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M. Gubens
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MA09 - Immunotherapy Combinations (ID 390)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:M. Sebastian, E.B. Garon
- Coordinates: 12/06/2016, 14:20 - 15:50, Strauss 2
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MA09.02 - Pembrolizumab + Carboplatin and Pemetrexed as 1st-Line Therapy for Advanced Non–Small Cell Lung Cancer: KEYNOTE-021 Cohort G (ID 5787)
14:20 - 15:50 | Author(s): M. Gubens
- Abstract
- Presentation
Background:
Platinum doublet chemotherapy ± bevacizumab is standard first-line therapy for patients with advanced non–small cell lung cancer (NSCLC) without genetic aberrations. Single-agent pembrolizumab exhibits robust antitumor activity in PD-L1–positive advanced NSCLC. Cohort G of the multicenter, open-label, phase 1/2 multicohort KEYNOTE-021 study (ClinicalTrials.gov, NCT02039674) evaluated the efficacy and safety of pembrolizumab + carboplatin and pemetrexed compared with carboplatin and pemetrexed in patients with treatment-naive advanced nonsquamous NSCLC with any PD-L1 expression.
Methods:
Cohort G enrollment criteria included patients with stage IIIB/IV nonsquamous NSCLC, no activating EGFR mutation or ALK translocation, no prior systemic therapy, measurable disease, ECOG performance status 0-1, and adequate tumor sample for assessment of PD-L1 status, regardless of PD-L1 expression. Patients were randomized 1:1 to 4 cycles of pembrolizumab 200 mg Q3W + carboplatin AUC 5 (5 mg/mL/min) + pemetrexed 500 mg/m[2] Q3W or carboplatin AUC 5 (5 mg/mL/min) + pemetrexed 500 mg/m[2] Q3W alone, followed by maintenance pemetrexed ± pembrolizumab. Pembrolizumab was given for ≤35 cycles. Randomization was stratified by PD-L1 expression (positive [tumor proportion score, or TPS, ≥1%] vs negative [TPS <1%]). Crossover to pembrolizumab monotherapy was allowed for eligible patients who experienced disease progression (RECIST v1.1) on chemotherapy. Response was assessed by central imaging vendor review every 6 weeks for first 18 weeks, every 9 weeks through year 1, and every 12 weeks in year 2. The primary end point was objective response rate (ORR); secondary end points included progression-free survival (PFS), duration of response, and overall survival (OS). Comparison between arms was assessed using the stratified Miettinen and Nurminen method (ORR) and stratified log-rank test (PFS, OS).
Results:
As of January 2016, 123 patients (60 in the pembrolizumab + chemotherapy arm, 63 in the chemotherapy arm) had been enrolled in cohort G. Data on ORR, duration of response, safety, and preliminary PFS and OS results will be available by August 2016.
Conclusion:
The conclusion will be updated at the late-breaking submission stage.
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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 - 15:45 | Author(s): M. Gubens
- 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.
