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Rebecca Nagy
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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): Rebecca Nagy
- 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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P1.03 - Biology (ID 161)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.03-31 - BRAF Mutations: Classes I, II and III in NSCLC Patients Included in the SLLIP Trial, Targeted Treatment According to Class (Now Available) (ID 897)
09:45 - 18:00 | Author(s): Rebecca Nagy
- Abstract
Background
BRAF V600 mutations have been found in 2% of non-small cell lung cancer (NSCLC) patients, with FDA approved treatment of dabrafenib plus trametinib and progression free survival (PFS) of 10.9 months. However, 50-80% of BRAF mutations in lung cancer are non-V600, and can be class 2, with intermediate to high kinase activity and RAS independence, or class 3, with impaired kinase activity, upstream signaling dependence and consequently sensitivity to receptor tyrosine kinase (RTK) inhibitors. Non-V600 tumors require combinatory therapy with RAF/MEK inhibitors and blockers of RTK signaling, like SHP2 (PTPN11) inhibitors.
Method
Plasma DNA of 185 newly diagnosed advanced lung adenocarcinoma patients was examined for BRAF and other mutations with a clinically validated cell-free DNA (cfDNA) assay (Guardant360, Guardant Health Inc. CA, U.S), and results were correlated with patient outcome. In addition, two NSCLC cell lines and one Triple Negative Breast Cancer (TNBC), H1395 (class 2 BRAF mutation), H1666 (class 3 BRAF mutation) and MDA-MB-231 (class 2 BRAF mutation) were treated with single or combined BRAF, MEK and SHP2 inhibitors and cell viability was assessed.
Result
BRAF mutations were found in 17/185 (9%) and BRAF amplification in five patients (3%). Three patients had BRAF V600E mutations (2%) and 14 patients non-V600 BRAF mutations (8%), including four class 2 and four class 3 mutations. Patients were treated with chemotherapy and/or immunotherapy, or targeted therapy for other co-alterations. PFS was 1.8, 6.1, 5.0, 5.3 and 5.3 months for Class 1, 2, 3, other BRAF, and BRAF amplification, respectively. These low survival rates indicate that new treatment options are urgently needed. In vitro results confirm sensitivity of class 3, and resistance of class 2 BRAF mutations to single SHP2 inhibition with RMC-4550 and SHP099, with similar results in TNBC and lung cancer cells. Combined dabrafenib and trametinib treatment indicated antagonistic effects, especially in the class 3 BRAF mutant cell line. Concomitant MEK and SHP2 inhibition was synergistic in both class 2 and 3 BRAF mutations.
Conclusion
It is evident that different classes of BRAF mutations require distinct treatments, which could even outweigh tumor type. Therefore, we should examine BRAF class in daily clinical practice. Upfront targeting of the MAPK signaling pathway combined with SHP2 inhibitors reveals synergistic interactions, and additional inquisition may pave the way for new treatment options in the most frequently found mutations in BRAF patients.
