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Afshin Dowlati



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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): Afshin Dowlati

      • 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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    MA08 - Advances in Biomarkers for Immune Checkpoint Blockade and Targeted Therapy in Non Small Cell Lung Carcinoma (ID 166)

    • Event: WCLC 2020
    • Type: Mini Oral
    • Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
    • Presentations: 1
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      MA08.10 - LUNGMAP Master Protocol (LUNGMAP): Concordance Between Plasma ctDNA and Tissue Molecular Analysis (ID 3146)

      16:45 - 17:45  |  Author(s): Afshin Dowlati

      • Abstract
      • Slides

      Introduction

      The national LUNGMAP clinical trial is predicated on molecular screening enabling patient enrollment to biomarker-matched sub-studies for rapid evaluation of new precision medicine concepts in advanced NSCLC. To date, LUNGMAP has used a tissue-based Next-Generation Sequencing (NGS) approach for biomarker assessment. Given the utility of circulating tumor DNA (ctDNA) for biomarker identification, LUNGMAP investigators are evaluating the feasibility of plasma ctDNA as a screening approach.

      Methods

      Plasma samples for ctDNA testing were required for patients submitting fresh tissue biopsies for LUNGMAP screening. Tissue and plasma ctDNA were analyzed using the FoundationONE CDx and FoundationACT platforms at Foundation Medicine, Inc., respectively. Alterations detectable in both platforms were evaluated. Using tissue-detected driver alterations (referred to as drivers) as the gold standard, sensitivity was calculated as the proportion of patients with drivers also detected in ctDNA in addition to tissue, and specificity was calculated as the proportion of patients without drivers in ctDNA among those without drivers in tissue. Proportions and 95% exact confidence interval (CI) estimates were calculated.

      Results

      From January 2019 to June 2020, 129 patients had paired data and 54 (42%) had recognized oncogene drivers detected (EGFR [n=7], KRAS [n=37], MET [n=7], RET [n=2], BRAF [n=1], Table 1). Fifty-two patients had drivers detected in tissue; of these 43 were also observed in ctDNA, with 9 found in tissue only, for a ctDNA driver sensitivity of 83% (43/52, 95% CI: 74-93%). Of the 77 patients with no drivers in tissue, 2 drivers were detected in ctDNA (EGFR Ex20ins, MET amp) for a ctDNA specificity of 97% (75/77, 95% CI: 91-100%). For drivers, median variant allele frequency (VAF) in ctDNA was 2.22% (range: 0.13%-46.27%). For all single nucleotide variants (SNVs) and rearrangements detectable on both platforms, 386 variants were detected. Short variants (point mutations and small in/dels) showed the most fidelity, with 54% detected in both platforms (Table 1). Copy number alterations using an earlier platform version were least reproduced, with 8% identified by both.

      Conclusion

      In the LUNGMAP population, ctDNA (FoundationAct) had an 83% sensitivity and 97% specificity for NSCLC drivers detected in tissue. For non-driver alterations, additional variants were detected exclusively in plasma or tissue, likely reflecting differential sensitivity and/or non-shedding and tissue heterogeneity. These results, consistant with other recent studies, support the planned use of ctDNA for enrollment onto LUNGMAP sub-studies, with a positive finding meriting inclusion in study but a negative finding, considered inconclusive, requiring use of tissue results.

      Table 1

      N (%)

      Total Alterations Detected

      Number of Patients

      ................... In ctDNA ................

      ...................... In Tissue ................

      Overall

      In Tissue

      Not in Tissue

      Overall

      In ctDNA

      Not in ctDNA

      Driver Alterations

      54

      54

      45

      43 (96%)

      2 (4%)

      52

      43 (83%)

      9 (17%)

      Non-driver Alterations

      439

      75

      294

      169 (57%)

      125 (43%)

      314

      169 (54%)

      145 (46%)

      Short Variants

      316

      273

      158 (58%)

      115 (42%)

      201

      158 (79%)

      43 (21%)

      Copy Number Alts

      104

      10

      8 (80%)

      2 (20%)

      102

      8 (8%)

      94 (92%)

      Rearrangements

      19

      11

      3 (27%)

      8 (73%)

      11

      3 (27%)

      8 (73%)

      Overall

      493

      129

      339

      212 (63%)

      127 (37%)

      366

      212 (58%)

      154 (42%)

      Short Variants

      365

      314

      198 (63%)

      116 (37%)

      249

      198 (80%)

      51 (20%)

      Copy Number Alts

      107

      12

      9 (75%)

      3 (25%)

      104

      9 (9%)

      95 (91%)

      Rearrangements

      21

      13

      5 (38%)

      8 (62%)

      13

      5 (38%)

      8 (62%)

      TP53

      150

      128

      77 (60%)

      51 (40%)

      99

      77 (78%)

      22 (22%)

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    MA13 - Tumor Biology: Focus on EGFR Mutation, DNA Repair and Tumor Microenvironment (ID 214)

    • Event: WCLC 2020
    • Type: Mini Oral
    • Track: Tumor Biology and Systems Biology - Basic and Translational Science
    • Presentations: 1
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      MA13.02 - Novel Non-Invasive Radiomic Signatures Extracted from Radiographic Images can Predict Response to Systemic Treatment in Small Cell Lung Cancer (ID 3151)

      16:45 - 17:45  |  Author(s): Afshin Dowlati

      • Abstract
      • Slides

      Introduction

      SCLC is an aggressive malignancy characterized by inevitable resistance to chemotherapy. There are no predictive biomarkers that can accurately guide use of systemic therapy in SCLC patients. We hypothesized that quantitative radiomic features (i.e. computer extracted imaging) from pretreatment CT scans can prognosticate survival and predict sensitivity to chemotherapy. We sought to train a prognostic classifier and use it to predict response to chemotherapy.

      Methods

      180 SCLC patients who recieved platinum-based chemotherapy were selected. 27 patients were excluded, with no measurable disease. Remaining 153 patients were randomly divided into training (n=77) and validation set (n=76). Lung tumors were contoured on 3D-Slicer® software by an expert reader. 1542 radiomic features (textural and shape) were extracted from intra and peritumoral regions. Primary endpoints of this study were overall survival (OS) and objective response to chemotherapy per RECIST. Patients with complete or partial response were defined as responders (R) and those with stable or progression of disease as non-responders (NR). Radiomic risk score (RRS) was generated by using least absolute shrinkage and selection operator, and Cox regression model was used to predict OS. Kaplan Meier and log-rank tests were performed to assess discriminative ability of the features. Features prognostic of OS were used to train a machine learning classifier to predict response to chemotherapy. A linear discriminant analysis (LDA) classifier was trained and used to predict response. Area under receiver operating characteristic curve (AUC) was calculated for response to chemotherapy.

      Results

      153 SCLC patients were included, median age 66 years, 72.8% men and median OS of 9.37 months. 75% had ES and 35% LS disease. Multivariate Cox regression analysis indicated that RRS was significantly associated with OS in the training set [HR: 1.53; 95% CI, 1.1–2.2; P=0.021; C-index=0.72) and validation set [HR: 1.4; 95% CI, 1.1–1.82; P=0.0127; C-index=0.69). Chemotherapy response was achieved in 71 (66%); labeled responders (R) and the rest 36 (34%) labeled as non-responders (NR). LDA classifier trained with prognostic features was able to predict response with AUC of 0.76 ± 0.03 within the training set and corresponding AUC of 0.72 within the validation set. Multivariate Cox regression analysis with radiomic features and clinical biomarkers identified the RRS and cancer stage (LS or ES) as two risk factors in OS for patients in the training set (RRS: HR, 2.1, 95 % CI: 1.53, 2.85, P = 0.0076; clinical stage: HR, 1.66, 95 % CI: 1.01, 2.7, P = 0.048; and age: HR, 1.04, 95 % CI: 0.99, 1.09, P = 0.071; C-index = 0.75) and corresponding validation set (RRS: HR, 1.9, 95 % CI: 1.23, 2.2, P = 0.0012; clinical stage: HR, 1.61, 95 % CI: 1.2, 2.17, P = 0.041 and age: HR, 1.01, 95 % CI: 0.99, 1.03, P = 0.22; C-index = 0.71).

      Conclusion

      Texture features extracted from within and around the lung tumor from pretreatment CT images were both prognostic of OS and predictive of response in SCLC patients. Pretreatment radiomic features may permit early assessment of benefit and expedite alternative treatment options. Additional independent validation of these image-based biomarkers is warranted.

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    OA11 - A Symphony of Progress (ID 229)

    • Event: WCLC 2020
    • Type: Oral
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
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      OA11.03 - A Phase 1 Study of AMG 757, Half-Life Extended Bispecific T-Cell Engager (BiTE®)Immune Therapy Against DLL3, in SCLC (ID 3414)

      15:30 - 16:30  |  Author(s): Afshin Dowlati

      • Abstract
      • Presentation
      • Slides

      Introduction

      Delta-like ligand 3 (DLL3), an inhibitory Notch ligand that is highly expressed in small cell lung cancer (SCLC) compared to normal tissues, is a potential therapeutic target.1 AMG 757, a half-life extended BiTE® immune therapy, binds DLL3 on tumor cells and CD3 on T cells, leading to T cell‑dependent killing of tumors. Emerging data from the ongoing phase 1 study of AMG 757 in SCLC are reported (NCT03319940).

      Methods

      AMG 757 (0.003–10.0 mg) was administered intravenously every two weeks with/without step dose. Eligible patients had SCLC that progressed or recurred following ≥1 platinum-based regimen. Antitumor activity was assessed using modified RECIST 1.1. Tumor DLL3 expression was assessed by immunohistochemistry. T-cell activation and cytokine profiles pre and post AMG 757 treatment were evaluated.

      Results

      As of 7 August 2020, 40 patients (median age [range], 64 years [44–80]; ECOG PS: 0-1, n=39 [97.5%], median prior lines: 2.0 [1–6]; prior PD-1/PD-L1 treatment: n=17 [42.5%]) enrolled at eight dose levels (DL) received ≥1 AMG 757 dose. Median treatment duration was 6.1 weeks (0.1–59.4). Adverse events occurred in 39 (97.5%) patients, resulting in discontinuation in 4 (10.0%); 32 (80.0%) were treatment-related, including 7 (17.5%) grade ≥3 and 1 (2.5%) grade 5 (pneumonitis; DL5 [0.3 mg]). Cytokine release syndrome (CRS) was reported in 18 (45.0%) patients; grade 2 CRS in 5 (12.5%); no grade ≥3 CRS. CRS presented mainly as fever ± hypotension, was reversible, did not lead to treatment interruption or discontinuation, occurred mostly within 24 hours of the first two doses of AMG 757, and was managed with supportive care, corticosteroids, and/or anti-IL-6 treatment. AMG 757 showed dose proportional increase in exposures.

      Confirmed partial response (PR) was reported for 6 (15.8%) patients (1/12 [8.3%] in DL5, 1/8 [12.5%] in DL6, 3/7 [42.9%] in DL7, and 1/7 [14.3%] in DL8 [Figure]). Stable disease was reported for 11 (28.9%). One patient has ongoing unconfirmed PR in DL8. Evaluation of DL8 is ongoing. Patients with confirmed PR had a median of 2 (1–4) prior lines of therapy and duration of response of 1.9+ to 9.4+ months. DLL3 expression at any level was observed in 31/32 (96.9%) patient tumor samples, with overall H-score 40–300. Tumor shrinkage occurred across a wide range of DLL3 expression (H-score, 55–300).

      amg 757 phase1_ figure.jpg

      Conclusion

      AMG 757 has acceptable safety at doses of up to 10 mg and shows anti-tumor activity in patients with SCLC. Dose escalation is ongoing.

      References

      1. Leonetti A, et al. Cell Oncol (Dordr). 2019;42(3):261-273.

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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: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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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): Afshin Dowlati

      • 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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    P68 - Tumor Biology and Systems Biology - Basic and Translational Science - Radiomics (ID 207)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Tumor Biology and Systems Biology - Basic and Translational Science
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P68.02 - Computer Extracted Morphology Features of Tumor Nuclei Predict Response to Chemotherapy and Prognostic of OS in Small Cell Lung Cancer (ID 3574)

      00:00 - 00:00  |  Author(s): Afshin Dowlati

      • Abstract

      Introduction

      Small cell lung cancer (SCLC) is an aggressive malignancy that accounts for ~15% of all lung cancers and is characterized by inevitable chemotherapy resistance and rapid progression. To date, there are no consistent predictive biomarkers that can accurately guide the use of systemic therapy in patients with SCLC. We hypothesize that computer extracted morphology features of cancer nuclei from digitized whole slide images (WSI) of pre-treatment H&E biopsy specimens are prognostic of overall survival (OS) and also predict sensitivity to platinum-based chemotherapy.

      Methods

      106 patients with extensive and limited-stage SCLC who received platinum-doublet chemotherapy were selected for this study. WSIs of SCLC tumor tissues were retrospectively digitized at 40x magnification. Tumor regions were manually annotated by an expert pathologist. An automated machine learning model was employed to automatically identify cancer nuclei. A set of 100 features related to the morphological phenotype and functional characteristics (shape, size, intensity, cellular texture) of the cancer nuclei were extracted from each case. Primary endpoints of the study were overall survival (OS) and the best objective response to chemotherapy (RECIST criteria). The predictive and prognostic capabilities of the features were assessed by a Naive Bayes classifier and cross-validation scheme with a Cox regression model respectively. The median risk score was used as a threshold for labeling the patient as either having a low or high risk of death. Kaplan-Meier survival analysis was used to evaluate the procedure. The statistical significance of the cross-validated Kaplan-Meier curves was evaluated by using a permutation test.

      Results

      The median age was 66 years, 68% had extensive stage disease and 32% had limited stage, median follow-up was 9 months. Based on the approach, median OS for patients identified by our model as being at high risk of death was 11 months vs. 14 months for low-risk patients. No statistically significant difference between extensive stage and limited stage disease was found (p=0.3916). On univariable survival analysis, high-risk patients had a hazard ratio of 1.66 (95% CI: 1.03-2.68, p=0.0367), with a statistical significance of 4% after 500 permutations. The model predicted responders from non-responders with an accuracy of 0.63 and a precision-recall of 0.83.

      Conclusion

      A computerized image analysis model based on the morphological features of cancer nuclei on pretreatment H&E biopsy slide images were found to be predictive of response and prognostic for OS in SCLC patients. Future work will entail additional independent multi-site validation of the signature.