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S.L. Geater



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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)

      10:30 - 12:00  |  Author(s): S.L. Geater

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 2
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      P3.11-011 - Serum albumin as a potential pharmacodynamic biomarker in patients treated with the anti-hepatocyte growth factor monoclonal antibody ficlatuzumab (ID 1067)

      09:30 - 16:30  |  Author(s): S.L. Geater

      • Abstract

      Background
      Ficlatuzumab is an anti-hepatocyte growth factor (HGF) monoclonal antibody (mAb) being tested in clinical trials for cancer. Hypoalbuminemia has been observed in these trials, as well as in trials with other HGF/c-Met inhibitory mAbs. The relationship between serum albumin (SA) and ficlatuzumab treatment is examined.

      Methods
      Ficlatuzumab was studied in P05538, a first-in-human dose escalation trial; in P05670, a dose ranging trial investigating the pharmacodynamic (PD) effect of ficlatuzumab; and in P06162, a phase II study in combination with gefitinib (FG arm) versus gefitinib alone (G arm) in NSCLC patients. Patient data from these studies were evaluated longitudinally for peripheral edema, changes in SA, serum Ca[2+] (Ca), liver function tests (LFTs), prothrombin time (PT) and proteinuria.

      Results
      In P05538, all 23 evaluable patients had SA decrease with median change to nadir of -29% (-46 to -11%) and median nadir SA level of 25 g/L (15 to 33 g/L). In P05670, all 19 evaluable patients had decreased SA, with median change to nadir of -20% (-49 to -7%) and median nadir SA level of 31 g/L (14 to 40 g/L). In P06162, 88 of 90 (98%) evaluable patients in FG arm experienced SA decrease, with a median nadir change of -27% (range -62 to 8%). No significant SA changes were observed in the G arm. LFTs and PT were not significantly changed in any of the trials. Peripheral edema was observed in 52%, 32%, 38%, and 4% of the patients in P05538, P05670, FG, and G arms of P06162, respectively. In P06162, low Ca laboratory findings (not corrected for albumin) were reported in 72% of patients, with median change to nadir of -11% (-24% to 5%). Changes in uncorrected Ca were secondary to changes in albumin (% changes Pearson correlation=0.68, P<0.0001). No difference in the rate of proteinuria was observed across FG and G arms of the 6162 trial.

      Conclusion
      Decrease in SA during ficlatuzumab treatment was seen in almost all patients and appears to be unrelated to hepatotoxicity. Decrease in SA resulting from ficlatuzumab treatment may be the cause of peripheral edema. Both hypoalbuminemia and peripheral edema were frequently observed with other HGF/c-Met inhibitors, suggesting they may be class adverse events. Decrease in SA could be explored as a PD marker for HGF/c-Met inhibition.

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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 - 16:30  |  Author(s): S.L. Geater

      • 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.