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ORAL 17 - EGFR Mutant Lung Cancer (ID 116)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:P. Meldgaard, E. Felip
- Coordinates: 9/08/2015, 10:45 - 12:15, Four Seasons Ballroom F3+F4
ORAL17.08 - Gefitinib/Chemotherapy vs Chemotherapy in EGFR Mutation-Positive NSCLC Resistant to First-Line Gefitinib: IMPRESS T790M Subgroup Analysis (ID 3287)
10:45 - 12:15 | Author(s): J. Yang
Exon 20 T790M mutation is the most common cause of acquired resistance to first-line epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs). The IMPRESS study (NCT01544179; Phase III, double-blind IRESSA[TM ]Mutation Positive Multicentre Treatment Beyond ProgRESsion Study; Lancet Oncology: in press) reported no statistically significant difference in progression-free survival (PFS; primary endpoint) between gefitinib plus cisplatin/pemetrexed (cis/pem) (G) vs placebo plus cis/pem (P) in patients with acquired resistance to first-line gefitinib (hazard ratio [HR] 0.86; 95% confidence interval [CI] 0.65–1.13; p=0.273; median PFS 5.4 months in both arms) and other secondary endpoints. Among the subgroup analyses performed for IMPRESS, the most noticeable difference was observed by T790M status as tested via plasma circulating free tumor-derived DNA (ctDNA).
Patients (age ≥18 years [Japan ≥20 years], chemotherapy-naïve, locally advanced/metastatic NSCLC with an activating EGFR mutation, prior disease progression on first-line gefitinib) from 71 centers (Europe/Asia Pacific) were randomized to G or P (gefitinib 250 mg/day or placebo, plus cis 75 mg/m/pem 500 mg/m). For biomarker analysis, consenting randomized patients provided 10-mL blood samples (at Visit 1 [baseline], 4, 6; then every 6 weeks and at discontinuation) from which to obtain ctDNA. ctDNA levels of EGFR mutations, including T790M, were detected using a quantitative emulsion (BEAMing) digital PCR assay (Sysmex[®]) conducted at a central laboratory (positivity defined as ≥0.02% mutant DNA fraction).
Data are reported for plasma samples from baseline visits (serial data will be available in the future). Blood samples were available for all 261 randomized patients, of whom T790M status was known for 247 (93.2%): T790M mutation-positive n=142 (57.5%; G=81, P=61) and T790M mutation negative n=105 (42.5%; G=46, P=59). Median PFS for the T790M mutation-positive subgroup was 4.6 vs 5.3 months for G and P, respectively (HR 0.97, 95% CI 0.67 to 1.42, p=0.8829). Median PFS for the T790M mutation-negative subgroup was 6.7 vs 5.4 months for G and P, respectively (HR 0.67, 95% CI 0.43 to 1.03, p=0.0745). See Table for additional study endpoints.
Following acquired resistance to first-line gefitinib, these data suggest there were two distinct patient populations defined by T790M genotype. For plasma T790M-positive, gefitinib should not be continued when platinum-based doublet chemotherapy is used as second-line therapy. For plasma T790M-negative, continuation of gefitinib in combination with platinum-based doublet chemotherapy may offer clinical benefit, which would require further confirmation in a prospective randomized study.
IMPRESS subgroup populations (plasma) T790M mutation-positive N=142 T790M mutation-negative N=105 ORR, % (G vs P) 28.4 vs 39.3 p=0.282 37.0 vs 27.1 p=0.171 DCR, % (G vs P) 81.5 vs 77.0 p=0.5175 93.5 vs 83.1 p=0.0895 OS, HR (95% CI)* 2.16 (1.26, 3.82) p=0.0067 0.83 (0.36, 1.85) p=0.6644 Plasma BEAMing PCR (compared with tumor), % (n/N) Exon 19 Deletions L858R Sensitivity 73.8 (124/168) 81.6 (62/76) Specificity 96.7 (89/92) 95.3 (161/169) Concordance 81.9 (213/260) 91.0 (224/247) *OS immature, follow up ongoing G: gefitinib plus cisplatin/pemetrexed; P: placebo plus cisplatin/pemetrexed ORR, objective response rate; DCR, disease control rate; OS, overall survival
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
P3.04-036 - Rare Discrepancies in a Driving Gene Alteration within Histologically Heterogeneous Primary Lung Cancers (ID 2229)
09:30 - 17:00 | Author(s): J. Yang
Most lung adenocarcinomas consist of a mixture of histological subtypes among which driving gene mutations occurred with different frequencies. However, little is known about intratumoral heterogeneity within histologically heterogeneous primary lung cancers. Investigating key driver genes in respective morphological pattern is crucial to clinical practice and personalized treatment.
Morphologically different tumor areas within the same surgically resected primary tumors were extracted from tissue sections and the gene status in each growth pattern was analyzed. Driving genes, epidermal growth factor receptor (EGFR), KRAS, and rearrangements in echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK), were assessed by assays of different sensitivity.
Seventy-nine consecutive, surgically resected, adenocarcinomas or adeno-squamouse cell carcinomas harboring a driving gene mutation or rearrangement (EGFR, n = 65; KARS, n = 10; EML4-ALK, n = 4) were selected. For EGFR mutations in adenocarcinomas, ITH occurred in 13.3% (8/60) as determined by direct sequencing, but in only 1.7% (1/60) by ARMS(P= 0.016). A consistent intratumoral EGFR mutation status was found within 5 histologically heterogeneous adeno-squamous cell carcinomas, as shown with ARMS. ITH among KRAS mutations were detected in 20% (2/10) of regions examined by direct sequencing ,whereas a consistent status (10/10) was obtained with HRM. There were no discrepancies in EML4-ALK rearrangements according to FISH for four tumors.
Rare ITHs deriving from EGFR/KRAS/EML4-ALK alterations within histologically heterogeneous primary lung adenocarcinomas were found with methods of high sensitivity. Discrepancies might be due to the abundance of cells harboring driving gene and detection assays.