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Nick Pavlakis
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MA 19 - Mesothelioma: Bench to Bedside (ID 680)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Mesothelioma
- Presentations: 1
- Moderators:Dean A Fennell, Hedy Lee Kindler
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 315
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MA 19.03 - Nintedanib + Pemetrexed/Cisplatin in Malignant Pleural Mesothelioma (MPM): Phase II Biomarker Data from the LUME‑Meso Study (ID 8111)
11:00 - 12:30 | Author(s): Nick Pavlakis
- Abstract
- Presentation
Background:
Nintedanib is a triple angiokinase inhibitor. LUME-Meso (NCT01907100) is a randomised, Phase II/III study of ≤6 cycles of nintedanib+pemetrexed/cisplatin versus placebo+pemetrexed/cisplatin, followed by nintedanib or placebo maintenance, in chemo-naïve patients with MPM. In Phase II results, nintedanib+pemetrexed/cisplatin improved progression-free survival (PFS) versus control (hazard ratio [HR]=0.54; p=0.010), with a trend for prolonged overall survival (OS; HR=0.77; p=0.319). Benefit was most pronounced in patients with epithelioid tumours. Since no pharmacodynamic/predictive biomarkers are validated for anti-angiogenic therapies, exploratory analyses were conducted to investigate potential associations of plasma-derived angiogenic factors and genomic markers with treatment outcome in the LUME-Meso Phase II epithelioid population.
Method:
Blood samples were collected at baseline and, for patients receiving maintenance, at monotherapy Cycle 3 (C3mono) and end of monotherapy (EoTmono). Analyses focused on 58 angiogenic factors (Human AngiogenesisMAP[®] panel, Myriad RBM) and single-nucleotide polymorphisms (SNPs) in genes implicated in mesothelioma and/or associated with response to anti-angiogenic therapies in other tumour types (VEGFR1, VEGFR3 and mesothelin). Associations of biomarkers with treatment effect were evaluated by Cox regression and tested for interaction with false discovery rate (FDR) adjustment. Adjusted mean changes in angiogenic factor levels were compared between arms by ANCOVA. Analyses were exploratory, limited by small sample size, and considered hypothesis generating.
Result:
Of 77 patients with epithelioid tumours, angiogenic factor and genomic data were available for 71 and 67 patients, respectively. PFS/OS benefit of nintedanib appeared potentially more pronounced in patients with baseline plasma endoglin level below the median. There were possible weak associations between major homozygous genotypes for two VEGFR3 SNPs (rs307821 G/G and rs307826 A/A), and OS benefit and between VEGFR1 SNP rs9582036 A/A genotype and PFS benefit. Biomarker treatment associations were limited by small subgroup size, especially for low-frequency SNPs, and interaction tests were not significant after FDR adjustment. Regarding pharmacodynamic effects, adjusted mean change in interleukin-8 levels with nintedanib was greater from baseline to C3mono and lower from C3mono until EoTmono, compared with placebo. Nintedanib showed lower adjusted mean changes versus placebo for VEGFR2 from baseline to C3mono, and for VEGFR2 and VEGFR3 from baseline to EoTmono.
Conclusion:
These analyses represent the first biomarker results for nintedanib-treated MPM. While there seemed to be signals for greater PFS and OS improvement in patients with low plasma endoglin and major homozygous VEGFR1/3 genotypes, no biomarkers showed clear significant association with treatment benefit. These findings warrant further evaluation in the Phase III study.
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MS 27 - Engaging Patients in Research: Best Practices (ID 549)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Patient Advocacy
- Presentations: 1
- Moderators:S. Shilo, J. Kerr
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 311 + 312
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MS 27.01 - The Multi-Centre Clinical Trials Network (MCTN): Matching Lung Cancer Patients to Trials in Australia (ID 7769)
14:30 - 16:15 | Presenting Author(s): Nick Pavlakis
- Abstract
- Presentation
Abstract not provided
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OA 10 - Liquid Biopsy for Genomic Alterations (ID 678)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Adrian G. Sacher, Pasi A Jänne
- Coordinates: 10/18/2017, 11:00 - 12:30, F201 + F202 (Annex Hall)
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OA 10.03 - Liquid Biopsy in the Lung Cancer Clinic: A Prospective Study of Plasma DNA next Generation Sequencing to Guide Matched Therapy (ID 8218)
11:00 - 12:30 | Author(s): Nick Pavlakis
- Abstract
- Presentation
Background:
Liquid biopsy for plasma circulating tumor DNA (ctDNA) next generation sequencing (NGS) is now commercially available and increasingly adopted in clinical practice with a paucity of evidence based guidance. We set out to prospectively determine the utility of plasma ctDNA NGS in the lung cancer clinic.
Method:
Patients (pts) with advanced NSCLC who were driver unknown or resistance mechanism unknown were eligible. Pts were enrolled prospectively at Memorial Sloan Kettering (NY, USA) and Northern Cancer Institute (Sydney, Australia). Peripheral blood was collected in Streck tubes (10-20mL) and sent to Resolution Bioscience (Bellevue, WA) for targeted NGS of extracted DNA using a bias corrected hybrid capture 21 gene assay in a CLIA laboratory with unique reads at 3000x and sensitive detection at variant allele frequency above 0.1%. Clinical endpoints included detection of oncogenic drivers, turnaround time, comparison to tissue NGS when available, and ability to match pts to targeted therapy along with their treatment outcomes.
Result:
Seventy-six pts were prospectively accrued. Plasma NGS detected an oncogenic driver in 36% (27/76) of pts, of whom 14% (11/76) were matched to targeted therapy; including pts matched to clinical trials for HER2 exon 20 insYVMA, BRAF L597Q and MET exon14. Of the 10 evaluable pts, 10 partial responses were observed. Mean turnaround time for plasma was 6 days (3-12) vs 21 days (16-30) for tissue (P <0.0001). Plasma ctDNA was detected in 60% (46/76) of pts; detection rate was 46% (16/35) if blood was drawn on active therapy and 73% (30/41) if drawn off therapy, either at diagnosis or progression (Odds ratio 0.31, 95% CI 0.12 – 0.81; P=0.02). Of the 25 concurrent tissue NGS performed to date, there was a 96% plasma concordance with tissue and a 60% tissue concordance with plasma for driver mutations.
Conclusion:
In pts who were driver or resistance mechanism unknown, plasma NGS identified a variety of oncogenic drivers with significantly shorter turnaround time compared to tissue NGS, and matched patients onto targeted therapy with clinical benefit. Plasma ctDNA is best detected at diagnosis of metastatic disease or at progression. A positive finding of an oncogenic driver in plasma is highly specific and can immediately guide treatment, but a negative finding may still require tissue biopsy. Our findings provide evidence to support the incorporation of plasma NGS into practice guidelines.
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-011 - Pattern of Care and Survival of ALK Rearranged Non-Small Cell Lung Cancer in Two Australian Referral Centres (ID 8893)
09:30 - 16:00 | Author(s): Nick Pavlakis
- Abstract
Background:
ALK rearranged non-small cell lung cancer (ALK+NSCLC) represents a unique sub-group of lung cancer. Multiple effective treatments have been investigated and reported with the optimal strategy to treat advanced disease evolving rapidly with new data. First, second and now third generation single agent ALK inhibitors (ALKi) achieve excellent objective response rates (ORR), superior to chemotherapy; however, drug resistance is inevitable and remains under ongoing evaluation. Further studies are underway incorporating combination treatments, particularly immunotherapy with ALKi. Overall survival data from clinical trials continues to mature, as few non-trial series have been reported. We report our overall survival (OS) experience in treating ALK+NSCLC in a real-world cohort.
Method:
All patients with advanced lung cancer and a diagnosis of ALK+ NSCLC treated until Jan 2017 in two tertiary referral centres in Sydney, Australia were pooled together for analysis. Baseline demographic, symptom, treatment and sequencing, ORR and central nervous system (CNS) ORR, survival, toxicity and cause of death data were collected. Data will be presented on updated survival via Kaplan-Meir plots with 95% confidence intervals and a swimmer plot of treatment sequencing and ORR via RECIST 1.1.
Result:
Between 18/2/2010 and 28/1/2017, 56 ALK-rearranged lung cancer patients were identified. Median age was 63 years, 41% were female; 62% never-smokers, 63% non-Asian and 66% managed on a clinical trial. At first data cut (March 31, 2017), 52% had died. Median OS in the whole cohort was 44.6 months (95%CI: 27.8-61.4mo). Two patients were not fit for active treatment; one did not receive CNS imaging. All current ALKi therapies, chemotherapy, brain directed therapy, treatment to oligo-progressive disease and combination ALKi/immunotherapy were represented. Sixty-one percent of patients received an ALKi first line with an ORR 87%; 85% of the 34 (61%) patients who received second line therapy received an ALKi, ORR 52%. Thirty-percent received at least two lines of ALKi; 44% who received only one line of ALKi remained on and are still responding at data cut-off. Median OS in the 59% of patients with CNS metastases was 44.6mo (95% CI 14.7-74.6 mo).
Conclusion:
Analysis of real world data from two ALK referral centres in Australia reveals an imposing survival, despite many patients being managed before next generation inhibitors were available in the early line setting. While CNS disease is common in ALK patients, with aggressive local therapy and evolving treatments, survival in this cohort was comparable to those without brain metastases.
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P2.03 - Chemotherapy/Targeted Therapy (ID 704)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.03-044 - OSCILLATE - Phase 2 Trial of Alternating Osimertinib with Gefitinib in Patients with EGFR-T790M Mutation Positive Advanced NSCLC (ID 9711)
09:30 - 16:00 | Author(s): Nick Pavlakis
- Abstract
Background:
Activating mutations of the epidermal growth factor receptor (EGFR) are key drivers of non-small cell lung cancer (NSCLC) in approximately 10-15% of Western patients and 30-35% of Asian patients. Patients with common activating mutations (L858R and del19) typically have objective tumour response rates (OTRR) of 56-74% and median progression free survival (PFS) of 9-13 months with first-generation EGFR tyrosine kinase inhibitors (TKI) such as erlotinib or gefitinib. The most common mechanism of acquired resistance to first generation EGFR TKI is the T790M mutation (50-60% of cases). Osimertinib is an irreversible EGFR TKI effective against the T790M resistance mutation with OTRR of 51-71% in T790M positive disease. However, acquired resistance invariably develops, and median PFS is approximately 10 months. Mechanisms of resistance include C797S mutations and loss of T790M. Novel strategies that prevent or delay resistance to osimertinib are likely to enhance its durability of response and clinical benefit in EGFR-T790M positive NSCLC.
Method:
DESIGN: Open-label, single arm, multi-centre, phase 2 trial with safety run in. ELIGIBILITY: Adults with advanced, EGFR mutated NSCLC, acquired resistance to first or second generation EGFR TKIs, and mutation of T790M. ENDPOINTS: PFS rate at 12 months, feasibility of alternating osimertinib and gefitinib, time to progression and PFS time, objective tumour response rate, overall survival and adverse events. Tertiary correlative objectives include changes in plasma cfDNA levels for activating EGFR mutations and T790M over time, their relationships with OTRR and the mechanism of resistance. TREATMENT: Osimertinib 80mg daily for 8 weeks (2 cycles), then gefitinib 250mg daily for 4 weeks alternating with osimertinib 80mg daily for 4 weeks (i.e. alternating 4 weekly cycles of each drug) until disease progression or prohibitive toxicity. STATISTICS: A total of 45 participants provides 90% power, with a 1-sided type 1 error rate of 10%, to distinguish the observed proportion alive and progression free at 12 months from true rates of 45% (not worthy of pursuit) and 65% (worthy of pursuit) using a Simon, 2-stage, minimax design allowing for 4 ineligible or inevaluable participants. ASSESSMENT: CT scans 8-weekly until disease progression. Plasma collections at baseline and at the start of each 4-week cycle. OSCILLATE is an investigator-initiated cooperative-group trial led by ALTG, in collaboration with NHMRC Clinical Trials Centre, University of Sydney, with support from Astra-Zeneca.
Result:
Section not applicable
Conclusion:
Section not applicable
