E-Learning Metastatic Melanoma Treatment
Transcript of 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.
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.
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.
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.
Citation of data without the intention of direct or indirect comparison in the absence of head-to-head clinical trials
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
Citation of data without the intention of direct or indirect comparison in the absence of head-to-head clinical trials
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%
1-yr rate 2-yr rate 3-yr rate 4-yr rate
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
Citation of data without the intention of direct or indirect comparison in the absence of head-to-head clinical trials
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
Citation of data without the intention of direct or indirect comparison in the absence of head-to-head clinical trials
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
1-yr rate 2-yr rate 3-yr rate 4-yr rate
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
1-yr rate 2-yr rate 3-yr rate 4-yr rate
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
Citation of data without the intention of direct or indirect comparison in the absence of head-to-head clinical trials
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
Median duration of exposure:
12.2 months
CoBRIM
vemurafenib/cobimetinib
Median duration of exposure:
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
Citation of data without the intention of direct or indirect comparison in the absence of head-to-head clinical trials
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
PROGRESSION-FREE SURVIVAL
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)
PROGRESSION-FREE SURVIVAL
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
IS THERE A PATIENT SUBGROUP WHERE COMBINATION
THERAPY MAY HAVE GREATER CLINICAL BENEFIT?
Patient history
(eg, autoimmune disease)
Performance status
tumour burden
Organ system function,
especially cardiac function
Patient’s wishes and
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
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.
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
Massachusetts Medical Society.
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
Massachusetts Medical Society.
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)
NIVO+IPI vs NIVOa: 0.83 (0.62‒1.12)
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)
NIVO+IPI vs NIVOa: 0.82 (0.59‒1.13)
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)
NIVO+IPI vs NIVOa: 0.77 (0.56‒1.05)
21%22%
NIVO+IPI NIVO IPI
HR
0.76 HR
0.77
HR
0.83
HR
0.82
IS THERE A PATIENT SUBGROUP WHERE COMBINATION
THERAPY MAY HAVE GREATER CLINICAL BENEFIT?
Patient history
(e.g., autoimmune disease)
Performance status
tumour burden
Organ system function,
especially cardiac function
Patient’s wishes and
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
Massachusetts Medical Society.
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)
NIVO+IPI vs NIVOa: 0.76 (0.55‒1.04)
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)
NIVO+IPI vs NIVOa: 0.74 (0.49‒1.11)
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)
NIVO+IPI vs NIVOa: 0.87 (0.60‒1.27)
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 vs NIVOa: 0.87 (0.58‒1.32)
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.
IS THERE A PATIENT SUBGROUP WHERE COMBINATION
THERAPY MAY HAVE GREATER CLINICAL BENEFIT?
Patient history
(e.g., autoimmune disease)
Performance status
tumour burden
Organ system function,
especially cardiac function
Patient’s wishes and
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)
SEQUENTIAL COMBO IMMUNO AND TARGET THERAPY
(SECOMBIT): BORR
Ascierto PA, et al. Presented at ESMO 2020 Abstract Number LBA#2621. By permission of Prof PA Ascierto.
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.
SEQUENTIAL COMBO IMMUNO AND TARGET THERAPY
(SECOMBIT): SAFETY OVERVIEW
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)
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
loco-regional treatment
Potential
combinations
POTENTIAL COMBINATION STRATEGIES FOR THE
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.
Dabrafenib + trametinib
+ spatalizumab
Vemurafenib + cobimetinib
+ atezolizumab
Dabrafenib + trametinib
+ pembrolizumab
Dabrafenib + trametinib
+ 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
PROGRESSION-FREE SURVIVAL
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
Citation of data without the intention of direct or indirect comparison in the absence of head-to-head clinical trials
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)
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
Citation of data without the intention of direct or indirect comparison in the absence of head-to-head clinical trials
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
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
Citation of data without the intention of direct or indirect comparison in the absence of head-to-head clinical trials
OS FROM KEYNOTE-022, IMSPIRE 150 AND COMBI-I
(CONTROL 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
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%
Citation of data without the intention of direct or indirect comparison in the absence of head-to-head clinical trials
OS FROM KEYNOTE-022, IMSPIRE 150 AND COMBI-I
(CONTROL 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
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%
Citation of data without the intention of direct or indirect comparison in the absence of head-to-head clinical trials
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
Ascierto P. ESMO Educational Session 2020. By permission of Prof P Ascierto.
Ferrucci P, et al. SMR 2019; Gutzmer et al. Lancet 2020; Nathan P, et al. ESMO 2020
Citation of data without the intention of direct or indirect comparison in the absence of head-to-head clinical trials
DO WE REALLY NEED A TRIPLET COMBO…?
OS FROM KEYNOTE-022, IMSPIRE 150 AND COMBI-I
(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
Citation of data without the intention of direct or indirect comparison in the absence of head-to-head clinical trials
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
OS FROM KEYNOTE-022, IMSPIRE 150 AND COMBI-I
(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
Citation of data without the intention of direct or indirect comparison in the absence of head-to-head clinical trials
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
loco-regional treatment
Potential
combinations
POTENTIAL COMBINATION STRATEGIES FOR THE
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
loco-regional treatment
Potential
combinations
POTENTIAL COMBINATION STRATEGIES FOR THE
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.)
NEW EMERGING PATHWAYS FOR FUTURE
COMBINATION WITH ANTI-PD-1/PD-L1 COMPOUNDS
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
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 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]