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J. Pujol
Moderator of
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OA05 - Treatment Advances in SCLC (ID 373)
- Event: WCLC 2016
- Type: Oral Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 8
- Moderators:A. Ardizzoni, J. Pujol
- Coordinates: 12/05/2016, 14:20 - 15:50, Strauss 2
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OA05.01 - Pembrolizumab in Patients with Extensive-Stage Small Cell Lung Cancer: Updated Survival Results from KEYNOTE-028 (Abstract under Embargo until December 5, 7:00 CET) (ID 6198)
14:20 - 15:50 | Author(s): P.A. Ott, E. Felip, S. Hiret, D. Kim, A. Morosky, S. Saraf, B. Piperdi, J.M. Mehnert
- Abstract
- Presentation
Background:
Patients with extensive-stage disease (ED) small cell lung cancer (SCLC) have limited treatment options and poor survival following failure of platinum-based chemotherapy. Pembrolizumab, a humanized anti–programmed death 1 (PD-1) antibody, has demonstrated robust antitumor activity and a favorable safety profile in multiple tumor types. Here, we present updated safety and efficacy data, including survival, for patients with ED SCLC enrolled in the KEYNOTE-028 (ClinicalTrials.gov, NCT02054806) study.
Methods:
KEYNOTE-028 is a nonrandomized, multicohort phase 1b trial of pembrolizumab in patients with PD-L1–positive advanced solid tumors. Patients received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years or until confirmed progression or intolerable toxicity, death, withdrawal of consent, or physician decision. Response was assessed per RECIST v1.1 by investigators every 8 weeks for the first 6 months and every 12 weeks thereafter. The primary end point was objective response rate (ORR; per RECIST v1.1, investigator assessed). Secondary end points included safety, tolerability, progression-free survival (PFS), and overall survival (OS).
Results:
24 patients with ED SCLC and tumor PD-L1 positivity were enrolled and received ≥1 dose of pembrolizumab. At the data cutoff date (June 9, 2016), median follow-up duration was 9.8 months (range, 0.5-24.0 months); 3 patients (12.5%) remain on treatment. The ORR was 37.5% (95% CI, 18.8%-59.4%), including 1 complete and 8 partial responses in 24 evaluable patients. Median duration of response was 9.0 months (range, 1.9-19.9+ months). Median PFS was 1.9 months (95% CI, 1.7-5.9 months); the 6- and 12-month PFS rates were 29.8% and 24.8%, respectively. Median OS was 9.7 months (95% CI, 4.1 months-not reached); the 6- and 12-month OS rates were 66.0% and 35.7%, respectively. No new safety concerns were noted. Sixteen of 24 (66.7%) patients experienced treatment-related AEs. Two patients experienced grade 3-5 treatment-related AEs: 1 patient had blood bilirubin increased (grade 3) and 1 patient experienced grade 3 asthenia and grade 5 colitis.
Conclusion:
Pembrolizumab demonstrated promising antitumor activity in this pretreated, PD-L1–positive ED SCLC population. The responses were found to be durable and may have led to an OS benefit for the subset of patients who achieved objective responses with pembrolizumab.
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OA05.02 - Anti-Tumor Immunity is a Key Determinant of SCLC Survivorship (ID 5759)
14:20 - 15:50 | Author(s): F. Kosari, S.B. Terra, A. Nasir, P. Muppa, M.C. Aubry, J.E. Yi, N. Janaki, A. Mansfield, M. De Andrade, P. Yang, G. Vasmatzis, V.P. Van Keulen, T. Peikert
- Abstract
- Presentation
Background:
While the majority of small cell lung cancer (SCLC) patients succumb to their disease within a few months, there is a small group of patients who survive for many years after their diagnosis. Factors contributing to the SCLC long-term survivorship remain largely unknown. Herein, we compared tumors from exceptional survivors (EXS) and patients with the expected outcome (EOP) to determine genomic and immunological determinant of SCLC survivorship.
Methods:
In the Mayo Clinic tissue registry, we identified surgical blocks from 12 EXS who survived > 4 years after surgery and 14 EOP who died < 2 years of surgery. These cohorts were created to have no statistical differences in clinical TNM stage, curative versus non-curative intent surgery, age, gender, and smoking status between EXS and EOP. Tumor areas were macro-dissected for gene expression profiling by the Human Transcriptome Array (Affymetrix). Also, tissue sections were stained for key immunological markers, including CD8, CD4, CD3, CD279, FoxP3, CD138, CD20, CD21, CD14, CD68, and also LYZ. Concentrations of immune cells in intra-tumor areas (IE), stroma (ST), and tumor/non-tumor interface (IF) were assessed by an image processing program (Aperio). Staining patterns in each of the three zones in EXS and EOP tumors were compared.
Results:
More than 90% of differentially expressed genes were over-expressed in EXS compared with EOP. Furthermore, over 75% of the known over-expressed genes were either immunoglobulin or MHC related and a majority of the remaining genes were immune function related such as cytokines. We then performed IHC for key immunological markers and found significantly higher concentration of immune cells including CD8 and PD-1 positive cells in the tumor microenvironment, especially at the tumor stromal interface in EXS compared with EOP (p < 0.005 for both markers). Furthermore, the total number of infiltrating immune cells (T-cells, B-cells, Plasma cells, monocytes and macrophages was significantly higher in EXS in the interface region (p < 0.0005).
Conclusion:
Gene expression profiling revealed that anti-tumor immunity is an important factor for SCLC survival. Further studies by IHC suggested the presence of immune cells especially cytotoxic T-cells in the tumor microenvironment and particularly at the tumor-stromal interface to be major contributors to long term survivorship in SCLC. These findings suggest that immunotherapeutic strategies may be effective for patients with SCLC.
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OA05.03 - Single-Agent Rovalpituzumab Tesirine, a Delta-Like Protein 3 (DLL3)-Targeted Antibody-Drug Conjugate (ADC), in Small-Cell Lung Cancer (SCLC) (ID 4648)
14:20 - 15:50 | Author(s): D.R. Spigel, M.C. Pietanza, T.M. Bauer, N. Ready, D. Morgensztern, B.S. Glisson, L.A. Byers, M.L. Johnson, H.A. Burris, F. Robert, T.H. Han, S. Bheddah, N. Theiss, S. Watson, D. Mathur, B. Vennapusa, D.K. Strickland, H. Zayed, S.J. Dylla, S.L. Peng, R. Govindan, C. Rudin
- Abstract
- Presentation
Background:
SCLC is one of the most deadly malignancies. Rovalpituzumab tesirine (SC16LD6.5, Rova-T) is a first-in-class ADC directed against DLL3, a novel target identified in tumor initiating cells and expressed in over 80% of SCLC cases.
Methods:
Seventy-four patients with progressive SCLC after at least one previous systemic therapy were enrolled in a first-in-human study (NCT01901653), irrespective of DLL3 expression, including 68 at active doses of 0.2-0.4 mg/kg administered intravenously every 3 or 6 weeks. Available archived tumor tissue (n=48) was assessed retrospectively by immunohistochemistry for DLL3.
Results:
Among 60 evaluable subjects, active dose levels resulted in a confirmed objective response rate (ORR) of 18% and a confirmed clinical benefit rate (CBR; stable disease or better) of 68%. Among 26 evaluable subjects with DLL3 expression in at least 50% of tumor cells (DLL3-high), confirmed ORR and CBR were 39% and 89%, respectively. Median duration of response was 5.6 months. One-year survival rates among all and DLL3-high subjects were 18% and 32%, respectively. Among primary sensitive relapse patients, confirmed ORR and CBR among all subjects were 24% (8/33) and 67% (22/33); and among DLL3-high subjects were 53% (8/15) and 100% (15/15), with one-year survival rates of 17% and 33%, respectively. Among primary resistant/refractory relapse patients, confirmed ORR and CBR among all subjects were 12% (3/25) and 72% (18/25); and among DLL3-high subjects were 18% (2/11) and 73% (8/11), with one-year survival rates of 21% and 29%, respectively. The most common grade 3 or higher toxicities included thrombocytopenia (12%), serosal effusions (11%), and skin reactions (8%). ADC pharmacokinetics were linear with a terminal half-life of 10 - 14 days and anti-therapeutic antibodies did not develop
Conclusion:
Rovalpituzumab tesirine demonstrates encouraging single-agent anti-tumor activity with a manageable safety profile, including among patients with disease resistant or refractory to primary chemotherapy. Further development of rovalpituzumab tesirine in SCLC is warranted.
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OA05.04 - Discussant for OA05.01, OA05.02, OA05.03 (ID 6977)
14:20 - 15:50 | Author(s): L. Horn
- Abstract
- Presentation
Abstract not provided
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OA05.05 - Randomized Phase 2 Study: Alisertib (MLN8237) or Placebo + Paclitaxel as Second-Line Therapy for Small-Cell Lung Cancer (SCLC) (ID 4855)
14:20 - 15:50 | Author(s): T.K. Owonikoko, K. Nackaerts, T. Csoszi, G. Ostoros, C.S. Baik, C. Dansky Ullmann, E.A. Zagadailov, E. Sheldon-Waniga, D. Huebner, E.J. Leonard, D.R. Spigel
- Abstract
- Presentation
Background:
Alisertib, an investigational selective Aurora A kinase inhibitor, showed single-agent antitumor activity in preclinical in vivo SCLC models and was synergistic with paclitaxel in this setting. We report the efficacy, quality of life (QoL), and safety from this study.
Methods:
Patients ≥18 years with SCLC relapsed <180 days after standard first-line platinum-based chemotherapy were randomized 1:1 to alisertib 40 mg orally twice-daily on days 1–3, 8–10, 15–17 + paclitaxel 60 mg/m[2] IV on days 1, 8, 15 (Arm A) or matched placebo + paclitaxel 80 mg/m[2] (Arm B) in 28-day cycles. Patients were stratified using an interactive voice response system (IVRS) by type of relapse post-frontline platinum (sensitive vs resistant/refractory) and presence/absence of brain metastases at baseline. Protocol Amendment 2 corrected the definition for relapse per standard guidance; stratification factors were corrected accordingly. Primary endpoint was progression-free survival (PFS) per stratified log-rank test. QoL outcomes were assessed per EORTC QLQ-C30 and -LC13.
Results:
178 patients were randomized, 89/89 to Arm A/B (median age 62/62 years). Survival, response, QoL, and safety results are presented in the Table. The analysis of PFS using IVRS stratification favored Arm A, as did the analysis per corrected stratification factors. Mean EORTC QLQ-C30 QoL scores were similar between arms, as were mean change-from-baseline values at end of treatment (-5.7 in Arm A vs -4 in Arm B). Figure 1
Conclusion:
Alisertib + paclitaxel shows favorable PFS over placebo + paclitaxel with both initial and updated IVRS stratification. A similar favorable trend was also observed for OS and ORR although not statistically significant. Comparable changes in QoL scores were observed from baseline in both arms. The alisertib + paclitaxel arm showed higher rates of AEs and discontinuation due to AEs. Updated survival analyses are pending.
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OA05.06 - Compliance and Outcome of Elderly Patients Treated in the Concurrent Once-Daily versus Twice-Daily RadioTherapy (CONVERT) Trial (ID 4061)
14:20 - 15:50 | Author(s): M. Christodoulou, F. Blackhall, L. Ashcroft, A. Leylek, J. Knegjens, V. Remouchamps, I. Martel-Lafay, N. Farré, M. Zwitter, D. Lerouge, N. Pourel, H. Janicot, A. Scherpereel, C. Tissing-Tan, K. Peignaux, X. Geets, K. Konopa, C. Faivre-Finn
- Abstract
- Presentation
Background:
A significant proportion of limited-stage small cell lung cancer are elderly. However, there is paucity of data on the efficacy and safety of concurrent chemo-radiotherapy in the elderly to guide treatment decision-making.
Methods:
Data from the CONVERT trial was retrospectively analysed to compare the outcome of patients 70 years or older to patients younger than 70 years. Patients were randomised 1:1 to receive 45Gy in 30 twice-daily fractions over 3 weeks or 66Gy in 33 once-daily fractions over 6.5 weeks starting on day 22 of cycle 1 chemotherapy (4 to 6 cycles of Cisplatin 25mg/m2 days 1-3 or 75mg/m2 day 1 with Etoposide 100mg/m2 days 1-3), followed by Prophylactic Cranial Irradiation if indicated. Radiotherapy planning was with a 3D conformal technique or intensity modulated radiotherapy.
Results:
Of 547 patients randomised between April 2008 and November 2013, 57 patients were excluded for the purposes of this analysis as they did not receive concurrent chemo-radiotherapy. Of the 490 included patients, 67 (13.7%) were age 70 years or older with median age of 73 years (70-82). Patients’ characteristics were well balanced apart from more male in the elderly group (p=0.02). There was no significant difference in the number of chemotherapy cycles administered in the two groups (p=0.24). A higher proportion of patients received 30 or 33 fractions of radiotherapy as per protocol in the younger group (85% vs. 73%; p=0.03). Neutropenia grade 3/4 occurred more frequently in the elderly group (84% vs. 70%; p=0.02) but there was no statistically significant difference in neutropenic sepsis (4% vs. 7%; p=0.07) and non-haematological acute/late toxicities. There were two vs. six treatment-related deaths in the elderly and younger group respectively (p=0.67). At median follow up of 46 months for those alive; two-year survival was 53% (95% CI 41-64) vs. 57% (95% CI 52-61), median survival was 29 months vs. 30 months in the elderly vs. younger group respectively. Hazard ratios for overall survival and progression free survival were 1.15 (95% CI 0.84-1.59; log-rank p=0.38) and 1.04 (95% CI 0.76-1.41; log-rank p=0.81) respectively. In the elderly group median survival was not significantly different in patients who received once vs. twice daily radiotherapy (p=0.91).
Conclusion:
Radiotherapy treatment delivery was higher in the younger group but toxicity and survival rates were similar in elderly compared to younger patients. Concurrent chemo-radiotherapy with modern radiotherapy techniques is a treatment option for elderly patients with good performance status.
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OA05.07 - Prognostic Value of Circulating Tumour Cells in Limited-Disease Small Cell Lung Cancer Patients Treated on the CONVERT Trial (ID 5431)
14:20 - 15:50 | Author(s): F. Fernandez-Gutierrez, V. Foy, K. Burns, J. Pierce, K. Morris, L. Priest, J. Tugwood, L. Ashcroft, C. Faivre-Finn, C. Dive, F. Blackhall
- Abstract
- Presentation
Background:
Circulating tumour cells (CTCs) are prevalent in patients with small cell lung cancer (SCLC) (Hou et al. JCO 2012) but their clinical utility is not known for patients with limited disease (LD) who receive concurrent chemoradiation. Here we report on a patient subgroup who underwent CTC analysis and treatment on the Concurrent ONce-daily (OD) VErsus Twice-daily (BD) RadioTherapy (CONVERT) trial (Faivre-Finn Proc. ASCO 2016) that demonstrated a non-significant difference in the primary endpoint of two-year survival for the OD (51%) and BD (56%) arms.
Methods:
Blood samples (7.5mls) were collected at baseline, prior to any treatment from patients who were enrolled to the CONVERT trial at The Christie Hospital site, Manchester, UK. CTCs were enumerated prospectively using the Cellsearch platform. Patients were randomised 1:1 to receive 45Gy in 30 twice-daily fractions over 3 weeks (Arm 1) or 66Gy in 33 once-daily fractions over 6.5 weeks (Arm 2) starting on day 22 of cycle 1 chemotherapy (4 to 6 cycles of Cisplatin 25mg/m2 days 1-3 or 75mg/m2 day 1 with Etoposide 100mg/m2 days 1-3), followed by prophylactic cranial irradiation if indicated. Radiotherapy planning was with a 3D conformal technique or intensity modulated radiotherapy. Staging by Positron Emission Tomography (PET) was permitted. Standard statistical methods were used to examine associations between CTC number (CTC#), clinical factors and outcomes.
Results:
Of 547 patients randomised between April 2008 and November 2013, 79 patients (41 in Arm1 and 38 in Arm 2) underwent CTC enumeration (CTC subgroup). The clinical demographics and median overall survival (OS) of the CTC subgroup did not differ significantly from the overall study population. The median number (range) of CTCs per 7.5mls blood for all 79 patients was 1 (0-3750) and for arm 1 and arm 2 patients respectively, 12 (0-164) and 158 (0-3750) (p=0.495). There was a trend for association of CTC# with higher TNM stage. CTC# was significant for survival in univariate and multivariate analysis. The median (95% CI) OS for ≥15 CTCs (n=18) was 6.01 (4.2-11.5) months compared to 30.77 (19.7-39.3) months for < 15 CTCs (n=61), p <0.001. The positive predictive value of CTC# ≥15 for survival ≤ 2 years is 100%, and ≤ 1 year is 72%. CTC# also predicted for worse outcome in patients who had undergone PET staging.
Conclusion:
CTC# is highly prognostic for poor survival in patients with LD-SCLC, treated with concurrent chemoradiotherapy, and could aid treatment decision making for this disease.
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OA05.08 - Discussant for OA05.05, OA05.06, OA05.07 (ID 6956)
14:20 - 15:50 | Author(s): J.B. Sørensen
- Abstract
- Presentation
Abstract not provided
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Author of
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MA11 - Novel Approaches in SCLC and Neuroendocrine Tumors (ID 391)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:P. Lara, A. Mohn-Staudner
- Coordinates: 12/06/2016, 14:20 - 15:50, Strauss 3
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MA11.04 - Discussant for MA11.01, MA11.02, MA11.03 (ID 7083)
14:20 - 15:50 | Author(s): J. Pujol
- Abstract
- Presentation
Abstract not provided
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-012 - Phase 2 Study of Abemaciclib + Pembrolizumab in KRAS Mutation, PD-L1+, Stage IV Non-Small Cell or Squamous Cell Lung Cancer (ID 3762)
14:30 - 15:45 | Author(s): J. Pujol
- Abstract
Background:
Stage IV non-small cell lung cancer (NSCLC) harboring KRAS mutations remains a treatment challenge. Abemaciclib, a small molecular inhibitor of both cyclin-dependent kinase (CDK) 4 and CDK6, demonstrated acceptable safety, tolerability, and single-agent activity for patients with different tumors, including NSCLC. Preclinical evidence suggests a lethal interaction between CDK4 inhibition in lung cells and KRAS oncogenes. Pembrolizumab, a humanized monoclonal antibody against PD-1 protein, is approved in the US for patients with metastatic PD-L1+ NSCLC. Both compounds demonstrated manageable toxicities. We thus aim to study the combination of abemaciclib and pembrolizumab in pretreated patients with NSCLC.
Methods:
This open-label phase 2 study will evaluate safety and preliminary efficacy of abemaciclib 150 mg given orally every 12 hours on a continuous schedule on days 1-21 in combination with intravenous pembrolizumab 200 mg on day 1 of a 21-day cycle to patients in 1 of 3 disease cohorts: KRAS mutation, PD-L1+, stage IV NSCLC (Part A); stage IV NSCLC with squamous histology (Part B); or hormone receptor+, HER2- metastatic breast cancer (Part C). Total target accrual is approximately 75 patients (25 per cohort). Only the 2 NSCLC cohorts will be presented here. Patients eligible for Part A have a confirmed KRAS mutation, PD-L1+ expression score of ≥1%, and are chemotherapy-naïve for metastatic NSCLC. Part B includes patients with predominately squamous NSCLC who have received 1 prior platinum-based chemotherapy for advanced NSCLC. Patients must provide tumor tissue before and after treatment (cycle 3, day 1); have measurable disease, adequate organ function, an ECOG PS ≤1, and a life expectancy ≥12 weeks; and be ≥18 years of age and able to swallow oral medications. The primary objective is to characterize the safety profile of abemaciclib plus pembrolizumab. Secondary objectives include objective response rate (ORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), characterization of pharmacokinetics, and health outcomes. Patients who receive any study drug will be included in the analyses. Analyses of ORR, DCR, DoR, and PFS will be evaluated according to RECIST v.1.1 and irRECIST. Time-to-event variables will be estimated by Kaplan-Meier methodology. An interim analysis of safety and preliminary efficacy may occur after all patients have completed (or discontinued from) approximately 24 weeks of treatment. The final OS analysis will occur based on data collected for approximately 12 months after the last patient receives treatment.
Results:
Section not applicable
Conclusion:
Section not applicable
