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Maria Rita Migliorino



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    OA02 - A New Vision of Targets and Strategies (ID 120)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      OA02.07 - Phase 3 ALUR Study of Alectinib in Pretreated ALK+ NSCLC: Final Efficacy, Safety and Targeted Genomic Sequencing Analyses (Now Available) (ID 2267)

      10:30 - 12:00  |  Author(s): Maria Rita Migliorino

      • Abstract
      • Presentation
      • Slides

      Background

      The ALUR (NCT02604342) primary analysis (cut-off January 2017) demonstrated improved efficacy and safety with alectinib versus chemotherapy in patients with ALK+ NSCLC previously treated with chemotherapy and crizotinib. These patients can develop crizotinib resistance through ALK secondary mutations, but limited data exist regarding alectinib’s efficacy in patients with different post-crizotinib genetic profiles. We report final data from ALUR including treatment outcomes according to genetic profile.

      Method

      Overall, 119 patients with locally determined ALK+ NSCLC were randomised 2:1 to receive alectinib 600mg bid or chemotherapy (pemetrexed 500mg/m2 or docetaxel 75mg/m2 q3w). The primary endpoint was PFS by investigator. Targeted genomic sequencing (FoundationONE® [tissue; 315 genes] and FoundationACT® [plasma; 62 genes]) was performed retrospectively using tumour tissue (n=33) and baseline plasma (n=59).

      Result

      Final efficacy data confirmed those of the primary analysis (table). Grade ≥3 treatment-emergent adverse events were lower with alectinib (37.7%) than with chemotherapy (43.2%); adverse events causing treatment discontinuation were lower with alectinib (5.2% versus 10.8% chemotherapy), despite alectinib’s longer treatment duration. ALK fusions were confirmed retrospectively in 26/33 (78.8%) tissue and 41/59 (69.5%) plasma (post-crizotinib) samples. ORR in alectinib-treated patients with ALK fusions was 72.2% (13/18, tissue) and 63.0% (17/27, plasma) versus 0% for chemotherapy (tissue [0/8], plasma [0/14]). ALK secondary mutations were detected in 16/59 (27.1%) patients (plasma, both arms). ORR in the alectinib arm (plasma) was similar in patients with ALK fusions with (60.0%, 6/10) or without (64.7%, 11/17) ALK secondary mutations, but lower in patients with gene mutations other than ALK (23.1%, 3/13).

      Conclusion

      Final data from ALUR confirm the primary analysis, demonstrating improved efficacy and safety with alectinib versus chemotherapy in post-crizotinib ALK+ NSCLC. The role of reconfirming ALK status upon sequential ALK inhibitor treatment requires further investigation, due to the limited data and known technical challenges of plasma testing.

      Funding: F. Hoffmann-La Roche Ltd.

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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
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      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): Maria Rita Migliorino

      • 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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