efficacy of tkis based on the alk resistance mutations on ......single alk 7% complex alk 4% alk +...
TRANSCRIPT
Single ALK 7%
Complex ALK 4%
ALK + others 11%
Others 30%
None 48%
None
Other mutations
Complex ALK
Single ALK
Efficacy of TKIs based on the ALK resistance mutations on amplicon-based liquid biopsy in ALK positive Non-Small Cell Lung Cancer (NSCLC) patients
L Mezquita1*, A Swalduz2*, C Jovelet1, S Ortiz-Cuaran2, D Planchard1, G Recondo3, JC Benitez1, K Howarth4, F de Kievit4, C Morris4, E Green4, L Lacroix5, L Odier6, E Rouleau5, P Fournel7,
C Caramella8, C Tissot9, C Nicotra10, M Pérol2, C Massard10, L Friboulet3, B Besse1+, P Saintigny2+
* L.M. and A.S. and + P.S. and B.B. contributed equally to this work. 1 Medical Oncology Department, Gustave Roussy, Villejuif, France; 2 Medical Oncology Department, Centre Léon Bérard Lyon,France ; 3 INSERM U981, Gustave Roussy, Université Paris Saclay, Villejuif, France; 4 Inivata, Cambridge UK, Cambridge/United Kingdom; 5 Biopathology Department, Gustave Roussy, Villejuif, France ; 6 Department of Pneumology, Hôpital Nord-Ouest Villefranche, Villefranche Sur Saône/France; 7 Department of Medical Oncology, Institut de Cancérologie de la Loire, St. Priest En Jarez/France ; 8 Radiology Department, Gustave Roussy, Villejuif, France; 9 Department of Pneumonology and Thoracic Oncology,
CHU Nord Saint-Etienne, Saint-Priest-en-Jarez/France; 10 Early Drug Development Department, Gustave Roussy, Villejuif, France.
§ Acquired ALK resistance mutations (mut.) are the main mechanism of tyrosine kinase inhibitor (TKI) resistance (30-50%)
§ While next-generation TKIs are more active on mut. than earlier TKIs, compound ALK resistance are associated with failure to next-generation TKIs
§ Advanced ALK NSCLC patients were prospectively enrolled from October 2015 to April 2018 across 9 French institutions
§ All patients were ALK positive by an approved molecular diagnostic test: immunochemistry (IHC) or Fluorescent In Situ Hybridization (FISH) using dual-color break-apart rearrangement probes and/or other validated test
§ ctDNA molecular analysis was performed using amplicon-based NGS (InVision® liquid biopsy platform, InVisionFirst®-Lung) for ALK (EML4 variants v1, v2, v3), ROS1 (CD74, SLC34A2, SDC4 and EZR) fusions, and other somatic mutations
§ A total of 20 to 30 ml of blood were collected in Streck BCT or EDTA tubes and processed for DNA extraction
§ Correlation with clinical outcomes: overall survival (OS) and progression-free survival (PFS) to the current and subsequent TKIs
§ ctDNA genomic alterations were stratified as: - Negative ctDNA, if no mutation detected - ALK mut. group:
ü Single ALK mut., if one ctDNA ALK mut. ü Complex ALK mut., if ≥ 2 ctDNA ALK mut.
- Other mut.: if ctDNA non-ALK mut.
INTRODUCTION
©2018 Inivata Ltd. ©2018 Inivata Ltd.
REFERENCES 1. Gainor JF, Dardaei L, Yoda S, Friboulet L, Leshchiner I, Katayama R, et al. Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer. Cancer Discov. 2016 Jul 18;
2. Yoda S, Lin JJ, Lawrence MS, Burke BJ, Friboulet L, Langenbucher A, et al. Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound ALK Mutations in ALK-Positive Lung Cancer. Cancer Discov. 2018 Jun;8(6):714–29. 3. J Remon, L Lacroix, C Jovelet, C Caramella, et al. Real-World Utility of an Amplicon-Based Next-Generation Sequencing Liquid Biopsy for Broad Molecular Profiling in Patients With Advanced Non–Small-Cell Lung Cancer. JCO Precision Oncology 2019 :3, 1-14
Figure 1. The InVisionFirst™-Lung assay identifies SNVs, indels, CNVs and gene fusions with whole gene and gene hotspots, using an amplicon-based technology to selectively amplify genomic breakpoints. The sequence of the junctions are then identified using NGS, allowing the genomic breakpoint in ctDNA to be mapped4
Poster Board Number: P.47 (Abstract 3055)
§ We evaluated the clinical utility of detecting ALK resistance mut. in blood (ctDNA) to predict TKI efficacy
METHODS
RESULTS
CONCLUSIONS
§ 101 ALK positive patients were enrolled in the study, with 328 blood samples collected. Of these, 74 samples were at progression (PD) to TKIs, from 55 patients)
§ Routine liquid biopsies can assess the heterogeneity of the TKI resistance, detecting ALK resistance and other acquired mutations in pretreated advanced ALK positive NSCLC patients
§ The absence of ctDNA mutations at TKI failure was associated with prolonged OS, whereas complex ALK mutations at TKI failure may predict resistance to subsequent therapy
§ These results will be validated in a larger cohort in the future
Table 1. Baseline characteristics of patients at PD to TKI therapy
§ Median follow-up (FU) from 1st liquid biopsy was 9.9 mo. [95%CI, 1.0-30.1]. The median PFS to the therapy to which the patients progressed (“current” therapy) was 9.6 mo [95%CI, 7.9-11.8]
§ No differences were observed in PFS to current therapy by ctDNA mutations detected (P=0.31)
Figure 2. Distribution of ctDNA mutations at PD
§ The median PFS to the subsequent therapy was 7.3 mo. [95%CI, 4.6-20.7]
§ The ALK complex mut. group had median PFS of 1.7 mo. [95% CI, 0.9-NR] vs. 6.3 mo. [95% CI, 1.8-NR] in the ALK single mut. group (P=0.003)
§ In the 4 cases with emergence of ALKG1202R PFS to the sequential therapy was 3.7 mo. [95% CI, 1.2-NR]
OBJECTIVE
PFS, CURRENT therapy based on ctDNA ALK mut.
Figure 5. OS according the presence of ctDNA ALK resistance mut.
N=8 N=1
N=1
N=1
OVERALL SURVIVAL (OS) by ctDNA resistance mutations PFS, SUBSEQUENT therapy based on ctDNA ALK mut.
0
10
20
30
40
50
60
70
80
90
100
Crizotinib 2nd gen TKI Next-gen TKI
None Others ALK + others Complex ALK Single ALK
Figure 3. Distribution of ctDNA mutations at PD according to the previous TKI
§ Higher incidence of ALK mut. after 3rd -gen TKI (43%) vs. 2nd-gen (29%) vs. crizotinib (11%)
None
ALK mutation
Other mutations
Single ALK 7%
Complex ALK 4%
NFE2L2 + NFE2L2 + NFE2L2 + NFE2L2 +
Complex ALK 1%
TP53+ TP53 + TP53 + Complex ALK
1%
TP53 + Complex ALK 1%
TP53 + MYC + Complex ALK 1%
TP53 + Complex ALK 1%
TP53 + Single ALK 3%
TP53+KRAS+PI3KCA 1%
TP53+PTEN+PI3KCA 3%
TP53 + MYC 1%
TP53+STK11 1%
TP53 19%
GNAS 1%
CKN2A 1%
MET 1%
None 49%
Table 4. Clinical efficacy of TKIs according to the ALK resistance mutations in blood. Green: mPFS to subsequent therapy ≥ 6 mo.; orange: mPFS between 3-6 mo.; red: mPFS < 3 mo.;
✓ : patient has previously received this TKI; ** : de novo mutations (in blood); - fusion not detected/not tested.
ALK & non- ALK mutations
§ The median OS from 1st line beginning was 100.4 months (mo.) [95% CI 51.3-not reached-NR-]
§ The median OS was 105 mo. [95%CI 105.7-NR] if negative ctDNA vs. 58.5 mo. [95%CI 26.9-NR] if ≥1 ALK mut.(s) vs. 44.1 mo. [95%CI 21.7-NR] if non-ALK mut.
§ This effect was observed regardless of the number of lines of TKI received (P=0.01)
§ The presence of complex ALK mut. was associated with poor OS [median 26.9 mo.; (95% CI13.9-NR)] compared to single ALK mut. [median NR; (95% CI 57.0-NR)] (P=0.003)
§ 74 samples were collected at PD to TKIs
§ ALK mut. in 22% (16/74)
ü 9, ALK single mut. - 5 ALK mut. only - 4 ALK mut. + others
ü 7, ALK complex mut. - 3 complex ALK only - 4 complex ALK + others
N=16 N=31 N=7
Figure 4: Distribution of ctDNA non- ALK mutations and at PD to TKIs.
N=55 patients (74 samples)
P=0.009
P=0.003
OS
OS
Median PFS to current therapy
All population 9.6 mo. [95%CI 7.9-11.8]
Negative ctDNA 14.8 mo. [95% CI, 8.1-23.1]
≥1 ALK mut. 9.6 mo. [95% CI, 6.6-19.9]
Non-ALK mut. (other) 7.8 mo. [95% CI, 4.5-11.7] Table 3:
Progression-free survival to current TKI therapy (n=74 samples)
§ We explored it specifically in the subgroup with ctDNA ALK mut. (n=16 samples)
ctDNA mutations
Time point ctDNA mutations
ctDNA mutations
De novo ALK mutations*
N#1 CTC925
Post CRIZOTINIB
Single ALK* ALKL1196M TP53
ALKL1196M
N#2 G-A-01-034
Post ALECTINIB
Single ALK* ALKC1156Y ALKC1156Y
N#3 CTC534
Post CERITINIB
Single ALK ALKT1151R TP53
NA
N#4 R-C-01-020
Single ALK ALKF1174L NA
N#5 CTC435
Single ALK ALKG1202R NA
N#6 L-Y-01-045
Post BRIGATINIB
Single ALK ALKF1174V NA
N#7 B-B-01-127
Single ALK* ALKR1192P TP53
ALKR1192P
N#8 CTC861
Single ALK ALKG1202R
-
N#9 CTC1342
Single ALK* ALKG1202R TP53
ALKG1202R
N#10 CTC861
Post CRIZOTINIB
Complex ALK* ALKG1202R ALKI1268V
ALKG1202R ALKI1268V
N#11 B-B-01-127
Complex ALK* ALKL1196M ALKC1156Y
TP53
ALKL1196M ALKC1156Y
N#12
CTC1105
Complex ALK*
ALKF1174L ALKF1174L ALKL1196Q ALKC1156Y ALKG1269A ALKR1264K NFE2L2(x4)
ALKF1174L ALKF1174L ALKL1196Q ALKC1156Y ALKG1269A ALKR1264K
N#13
R-C-01-020 Post
BRIGATINIB
Complex ALK*
ALKG1202R ALKF1174L
TP53
ALKG1202R
N#14 R-C-01-020
Post LORLATINIB
Complex ALK ALKG1202R ALKF1174L
-
N#15 CTC861
Complex ALK*
ALKG1202R ALKF1174L ALKC1156Y ALKG1269A ALKS1206F ALKT1151M
ALKF1174L ALKC1156Y ALKG1269A ALKS1206F ALKT1151M
N#16 L-Y-01-045
Complex ALK*
ALKF1174V ALKL1198F
TP53 MYC
ALKL1198F
!
Table 2: Distribution of ctDNA ALK mut. at PD to TKIs (n=16)
Characteristics Patients included, N=55 (%)
Age, Median (year-old), range 56 (20-82) Sex Female
29 (53%) Smoking status Never Smoker
30 (55%) 23 (42%)
Histology Adenocarcinoma
54 (98%) Stage at diagnosis I-IIIA IIIB-IV
2 (4%) 53 (96%)
Brain metastasis at baseline 19 (36%) Molecular diagnosis FISH (+) IHC (+) Other (+)
34 (49%) 34 (49%)
1 N# prior systemic lines at inclusion Median, range
3 (1-8)
Patients
PD Sites
Variant
Time point
ALK resistance
mutations
ALK
G1202R
Crizotinib
Alectinib
Ceritinib
Brigatinib
Lorlatinib
Chemo
CTC861 Liver
V3
Post CRIZOTINIB
Complex ALK**
G1202R ✓
- - -
-
CTC 1105 Bone
V3
Complex ALK**
✓ - - -
-
BB 01-127 Adrenal Brain, Liver
V2
Complex ALK**
✓ - - -
-
RC01-020 Brain Bone
- Post BRIGATINIB
Complex ALK**
G1202R ✓ - ✓ ✓
-
LY 01-045 Brain, Lung, Nodal, Pleural
-
Post LORLATINIB
Complex ALK**
✓ - ✓ ✓ ✓
RC01-020 Brain - Complex ALK
G1202R ✓ - ✓ ✓ ✓
CTC861 Liver V3
Complex ALK
G1202R ✓ - ✓ ✓ ✓
CTC 925 Nodal
-
Post CRIZOTINIB
Single ALK**
✓ - - - -
CTC 435 Pleural
V3
Post CERITINIB
Single ALK
G1202R ✓
- ✓ - -
CTC 534 Liver - Single ALK ✓ - ✓
-
-
RC01-020 Brain - Single ALK ✓ - ✓
-
-
GA 01-034 Brain - Post ALECTINIB
Single ALK ** ✓ ✓ - - -
LY 01-045 Brain, Lung, Nodal
-
Post BRIGATINIB
Single ALK
✓ - ✓ ✓
-
CTC861 Liver
V3
Single ALK **
G1202R ✓ - ✓ ✓ -
CTC 1342 Bone
V3
Single ALK **
G1202R ✓
- ✓ ✓
-
BB 01-127 Brain Liver
V2
Single ALK **
✓ - ✓ ✓
-
!
3rd-gen TKI
N=56 samples