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J. Kim
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MINI 30 - New Kinase Targets (ID 157)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:K. Park, M. Villalona
- Coordinates: 9/09/2015, 18:30 - 20:00, Four Seasons Ballroom F3+F4
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MINI30.11 - Efficacy and Safety of Dovitinib in Advanced Squamous Cell Lung Cancer with FGFR1 Amplification: A Single-Arm, Phase II Study (ID 666)
19:30 - 19:35 | Author(s): J. Kim
- Abstract
- Presentation
Background:
FGFR1 amplification is one of the most common potential driving oncogenes in squamous cell carcinoma (SCC), which accounts for 20% of non-small cell lung cancer (NSCLC) squamous cell carcinoma. This phase II study evaluated the efficacy and toxicity profile of dovitinib, an orally active FGFR (fibroblast growth factor receptor) inhibitor, in advanced SCC patients.
Methods:
Patients with histological confirmed advanced squamous cell NSCLC and previously treated with at least one cytotoxic chemotherapy were enrolled from April 2013 to December 2014. All patients had FGFR1 gene amplification more than 5 copies by fluorescent in situ hybridization (FISH). Each 7-day treatment cycle consisted of dovitinib 500mg orally administration on days 1 to 5 and 2 days off. Primary endpoint was overall response rate and secondary endpoints included PFS, OS and toxicity.
Results:
All 26 patients were male with the median age of 68 years (range, 52 – 80). Most patients were ever smokers (96%) and had good ECOG (0-1) performance status (85%). The median number of dovitinib treatment cycles administered was 2.5 (range, 1-12). The overall response rate (ORR) was 11.5% (95% CI, 0.8 – 23.8) and disease control rate (DCR) was 50% (95% CI, 30.8 – 69.2). There were three partial responses (PR) and ten stable diseases (SD). Duration of response in 3 patients who achieved PR was 4.5+, 5.1+ and 6.1months. After the median follow-up duration of 15.7 months (range, 5.8 – 25.6 ), the median overall survival (OS) was 5.0 months (95% Confidential Interval, 3.61 – 6.39) and progression-free survival (PFS) was 2.9 months (95% CI, 1.54 – 4.26). Grade 1/2 fatigue (69%) and anorexia (85%) were most commonly reported adverse events and 12 patients (46%) required dose reduction of dovitinib.
Conclusion:
Dovitinib treatment a showed modest efficacy in advanced squamous cell lung cancer patients with FGFR1 amplification. Further studies to evaluate other biomarkers correlated with the efficacy of dovitinib in SCC should be warranted.
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ORAL 06 - Next Generation Sequencing and Testing Implications (ID 90)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:G. De Lima Lopes, V. Miller
- Coordinates: 9/07/2015, 10:45 - 12:15, Mile High Ballroom 1a-1f
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ORAL06.02 - Targeted Deep Sequencing of EGFR/KRAS/ALK-Negative Lung Adenocarcinoma Reveals Potential Therapeutic Targets (ID 622)
11:16 - 11:27 | Author(s): J. Kim
- Abstract
- Presentation
Background:
Identification of clinically relevant molecular drivers in patient tumors is essential in selecting appropriate targeted therapy. Using next-generation sequencing (NGS) -based clinical cancer gene test, we performed genomic profiling of lung adenocarcinoma tumors.
Methods:
We collected formalin-fixed paraffin-embedded tumors from 41 lung adenocarcinoma patients whose tumors previously tested negative for EGFR/KRAS/ALK by conventional methods in an ongoing trial (NCT01964157). We performed hybridization capture of 4,557 exons from 287 cancer-related genes and 47 introns from 19 genes frequently rearranged in cancer (FoundationOne). Illumina HiSeq2000 platform was used to sequence to high uniform depth.
Results:
Figure 1Tumors were sequenced to a median coverage of 529x. Overall, we identified a total of 170 known and 492 unknown individual genomic alterations. The number of known alterations per sample was average of 3.8 alterations (range 0-10). Cancer genomes are characterized by 45% (77/170) non-synonymous base substitutions, 17% (29/170) insertions or deletions, 2% (4/170) splice site mutations, 20% (34/170) gene amplifications, 5% (8/170) homozygous loss and 5% (8/170) gene fusions. TP53 was the most commonly mutated gene (13%, n=10/77) among non-synonymous base substitutions, followed by KRAS (10%, n=8/77) and PIK3CA (8%, 6/77). Insertions or deletions commonly occurred TP53 (17%, 5/29) and ERBB2 (14%, 4/29), and splice site mutations occurred in TP53, INPP4B, ATR, and MAP2K4 (n=1 each). Among gene amplification, MDM2 amplification was the most frequent (12%, 4/34), followed by ERBB2 (8%, 3/34) and CDK4 (8%, 3/34) amplification. All 8 cases of homozygous loss were observed with CDKN2A and CDKN2B. Fusion genes were most commonly observed with RET (50%, n=4/8). Based on NCCN guidelines, actionable genomic alterations with a targeted agent were identified in 16 patients (39%) (BRAF mutation [n=1], EGFR mutation [n=7], ERBB2 mutation [n=4], MET amplification [n=1], KIF5B-RET rearrangement [n=2], CCDC6-RET rearrangement [n=1], and CD74-ROS1 rearrangement [n=1]). Nine out of all patients (22%) showed discordance in targetable alterations when compared between NGS and conventional non-NGS methods.
Conclusion:
Thirty-nine percent of lung adenocarcinoma wild type for EGFR/KRAS/ALK may harbor a genomic alteration revealed by NGS approach. These results highlight the importance of profiling lung adenocarcinomas using NGS in the clinic.
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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
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ORAL17.02 - Randomized Trial of Gefitinib with and without Pemetrexed as First-Line Therapy in East-Asian Patients with Advanced NS NSCLC with EGFR Mutations (ID 1319)
10:56 - 11:07 | Author(s): J. Kim
- Abstract
- Presentation
Background:
Pemetrexed (P) is the standard of care for non-squamous non-small cell lung cancer (NS NSCLC), whereas epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib (G), are the standard of care for advanced NSCLC with EGFR mutations. Clinical and nonclinical studies have demonstrated synergistic effects of EGFR TKIs and P. Based on these observations, the efficacy and safety of G+P was compared with G monotherapy in patients with NS NSCLC positive for activating EGFR mutations.
Methods:
The primary objective of this randomized, multicenter, open-label, parallel-arm, phase 2 East-Asian study was to assess whether G+P prolongs progression-free survival (PFS) versus G alone. Secondary endpoints included overall survival (OS), overall response rate, disease control rate, time to progressive disease, duration of response, and treatment-emergent adverse events (TEAEs). Eligible patients had stage IV NS NSCLC with activating EGFR mutations, were chemonaïve, and had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. Patients were randomized in a 2:1 ratio (G+P:G). Dosing schedule was concurrent G (250 mg/day) and P (500 mg/m[2] every 3 weeks) in the G+P arm and G monotherapy (250 mg/day) in the G arm. Treatment continued until progression or unacceptable toxicity. The primary endpoint was analyzed after 144 events, which provided 70% power at a 1-sided 20% significance level, assuming a true hazard ratio (HR) of 0.79.
Results:
Between February 2012 and August 2013, 191 patients were randomized and treated (G+P: N=126; G: N=65). Patients were mostly female (64.4%) with a mean age of 62 years; most were never-smokers (67.0%), had confirmed stage IV disease (84.8%), and ECOG PS of 1 (68.6%). Overall, 55.0% had exon 19 deletions, 39.3% had exon 21 L858R mutations, and 5.8% had other activating EGFR mutations. Baseline characteristics were balanced between treatment arms. Patients in the G+P arm received 96.3% and 92.9% of the planned mean dose of G and P, respectively; patients in the G arm received 97.9% of the planned mean dose of G. Median PFS for G+P (15.8 months) was significantly longer than for G (10.9 months); HR=0.68; 95% confidence interval 0.48, 0.96; 1-sided P=0.014; 2-sided P=0.029. OS data are immature and will be reported at study completion. The incidence of grade 3/4 study drug-related TEAEs was significantly higher for G+P (42.1%) than for G (18.5%); P=0.001. The most common study drug-related TEAEs for G+P were diarrhea (44.4%), aspartate aminotransferase increased (41.3%), and dermatitis acneiform and alanine aminotransferase increased (38.1% for each), and for G were diarrhea (47.7%), dermatitis acneiform (43.1%), and dry skin (35.4%). The proportion of treatment discontinuations due to TEAEs was 16.7% in the G+P arm and 9.2% in the G arm; 2 patients (G+P arm) died due to study drug-related adverse events.
Conclusion:
The combination of G+P led to a significant improvement in PFS compared with G monotherapy for East-Asian patients with EGFR mutation-positive NS NSCLC, and met the primary study endpoint. The incidence of grade 3/4 study drug-related AEs was higher for G+P than for G. ClinicalTrials.gov identifier: NCT01469000.
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-101 - Utility of Patient-Derived Cell Line Models Using Conditional Reprogramming for in Vitro Pharmacogenomics Platform (ID 963)
09:30 - 09:30 | Author(s): J. Kim
- Abstract
Background:
To evaluate the potential of conditional reprogrammed cells (CRCs) established from biopsy or effusion samples of advanced non-small cell lung cancer (NSCLC) for in vitro pharmacologic screen and identification of drug resistance mechanisms.
Methods:
A total of 48 tumor specimens obtained from 46 patients with NSCLC were cultured with irradiated fibroblast feeder cells and Rho kinase inhibitor (Y-27632) to induce tumor cells to proliferate indefinitely. The cell lines established from patients harboring EGFR mutation or other druggable oncogenes were subjected to genetic analyses and pharmacologic screen. Corresponding tumor cells were injected into nude mice to test for tumorigenicity and efficacy of targeted agents in vivo.
Results:
Twenty one male patients and twenty five female patients were assessed for establishment of CRC. Adenocarcinoma was the most frequent histologic type (84.7%). There were 21 patients (46%) who harbored an active EGFR mutation. There were four patients with ALK fusion and five with ROS1 fusion. Twenty-six patients experienced disease progressed while on treatment with EGFR (20), ALK (2) or ROS1 (4) tyrosine kinase inhibitors. Tumor cells came from primary or distant metastases in 48% and 52%, respectively. Thirty one (65%) samples were obtained by tumor biopsy and 17 from malignant pleural effusion. Nine CRC model were successfully established (18.7%, 9/48). The successful growth was not dependent on the clinicopathologic characteristics. Both cells from pleural effusion (4 of 17) and biopsy (5 of 31) and adenocarcinoma (8 of 41) and squamous cell carcinoma (1 of 3) were successfully cultured. For biopsy samples, the success rate of cells obtained from primary lung lesion was 21.7% (5 of 23) and cells from metastatic site outside lung was 0% (0 of 8) (P = 0.3). For effusion samples, volume of effusion required for CRC was not significant factors for establishment (success vs. failure cases: mean volume 500 ml vs. 267 ml). The genetic characteristics of patients with non-squamous cell carcinoma did not affect the success rate of CRC (EGFR mutation, 4 of 21; ALK translocation, 0 of 4; ROS1 translocation, 2 of 5; wild or unknown, 2 of 15). Two xenograft models with CRC were successfully established and passaged to maintain tumor in vivo.
Conclusion:
The CRC models derived from NSCLC patients provide useful in vitro platforms of preclinical studies evaluating novel targeted therapies and uncovering the drug resistance mechanisms.
