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Emma Green
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MA21 - Non EGFR/MET Targeted Therapies (ID 153)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:Benjamin Besse, Michael Thomas
- Coordinates: 9/10/2019, 14:30 - 16:00, Vienna (2016)
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MA21.07 - Circulating Tumor DNA Analysis Depicts Potential Mechanisms of Resistance to BRAF-Targeted Therapies in BRAF+ Non-Small Cell Lung Cancer (Now Available) (ID 1365)
14:30 - 16:00 | Author(s): Emma Green
- Abstract
- Presentation
Background
Oncogenic BRAF-V600 mutations are observed in 1-2% of non-small cell lung cancer (NSCLC). Targeted therapies including vemurafenib (V), dabrafenib (D) or combination of dabrafenib plus trametinib (D+T) are associated with favorable outcomes in these patients (pts). The mechanisms of resistance to BRAF-targeted therapies (BRAF-TT) in NSCLC are largely unknown.
Method
We performed genomic profiling of serial circulating-tumor DNA (ctDNA) in a cohort of 79 metastatic BRAF-mutant NSCLC pts (96% V600E, 4% non-V600). BRAFmutational status was ascertained based on local testing. Plasma samples were collected, from 2014-2018 in 27 Hospitals, from pts treated with V (n=34), D (n=2) or D+T (n=23). We collected 41 plasma samples at baseline to BRAF-TT, 40 at progressive disease (PD) and ~200 samples during treatment follow-up, concomitant to routine radiological evaluation. Inivata InVisionSeq™ assay was used to detect the presence of SNVs, indels and CNAs in 36-cancer related genes.
Result
At baseline, 72,5% of BRAF mutations (V600E and non-V600E) were detected in plasma. BRAF-V600E detection in plasma was associated with the presence of liver metastasis, versus BRAF-V600E-negative cases (22% vs. 7%, respectively). Co-occurring molecular alterations at baseline, besides BRAF-V600E, were observed in 18/26 (70%) cases: FGFR2 (1pt), PIK3CA (2pts), ERBB2 (1pt), CTNNB1 (2pts) and IDH1 (2pts). FGFR2, PIK3CA or CTNNB1 alterations were associated with PD as the best response to the subsequent BRAF-TT. TP53 and STK11 mutations were observed in 54% (14/26) and 8% (2/26) of pts, respectively. Complete clearance of BRAF-V600E in plasma at baseline was observed at the first CT-scan evaluation in 42% (3/7) and 82% (9/11) pts treated with V or D+T, respectively. These pts were in complete or partial response, suggesting that monitoring BRAF-V600E levels in plasma on treatment may be a clinically useful marker of tumor response. At PD, a consistent rebound in BRAF-V600E plasma levels was observed in 60% (24/40) pts. Resistance to V was associated with alterations in the MAPK pathway: 1pt (KRAS), 1pt (GNA11), 1pt (NRAS and GNAS) and 1pt (MAP2K1 and NFE2L2). Activating PI3KCA mutations were observed in 4 pts who progressed in <6 months on V treatment. ctDNA analyses at PD under D+T revealed that, similar to what we observed in patients who progressed on V, alterations in KRAS, NRAS, PIK3CA and CTNNB1 are associated with D+T resistance. Prediction of the impact of these alterations, at the protein level, was assessed using in silico structure modeling and will be presented.
Conclusion
ctDNA monitoring might be an informative tool for assessing disease response and resistance in NSCLC pts treated with BRAF-TT. MAPK reactivation remains an important resistance mechanism to BRAFi-monotherapy or to BRAFi and MEKi combination therapy.
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-62 - Circulating Tumor DNA Assay and Survival in Patients with Metastatic, Non-Small Cell Lung Cancer (ID 935)
10:15 - 18:15 | Presenting Author(s): Emma Green
- Abstract
Background
Circulating tumor DNA (ctDNA) sampling has emerged as a non-invasive approach to characterizing genomic alterations in blood of patients (pts) with metastatic, non-small cell lung cancer (mNSCLC). ctDNA or ‘liquid biopsy’ may be used to guide treatment and prognosis.
Method
This was a prospective pilot study of pts with histologically confirmed mNSCLC. Pts were enrolled prior to initiating a new line of therapy. Tumor and ctDNA specimens were collected prior to treatment and radiology scans were performed at standard intervals; ctDNA collections continued until progression. ctDNA was assessed by Inivata (InvisionFirst) using amplicon-based targeted next generation sequencing with 36-gene panel to detect single nucleotide variants, short insertions/deletions, copy number variations and structural variants.
ctDNA features were calculated for each pt and included number of genomic alterations (numGA), number of mutations (numMUT), number of amplifications/fusions (numAMPFUS), sum mutant allele frequency (sumMAF), and maximum mutant allele frequency (maxMAF).
Univariate and multivariable Cox proportional hazards models were used to identify ctDNA features associated with progression-free survival (PFS). ctDNA from baseline (T0) to the blood collection closest to progression or censor date (T1) was used to assess change in sumMAF and maxMAF. All models included ctDNA features as continuous variables.
Result
27 pts were evaluable. 85.19% were white; 37.04% were male. 85.19% were adenocarcinoma histology; remaining were squamous. 45.83% received prior systemic therapy. Average number of lines of prior therapy was 1.81. 44.44% had prior radiation therapy. 81.48% of pts had at least one genomic alteration detected in ctDNA at baseline. The median numGA, numMUT, and numAMPFUS, maxMAF, sumMAF was 2.00, 2.00, 0.00, 1.61, and 2.34 respectively. TP53, KRAS, and EGFR were the most frequently identified genomic alterations (59.26%, 25.93%, and 22.22%, respectively). EGFR alterations were the most commonly identified genomic alteration in ctDNA. 86.00% of EGFR alterations were actionable. Univariate Cox regression analysis identified numAMPFUS (HR=3.12, p=0.01), sumMAF (HR=1.02, p=0.02), and maxMAF (HR=1.05, p=0.00) to be significantly associated with PFS. Only maxMAF was retained in the final multivariable Cox model. Each percentage point increase in maxMAF from T0 to T1 resulted in a 4% decrease in the risk of progression/death (HR=0.96, p=0.08).
Conclusion
In this pilot study, pts with higher levels of baseline maxMAF detected in ctDNA were associated with increased risk of progression/death. Following initiation of treatment, results suggest increased change in maxMAF may be associated with a decreased risk of progression/death.
