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David Vicente



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    MA02 - Improving Outcomes for Patients with Lung Cancer (ID 895)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 201 BD
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      MA02.03 - ASTRIS: A Real World Treatment Study of Osimertinib in Patients with EGFR T790M-Positive NSCLC (ID 12972)

      10:40 - 10:45  |  Author(s): David Vicente

      • Abstract
      • Presentation
      • Slides

      Background

      Osimertinib is a third-generation, CNS-active EGFR-TKI that potently and selectively inhibits both EGFR-TKI sensitizing and EGFR T790M resistance mutations. We report results from a second planned protocol, optimal interim analysis of the ongoing ASTRIS study (NCT02474355).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligible patients receive osimertinib 80 mg once daily. Inclusion criteria: stage IIIB/IV T790M-positive non-small cell lung cancer (NSCLC); T790M status confirmed locally by validated test, not restricted by sample type; prior EGFR-TKI therapy received; WHO performance status (PS) 0−2; acceptable organ and bone marrow function and no history of interstitial lung disease (ILD) or QTc prolongation. Asymptomatic, stable CNS metastases are permitted. The primary efficacy outcome is overall survival (OS).

      4c3880bb027f159e801041b1021e88e8 Result

      From Sept 18, 2015, first patient in, to Oct 20 2017 data cut-off (DCO), 3014 patients were enrolled across 16 countries and received ≥1 dose of osimertinib (full analysis set [FAS]): median follow-up 7.9 months (range <1−24), median age 62 yrs (27–92), 64% female, 69% Asian, 30% White, 11% WHO PS 2, 45% prior chemotherapy, 34% prior radiotherapy. All patients had T790M-positive status, identified from tissue in 1610 patients (53%), plasma ctDNA in 1241 patients (41%) and from other sources in 162 patients (5%). At DCO, 1276 patients (42%) had discontinued treatment (1738 [58%] ongoing); median duration of exposure 7.4 months (<1–25); 1289 patients (43%) had a progression-free survival (PFS) event, 1276 (42%) had a time to treatment discontinuation (TTD) event, and 593 (20%) had died. In patients evaluable for response, the investigator-assessed clinical response rate was 56.6% (1625/2872; 95% confidence interval [CI] 54.7, 58.4). In the FAS, estimated median PFS was 11.0 months (95% CI 10.6, 11.1), median TTD was 12.6 months (95% CI 12.2, 13.7), and median OS was not reached (OS at 12 months was 75.8% (95% CI 73.7, 77.8). Adverse events (AEs) leading to dose modification and treatment discontinuation were reported in 321 patients (11%) and 147 patients (5%), respectively. Serious AEs were reported in 505 patients (17%). ILD/pneumonitis-like events were reported in 41 patients (1%), and QTc prolongation in 48 patients (2%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      ASTRIS, the largest reported study of osimertinib in T790M-positive NSCLC, demonstrates clinical activity similar to that observed in the osimertinib clinical trial program with no new safety signals.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.16 - Treatment of Early Stage/Localized Disease (Not CME Accredited Session) (ID 948)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 3
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.16-04 - Outcomes of Patients < 70 or ≥70 Years of Age in PACIFIC (ID 13012)

      16:45 - 18:00  |  Author(s): David Vicente

      • Abstract
      • Slides

      Background

      In the Phase 3 PACIFIC study of durvalumab versus placebo in patients with stage III, unresectable NSCLC without progression after concurrent chemoradiotherapy (cCRT), the co-primary endpoint PFS was significantly longer with durvalumab (stratified HR 0.52, 95% CI, 0.42–0.65; P<0.0001). In a prespecified analysis, PFS benefit with durvalumab was observed regardless of a 65-year age cutoff. However, median age at NSCLC diagnosis is 70 (CA Cancer J Clin, 2014). We therefore performed subgroup analyses to explore outcomes using a 70-year age cutoff.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      PACIFIC (NCT02125461) was a Phase 3, randomized, double-blind, all-comers study of patients with WHO PS 0/1 who did not progress following ≥2 cycles of platinum-based cCRT. Patients were stratified by age, sex, and smoking history and randomized (2:1) 1–42 days after cCRT to receive durvalumab 10 mg/kg IV Q2W or placebo up to 12 months. Co-primary endpoints were PFS (BICR, RECIST v1.1) and OS (not available). Secondary endpoints included ORR, time to death/distant metastasis (TTDM), and safety. Between-treatment endpoint comparisons were performed for patients <70 and ≥70 years.

      4c3880bb027f159e801041b1021e88e8 Result

      As of Feb 13, 2017, 713 patients were randomized; 78% and 22% were <70 and ≥70 years, respectively. Baseline patient and tumor characteristics were generally well balanced across subgroups. However, patients ≥70 were more likely to be male, have PS 1, and, within the placebo arm, to be Asian. Older patients more commonly received carboplatin-based CT than younger patients. Durvalumab demonstrated PFS benefit compared with placebo, regardless if patients were <70 years (median 16.9 vs 5.6 months, HR=0.53, 95% CI: 0.42–0.67) or ≥70 years (median 12.3 vs 6.1 months, HR=0.62, 95% CI: 0.41–0.95). Durvalumab improved TTDM (<70 years: HR=0.53, 95% CI: 0.39–0.71; ≥70 years: HR=0.66, 95% CI: 0.39–1.13) and ORR (<70 years: 27.6% vs 15.4%; ≥70 years: 31.9% vs 17.6%) regardless of age. Younger patients on durvalumab received treatment longer (median total duration 45.5 vs 36.0 weeks). Regardless of treatment, older patients discontinued more due to AEs (durvalumab: 22.0% vs 13.7%; placebo: 16.1% vs 7.8%) and had more grade 5 AEs (durvalumab: 10.9% vs 2.7%; placebo: 9.1% vs. 4.5%). Among patients receiving durvalumab, older patients experienced more all-cause SAEs (42.6% vs 24.9%) and grade 3/4 AEs (41.6% vs 29.4%) but fewer AESIs (56.4% vs 67.9%) than younger patients.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Patients achieved clinical benefit with durvalumab regardless of age. Increased AEs/SAEs observed in older patients across treatments may reflect age/cCRT related morbidity.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.16-05 - Effect of Induction Chemotherapy in the PACIFIC Study (ID 13864)

      16:45 - 18:00  |  Author(s): David Vicente

      • Abstract
      • Slides

      Background

      The Phase 3 PACIFIC study of patients with stage III, unresectable NSCLC without progression after concurrent chemoradiotherapy (cCRT) demonstrated significantly longer PFS with durvalumab versus placebo (stratified HR 0.52; 95% CI 0.42–0.65; P<0.0001). Overall, 26% and 29% in the durvalumab and placebo groups, respectively, received induction chemotherapy (ICT) before cCRT. Here, we report exploratory analyses of baseline characteristics, disposition, and outcomes from this study based on the presence or absence of prior ICT.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      PACIFIC (NCT02125461) was a Phase 3, randomized, double-blind study of patients with WHO PS 0/1 and any tumor PD-L1 status without progression after ≥2 cycles of platinum-based cCRT. Patients were stratified by age, sex and smoking history and randomized (2:1) to durvalumab 10 mg/kg IV Q2W or placebo up to 12 months. Co-primary endpoints were PFS (blinded independent central review, RECIST v1.1) and overall survival (not available). We investigated associations between the presence/absence of ICT and disposition, baseline characteristics, and efficacy and safety endpoints.

      4c3880bb027f159e801041b1021e88e8 Result

      As of February 13, 2017, 713 patients were randomized; 27% had prior ICT. Baseline characteristics were similar between treatment arms; however, patients with ICT were generally younger, less frequently Asian, had lower incidence of squamous histology, and more often had stage IIIB disease. There were no differences between groups in terms of prior RT dose. PFS benefit with durvalumab was demonstrated irrespective of ICT use (ICT: HR=0.61, 95% CI, 0.41–0.88; no ICT: HR=0.54, 95% CI, 0.42–0.69). Similarly, ORR with durvalumab was numerically higher than with placebo irrespective of ICT use (ICT: 16.1% vs 13.1%; no ICT: 32.9% vs 17.1%). ICT did not affect treatment duration for durvalumab or placebo. Between-treatment safety differences were minimal across subgroups; however, patients with ICT experienced fewer SAEs, treatment-related SAEs and pneumonitis/radiation pneumonitis regardless of treatment arm.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Durvalumab demonstrated clinical benefit irrespective of ICT. The safety profile of durvalumab was consistent in patients with or without ICT. A lower rate of toxicity was observed in patients with ICT regardless of treatment arm.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.16-06 - Expanded Efficacy and Safety Analysis of PACIFIC Based on a PD-L1 Cutpoint of 25% (ID 12992)

      16:45 - 18:00  |  Author(s): David Vicente

      • Abstract
      • Slides

      Background

      In the Phase 3 PACIFIC study of patients with stage III, unresectable NSCLC without progression after concurrent chemoradiotherapy (cCRT), PFS was significantly longer with durvalumab versus placebo (stratified HR 0.52; 95% CI 0.42–0.65; P<0.0001). We report exploratory analyses of PACIFIC outcomes by PD-L1 expression assessed in tumor samples collected prior to cCRT.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      PACIFIC (NCT02125461) was a Phase 3, randomized, double-blind study of patients with WHO PS 0/1 without progression after ≥2 cycles of platinum-based cCRT. Eligibility was irrespective of PD-L1 expression; archived samples were optional for testing (VENTANA PD-L1 [SP263] assay). No samples were obtained after cCRT, prior to infusion with durvalumab or placebo. Patients were randomized (2:1) to durvalumab 10 mg/kg IV Q2W or placebo up to 12 months, stratified by age, sex and smoking history. Co-primary endpoints were PFS (blinded independent central review, RECIST v1.1) and OS (not available). Secondary endpoints included ORR and safety. We investigated associations between subgroups of patients with PD-L1 expression on tumor cells (TC) of <25% or ≥25% and efficacy.

      4c3880bb027f159e801041b1021e88e8 Result

      As of February 13, 2017, 713 patients were randomized; 451 (63.3%) had known PD-L1 status (TC<25%, 64.7%; TC≥25%, 35.3%; Table). Baseline characteristics and prior therapy (including best response to prior therapy) were generally well balanced between arms across both PD-L1 subgroups. PFS benefit with durvalumab was demonstrated irrespective of PD-L1 status (HR 0.59; 95% CI, 0.43–0.82 for TC<25% and HR 0.41; 95% CI, 0.26–0.65 for TC≥25%) (Table). ORR was greater with durvalumab compared to placebo regardless of PD-L1 status (Table). The overall safety profile of durvalumab in each PD-L1 subgroup was consistent with the ITT population treated with durvalumab.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Durvalumab demonstrated clinical benefit and had a well-tolerated, manageable safety profile irrespective of PD-L1 status obtained from archival tumor samples prior to cCRT.

      PD-L1 TC<25%

      PD-L1 TC≥25%

      Durvalumab (n=187)

      Placebo
      (n=105)

      Durvalumab (n=115)

      Placebo
      (n=44)

      Completed 12 months treatment, n (%)

      74 (39.6)

      35 (33.3)

      55 (47.8)

      13 (29.5)

      PFS*

      Median (95% CI), months

      16.9 (11.0–NR)

      6.9 (5.0–11.0)

      17.8 (11.1–NR)

      3.7 (2.0–13.2)

      HR (95% CI)

      0.59 (0.43–0.82)

      0.41 (0.26–0.65)

      ORR

      n=170

      n=96

      n=108

      n=40

      n (%)

      [95% CI]

      50 (29.4)

      [22.7–36.9]

      19 (19.8)

      [12.36–29.17]

      31 (28.7)

      [20.4–38.2]

      6 (15.0)

      [5.71–29.84]

      *In the overall ITT population, median PFS was 16.8 months (95% CI, 13.0–18.1) with durvalumab (n=476) vs. 5.6 months (95% CI, 4.6–7.8) with placebo (n=237), with an HR of 0.52 (95% CI, 0.42–0.65; P<0.001) (stratified log-rank); PD-L1 assessment was not required in the study; in PD-L1 unknown patients, median PFS was 14.0 months (95% CI, 9.2–NR) with durvalumab (n=174) vs. 6.4 months (95% CI, 3.8–9.0) with placebo (n=88), with an HR of 0.59 (95% CI, 0.42–0.83) (unstratified Cox proportional hazards model); ORR for n evaluable patients included unconfirmed responses. ITT, intention-to-treat; NR, not reached; ORR, objective response rate; PFS, progression-free survival.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    PL02 - Presidential Symposium - Top 5 Abstracts (ID 850)

    • Event: WCLC 2018
    • Type: Plenary Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 08:15 - 09:45, Plenary Hall
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      PL02.01 - Overall Survival with Durvalumab Versus Placebo After Chemoradiotherapy in Stage III NSCLC: Updated Results from PACIFIC (ID 14701)

      08:15 - 08:25  |  Author(s): David Vicente

      • Abstract
      • Presentation
      • Slides

      Background

      In the global, Phase 3 PACIFIC study (Antonia 2017; NCT02125461), durvalumab significantly improved progression-free survival (PFS) versus placebo in Stage III, unresectable NSCLC patients without progression after chemoradiotherapy (CRT) (stratified HR, 0.52; 95% CI, 0.42–0.65; P<0.001). This was the first major advance in this disease setting for many years. Here we report the second primary endpoint overall survival (OS) for PACIFIC.

      Patients with WHO PS 0/1 (any PD-L1 tumor status) who received ≥2 cycles of platinum-based CRT were randomized (2:1) 1–42 days post-CRT to durvalumab 10 mg/kg IV Q2W or placebo up to 12 months, stratified by age, sex, and smoking history. Primary endpoints were PFS from randomization (blinded independent central review; RECIST v1.1) and OS (interim analysis reported). Secondary endpoints included time to death or distant metastasis (TTDM) and PFS2 (time to second progression) from randomization and safety. Time to first/second subsequent therapy or death (TFST/TSST) were supportive assessments for PFS/PFS2.

      Between May 2014 and April 2016, 713 patients were randomized of whom 709 received treatment (durvalumab, n=473; placebo, n=236). As of March 22, 2018 (data cutoff), median follow-up duration was 25.2 months (range, 0.2–43.1). After discontinuation, 41.0% and 54.0% in the durvalumab and placebo groups received subsequent anticancer therapy; overall, 8.0% and 22.4% received additional immunotherapy. Durvalumab significantly improved OS versus placebo (stratified HR 0.68, 99.73% CI, 0.469–0.997; P=0.00251), with the median not reached (NR; 95% CI, 34.7 months–NR) and 28.7 months (95% CI, 22.9–NR), respectively. Durvalumab improved OS in all pre-specified subgroups. Updated PFS remained similar (stratified HR 0.51, 95% CI, 0.41–0.63), with medians of 17.2 and 5.6 months with durvalumab and placebo, respectively. Durvalumab improved the updated TTDM (stratified HR 0.53, 95% CI, 0.41–0.68), as well as PFS2 (stratified HR 0.58, 95% CI, 0.46–0.73), TFST (stratified HR 0.58, 95% CI, 0.47–0.72) and TSST (stratified HR 0.63, 95% CI, 0.50–0.79). Within the durvalumab and placebo groups, 30.5% and 26.1% had grade 3/4 any-causality AEs, 15.4% and 9.8% discontinued due to AEs, and no new safety signals were identified.

      Durvalumab demonstrated statistically significant and clinically meaningful improvement in OS compared with placebo, supported by secondary endpoints such as PFS2. PACIFIC is the first study to show a survival advantage following CRT in this population, providing compelling evidence for the unprecedented benefit of durvalumab treatment as the standard of care.

      a9ded1e5ce5d75814730bb4caaf49419

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