 6 15 33 3921 2724 30 42 48 66636057545145

OS

(%

)

100

90

70

50

30

0

80

60

40

20

10

Dabrafenib + trametinib + placebo (KN022)

Vemurafenib + cobimetinib + placebo

Dabrafenib + trametinib + placebo (COMBI-i)

2-yr OS

62%

52%

53,1%

HR (95% CI)0.64 (0.38–1.06)

0.785 (0.589-1.047)

0.85 (0.64–1.11)

Elevated LDH43%

39,2%

33%


KEYNOTE-022(n=60)

IMspire 150(n=230)

Combi-I(n=267)

Patients reporting event Any grade Grade 3/4 Any grade Grade 3/4 Any grade Grade 3/4

Any Adverse Event, n, (%) 60 (100) 42 (70) NR NR 265 (99.3) 188 (70.4)

Treatment-related AE, n, (%) 57 (95) 35 (58.3) 228 (99) 182 (79) 263 (98.5) 146 (54.7)

Deaths 2 (3) 7 (3.0) NR

Treatment-related deaths, n, (%) 1 (2) 2 (0.8) NR

Treatment-related AE leading to discontinuation > 1 study drug, n, (%)

28 (46.7) NR 85 (31.8)

Treatment-related AE leading to discontinuation of all 3 study drugs, n, (%)

18 (30) 29 (13) 33 (12.4)

NR = not reported

TRIPLET COMBOS SAFETY PROFILE


Ferrucci P, et al. SMR 2019; Gutzmer et al. Lancet 2020; Nathan P, et al. ESMO 2020


DO WE REALLY NEED A TRIPLET COMBO…?


(TRIPLET ARMS) AND …

Ascierto PA. ESMO Educational Session 2020. By permission of Prof P Ascierto.

Larkin et al. NEJM 2019; Ferrucci et al. SMR 2019; McArthur et al. AACR 2020; Nathan et al. ESMO 2020

0 9 12 18 36 693 6 15 33 3921 2724 30 42 48 66636057545145

OS

(%

)

100

90

70

50

30

0

80

60

40

20

10

Dabrafenib + trametinib + pembrolizumab

Vemurafenib + cobimetinib + atezolizumab

Dabrafenib + trametinib + spartalizumab

2-yr OS

68%

63%

60,4%

HR (95% CI)0.64 (0.38–1.06)

0.785 (0.589-1.047)

0.85 (0.64–1.11)

mFollow-up29,6 mos

27,2 mos

18,9 mos

52%53%

64%

58%60%

68%71%

NIVO+IPI in BRAF Mut

NIVO+IPI


IS THERE A PATIENT'S SUBGROUP WHERE COMBINATION MIGHT BE MORE USEFUL…?

CHECKMATE 204:

PFS AND OS IN BM SYMPTOMATIC PATIENTS

Tawbi W, et al. ASCO 2019. By permission of Prof W Tawbi.

Progression-free survival – Symptomatic patients Overall survival – Symptomatic patients

ANY ROLE IN CASE OF PD AFTER/DURING ADJUVANT…?

Measure

All Patients

(N=26)

Age, n (%)

< 65 years 19 (73)

≥ 65 years 7 (27)

Gender, n (%)

Male 15 (58)

Female 11 (42)

ECOG status, n (%)

0 17 (65)

1 9 (35)

LDH, n (%)

≤ 1 x ULN 15 (58)

> 1 – ≤ 2 x ULN 6 (23)

> 2 x ULN 5 (19)

Sites of disease, n (%)

≤ 3 9 (35)

> 3 17 (65)

Follow-up time in months (all patients)

Median (range)

13.1 (0.3 – 30.6)

TRIDeNT STUDY: PATIENT DEMOGRAPHICS

Burton E, et al. ESMO 2019; Burton EM, et al. Immunotherapy Bridge 2019. By permission of Prof E Burton.

PD1 naïve

N=10

BRAF-V600+ unresectable stage III/IV MM

N=26

PD1 refractory

N=16

No brain mets

N=7

Brain mets

N=3

No brain mets

N=10

Brain mets

N=6

Median PFS:

w/ brain mets 8.6 mos

w/out brain mets 8.4 mos

TRIDeNT STUDY: OUTCOMES BY BRAIN METS STATUS

Burton E, et al. ESMO 2019; Burton EM, et al. Immunotherapy Bridge 2019. By permission of Prof E Burton.

88% (7/8) ORR in pts w/ brain mets (2 CR)

93% (13/14)ORR in pts w/out brain mets (1 CR)

67% (4/6) evaluable pts experienced an intracranial response,

including 2 CRs

ORR = 91% (3 CR, 14%)

100% ORR in PD1 naive patients (2 CR)

83% ORR in PD1 refractory patients (1 CR)

TRIDENT STUDY: OUTCOMES BY PD1

TREATMENT STATUS

Burton E, et al. ESMO 2019; Burton et al. Bridge meeting 2019. By permission of Prof E Burton.

Prior PD1 treatment N

Recurrence after adjuvant tx 4

Primary resistance 10

PD1 + Ipi

PD1 + other

PD1 single agent

2

6

2

Secondary resistance 2


(TRIPLET ARMS)

Ascierto P. ESMO Educational Session 2020; by permission of Prof P Ascierto.

Larkin, et al. NEJM 2019; Ferrucci, et al. SMR 2019; McArthur, et al. AACR 2020; Nathan, et al. ESMO 2020.

0 9 12 18 36 693 6 15 33 3921 2724 30 42 48 66636057545145

OS

(%

)

100

90

70

50

30

0

80

60

40

20

10

DABRAFENIB + TRAMETINIB + PEMBROLIZUMAB

VEMURAFENIB + COBIMETINIB + ATEZOLIZUMAB

DABRAFENIB + TRAMETINIB + SPARTALIZUMAB

2-yr OS

68%

63%

60,4%

HR (95% CI)0.64 (0.38–1.06)

0.785 (0.589-1.047)

0.85 (0.64–1.11)

mFollow-up29,6 mos

27,2 mos

18,9 mos

52%53%

64%

58%60%

68%71%

NIVO+IPI in BRAF Mut

NIVO+IPI


IMMUNE EFFECTS OF VEGF

Presented By FS Hodi at 2011 ASCO Annual Meeting; Tartour E, et al. Cancer Metastasis Rev 2011;30(1):83–95. Reprinted by permission from Springer Nature, Cancer and Metastasis Reviews, Angiogenesis and immunity:

a bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy,Tartour E, et al.. Copyright 2011

BEVACIZUMAB PLUS IPILIMUMAB

Bevacizumab plus Ipilimumab in Patients with Metastatic MelanomaClinical Trial

Cancer Immunol Res 2014 Jul;2(7):632–42.

F Stephen Hodi, Donald Lawrence, Cecilia Lezcano, Xinqi Wu, Jun Zhou, Tetsuro Sasada, Wanyong Zeng, Anita Giobbie-Hurder, Michael B Atkins,

Nageatte Ibrahim, Philip Friedlander, Keith T Flaherty, George F Murphy, Scott Rodig, Elsa F Velazquez, Martin C Mihm Jr , Sara Russell, Pamela

J DiPiro, Jeffrey T Yap, Nikhil Ramaiya, Annick D Van den Abbeele, Maria Gargano, David McDermott

LENVATINIB PLUS PEMBROLIZUMAB IN PATIENTS

WITH ADVANCED MELANOMA

Previously exposed to anti-PD-1/anti-PD-L1 agents: Phase 1 LEAP-004 study

Arance A, et al. ASCO 2019. By permission of Dr A Arance.

Pembrolizumab

200 mg IV Q3W

+

Levatinib

20 mg PO QD

Up to 35 cycles

Patients

• Unresectable stage III or IV

melanomaa

• All comers with regard to

PD-L1 and BRAF status

• Confirmed progressionb with ≥2

doses of anti-PD-1/anti-PD-L1

monotherapy or combination

therapy

• ECOG PS 0 or 1

Levatinib

20 mg PO QD

Treatment to

continue until

Disease progression

or unacceptable

toxicity

Posttreatment

follow-up to assess

• Safety

• Disease

• Survival status

LEAP-004: BICR-CONFIRMED RESPONSE BY PD ON

PRIOR ANTI-CTLA-4 + ANTI-PD-(L)1

aPatients who had no post-baseline imaging assessments. Data cut-off date: June 10, 2020. Arance A, LEAP-004 ESMO 2020; abstract LBA44.

Immunotherapy plus

immunotherapy

Immunotherapy plus

chemotherapy

Immunotherapy plus

targeted therapy

Immunotherapy plus


Potential

combinations


TREATMENT OF CANCER

TUMOUR-DIRECTED IMMUNO-ONCOLOGY

Adapted from Ellmark P, et al. Cancer Immunol Immunother 2017;66(1):1–7. Reproduced under the terms of the Creative Commons Attribution 4.0 International License (available at:

http://creativecommons.org/licenses/by/4.0/; accessed April 2021).

All lesions1

Non injected visceral lesions1

T-VEC + IPILIMUMAB

1. Chesney J, et al. , tRandomized, Open-Label Phase II Study Evaluating the Efficacy and Safety of Talimogene Laherparepvec in Combination With IpilimumabVersus Ipilimumab Alone in Patients With Advanced,

Unresectable Melanoma, J Clin Oncol, 36(17), 1658–67. Available at: https://ascopubs.org/doi/10.1200/JCO.2017.73.7379?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed; accessed April

2021. © 2017 by American Society of Clinical Oncology.; 2. Puzanov I, et al. SITC 2020. By permission of Prof I Puzanov.

4-year PFS2

4-year OS2

T-VEC + PEMBROLIZUMAB

1. Long GV, et al. SMR 2015 (NCT02263508); by permission of Dr Georgina Long; 2. Long GV, et al. Pigment Cell Melanoma Res 2019;32:133–134 (SMR Congress 2018); by permission of Dr Georgina Long; 3.

THOUSAND OAKS, Calif., Feb. 2, 2021 /PRNewswire/ -- Amgen (NASDAQ:AMGN) today announced financial results for the fourth quarter and full year 2020 versus comparable periods in 2019; available at:

https://www.amgen.com/newsroom/press-releases/2021/02/amgen-reports-fourth-quarter-and-full-year-2020-financial-results; accessed April 2021.

MASTERKEY-265 Phase 3 study design

Overall survivalProgression-free survival

TOLL-LIKE RECEPTOR 9 (TLR9) INHIBITION

Intratumoural mechanism of action of tilsotolimod

Extracted from Babiker HM, et al. Presented at AACR 2019; abstract 4062. By permission of Dr Shah Rahimian

Efficacy Endpoint In 49 Patients

mOS, months

(95% CI)

21.0

(9.8-NR)

mPFS, months

(95% CI)

5.1

(3.65-7)

ORR, % (95% CI)22.4

(11.8-36.6)

DCR, % (95% CI)71.4

(56.7-83.4)

mDOR, months

(95% CI) 11.4 (3.3-NR)

FINAL RESULTS FROM ILLUMINATE-204

A Phase I/II trial of intratumoural tilsotolimod in combination with

ipilimumab in PD-1 inhibitor refractory advanced melanoma

DCR = disease control rate; IPI = ipilimumab; irAEs = immune-related adverse events; mDOR = median duration of response; mOS = median overall survival; NR = not reached; ORR =

objective response rate; PD-1 = programmed cell death protein 1; RECIST = Response Evaluation Criteria in Solid Tumours; TEAE = treatment-emergent adverse event.

Haymaker C, et al. ESMO 2020; by permission of Prof C. Haymaker. Clinical trial information: https://clinicaltrials.gov/ct2/show/NCT02644967.

◆ Tumour reduction was observed in both

injected and noninjected tumours

A RANDOMISED PHASE 3 COMPARISON OF IMO-2125

With ipilimumab vs. ipilimumab alone in subjects with anti-PD-1 refractory melanoma

Ascierto PA, et al. ESMO 2018. By permission of Prof PA Ascierto.

ORR (2 mg/kg) = 70%

ORR (8 mg/kg) = 70%

OTHER TLRS AGONIST ON DEVELOPMENT:

SD101 AND CMP-001

Ribas A, et al. ASCO 2018; By permission of Prof A. Ribas; Kirkwood, et al. SITC 2019; by permission of Prof J. Kirkwood.

KEYNOTE 695 INTERIM DATA

Durable responses and immune activation with intratumoural electroporation of pIL-12 plus

pembrolizumab in actively progressing anti-PD-1 refractory advanced melanoma

Fernandez-Penas P, et al. 2020 SITC Annual Meeting; abstract 799. By permission from: Prof P. Fernandez-Penas and Prof S. Aung, OncoSec..

Treated and untreated lesions from 16 responding patients

Best overall response

Percent change in tumour size over time

Immunotherapy plus

immunotherapy

Immunotherapy plus

chemotherapy

Immunotherapy plus

targeted therapy

Immunotherapy plus


Potential

combinations


TREATMENT OF CANCER

IDO1 inhibitor

(e.g., epacadostat [Ph 3], etc.)

Anti-LAG-3

(e.g., relatlimab [Ph 1/2])

HDAC inhibitor

(e.g., entinostat [Ph 2])

Anti-GITR

(e.g., BMS-986156 (Ph 1/2])

NEW EMERGING PATHWAYS FOR FUTURE

COMBINATION WITH ANTI-PD-1/PD-L1 COMPOUNDS

GITR, glucocorticoid-induced TNFR-related protein; HDAC, histone deacetylases; IDO1, indoleamine 2,3-dioxygenase 1; LAG-3, lymphocyte-activation gene 3. Presented by Paolo A. Ascierto at ASCO 2018; Ascierto PA, McArthur JA. J Transl Med 2017;15:173. Reproduced under the terms of the Creative Commons Attribution 4.0 International License (available at:

http://creativecommons.org/licenses/by/4.0/; accessed April 2021).

INITIAL EFFICACY OF ANTI-LYMPHOCYTE ACTIVATION

GENE-3 (ANTI-LAG-3; BMS-986016)

In combination with nivolumab in patients with melanoma

previously treated with anti-PD-1/PD-L1 therapy

Ascierto PA, et al. ESMO 2017. By permission of Prof PA Ascierto.

CA224-047

Randomised, double-blind Phase 2/3 study of relatlimab combined with nivolumab vs.

nivolumab in participants with previously untreated metastatic or unresectable melanoma

Presented by Paolo A. Ascierto at ASCO 2018. Clinicaltrial.gov identifier NCT03470922.

Phase 2 primary endpoint: PFS assessed by a BICR

Phase 2 secondary endpoint: ORR, DOR, DCR, PFS rates, and 1- and 2-year OS rates according LAG-3 and PD-L1 status, safety and tolerability

Phase 3 primary endpoint: PFS

Phase 3 secondary endpoint: ORR, OS

Unresectable or metastatic

melanoma• Previously untreated

• Tissue available for LAG-3, PD-L1,

TMB assessment

Stratify by:• LAG-3 status

• PD-L1 status

• BRAF status

• AJCC M-stage

R

1:1

N = 400 pts

ARM A

relatlimab + nivolumab

160/480 mg IV Q4W

ARM B

nivolumab

480 mg IV Q4W

Phase 2

Interim

analysis

Phase 3

R

1:1

Additional

N = 300 pts

ARM A

relatlimab + nivolumab

160/480 mg IV Q4W

ARM B

nivolumab

480 mg IV Q4W

Positive

HDAC inhibitors

(eg., entinostat, etc.)



HDAC inhibitors

McArthur JA. J Transl Med 2017;15:173. Reproduced under the terms of the Creative Commons Attribution 4.0 International License (available at: http://creativecommons.org/licenses/by/4.0/; accessed April 2021).

RATIONALE FOR ENTINOSTAT IN COMBINATION WITH

ANTI-PD-(L)1 THERAPY

◆ Entinostat (ENT) is an oral class I-selective histone deacetylase inhibitor

◆ ENT leads to downregulation of immunosuppressive cell types in the tumour microenvironment

◆ Synergy with anti-PD-1 inhibition in preclinical models

† In vivo and in vitro studies were performed using Lewis Lung Carcinoma (LLC) cells. **p<0.001; *p<0.05.

Ab, antibody; Arg1, arginase 1; COX2, cytochrome oxidase subunit 2; iNOS, inducible nitric oxide synthase; MDSC, myeloid-derived suppressor cells.Orillion A, et al. Clin Cancer Res 2017;23(17):5187–201; Sullivan R, et al. AACR 2019. By permission ofProf R. Sullivan

MDSC mRNA expression1†MDSC function1† Tumour growth1†

Entinostat treated

Vehicle treated

Entinostat treated

Vehicle treated

ENCORE-601:

OPEN-LABEL STUDY EVALUATING ENT + PEMBRO

In patients with recurrent or metastatic melanoma and prior progression on or after

anti-PD-1 therapy

CBR, clinical benefit rate; CRC, colorectal cancer; ECOG, Eastern Cooperative Oncology Group; ENT, entinostat; irRECIST, immune-related Response Evaluation Criteria in Solid

Tumours; IV, intravenous; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PEMBRO, pembrolizumab; PFS, progression-free survival; PO, orally;

QW, once a week; Q3W, every 3 weeks; RECIST, Response Evaluation Criteria in Solid Tumours.Sullivan R, et al. AACR 2019. By permission of Prof R. Sullivan.

Primary Endpoint

• ORR (irRECIST)

Secondary Endpoints

• CBR, PFS, OS, safety & tolerability

Phase 1b:

Phase 2:

ENT 5 mg PO QW +

PEMBRO 200 mg IV Q3W

Mismatch

Repair-Proficient CRC

Anti-PD-1/PD-L1-naive

NSCLC

Anti-PD-1/PD-L1–naive

Melanoma

Progressing On/After

Anti-PD-1

NSCLC

Progressing on

Anti-PD-1/PD-L1

53 patients enrolled, last

patient enrolled April 2018

Dose & safety confirmation

Inclusion criteria

◆ Recurrent or metastatic

melanoma, measurable by

RECIST 1.1

◆ Prior progression on or after

anti-PD-(L)1 treatment

◆ Prior BRAF treatment if indicated

◆ ECOG Performance Status < 2

◆ Willingness to participate in

baseline and on-treatment

biopsy and blood samples

CHANGE IN TUMOUR VOLUME AND CHANGE IN

TUMOUR VOLUME OVER TIME PER irRECIST IN ENCORE-601

10 confirmed responses of 53 treated [19% ORR

(95% CI: 9, 32)]

◆ 1 CR, 9 PRs

Median duration of response: 13 months (range 3–20)

◆ 4 responders ongoing

An additional 9 patients have had SD for >6 months

◆ 36% CBR (95% CI: 23, 50)

CBR, clinical benefit rate; CI, confidence interval; CR, complete response; irRECIST, immune-related Response Evaluation Criteria in Solid Tumours; ORR, objective response rate; PD,

progressive disease; PR, partial response; SD, stable disease.Sullivan R, et al. AACR 2019. By permission of Prof R. Sullivan

PD

SD

PR Confirmed

CR Confirmed

-100

-60

-20

0

20

40

100

% C

hang

e fr

om b

asel

ine

-80

-40

60

80

STUDY DESIGN AND OBJECTIVES SENSITISE STUDY

(NCT03278665)

3 dose escalation cohorts (up to 10 patients/

cohort)

◆ QD and BID dosing explored

Dose optimisation* cohort with 6 patients

Phase II expansion planned with defined

optimal biological dose and schedule

Study conducted at 7 sites in Europe;

including National Tumour Institute

Fondazione G. Pascale in Naples

*currently recruiting; not discussed today

BID: twice daily; QD: once daily; q3w: every 3 weeksAscierto PA, et al. Presented at Melanoma Bridge 2019; abstract 22. By permission of Prof PA Ascierto.

1 PR

1 SD

2 SD; 1 confirmed

4 SD; 3 confirmed

LAST PRIOR THERAPY AND PRELIMINARY EFFICACY

(N=23)

Preliminary data; study is still ongoing and patients are currently recruited/ treated; data cut-off date: 14-Nov-2019Ascierto PA, et al. Presented at Melanoma Bridge 2019; abstract 22. By permission of Prof PA Ascierto.

Heavily pre-treated patient population with >50% 3+ lines of prior therapies

◆ Last treatment with anti-PD1/ anti-CTLA4 + anti-PD1, last dose within 6 months

All patients primary refractory to prior checkpoint inhibitor therapy

Treatment currently ongoing for 3 patients in cohort 3

BACKGROUND

Bempegaldesleukin preferential signalling through the IL-2 receptor pathway

Bempegaldesleukin (BEMPEG; NKTR-214): is a CD122-

preferential IL-2 pathway agonist shown to increase tumour-

infiltrating lymphocytes (TILs), T cell clonality and PD-1

expression1,2

BEMPEG plus checkpoint inhibitor (CPI) nivolumab (NIVO)

has been shown to convert baseline tumours from PD-L1(-)

to PD-L1(+)3-6

Low levels of baseline TILs7-9 and T cell-inflammation10 is

predictive of a poor response to CPIs

Diab A, et al. SITC 2019; Abstract O35. By permission of Prof A. Diab.

1. Charych D, et al. PLoS One 2017;12: e0179431; 2. Bentebibel SE, et al. Cancer Discov 2019;9:711-721; 3. Diab A, et al. SITC 2018; Abstract O4; 4. Siefker-Radtke, et al. ASCO GU 2019; Abstract 388; 5. Hurwitz M, et al.

ASCO 2019; Abstract 2623; 6. Tolaney S, et al. CICON 2019; Poster A001; 7. Daud AI, et al. J Clin Oncol 2016;34:4102–09; 8. Daud AI, et al. J Clin Invest 2016;126:3447–52; 9. Tumeh PC, et al. Nature 2014;515:568–71;

10. Ayers M, et al. J Clin Invest 2017;127:2930–40.

STAGE IV 1L MELANOMA: BEST OVERALL RESPONSE

BY INDEPENDENT RADIOLOGY

PIVOT-02

Data cut-off: 01 Sept 2020. Response evaluable population includes eligible patients with measurable disease (per RECIST 1.1) at baseline and have ≥1 post-baseline tumour assessment.

All objective responses are confirmed. #Best overall response is progressive disease due to non-target lesion progression or presence of new lesion; *Best overall response is SD;

+Best overall response is PR. CR for target lesion, non-target lesion still present.

CR, complete response; LDH, lactate dehydrogenaseDiab A, et al. SITC 2019; Abstract O35. By permission of Prof A. Diab.

RESPONSES WITH BEMPEG PLUS NIVO WERE

DURABLE AND DEEPENED OVER TIME

Stage IV 1L melanoma: ORR 53% with CR 34%

Datacutoff: 1 Sept 2020. aPatient achieved PR in Mar 2018; EoT in Jul 2018; achieved CR in Oct 2018. bPatient achieved PR in Mar 2018; EoT in May 2018 due to patient decision (QoL

issues); achieved CR in May 2018; disease relapse in Sept 2018 due to new lesion (brain).Diab A, et al. SITC 2019; Abstract O35. By permission of Prof A. Diab.

OVERALL STUDY DESIGN CA045-001

PIVOT IO 001: Phase 3

ClinicalTrials.gov. NCT03635983.

Khushalani NI, et al. Future Oncol 2020;16(28):2165–75.

Screening Treatment Follow-up

Population:

• Treatment naïve

(1L setting)

• Unresectable

stage III or stage

IV

Ra

nd

om

isa

tion

1:1

Arm A

NKTR-214

and

Nivolumab

Arm B

Nivolumab

Treat until

RECIST 1.1

progression or

unacceptable

toxicity

Follow-up for

safety, RECIST 1.1

progression, and

survival

Endpoints

Primary:

• ORR by BICR

• PFS by BICR

• OS

FUTURE PERSPECTIVES

MGD019: BISPECIFIC MOLECULE ENGINEERED FOR

CO-BLOCKADE OF PD-1 AND CTLA-4

PD-1 and CTLA-4 are checkpoint molecules with complementary mechanisms of action

Dual blockade has yielded enhanced efficacy with approved agents, albeit with

increased toxicity

MGD019, an investigational DART molecule:

◆ Maintains uncompromised PD-1 blockade vs benchmark mAbs

◆ Blocks both PD-1 and CTLA-4 pathways with potentially enhanced CTLA-4

blockade on dual-expressing cells prevalent in TME

Sharma MR, et al. ESMO 2020; abstract 1020O. By permission of Prof Manish R. Sharma

DART bispecific platform:

◆ Diabody based structure

◆ Flexible design supports various

configurations (e.g. bivalent or

tetravalent)

10-100 fold enhanced activity by MGD019 relative to PD-1/CTLA-4 mAb combination

CTLA-4-NF DEPLETES IMMUNOSUPPRESSIVE TREGS

AND INCREASES T-CELL ACTIVATION

Anti-CTLA-4-NF monoclonal antibody

Non-fucosylated antagonists of CTLA-4

demonstrate increased effector T-cell

activation due to reduced

immunosuppressive Tregs

◆ Non-fucosylated antibodies bind with

high affinity to FcγR, leading to potent

depletion of Tregs by immune-

mediated ADCC

BMS’ CTLA-4-NF antagonistic antibody alone

or in combination with an anti–PD-1 has the

potential for antitumour activity

Korman AJ, et al. Oral presentation at AACR 2017; Abstract SY09-01; Image courtesy of Prof AJ Korman; Simpson TR, et al. J Exp Med. 2013;210(9):1695–710.

By suppressing immune responses

A NEW EMERGING PATHWAY FOR I-O: ADENOSINE

PROMOTES TUMOUR GROWTH

1. Reprinted by permission from Springer Nature, Nat Rev Cancer 2013;13(12):842–57, Immunity, inflammation and cancer: a leading role for adenosine, Antonioli L, et al., Copyright 2013;

2. Reprinted by permission from from Springer Nature, Nat Rev Cancer 2017;17(12):709–24,Targeting immunosuppressive adenosine in cancer, Vijayan D, et al., Copyright 2017.

And promoting tumour cells proliferation,

angiogenesis and metastasis

ADENOSINE: A KEY SUPPRESSOR OF IMMUNE CELLS

IN THE TUMOUR MICROENVIRONMENT

Image: Halozyme Inc. Available at: https://www.halozyme.com/default.aspx?SectionId=aaf28594-4bb3-438d-917b-d720e26fe088&LanguageId=1; accessed April 2021; by permission from Halozyme Inc.

Adapted from Stagg J, Smyth MJ. Oncogene 2010;29:5346–58.

CD73 high (red line) is >38.8 pmol/min/mg protein and CD73 low is <38.8 pmol/min/mg protein (blue line)

PROGNOSTIC VALUE OF SOLUBLE CD73 IN PATIENTS

WITH METASTATIC MELANOMA

Turiello R, et al. J Immunother Cancer 2020;8:e001689. © Author(s) 2020. Reproduced under the tersm of the Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) licence (avalable at:

https://creativecommons.org/licenses/by-nc/4.0/; accessed April 2021).

Nivolumab or pembrolizumab Nivolumab plus ipilimumab

PROGNOSTIC VALUE OF SOLUBLE CD73

In subgroups of patients with metastatic melanoma

Turiello R, et al. J Immunother Cancer 2020;8:e001689. © Author(s) 2020. Reproduced under the terms of the Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) licence (avalable at:

https://creativecommons.org/licenses/by-nc/4.0/; accessed April 2021).

CO-INHIBITION OF CD73 AND A2AR ADENOSINE

SIGNALLING IMPROVES ANTI-TUMOUR IMMUNE RESPONSES

Reprinted from Cancer Cell, 30(3) Young A, et al. Co-inhibition of CD73 and A2AR Adenosine Signaling Improves Anti-tumour Immune Responses/, 391–403. Copyright 2016, with permission from Elsevier.

IDO1 inhibitors

Anti-LAG-3s

HDAC inhibitors

Anti-GITRs



GITR, glucocorticoid-induced TNFR-related protein; HDAC, histone deacetylases; IDO1, indoleamine 2,3-dioxygenase 1; LAG-3, lymphocyte-activation gene 3 Ascierto PA, McArthur JA. J Transl Med 2017;15:173. Reproduced under the terms of the Creative Commons Attribution 4.0 International License(available at: http://creativecommons.org/licenses/by/4.0/; accessed April

2021).

Relatlimab

+

Nivolumab

+

IDO-1i

Relatlimab

+

Nivolumab

+

Ipilimumab

Primary endpoint: Safety, ORR, DCR, mDOR

Secondary endpoint: PFS

• Selected solid tumour types

except primary CNS

tumours

• Subjects naïve to IO

therapy

• IO pretreated including but

not limited to anti-PD-

1/anti-PD-L1/CTLA-4

therapy allowed

• ECOG 0-1

• Melanoma, NSCLC, RCC,

SCCHN, GC/GEJ, will be

enrolled in Parts 1A and 1B

Treatment Clinical Safety

Follow-up

Survival Follow-up

Response Follow-up

Screening

(28 Days)

Safety Follow-up:

ALL Participants

Clinic Visits:

Day 30, 60, 100

after EOT

Survival Follow-up:

ALL Participants

Contact:

Every 3 months

after EOT

RELATLIMAB TOWARDS TRIPLE COMBINATIONS:

CA224-048A Phase 1/2 study of relatlimab administered in combination with both nivolumab and BMS-986205 (IDO1 Inhibitor)

or in combination with both nivolumab and ipilimumab in advanced malignant tumours

ClinicalTrils.gov. NCT 03459222

230 solid tumour patients,

Parallel assignment

EVALUATION OF THE HDACI +ANTI-PD1+ANTI-LAG3

TRIPLE COMBINATION

Hamm S, et al. AACR 2018 Abstract #4722. By permission of Dr Svetlana Hamm; Bretz AC, et al. J Immunother Cancer 2019;7:294.

TRIPLE CHECKPOINT BLOCKADE TARGETING PD-1,

TIM-3, AND LAG-3

Improves T cell reinvigoration and antitumour efficacy over single and double combinations

Kaufmann JK, et al. SITC 2018; Abstract P365.

IL-6 AND CRP AS POSSIBLE BIOMARKERS

Weber J, et al. ASCO 2019. By permission of Prof Jeff Weber.

PHASE 2 TRIAL OF IPI + NIVO + TOCILIZUMAB

IN MELANOMA

Simon design, two-stage study of “flipped dose” IPI + NIVO with IL-6R blocking antibody tocilizumab in first-line

stage IV melanoma; 18 patients in stage I, 49 patients in stage II = 67 total patients

IPI at 1 mg/kg and NIVO at 3 mg/kg X 4 doses then NIVO at 240 mg every 2 weeks X 12 weeks, then NIVO at

480 mg every 4 weeks up to 2 years; TOCI at 4 mg/kg every 6 weeks X 5 total up to week 24

Primary endpoints: reduction in grades 3-4 irAEs to 25% or less, and/or increase ORR to 60% from 45% (seen

in the Checkmate 511 trial)

Secondary endpoints are PFS, duration of response, and correlative endpoints; so far 14 patients treated since

February 2020; finish first stage by end of 2020, and finish second stage by end of 2021/early 2022

ClinicalTrials.gov: NCT03999749. Courtesy of Prof Jeff Weber

◆ ORR by investigator was 36.4% (2 CR, 22 PR)

◆ DCR was 80.3%

◆ Mean time to response was 1.9 months (range: 1.3-5.6)

◆ mDOR was not reached at 17.0 months of median study follow up

LONG-TERM FOLLOW UP OF LIFILEUCEL (LN-144)

Cryopreserved autologous tumour infiltrating lymphocyte therapy in patients with

advanced melanoma progressed on multiple prior therapies

Sarnaik A, et al. Virtual meeting ASCO 2020

Treatment ClinicalTrials.gov Status

CD20 NCT03893019 Recruiting

IL13Ralpha2 NCT04119024 Recruiting

GPA-TriMAR-T NCT03649529 Recruiting

Anti-VEGFR2 NCT01218867 Completed

Anti-GD2 NCT02107963 Completed

Multi-target Gene-

modified CAR-T/TCR-TNCT03638206 Recruiting

B7H3 NCT04483778 Recruiting

Anti-hCD70 NCT02830724 Suspended

CLINICAL TRIALS FOR MELANOMA USING CHIMERIC

ANTIGEN RECEPTORS

Simon B, Uslu U. CAR-T cell therapy in melanoma: A future success story? Exp Dermatol 2018;27:1315–21;

Image adapted from: Zhao Z, et al. Acta Pharmaceutic Sinic B 2018;8(4):539–51. reproduced under the terms of theAttribution-NonCommercial-NoDerivatives 4.0 International license

(CC BY-NC-ND 4.0; available at: https://creativecommons.org/licenses/by-nc-nd/4.0/; accessed April 2021).

CAR-T cell administration

CAR-T cell expansion

T-cell engineering

with tumour-reactive

CAR

Thank you!

Via Mariano Semmola, 80131, Napoli, Italy

Tel. +39 081 5903 431; Fax +39 081 5903 841

Email: [email protected]

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E-Learning Metastatic Melanoma Treatment