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Wan-Teck Lim
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P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.01-11 - Named Patient Use Program for Afatinib in Advanced NSCLC with Progression on Prior Therapy: Experience from Asian Centers (ID 12968)
16:45 - 18:00 | Author(s): Wan-Teck Lim
- Abstract
Background
A global named patient use (NPU) program for afatinib in patients with advanced/metastatic NSCLC who had progressed during prior therapy was conducted between May 2010 and January 2016 (Cappuzzo F et al, Future Oncol 2018). Here we describe treatment outcomes for patients at Asian centers.
a9ded1e5ce5d75814730bb4caaf49419 Method
Eligible patients had progressed after clinical benefit on prior erlotinib/gefitinib and/or had an activating EGFR/HER2 mutation, had exhausted all other treatments, and were ineligible for afatinib trials. Patients received afatinib (starting dose:30-50 mg/day). Dose modifications were allowed as tolerated. Time to treatment failure (TTF) was calculated from treatment initiation to discontinuation. Adverse event (AE) reporting was mandatory.
4c3880bb027f159e801041b1021e88e8 Result
Data were collected from 2242 NSCLC patients across 10 Asian countries. Patients were heavily pretreated, 62% received ≥2 prior chemotherapy lines, and for most, afatinib was 4th-line therapy; almost all had received erlotinib/gefitinib (Table 1). 97% of patients with known tumor status were EGFR mutation-positive (m+). Median TTF was 7.6 months overall, and 7.2 months in patients with EGFR m+ tumors (Table 1). TTF was >12 months in patients with EGFR exon20 insertions and Her2 mutations. ORR was numerically higher in patients with exon20 insertions and G719X/L861Q/S761I mutations than other subgroups (Table 1). Disease control rate was 78% overall. The most frequently reported AEs were rash and diarrhea; no new/unexpected safety signals were identified.
Table 1. Named patient use (NPU) program for afatinib in advanced/metastatic NSCLC: results from Asian centers Total number of patients 2242 Age; years, median 61 Female/male; % 60/40 Any prior treatment; n (%) 2223/2242 (99.2) Prior erlotinib and/or gefitinib; n (%) 2202/2223 (99.1) Prior erlotinib only; n (%) 866/2202 (39) Prior gefitinib only; n (%) 927/2202 (42) Prior lines of chemotherapy ≥3, 32%; ≥2, 62%; 1, 23%; 0, 15% Prior lines of systemic therapy ≥4, 37%; ≥3, 65%; 2, 21%; 1, 14%; 0, 0% EGFR m+; n (%) 1240/1281 (97) Specified EGFR mutation; n (%) 1101/1240 (89) TTF; months* n ORR, % n All patients with data available 7.6 1550 24.4 431 EGFR m+ 7.2 834 27.7 267 EGFR mutation specified 6.5 740 - - Common mutations (Del19 or L858R) 6.4 692 27.4 230 Uncommon mutations (all) 8.0 84 30.3 33 T790M 6.0 34 21.1 19 G719X, L861Q, or S761I 7.8 28 42.9 7 Exon 20 insertion 18.0 25 42.9 7 Her2 m+ 12.2 12 14.2 7 p.A775 G776insYVMA 12.4 7 25.0 4 *median
m+ve, mutation-positive; ORR, objective response rate;
TTF, time to treatment failure
8eea62084ca7e541d918e823422bd82e Conclusion
This analysis from Asian countries in the afatinib NPU program revealed clinically meaningful TTF/ORR in this heavily pre-treated and refractory advanced NSCLC patient population, including activity in common and uncommon EGFR mutations. TTF was numerically longer in patients with uncommon mutations (particularly EGFR exon20 insertions) and HER2 mutations than in those with common EGFR mutations. The safety profile of afatinib was consistent with non-Asian centers.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.13-21 - MET Addiction Can be Circumvented Through EGFR Inhibition Via AXL in MET-Amplified Primary Resistant EGFR-Mutant NSCLC (ID 14384)
16:45 - 18:00 | Author(s): Wan-Teck Lim
- Abstract
Background
Primary resistance to EGFR-TKI is observed in approximately 10% of patients with activating EGFR mutations. In a patient harboring L858R mutation and high cMET amplification (MET copy number 7.3, CEP7 ratio 3.4) who progressed after just 4 weeks of erlotinib (ERL), significant tumor regression was achieved with MET inhibition alone (Crizotinib, CRZ). We confirmed this phenotype in the corresponding patient-derived cell line model (A482) and identified EGFR-AXL interaction as a mechanism that can circumvent clonal cMET addiction.
a9ded1e5ce5d75814730bb4caaf49419 Method
We generated patient-derived cell lines from the patient’s baseline neck excision biopsy (A482) and evaluated the effect of mono and combination therapy (ERL, CRZ, ERL-CRZ) on A482, including viability (CellTiter-Glo Luminescent Assay, Promega), colony forming (Crystal Violet Assay), downstream signaling (Western blots) and adaptive pathways (Human Phosho-Receptor Tyrosine Kinase Array Kit, R&D systems). AXL was identified as a key mediator of resistance and subsequently subjected to further functional validation. Finally, we examined the prevalence of this clinical phenomenon in a retrospective series of MET amplified EGFR-mutant NSCLC.
4c3880bb027f159e801041b1021e88e8 Result
Cell viability assays confirmed the patient-derived cell line to be more sensitive to CRZ as compared to ERL alone or with combination CRZ-ERL. Upregulation of AXL, RET and FGFR3 expression were identified as adaptive changes 24 hours upon ERL exposure. A targeted pharmacologic screen revealed A482 to be exquisitely sensitive to combination EGFR and AXL inhibition. Immunoprecipitation revealed a direct interaction between EGFR and AXL, which upon treatment with ERL resulted in attenuation of cMET addiction. Co-existing cMET amplification with demonstrated suboptimal response to EGFR TKI was found in 3% of EGFR-mutant NSCLC in a retrospective series of patients.
8eea62084ca7e541d918e823422bd82e Conclusion
Targeting the EGFR-AXL axis through EGFR inhibition alone can lead to paradoxical MET pathway activation, while the combination of EGFR and AXL inhibition can circumvent downstream signaling in MET amplified EGFR-mutant NSCLC. AXL expression levels can potentially identify patients in whom combination or monotherapy with MET inhibitors may be most beneficial. Our data highlights the challenge in interpreting genomic alterations alone; and how cellular context can lead to differential sensitivities to EGFR and MET inhibitors alone and/or in combination in MET amplified EGFR-mutant NSCLC.
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