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Yuanbin Chen



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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  |  Author(s): Yuanbin Chen

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

    • Event: WCLC 2020
    • Type: Posters
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 3
    • 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): Yuanbin Chen

      • 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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      P48.14 - RESILIENT Part 2: A phase 3 Study of Liposomal Irinotecan in Patients with Small-Cell Lung Cancer in the Second-Line Setting (ID 3485)

      00:00 - 00:00  |  Author(s): Yuanbin Chen

      • Abstract
      • Slides

      Introduction

      Small cell lung cancer (SCLC) accounts for approximately 15% of lung cancers. SCLC is usually sensitive to established first-line therapies, but many patients relapse and develop resistance to platinum-based first-line treatment. Currently, the topoisomerase 1 inhibitor topotecan is the only approved second-line therapy for SCLC in the USA and Europe. Liposomal irinotecan is an intravenous formulation that encapsulates the topoisomerase 1 inhibitor irinotecan in a lipid-bilayer vesicle, leading to prolonged circulation. The safety, tolerability and efficacy of liposomal irinotecan monotherapy in patients with SCLC who progressed with platinum-based first-line therapy is being evaluated in RESILIENT (NCT03088813), a two-part phase 2/3 study. Preliminary data from the dose-ranging part of the study (part 1) indicated that liposomal irinotecan 70 mg/m2 (free base equivalent) administered every 2 weeks was well tolerated and had promising antitumour activity.1 Here, we present the design of RESILIENT part 2, which will assess the efficacy and safety of liposomal irinotecan versus topotecan in the same patient population.

      References

      Paz-Ares L et al. Poster presented at the 2019 American Society of Clinical Oncology conference, May 31–June 4, 2019, Chicago, IL, USA

      Methods

      RESILIENT part 2 is a phase 3, open-label study with a planned sample size of 450. Participants are randomized 1:1 to intravenous liposomal irinotecan or intravenous topotecan. Liposomal irinotecan is administered at 70 mg/m2 every 2 weeks and topotecan is administered at 1.5 mg/m2 for 5 consecutive days every 3 weeks. A total of 254 patients have been randomized and received treatment to date (as of August 8, 2020). Tumour assessments are performed using the Response Evaluation Criteria in Solid Tumors version 1.1 and the Response Assessment in Neuro-oncology criteria for CNS lesions. Improvements in symptoms are measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and the European Organization for Ressearch and Treatment of Cancer Quality of Life Questionnaire Lung Cancer 13. Safety assessments include monitoring for adverse events. Overall survival is the primary endpoint of the study. Progression-free survival, objective response rate and proportion of patients reporting symptom improvement are secondary endpoints. Participants will continue study treatment until disease progression, unacceptable toxicity or study withdrawal. Participants will be followed for survival until death or study end, which is when all patients have died, withdrawn consent or are lost to follow-up.

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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): Yuanbin Chen

      • 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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