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A. Märten



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    Immunotherapy and next-generation TKIs: From second to frontline treatment (ID 55)

    • Event: ELCC 2018
    • Type: Poster Discussion session
    • Track:
    • Presentations: 1
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      143PD - Competing central nervous system or systemic progression analysis for patients with EGFR mutation-positive NSCLC receiving afatinib in LUX-Lung 3, 6, and 7 (ID 561)

      07:45 - 09:00  |  Author(s): A. Märten

      • Abstract
      • Slides

      Background:
      CNS metastases are known complications of advanced EGFRm+ NSCLC, thus, LUX-Lung (LL) trials investigating afatinib allowed enrolment of patients (pts) with brain metastases (BM). LL3, 6 and 7 previously demonstrated activity of afatinib in pts with BM, with the magnitude of progression-free survival (PFS) improvement with afatinib vs chemotherapy or gefitinib in pts with BM being similar to that observed in pts without BM (HR 0.54, 0.47, and 0.76 in LL3, 6 and 7, respectively).[1,2] PFS was significantly improved with afatinib vs chemotherapy in a combined analysis of LL3 and 6 in pts with asymptomatic BM (HR 0.50, p = 0.0297).[1] To investigate whether afatinib can prevent CNS progression or metastasis, competing risk analyses for the progression and metastasis pattern in the CNS or non-CNS region were carried out in pts with and without BM in LL3, 6 and 7.

      Methods:
      Competing risk analyses were performed in pts with stage IIIB/IV EGFRm+ NSCLC who received afatinib 40 mg/d in LL3, 6 and 7. Analyses were performed separately for pts with baseline BM and without baseline BM. Risk of CNS progression vs non-CNS progression or death was calculated based on the cumulative frequency of the event of interest vs the competing risk event.

      Results:
      In pts with baseline BM receiving afatinib in LL3 and 6 (n = 48; median follow-up 10.3 mo), 31.3% had CNS progression vs 52.1% with non-CNS progression: cumulative incidence at 6 and 12 mo (CNS vs non-CNS) was 15.5% vs 17.7%, and 24.5% vs 24.4%, respectively. In pts without baseline BM receiving afatinib in LL3, 6 and 7 (n = 485; median follow-up 13.0 mo), risk of de novo CNS progression was very low (6.4%) compared with non-CNS progression (78.4%). Cumulative incidence at 6 and 12 mo (CNS vs non-CNS) was 1.3% vs 17.2%, and 2.6% vs 41.2%, respectively.

      Conclusions:
      Competing risk analyses using data from LL3, 6 and 7 add to the existing evidence that support afatinib use in pts with EGFRm+ NSCLC and CNS metastases. Taken together, these results suggest afatinib delays the onset/progression of BM. 1. Schuler. J Thorac Oncol 2016;11:380–90 2. Park. Lancet Oncol 2016;17: 577–89

      Clinical trial identification:
      NCT00949650, NCT01121393, NCT01466660

      Legal entity responsible for the study:
      Boehringer Ingelheim

      Funding:
      Boehringer Ingelheim

      Disclosure:
      J.C-H. Yang: Honoraria/advisory board: Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech/Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Clovis Oncology, Celgene, Merrimack, Yuhan Pharma, BMS, Ono Pharma Daiichi Sankyo, Astrazeneca. Y-L. Wu: Honoraria: AstraZeneca, Roche, Eli Lilly, Pfizer, Sanofi. V. Hirsh: Advisory Board: BI. K. O'Byrne: Advisory board & Honoraria: Astrazeneca, BMS, Roche-Genentech, MSD, Pfizer, Boehringer-Ingelheim, Novartis Speaker bureau activities: Astrazeneca, BMS, Roche-Genentech, MSD, Pfizer, Boehringer-Ingelheim Travel to international conferences: Astrazeneca, BMS, Roche-Genentech, MSD, Pfizer, Boehringer-Ingelheim 3 patents –1 on novel drugs and 2 on biomarkers – IP held by University. N. Yamamoto: Membership on an advisory board or board of directors: BI, AZ, Chugai Corporate-sponsored research: BI. S. Popat: Membership on an advisory board or board of directors: BI. A. Tamiya: Grants from Ono Pharmaceutical, Bristol-Myers Squibb Received personal fees from Eli Lilly, Ono Pharmaceutical, Chugai Pharmaceutical, Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb. A. Märten: Employment Boehringer Ingelheim. M. Schuler: Employment: Universität Duisburg-Essen, Universitätsklinikum Essen, Ruhrlandklinik Consultant (compensated): AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Novartis, Roche Consultant (not compensated): Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) Honoraries (CME presentations): Abbvie, Alexion, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, MSD, Novartis Research funding (institution) Boehringer Ingelheim, Bristol Myers-Squibb, Novartis Pantent: Universität Duisburg-Essen.

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    Poster Display session (Friday) (ID 65)

    • Event: ELCC 2018
    • Type: Poster Display session
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 4/13/2018, 12:30 - 13:00, Hall 1
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      158P - Afatinib in patients with EGFR mutation-positive (EGFRm+) NSCLC harbouring uncommon mutations: Overview of clinical data (ID 567)

      12:30 - 13:00  |  Presenting Author(s): A. Märten

      • Abstract
      • Slides

      Background:
      Approximately 10–12% of patients with EGFRm+ NSCLC have tumours harbouring uncommon EGFR mutations; however, there is a paucity of clinical data on the sensitivity of these tumours to EGFR TKIs. Preclinical data indicate that the irreversible ErbB family blocker, afatinib, has similar activity against certain uncommon mutations (e.g. L858M/S768I) to that against the common L858R mutation.[1,2]

      Methods:
      Here, we review the key clinical data available for first-line afatinib in EGFRm+ NSCLC harbouring uncommon EGFR mutations.

      Results:
      Post-hoc analysis of the randomised LUX-Lung 2/3/6 trials[3] demonstrates that afatinib is clinically active against certain uncommon EGFR mutations. Among 75 afatinib-treated patients with tumours harbouring uncommon mutations in these trials the objective response rate against G719X (n = 18), L861Q (n = 16) and S768I (n = 8) single/compound mutations was 78%, 56% and 100%. Response rate was lower in patients with exon 20 insertions (n = 23; 9%) or de novo T790M (n = 14; 14%). In 38 patients with uncommon mutations/duplications in exons 18–21 PFS was 10.7 months (95% CI 5.6–14.7) and OS was 19.4 months (95% CI 16.4–26.9). The clinical activity of afatinib against uncommon mutations is substantiated by observations outside of the randomised controlled trial setting. In a Phase IIIb single-arm open-label study of afatinib in its registered indication, 67 of 479 TKI-naïve patients had NSCLC with uncommon mutations[4] (exon 20 insertions; L861Q; G719S/A/C; T790M; S768I: 5.2; 4.6; 2.3; 1.0; 1.9%, respectively). Median PFS in these patients was 9.1 months (95% CI 5.6–13.6).[4] In an analysis of 165 EGFRm+ NSCLC patients treated with first-line afatinib in real-world practice in South Korea median PFS in those with uncommon mutations excluding T790M (n = 10) was not reached vs 4.7 months in those with T790M (n = 4; p = 0.01).[5]

      Conclusions:
      Afatinib has shown preclinical and clinical activity in patients with NSCLC harbouring uncommon EGFR mutations, including G719X, L861Q and S768I. These data could help inform clinical decisions in this patient population. 1. Saxon. J Thorac Oncol 2017;12:884 2. Banno. Cancer Sci 2016;107:1134 3. Yang. Lancet Oncol 2015;16:830 4. Wu. WCLC 2017 P3.01-036 5. Kim. WCLC 2017 P3.01-023

      Clinical trial identification:
      N/A

      Legal entity responsible for the study:
      Boehringer Ingelheim

      Funding:
      Boehringer Ingelheim

      Disclosure:
      A. Märten: Employment: Boehringer Ingelheim. N. Yamamoto: Membership on an advisory board or board of directors: BI, AZ, Chugai Corporate-sponsored research: BI. C-J. Yu: Membership on an advisory board or board of directors: Roche, ONO, Chugai, Novartis. Y-L. Wu: Honoraria: AstraZeneca, Roche, Eli Lilly, Pfizer, Sanofi. All other authors have declared no conflicts of interest.

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