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A. Cseh
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P2.03 - Chemotherapy/Targeted Therapy (ID 704)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.03-025 - Prevalence of EGFR T790M Mutation in NSCLC Patients after Afatinib Failure, and Subsequent Response to Osimertinib (ID 8797)
09:30 - 09:30 | Author(s): A. Cseh
- Abstract
Background:
In patients with EGFR-mutant non-small-cell lung cancer (NSCLC), progression inevitably occurs after 9 to 14 months of treatment with EGFR tyrosine kinase inhibitors (TKIs). EGFR T790M mutations have been identified as the most common mechanism of acquired resistance. Analyses assessing the frequency of acquired T790M mutations have mainly been conducted in patients receiving the first-generation EGFR TKIs erlotinib and gefitinib, however limited data is available on the prevalence of this mutation after failure of the ErbB family blocker afatinib. This retrospective analysis aimed at determining the prevalence of EGFR T790M mutation in patients who had benefitted from afatinib therapy, but ultimately developed progression. Another objective was the assessment of response to the subsequent treatment with the third-generation EGFR TKI osimertinib, which is the treatment of choice for patients who have developed T790M mutations.
Method:
The analysis included consecutive patients with stage IV adenocarcinoma of the lung and sensitizing EGFR mutations who had progressed on first-, second- or third-line afatinib treatment after experiencing at least 3 months of disease stabilization. Mutation status was assessed using liquid biopsy or both liquid biopsy and tissue re-biopsy. Patients with confirmed T790M mutation received osimertinib.
Result:
T790M mutations were found in 27 of 48 patients, corresponding to a prevalence rate of 56.3%. The concordance rate between liquid biopsy and re-biopsy was 80%. In the total cohort, the objective response rate (ORR) obtained with afatinib was 89.6%, and in the patients who developed T790M mutation, 92.6%. Complete responses (CR) occurred in 25.0% and 37.0%, respectively, and partial responses (PR) in 64.6% and 55.6%, respectively. In the patients who received osimertinib after the discovery of T790M mutations, ORR was 81.5%, with CR and PR rates of 22.2% and 59.3%, respectively.
Conclusion:
The prevalence of acquired T790M mutations as assessed in this cohort was consistent with the mutation rates reported for patients who progressed on first-generation EGFR TKI treatment. T790M mutation appears to be the main mechanisms of acquired resistance to afatinib. The development of this mutation was not affected by any baseline characteristics. These real-world data confirm that for patients with advanced, EGFR-positive NSCLC who progressed on afatinib and developed T790M mutations, osimertinib therapy elicited excellent response rates, with a substantial proportion of patients achieving complete remissions.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-043 - Impact of ErbB Mutations on Clinical Outcomes in Afatinib- or Erlotinib-Treated Patients with SCC of the Lung (ID 9457)
09:30 - 09:30 | Author(s): A. Cseh
- Abstract
Background:
In LUX-Lung 8 (LL8), second-line afatinib (an irreversible ErbB family blocker) significantly improved OS (median 7.9 versus 6.8 months; HR [95% CI]: 0.81 [0.69‒0.95]; p=0.0077), and PFS (2.6 versus 1.9 months; 0.81 [0.69‒0.96]; p=0.0103) versus erlotinib in lung SCC (N=795). Comprehensive genetic analysis in LL8 patients assessed whether afatinib efficacy varied according to genetic aberrations in cancer-related genes, including ErbB family mutations.
Method:
Tumor genetic analysis (TGA) was performed using Foundation Medicine FoundationOne™ next-generation sequencing (NGS). The cohort was enriched for patients with PFS >2 months, reflecting a range of responsiveness to EGFR-TKIs. EGFR expression was assessed by immunohistochemistry (IHC) in a largely separate cohort. Cox regression analysis correlated PFS/OS with genetic mutations (individual/grouped) and EGFR expression.
Result:
Of 440 patients selected for TGA (PFS >2 months: n=320; ≤2 months: n=120), samples from 245 were eligible (afatinib: n=132; erlotinib: n=113). In the selected TGA population, PFS/OS outcomes were improved in the afatinib versus erlotinib arm. Baseline characteristics were similar in TGA and IHC cohorts and LL8 overall. In the TGA subset, 53 patients (21.6%) had ≥1 ErbB family mutation (EGFR: 6.5%; HER2: 4.9%; HER3: 6.1%; HER4: 5.7%). Beyond the benefit seen for afatinib in the overall population, in afatinib-treated patients, PFS/OS were longer when ErbB mutations were present (PFS: 4.9 versus 3.0 months; OS: 10.6 versus 8.1 months). Conversely, survival outcomes in erlotinib-treated patients were similar with/without ErbB mutations. Presence of HER2 mutations predicted favorable PFS/OS with afatinib versus erlotinib. The Table shows outcomes in patients with/without ErbB family mutations, and by EGFR expression levels (afatinib: n=157; erlotinib: n=188).
Conclusion:
These data are provocative and suggest that NGS may enable identification of lung SCC patients who would derive additional clinical benefit from afatinib. Differential outcomes with respect to ErbB mutations for afatinib and erlotinib are hypothesized to reflect afatinib’s broader mechanism of action.Subgroup n Afatinib vs erlotinib PFS OS HR (95% CI) p~interaction~ HR (95% CI) p~interaction~ ErbB mutation-positive ErbB mutation-negative 53 192 0.56 (0.29–1.08) 0.70 (0.50–0.97) 0.718 0.62 (0.35‒1.12) 0.76 (0.56‒1.03) 0.683 EGFR mutation-positive EGFR mutation-negative 16 229 0.64 (0.17–2.44) 0.67 (0.50–0.91) 0.981 1.01 (0.32–3.16) 0.72 (0.54–0.95) 0.529 HER2 mutation-positive HER2 mutation-negative 12 233 0.06 (0.01–0.59) 0.72 (0.54–0.97) 0.006 0.06 (0.01–0.57) 0.76 (0.58–1.00) 0.004 HER3 mutation-positive HER3 mutation-negative 15 230 0.52 (0.16–1.72) 0.69 (0.51–0.94) 0.692 0.84 (0.27–2.59) 0.73 (0.56–0.97) 0.998 HER4 mutation-positive HER4 mutation-negative 14 231 0.21 (0.02–1.94) 0.67 (0.50–0.91) 0.909 0.22 (0.05–1.04) 0.75 (0.56–0.99) 0.272 EGFR IHC positive EGFR IHC negative 292 53 0.74 (0.56–0.97) 0.76 (0.41–1.40) 0.985 0.82 (0.63–1.06) 0.75 (0.41–1.40) 0.882 EGFR amplification present EGFR amplification absent 17 228 0.72 (0.18–2.90) 0.68 (0.50–0.92) 0.994 0.50 (0.15–1.65) 0.76 (0.58–1.00) 0.413 HER2 amplification present HER2 amplification absent 9 236 0.94 (0.20–4.38) 0.68 (0.50–0.91) 0.861 1.10 (0.27–4.48) 0.72 (0.54–0.94) 0.388
