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Corinne Faivre-Finn



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    MA05 - Improving Outcomes in Locoregional NSCLC II (ID 901)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 105
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      MA05.02 - PACIFIC Subgroup Analysis: Pneumonitis in Stage III, Unresectable NSCLC Patients Treated with Durvalumab vs. Placebo After CRT (ID 13876)

      13:35 - 13:40  |  Author(s): Corinne Faivre-Finn

      • Abstract
      • Presentation
      • Slides

      Background

      In the Phase 3 PACIFIC study of durvalumab versus placebo in patients with stage III, unresectable non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (cCRT), on-treatment pneumonitis or radiation pneumonitis (‘pneumonitis’) occurred in both arms with similar rates of grade 3/4 pneumonitis (durvalumab, 3.4%; placebo, 2.6%). We performed exploratory analyses to further characterize time to onset and duration of pneumonitis and examine its relationship with underlying risk factors, including patient characteristics and prior CRT.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      PACIFIC (NCT02125461) was a randomized, double-blind study of patients with WHO PS 0/1 without progression after ≥2 cycles of platinum-based cCRT. Patients were stratified by age, sex, and smoking history and randomized (2:1) 1–42 days after completing cCRT to durvalumab 10 mg/kg IV Q2W or placebo up to 12 months. Potential associations between the presence of the AE pneumonitis (investigator assessed with review/adjudication by study sponsor) and baseline characteristics or patient disposition were investigated.

      4c3880bb027f159e801041b1021e88e8 Result

      As of Feb 13, 2017, 709 patients had received treatment; 33.6% on durvalumab and 24.9% on placebo had any-grade pneumonitis. Treatment exposure was similar in patients with or without pneumonitis across both arms. Median time to onset of pneumonitis from treatment start was the same for both durvalumab and placebo, 55.0 days (73.0 and 76.5 days from RT completion). Pneumonitis was self-limited, with median durations of 64.0 and 57.0 days, respectively. Patients with pneumonitis were more likely to be Asian (47.9% vs 17.6%) or have EGFR mutations (11.0% vs 3.8%); however, the proportions of patients with pneumonitis and these risk factors were numerically lower with durvalumab than with placebo (Asian: 44.4% [71/160] vs 57.6% [34/59]; EGFRm: 10.6% [17/160] vs 11.9% [7/59]), suggesting no apparent interaction with treatment. There were no apparent associations of pneumonitis with baseline respiratory disorders, prior RT dose, or prior cisplatin or carboplatin use. Previous induction CT was more commonly associated with the absence of pneumonitis in both treatment arms (durvalumab: 30.1% vs 17.5%; placebo: 31.5% vs 20.3%). The presence of pneumonitis was associated with greater discontinuation due to AEs (durvalumab: 25.6% vs 10.2%; placebo: 18.6% vs 6.8%) regardless of treatment.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Rates of pneumonitis were higher in Asian patients and those with EGFRm, as previously reported. Durvalumab did not increase pneumonitis in patients with these risk factors. There were no differences in treatment exposure in patients based on the presence/absence of pneumonitis. Multivariate analyses may further assist in the discernment of etiologic risks.

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    MA23 - Early Stage Lung Cancer: Present and Future (ID 926)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 105
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      MA23.06 - Small Residual Setup Errors After Image-Guided Radiotherapy Affect Heart Dose and Are Linked to Overall Survival (ID 13785)

      11:05 - 11:10  |  Author(s): Corinne Faivre-Finn

      • Abstract
      • Presentation
      • Slides

      Background

      There is limited evidence of the effect of radiotherapy image guidance on survival. This work investigates the relationship between small residual set-up errors following IGRT and overall survival in lung cancer patients (mostly with significant comorbidities), and explores which anatomy may be responsible for observed differences.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Residual setup errors of 546 NSCLC patients treated with an off-line 5mm action threshold correction protocol for bony anatomy were summarized per patient as the mean and standard deviation for each axis, as well as the vector magnitude in a direction from tumour towards the heart, and included in multivariate Cox regression. Delivered dose distributions including residual setup errors were estimated and the difference between the delivered and planned dose was compared for patients who did/did not survive longer than 1 year. Permutation testing (n=1000) assessed significance.

      4c3880bb027f159e801041b1021e88e8 Result

      Residual setup errors were not correlated with any pre-treatment clinical variable. Patients with a residual shift towards the heart (mean ~2 mm, max 5mm) have significantly worse overall survival (hazard ratio 1.310, p = 0.001). The average dose in the heart region changes linearly with the residual shift magnitude towards the heart (~0.8Gy/mm). A higher delivered dose than planned in a region at the heart base (Figure 1, arrow) is associated with poorer survival in multivariate analysis (hazard ratio 1.214/Gy, p<0.001).

      figure1.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      Small residual shifts after IGRT are strongly associated with overall survival in NSCLC patients, with shifts of the high dose region towards the heart leading to worse survival. The most likely cause of shorter survival is a corresponding increase in dose to the heart base. This analysis provides direct evidence of the importance of accurate patient positioning and highlights the significance of the heart base as a dose sensitive organ in thoracic radiotherapy patients with early effects on survival.

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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): Corinne Faivre-Finn

      • 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): Corinne Faivre-Finn

      • 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.

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    MS28 - IO Combinations in Advanced NSCLC (ID 806)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Immunooncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 106
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      MS28.05 - Combining IO with Radiation (ID 11524)

      14:30 - 14:45  |  Presenting Author(s): Corinne Faivre-Finn

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    OA01 - Improving Outcomes in Locoregional NSCLC I (ID 892)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 107
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      OA01.03 - Interaction Between Dose and Calcifications Is a Predictor for Overall Survival in Lung Cancer Patients Receiving Radiotherapy (ID 13920)

      10:50 - 11:00  |  Author(s): Corinne Faivre-Finn

      • Abstract
      • Presentation
      • Slides

      Background

      Recently, incidental dose to the heart was found to be predictive for overall survival in lung cancer patients receiving radiotherapy [McWilliam et al EJC 2017, Johnson et al Radiother Oncol 2018]. These patients often present with multiple comorbidities that should be incorporated in survival analysis. However, such data is often missing. We investigated whether calcifications, identified on the radiotherapy planning CT, can be used as a surrogate for cardiac health. In particular, we investigated the interaction between calcifications, dose and survival.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Data from 814 unselected non-small cell lung cancer patients was used, all treated with 55Gy in 20 fractions. Methodology was developed to automatically segment calcifications within the heart, the aortic arch and their surroundings. The 3D planning CT scans, and the associated lung and spinal cord delineations were processed using well-established image processing algorithms, e.g., convex hull, thresholding, morphological operations, connected pixel analysis and flood filling to detect calcifications. Moreover, shape analysis was included to enhance regions that presented tubular or plate-like appearance. The detection algorithm was validated in a small subset of 10 patients, and this group was used to determine the success and error rate of the automatic segmentation. Finally, a Cox-proportional hazards multivariate analysis was performed for overall survival of all patients accounting for tumour size, total calcification volume, mean dose across all identified calcifications, and interaction between calcification volume and dose.

      4c3880bb027f159e801041b1021e88e8 Result

      The success rate of the algorithm for identifying calcifications was 81.8%, its error rate was 8.8%. The multivariate survival analysis identified tumour size (continuous, p<<0.0001) and the interaction of calcification volume and their mean dose (continuous, p=0.029) as significant. Calcification volume (p=0.57) or mean calcification radiation dose alone (p=0.269) were not found to be significant.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Multivariate analysis shows a significant interaction between volume of the identified calcifications and their mean radiotherapy dose predicting survival. Further improvements to identify calcifications in the descending thoracic aorta and validation of our methodology are required. Further work linking our results with the established Agatston or Coronary Artery Calcium score is in progress.

      * EVO-FB share first authorship

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    OA13 - Therapeutics and Radiation for Small Cell Lung Cancer (ID 927)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 203 BD
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      OA13.01 - The Impact of [<sup>18</sup>F]fludeoxyglucose PET/CT in Small-Cell Lung Cancer: Analysis of the Phase 3 CONVERT Trial  (ID 13319)

      10:30 - 10:40  |  Presenting Author(s): Corinne Faivre-Finn

      • Abstract
      • Presentation
      • Slides

      Background

      The role of 18fludeoxyglucose (18F-FDG) PET/CT in the management of limited stage small-cell lung cancer (LS-SCLC) is uncertain. Previous studies have shown that 18F-FDG PET/CT upstages up to 30% of LS-SCLC patients. Data from the CONVERT trial was analysed to investigate the impact of 18F-FDG PET/CT in the management of LS-SCLC. The prognostic significance of pre-treatment 18F-FDG PET parameters was also investigated in an exploratory analysis.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      CONVERT is an international multi-centre phase III trial that randomly assigned fit patients to receive either twice-daily (45Gy in 30 fractions) or once-daily (66Gy in 33 fractions) radiotherapy starting on day 22 of chemotherapy cycle 1 (NCT00433563). Chemotherapy consisted of 4-6 cycles of cisplatin and etoposide. Prophylactic cranial irradiation was offered, if indicated. Contrast-enhanced thorax and abdomen CT and brain imaging (with/without bone scintigraphy according to clinical indication) were mandated for all CONVERT participants (conventional imaging). Staging with 18F-FDG PET/CT was allowed but not mandated. The primary endpoint was overall survival. Pre-treatment 18F-FDG PET metabolic parameters were investigated in a subset of patients (n=96) including standardised uptake values (max, mean and peak), volumetric and heterogeneity parameters.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 547 patients recruited to CONVERT, 540 patients with data on staging investigations and outcome were included in this analysis. The use of staging 18F-FDG PET/CT was variable in the 8 countries recruiting to CONVERT (range, 41-100%). Compared to patients who underwent conventional imaging (n=231), patients who were also staged with 18F-FDG PET/CT (n=309) had smaller gross tumour volume (p=0·003), were less likely to have elevated pre-treatment serum lactate dehydrogenase (p=0·035), and received more chemotherapy cycles (p=0·026). There were no other significant differences in baseline and treatment characteristics between the two groups. There were no significant differences in overall (hazard ratio 0·87 [95% CI 0·70-1·08]; p=0·192) and progression-free survival (hazard ratio 0·87 [95% CI 0·71-1·07]; p=0·198) between patients staged with 18F-FDG PET/CT in addition to conventional imaging or with conventional imaging alone. These results were observed irrespective of treatment group (once-daily and twice-daily radiotherapy). Pre-treatment 18F-FDG PET parameters were also not prognostic.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In CONVERT, survival outcomes were not different in LS-SCLC patients staged with or without 18F-FDG PET/CT. This was despite those patients staged with 18F-PET/CT having more favourable baseline and treatment characteristics. Our findings suggest that conventional imaging is sufficient to select LS-SCLC patients for concurrent chemoradiotherapy.

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      OA13.05 - Prophylactic Cranial Irradiation (PCI) for Limited-Stage Small-Cell Lung Cancer: Results from the Phase 3 CONVERT Trial (ID 13762)

      11:15 - 11:25  |  Author(s): Corinne Faivre-Finn

      • Abstract
      • Presentation
      • Slides

      Background

      PCI is considered standard of care in limited-stage small-cell lung cancer (LS-SCLC) patients. However the impact of the dose and fractionation of thoracic radiotherapy (RT) on the risk of developing brain metastasis (BM) has not been evaluated prospectively.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      CONVERT is an international, phase 3 trial that randomly assigned patients to receive twice-daily (BD 45Gy in 30 fractions) or once-daily (OD 66Gy in 33 fractions) RT starting on day 22 of chemotherapy (CT) cycle 1 (NCT00433563). PCI was offered, if indicated. Data on thoracic and brain RT delivery and timing, rate of BM and overall survival (OS) in patients treated with PCI was analysed. The association of the risk of developing BM/OS and predictor variables, using a competing risk regression model developed by Fine and Gray for BM or the standard Cox proportional hazards model for OS, was investigated.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 547 patients recruited to the study, 449 (82%) received PCI after completion of CTRT. PCI was delivered to 220/273 participants (81%) in the BD group and 229/270 in the OD group (85%; p=0.49). Pre-CTRT brain imaging consisted of CT-scan in 356/449 patients (79%) and MRI in 83/449 (18%) patients. Total median PCI dose was 25 Gy in both BD and OD groups (p=0.74). PCI was delivered later after CT in the OD group compared to the BD group (median days post CT 37 vs. 35 days, respectively; p=0.04). In patients who received PCI, 75 (17%) developed BM (35 [8%] in OD and 40 [9%] in BD) and 173 (39%) other extracranial progression. In the univariate analysis, GTV was associated with an increased risk of BM (HR: 1.37 [95%CI 1.09-1.73]; p=0.007) or other radiological progression events (HR: 1.43 [95%CI 1.11-1.85]; p=0.006), whereas in a multivariate analysis both GTV and PS were associated with either progression type. The median OS of patients treated with PCI was 29 months (95%CI 25.8-35.7). Median OS was 28 months in BD (95%CI 22-35) and 31 months in OD (95%CI 27-52; p=0.1). In the univariate analysis of OS, PCI timing from end of CT, weight loss >10%, and thoracic GTV were prognostic factors associated with OS. In the multivariate analysis, only thoracic GTV was associated with OS. Delay between end of CT and PCI was not associated with OS (p=0.2).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Patients receiving OD or BD thoracic RT have the same risk of developing BM. Larger tumours are associated with a higher risk of BM.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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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: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.13-35 - Hypoxia Mapping Using Oxygen-Enhanced MRI in Lung Cancer (ID 14283)

      16:45 - 18:00  |  Author(s): Corinne Faivre-Finn

      • Abstract
      • Slides

      Background

      Oxygen deprivation (hypoxia) is associated with worse non-small cell lung cancer (NSCLC) outcomes and predicts poor response to NSCLC treatments, including radiotherapy. There is an unmet need to develop non-invasive hypoxia biomarkers. We report the first preclinical and clinical evidence that oxygen-enhanced MRI (OE-MRI) can map and quantify therapy-induced change in NSCLC hypoxia.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In the preclinical study, radiation-induced changes in OE-MRI were first examined in a Calu-6 xenograft model of NSCLC. Tumours received a single 10Gy fraction of radiotherapy (n=9), chemoradiotherapy (5 x 2Gy fractions plus cisplatin; n=6) or control (n=9). Mice were imaged longitudinally using a multi-parametric MRI protocol (diffusion-weighted imaging (DWI), OE and dynamic contrast-enhanced (DCE)-MRI) at days 0, 3, 6 and 10 in all groups and then at day 13 (control), day 18 and 25 (radiotherapy) and day 18 (chemoradiotherapy). Pathology was obtained at cull in imaged mice and in a separate Calu6 cohort treated with a single 10Gy radiotherapy fraction (n=6) or control (n=9) at day 10. In the clinical study, twenty three stage I-IV NSCLC patients underwent an identical multi-parametric MRI for protocol development (n=6), twice prior to radiotherapy (n=10) and after 14±4 radiotherapy fractions (n=12). In all tumours we quantified the validated MRI hypoxia biomarker perfused oxygen-refractory (Oxy-R), which identifies absence of OE-MRI signal change in perfused tumour.

      4c3880bb027f159e801041b1021e88e8 Result

      By day 10, perfused Oxy-R (hypoxic) volume decreased relative to control in xenografts treated with either radiotherapy (p=0.029) or fractionated chemoradiotherapy (p=0.047). Hypoxia modification persisted in chemoradiotherapy treated tumors to day 16 and in radiotherapy treated tumors to day 22 (both p<0.001). Pimonidazole immunohistochemistry at day 10 showed lower hypoxic fraction in tumors treated with radiotherapy (p=0.026), relative to time matched controls. In addition, imaged xenografts also showed lower hypoxic fractions in radiotherapy (p=0.042) and chemoradiotherapy (p=0.041) treated tumors, relative to size matched control at cull. In the clinical study, OE-MRI was safe, feasible and well-tolerated. Perfused Oxy-R (hypoxic) volume demonstrated excellent repeatability with interclass correlation coefficient of 0.961 (95% CI 0.858-0.990). Visual inspection revealed that MRI hypoxia maps were spatially repeatable across a range of tumour and hypoxic volumes. In the absence of volumetric tumour change, perfused Oxy-R (hypoxic) volume decreased at mid-treatment (3.23 cm3 (95% CI 0-9.41 cm3)), compared to baseline (4.16 cm3 (95% CI 0-10.6 cm3)); p=0.0150.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our findings support using OE-MRI to detect and monitor hypoxia in clinical trials of hypoxia-modifying therapies or radiotherapy dose painting studies in patients with NSCLC.

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    P1.17 - Treatment of Locoregional Disease - NSCLC (Not CME Accredited Session) (ID 949)

    • 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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      P1.17-01 - Robustness of an Image-Based Data Mining Approach in Lung Cancer Patients (ID 13384)

      16:45 - 18:00  |  Author(s): Corinne Faivre-Finn

      • Abstract

      Background

      Image-based data mining (IBDM) enables exploring the correlation of dose distributions and outcomes in large cohorts of patients without the requirement of additional contouring. IBDM has recently identified the dose to the base of the heart as an important predictor for overall survival (OS) in lung cancer patients receiving radiotherapy [McWilliam et al EJC 2017]. IBDM relies on non-rigid registration to set inter-patient dosimetric data into a common reference anatomy or reference patient. Here, we investigated the uncertainties associated with the choice of reference patient, and their influence on the correlation between incidental dose to the base of the heart and OS.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In previous work, 1101 NSCLC patients (55Gy / 20 fractions) were randomly selected, and their planning CT images non-rigidly registered to a reference patient CT scan using NiftyReg (http://cmictig.cs.ucl.ac.uk/wiki/) as part of IBDM process. In this work, 5 additional patients with small cell lung cancer (i.e. without a large tumour burden) were used as “reference patients” and the IBDM analysis in the whole cohort was repeated for each reference patient. Permutation testing with 100 iterations was applied to assess statistical significance.

      4c3880bb027f159e801041b1021e88e8 Result

      slide1.jpg

      Figure 1 shows the regions of highly significant correlation between dose and OS for each reference patient. In spite of large variations in anatomy between the reference patients, each analysis identified similar anatomical regions as significantly associated with OS (t>5). Moreover, permutation testing was consistent with the original findings.

      8eea62084ca7e541d918e823422bd82e Conclusion

      IBDM is a robust approach and, in this analysis, does not appear to be sensitive to the choice of reference patient for the investigated dose-effect correlation. Prospective studies are necessary to confirm the correlation between dose to the base of the heart and OS in NSCLC patients. Methodological studies are needed to determine the level of effect strength and region size that this general technique can identify.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 3
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.01-15 - A Radiologist-Led Training Workshop for MR Based Normal Tissue and Tumour Delineation for Lung Cancer Radiotherapy. (ID 13857)

      16:45 - 18:00  |  Author(s): Corinne Faivre-Finn

      • Abstract
      • Slides

      Background

      A potential benefit of MR-image guided radiotherapy (MRIgRT) in lung cancer is the reduction of treatment related uncertainties through improved soft tissue contrast. However, this benefit may be obscured by inter-observer variation in gross tumour volume (GTV) and organ at risk (OAR) contouring. A radiologist led workshop was organised to provide training in such contouring on MR.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Planning CT, PET-CT and MRI were acquired in four lung cancer patients. MR sequences included 3D radial gradient echo, T2 DIXON Turbo Spin Echo (TSE), and T2 TSE with and without fat-sat. Data sets were local rigidly registered and imported into the so-called “Big Brother” contouring software.

      The radiologist led teaching on OAR and GTV contouring used an MR lung atlas (produced by this group). Seven radiation oncologists contoured the brachial plexus (BP), heart, proximal bronchial tree, oesophagus and GTV. This was followed by a multi-disciplinary group discussion (oncologists, radiologists and physicists) on the contouring challenges and subsequently contours were reviewed and the atlas adjusted.

      4c3880bb027f159e801041b1021e88e8 Result

      The BP and heart were the most difficult OARs to contour and showed the largest inter-observer variation. Following contour review and discussion between radiologist and oncologists updates to atlas and protocols were made. The GTV was found to be most challenging at the soft tissue interfaces and requires further work (Figure 1).

      contours.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      This early work demonstrates the need for radiologist-led training in OAR and GTV contouring in lung cancer patients using MR images. This will be especially important for the integration of MR into treatment planning and an MRIgRT adaptive workflow. We have arranged future workshops in order to provide further training and to assess inter-observer variation in OAR and GTV contouring using MR on more cases.

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      P2.01-27 - MR, CT and Cone-Beam CT for Lymph Node Visualisation in Locally-Advanced Lung Cancer (ID 11800)

      16:45 - 18:00  |  Author(s): Corinne Faivre-Finn

      • Abstract
      • Slides

      Background

      The largest benefit of MR-guided radiotherapy in lung cancer may be on-board visualisation of malignant lymph nodes (LNs). In this study, we assessed whether MR images were suitable for LN visualisation for treatment adaptation. We hypothesised that MR would outperform CT and Cone-Beam-CT (CBCT).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      CT, CBCT and MR images were acquired in four lung cancer patients with malignant LNs, confirmed using PET-CT and/or endobronchial ultrasound-guided biopsies. A total of 15 LNs from mediastinal and hilar nodal stations were assessed. Imaging datasets included: (1) CT planning scan with IV contrast; (2) MR1 (within 1 week of CT); (3) Mid-treatment CBCT (without contrast); and (4) MR2 (day of CBCT). MR sequences included: Turbo Spin Echo (TSE), TSE with fat-sat and 3D radial gradient echo. The images were randomised and independently scored by four thoracic radiation oncologists according to whether the malignant LN in each nodal station was visualised well enough to permit contouring. Scores were: not visible (1), unclear (2), clear (3) and very clear (4). Scores 3 and 4 were designated as ‘suitable for contouring’.

      4c3880bb027f159e801041b1021e88e8 Result

      As shown in figure 1, there was no significant difference in the number of LNs deemed suitable for contouring on CT (87%) compared to MR1 (82%). A significant difference was found between CBCT (10%) and MR2 (80%).

      picture11.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      MR did not out-perform CT with contrast for malignant LN visualisation, possibly due to greater observer familiarity with CT. MR was significantly better than CBCT, likely due to superior soft tissue contrast. These findings support the use of MR-guided radiotherapy in locally-advanced lung cancer for adaptive planning or treatment verification. The greater variation in MR scores between oncologists (especially between sequences) could be due to lack of experience with thoracic MR. Future research will optimise MR for this task and assess LN localisation on a larger dataset.

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      P2.01-43 - ADSCaN: A Randomised Phase II Study of Accelerated, Dose Escalated, Sequential Chemo-Radiotherapy in Non-Small Cell Lung Cancer (NSCLC) (ID 13934)

      16:45 - 18:00  |  Author(s): Corinne Faivre-Finn

      • Abstract
      • Slides

      Background

      Lung cancer is the most common cause of cancer mortality in the UK, and NSCLC accounts for approximately 85% of all lung cancers. Most patients present with inoperable disease therefore radiotherapy plays a major role in treatment. However, the majority of patients are not suitable for gold standard treatment (concurrent chemo-radiotherapy) due to performance status and comorbidities. Novel strategies integrating radiotherapy advances and radiobiological knowledge need to be evaluated in patients treated with sequential chemo-radiotherapy. Four separate accelerated dose escalated radiotherapy schedules have been completed in UK (CHART-ED{1}, IDEAL-CRT{2}, I-START{3} and Isotoxic IMRT{4}). ADSCaN will compare these schedules with a UK standard sequential chemo-radiotherapy schedule. A combined randomized phase II screening / ‘pick the winner’ approach will identify the best schedule to take into a randomised phase III study against conventionally fractionated radiotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Suitable patients will have histologically / cytologically confirmed, stage III NSCLC and be able to undergo chemo-radiotherapy treatment. The study will recruit 360 patients; 130 on the standard arm and 60 on each experimental arm. Patients will complete 2-4 cycles of platinum based chemotherapy before being randomised to one of the radiotherapy schedules.

      Logistic / capacity challenges make it impractical for sites to open all experimental trial arms; a novel trial design allows centres to select upfront the experimental arms they are able to participate in and all will offer the standard arm.

      adscan_trial_schema_v5_17jan2017.jpg

      4c3880bb027f159e801041b1021e88e8 Result

      CURRENT STATUS

      CRUK is funding this multicentre study which is being co-ordinated by the CRUK CTU Glasgow. The study opened to recruitment on 22/08/2017 with planned recruitment lasting 3 years 8 months. The study includes a tailored QA programme through the UK RTTQA Group. 20 of the 36 sites expressing interest have started the QA process, 12 have completed with a further 8 expected to complete in the next few months.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section Not Applicable

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    P2.12 - Small Cell Lung Cancer/NET (Not CME Accredited Session) (ID 961)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.12-15 - Prognostic and Predictive Covariates in Limited-Stage Small-Cell Lung Cancer: Analysis of the Phase 3 CONVERT Trial (ID 13320)

      16:45 - 18:00  |  Presenting Author(s): Corinne Faivre-Finn

      • Abstract

      Background

      The majority of patients with limited-stage small cell lung cancer (LS-SCLC) progress after concurrent chemo-radiotherapy (cCTRT). Data from the CONVERT trial was analysed to investigate prognostic and predictive covariates in LS-SCLC patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      CONVERT is an international multi-centre phase III trial that randomly assigned fit patients to receive either twice-daily (45Gy in 30 fractions) or once-daily (66Gy in 33 fractions) radiotherapy starting on day 22 of chemotherapy cycle 1 (ClinicalTrials.gov NCT00433563). Chemotherapy consisted of 4 or 6 cycles (centres choice) of cisplatin and etoposide. Prophylactic cranial irradiation was offered, if indicated. The following covariates were investigated for prognostic and predictive significance (benefit from twice-daily radiotherapy and completion of cCTRT): clinical (age, performance score, TNM staging, smoking status, weight loss >10% and lung function), laboratory (alkaline phosphatase, sodium and lactate dehydrogenase) and dosimetric (gross tumour volume (GTV), heart and lung dose). Completion of chemotherapy was defined as delivery of all planned cycles while completion of radiotherapy was defined as delivery of all fractions. Results of the multivariate regression analysis of overall survival (OS) and progression-free survival (PFS) were reported after correcting for multiple comparisons.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 547 patients recruited to CONVERT, 449 with complete covariate and outcome data were eligible for this analysis. GTV was the strongest prognostic covariate of OS (hazard ratio (HR) 1.37 (95% confidence interval (CI) 1.21-1.56); p<0.001). The addition of weight loss and performance score modestly improved the concordance probability (0.59 to 0.61) of this model. The HR for OS between high and low risk groups using this model was 2.72 (95% CI 1.94-3.81), median OS: 21 months (95% CI 19-26) vs 44 months (95% CI 36-not reached), respectively. For PFS, the HR between high and low risk groups was 2.55 (95% CI 1.86-3.5), median PFS: 13 months (95% CI 12-15) vs 26 months (95% CI 18-48), respectively. None of the tested covariates predicted patient benefit from twice-daily radiotherapy. Increase in patient age (continuous variable) predicted non-completion of planned chemotherapy (p=0.002). Due to the high completion of radiotherapy (86% in twice-daily and 80% in once-daily group), a multivariate analysis to predict radiotherapy completion was not performed.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We report a clinical prognostic model in LS-SCLC, providing information that clinicians can relay to their patients to aid clinical decisions. The addition of biological covariates could help refine these prognostic models in the future.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.16 - Treatment of Early Stage/Localized Disease (Not CME Accredited Session) (ID 965)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.16-08 - Influence of Tumour Location and Histological Sub-Type of Non-Small Cell Lung Cancer on Patient Survival (ID 13836)

      16:45 - 18:00  |  Author(s): Corinne Faivre-Finn

      • Abstract
      • Slides

      Background

      In non-small cell lung cancer (NSCLC), adenocarcinomas tend to arise peripherally and squamous cell carcinomas (SCC) centrally. Tumour location is known to impact patient survival: in previous work, we showed that right-sided tumours show worse survival, n=1101; HR=1.25, p<0.01. In this study we extended the laterality analysis by including histological sub-type and explore its correlation with overall survival.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      529 unselected NSCLC patients (treated with 55Gy/20fr), with confirmed adenocarcinoma or SCC, were included. All patients were spatially normalised using non-rigid registration to a reference anatomy, allowing tumour probability maps to be created from the outlined tumours. A Kolmogorov-Smirnov test assessed differences in distributions.

      Kaplan-Meier curves, grouped by histological sub-type, were plotted. Tumour volumes were extracted for all patients and included in a multi-variate analysis including N-stage, performance status, gender and median dose to left and right lungs, encoding laterality.

      4c3880bb027f159e801041b1021e88e8 Result

      326 adenocarcinomas and 203 SCC were found. Tumour probability maps show a clear separation in tumour locations between the sub-types (Fig.1a, p<0.001) and a general location of SCC tumours along the major airways. Tumour volumes were significantly different (SCC larger, median 56cm3 versus 14cm3, p<0.001, Fig.1b). Histology also influences nodal involvement, 20% adenocarcinomas versus 80% SCC are N+. Location and volume impacts on normal tissue doses, mean lung and heart doses: 8.8Gy and 4.9Gy for adenocarcinomas, 15.6Gy and 18.8Gy for SCC.

      SCC patients showed worse survival (median 12 versus 21 months, Fig.1c). Multivariate analysis shows right lung mean doses significantly correlate with survival for adenocarcinomas, p=0.04, but not for SCC, p=0.2, indicating the spatial location of the tumour may have an interaction with our previously described laterality effect.

      figure.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      Differences in the spatial locations and volumes of histological sub-types influence normal tissue doses including the effect of tumour laterality on survival. Further work will explore possible mechanisms, including ventilation/perfusion variation in the lungs.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.16-16 - SABRTOOTH: A Fasibility Study of SABR Versus Surgery in Patients with Peripheral Stage I NSCLC Considered to be at Higher Risk for Surgery. (ID 13679)

      16:45 - 18:00  |  Author(s): Corinne Faivre-Finn

      • Abstract
      • Slides

      Background

      Stage I NSCLC is curable by surgery and Stereotactic Ablative Radiotherapy (SABR). Many patients have co-morbidities that place them at higher risk of surgical complications. For such patients it is unknown whether the potential benefits of surgery are outweighed by the risks since published randomised trials comparing surgery with SABR have been underpowered. The SABRTooth study was designed to determine the feasibility of randomising patients between the two treatments and thus performing a larger RCT.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Four thoracic oncology centres and a referral site participated. Patients with peripheral (>2cm from the main airways) stage T1-T2bN0M0 NSCLC were considered for study entry. Patients at higher risk were identified using several criteria including Thoracoscore and the Nottingham Risk Score and confirmed by multidisciplinary team consensus.

      Eligible patients were approached by a respiratory physician and research nurse, consented and randomised (1:1) before consulting a surgeon or oncologist. Surgery was preferably by lobectomy with lymph node sampling/resection although sub-lobar resection was permitted. SABR was delivered as per the UK SABR guidelines.

      An average recruitment rate of 3 patients/month from the 5 centres over a formal monitoring period was set to prove feasibility of a larger RCT. Meetings with the trial sites and patient representatives were held through-out to improve recruitment. Qualitative research was embedded into the study with interviews for patients who declined participation or randomised treatment.

      4c3880bb027f159e801041b1021e88e8 Result

      Between July 2015-January 2017 318 patients were assessed for eligibility of which 106 were initially considered eligible. 84 patients were approached for the study and 24 (29%) were randomised (10 surgery, 14 SABR); a mean recruitment rate of 1.7 per month. The median age was 75 (range 54-88). The main reason for declining the study was patient preference with 29% preferring surgery and 42% SABR. Overall 9/24 (38%) did not receive their randomised treatment. Of 7 patients randomised to surgery, 6 received SABR, 1 radical radiotherapy and of 2 patients randomised to SABR, 1 received radical radiotherapy, 1 was lost to follow-up.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Despite recruiting at higher rate/centre than previous SABR versus surgery trials, the SABRTooth study failed to meet its recruitment target and the majority of patients randomised to surgery subsequently underwent SABR. Therefore, conducting a large RCT in the UK was shown not to be feasible. However, establishing which patients should have surgery or SABR for early stage NSCLC remains a critical question and alternative study designs are being developed to provide an answer for patients and clinicians.

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    P3.01 - Advanced NSCLC (Not CME Accredited Session) (ID 967)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.01-26 - A Framework for Systematic Clinical Evaluation of Technical Innovations in Lung Cancer Patients Treated on the MR-Linac (MRL) (ID 12562)

      12:00 - 13:30  |  Presenting Author(s): Corinne Faivre-Finn

      • Abstract
      • Slides

      Background

      A recent innovation in radiotherapy is the MRL developed by Elekta and Philips. The MRL combines a 1.5 T MRI with a 7 MV linac. It allows the acquisition of high resolution MR images for on treatment verification, adaption and response monitoring.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Seven cancer institutions from Europe and North America, are working within the Elekta MR-Linac Consortium to evaluate the MRL within a framework called ‘R-IDEAL’ (Radiotherapy Idea Development Exploration Assessment Long-term Evaluation) 1.

      4c3880bb027f159e801041b1021e88e8 Result

      The table below summarizes the ongoing and planned work within the Elekta MR-Linac Consortium.

      table for wlcc 3-5-2018.jpg

      Progress to date:
      Stage 0:
      We defined in 80 patients the optimal MRI sequences suitable for GTV and organ at risk (OAR) contouring: T2 Turbo Spin Echo (TSE), T2 TSE with fat sat, T1 radial gradient echo, and DIXON TSE. Two radiology-led workshops were organized and inter-observer agreement was assessed for OARs. These led to a consensus-based OAR atlas. A study is being prepared to compare the image quality of the current standard CBCT and MR images at baseline and mid-treatment for treatment verification and set-up correction.
      Stage 1: we will investigate the clinical feasibility of the MRL for standard of care radiotherapy and the scope for adaptive radiotherapy (margin reductions) and detecting changes in oxygenation during treatment on the MRL in patients with locally advanced (LA) NSCLC .
      Stage 2a/b : Based on the results from stage 1 we will design a study aiming to reduce margins around the tumour and dose escalate in patients with LA NSCLC.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The aim of this programme of work is to generate robust evidence to support the introduction of the MRL and to improve outcomes of patients with LA NSCLC.

      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): Corinne Faivre-Finn

      • 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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