TMB in liquid biopsy as a predictive biomarker for ... · BEP, biomarker -evaluable population;...
Transcript of TMB in liquid biopsy as a predictive biomarker for ... · BEP, biomarker -evaluable population;...
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Enriqueta Felip, Vall d’Hebron Hospital
IMMUNOLIQUID BIOPSY
TMB in liquid biopsy as a predictive biomarker for immunotherapy
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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
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MSKCC-IMPACT Lung ADENOCARCINOMA
Jordan Cancer Discov 2017
1.3%
Progress in NSCLC in the last 15 years
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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
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Nonsynonimous mutations determines sensitivity to pembrolizumab in NSCLC
Rizvi Science 2015
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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
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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
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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
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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
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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
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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
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Cristescu et al., Science 362, eaar3593 (2018)
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≈ 30% of patients with NSCLC have inadequate tumour tissue for testing at diagnosis (Lim C, et al. Ann Oncol, 2015)
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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
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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
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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)
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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
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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)
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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.
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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%
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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%
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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
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Mystic trial: OS
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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)
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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)
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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 +
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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
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BFAST (Blood first assay screening trial): Phase II/III in advanced treatment-naïve NSCLC
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• 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