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Martina I. Lefterova
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MA25 - Precision Medicine in Advanced NSCLC (ID 352)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:Sebastian Defranchi, Karen Kelly
- Coordinates: 9/10/2019, 14:30 - 16:00, Dublin (1997)
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MA25.04 - Blood-Based Tumor Mutation Burden as a Predictive Biomarker for Outcomes After Pembrolizumab Based First Line Therapy in Metastatic NSCLC (Now Available) (ID 2717)
14:30 - 16:00 | Author(s): Martina I. Lefterova
- Abstract
- Presentation
Background
PD-1 blockade with pembrolizumab (P) as monotherapy in patients with PD-L1 TPS > 50% or in combination with platinum based chemotherapy (PC) is the current standard front-line therapy for metastatic non-small cell lung cancer (mNSCLC). We explored the correlation of blood (b) based tumor mutational burden (TMB) using circulating tumor DNA (ctDNA) with outcomes after front line P and PC therapy.
Method
Patients with newly diagnosed metastatic NSCLC starting standard of care front line P-based therapy were enrolled. Plasma was prospectively collected at baseline prior to initiation of P or PC therapy for mNSCLC. A 2.145 megabase (Mb) next-generation sequencing panel was used to assess bTMB. A bTMB cutoff of ≥16 mut/Mb was selected based on previously published data (Gandara et al, Nature 2018). Response was assessed using RECIST 1.1. Durable clinical benefit (DCB) was defined as complete response/ partial response/ stable disease that lasted > 6 months. Correlations were made for patient demographics, tumor characteristics, DCB, progression free survival (PFS), and overall survival (OS) using logistic regression and Cox proportional hazards models. Significance was determined at the 0.05 level.
Result
66 pts with mNSCLC were enrolled, median age 67 years (range 47-89), current or ex-smokers (n=61, 92%). Thirty-one patients (47%) received P (all PD-L1>50%); 35 received platinum-pemetrexed based PC. At the time of data cut off, median OS for P was 14.8 months, and not reached for PC. bTMB was evaluable for 52 patients (n=26 P, 26 PC), median bTMB was 16.8 mutations per Mb (mut/Mb, range 1.9-52.5). There was no correlation between bTMB and tumor PD-L1 (p=0.28). Median bTMB for patients achieving DCB was higher than for those with no clinical benefit, 21.3 mut/Mb vs. 12.4 mut/Mb, p=0.004. For patients with bTMB ≥ 16 mut/Mb, median PFS was 13.8 vs. 4.7 months for patients with bTMB <16 mut/Mb (HR 0.27 [0.13-0.55]). Median OS was not reached for bTMB ≥ 16 mut/Mb (HR 0.47 [0.20-1.1]). Loss of function mutations in STK11, KEAP1, or PTEN, or ERBB2 exon 20 insertion were enriched in patients with no clinical benefit. Combined score using bTMB ≥ 16 mut/Mb and mutations in STK11, KEAP1, or PTEN, or ERBB2 exon 20 insertions resulted in improved prediction for DCB; PFS HR of 0.18 [0.08-0.41] and OS HR of 0.27 [0.10-0.73].
Conclusion
Our early results suggest that bTMB using plasma ctDNA may predict therapeutic outcomes after first line P-based therapy in mNSCLC. Loss of function mutations in STK11/KEAP/PTEN and ERBB2 exon 20 insertion mutations appear to be negative predictors of benefit. As the sample size is limited and findings are reported on a pooled group of P and PC patients, the role of bTMB and response to P and PC based therapy separately should be validated in a larger prospective study.
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P1.04 - Immuno-oncology (ID 164)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.04-47 - Tumor Mutation Burden Through Hybrid Capture – Circulating Tumor DNA May Predict Response to Immunotherapy in NSCLC (ID 3011)
09:45 - 18:00 | Author(s): Martina I. Lefterova
- Abstract
Background
Immunotherapy has become the therapy backbone for patients with NSCLC. Currently, prediction to therapy response is based on tissue biopsy biomarkers such as PD-L1 expression, tumor mutation burden (TMB), genomic alterations in EGFR/ALK/ROS1 and KRAS/TP53/STK11 mutations, all competing for limited tissue biopsy samples. Therefore, we investigated whether these biomarkers can be detected from a non-invasive plasma sample. Challenges of assessment of TMB with cell-free DNA next-generation sequencing (NGS) include the limited size of liquid biopsy gene panels and the fact that low shedding of tumor DNA into circulation may fail to detect hypermutated tumors.
Method
In this retrospective study, data was collected from 100 NSCLC patients treated in medical centers in Israel and USA between 2014 and 2018. NGS on ctDNA was used to evaluate whether mutational burden influence the response to immunotherapy in these patients. Response to immunotherapy was defined by a cutoff of four months of progression free survival (PFS). Liquid biopsy tests were obtained three months or less before immunotherapy treatment start.
Result
Overall, 100 NSCLC patients underwent NGS on ctDNA.
Clinical treatment information and full clinical data was available for 66 patients. 23 patients underwent liquid biopsy tests within a range of 3 months or less before immunotherapy initiation. 9 patients were considered responders and 14 patients progressors by a cutoff of 4 months PFS. Preliminary results showed that in the group of responders, the median TMB was 5 with a standard deviation of 5.49. An average TMB of 2.3 was calculated for the group of progressors with a standard deviation of 1.44.
ctDNA signature will be further presented based on a 73-gene ctDNA NGS panel that adjusts for the degree of tumor shedding.
Conclusion
ctDNA collection was feasible in 66 patients, amongst which 23 underwent liquid biopsy testing 3 months or less before immunotherapy treatment initiation. As the preliminary data is promising on this pilot cohort, we are planning on expending the cohort study and presenting a complex analysis that includes multifactorial mutation load approach that integrates TMB and prediction to immunotherapy response.
