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Vincent A Miller
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MA03 - Clinomics and Genomics (ID 119)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:Heather A Wakelee, Wilfried Ernst Erich Eberhardt
- Coordinates: 9/08/2019, 10:30 - 12:00, Colorado Springs (1994)
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MA03.05 - BRAF Mutations Are Associated with Increased Benefit from PD1/PDL1 Blockade Compared with Other Oncogenic Drivers in Non-Small Cell Lung Cancer (Now Available) (ID 1472)
10:30 - 12:00 | Author(s): Vincent A Miller
- Abstract
- Presentation
Background
PD-1/PD-L1 immune checkpoint blockade (ICB) has revolutionized the treatment of non-small cell lung cancer (NSCLC), but only a minority of patients achieve durable clinical benefit. Although classic EGFR/ALK alterations are correlated with ICB resistance, it is unknown if patients with other molecular subtypes of NSCLC also derive poorer outcomes from ICB. We investigated if there are oncogene-driven NSCLC associated with higher response rates (RR) and progression-free survival (PFS) to ICB.
Method
Two independent retrospective cohorts of oncogene-driven NSCLC treated with ICB monotherapy were analyzed for clinical outcome: MD Anderson (MDACC) and Flatiron Health-Foundation Medicine Clinico-Genomic Database (FH-CGDB). PD-L1 expression (Dako 22C3 - FoundationCore) and tumor mutational burden (TMB - FoundationCore; TCGA and MSK-IMPACT – cbioportal.org) were compared across distinct molecular subtypes of NSCLC to determine differences in clinical outcome.
Result
Among five oncogene defined groups from the MDACC cohort, BRAF-mutant NSCLC had the highest response rate (RR) (RECIST 1.1) (P<0.01) and PFS (P<0.01) when treated with ICB (Table). These differences remained significant after adjusting for PD-L1 expression. Classic EGFR and HER-2 mutant NSCLC had the lowest RR and PFS (Table). Similar results were observed in the independent FH-CGDB cohort where BRAF-mutant NSCLC had longer real-world (rw) PFS and OS to ICB monotherapy (Table). PD-L1 expression (tumor score ≥1% and ≥50%) and TMB were higher in BRAF-mutant NSCLC compared to EGFR and HER-2 (P<0.01). BRAF V600E NSCLC had lower TMB compared to non-V600E (5.9 vs 13.7 mut/Mb, P<0.01), but both had high PD-L1 expression (≥1%: 72% vs 61%; ≥50%: 42% vs 32%).
ConclusionKRAS
BRAF
Classic EGFR
EGFR exon 20
HER2
MDACC cohort
Patients – N
87
10 (V600E 3 / non-V600E 7)
28
25
15
RR – %
24.3
62.5
4.5b
10b
8.3
Median PFS – mo (95% CI)
2.76
(2.23-3.30)
7.37 (not estimable)a
1.78 (1.18-2.37)
2.73 (1.71-3.75)
1.88 (1.63-2.12)
FH-CGDB
Patients – N
503
68 (V600E 32 / non-V600E 36)
52
42
25
Median rwPFS -
mo (95% CI)
3.55
(3.15-4.24)
6.0
(2.89-11.6)
2.17b
(1.77-2.63)
2.66b
(2.23-5.13)
1.87b (1.31-4.34)
Median rwOS – mo (95% CI)
10.28
(8.51-12.02)
16.07
(8.64-NA)
5.29b
(3.25-17.68)
9.89b
(3.68-20.86)
10.81
(4.17-NA)
FoundationCore cohort – N
NA
188 (V600E 74 / non-V600E 114)
386
96
57
TMB – mean (mut/Mb)
NA
10.6a
3.7
3.8
5.8
PD-L1 TPS ≥ 50% (%)
NA
36a
19
23
16
a: P<0.01 vs all groups; b: P<0.05 for pairwise comparison vs BRAF.
NSCLCs with BRAF mutations are associated with increased benefit from ICB when compared to tumors harboring other targetable oncogenic drivers. Oncogene driver mutations are associated with distinct patterns of TMB and PD-L1 expression. These findings highlight the importance of developing mutation-specific clinical trials in NSCLC.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-23 - Retrospective Analysis of Real-World Clinico-Genomic Data for Clinical Impact of Genomic Profiling of ctDNA in NSCLC (ID 1883)
09:45 - 18:00 | Author(s): Vincent A Miller
- Abstract
Background
Liquid biopsy (LBx) and comprehensive genomic profiling (CGP) of circulating tumor DNA (ctDNA) is a minimally-invasive approach that is increasingly used for detection of targetable genomic alterations (GA) in patients with NSCLC. To determine the clinical utility of LBx-based CGP in routine clinical practice, we evaluated responses to targeted therapy post-LBx in the real-world setting.
Method
The Flatiron Health-Foundation Medicine Clinico-Genomic Database included 475 NSCLC patients with LBx CGP results (FoundationACT): clinical characteristics and real-world tumor response (rwTR) were obtained via technology-enabled abstraction of clinician notes and radiology/pathology reports and linked to CGP data. Targetable GAs were defined as genomic alterations with a matched FDA-approved targeted therapy or in NCCN guidelines (Table). Patients with a targetable GA were evaluated for rwTR to matched targeted therapy. Real-world overall response rates (rwORR: fraction of patients with partial or complete response) to matched targeted therapy after LBx versus tissue-based CGP (TBx, [FoundationOne/FoundationOneCDx, N=3,956]) were compared.
Result
At the time of LBx, 61% of patients had ≥1 line of prior therapy (vs 49% for TBx). Median ctDNA fraction was 1%. There was evidence of ctDNA in 86% (408/475) of LBx cases; among these 24% (96/408) had a targetable GA (vs 21% for TBx). Post-detection of a targetable GA, 35% (34/96) of LBx patients received matched targeted therapy (vs 38% for TBx). 21 patients with targetable GAs were evaluated for LBx-based rwTR to matched targeted therapy (Figure): rwORR was 76.2% (vs 62.8% for TBx; p=0.25), including 76.5% (13/17) for FDA-approved matched targeted therapy and 75.0% (3/4) for NCCN targeted therapies (Table).
Conclusion
Retrospective analysis of real-world clinico-genomic data from a large series of NSCLC cases demonstrated that the frequency of detected targetable GAs and rwTR to matched targeted therapy was similar for LBx and TBx CGP.
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P1.01-86 - Occurrence of de Novo Dual HER2/HER3 or HER2/EGFR TMD Mutations: Extending the Spectrum of Targetable Mono-HER2 TMD in NSCLC? (ID 956)
09:45 - 18:00 | Author(s): Vincent A Miller
- Abstract
Background
HER2 (ERBB2) TMD mutations have recently been described as novel solo actionable drivers in NSCLC responsive to afatinib in small series. However, dual occurrence of de novo EGFR or HER3 (ERBB3) TMD mutations together with HER2 TMD mutations, which may have implications for dimerization patterns and treatment, has not been described.
Method
Hybrid-capture based comprehensive genomic profiling was performed on blood-based circulating tumor DNA (n=5,200) or FFPE tissue (n= 45,780) samples collected during clinical care from 50,980 unique NSCLC patients.
Result
HER2 TMD mutations were identified in 0.12% (60/50,980) of cases and included V659E (n=33), V659D (n=8), G660D (n=15), V659E+G660R, V659_I661>VVEGI, G660E>R, and S653C (1 each). Within this subset, the median age of patients was 61 years (range 33-91) and 62% were female. No co-occurring known NSCLC driver alterations were detected, except one case with EGFR exon 19 deletion and one case with EGFR L858R and lung co-primary tumors noted. However, co-occurring HER3 (I649R) or EGFR (G652R) TMD mutations were found in 18% (11/60) and 5.0% (3/60) of cases, respectively. Notably, these ERBB3 or EGFR TMD mutations only co-occurred with HER2 TMD V>D (8/9 cases) or G>D (7/15 cases), but not with V>E changes (0/34 cases; p=0.0002). HER2 amplification co-occurred with V659E in 15% (5/34) of cases, and G660D mutation was seen with the oncogenic extracellular domain S310F mutation in one case. Importantly, neither EGFR G652R nor ERBB3 I649R was found in the absence of a HER2 TMD mutation. Preliminary modelling studies suggest formation of a salt-bridge which would increase propensity for HER2/HER3 and HER2/EGFR heterodimerization favoring receptor activation. Two patients in this series with V659E were previously reported to have responded to afatinib and 1 patient with G660D+I649R did not respond to afatinib. Updated clinical data for these patients and others treated with HER2-tageted therapies will be presented.
Conclusion
HER2 TMD mutations (V659D/E or G660D/R) are uncommon but targetable driver alterations in NSCLC. In cases with HER2 TMD V>D or G>D, a de novo co-existing EGFR or HER3 TMD mutation was frequently observed (88% and 47%, respectively), which may explain differential dimerization preference and in turn response to ERBB inhibitors. We hypothesize that dual HER2/HER3 or HER2/EGFR TMD mutants may be more aggressive than single HER2 TMD mutants due to the arginine-aspartic acid interaction, and these dual mutants may require combined kinase inhibitor + antibody therapy to block dimerization. Studies utilizing models to further characterization these co-alterations are in progress.
