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Lin Li
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OA07 - Immuno-biology and Novel Immunotherapeutics from Bench to Bed (ID 228)
- Event: WCLC 2020
- Type: Oral
- Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
- Presentations: 1
- Moderators:
- Coordinates: 1/30/2021, 10:30 - 11:30, Scientific Program Auditorium
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OA07.06 - Interdependence of KRAS and TP53 Mutations in Predicting ICI Efficacy in EGFR/ALKWT Non-Squamous NSCLC: Results From 1129 Patient-Level Data (ID 691)
10:30 - 11:30 | Presenting Author(s): Lin Li
- Abstract
- Presentation
Introduction
A previous retrospective study in 34 patients with lung adenocarcinoma who had received pembrolizumab monotherapy suggested that KRAS mutation and TP53 mutaiton might predict the progression-free survival (PFS) of immune checkpoint inhibitor (ICI). The extremely small sample size may reduce statistical power and cause serious biases. Therefore, we hereby interrogate the inter-relation between TP53 and KRAS mutations by meta-cohort analysis involving 8 cohorts of 1129 patient-level data.
Methods
We retrospecively collected the clinical and mutational data of the patients with EGFR/ALKWT non-squamous NSCLC receiving ICI treatment (the 3DMed cohort, n=37). In addition, another 7 public cohorts (SNCC, Van Allen, Rizvi-34, Rizvi-240, MSKCC-75, MSKCC-350, and POPLAR/OAK) involving 1092 patient-level data were included to comprehensively explore the impact of KRAS/TP53 mutations on the immunotherapeutic benefit, including objective response rate (ORR), PFS, and overall survival (OS).
Results
In the overall population, higher ORR was linked with KRAS/TP53 mutation, while longer PFS was merely associated with the mutation in TP53 (HR 0.72, 95%CI 0.55-0.95, P=0.019), but not KRAS (P=0.295). It is of great interest that the beneficial effect of each mutation was based on the mutation of the other one. TP53 mutation brought improvement of ORR and PFS in patients with KRAS mutation (ORR, p=0.002; PFS, p<0.001), but not KRAS-WT population (ORR, p=0.104; PFS, p=0.566). Conversely, KRAS mutation was associated with better ORR and PFS in TP53-mut (ORR, p=0.011; PFS, p=0.017), but not TP53-WT population (ORR, p=0.518; PFS, p=0.885). We further investigated the predictive efficacy of the co-mutation of TP53 and KRAS, and observed remarkably improved ORR (2.59-fold, P0.001) and PFS (HR 0.47, 95%CI 0.32-0.68, P=0.001) n co-mutated patients.
Table 1. Pooled estimate from 8 cohorts involving 1129 patient-level data with non-squamous NSCLC receiving immunotherapy
ConclusionTotality
Variable
ORR
PFS
OS
RR (95%CI)
P
HR (95%CI)
P
HR (95%CI)
P
All
TP53-mut vs. TP53-WT
1.94 (1.31-2.87)
0.001
0.72 (0.55-0.95)
0.019
1.21 (0.98-1.50)
0.071
All
KRAS-mut vs. KRAS-WT
1.54 (1.02-2.32)
0.040
0.82 (0.56-1.19)
0.295
1.01 (0.70-1.47)
0.947
KRAS-mut
TP53-mut vs. TP53-WT
2.86 (1.46-5.57)
0.002
0.47 (0.32-0.68)
0.001
0.75 (0.51-1.12)
0.159
KRAS-WT
TP53-mut vs. TP53-WT
1.53 (0.92-2.56)
0.104
0.91 (0.65-1.27)
0.566
1.47 (1.14-1.91)
0.003
TP53-mut
KRAS-mut vs. KRAS-WT
1.98 (1.17-3.35)
0.011
0.66 (0.47-0.93)
0.017
0.73 (0.51-1.04)
0.078
TP53-WT
KRAS-mut vs. KRAS-WT
1.28 (0.61-2.71)
0.518
1.04 (0.60-1.79)
0.885
1.19 (0.79-1.77)
0.338
All
TP53/KRAS-co-mut vs. the rest
2.59 (1.63-4.12)
0.001
0.58 (0.43-0.79)
0.001
0.86 (0.62-1.18)
0.356
8 immunotherapeutic cohorts of 1129 patient-level data demonstrate the predictive effect on ICI efficacy of KRAS or TP53 mutation is based on the existence of the other. Co-mutation of KRAS and TP53 is identified as a potential immunotherapeutic predictor of better ORR and PFS in patients with EGFR/ALKWT non-squamous NSCLC.
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P14 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) - Immuno-Biology (ID 153)
- Event: WCLC 2020
- Type: Posters
- Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P14.07 - Clinically Predictive Value of Plasma Cell-Free DNA in Lung Cancer Immunotherapy (ID 1716)
00:00 - 00:00 | Presenting Author(s): Lin Li
- Abstract
Introduction
Anti-programmed cell death protein 1 (PD-1) and anti-programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) has provided clinical benefit for lung cancer (LC). Plasma cell-free DNA (cfDNA) could be used to characterize the genomic profiles of LC. Here, we examined cfDNA to explore mutational features related to the effectiveness of immunotherapy for LC.
Methods
Patients with advanced LC, including lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung carcinoma (SCLC), were enrolled and treated by immunotherapy or immunotherapy plus chemoradiotherapy. The best response was evaluated according to RECIST 1.0. Baseline plasma samples were collected before treatment. Next-generation sequencing (NGS) was performed on plasma cfDNA using a 1021-gene-panel. Blood-based tumor mutation burden (bTMB) was assessed. Cancer-related signaling pathways were compared.
Results
We collected 27 LCs receiving immunotherapy (n=21) and immunotherapy plus chemoradiotherapy (n=6). Of these, 8 patients (7 smokers) were LUADs, 12 were (10 smokers) LUSCs, 4 (4 smokers) were LCNECs, and 3 were (1 smoker) SCLCs. 6, 9, and 7 patients had partial response (PR), stable disease (SD), and progressed disease (PD), while 5 had not reach best response. Each patient was detected with at least one somatic mutation, with a median bTMB of 7.68 mutations/Mb (from 0.96 to 41.28). The most common mutated genes were TP53 (78%), LRP1B (26%), RB1 (22%), ERBB4 (19%), and FANCM (15%). LRP1B mutant patients showed high proportion (5/7) of PR/SD, as well as FANCM (3/4) (a gene included in DNA damage repair pathway), suggesting their potentially ICI sensitive genotype. NOTCH pathway was increased in PR/SD group, although with no statistical differences due to the small size cohort, indicating the probably ICI sensitive relationship. Higher mutational prevalence of RTK RAS, PIK, cell cycle, and MYC pathways might relate to ICI resistance. Interestingly, LRP1B and FANCM might be mutually exclusive each other but co-altered with TP53 mutations, respectively. TP53 co-mutation affected 100% LRP1B and 100% FANCM. TP53/LRP1B and TP53/FANCM co-altered patients were found with higher bTMB than TP53/LRP1B and TP53/FANCM wild-type (median 13.44 vs. 6.72, Mann-Whitney test, p = 0.0058), suggesting their involvement of biological processes associated with tumor neoantigen production. Higher bTMB of the two type of co-mutant LCs were validated in the POPLAR / OAK cohort.
Conclusion
TP53/LRP1B and TP53/FANCM co-mutations were associated with high bTMB and ICI response rate. Genomic profiling by plasma cfDNA showed high clinically predictive potential in lung cancer immunotherapy.
