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Luis G. Paz-Ares



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    FP10 - Small Cell Lung Cancer/NET (ID 231)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP10.04 - RESILIENT Part 1: Safety and Efficacy of Second-Line Liposomal Irinotecan in Patients with Small Cell Lung Cancer (ID 3657)

      00:00 - 00:00  |  Presenting Author(s): Luis G. Paz-Ares

      • Abstract
      • Presentation
      • Slides

      Introduction

      Many patients with small cell lung cancer (SCLC) develop drug resistance to first-line platinum-based chemotherapy, and second-line therapies are limited. RESILIENT (ClinicalTrials.gov identifier NCT03088813) is a two-part phase 2/3 study assessing the safety, tolerability and efficacy of liposomal irinotecan monotherapy as second-line treatment for patients with SCLC. Here we report data from part 1 of the RESILIENT study (data cut off, 2 December 2019).

      Methods

      RESILIENT part 1 was an open-label, single-arm study comprising dose-exploration and dose-expansion phases. Eligible patients with SCLC were aged ≥ 18 years, had progressed with platinum-based first-line therapy, had an Eastern Cooperative Oncology Group performance status score of 0 or 1, and had adequate organ function; prior exposure to immunotherapy was permitted. During dose exploration, participants received liposomal irinotecan 85 mg/m2 or 70 mg/m2 free base administered every 2 weeks; the identified recommended dose was used during dose expansion. Primary endpoints were safety and tolerability. Efficacy assessments included objective response rate (ORR), best overall response (BOR), progression-free survival (PFS), and overall survival (OS).

      Results

      In total, 30 patients received liposomal irinotecan in RESILIENT part 1 (women, 56.7%; median age, 61.5 years). During dose exploration, four patients who received liposomal irinotecan 85 mg/m2 experienced dose limiting toxicities, including diarrhea (n = 3) and abnormal liver function test (n = 1). Thus, this dose was not considered tolerable and enrollment into the 70 mg/m2 cohort was initiated; a total of 25 patients (platinum resistant, 40%) received liposomal irinotecan 70 mg/m2 (dose exploration, 12 patients; dose expansion, 13 patients). Among the 25 patients who received the recommended dose of 70 mg/m2, 40% had one or more grade ≥ 3 treatment-related treatment-emergent adverse events (TEAEs), most commonly diarrhea (20%), neutropenia (16%), and anemia, thrombocytopenia, asthenia and abdominal sepsis (each 8%); 8% of patients discontinued treatment owing to TEAEs. Median (95% CI) PFS was 3.98 (1.45–4.24) months and OS was 8.08 (5.16–9.82) months. ORR (complete response + partial response) was 44% and BOR was: complete response, 4%; partial response, 40%; stable disease, 28%; progressive disease, 20%; non-evaluable, 8%.Thirty patients were treated in RESILIENT part 1. Full results to be presented in the updated abstract.

      Conclusion

      In participants with SCLC who had progressed with platinum-based first-line therapy, liposomal irinotecan at the recommended dose of 70 mg/m2 showed promising antitumor activity and safety findings were aligned with the known safety profile. RESILIENT part 2, an ongoing, phase 3, randomized controlled trial versus topotecan will provide further data regarding the efficacy and safety of liposomal irinotecan 70 mg/m2 for the second-line treatment of patients with SCLC.

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    OA04 - New Data from Rare EGFR Alterations (ID 223)

    • Event: WCLC 2020
    • Type: Oral
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
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      OA04.05 - Trastuzumab Deruxtecan in HER2-Overexpressing Metastatic Non-Small Cell Lung Cancer: Interim Results of DESTINY-Lung01 (ID 1419)

      11:45 - 12:45  |  Author(s): Luis G. Paz-Ares

      • Abstract
      • Presentation
      • Slides

      Introduction

      Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor payload. DESTINY-Lung01 (NCT03505710) is an ongoing, multicenter, phase 2 study evaluating T-DXd in 2 separate cohorts of patients with unresectable and/or metastatic nonsquamous non-small cell lung cancer (NSCLC): overexpressing HER2 (centrally confirmed, IHC 2+ or 3+) or containing a HER2-activating mutation. We have previously shown promising activity of T-DXd in patients with HER2-mutated NSCLC (confirmed objective response rate [cORR] by independent central review [ICR], 61.9%; Smit ASCO 2020). Here we report data from an interim analysis of the HER2-overexpressing cohort.

      Methods

      Patients with HER2-overexpressing metastatic NSCLC were treated with T-DXd 6.4 mg/kg every 3 weeks. The primary endpoint was ORR (CR + PR) by ICR. Additional endpoints were disease control rate (DCR; CR + PR + stable disease), duration of response (DOR), progression-free survival (PFS), and safety.

      Results

      At data cutoff (May 31, 2020), 49 patients had received T-DXd. Median age was 63 years (range, 37-85 years); 61.2% were male; 34.7% had CNS metastases at enrollment; 32.7% were never-smokers. 79.6% of patients (n=39) had HER2 IHC 2+ and 20.4% (n = 10) had HER2 IHC 3+. 91.8% of patients had received prior platinum-based chemotherapy and 73.5% had received anti−PD-1/PD-L1 treatment; median number of prior regimens was 3 (range, 1-8). Median treatment duration was 18.0 weeks (range, 3.0-57.1 weeks); 22.4% of patients remained on treatment.

      Confirmed ORR by ICR was 24.5% (95% CI, 13.3%-38.9%), including 1 CR and 11 PRs; IHC 2+, 25.6% (95% CI, 13.0%-42.1%); IHC 3+, 20.0% (95% CI, 2.5%-55.6%). Median DOR was 6.0 months (95% CI, 3.2-NE months); DCR was 69.4% (95% CI, 54.6%-81.8%); estimated median PFS was 5.4 months (95% CI, 2.8-7.0 months).

      All patients had ≥ 1 treatment-emergent adverse event (TEAE); the most common any-grade TEAEs were nausea (59.2%), decreased appetite (38.8%), and fatigue (32.7%). Grade ≥ 3 TEAEs were reported in 73.5% of patients (55.1% drug-related); the most common were decreased neutrophil count (20.4%) and fatigue (10.2%). There were 8 cases (16.3%) of drug-related interstitial lung disease (ILD) as adjudicated by an independent committee (grade 1, n = 2; grade 2, n = 3; grade 5, n = 3). TEAEs were associated with dose interruption in 26 patients (53.1%), dose reduction in 17 patients (34.7%), and treatment discontinuation in 11 patients (22.4%).

      Conclusion

      In this interim analysis, T-DXd demonstrated preliminary evidence of antitumor activity in heavily pretreated patients with HER2-overexpressing NSCLC. The safety profile of T-DXd was generally manageable, but ILD remains a known serious risk that requires proactive monitoring and care. An additional cohort to evaluate T-DXd 5.4 mg/kg in patients with HER2-overexpressing NSCLC has opened and started enrollment to further understand and characterize the safety and efficacy profile of T-DXd in this population.

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    OA11 - A Symphony of Progress (ID 229)

    • Event: WCLC 2020
    • Type: Oral
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 2
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      OA11.02 - Chair (ID 4245)

      15:30 - 16:30  |  Presenting Author(s): Luis G. Paz-Ares

      • Abstract

      Abstract not provided

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      OA11.04 - Lurbinectedin With Irinotecan in Relapsed Small Cell Lung Cancer. Results From the Expansion Stage of a Phase I-II Trial (ID 3132)

      15:30 - 16:30  |  Author(s): Luis G. Paz-Ares

      • Abstract
      • Presentation
      • Slides

      Introduction

      Lurbinectedin is a novel anti-cancer agent that exerts antitumor activity through inhibition of trans-activated transcription and modulation of the tumor microenvironment. In June 2020, the US FDA granted accelerated approval to lurbinectedin (ZepzelcaTM) for the treatment of adult patients (pts) with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy based on the results of a phase II study (Trigo et al. Lancet Oncol 2020). Preclinical evidence of synergism was observed for lurbinectedin in combination with irinotecan.

      Methods

      Antitumor activity and the safety of lurbinectedin in combination with irinotecan in SCLC were evaluated in this phase I-II trial. Data are presented here for advanced SCLC (pts) with no more than 2 prior lines of chemotherapy and ECOG performance status (PS) score of 0-1 treated at the recommended dose (RD).

      Results

      21 pts were treated at the RD (lurbinectedin 2 mg/m2 Day 1 + irinotecan 75 mg/m2 Days 1 and 8 every three weeks + prophylactic G-CSF); all were evaluable for safety and efficacy. Baseline characteristics were: males/females, 48%/52%; median age, 61 years (52-74); ECOG PS score 0/1, 24%/76%; chemotherapy-free interval (CTFI) ≥90 days/<90 days, 62%/38%; number of prior lines, 1 (62%), 2 (38%); prior immunotherapy (19%); liver metastases 48%; CNS involvement 24%. At cut-off (12 August 2020), 11 patients were still on treatment.

      All patients

      (n=21)

      CTFI

      Setting

      90 days (n=13)

      <90 days (n=8)

      2nd line (n=13)

      3rd line (n=8)

      Median number of cycles

      (range)

      7

      (1-16)

      9

      (3-16)

      3

      (1-7)

      7

      (3-16)

      7

      (1-13)

      Overall Response Rate (PR)

      62%

      69%

      50%

      77%

      37%

      Clinical Benefit Rate (PR+SD>4m)

      71%

      85%

      50%

      77%

      63%

      Disease Control Rate (PR+SD)

      90%

      100%

      75%

      100%

      75%

      Median DOR (m)

      (95% CI)

      5.7+

      (2.8-n.r.)

      6.7+

      (3.0-n.r.)

      3.2+

      (2.8-3.7)

      6.7+

      (3.0-n.r.)

      3.0+

      (2.8-n.r.)

      Median PFS (m)

      (95% CI)

      6.2+

      (4.1-n.r.)

      8.5+

      (4.3-n.r.)

      3.7+

      (0.7-5.0)

      8.1+

      (3.3-n.r.)

      4.3+

      (0.7-n.r.)

      Median follow-up: 8.7 months

      + patients ongoing; CTFI, chemotherapy-free interval; DOR, duration of response; m, months; n.r. not reached; PFS, progression-free survival; PR, partial response; SD, stable disease.

      Adverse events (AEs) included: grade (G) 4 neutropenia in 6 pts (28.6%); febrile neutropenia in 2 pts (9.5%); no G4 anemia or G4 thrombocytopenia. Severe non-hematological toxicities were G3 only and consisted mainly of fatigue in 4 pts (19.0%), diarrhea in 3 pts (14.3%), and vomiting in 1 pt (4.5%). No deaths or discontinuations were reported due to treatment-related AEs.

      Conclusion

      The combination of lurbinectedin and irinotecan demonstrated efficacy in SCLC after failure of first-line therapy, including remarkable activity in pts with resistant disease (CTFI <90 days) and in the 3rd line setting. Toxicity was transient and manageable, and consisted mainly of hematological abnormalities, fatigue and diarrhea. Further development of this combination is warranted in pts with SCLC. Updated results of this cohort will be presented.

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    P15 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) - Novel Immunotherapeutics (Phase I) (ID 154)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P15.06 - Safety of BMS-986012, an Anti–Fucosyl-GM1 Monoclonal Antibody Plus Platinum/Etoposide in Untreated Extensive-Stage SCLC (ID 3416)

      00:00 - 00:00  |  Presenting Author(s): Luis G. Paz-Ares

      • Abstract
      • Slides

      Introduction

      Small cell lung cancer (SCLC) is an aggressive lung tumor, with patients often presenting with metastatic disease at the time of diagnosis. Treatments for patients with extensive-stage SCLC have advanced little over the years, with 5-year overall survival (OS) rates remaining dismal. Immunotherapy has demonstrated clinical activity in ES-SCLC; however, the OS improvements have been only modest, with the first-line population remaining an unmet need in terms of treatment options (Horn et al. N Engl J Med 2018;379:2220–2229; Paz-Ares et al. Lancet 2019;394:1929–1939). Fucosyl-GM1, a tumor-associated antigen, is expressed in 50%–70% of cases with limited expression on normal tissue (Brezicka et al. Cancer Res 1989;49:1300–1305; Zhang et al. Int J Cancer 1997;73:42–49). Therefore, fucosyl-GM1 constitutes a potential target in SCLC. BMS-986012, a novel, first-in-class, nonfucosylated, fully human monoclonal antibody with high binding specificity for fucosyl-GM1 and enhanced antibody-dependent cellular cytotoxicity (Ponath et al. Clin Cancer Res 2018;24:5178–5189), was well tolerated and demonstrated promising antitumor activity in patients with relapsed/refractory SCLC (Chu et al. Ann Oncol 2016;27[suppl 6]. Abstract 1427PD). Here, we report the preliminary safety findings from a phase 1/2 trial of the combination of BMS-986012 and platinum/etoposide followed by BMS-986012 monotherapy maintenance in previously untreated patients with extensive-stage SCLC (NCT02815592).

      Methods

      Patients received BMS-986012 400 mg or 1000 mg on day 1, combined with either cisplatin 80 mg/m2 (part 1) or carboplatin area under the curve (AUC) 5 (part 2) on day 1 plus etoposide 100 mg/m2 on days 1, 2, and 3 (both parts) over four 21-day cycles, followed by BMS-986012 monotherapy maintenance. The primary endpoint was safety.

      Results

      As of Feb 6, 2020, 14 patients had received BMS-986012 (400 mg, n=12; 1000 mg, n=2) combined with platinum/etoposide, with 11 patients continuing into the monotherapy period. The median age was 62 years (range, 49–81 years), and 11 patients (79%) were men. BMS-986012 in combination with platinum/etoposide was well tolerated, and most treatment-related adverse events (TRAEs) were grade 1–2. The most common TRAEs (all grade; grade ≥3) was pruritus (86%; 7%). In most cases, pruritus resolved with antihistamines or low dose corticosteroids. Urticaria (7%; 7%), neutropenia (7%; 7%), xerosis (7%; 0%), conjunctivitis (7%; 0%), infusion-related reaction (7%; 0%), and dizziness (7%; 0%) were also observed. No serious TRAEs or dose-limiting toxicities were reported. One patient (BMS-986012 400 mg/carboplatin/etoposide) discontinued due to acute coronary syndrome determined to be unrelated to treatment. No notable differences were observed in the safety profiles of BMS-986012 plus cisplatin/etoposide (n=7) and BMS-986012 plus carboplatin/etoposide (n=7) in this study.

      Conclusion

      BMS-986012 in combination with platinum/etoposide was well tolerated in a treatment-naive patient population with extensive-stage SCLC. The safety profile was comparable to the profile observed historically with platinum/etoposide chemotherapy alone, except for clinically manageable pruritis. The safety findings support the ongoing evaluation of BMS-986012 as first-line therapy for extensive-stage SCLC.

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    P18 - Locoregional and Oligometastatic Disease - Misc. Topics (ID 128)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Locoregional and Oligometastatic Disease
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P18.05 - Immunotherapy Beyond First-Line in NSCLC, Still An Option. (ID 3220)

      00:00 - 00:00  |  Author(s): Luis G. Paz-Ares

      • Abstract
      • Slides

      Introduction

      Atezolizumab and nivolumab are approved in patients with advanced previously treated non-small cell lung cancers (NSCLC) irrespective of programmed death-ligand 1 (PD-L1) expression, while pembrolizumab is only approved if PD-L1 ≥1%. At present, immunotherapy alone or in combination with chemotherapy is the treatment of choice for first-line NSCLC, however treatment with anti-PD-1/PD-L1 agents should be reconsidered after progression to chemotherapy in patients which did not receive immunotherapy at first time.

      Methods

      In this retrospective analysis, we analysed the impact of immunotherapy in second and subsequent lines in terms of median progression-free survival (mPFS) and median overall survival (mOS) in patients with advanced NSCLC treated in University Hospital 12 Octubre from October, 2015 to March, 2020.

      Results

      We identified 87 patients with NSCLC treated with immunotherapy in second or posterior lines (42 received nivolumab, 32 atezolizumab and 13 pembrolizumab). 79.32% were men, median age was 67.6 years and 67.8% of them received at least 3 doses of treatment. In the total population, mPFS was 4 months and mOS was 10 months. Significant differences were observed when divided by histology subtypes: mPFS 2 months for adenocarcinoma vs 5 months for squamous (HR: 1.85 [95% CI: 1.08-3.15], p=0.01). Nevertheless, in terms of survival no significant differences were observed, mOS was 9 vs 11 months, respectively (HR: 1.36, [95% CI: 0.73 - 2.53], p=0.29). Among patients with stage III at diagnosis, mPFS and mOS were significantly longer than those with stage IV. mPFS was 7 vs 2 months (HR: 0.53 [95% CI: 0.31–0.90], p=0.009), and mOS was 15 vs 9 months (HR: 0.49, [95% CI: 0.28-0.91], p=0.02). The expression of PD-L1 was not predictive of immunotherapy benefit, although 45% patients were unknown. We also observed a benefit for those patients with ECOG 0-1 compared with ≥2 (mOS: 11 vs 5.5 months; HR: 0.49 [95% CI: 0.23-1.05], p= 0.01).

      mPFS (months)

      mOS (months)

      Histology

      Adenocarcinoma

      2

      HR: 1.85 [95% CI: 1.08-3.15],

      p=0.01).

      9

      HR: 1.36, [95% CI: 0.73-2.53],

      p=0.29).

      Squamous

      5

      11

      Stage

      III

      7

      HR: 0.53 [95% CI: 0.31–0.90], p=0.009

      15

      HR: 0.49, [95% CI: 0.28-0.91], p=0.02

      IV

      2

      9

      ECOG

      0-1

      3

      HR 0.62 (95% CI 0.31 - 1.24)

      P = 0.08

      11

      HR: 0.49 [95% CI: 0.23-1.05], p= 0.01

      ≥2

      2

      5.5

      Conclusion

      Patients with NSCLC not suitable to receive chemoimmunotherapy in first-line setting must be reconsider in second or posterior lines due to the important benefit observed. These results based on our clinical practice seem to be similar to those observed in previous clinical trials.

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    P21 - Locoregional and Oligometastatic Disease - Treatment of Locally Advanced NSCLC (ID 131)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Locoregional and Oligometastatic Disease
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P21.14 - The Promising role of Chemo-Immunotherapy in Non-Small Cell Lung Cancer Neoadjuvant Setting (ID 3551)

      00:00 - 00:00  |  Author(s): Luis G. Paz-Ares

      • Abstract
      • Slides

      Introduction

      Stage III non-small cell lung cancer (NSCLC) is a heterogeneous disease which includes patients with different prognosis depending on resectable, potentially resectable or unresectable tumours. Chemo-immunotherapy in neoadjuvant setting is currently under evaluation in clinical trials. We present two case reports of patients who received this therapeutic approach due to tumour unresectability at diagnosis.

      Methods

      Data were collected from electronic history and clinical records. All procedures performed were in accordance with ethical standards of the institutional research Committee and the treatment strategy was approved as compassionate use in both cases.

      Results

      A 56-year old male and a 48-year old female (37 and 45 pack-year history, respectively) presented with two-month history of productive cough and moderate progressive dyspnoea. In Case 1, the 18F-FDG PET/CT showed a 12 cm (diameter greater) necrotic mass (SUVmax 18.43) and non-metabolic ipsilateral pleural effusion (Figure 1A), staging cT4N0M0 (IIIA). On the other hand, a 5.8 cm (diameter greater) right hilar mass (SUVmax 20.25), ipsilateral pleural effusion (SUVmax 6.45) and a right subcarinal suspicious adenopathy were shown in Case 2 (Figure 1C). Bronchoscopic biopsy revealed a primary pulmonary squamous cell carcinoma with PD-L1 expression 90% (22C3) in both cases and they were presented in Multidisciplinary Tumour Board. In Case 1, the mass was considered unresectable and the patient was not eligible for radical chemo-radiotherapy, so systemic therapy was finally decided. Otherwise, pleural effusion cytological assessment was performed several times without showing malignant cells in Case 2 (staging cT3N2Mx) and systemic treatment was started too due to the tumour unresectability. Chemo-immunotherapy combination with carboplatin AUC 5mg/ml/min, paclitaxel 175mg/m2 and pembrolizumab 200mg every three weeks according to the results of KEYNOTE-407 was given in both cases. Favourable response was achieved after four cycles (Case 1, Figure 1B; Case 2, Figure 1D), therefore both cases were discussed again in Multidisciplinary Session in order to reevaluate surgical indication. After mediastinoscopy, Case 1 underwent right pneumonectomy in December 2019 (postoperative staging ypT1cN0M0) and Case 2 underwent middle and lower bilobectomy in June 2019, with major pathological response (MPR). At present, both patients are asymptomatic, with no evidence disease and no antineoplastic treatment.

      figure 1.jpg

      Conclusion

      Radiological response achieved with chemo-immunotherapy allowed a surgical approach in patients with non-resectable tumours at diagnosis. MPR is a surrogate of overall survival in resectable NSCLC, so results of ongoing clinical trials exploring this combination strategy are expected with much interest because they could change the therapeutic paradigm of these patients.

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    P48 - Small Cell Lung Cancer/NET - Chemo - IO (ID 236)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 2
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P48.03 - First-Line Durvalumab plus Platinum-Etoposide in ES-SCLC: Exploratory Analyses Based on Extent of Disease in CASPIAN (ID 3437)

      00:00 - 00:00  |  Author(s): Luis G. Paz-Ares

      • Abstract
      • Slides

      Introduction

      In the Phase 3, randomised, open-label CASPIAN study, first-line durvalumab plus etoposide and cisplatin or carboplatin (EP) significantly improved overall survival (OS) compared with EP alone in patients with extensive-stage small-cell lung cancer (ES-SCLC) at the planned interim analysis (data cut-off: 11 March 2019): hazard ratio (HR) 0.73 (95% confidence interval [CI] 0.59–0.91; p=0.0047). This OS benefit was sustained after a median follow-up of more than 2 years (data cut-off 27 Jan 2020): HR 0.75 (95% CI 0.62‒0.91; nominal p=0.0032). Here we present post-hoc exploratory analyses at the updated data cut-off based on the extent of disease at baseline.

      Methods

      Treatment-naïve patients (WHO performance status 0/1) with ES-SCLC received 4 cycles of durvalumab 1500 mg + EP q3w followed by maintenance durvalumab 1500 mg q4w until disease progression (PD) or up to 6 cycles of EP q3w and optional prophylactic cranial irradiation (investigator’s discretion). Planned consolidation thoracic radiotherapy (TRT) was not permitted. The primary endpoint was OS. Progression-free survival (PFS) was a secondary endpoint. Patients with M0 or M1a classification at diagnosis were included in the thoracic-only disease subgroup and M1b in the extra-thoracic disease subgroup. Data cut-off: 27 Jan 2020.

      Results

      At baseline, 151 (28.1%) of 537 patients had thoracic-only disease, of whom 77 (28.7%) were in the durvalumab + EP arm and 74 (27.5%) were in the EP arm. Among 386 (71.9%) patients with any extra-thoracic disease at baseline, 191 (71.3%) were in the durvalumab + EP arm and 195 (72.5%) were in the EP arm; across both arms, the most common sites of extra-thoracic disease were liver (52.8%), adrenal gland (35.8%), bone (31.3%) and brain (13.7%). Durvalumab + EP improved OS vs EP regardless of the extent of disease (thoracic-only HR 0.73 [95% CI 0.51–1.06]; extra-thoracic HR 0.77 [0.62–0.96]); PFS was also improved with durvalumab + EP vs EP in these subgroups (HR 0.70 [95% CI 0.49–1.00] and 0.85 [0.68–1.05], respectively). Among patients with extra-thoracic disease, 52.8% in the EP arm developed new lesions at first PD vs 44.5% in the durvalumab + EP arm (EP vs durvalumab + EP: lung 14.4% vs 8.9%; liver 11.8% vs 6.8%; bone 8.7% vs 4.7%). In the thoracic-only disease subgroup, a similar proportion of patients had new lesions at first PD in the EP (36.5%) and durvalumab + EP (36.4%) arms, however more patients developed new lesions in the lung in the EP arm compared with the durvalumab + EP arm (20.3% vs 7.8%). TRT was administered concurrently with study treatment in 1.1% of all patients across both arms. TRT was administered subsequent to study treatment in a higher proportion of patients in the EP arm compared with the durvalumab + EP arm, regardless of whether patients had thoracic-only disease (31.1% vs 7.8%) or extra-thoracic disease (12.3% vs 7.3%).

      Conclusion

      In CASPIAN, OS and PFS were improved with durvalumab + EP vs EP, regardless of the presence or absence of extra-thoracic disease, consistent with the intention-to-treat analyses.

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      P48.21 - Population Pharmacokinetics and Exposure-Response with Durvalumab Plus Platinum-Etoposide in ES-SCLC: Results from CASPIAN (ID 1881)

      00:00 - 00:00  |  Author(s): Luis G. Paz-Ares

      • Abstract
      • Slides

      Introduction

      In the Phase 3 CASPIAN trial, first-line durvalumab in combination with etoposide and either cisplatin or carboplatin (EP) significantly improved overall survival (OS) versus EP alone at the planned interim analysis (data cutoff: 11 March 2019): hazard ratio 0.73 (95% confidence interval [CI] 0.59–0.91; p=0.0047). This OS benefit was sustained after >2 years of median follow-up (data cutoff 27 January 2020): hazard ratio 0.75 (95% CI 0.62‒0.91; nominal p=0.0032). Safety findings were consistent with the known safety profiles of the individual agents, and no patients developed treatment-emergent anti-drug antibodies to durvalumab. Here we present population pharmacokinetics (popPK) and exposure-response (ER) analyses based on the interim analysis to support the recommended durvalumab fixed-dose regimen for treatment-naïve patients with extensive-stage (ES)-SCLC.

      Methods

      Treatment-naïve patients (WHO performance status 0/1) with ES-SCLC received 4 cycles of durvalumab 1500 mg + EP q3w followed by maintenance durvalumab 1500 mg q4w until disease progression or up to 6 cycles of EP q3w and optional prophylactic cranial irradiation (investigator’s discretion). Pharmacokinetic (PK) data of durvalumab from CASPIAN were analysed using a previously developed popPK model, while key PK parameters were re-estimated with CASPIAN data. The effects of covariates, such as demographics and baseline disease characteristics, on the PK of durvalumab were evaluated. The model-predicted durvalumab exposure was correlated with observed efficacy and safety outcomes to explore ER relationships, including evaluation of potential confounding effects of baseline prognostic factors. The effect of body weight on efficacy and safety outcomes in patients treated with durvalumab + EP was also analysed.

      Results

      Of 265 patients treated with durvalumab + EP, 259 had ≥1 measurable durvalumab PK sample post-dose and were included in the popPK analysis. There were no clinically meaningful PK differences between durvalumab when given in combination with EP and previous data from durvalumab monotherapy studies. Covariate analysis suggested generally limited or no effects of body weight, race, age, gender or other covariates on durvalumab PK compared with overall PK variability. In total, 265 patients treated with durvalumab + EP were included in the exposure-efficacy and exposure-safety analyses. No clinically meaningful ER relationships were observed for efficacy or safety. Although a slightly longer median OS was observed in patients with the greatest exposure to durvalumab + EP (15.8 months in quartile 4 versus 11.6, 11.3 and 12.6 months, respectively, for quartiles 1, 2 and 3 of durvalumab AUCss), durvalumab exposure (AUCss and Cmin1) was not identified as a significant covariate (p >0.05) for OS when accounting for confounding baseline prognostic factors. Additionally, there was no clear impact of body weight (31–128 kg) on efficacy or safety in patients receiving durvalumab + EP.

      Conclusion

      There was no meaningful impact of exposure or body weight (>30 kg) observed on either efficacy or safety in patients treated with a fixed-dose of 1500 mg durvalumab in CASPIAN. These results support the use of a 1500 mg fixed-dose of durvalumab in combination with EP for the treatment of patients with ES-SCLC.

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