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A.T. Shaw
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P3.02a - Poster Session with Presenters Present (ID 470)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02a-015 - Ceritinib as First-Line Therapy in Patients with ALK-Rearranged Non-Small Cell Lung Cancer: ASCEND-1 Subgroup Analysis (ID 5686)
14:30 - 14:30 | Author(s): A.T. Shaw
- Abstract
Background:
In the open-label, phase 1 ASCEND-1 study (NCT01283516), ceritinib demonstrated durable whole body and intracranial responses in patients with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) (Kim et al. Lancet Oncol 2016). Median progression-free survival (PFS) was promising in ALK inhibitor (ALKi)-naïve patients (18.4 months), most of whom had received one or more lines of chemotherapy. Here, efficacy and safety of ceritinib are summarized in a subset of treatment-naïve patients enrolled in ASCEND-1.
Methods:
Patients with ALK+ NSCLC enrolled worldwide received ceritinib 750 mg/day (fasted). Efficacy and safety were evaluated in a subset of patients who had not received any prior systemic antineoplastic therapy. Data cut-off was 16 November 2015.
Results:
Overall, 246 patients with ALK+ NSCLC (83 ALKi-naïve and 163 ALKi-pretreated) received ≥1 dose of ceritinib, of whom 16 had not received any prior systemic antineoplastic therapy. Among the 16 treatment-naïve patients, three (18.8%) had baseline brain metastases, five (31.3%) an ECOG performance status of 0, and all had stage IV disease. Median time from primary site diagnosis to ceritinib initiation (range) was 1.8 months (1.0–35.9). At data cut-off, median duration of exposure (range) was 18.5 months (0.9–35.7) and median duration of follow-up (range) was 29.6 months (4.7–39.1). In these 16 treatment-naïve patients, per investigator assessment, the overall response rate was 68.8% (95% confidence interval [CI]: 41.3, 89.0) and the disease control rate was 87.5% (95% CI: 61.7, 98.4). Median duration of response was 21.1 months (95% CI: 5.5, 31.1). Median investigator-assessed PFS was 19.3 months (95% CI: 4.2, 26.3), and median overall survival was 39.1 months (95% CI: 19.1, 39.1). Among three patients with baseline brain metastases, one had brain metastases selected as target lesion and achieved a partial intracranial response. The most frequently reported any-grade adverse events (AEs), regardless of study drug relationship, were diarrhea (93.8%), nausea (81.3%), ALT or AST increase (each 81.3%), and vomiting (62.5%). AEs requiring intervention were predominantly managed with dose reduction/interruption. Overall, 13 patients (81.3%) discontinued treatment, due to disease progression (n=6), consent withdrawal (n=3), AEs (n=2), administrative problems or death (each n=1).
Conclusion:
Ceritinib demonstrated durable efficacy in treatment-naïve patients with ALK+ NSCLC. Safety was consistent with the overall ASCEND-1 study population. An ongoing, prospective, phase 3 study (ASCEND-4) in which patients are randomized to receive either ceritinib or chemotherapy will provide further evidence for the clinical benefit of ceritinib in previously untreated patients with ALK+ NSCLC.
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-103 - Identification of On-Target Mechanisms of Resistance to EGFR Inhibitors Using ctDNA Next-Generation Sequencing (ID 5645)
14:30 - 14:30 | Author(s): A.T. Shaw
- Abstract
Background:
Osimertinib (OSM) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) recently approved for use in EGFR T790M-positive non-small cell lung cancer (NSCLC) with a 65-70% response rate. However, patients invariably develop resistance to OSM, in ~30% of cases due to an acquired EGFR C797S mutation. Understanding additional, non-C797S resistance mechanisms will be critical to developing new therapeutic approaches. Here, we describe a case of T790M-positive NSCLC with progression on OSM, genotyped using cell-free circulating tumor DNA (ctDNA) next-generation sequencing (NGS).
Methods:
A 68-year-old male with EGFR L858R-mutant metastatic NSCLC whose disease progressed despite multiple lines of EGFR inhibitors (erlotinib, afatinib, cetuximab/afatinib) and chemotherapy was found to be T790M-positive, and initiated on OSM. Initial restaging scans demonstrated response. On disease progression 7 months later, ctDNA testing was performed with a highly sensitive and ultra-specific 70-gene NGS panel (Guardant360™) that includes all EGFR exons and reports on all EGFR single nucleotide variants, indels, and amplification.
Results:
Twelve somatic alterations were identified, including 7 mutations in EGFR. The original L858R driver mutation was present at a mutant allele fraction (MAF) of 16.9%, and T790M at MAF of 8.4%. C797S was detected at MAF of 4.6%. Four additional subclonal TK domain mutations were identified: L792H (1.4%), L718Q (0.7%), F795C (0.4%) and L792F (0.1%). Mutations within sufficient genomic proximity were phased to determine allelic origin, and a presumptive evolutionary history was constructed. T790M and C797S were in cis, and the F795C mutation arose on that allele. L792H and L792F were in cis to T790M, but arose independently from each other and from C797S. Review of the Guardant Health database, which includes 5,609 NSCLC samples, identified 1,228 samples with EGFR activating mutations L858R and exon 19 deletion. Of these, 341 (28%) had T790M, of which 17 (5%) carried C797S. Sixteen of 17 C797S mutations were in cis with T790M, and 1 in trans. There were 3 additional cases with L718 mutation and 1 with L792.
Conclusion:
Deep sequencing of ctDNA can reveal the global landscape and evolution of resistance mutations within a patient’s tumor. The T790M and C797S mutations were predominantly in cis configuration, underscoring the importance of developing new EGFR TKIs. The role of mutations L792H, L792F, and F795C is currently unknown. These mutations impinge on the ATP-binding pocket, which could be a potential structural resistance mechanism. Further studies are needed to validate and functionally characterize these candidate resistance mutations.
