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Maya Gottfried



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    OA14 - Update of Phase 3 Trials and the Role of HPD (ID 148)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
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      OA14.01 - KEYNOTE-024 3-Year Survival Update: Pembrolizumab vs Platinum-Based Chemotherapy for Advanced Non–Small-Cell Lung Cancer (ID 1465)

      11:30 - 13:00  |  Author(s): Maya Gottfried

      • Abstract
      • Slides

      Background

      In the phase 3 KEYNOTE-024 trial (NCT02142738), first-line pembrolizumab significantly improved PFS (hazard ratio [HR] 0.50, P<0.001) and OS (HR 0.60, P=0.005) vs platinum-based chemotherapy in patients with advanced NSCLC, PD-L1 tumor proportion score (TPS) ≥50%, and no targetable EGFR/ALK alterations (median follow-up, 11.2 months). We present data with 3-years minimum follow-up.

      Method

      Patients were randomized to pembrolizumab 200 mg Q3W for 2 years or platinum doublet (investigator’s choice) for 4‒6 cycles plus optional maintenance (nonsquamous), with stratification by ECOG PS (0/1), tumor histology (squamous/nonsquamous), and region (East Asia/non‒East Asia). Patients in the chemotherapy arm could cross over to pembrolizumab upon disease progression if they met eligibility criteria. The primary endpoint was PFS; OS was a key secondary endpoint. Response per investigator by RECIST version 1.1 is reported.

      Result

      305 patients were randomized (pembrolizumab, n=154; chemotherapy, n=151). At data cutoff (February 15, 2019), median (range) follow-up was 44.4 (39.6‒52.9) months. 210 patients had died (pembrolizumab, n=97; chemotherapy, n=113). 98 (64.9%) patients crossed over from chemotherapy to anti‒PD-(L)1 therapy during/outside of the study. Median (95% CI) OS in the pembrolizumab arm was 26.3 (18.3‒40.4) months vs 14.2 (9.8‒18.3) months in the chemotherapy arm (HR, 0.65; 95% CI, 0.50‒0.86). 36-month OS rate was 43.7% in the pembrolizumab arm vs 24.9% in the chemotherapy arm. Despite longer mean treatment duration in the pembrolizumab arm (11.1 vs 4.4 months), grade 3‒5 treatment-related adverse events (AEs) were less frequent with pembrolizumab vs chemotherapy: 31.2% vs 53.3%. 38 patients in the pembrolizumab arm completed 2 years (35 cycles) of therapy. Among these, 34 were alive, 31 (81.6%) had an objective response (including 3 with complete response), and median duration of response was not reached (range, 4.2‒46.7+ months). OS rate 12 months after completing pembrolizumab treatment (ie, ~36 months after initiating treatment) was 97.4% (95% CI, 82.8‒99.6). Among the 38 patients who completed 2 years, 5 (13.2%) had treatment-related grade 3-4 AEs; no fatal treatment-related AEs occurred. 10 patients who completed 2 years (1 completed 34 cycles) and subsequently progressed received second-course pembrolizumab; 7 had an objective response, 8 remain alive.

      Conclusion

      With >3 years’ follow-up, first-line pembrolizumab monotherapy continued to provide durable long-term OS benefit vs chemotherapy despite a majority of patients assigned to chemotherapy crossing over to pembrolizumab. Pembrolizumab was associated with less toxicity than chemotherapy. Patients who completed 35 cycles of pembrolizumab had durable clinical benefit and most were alive at data cutoff.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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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): Maya Gottfried

      • 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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    P2.14 - 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): Maya Gottfried

      • 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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