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Enriqueta Felip, Vall d’Hebron Hospital
IMMUNOLIQUID BIOPSY
TMB in liquid biopsy as a predictive biomarker for immunotherapy
Near-future approach (patient-based therapy): Genomic profiling by high throughput next generation sequencing for decision-making in individual patients
Next Generation Sequencing (NGS): •Whole Genome or Exome capture Sequencing (DNA) •Whole or Targeted Transcriptome Sequencing (RNA) •Epigenetic profiling
1. Histomorphological Diagnosis:
Cancerous
Evolving approach (target-based therapy V2.0): Multiplexed molecular tests with increased sensitivity
& output for decision-making in individual patients
Current approach (target-based therapy V1.0): Single gene molecular testing for decision-making in
individual patients
2. Molecular Diagnosis:
Multiplex, Hot Spot Mutation Tests: •PCR-based SNapShot •PCR-based Mass Array SNP •Sequenom Initial High-Throughput Technologies: •SNP/CNV DNA microarray •RNA microarray
Single Biomarker Tests: •Sanger DNA Sequencing •RT-PCR •FISH •IHC
Representative technologies:
Extract tumor nucleic acids: Archival cancer
specimens
Archival FFPE tumor specimens
Macro- or Micro-dissection
of Tumors
DNA and RNA
Empiric approach (past) (Compound-based therapy):
Clinical-histologic factors to select drugs for individual patients
Evolution of biomarker testing in NSCLC: past, current & future
Adapted from Li, Gandara JCO 13 Plasma ct DNA by NGS
MSKCC-IMPACT Lung ADENOCARCINOMA
Jordan Cancer Discov 2017
1.3%
Progress in NSCLC in the last 15 years
Immunotherapy in NSCLC
• Essential treatment in 2L / 1L / unresectable stage III
• PDL1 predictive biomarker
• TMB a potential biomarker
immune checkpoints inhibitors typically active in tumours with high TMB
Schumacher & Schreiber Science 15
Nonsynonimous mutations determines sensitivity to pembrolizumab in NSCLC
Rizvi Science 2015
Nivolumab Chemotherapy
47 30 26 21 16 12 4 1 60 42 22 15 9 7 4 1
111 54 30 15 9 7 2 1 1 94 65 37 23 15 12 5 0 0
Nivolumab n = 47 n = 60
9.7 (5.1, NR)
5.8 (4.2, 8.5)
Chemotherapy
Median PFS, months (95% CI)
High TMB P
FS, %
3 6 9 12 15 18 21
No. at Risk Months
100
90
80
70
60
50
40
30
20
10
0 0
Nivolumab
Chemotherapy
0 3 6 9 12 Months
15 18 21 24
Nivolumab
Chemotherapy
100
90
80
70
60
50
40
30
20
10
0
n = 111 n = 94
4.1 (2.8, 5.4)
6.9 (5.5, 8.6)
HR = 1.82 (95% CI: 1.30, 2.55)
Nivolumab Chemotherapy
(95% CI) Median PFS, months
Low/medium TMB
HR = 0.62 (95% CI: 0.38, 1.00)
>240 somatic mutations <100/100- 240 somatic mutations
PFS by tumor mutation burden subgroup CheckMate 026 TMB analysis
Carbone NEJM 17
Total exome mutations vs genes in foundationOne panel CheckMate 026 TMB analysis
100
50
1
FoundationOne Panela, Mutations/MB
Tota
l Exo
me
Mu
tati
on
s, M
uta
tio
ns/
MB
10
50 1 10 100
Carbone NEJM 17
CheckMate 227 part 1 study designa
Database lock: January 24, 2018; minimum follow-up: 11.2 months
N = 1189
<1% PD-L1 expression
N = 550
Nivolumab 3 mg/kg Q2W Ipilimumab 1 mg/kg Q6W
n = 396
Histology-based chemotherapyb
n = 397
Nivolumab 240 mg Q2W n = 396
Nivolumab 3 mg/kg Q2W Ipilimumab 1 mg/kg Q6W
n = 187
Histology-based chemotherapyb
n = 186
Nivolumab 360 mg Q3W + histology-based chemotherapyb
n = 177
R 1:1:1
Key Eligibility Criteria • Stage IV or recurrent NSCLC • No prior systemic therapy • No known sensitizing EGFR/ALK
alterations • ECOG PS 0–1
Stratified by SQ vs NSQ
R 1:1:1
aNCT02477826 bNSQ: pemetrexed + cisplatin or carboplatin, Q3W for ≤4 cycles, with optional pemetrexed maintenance following chemotherapy or nivolumab + pemetrexed maintenance following nivolumab + chemotherapy; SQ: gemcitabine + cisplatin, or gemcitabine + carboplatin, Q3W for ≤4 cycles; cThe TMB co-primary analysis was conducted in the subset of patients randomized to nivolumab + ipilimumab or chemotherapy who had evaluable TMB ≥10 mut/Mb
≥1% PD-L1 expression
Nivolumab + ipilimumab n = 396
Chemotherapyb
n = 397
Patients for PD-L1 co-primary analysis
Co-primary endpoints: Nivolumab +
ipilimumab vs chemotherapy
• OS in PD-L1–selected populations
• PFS in TMB-selected populations
Nivolumab + ipilimumab n = 139
Chemotherapyb n = 160
Patients for TMB co-primary analysisc
Hellmann AACR 18, NEJM 18
TMB and tumor PD-L1 expression identify distinct and independent populations of NSCLC
Tumor PD-L1 expression TMB and tumor PD-L1 expression
PD-L1 expression (%)
TM
B (
nu
mb
er
of
mu
tati
on
s/M
b)
0
20
40
60
80
100
160
120
140
0 20 40 60 80 100
TMB ≥10 mut/Mbb
TMB <10 mut/Mbb
<1%
29% ≥1%
71%
<1%
29% ≥1%
71%
<1%
29% ≥1%
71%
<1%
29% ≥1%
71%
Hellmann AACR 18 , NEJM 18
Is TMB a relevant biomarker for patient selection?
• 95% CI, 95% confidence interval; chemo, chemotherapy; HR, hazard ratio; ipi, ipilimumab; mut/Mb, mutations per megabase; nivo, nivolumab; OS, overall survival; PFS, progression free survival; TMB, tumour mutational burden. 1. Hellmann M.D, et al. NEJM 2018;378:2093-2104; 2. Hellmann M.D, et al. NEJM 2018;378:[suppl] ; 3. Nivolumab Press Release 2018; Figures reproduced from: a, Hellman, et al. 2018; b, Hellman, et al. 2018 [suppl].
No. at Risk Nivo + ipi
Chemo 139 85 66 55 36 24 11 3 0 160 103 51 17 7 6 4 0 0
Pat
ien
ts w
ith
p
rogr
essi
on
-fre
e su
rviv
al (
%)
0 24 15 12 9 6 3 0
50
60
70
80
90
100
40
30
20
10
18 21
Months No. at Risk
Nivo + ipi Chemo
191 92 58 46 31 18 6 1 0 189 122 53 30 17 6 3 0 0
P
rogr
essi
on
-fre
e su
rviv
al (
%)
0 24 15 12 9 6 3 0
50
60
70
80
90
100
40
30
20
10
18 21
Months
Chemotherapy
Nivolumab + ipilimumab
13
43
HR (97.5% CI ) 0.58 (0.41, 0.81) P<0.001
TMB ≥10 mut/Mb TMB <10 mut/Mb
Chemotherapy
Nivolumab + ipilimumab
1-yr PFS=25%
1-yr PFS=17%
October 19, 20183
Updated descriptive analysis: HR for OS with nivolumab + ipilimumab vs. chemotherapy
in patients with TMB ≥10 mut/Mb = 0.77 (95% CI: 0.56, 1.06)
Exploratory analysis in patients with TMB <10 mut/Mb:
HR for OS with nivolumab + ipilimumab vs. chemotherapy = 0.78 (95% CI: 0.61, 1.00)
HR (97.5% CI ) 1.07 (0.84, 1.35) a b
PFS in patients with high TMB (≥10 mut/Mb) by tumor PD-L1 expression
≥1% PD-L1 expression <1% PD-L1 expression
38 20 16 15 10 8 4 1 0
48 30 16 4 1 1 1 0 0
Nivo + ipi (n = 38)
Chemo (n = 48)
Median PFS, mob 7.7 5.3
HR 95% CI
0.48 0.27, 0.85
Chemotherapy
Nivolumab + ipilimumab
Months
0
20
40
60
80
100
0 6 12 18 3 9 15 21 24
1-y PFS = 45%
1-y PFS = 8%
101 65 50 40 26 16 7 2 0
112 73 35 13 6 5 3 0 0
1-y PFS = 42%
1-y PFS = 16%
PFS
(%
)
Chemotherapy
Nivolumab + ipilimumab
Months
0
20
40
60
80
100
0 6 12 18 3 9 15 21 24
Nivo + ipi (n = 101)
Chemo (n = 112)
Median PFS, moa 7.1 5.5
HR 95% CI
0.62 0.44, 0.88
Nivo + ipi
No. at risk
Chemo
a95% CI: nivo + ipi (5.5, 13.5 mo), chemo (4.3, 6.6 mo); b95% CI: nivo + ipi (2.7 mo, NR), chemo (4.0, 6.8 mo) Hellmann AACR 18, NEJM 18
Cristescu et al., Science 362, eaar3593 (2018)
≈ 30% of patients with NSCLC have inadequate tumour tissue for testing at diagnosis (Lim C, et al. Ann Oncol, 2015)
Tumor mutational burden in blood (bTMB) is associated with Atezolizumab efficacy in 2nd-Line+ NSCLC (POPLAR & OAK Trials)
Gandara DR, et al. ESMO 2017. Abstr 1295O.
OAK Study
Gandara DR, et al. bTMB in POPLAR & OAK
Increasing Atezolizumab benefit with higher bTMB cut-points in OAK
BEP, biomarker-evaluable population; ITT, intention-to-treat.
Progression-Free Survival – OAK Overall Survival – OAK
• Enrichment of PFS benefit was observed in the bTMB ≥16 subgroup. • OS was consistent between the bTMB ≥16 subgroup and the BEP • The bTMB ≥16 subgroup represents 27% of the study population
adapted from Gandara et al: NatMed
Gandara DR, et al. bTMB in POPLAR & OAK
LIMITED Overlap between bTMB ≥16 and PD-L1 expressiona (OAK BEP)
a PD-L1 expression was evaluated by immunohistochemistry (IHC) using the VENTANA SP142 assay; TC3 or IC3, ≥50% of TC or ≥10% of IC express PD-L1. BEP, biomarker-evaluable population; IC, tumor-infiltrating immune cell; TC, tumor cell.
• Non-significant overlap between the bTMB ≥16 and TC3 or IC3 subgroups (Fisher exact test, P = 0.62)
– 19.2% of tumors with bTMB ≥16 were also TC3 or IC3
– 29.1% of tumors with TC3 or IC3 also had bTMB ≥16
• Efficacy was greatest in those patients with specimens positive for both PD-L1 TC3 or IC3 plus bTMB ≥16
PFS HR (95% CI)
bTMB ≥16 0.64 (0.46, 0.91)
TC3 or IC3 0.62 (0.41, 0.93)
bTMB ≥16 + TC3
or IC3 0.38 (0.17, 0.85)
Kim et al. B-F1RST Primary Analysis
http://bit.ly/2C2oq6A
Primary analysis
All enrolled patients with at least 6 months of follow-up
Prespecified bTMB biomarker cutoff of 16
Co-Primary Endpoints
Efficacy endpoint: INV-assessed ORR per RECIST v1.1
Biomarker endpoint: INV-assessed PFS per RECIST v1.1
Secondary Objectives
Safety and assessment of efficacy by INV-assessed DOR, OS
20
B-F1RST: Study design
ALK, anaplastic lymphoma kinase. a Staging based on IASLC Lung Cancer Staging Project 8th Edition of the TNM Classification for Lung Cancer. J Thorac Oncol 2015. b Total enrolled, N = 153; however, 1 patient was never treated and was not included in the intent-to-treat population. c Tissue biopsy was optional.
Inclusion Criteria
• Measurable disease per
RECIST v1.1
• ECOG PS of 0 or 1
• Immunotherapy naive
• PD-L1 unselected
• Provision of bloodc
Exclusion Criteria
• Sensitizing EGFR
mutations or ALK
rearrangements
• Active brain metastases
requiring treatment
Patients with stage IIIb-IVaa locally
advanced or metastatic NSCLC
(any histology; N = 152b)
Atezolizumab
1200 mg IV q3w
Until PD, unacceptable
toxicity or loss of
clinical benefit
Kim et al. B-F1RST Primary Analysis
http://bit.ly/2C2oq6A 21
B-F1RST: Patient population
FMI, Foundation Medicine. a Excludes 1 patient who was never treated. b Assay quality-control failures. c The MSAF < 1% population was considered as non–biomarker evaluable (non-BEP).
The biomarker-evaluable population (BEP) included patients
with a baseline evaluable blood sample with adequate tumour
content (i.e., maximum somatic allele frequency [MSAF] ≥ 1%)
to test on the FMI bTMB assay
Enrolled
(N = 153)
ITT a
(n = 152)
bTMB low,
< 16
(n = 91)
bTMB high,
≥ 16
(n = 28)
MSAF
< 1%c
(n = 29)
bTMB not
evaluableb
(n = 4)
BEP
MSAF ≥ 1%
(n = 119)
ITT analysis population enrolled from 20 US regional
and community practice sites
The bTMB cutoff score of 16 was prespecified to
evaluate efficacy (bTMB high, ≥ 16; bTMB low, < 16)
Kim et al. B-F1RST Primary Analysis
http://bit.ly/2C2oq6A 22
Minimum follow-up: 6 months
0%
10%
20%
30%
40%PR CR
14.5%
BEP
(n = 119)
High
(n = 49)
Low
(n = 70)
High
(n = 28)
Low
(n = 91)
High
(n = 19)
Low
(n = 100)
≥ 10 Cutoff ≥ 16 Cutoff ≥ 20 Cutoff
10.1%
16.3%
5.7%
bTMB Subgroups
Ove
rall
Re
sp
on
se
Rate
(%
)
28.6%
4.4%
36.8%
5.0%
ITT b
(N = 152)
P = 0.0595
P = 0.0002
P < 0.0001
B-F1RST: Atezolizumab overall response
ratea per RECIST v1.1
BEP, biomarker-evaluable population. a Confirmed. b ORR in non-BEP population (MSAF < 1%) was 34.5% (n = 29).
Data cutoff: May 21, 2018.
Kim et al. B-F1RST Primary Analysis
http://bit.ly/2C2oq6A 23
B-F1RST: PFS with atezolizumab in bTMB
high (≥ 16) vs low (< 16) subgroups
Data cutoff: May 21, 2018.
≈ 70% of events for PFS
bTMB High
(n = 28)
bTMB Low
(n = 91)
Median PFS 4.6 mo 3.7 mo
90% CI 1.6, 11.0 2.6, 4.3
HR 0.66
90% CI 0.42, 1.02
P value 0.12 9-month PFS
37.4% vs 9.7%
6-month PFS
41.6% vs 32.8%
Kim et al. B-F1RST Primary Analysis
http://bit.ly/2C2oq6A 24
B-F1RST: OS with atezolizumab in bTMB
high (≥ 16) vs low (< 16) subgroups
NE, not estimable.
Data cutoff: May 21, 2018.
bTMB High
(n = 28)
bTMB Low
(n = 91)
Median OS NE 13.1 mo
90% CI 8.8, NE 10.5, NE
HR 0.77
90% CI 0.41, 1.43
P value 0.48
≈ 30% of events for OS
6-month OS
85.3% vs 72.3%
9-month OS
68.1% vs 66.3%
MYSTIC study design
• Phase 3, global, randomised, open-label, multicentre study
Primary endpoints (PD-L1 TC ≥25%*): • PFS‡ (D+T vs CT) • OS (D vs CT) • OS (D+T vs CT) Key secondary endpoints: • PFS‡ (D vs CT; PD-L1 TC ≥25%*) • OS (D+T vs CT; PD-L1 TC ≥1%*) • ORR‡ • DoR • Safety and tolerability
*Ventana PD-L1 (SP263) assay using newly acquired or archival (<3 months) tumour biopsy; †Followed by pemetrexed maintenance therapy if eligible; ‡Blinded independent central review per RECIST v1.1
CT, chemotherapy; D, durvalumab; DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; ORR, objective response rate; PFS, progression-free survival; PS, performance status; q4w, every 4 weeks; T, tremelimumab
R Durvalumab + tremelimumab (n=372)
D 20 mg/kg q4w until disease progression + T 1 mg/kg q4w for up to 4 doses
Platinum-based chemotherapy (n=372) • Paclitaxel + carboplatin OR • Gemcitabine + cisplatin/carboplatin (squamous) OR • Pemetrexed + cisplatin/carboplatin (non-squamous)†
for up to 6 cycles
Durvalumab (n=374) 20 mg/kg q4w until disease progression
Stratified by PD-L1 TC (<25% vs ≥25%*) and histology
• Stage IV NSCLC
• All-comers population (i.e. irrespective of PD-L1 status)
• No sensitising EGFR mutation or ALK rearrangement
• ECOG PS 0/1
• Immunotherapy- and CT-naïve
N=1118 randomised
1:1:1
Mystic trial: OS
MYSTIC TRIAL: BLOOD TMB ANALYSIS
TMB evaluable dataset
Large bTMB dataset: 809 samples (72.4% of patients)
Durvalumab Durvalumab + tremelimumab Chemotherapy
ITT, n (%) 374 (100) 372 (100) 372 (100)
tTMB, n (%) 145 (38.8) 164 (44.1) 151 (40.6)
bTMB, n (%) 286 (76.5) 268 (72.0) 255 (68.5)
• tTMB ≥10 mut/Mb cutoff used to define high TMB in CheckMate 227 for the primary PFS endpoint
• This correlated with a bTMB 16 mut/Mb cutoff in MYSTIC (overall tTMB vs bTMB correlation: rho=0.6)
bTMB ≥16 mut/Mb population bTMB <16 mut/Mb population
Durvalumab (n=175)
Durvalumab + tremelimumab
(n=162) Chemotherapy
(n=153)
mOS, months (95% CI)
12.2 (9.0–15.5)
8.5 (6.6–9.7)
11.6 (9.1–13.1)
HR vs CT* (95% CI)
0.92 (0.715–1.174)
1.23 (0.964–1.575)
–
Durvalumab (n=111)
Durvalumab + tremelimumab
(n=106) Chemotherapy
(n=102)
mOS, months (95% CI)
11.0 (7.8–16.1)
16.5 (10.3–22.9)
10.5 (8.8–12.4)
HR vs CT* (95% CI)
0.80 (0.588–1.077)
0.62 (0.451–0.855)
–
Pro
bab
ility
of
OS
Time from randomisation (months)
Pro
bab
ility
of
OS
Time from randomisation (months)
0.0
0.2
0.4
0.6
0.8
1.0
0 3 6 9 12 15 18 36 30 24 21 33 27 0.0
0.2
0.4
0.6
0.8
1.0
0 3 6 9 12 15 18 36 30 24 21 33 27
No. at risk D 175 138 112 97 85 74 62 55 48 42 17 6 0
D+T 162 128 101 78 57 49 41 34 29 26 12 3 0
CT 153 132 111 90 73 55 46 40 36 29 15 1 0
111 93 75 61 52 47 40 33 32 30 14 3 0
106 83 75 63 58 53 49 43 39 38 20 3 0
102 95 75 61 43 38 28 21 17 16 8 0 0
19%
29%
24%
30%
18%
39%
OS: bTMB subgroups (exploratory analysis)
IMpower133 Presented by Stephen V. Liu 29 Download from http://bit.ly/2CvY9iT
IMpower133: Phase 1/3, randomized, placebo-controlled trial evaluated
atezolizumab + carboplatin + etoposide in 1L ES-SCLC: OS
a Clinical data cutoff date: April 24, 2018, 11 months after the last patient was enrolled. CI, confidence interval; HR, hazard ratio; CP/ET, carboplatin + etoposide.
Atezolizumab
+ CP/ET
(N = 201)
Placebo
+ CP/ET
(N = 202)
OS events, n (%) 104 (51.7) 134 (66.3)
Median OS, months (95% CI)
12.3 (10.8, 15.9)
10.3 (9.3, 11.3)
HR (95% CI) 0.70 (0.54, 0.91)
p = 0.0069
Median follow-up, monthsa 13.9
No. at risk
Atezolizumab 201 191 187 182 180 174 159 142 130 121 108 92 74 58 46 33 21 11 5 3 2 1
Placebo 202 194 189 186 183 171 160 146 131 114 96 81 59 36 27 21 13 8 3 3 2 2
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Months
100
90
80
70
60
50
40
30
20
10
0
Ove
rall
su
rviv
al
(%)
12-month OS
51.7%
38.2%
Atezolizumab
+ CP/ET
Placebo
+ CP/ET
Censored +
IMpower133 Presented by Stephen V. Liu 30 Download from http://bit.ly/2CvY9iT
Median overall survival (months) OS hazard ratioa
(95% CI) Population Atezolizumab + CP/ET Placebo + CP/ET
Male (n = 261) 12.3 10.9 0.74 (0.54, 1.02)
Female (n = 142) 12.5 9.5 0.65 (0.42, 1.00)
< 65 years (n = 217) 12.1 11.5 0.92 (0.64, 1.32)
≥ 65 years (n = 186) 12.5 9.6 0.53 (0.36, 0.77)
ECOG PS 0 (n = 140) 16.6 12.4 0.79 (0.49, 1.27)
ECOG PS 1 (n = 263) 11.4 9.3 0.68 (0.50, 0.93)
Brain metastases (n = 35) 8.5 9.7 1.07 (0.47, 2.43)
No brain metastases (n = 368) 12.6 10.4 0.68 (0.52, 0.89)
Liver metastases (n = 149) 9.3 7.8 0.81 (0.55, 1.20)
No liver metastases (n = 254) 16.8 11.2 0.64 (0.45, 0.90)
bTMB < 10 mut/mb (n = 139) 11.8 9.2 0.70 (0.45, 1.07)
bTMB ≥ 10 mut/mb (n = 212) 14.6 11.2 0.68 (0.47, 0.97)
bTMB < 16 mut/mb (n = 271) 12.5 9.9 0.71 (0.52, 0.98)
bTMB ≥ 16 mut/mb (n = 80) 17.8 11.9 0.63 (0.35, 1.15)
ITT (N = 403) 12.3 10.3 0.70 (0.54, 0.91)
OS in key subgroups
Clinical data cutoff date: April 24, 2018. bTMB (blood tumor mutational burden) assessed as reported in Gandara DR, et al. Nat Med, 2018. a Hazard ratios are unstratified for patient subgroups and stratified for the ITT.
0.1 1.0 2.5
Atezolizumab better Placebo better
BFAST (Blood first assay screening trial): Phase II/III in advanced treatment-naïve NSCLC
• Growing body of evidence that TMB in blood is predictive of immunotherapy efficacy in NSCLC
• TMB and PD-L1 do not significantly overlap
• Preliminary data also suggest a predictive role of TMB in SCLC
• Relevant challenges
– Methodology standardization
– Definition of high/low TMB
– Clinical validation
TMB in liquid biopsy as a predictive biomarker for immunotherapy
