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Mizuki Nishino
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MA09 - EGFR & MET (ID 128)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:Jordi Remon, Juergen Wolf
- Coordinates: 9/08/2019, 15:15 - 16:45, Melbourne (1991)
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MA09.05 - Genomic Correlates of Differential Response to EGFR-Directed Tyrosine Kinase Inhibitors (Now Available) (ID 1169)
15:15 - 16:45 | Author(s): Mizuki Nishino
- Abstract
- Presentation
Background
Oncogenic mutations in EGFR are powerful biomarkers of response to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). However, there remains significant heterogeneity in duration of response to therapy and overall survival, and the molecular determinants of this differential response have been incompletely characterized.
Method
We identified NSCLC patients at our institution with sensitizing oncogenic EGFR mutations who had been treated with EGFR TKI(s) and who had at least one tumor specimen profiled via targeted next generation sequencing (OncoPanel). Duration of therapy (DOT) on first-line EGFR TKI and overall survival (OS) were assessed. Mutations associated with differential benefit to therapy were identified by comparing mutation rates in outliers with DOT or OS ≥75th percentile vs ≤25th percentile. Fisher’s exact test was used to calculate statistical significance, and the Benjamini-Hochberg method was used to correct for false discovery rate (FDR). Time to event outcomes were assessed with the Kaplan-Meier method.
Result
We identified 270 patients for inclusion in our cohort. 70% were female (190/270), 60% were never smokers (163/270), and median age was 62 (range 29-93). Sensitizing EGFR mutations were predominantly exon 19 deletion (51%, 138/270) or L858R (38%, 103/270). 94% of patients were treated with first-line erlotinib (253/270), and 30% received second-line osimertinib (82/270). The median DOT on first-line TKI was 12 months (range 0-72 months) and median OS was 28 months (range 1-133 months). Pre-treatment sequencing was available for 188 patients, 65 of whom also had documented assessment of resistance mechanism (T790M 78%, other 22%). Pre-existing concurrent TP53 mutations were associated with shorter DOT (median 10 vs 16 mo, p=0.0017), but there was no significant difference in OS (median 25 vs 36 mo, p=0.2) and no association with resistance mechanism (p=0.674). In addition to TP53, BCOR and SMARCA4 mutations were enriched in patients with shorter DOT, whereas MTOR mutations were enriched in patients with DOT in the top quartile, though these analyses did not pass FDR correction. Pre-treatment SMARCA4 mutations were more frequent in patients with survival in the bottom quartile (Fisher’s p=0.01), and were associated with decreased OS (median 32 vs 12 mo, log-rank p<0.0001).
Conclusion
Genomic features may contribute to differential outcomes in patients with EGFR-mutated NSCLC. In addition to TP53 mutations, pre-treatment SMARCA4 mutations may associate with worse outcomes in these patients.
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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
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.04-04 - DNA Damage Response Gene Alterations Are Associated with High Tumor Mutational Burden and Clinical Benefit from PD-1 Axis Inhibition in NSCLC (Now Available) (ID 2620)
09:45 - 18:00 | Author(s): Mizuki Nishino
- Abstract
Background
DNA damage response (DDR) gene alterations are associated with increased tumor infiltrating lymphocytes, higher genomic instability, and higher tumor mutational burden (TMB) in cancer. Whether DDR alterations are associated with benefit from immune-checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) is unknown.
Method
Clinicopathologic and genomic data were collected from patients (pts) with advanced NSCLC at the Dana-Farber Cancer Institute treated with PD-(L)1 inhibitors. Targeted next-generation sequencing (NGS) by OncoPanel was used to determine DDR gene mutation status and TMB. All loss-of-function alterations in DDR genes (including nonsense, frameshift, or splice site) were classified as pathogenic. Missense mutations were manually evaluated and classified as pathogenic if considered to be deleterious in the Catalogue of Somatic Mutations in Cancer (COSMIC) and ClinVar databases, as well as the PolyPhen-2 (Polymorphism Phenotyping v2) functional prediction tool.
Result
Of 223 pts with successful NGS who received ICIs, 116 (52.0%) were identified as having pathogenic DDR mutations (DDRpos) with alterations in the following genes: FANC genes (20%) ATM (13.9%), POL genes (11%), ERCC genes (8%), BRCA1/2 (8%), MLH1/MSH2/MSH6 (7%), CHEK1/2 (7%), RAD genes (6%), ATR (5%), BRIP1 (3%), XRCC genes (3%), BARD1 (2%), PMS (2%), NEIL (2%), BAP1 (1%), PALB2 (1%). DDRpos and DDR negative (DDRneg) groups were well balanced in terms of age, gender, histology, performance status (PS), smoking status, baseline presence of brain metastasis. The median TMB was significantly higher in the DDRpos group compared to the DDRneg group (12.9 vs 8.3 mutations/megabase [mut/Mb], P < 0.001), including among never smokers (11.0 vs 6.8 mut/Mb, P = 0.02). No difference in median PD-L1 expression was observed between groups (50% vs 50%, P = 0.52). Compared to DDRneg pts (N=107), DDRpos pts had a significantly higher objective response rate (30.4% vs 16.8%, P = 0.001), longer median progression-free survival (4.3 vs 2.3 months, HR: 0.64 [95%CI: 0.48-0.86], P = 0.003) and median overall survival (16.5 vs 11.2 months, HR: 0.62 [95%CI: 0.44-0.88], P = 0.008) with PD-(L)1 therapy. After adjusting for ECOG PS, smoking status, baseline brain metastasis, and line of therapy, DDRpos status was associated with significantly longer PFS (HR: 0.64 [0.48-0.86], P < 0.01) and OS (HR: 0.58 [95%CI: 0.41-0.83], P < 0.01) in multivariate analysis.
Conclusion
Pathogenic DDR alterations are frequent in NSCLC and are associated with higher TMB and improved clinical outcomes among NSCLC pts treated with PD-1 axis inhibition.
