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J. Laskin



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    MA08 - Treatment Monitoring in Advanced NSCLC (ID 386)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
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      MA08.03 - Osimertinib vs Platinum-Pemetrexed for T790M-Mutation Positive Advanced NSCLC (AURA3): Plasma ctDNA Analysis (ID 4733)

      11:12 - 11:18  |  Author(s): J. Laskin

      • Abstract
      • Presentation
      • Slides

      Background:
      AURA3 (NCT02151981) is a Phase III, open-label, randomised study assessing the efficacy and safety of osimertinib, a T790M directed EGFR-TKI, vs platinum-based doublet chemotherapy in patients with EGFR T790M-positive advanced NSCLC, whose tumours progressed on previous EGFR-TKI therapy. Concordance between plasma and tissue testing, and efficacy outcomes by baseline plasma T790M status, were evaluated.

      Methods:
      Eligible patients were randomised 2:1 to osimertinib 80 mg orally once daily or platinum-pemetrexed (pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 or carboplatin AUC5) every three weeks for up to six cycles. Patients were tumour tissue T790M-positive (by cobas[®] EGFR Mutation Test v2) from a biopsy after disease progression prior to study entry. Blood samples were taken at baseline for retrospective analysis of T790M mutation status by plasma ctDNA using the cobas[®] EGFR Mutation Test v2.

      Results:
      Concordance data are reported in the table. Within the intent-to-treat (ITT) population (n=419), patients plasma T790M-positive and randomised to treatment (n=172) had markedly improved progression-free survival (PFS) by investigator assessment (IA) with osimertinib vs platinum-pemetrexed: hazard ratio 0.42 (95% CI: 0.29, 0.61); median 8.2 vs 4.2 months. Objective response rate (ORR) by IA was also distinctly improved with osimertinib vs platinum-pemetrexed: 77% vs 39% (odds ratio 4.96 [95% CI: 2.49, 10.15]; p<0.001). This is consistent with the ITT population: PFS hazard ratio 0.30 (95% CI: 0.23, 0.41); p<0.001 (median 10.1 vs 4.4 months); ORR 71% vs 31% (odds ratio 5.39 [95% CI: 3.47, 8.48]; p<0.001). Figure 1



      Conclusion:
      In plasma T790M-positive patients the clinical benefit of osimertinib was superior to platinum-pemetrexed, consistent with the ITT T790M-positive population selected by tumour tissue test. PFS with osimertinib was similar regardless of selection by tissue or plasma T790M-positive status. Based on these, and AURA Phase II data, routine biopsy testing is recommended for patients with a plasma T790M-negative test where feasible.

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    OA23 - EGFR Targeted Therapies in Advanced NSCLC (ID 410)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
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      OA23.05 - First-Line Afatinib versus Gefitinib in EGFRm+ Advanced NSCLC: Updated Overall Survival Analysis of LUX-Lung 7 (ID 5347)

      15:05 - 15:15  |  Author(s): J. Laskin

      • Abstract
      • Presentation
      • Slides

      Background:
      The irreversible ErbB family blocker afatinib and the reversible EGFR TKI gefitinib are approved for first-line treatment of advanced EGFRm+ NSCLC. This Phase IIb trial prospectively compared afatinib versus gefitinib in this setting.

      Methods:
      LUX-Lung 7 assessed afatinib (40 mg/day) versus gefitinib (250 mg/day) in treatment-naïve patients with stage IIIb/IV NSCLC harbouring a common EGFR mutation (Del19/L858R). Co-primary endpoints were PFS (independent review), time to treatment failure (TTF) and OS. Other endpoints included ORR and AEs. In case of grade ≥3/selected grade 2 drug-related AEs the afatinib dose could be reduced to 30 mg or 20 mg (minimum). The primary analysis of PFS/TTF was undertaken after ~250 PFS events. The primary OS analysis was planned after ~213 OS events and a follow-up period of ≥32 months.

      Results:
      319 patients were randomised (afatinib: 160; gefitinib: 159). At the time of primary analysis, PFS (HR [95% CI] 0.73 [0.57‒0.95], p=0.017), TTF (0.73 [0.58‒0.92], p=0.007) and ORR (70 vs 56%, p=0.008) were significantly improved with afatinib versus gefitinib. The most common grade ≥3 AEs were diarrhoea (13%) and rash/acne (9%) with afatinib and elevated ALT/AST (9%) with gefitinib. 42% of patients treated with afatinib had ≥1 dose reduction due to AEs; dose reductions were more common in females than males (77%/23%) and non-Asians than Asians (64%/36%). Dose reduction of afatinib did not negatively impact PFS (<40mg vs ≥40mg; HR [95% CI]: 1.34 [0.90‒2.00]) but reduced incidence and severity of drug-related grade ≥3 AEs. Treatment discontinuation due to drug-related AEs was the same in each arm (6%). The data cut-off for primary OS analysis occurred on 8 April 2016. At this time, median treatment duration (range) was 13.7 (0‒46.4) versus 11.5 (0.5‒48.7) months with afatinib and gefitinib. 25% (afatinib) and 13% (gefitinib) of patients received treatment for >24 months. 73% and 77% of patients in the afatinib and gefitinib arms had ≥1 subsequent systemic anti-cancer treatment, with 46% and 56% receiving a subsequent EGFR-TKI including osimertinib (14%)/olmutinib (14%). OS data, including subgroup analysis with respect to subsequent therapy will be presented at the meeting.

      Conclusion:
      Afatinib significantly improved PFS, TTF and ORR versus gefitinib in EGFRm+ NSCLC patients, with a manageable AE profile and few drug-related discontinuations. Dose adjustment of afatinib reduced drug-related AEs without compromising efficacy. Primary OS analysis will be reported.

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    P1.02 - Poster Session with Presenters Present (ID 454)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P1.02-011 - Comparison of EGFR and KRAS Mutations in Archival Tissue and Circulating Tumor DNA: The Impact of Tumor Heterogeneity (ID 4504)

      14:30 - 14:30  |  Author(s): J. Laskin

      • Abstract

      Background:
      In non-small cell lung cancer (NSCLC), circulating tumour DNA (ctDNA) has gained acceptance as a potential alternative to tissue biopsies to identify targetable mutations. Individual ctDNA platforms have varying abilities to detect specific mutations. A prospective, multicenter study was conducted to determine concordance, sensitivity, and specificity of ctDNA genotyping, with archival tissue DNA (atDNA) as the reference standard.

      Methods:
      Patients with incurable advanced NSCLC at the BC Cancer Agency were enrolled over 14 months. Next-Generation Sequencing (NGS) and high-throughput multiplex amplification of a 27-gene panel (Raindance) was used for atDNA analysis. Four mL of plasma was collected in Streck (Cell Free DNA BCT) tubes for ctDNA genotyping using the Boreal Genomic OnTarget. Analysis of concordance, sensitivity, and specificity was conducted with atDNA used as the standard.

      Results:
      Seventy-six patients were enrolled, median age 66, 33 (44%) male, 69 (91%) metastatic disease, 47 (62%) with primary disease in-situ. Twenty-six EGFR mutations in 22 atDNA samples, and 12 mutations in 11 ctDNA samples were detected, with a concordance of 78%, sensitivity of 39%, and specificity 98%. One EGFR T790M mutation was positive by ctDNA alone. Twenty-one KRAS mutations in 21 atDNA samples were detected. Within this subgroup, 10 ctDNA samples had KRAS mutations with a concordance of 76%, sensitivity of 50%, and specificity of 80%. Fourteen KRAS mutations were detected by ctDNA only. The interval between archival tissue and ctDNA collection, and time between treatment and ctDNA collection, did not significantly impact the rate of concordance (p> 0.05).

      Conclusion:
      Although the sensitivity is limited, the Boreal Genomic OnTarget ctDNA analysis is specific in identifying clinically relevant EGFR mutations and has acceptable concordance rates between ctDNA and atDNA testing. Targetable EGFR and KRAS mutations were detected in ctDNA but not atDNA, which may reflect site of biopsy, tumor heterogeneity, or technical limitations of assays used. Given the high specificity and non-invasive nature of this test, positive results in EGFR mutations can be used to direct therapeutic decisions, especially accounting for clonal evolution overtime in detection of resistance mutations.

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    P1.05 - Poster Session with Presenters Present (ID 457)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Early Stage NSCLC
    • Presentations: 1
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      P1.05-060 - Adherence to Surveillance Guidelines in Resected NSCLC: Physician Compliance and Impact on Outcomes (ID 4624)

      14:30 - 14:30  |  Author(s): J. Laskin

      • Abstract

      Background:
      Guidelines on resected NSCLC have varying recommendations on appropriate post-operative surveillance. There is general consensus that patients require follow up q6m with clinic visits or CT scans for the first 2 y. This study evaluated compliance with surveillance guidelines and the impact on outcomes.

      Methods:
      The BC Cancer Agency provides comprehensive cancer control for a population of 4.5 million. Inclusion criteria included referred patients from 2005-2010, resected stage Ib/II NSCLC, minimum 2 y f/u at the BCCA, no prior lung cancer diagnosis. Retrospective chart review collected baseline parameters, follow up visits, CT imaging, recurrence and death.

      Results:
      479 were referred and 263 were eligible. Baseline characteristics median age 68, male 52%, current/former/never smoker 38/52/10%, stage Ib/II 51/49%, squamous/non 30%/70%, wedge/lobectomy/pneumonectomy 8/76/16%, adjuvant chemotherapy 46%. Adherence to 4 interventions in 2 y: clinic visits 62%, CT scans 18%, visit and/or CT 67%. Multivariate analysis (MVA) for predictors of guideline adherence demonstrated only stage was significant. Recurrence rate was 46% at 2 y with patterns of recurrence and treatment in table 1. Surveillance below vs per/above guidelines; PFS 26.6 m vs 22 m (p=0.54), OS 47 m vs 41.8 m (p=0.27).

      Follow up visits and/or CT scans below guidelines n=87 Follow up visits and/or CT scans per or above guidelines n=176 p value
      Recurrence within 2 years 32 (37%) 88 (50%)
      Method of detection 0.41
      Surveillance 18 (56%) 41 (47%)
      Patient 14 (44%) 47 (53%)
      Distribution of recurrence 0.16
      Second primary 1 (3%) 2 (2%)
      Locoregional recurrence only 10 (31%) 14 (16%)
      Metastatic 21 (66%) 73 (82%)
      Curative intent treatment at recurrence 5 (16%) 6 (7%) 0.16
      Palliative chemotherapy 7/27 (26%) 32/82 (39%) 0.25


      Conclusion:
      Compliance with follow up recommendations for resected NSCLC was 67% in our study. Guideline conformity did not increase the rate of curative intent therapy at recurrence due to metastatic presentation nor did it increase the proportion of patients treated with palliative chemotherapy. Better adjuvant treatment and surveillance options need to be developed for resected NSCLC.