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Agnieszka Cseh



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    EP1.14 - Targeted Therapy (ID 204)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.14-49 - A Phase IIIb Open-Label Study of Afatinib in EGFR TKI-Naïve Patients with EGFRm+ NSCLC: Exploratory Biomarker Analysis (Now Available) (ID 1265)

      08:00 - 18:00  |  Author(s): Agnieszka Cseh

      • Abstract
      • Slides

      Background

      The safety and efficacy of EGFR TKIs in patients with EGFR mutation-positive (EGFRm+) NSCLC have previously been demonstrated. Here, we present results of a biomarker analysis from a subset of patients in a Phase IIIb study of afatinib in EGFR TKI-naïve patients with locally advanced/metastatic EGFRm+ NSCLC. The aim was to explore the relationship between tumor mutation type, and patients’ response to afatinib in terms of efficacy and tolerability.

      Method

      Patients with EGFR TKI-naïve EGFRm+ NSCLC received 40 mg/day afatinib until lack of clinical benefit (determined by investigator). The primary endpoint was incidence of serious adverse events (SAEs). Secondary endpoints were number of patients with drug-related AEs, and time to symptomatic progression (TTSP). Further endpoints included progression-free survival (PFS). For biomarker analysis, peripheral blood samples were collected during scheduled visits from patients entering the study at Beijing Cancer Hospital. DNA extracted from samples collected at Visit 3 and baseline was analyzed for EGFR and pre-specified non-EGFR mutations, respectively, using an amplification-refractory mutation system.

      Result

      In total, 64 patients were included in the biomarker analysis. Baseline characteristics: Chinese, 100%; female, 70.3%; mean age, 57.4 years; EGFR mutations: L858R, 50%; Del19, 42.2%. All patients experienced ≥1 drug-related AE, most commonly (grouped terms; any grade/≥3): diarrhea (n=63/9, 98.4%/14.1%) and rash or acne (n=52/5, 81.3%/7.8%). SAEs were reported for 15 patients (23.4%), most commonly cerebral infarction (n=3, 4.7%), malignant neoplasm progression, CNS metastases (both n=2, 3.1%). Median TTSP was 13.5 months (95% CI: 10.9, 18.0). At baseline, 19 of 42 patients analyzed (45.2%) had additional non-EGFR mutations; 17 (89.5%) progressed/died. Median PFS was 8.1 months in these patients, versus 12.5 months for patients with EGFR-only mutations (HR, 1.72; 95% CI 0.88, 3.36; p=0.1054). At Visit 3, mutation status had changed from EGFRm+ to EGFR mutation-negative in 33 of 40 patients analyzed (82.5%). Of these, 29 (87.9%) progressed/died; median PFS was 11.0 months versus 5.5 months for patients who remained EGFRm+ (HR, 1.25; 95% CI: 0.47, 3.30; p=0.6556).

      Conclusion

      In this analysis, safety data were consistent with the known safety profile of afatinib. Median PFS was twice as long in patients who became EGFR mutation-negative compared with those who remained EGFRm+; however, the difference was not statistically significant. There was no significant difference in PFS for patients with additional non-EGFR versus those with EGFR-only mutations. This exploratory analysis suggests that afatinib has clinical benefit for patients with EGFRm+ NSCLC across all the subgroups assessed.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-25 - Targeting NRG1-Fusions in Lung Adenocarcinoma: Afatinib as a Novel Potential Treatment Strategy (ID 1805)

      09:45 - 18:00  |  Author(s): Agnieszka Cseh

      • Abstract
      • Slides

      Background

      Neuregulin 1 (NRG1) gene fusions result in activation of ErbB2-/ErbB3-mediated signaling pathways, and may function as oncogenic drivers. NRG1 fusions have emerged as a potential therapeutic target across multiple tumor types, including non-small-cell lung cancer (NSCLC). Afatinib, a pan-ErbB-family blocker, may be a treatment option for patients with NRG1+ NSCLC, as supported by preclinical evidence and seven published case reports (Table).

      Method

      Here, we report clinico-pathological and molecular characteristics of four new cases of NRG1 fusion-positive lung adenocarcinoma treated with afatinib. Afatinib activity is reported.

      Result

      Case 1 is a 70-year-old, female, never-smoker, diagnosed with pan-wildtype, non-mucinous, adenocarcinoma. She received afatinib in the fifteenth-line setting and experienced a partial response (PR) for 24 months. Following further progression on chemotherapy, NRG1-fusion was identified using NanoString analysis (re-biopsy was performed to find an explanation for afatinib efficacy). The patient was re-challenged with afatinib (best response: PR [3 months]), before switching to atezolizumab (best response: progressive disease).

      Case 2 is a 66-year-old female, never-smoker, diagnosed with metastatic, non-mucinous adenocarcinoma. A CD74-NRG1 fusion was identified by Oncomine™ Comprehensive Assay, and fifth-line afatinib treatment was initiated. She experienced a PR, ongoing after 14 months of treatment.

      Case 3 is a 68-year-old male diagnosed with lung adenocarcinoma. A SDC4-NRG1 fusion was subsequently identified using Next Generation Sequencing and the patient initiated second-line afatinib treatment. He achieved stable disease as best response, lasting for four months.

      Case 4 is a 43-year-old, female, non-smoker, diagnosed with advanced invasive mucinous adenocarcinoma. A CD74-NRG1 fusion was subsequently identified by RNA sequencing and the patient initiated third-line afatinib treatment; PR is ongoing.

      Conclusion

      These findings add to a growing body of evidence suggesting afatinib activity in NRG1-fusion positive NSCLC. Prospective study of a larger cohort of patients with NRG1-fusion positive NSCLC treated with afatinib is warranted to better evaluate this potential activity.

      Patient

      Tumor type

      NRG1 fusion partner

      Best response

      Duration of response (months)

      Reference

      i

      Non-mucinous lung adenocarcinoma

      SLC3A2

      PR

      12

      Gay, et al. J Thoracic Oncol 2017

      ii

      IMA

      CD74

      PR

      10

      Gay, et al. J Thoracic Oncol 2017

      iii

      Non-mucinous lung adenocarcinoma

      SDC4

      PR

      12

      Jones, et al. Ann Oncol 2017

      iv

      IMA

      CD74

      PR

      6.5

      Cheema, et al. J Thoracic Oncol 2017

      v

      IMA

      CD74

      SD

      3

      Drilon, et al. Cancer Discov 2018

      vi

      IMA

      SDC4

      PD

      -

      Drilon, et al. Cancer Discov 2018

      vii

      IMA

      CD74

      PD

      -

      Drilon, et al. Cancer Discov 2018

      IMA, invasive mucinous lung adenocarcinoma; PD, progressive disease; SD, stable disease

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      P1.14-62 - Afatinib in EGFR TKI-Naïve Patients with EGFR Mutation-Positive NSCLC: Combined Analysis of Two Single-Arm Phase IIIb Studies (ID 1338)

      09:45 - 18:00  |  Author(s): Agnieszka Cseh

      • Abstract
      • Slides

      Background

      First-line afatinib significantly improved progression-free survival (PFS) compared with platinum-doublet chemotherapy in patients with EGFR mutation-positive (EGFRm+; including uncommon mutations) NSCLC in two Phase III studies (LUX-Lung 3: median 11.1 vs 6.9 months, hazard ratio [HR]=0.58; p=0.001; LUX-Lung 6: 11.0 vs 5.6 months, HR=0.28; p<0.0001). First-line afatinib also significantly improved PFS compared with gefitinib in the Phase IIb LUX-Lung 7 study (11.0 vs 10.9 months, HR=0.73; p=0.017). However, some patients still receive chemotherapy as a first-line treatment choice in clinical practice. Here, we report a combined analysis of outcomes from two large Phase IIIb studies of afatinib in EGFR TKI-naïve patients treated in a setting similar to real-world practice.

      Method

      In both studies, EGFR TKI-naïve, including chemotherapy-pretreated, patients with locally advanced or metastatic EGFRm+ NSCLC received 40 mg/day afatinib until progressive disease or lack of tolerability (dose reduction was permitted [minimum: 20 mg/day]). Study 1 enrolled patients across eight European countries, and Russia, Israel and Australia; Study 2 enrolled patients from centres in China, Hong Kong, India, Singapore, and Taiwan. Interim (Study 1; data cut-off: 30 April 2018) and final (Study 2; data cut-off: 06 July 2018) data were used for this combined analysis of time to symptomatic progression (TTSP), PFS, objective response, and safety.

      Result

      A total of 1020 patients were treated with afatinib (female: 59%; Asian/White/other: 54%/46%/<1%; median age [range]: 61 years [25–89]; ECOG PS 0/1/2: 26%/69%/5%; common/uncommon EGFR mutations: 82%/18%; treatment line 1st/2nd/≥3rd: 69%/23%/8%; presence of brain metastases: 18%). Overall, median TTSP was 14.6 months (95% confidence interval [CI]: 13.8–15.8 months); median PFS was 12.9 months (95% CI: 11.6–13.7 months). Objective response rate was 52.7%. Adverse events (AEs; all grade/grade ≥3) occurred in 1012/556 (99%/55%) patients; serious AEs were reported in 366 patients (36%). The most common grade ≥3 AEs were diarrhoea (14%) and rash (9%). Any-cause AEs leading to dose reduction were reported in 412 (40%) patients. Treatment discontinuation due to afatinib-related AEs occurred in 54 patients (5%).

      Conclusion

      In this combined analysis of two large, prospective ‘real-world’ afatinib studies in EGFR TKI-naïve patient populations, which included patients treated with afatinib in later lines, patients with ECOG PS 2, patients with brain metastases, and patients with uncommon mutations, safety data were consistent with previous results seen in the LUX-Lung 3, 6, and 7 studies. Efficacy findings are also encouraging, with a median TTSP of 14.6 months.

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-99 - A Phase IIIb Open-Label Study of Afatinib in EGFR TKI-Naïve Patients with EGFR Mutation-Positive NSCLC: Final Analysis (ID 1671)

      10:15 - 18:15  |  Author(s): Agnieszka Cseh

      • Abstract
      • Slides

      Background

      The safety and efficacy of afatinib, an orally administered irreversible EGFR TKI, have been demonstrated in patients with EGFR mutation-positive (EGFRm+) NSCLC in several Phase III clinical trials. However, prospective evidence supporting the clinical benefit of afatinib in the real-world setting is limited. Here, we report final data from a Phase IIIb open-label, multicenter trial evaluating safety and efficacy of afatinib in EGFR TKI-naïve Asian patients with locally advanced/metastatic EGFRm+ NSCLC, in a setting similar to real-world practice.

      Method

      EGFR TKI-naïve patients with locally advanced/metastatic EGFRm+ NSCLC were recruited from 34 sites in China, Hong Kong, India, Singapore, and Taiwan. Patients received 40 mg/day afatinib. Dose reduction to minimum 20 mg/day was permitted. Treatment continued until lack of clinical benefit as determined by the investigator. The primary and secondary safety endpoints were number of patients with serious adverse events (SAEs), and number of patients with drug-related AEs, respectively. The secondary efficacy endpoint was time to symptomatic progression (TTSP). Further endpoints included progression free survival (PFS), objective response, and duration of disease control.

      Result

      In total, 541 patients received afatinib. Baseline characteristics were representative of patients with EGFRm+ NSCLC (median age, 59 years; female, 52.9%; never smoked, 69.3%; EGFR mutations, common [Del19/L858R]/uncommon: 88.2% [48.2%/40.5%]/11.8%; ECOG performance status 0/1, 18.3%/79.7%; brain metastases, 19%). SAEs were reported in 164 patients (30.3%). 34 patients (6.3%) had drug-related SAEs, most commonly (grouped terms): diarrhea (1.8%), stomatitis (0.7%), and vomiting (0.7%). Drug-related AEs (DRAEs) of any grade were reported in 528 patients (97.6%). AEs leading to dose reduction occurred in 154 patients (28.5%); TRAEs leading to treatment discontinuation were reported in 17 patients (3.1%). Three patients experienced DRAEs leading to death (decreased appetite, dyspnea, and respiratory failure). Median TTSP was 14.0 months (95% confidence interval [CI]: 12.9, 15.9) and median PFS was 12.1 months (95% CI: 11.0, 13.6). Objective responses were reported in 312 patients (57.7%) by week 52; the median duration of response was 12.2 months (95% CI: 11.0, 13.5). 483 patients (89.3%) achieved disease control of median duration 13.6 months (95% CI: 12.1, 14.4).

      Conclusion

      Safety data for afatinib in this patient population were consistent with previously reported data, with no new safety signals. AEs were manageable and did not lead to discontinuation in most patients. This study also demonstrated the efficacy and clinical benefit of afatinib in Asian patients with locally advanced or metastatic EGFRm+ NSCLC in a near real-world setting.

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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
    • +

      P2.14-58 - A Phase IIIb, Open-Label Study of Afatinib in Caucasian EGFR TKI-Naïve Patients with EGFRm+ NSCLC: An Interim Analysis (ID 1371)

      10:15 - 18:15  |  Author(s): Agnieszka Cseh

      • Abstract
      • Slides

      Background

      First-line afatinib demonstrated significantly improved median PFS in patients with EGFR mutation-positive (EGFRm+) NSCLC versus chemotherapy in LUX-Lung 3/6 (HR [95% CI]: 0.58 [0.43–0.78]/0.28 [0.20–0.39]), and versus gefitinib in LUX-Lung 7 (0.73 [0.57–0.95]). Since these trials had strict inclusion criteria, it is important to support these findings with real-world studies of broader patient populations. We report interim results of a Phase IIIb study of afatinib treatment for EGFRm+ NSCLC in a patient population similar to real-world practice.

      Method

      EGFR TKI-naïve patients with locally advanced/metastatic EGFRm+ NSCLC, and ECOG PS 0–2, received afatinib 40 mg/day. Dose reduction was permitted (minimum 20 mg/day). Primary endpoint: adverse events (AEs; descriptive fashion). Efficacy was also assessed.

      Result

      At data cut-off (30-April-2018), 479 patients were enrolled and treated (Caucasian/Asian/other: 97%/2%/<1%; ECOG PS 0–1/2: 92%/8%; 1st/2nd/≥3rd-line therapy: 78%/17%/5%; common/uncommon mutations: 87%/13%; brain metastases: 17%). Median time on afatinib: 359 days. Objective response and disease control rates were 46% and 86%, respectively. Other efficacy outcomes are in the Table. The most common grade ≥3 afatinib-related AEs were diarrhoea (16%) and rash (11%). 258 (54%) patients had AEs leading to dose reduction (most frequently diarrhoea [25%]/rash [11%]), and 37 (8%) had TRAEs leading to discontinuation (most frequently diarrhoea [3%]; all others [<1%]). Serious afatinib-related AEs occurred in 39 (8%) patients.

      Median TTSP, months

      (95% CI)

      Median PFS, months

      (95% CI)

      All pts (n=479)

      14.9

      (13.8–17.6)

      13.4

      (11.8–14.5)

      Line of therapy

      1st (n=374)

      15.6

      (14.1–18.5)

      13.8

      (12.6–15.2)

      2nd (n=81)

      14.7

      (11.3–20.6)

      13.2

      (8.3–17.7)

      ≥3rd (n=24)

      8.1

      (3.7–14.4)

      6.6

      (3.2–12.6)

      Baseline brain metastases*

      No (n=395)

      15.8

      (14.1–18.8)

      13.9

      (12.7–15.5)

      Yes (n=83)

      13.7

      (9.7–17.2)

      10.1

      (8.2–13.9)

      Baseline mutation type*

      Common (n=416)

      15.9

      (14.5–19.1)

      14.1

      (13.0–15.7)

      Uncommon (n=62)

      6.7

      (5.4–8.3)

      5.9

      (4.0–7.4)

      Baseline ECOG PS*, including age

      01 (n=442)

      15.8
      (14.4–18.8)

      13.8
      (12.8–15.2)

      <65 years (n=221)

      14.7
      (12.7–17.6)

      13.4
      (11.6–15.5)

      65 years (n=221)

      18.9
      (14.7–21.7)

      14.1
      (12.6–16.4)

      2 (n=36)

      8.9
      (5.7–13.2)

      6.2
      (2.5–11.6)

      <65 years (n=16)

      6.0
      (2.4–13.2)

      3.2
      (1.5–9.1)

      65 years (n=20)

      9.9
      (7.6–13.9)

      7.7
      (5.7–13.9)

      *Missing (n=1); Del 19 and/or L858R with or without uncommon mutation; Includes, n (%, of those with uncommon mutations): ex 20 ins: 37 (60), T790M: 12 (19), G719S/A/C: 12 (19), L861Q: 10 (16), S768I: 9 (15). TTSP, time to symptomatic progression; PFS, progression-free survival

      Conclusion

      This interim analysis indicated predictable and manageable safety, and encouraging efficacy, with afatinib in a broad patient population. The high proportion of patients with tumours harbouring exon 20 insertions may account for the differences in TTSP/PFS by common/uncommon mutation subgroup. Independent of treatment line, median TTSP/PFS in patients with ECOG PS 0–1 (LUX-Lung trials’ inclusion criteria) was 15.8/13.8 months, and, notably, was 18.9/14.1 months in those also aged ≥65 years. These findings by ECOG PS/age are consistent with those of the LUX-Lung trials.

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