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Åslaug Helland
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OA01 - Established Drugs in Special Populations and New Drugs in Established Populations (ID 226)
- Event: WCLC 2020
- Type: Oral
- Track: Immunotherapy (Phase II/III Trials)
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 09:15 - 10:15, Scientific Program Auditorium
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OA01.07 - A Phase II Study of the Oral Selective AXL Inhibitor Bemcentinib with Pembrolizumab in Patients with Advanced NSCLC (ID 3647)
09:15 - 10:15 | Author(s): Åslaug Helland
- Abstract
- Presentation
Introduction
AXL is a mediator of resistance to immunotherapy and a negative prognostic factor for NSCLC. Bemcentinib (BGB324), a first-in-class, oral, selective and potent AXL kinase inhibitor, enhances checkpoint inhibitor (CPI) efficacy in pre-clinical models through tumor-immune mechanisms. Increasingly, the combination of doublet chemotherapy with checkpoint inhibitors (Chemo-CPI) is a commonly used option for advanced NSCLC, and recurrence following such first line therapy represents an area of great unmet need. BGBC008 addresses the unmet need for NSCLC patients who fail 1L SOC.
Methods
BGBC008 is a PhII single-arm, 2-stage study with bemcentinib (200mg/d) and pembrolizumab (200 mg/q3wk) for previously-treated Stage IV lung adenocarcinoma comprising 3 cohorts: chemotherapy-failed IO-naïve patients (post-Chemo), patients progressing on prior CPI therapy (post-CPI monotherapy) and platinum-doublet chemotherapy in combination with pembrolizumab (post-Chemo-CPI). Primary endpoint was ORR according to RECIST1.1 with pre-defined criteria to proceed from the first to second stage in each cohort. Secondary endpoints included DCR, PFS, OS and safety. Exploratory endpoints include biomarker analysis and correlation with clinical endpoints, including composite (tumor and immune cell) cAXL score, PD-L1 TPS, and genome-wide mutational and transcriptome analyses.
Results
As of August 2020, enrollment in the post-Chemo cohort and stage 1 of the post-CPI monotherapy cohort is completed. Results of the post-Chemo cohort (n=50) and post-CPI monotherapy stage 1 cohort (n=16) were previously presented. Stage 2 of the post-CPI monotherapy cohort and stage 1 of the post-Chemo-CPI cohort are currently recruiting into the study.
In patients treated to date, common TEAEs (>25% of patients) for NSCLC patients receiving the bemcentinib + pembrolizumab combination were: increased ALT (29%; 10% G3+), AST (29%; 5% G3+), and diarrhoea (29%; 1% G3+). All cases of treatment-related transaminase increase were reversible and managed with concomitant administration of steroids and treatment interruption.
Having previously demonstrated a very high clinical benefit rate in post-Chemo and post-CPI monotherapy (stage 1) in cAXL-positive patients (73% and 85%, respectively), and low probability of clinical benefit in cAXL-negative patients (40% and 0%, respectively) further focus on the predictive value of cAXL in second line patients following either CPI monotherapy or Chemo-CPI relapse will be reported, together with transcriptional analysis to identify gene based predictive signatures.
Conclusion
Overall, bemcentinib in combination with pembrolizumab was well-tolerated and shows promising clinical activity in relapsed lung cancer. The key unmet need population of second line patients refractory to CPI monotherapy or Chemo-CPI will be presented together with translational data. Clinical Trial Registration: NCT03184571
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P17 - Locoregional and Oligometastatic Disease - Biomarkers (ID 127)
- Event: WCLC 2020
- Type: Posters
- Track: Locoregional and Oligometastatic Disease
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P17.02 - Durvalumab After chemoRadioTherapy (DART) for NSCLC Patients – a Phase II Translational and Biomarker Study (ID 3645)
00:00 - 00:00 | Author(s): Åslaug Helland
- Abstract
Introduction
Lung cancer is the most common cause of cancer-related deaths world-wide. Approximately one third of patients with non–small-cell lung cancer (NSCLC) are diagnosed with locally advanced disease (stage III) at diagnosis1, for whom the standard of care is platinum-based doublet chemotherapy concurrent with radiotherapy resulting in 5-year survival of 15-20%. In the PACIFIC study, a superior outcome was observed for patients receiving the checkpoint inhibitor durvalumab after chemoradiation2. The median progression-free survival from randomization was 16.8 month with durvalumab versus 5.6 months with placebo (p<0.001). The benefit was found in the intention to treat-population, and PD-L1 expression was not a good predictive biomarker. Despite impressive results, many patients relapsed, and more knowledge of the biology underlying responses and resistance is needed. Durvalumab is approved by the FDA for patients regardless of PD-L1 status, while EMA limited the indication to patients whose tumours harbour PD-L1 expression of ≥1%.
Methods
This is an investigator initiated, multi-centre phase II translational study. A total of 100 stage III NSCLC patients not progressing after chemoradiotherapy will be included from the Nordic and Baltic countries, 50 PD-L1 negative and 50 PD-L1 positive patients. Astra Zeneca provides durvalumab for all patients. The DART trial aims to identify prognostic and predictive biomarkers which may be used to identify patients who would benefit from durvalumab after chemoradiation. Our hypothesis is that the immunological microenvironment in the tumour influences response. Tumour biopsies will be collected before treatment, after chemoradiation and at progression. Blood and stool samples will be collected and images will be performed before and during treatment as well as during follow-up. The analyses planned are described below linked to the study objectives
Primary objectives:
To investigate the immunological response, tumour development (if present) and dynamics in the tumour micro-environment and in circulation. This includes the following:
- Evaluation of immune cell infiltration in the primary tumour and in the relapse tumour (if present)
- Evaluation of circulating biomarkers related to tumour (ctDNA) and host response (immune cells)
- Evaluations of genomic characteristics of the primary tumour and the relapse (if present)To investigate tumour mutational burden in tumour tissue and blood samples, as predictors for clinical response
To evaluate imaging protocols for response prediction. PET-CT will be done for screening, after chemoradiation and after 12 months.
To investigate potential changes in gut microbiota in serial samples from patients treated with durvalumab and investigate whether microbiota profile prior to, or dynamic changes during treatment can predict clinical outcome
Secondary objectives:
To evaluate toxicity and quality of life in lung cancer patients receiving PDL1-inhibitor after chemoradiotherapy
To evaluate progression-free survival and overall survival
References
1. Aupérin A, Le Péchoux C, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol. 2010;28(13):2181-2190.
2. Antonia SJ, Villegas A, Daniel D, et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med. 2018
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P24 - Mesothelioma, Thymoma and Other Thoracic Malignancies - Mesothelioma Clinical and Trials in Progress (ID 138)
- Event: WCLC 2020
- Type: Posters
- Track: Mesothelioma, Thymoma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 01:00, ePoster Hall
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P24.07 - Nivolumab and Ipilimumab +/- UV1 Vaccination as 2nd Line Treatment in Patients with Malignant Mesothelioma (the NIPU-Study) (ID 3477)
00:00 - 01:00 | Presenting Author(s): Åslaug Helland
- Abstract
Introduction
Malignant pleural mesothelioma (MPM) is a rare malignant tumour originating from the cells lining the mesothelial surface in the lungs. The prognosis is poor, and treatment options are limited. Several studies have investigated the use of checkpoint inhibitors (CPIs) in MPM. Most of them are small studies investigating the efficacy of single-agent immunotherapy in few patients, inducing clinical response rates in a fraction of patients. The MAPS2 study was the first clinical trial that evaluated treatment with single-agent nivolumab or nivolumab plus ipilimumab (anti-CTLA-4) in previously treated mesothelioma, showing higher tumour response rates among patients assigned to receive combined immunotherapy compared to single-agent nivolumab. Recently, CheckMate 743 reported a HR of 0.74 (p=0.002) favouring nivolumab and ipilimumab for overall survival compared with doublet chemotherapy in the first line setting. Although this may become a standard of care, improvements are still needed.
UV1 is a peptide-based vaccine inducing a telomerase-directed T cell response. Telomerase is an essential enzyme for unlimited growth and immortality of cancer cells and is expressed in almost all cancers. Telomerase thus represents a unique cancer antigen and a promising target for immunotherapy. The UV1 vaccine consists of 3 long peptides, shown to induce immune responses in HLA-unselected patients across 3 completed phase I trials in different indications. UV1 may provide an increase in tumor-reactive T cells, and thus enhance CPI efficacy in patients with insufficient spontaneously primed T cells. Reciprocally, CPI may support the UV1-induced T cells and provide increased effector activity, as these cells may be restricted by intrinsic and tumor-induced suppressor mechanisms. The combination of UV1 and CPIs can thus induce synergistic immunological activity leading to increased clinical benefit as compared to CPIs alone. This question is valid in the second-line chemotherapy pre-treated setting but may also inform the first line setting in the future.
Methods
Methods - Trial design
The NIPU study (EudraCT no: 2019-002721-30) is an ongoing investigator-initiated, randomized, multi-center, open-label, proof of concept study comparing the efficacy and safety of nivolumab and ipilimumab with or without UV1 in patients with inoperable MPM after first-line platinum-based chemotherapy. A total of 118 patients will be randomized 1:1 to either arm A: nivolumab 240 mg q2w + ipilimumab 1 mg/kg q6w + 8 injections with 300 μg UV1 and 75 μg GM-CSF as adjuvant (UV1 vaccination) during the first 13 weeks, or arm B: nivolumab 240 mg q2w + ipilimumab 1 mg/kg q6w. Patients randomized to treatment arm A will receive three UV1 vaccinations in week 1 and one in week 2, followed by four UV1 vaccinations throughout the following 11 weeks, totaling to eight UV1 vaccinations.
CPI treatment will continue until disease progression or unacceptable toxicity for a maximum of 2 years in both arms. The primary endpoint is progression-free survival (PFS) per Modified Response Evaluation Criteria in Solid Tumours (RECIST) as determined by blinded independent central review (BICR)
Samples of blood, feces, and tumor tissue are collected for translational research purposes.
Results
Legal entity responsible for the study
Oslo University Hospital
