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M. Schuler



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    MO07 - NSCLC - Targeted Therapies II (ID 114)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO07.13 - Efficacy of afatinib vs. chemotherapy in treatment-naïve patients with non-small cell lung cancer (NSCLC) harbouring activating EGFR mutations with or without metastatic brain disease (ID 1923)

      17:25 - 17:30  |  Author(s): M. Schuler

      • Abstract
      • Presentation
      • Slides

      Background
      Afatinib, an irreversible ErbB Family Blocker, was superior to pemetrexed/cisplatin in previously untreated patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) in a global Phase III trial, LUX-Lung 3. In patients with the two most common EGFR mutations (Del19, L858R) median progression-free survival (PFS) was 13.6 vs. 6.9 months (HR=0.47, 95% CI: 0.34–0.65; p<0.0001). Here we present the results for subgroups of patients with or without brain metastases (BM) with NSCLC harbouring common EGFR mutations.

      Methods
      In LUX-Lung 3 EGFR mutation-positive patients were randomized 2:1 to afatinib 40 mg daily or up to 6 cycles of pemetrexed/cisplatin at standard doses. Patients with stable BM (asymptomatic, stable >4 weeks with no treatment required) were allowed. Presence of BM was documented by the investigator during screening. Tumour assessments were performed every 6 weeks until 48 weeks and every 12 weeks thereafter until progression, and reviewed independently and by the investigator.

      Results
      308 patients with common EGFR mutations were randomized (afatinib: 204, pemetrexed/cisplatin: 104), including 35 with baseline BM (afatinib: 20, pemetrexed/cisplatin: 15). Of these, Del19 mutation was detected in 11 (afatinib) and 8 (pemetrexed/cisplatin) patients and L858R in 9 (afatinib) and 7 (pemetrexed/cisplatin) patients. The baseline characteristics of patients with or without BM were comparable (females: 74% vs. 66%, median age: 61 vs. 62 years, ECOG 0: 31% vs. 41%, median time since diagnosis: 1.2 vs. 1.1 months, respectively). Within the BM group, baseline characteristics were balanced between treatment arms with the exception of ECOG 1; 80% of afatinib-treated patients had ECOG 1 compared with 53% of those treated with pemetrexed/cisplatin. Median PFS by independent review was 13.7 (afatinib) vs. 8.1 (pemetrexed/cisplatin) months in patients without BM (HR=0.47, 95% CI: 0.33–0.68; p<0.0001), and 11.1 (afatinib) vs. 5.4 (pemetrexed/cisplatin) months in patients with BM (HR=0.52, 95% CI: 0.22–1.23; p=0.13). Objective response in patients without BM was 59% (afatinib) vs. 23% (pemetrexed/cisplatin), odds ratio=4.8, p<0.0001, and 70% (afatinib) vs. 20% (pemetrexed/cisplatin), odds ratio=11.0, p=0.007, in patients with BM. Investigator review showed a median PFS of 13.6 (afatinib) vs. 6.9 (pemetrexed/cisplatin) months in patients without BM (HR=0.38, 95% CI: 0.27–0.53; p<0.0001), and 6.7 (afatinib) vs. 5.4 (pemetrexed/cisplatin) months in those with BM (HR=0.67, 95% CI: 0.29–1.57; p=0.36). By investigator review, progressive disease in the brain was observed for 4.2% (7/167) and 3.7% (3/82) of patients without BM at baseline for afatinib and pemetrexed/cisplatin, respectively. All but one of these patients (on afatinib) had intracranial progression only. The median (range) time to progression in the brain in this small group was 11.6 (1.3, 20.2) months (afatinib) and 5.5 (2.6, 8.2) months (pemetrexed/cisplatin).

      Conclusion
      In patients with previously untreated NSCLC harbouring common EGFR mutations afatinib remains efficacious regardless of the presence or absence of BM. Control of synchronous asymptomatic BM with afatinib compares favourably with existing data for cranial radiation therapy.

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    O03 - NSCLC - Targeted Therapies I (ID 113)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O03.05 - Activity of afatinib in uncommon epidermal growth factor receptor (EGFR) mutations: Findings from three trials of afatinib in EGFR mutation-positive lung cancer (ID 1114)

      11:15 - 11:25  |  Author(s): M. Schuler

      • Abstract
      • Presentation
      • Slides

      Background
      EGFR (ErbB1) mutations define a lung cancer subtype with exquisite sensitivity to EGFR tyrosine kinase inhibitors (TKIs). While in-frame deletion in exon 19 (Del19) and a point mutation (L858R) in exon 21 are the two most common sensitizing EGFR mutations in non-small cell lung cancer (NSCLC), approximately 10% of EGFR mutation-positive tumours harbour uncommon mutations. These mutations represent a heterogeneous group of rare molecular alterations (or combinations) within exons 18–21, whose oncogenicity and sensitivity to EGFR TKIs may vary and has not been prospectively studied. Here we present the first prospective data series on activity of afatinib, the irreversible ErbB Family Blocker, in patients with tumours harbouring uncommon EGFR mutations.

      Methods
      This analysis is based on data from EGFR mutation-positive patients included in the LUX-Lung 2 (Phase II), LUX-Lung 3 and LUX-Lung 6 (both Phase III) studies. EGFR mutations were identified prospectively by direct sequencing in LUX-Lung 2 and by central testing with TheraScreen EGFR RGQ PCR kit (TheraScreen29) in LUX-Lung 3 and 6. Patients were classified as having common (Del19 or L858R) or uncommon (all other single or complex) mutations. Uncommon mutations were categorized into three groups: de novo T790M (alone or in combination with other mutations); exon 20 insertions; and other. Objective response rate (ORR), disease control (DCR), duration of response and progression-free survival (PFS) were assessed by independent review.

      Results
      Seventy-five patients (LUX-Lung 2: n=23; LUX-Lung 3: n=26; and LUX-Lung 6: n=26) had uncommon mutations, accounting for 12.5% of all afatinib patients in these studies. The majority of patients received afatinib first line; 13 patients from LUX-Lung 2 received afatinib after chemotherapy. Breakdown into the three groups was T790M: n=14; Exon 20 insertions: n=23; other: n=38 (most frequent types were L861Q: n=12; G719X: n=8; G719X+S768I: n= 5; G719X+L861Q: n=3). Efficacy results for each group are shown below. Further details by mutation status will be presented.

      Mutation ORR, % (n=) Median duration of response, months (95% confidence interval) DCR (ORR + stable disease), % (n) Median PFS, months (95% confidence interval) Median survival, months (95% confidence interval)
      De novo T790M alone or in combination with other mutations (n=14) 14.3 (2) Individual response durations: 4.1, 12.4 64.2 (9) 2.9 (1.2−8.3) 14.9 (8.1−24.9)
      Exon 20 insertions (n=23) 8.7 (2) Individual response durations: 4.2, 10.1 65.2 (15) 2.7 (1.8−4.2) 9.4 (4.1−21.0)
      Other (n=38) 71.1 (27) 11.1 (4.1, 15.2) 84.2 (32) 10.7 (5.6−14.7) 18.6 (16.4−not estimable)

      Conclusion
      Afatinib was active in lung tumours harbouring uncommon EGFR mutations, such as G719X, L861Q, S768I. Rate and duration of response was comparable with that previously observed in patients with common mutations in these trials. The response rate was low in tumours with de novo T790M mutations and insertions in exon 20 but durable tumour control was achieved in some patients. To date this is the largest analysis of data for prospectively identified patients with uncommon EGFR mutations; treatment options in this heterogeneous group of tumours will be discussed.

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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-045 - TRY: A phase II study to evaluate safety and efficacy of combined trastuzumab and AUY922 in advanced non-small-cell lung cancer (NSCLC) with HER2 overexpression or amplification or mutation. (ID 3057)

      09:30 - 09:30  |  Author(s): M. Schuler

      • Abstract

      Background
      HER2 amplifications and/or mutations are rare genetic alterations in NSCLC accounting for approximately 4%. Preliminary clinical data suggested efficacy of trastuzumab in patients with HER2 IHC3+ status or FISH positivity. The heat shock protein HSP90 is a molecular chaperone that modulates stability and/or transport of intracellular client proteins including HER2. In breast cancer HSP90 inhibition has shown anticancer activity in HER2-positive patients after trastuzumab failure. Here we are investigating the efficacy of the combination of trastuzumab and the HSP90 inhibitor AUY922 in lung cancer patients with aberrant HER2.

      Methods
      This phase II study recruits metastatic NSCLC patients with HER2 overexpression (immunohistochemistry, DAKO-score 3+) or amplification (fluorescence in situ hybridization) or activating mutation after at least one previous standard treatment. In the first part of the study, patients are treated with trastuzumab only. CT scans are scheduled every 6 weeks during treatment. In case of disease progression, patients receive the combination of trastuzumab and AUY922.

      Results
      The study was initiated this year and NSCLC patients are screened within the Network of Genomic Medicine Lung Cancer on HER2 overexpression, amplifications and mutations. Until now, we tested 720 tumor samples by FISH and 63 by genomic sequencing. We identified 55 patients with HER2 amplification, 34 with HER2 overexpression (Dako score 3+) and 7 patients showed a mutation in the HER2 gene (1 exon 19; 6 exon 20).

      Conclusion
      HER2 overexpression, amplification or mutation is a rare genetic alteration in NSCLC patients. Data on treatment with HER2 antibody trastuzumab and HSP90 inhibitor AUY922 will be presented.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-023 - Comparative safety profile of afatinib in Asian and non-Asian patients with EGFR mutation-positive (EGFR M+) non-small cell lung cancer (NSCLC) (ID 2141)

      09:30 - 09:30  |  Author(s): M. Schuler

      • Abstract

      Background
      Afatinib is an oral, irreversible ErbB Family Blocker which showed superior efficacy to standard first-line chemotherapy in two large randomized Phase III trials in global (LUX-Lung 3) and Asian (LUX-Lung 6) EGFR M+ patients. In both trials, median progression-free survival on afatinib was 11 months by independent review. This was also reflected in median treatment duration of 11–12 months in both trials. With long-term treatment duration, the safety profile of afatinib becomes particularly relevant to patients and physicians, and needs to be well characterized. Furthermore, differences in the pattern of some adverse events (AEs; notably interstitial lung disease [ILD]) have been previously described in Asian and non-Asian patients with reversible EGFR tyrosine kinase inhibitors. Here, we present a detailed review of afatinib’s safety profile in Asian and non-Asian patients.

      Methods
      229 (LUX-Lung 3) and 239 (LUX-Lung 6) EGFR M+ patients were treated with afatinib 40mg daily until progression or intolerable AEs. Afatinib dose could be escalated to 50mg daily or reduced to 30mg or 20mg based on predefined study criteria. Patients from both trials were grouped according to ethnicity: Asian vs. non-Asian. On-treatment AEs were summarized by preferred/grouped terms and graded using NCI-CTCAEv3.0.

      Results
      404 Asian (66% China/Taiwan; 16% Southeast Asia; 13% Japan; 5% Korea) and 64 non-Asian patients (95% Caucasian; 3% American-Indian; 2% African-American) received afatinib, with median exposure of 359 and 261 days, respectively. There was no difference in afatinib pharmacokinetic exposure in Asian vs. non-Asian patients. All patients reported at least one AE. Most common AEs were EGFR-mediated and are summarized in the table. Figure 1 Drug-related AEs leading to discontinuation were slightly higher in Asian patients, but at a rate lower than with chemotherapy (28%). Related ILD-like events occurred in four Asian patients (three Grade ≥3) and no non-Asian patients.

      Conclusion
      Most common drug-related AEs with afatinib were EGFR mediated and occurred at similar frequency in Asian and non-Asian patients. Treatment discontinuation due to EGFR-related AEs was low in both groups, indicating that afatinib has a manageable safety profile in both populations and is suitable for long-term treatment of EGFR M+ NSCLC patients.