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Martin Reck



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    MA25 - Oligometastasis: Defining, Treating, and Evaluating (ID 929)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Oligometastatic NSCLC
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 203 BD
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      MA25.01 - EORTC Lung Cancer Group Survey to Define Synchronous Oligometastatic Disease in NSCLC (ID 13770)

      13:30 - 13:35  |  Author(s): Martin Reck

      • Abstract
      • Presentation
      • Slides

      Background

      Synchronous oligometastasic disease (sOMD) has been described as a separate disease entity; however there is no consensus on what specific criteria constitutes sOMD in NSCLC. A consensus group (CG) was formed aiming to agree on a common sOMD definition (sOMD-d) that could be used in future clinical trials. A European survey was circulated to inform the discussion on sOMD-d.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      An EORTC Lung Cancer Group (LCG) / sOMD-d CG survey containing 31 questions on sOMD-d was distributed between 14/12/17 and 19/02/18 to EORTC LCG, sOMD-d CG, and several European thoracic oncology societies’ members.

      4c3880bb027f159e801041b1021e88e8 Result

      444 responses were analyzed (radiation oncologist: 55% [n=242], pulmonologist: 15% [n=66], medical oncologist: 14% [n=64]; 78% with >5 years’ experience in treating NSCLC). Belgium (14%, n=62), Italy (12%, n=55), Germany (11%, n=47), and Netherlands (10%, n=44) contributed most. 81% (n=361) physicians aimed to cure sOMD NSCLC patients and 82% (n=361) included the possibility to treat the patient with radical intent in their sOMD-d. The maximum number of metastases considered in sOMD-d varied: 19%, 42%, 4%, and 17% replied <2, 3, 4, and >5 metastases, respectively. 79% (n=353) stated that the number of organs involved was important for sOMD-d, and most (80%, n=355) considered that only <3 involved organs (excluding primary) should be included in the definition. 317 (71.7%) allowed mediastinal lymph node involvement (MLN) in the sOMD-d, and 22.1% of them counted MLN as a metastatic site. For 195/327 (60%), when N2/N3 disease is included in the sOMD-d, there is no specific issue regarding the MLN volume/location as long as radical treatment is possible. 384 (86%) considered pulmonary metastasis (outside primary tumor: M1a) as metastatic site. Most physicians confirmed sOMD patients with brain MRI (91%, n=403) and PET-CT (98%, n=437). For mediastinum staging, most (64%, n=285) respondents stated that histology/cytology should be obtained when PET-CT shows suspected lymph nodes or in case of a central primary tumor. Pathology proof of metastatic disease was necessary in sOMD for 315 (71%) physicians, and 37% (n=163) acknowledged that histology should be obtained from at least from one metastatic site. Preferred primary outcome parameter in clinical trials of sOMD was overall survival (73%, n=325).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Although certain consensual answers were obtained (81% aimed to cure and >90% mandated baseline imaging with PET-CT and brain MRI), a number of issues remain unresolved and will require further discussion by a panel of experts to agree on a sOMD-d.

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      MA25.02 - Searching for a Definition of Synchronous Oligometastatic (sOMD)-NSCLC: A Consensus from Thoracic Oncology Experts (ID 13452)

      13:40 - 13:45  |  Author(s): Martin Reck

      • Abstract
      • Presentation
      • Slides

      Background

      Recent prospective single centre studies reported improved outcomes in patients with sOMD-NSCLC who were treated with radical intent. Since then sOMD has been perceived as a separate disease entity. However, a clear definition of sOMD-NSCLC is lacking. We aimed to develop a definition and diagnostic criteria of sOMD-NSCLC following a consensus process.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A European multidisciplinary consensus group was established with representatives from different scientific societies. Consensus questions were extracted from a survey, case series and a systematic review. The questions were discussed, and the statement formulated during a consensus meeting in Dublin (23.01.18).

      4c3880bb027f159e801041b1021e88e8 Result

      Summary of consensus statement

      Defining sOMD-NSCLC

      Definition of sOMD is relevant for patients in whom a radical treatment is technically feasible with acceptable toxicity, taking into account all sites, that may modify the course of the disease leading to a long-term disease control.

      All sites must be technically and safely treatable.

      The maximum number of metastases/organs meeting the criteria involved will depend on the possibility of offering a treatment strategy with radical intent, taking into account local control and toxicity. Based on the systematic review, a maximum of 5 metastases and 3 organs is proposed.

      Diffuse serosal metastases and bone marrow involvement are excluded.

      Mediastinal lymph node (MLN) involvement should be considered as locoregional disease in the definition of sOMD-NSCLC.

      MLN involvement is of importance in determining if a radical local treatment of the primary tumour may be applied and the MLN will not be counted as a metastatic site.

      Staging of sOMD-NSCLC

      PET-CT and brain imaging are considered mandatory.

      In case of a solitary liver metastasis a dedicated MRI of the liver and for a solitary pleural metastasis, thoracoscopy and biopsies of distant ipsilateral pleural sites are advised.

      Staging of the mediastinum requires a minimum of a FDG-PET scan, with pathological confirmation preferred if this influences the treatment strategy.

      Pathological proof is required unless the MDT decides that the risk outweighs the benefit. Pathology proof is advised for single metastatic location and if it may change the therapeutic strategy, confirmation of the MLN involvement is recommended.

      8eea62084ca7e541d918e823422bd82e Conclusion

      A multidisciplinary consensus statement on the definition and staging of sOMD-NSCLC was formulated taking into account results of a European survey, a systematic review and case discussion. This statement might be helpful to standardise inclusion criteria in future clinical trials. However, the definition of sOMD may change over time when more prospective data will become available.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    MS02 - The Future of IO (ID 781)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Immunooncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 106
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      MS02.02 - Combination Therapies: Where Are We in 2018? (ID 11406)

      10:45 - 11:00  |  Presenting Author(s): Martin Reck

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    OA05 - Clinical Trials in IO (ID 899)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 106
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      OA05.06 - CheckMate 227: Patient-Reported Outcomes of First-Line Nivolumab + Ipilimumab in High Tumor Mutational Burden Advanced NSCLC (ID 13450)

      14:25 - 14:35  |  Author(s): Martin Reck

      • Abstract
      • Presentation
      • Slides

      Background

      The randomized, open-label, multipart phase 3 study CheckMate 227 (NCT02477826) demonstrated a significant progression-free survival benefit (co-primary endpoint) with first-line nivolumab+ipilimumab versus histology-based, platinum-doublet chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) and high tumor mutational burden (TMB; ≥10 mutations/Mb). Patient-reported outcomes (PROs) for this population within CheckMate 227 are presented.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligible chemotherapy-naïve patients had stage IV or recurrent NSCLC, ECOG performance status 0−1, and no known sensitizing EGFR/ALK alterations. PROs were assessed as an exploratory endpoint; this analysis included patients with high TMB randomized to nivolumab+ipilimumab or chemotherapy; specific outcomes included proportion of patients with disease-related symptom deterioration by 12 weeks and time to deterioration in symptoms (by Lung Cancer Symptom Scale [LCSS] Average Symptom Burden Index [ASBI]), and assessment of quality of life and overall health status (by EuroQoL-5 Dimension [EQ-5D] utility index [UI] and visual analog scale [VAS]). PROs were evaluated each cycle (Q2W, nivolumab+ipilimumab; Q3W, chemotherapy) for the first 6 months, every 6 weeks thereafter during treatment, and at follow-up visits 1/2. EQ-5D was also assessed during survival follow-up.

      4c3880bb027f159e801041b1021e88e8 Result

      PRO completion rates were ~90% at baseline and >80% for nearly all on-treatment assessments. Among patients with high TMB, fewer patients in the nivolumab+ipilimumab (n=139) versus chemotherapy (n=160) groups reported symptom deterioration by week 12, irrespective of whether they were still on therapy or had discontinued (22.3% versus 35.0%; absolute risk reduction: 12.7% [95% CI: 2.4–22.5]). Time to first deterioration (TTD) using common assessment time points (on/off treatment) was delayed with nivolumab+ipilimumab versus chemotherapy for the LCSS ASBI (hazard ratio [HR]: 0.40; 95% CI: 0.26–0.63) and 3-Item Global Index (3-IGI; HR: 0.56; 95% CI: 0.38–0.82). The estimated benefit in TTD generally favored nivolumab+ipilimumab for individual symptoms in the ASBI and each item in the 3-IGI (HRs: 0.48–0.74), except for hemoptysis (HR: 1.20), which exhibited very low burden; an advantage for nivolumab+ipilimumab was also seen in the EQ-5D VAS (HR: 0.62; 95% CI: 0.42–0.92) and UI (HR: 0.50; 95% CI: 0.34–0.73). Mean changes from baseline with nivolumab+ipilimumab showed early and clinically meaningful improvements in LCSS ASBI/3-IGI and EQ-5D VAS/UI; for patients treated with chemotherapy, symptoms and quality of life remained stable (LCSS ASBI/3-IGI, EQ-5D UI) or improved following completion of chemotherapy (EQ-5D VAS).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Nivolumab+ipilimumab demonstrated early and sustained improvements in health-related quality of life versus chemotherapy in patients with advanced NSCLC and high TMB.

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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-70 - Efficacy and Safety of Second- or Third-Line Nab-Paclitaxel + Durvalumab in Patients with Advanced NSCLC (ABOUND.2L+) (ID 13042)

      16:45 - 18:00  |  Author(s): Martin Reck

      • Abstract

      Background

      Cytotoxic chemotherapy may enhance the effect of immune checkpoint blockers (ICBs) through interaction with the immune system (immunostimulation) and cancer cells (increased antigenicity). The phase II ABOUND.2L+ trial investigated second-/third-line nab-paclitaxel monotherapy, nab-paclitaxel + CC-486, or nab-paclitaxel + durvalumab in patients with previously treated advanced-stage NSCLC. This report presents an updated analysis of the efficacy and safety from the nab-paclitaxel + durvalumab treatment arm.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients ≥ 18 years with advanced NSCLC and no more than 1 prior line of platinum-containing chemotherapy (ICBs in prior line, first/second, allowed) were included. Patients were treated with nab-paclitaxel on days 1 and 8 + durvalumab 1125 mg on day 15 of a 21-day cycle until unacceptable toxicity or progressive disease as per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 or immune-related RECIST v1.1. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall response rate (ORR), disease control rate (DCR), overall survival (OS), and safety.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 79 patients were assigned to nab-paclitaxel + durvalumab. The median age of patients in that arm was 63.0 years; 68.4% were male, 97.5% were white, 77.2% had ECOG performance status 1, and 69.6% had nonsquamous histology; 8 patients received prior ICBs. Median and 1-year PFS were 4.5 months (95% CI: 3.45-5.88) and 25.7% (95% CI 16.3-36.2); median PFS in those with and without prior ICB treatment was NE (95% CI 1.38-NE) and 4.4 months (95% CI 2.96-5.68) and in those with squamous and nonsquamous histology was 6.0 months (95% CI 2.99-7.75) and 4.2 months (95% CI 2.86-5.75). The ORR was 27.8%, and DCR was 70.9%. Median OS was 10.1 months (95% CI: 7.75-NE). Median percentage of per protocol dose was 87.5% for nab-paclitaxel and 82.9% for durvalumab. All patients had at least 1 treatment-emergent adverse event (TEAE), and 67.9% had at least 1 grade 3 or 4 TEAE. Common TEAEs of special interest (all grades) included peripheral neuropathy (grouped term; 37.2%), diarrhea (34.6%), anemia (30.8%), dyspnea (25.6%), nausea (24.4%), cough (24.4%), pyrexia (19.2%), and neutropenia (17.9%). TEAEs leading to dose interruption/reduction (nab-paclitaxel and/or durvalumab) were reported in 73.1% of patients, and those leading to discontinuation in 11.5%.

      8eea62084ca7e541d918e823422bd82e Conclusion

      nab-Paclitaxel + durvalumab demonstrated promising antitumor activity and manageable toxicity in second- or third-line treatment of patients with advanced NSCLC. NCT02250326.

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      P1.01-93 - Quality of Life in Patients with Advanced NSCLC Treated in Second- or Third-Line with Nab-Paclitaxel + Durvalumab: ABOUND.2L+ (ID 12993)

      16:45 - 18:00  |  Author(s): Martin Reck

      • Abstract

      Background

      Quality of life (QoL) can be adversely affected in patients with advanced NSCLC, particularly those receiving second- or third-line treatment. In these patients, checkpoint inhibitors are a recommended treatment option. Through multiple mechanisms, including the release of tumor antigens via tumor cell lysis, chemotherapy can augment immunotherapeutic effects, which is the rationale for combining chemotherapy with immunotherapy agents. The phase II ABOUND.2L+ trial investigated second- or third-line nab-paclitaxel either alone or in combination with CC-486 or durvalumab in patients with advanced NSCLC. The objective of this analysis is to report QoL outcomes in patients treated with nab-paclitaxel + durvalumab from the ABOUND.2L+ trial.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Enrolled patients were ≥ 18 years with advanced NSCLC and no more than 1 prior line of platinum-containing chemotherapy. Immunotherapy in a prior line, first or second, was allowed. Patients were treated with nab-paclitaxel on days 1 and 8 + durvalumab 1125 mg on day 15 of a 21-day cycle. Treatment continued until unacceptable toxicity or disease progression per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 or immune-related RECIST v1.1. The primary endpoint was progression-free survival. QoL was a prespecified exploratory endpoint assessed using the Lung Cancer Symptom Scale (LCSS), EuroQol 5D-5L, and EORTC QLQ-C30 on day 1 of each cycle, and was examined through 6 cycles of treatment for this analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 79 patients were assigned to the nab-paclitaxel + durvalumab arm. The median age was 63.0 years. Most patients were white (97.5%), male (68.4%), and had ECOG PS of 1 (77.2%). For the entire study, baseline and ≥ 1 postbaseline QoL assessments were completed by 58 (73.4%) patients. 41 patients completed 6 cycles of treatment with nab-paclitaxel + durvalumab. After cycle 6, the mean change from baseline in LCSS total score and pulmonary symptom score was 0.1 and −0.2, respectively. LCSS hemoptysis score improved relative to baseline at every treatment cycle; mean change from baseline after 6 cycles was 0.8. Mean change from baseline in the EuroQol 5D-5L visual analog scale score and EORTC QLQ-C30 global health status/QoL scale score after 6 cycles of treatment was 2.5 and −1.19, respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In general, patients with advanced NSCLC treated with second- or third-line nab-paclitaxel + durvalumab maintained their QoL through 6 cycles of treatment. NCT02250326.

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    P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.13-02 -  eXalt3: Phase 3 Randomized Study Comparing Ensartinib to Crizotinib in Anaplastic Lymphoma Kinase Positive Non-Small Cell Lung Cancer Patients (ID 13294)

      16:45 - 18:00  |  Author(s): Martin Reck

      • Abstract
      • Slides

      Background

      Ensartinib (X-396) is a novel, potent ALK small molecule tyrosine kinase inhibitor (TKI). It is well-tolerated and has shown promising activity in NSCLC patients in a phase 1/2 study in patients that were both ALK TKI naïve and patients that received prior crizotinib, as well as those with CNS metastases. The safety profile of ensartinib appears to be different from other ALK TKIs.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In this global, phase 3, open-label, randomized study, approximately 270 patients with ALK+ NSCLC who have received no prior ALK TKI and up to one prior chemotherapy regimen will be randomized with stratification by prior chemotherapy (0/1), performance status (0-1/2), brain metastases at screening (absence/presence), and geographic region (Asia /other), to receive oral ensartinib (225 mg, once daily) or crizotinib (250mg, twice daily) until disease progression or intolerable toxicity.

      Eligibility also includes patients ≥ 18 years of age, stage IIIB or IV ALK+ NSCLC. Patients are required to have measurable disease per RECIST 1.1, adequate organ function, and an ECOG PS of ≤2. Adequate tumor tissue (archival or fresh biopsy) must be available for central testing. The primary endpoint is progression-free survival assessed by independent radiology review based on RECIST v. 1.1 criteria. Secondary efficacy endpoints include overall survival, response rates (overall and central nervous system [CNS]), PFS by investigator assessment, time to response, duration of response, and time to CNS progression. The study has > 80% power to detect a superior effect of ensartinib over crizotinib in PFS at a 2-sided alpha level of 0.05.

      Phase 3 recruitment began in June, 2016 and currently has 98 active sites in 21 countries. The duration of recruitment will be approximately 28 months. This study is registered with ClinicalTrials.Gov as NCT02767804.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.13-30 - Neutrophil-to-Lymphocyte Ratio as a Prognostic Factor and its Relationship to NSCLC Patient Outcomes in the REVEL Trial (ID 13126)

      16:45 - 18:00  |  Author(s): Martin Reck

      • Abstract
      • Slides

      Background

      Neutrophil-to-lymphocyte ratio (NLR) reflects underlying levels of systemic inflammation and has prognostic importance in solid tumors. Higher baseline NLR is an independent negative prognostic factor in advanced non–small cell lung cancer (NSCLC) and may indicate more aggressive disease. An exploratory analysis from REVEL demonstrated benefits of ramucirumab(RAM)/docetaxel(DOC) in NSCLC patients with rapidly progressing and refractory disease. We investigated the relationship between pretreatment NLR, prognosis and response to RAM/DOC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Pretreatment NLR was analyzed by dividing absolute neutrophil count by absolute lymphocyte count from peripheral blood. Multiple NLR cutoffs ≥4 were evaluated for prognostic significance by analyzing overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Kaplan-Meier analysis and Cox proportional hazards regression model were used for analyzing OS and PFS, and Cochran-Mantel-Haenszel test for ORR.

      4c3880bb027f159e801041b1021e88e8 Result

      Pretreatment NLR was determined for 1224 REVEL patients (n=611 RAM/DOC, n=613 placebo [PBO]/DOC), among whom 51%, 40%, and 32% had NLR ≥4, 5, and 6, respectively. Baseline characteristics were balanced between arms in NLR subgroups and the REVEL intent-to-treat (ITT) population. Patients with higher NLR values had worse OS, PFS, and ORR compared to the ITT population. For all NLR cutoff values, OS, PFS and ORR were improved in patients treated with RAM/DOC compared to patients receiving PBO/DOC (Table). Efficacy and safety outcomes across high NLR subgroups were consistent with those in the ITT population.

      table 1.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      In this exploratory analysis of REVEL, higher pretreatment NLR was an independent prognostic factor indicating poorer survival outcomes. Treatment benefit with RAM/DOC was preserved in patients with elevated NLR and was consistent with REVEL ITT results. NLR is an inexpensive and reproducible blood test and may provide a simple way to identify patients with more aggressive disease who can benefit from treatment with RAM/DOC in second-line NSCLC.

      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: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.16-05 - Effect of Induction Chemotherapy in the PACIFIC Study (ID 13864)

      16:45 - 18:00  |  Author(s): Martin Reck

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

    • Event: WCLC 2018
    • Type: Plenary Session
    • Track: Advanced NSCLC
    • Presentations: 2
    • 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): Martin Reck

      • 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.

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      PL02.07 - IMpower 133: Primary PFS, OS and Safety in a PH1/3 Study of 1L Atezolizumab + Carboplatin + Etoposide in Extensive-Stage SCLC (ID 12892)

      09:00 - 09:10  |  Author(s): Martin Reck

      • Abstract
      • Presentation
      • Slides

      Background

      First-line (1L) standard-of-care treatment for extensive-stage small cell lung cancer (ES-SCLC) is platinum (carboplatin or cisplatin) with etoposide. Despite high initial response rates, there has been limited progress in the last two decades and outcomes remain poor with a median overall survival (OS) of ~10 months. IMpower133 (NCT02763579), a global Phase 1/3, double-blind, randomized, placebo-controlled trial evaluated efficacy and safety of adding atezolizumab, a humanized monoclonal anti–PD-L1 antibody, or placebo to 1L carboplatin and etoposide in ES-SCLC.

      Patients with measurable (RECIST v1.1) ES-SCLC, ECOG performance status 0 or 1, who had not received prior systemic treatment for ES-SCLC were enrolled. PD-L1 immunohistochemical testing was not required. Patients were randomized 1:1 to receive four 21-day cycles of carboplatin (AUC 5 mg/mL/min IV, Day 1) plus etoposide (100 mg/m2 IV, Days 1-3) with either atezolizumab (1200 mg IV, Day 1) or placebo, followed by maintenance therapy with atezolizumab or placebo until intolerable toxicity or progressive disease per RECIST v1.1. Patients meeting predefined criteria could receive treatment beyond progression. Co-primary endpoints were OS and investigator-assessed progression-free survival (PFS). Adverse events (AEs) were graded per NCI-CTCAE v4.0. Blood-based tumor mutation burden (bTMB) was assessed using prespecified cutoffs of ≥16 vs. <16 and ≥10 vs. <10 mutations/Mb.

      In total, 201 patients were randomized to the atezolizumab group, and 202 to the placebo group. Median follow-up was 13.9 months. Median OS was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (hazard ratio [HR] 0.70 [95% confidence interval (CI): 0.54, 0.91; P=0.0069]). Median PFS was 5.2 months and 4.3 months, respectively (HR 0.77 [95% CI: 0.62, 0.96; P=0.017]). OS and PFS benefits were consistent across key patient subgroups. Investigator-assessed confirmed objective response rates were 60.2% and 64.4% in the atezolizumab and placebo groups, respectively; median duration of response, 4.2 and 3.9 months. Exploratory analyses showed OS survival benefits in subgroups above and below prespecified bTMB cutoffs. Grade 3-4 treatment-related AEs were reported in 56.6% vs. 56.1% patients in atezolizumab vs. placebo groups, respectively; serious treatment-related AEs occurred in 22.7% and 18.9% patients, respectively.

      Addition of atezolizumab to carboplatin and etoposide provided a significant improvement in OS and PFS in 1L ES-SCLC in an all-comer patient population. No unexpected safety signals were identified. Atezolizumab plus carboplatin and etoposide may represent a new standard regimen for patients with untreated ES-SCLC.

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