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Paul Baas
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IBS06 - Multimodality Treatment - Realtime Data from National Registries (Ticketed Session) (ID 37)
- Event: WCLC 2019
- Type: Interactive Breakfast Session
- Track: Mesothelioma
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 07:00 - 08:00, Dublin (1997)
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IBS06.01 - Realtime Data from Europe ETOP / ESTS Database (Now Available) (ID 3331)
07:00 - 08:00 | Author(s): Paul Baas
- Abstract
- Presentation
Abstract
Title: Mesothelioma Realtime Data from Europe - ETOP Mesoscape / ESTS Database
Introduction:
Malignant pleural mesothelioma (MPM) is an aggressive malignancy with increasing prevalence and poor prognosis. Despite a still increase in incidence, it remains an orphan disease and studying limited numbers of MPM cases hampers the derivation of solid conclusions.
The combination of two databases including clinical as well as pathological information will allow researchers to improve the knowledge and facilitate decision-making in patients with MPM.
The European Thoracic Oncology Platform (ETOP) Mesoscape project and the European Society of Thoracic Surgeons’ (ESTS) database are designed to address clinical, pathological, and molecular characteristics of mesothelioma patients and their impact on outcome. The joined analysis of both databases is a unique approach to real-time data reflecting the reality of mesothelioma characteristics, treatment and prognosis in Europe.
Materials and Methods:
A decentralized biobank with fully annotated tissue samples is established for ETOP Mesoscape. Selection criteria for participating centers included sufficient number of cases, and documented ethical approval. Patient selection is based on availability of comprehensive clinical data with adequate follow-up, and adequate quantity and quality of formalin-fixed tissue.
The ESTS database is a clinical database with pre-operative, intra-operative and post-operative data. A minimum set of data is captured, including demographic, histology, treatment, staging and follow up data.The characteristics between the two databases are compared using the Fisher’s exact test (for categorical variables) and Mann-Whitney test (for continuous variables), while Kaplan-Meier method (with log-rank test).
Results:
Up to 29 May 2019, the ETOP Mesoscape included information on 497 patients from 10 centers, diagnosed between 1999-2018. In the ESTS database, as of April 2019, 2269 patients are included, diagnosed between 1989-2019.
Patients in both databases are primarily men (84% in the ETOP, 71% in the ESTS), of 0/1 ECOG Performance status (46/46% and 59/29% in ETOP and ESTS respectively), with known previous exposure to asbestos (75% and 93%) and median ages 64 and 67 years old.
Significant differences are detected between the two data sources with respect to gender, exposure to asbestos and age (p-value <0.001).
The primary histology of patients is epithelioid (72% in ETOP and 70% in ESTS), followed by biphasic (22%; 17%) and sarcomatoid (6%; 9%) (not significantly different between the two databases).
Clinical staging is available for 77% of the patients in ETOP, but only for the 28% in the ESTS database. The stage distribution (I/II/III/IV) is 14/29/42/15% in the ETOP and 23/21/41/16% in the ESTS (significantly difference p<0.001).
Among the biomarkers common in both data sources, Calretinin and WT1 are detected in the vast majority of patients tested (Calretinin: 97% in both cases; WT1: 89% and 87% in the ETOP and ESTS database respectively).
For the ETOP cases 90% (of those tested) are CK5/6 positive, 91% D2-40 positive and 97% Pan-CK positive.
Palliative treatment has been administered in 41% of the ETOP cases. Among them, 84% received palliative chemotherapy (with the vast majority 92%, using multiple agents). Palliative surgery was undertaken in 32% (62 of 194 patients with available information) and palliative radiotherapy for 13% of the patients.
Complete resection has been performed in 59% of the ETOP Mesoscape patients. This was combined with induction chemotherapy (81%), while adjuvant chemotherapy and radiotherapy was administered in 4% and 37% respectively.
The surgical approach adopted for the ESTS patients was either video-assisted thoracoscopic surgery (VATS) (59%) or thoracotomy (41%) based on a subset of 887 patients with available information. Post-operation treatment information is available for 620 ESTS patients. Among them, 71% received chemotherapy, 54% underwent surgery and 15% radiotherapy.
Conclusion:
We present the combined results from the ETOP Mesoscape and the ESTS database, one of the largest databases. These two series allow us to report on mesothelioma epidemiology and treatment.
Up to now, the comparison of the baseline characteristics of the patients of the two data sources revealed some statistically significant differences with respect to gender, age, exposure to asbestos and clinical stage.
As tissue from all ETOP Mesoscape patients is preserved locally and is available for detailed molecular investigations, Mesoscape provides an excellent basis to evaluate the influence of molecular parameters on the disease outcome, besides providing an overview of the molecular landscape.
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MS13 - Immunotherapy for Mesothelioma (ID 76)
- Event: WCLC 2019
- Type: Mini Symposium
- Track: Mesothelioma
- Presentations: 1
- Now Available
- Moderators:Arnaud Scherpereel, Roberto Ferrara
- Coordinates: 9/10/2019, 11:30 - 13:00, Seoul (2007)
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MS13.04 - Biomarkers of Anti-PD1 Therapy in Mesothelioma (Now Available) (ID 3515)
11:30 - 13:00 | Presenting Author(s): Paul Baas
- Abstract
- Presentation
Abstract
Biomarkers of Anti-PD1 Therapy in Mesothelioma.
Biomarkers have attracted attention for their usefulness in selecting the right treatment for the right patient. There are different types of biomakers; blood based, clinical markers and histological markers. Most of the biomarker studies have focused on the prognosis of patients while only a limited number examined the predictive value of a marker; to correctly predict the outcome of a certain treatment.
After the reported successes of check-point inhibitors in melanoma and NSCLC (1-4), the use of these agents have found its way to mesothelioma(5-8).
Since 2015 many studies have been initiated whit a comparable efficacy compared to NSCLC outcomes. Around 20-25% of cases do respond favorably to this approach. This is considered to be of great importance since there is a limited 2 years survival rate (8) and no standard second line therapy has yet been defined. There are a number of factors that have to be considered before embarking on Immuno-Oncology (IO) therapies as single agent or in combination. The choice of the drug or combination; the expected outcome in short time; the toxicity profile and the costs. Because of the lack of registration, there is a limited availability and patients can only join in studies or be part of a compassionate use program. When registration is a fact we merely have to deal with the questions; who will benefit, who will experience toxicity and is the treatment cost effective?In a series of studies we performed in patients with pleural mesothelioma we have collected samples to be used as biomarkers (6,7). Currently we are analyzing the predictive value of these biomarkers.
1. Histological biopsies: It is well known that the expression PD-L1 can be predictive in NSCLC of a success while in melanoma there is a better correlation with tumor mutational burden. For mesothelioma the expression of PD-L1 varies between the different subtypes of mesothelioma (with sarcomatoid type expressing higher PD-L1 levels) (9). In general the high expression correlates with a worse survival. In addition, the expression of PD-L1 on tumor stroma also influences the outcome of IO treatment. In our study of 34 patients (7), we observed a clinical benefit of 18% in PD-L1 tumor negative patients compared with 15% in the (TIL+) stroma and 32% versus 35% in stroma for any PD-L1 expression. When analyzed for PD-L1 > 50% the stromal T+ cells showed a factor of 2 higher clinical benefit. This implies that a single analysis of the PD-L1 of the tumor cells might underestimate the effect of IO therapy.2. eNose analyses. The use of exhaled air has attracted clinical interest since early data indicate that the Volatile Organic Compounds (VOCs) can predict an outcome of IO therapy (11). These VOCs probably represent a complex combination of tumor and immune cell interactions. Ongoing studies focus on the use of these electronic noses to select only patients for whom a treatment has a high chance of success.
3. Blood based biomarkers have been tested in many studies in mesothelioma. For well-known markers such as mesothelin, cyfra 21-1, osteopontin and fibulin-3 no positive outcomes have been reported in prediction studies.
4. MicroRNAs. These short, non-coding RNA sequences have attracted attention because of their prognostic capability in mesothelioma and other cancers. The huge number of miR’s identified and the lack of comparative studies to date indicate that these markers can only be used for diagnostic and perhaps treatment purposes. (12)
5. BAP1 is a nuclear deubiquitinase which regulates the ubiquitination of selected histones and other translational factors. This mutation is occurring both in germline or, more frequently, as a somatic mutation in mesothelioma. It has different functions and can influence the inflammation status of the microenvironment. Although not tested in a proper study setting this marker may well have a predictive potential(13).
6. Other biomarkers. Finally there are a number of interesting biomarkers including chemokines like IL-6 which acts as a pro-inflammatory cytokine and is closely related to T cell function. Ongoing studies will try to elucidate the predictive effect of this and other markers.
To date there is a lot of activity ongoing in mesothelioma and the introduction of the IO drugs have been welcomed full-heartedly. Although we have identified an abundant number of prognostic factors in cancer, the high costs of IO therapies presses us to find solid predictive markers. The combination therapies of IO drugs now proposed do increase the toxicity profile and we must not lose precious time of patients and doctors spend on ineffective and costly therapies.
References are available at the author at request
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-06 - Comparative Effectiveness of First Line (1L) Therapies for Advanced Non-Small Cell Lung Cancer (aNSCLC): A Systematic Literature Review (SLR) (Now Available) (ID 1982)
09:45 - 18:00 | Author(s): Paul Baas
- Abstract
Background
The therapeutic landscape for aNSCLC has shifted in recent years. Novel therapies, including immunotherapies, have been tested in clinical trials but less is known about their effectiveness and safety in real-world (RW) settings. Our primary objective was to quantify the relative effectiveness and safety of 1L therapies for aNSCLC in a RW setting.
Method
An SLR was conducted using EMBASE and MEDLINE (2012-2018), alongside searches of conference proceedings (2015-2018). Two reviewers assessed eligibility and included observational studies involving at least two chemotherapy or immunotherapy-based 1L therapies for aNSCLC. EGFR+, ALK+, and KRAS+ mutation-targeting therapies and sub-populations were excluded. Effectiveness and safety endpoints were extracted; relative effects were presented using forest plots. Pooled estimates were not generated due to study design heterogeneity and limited number of studies per treatment comparison. Risk of bias was assessed using ROBINS-I.
Result
From 4,307 abstracts, 18 RW chemotherapy-based studies were included; no immunotherapy-based studies were identified. Of the 18 studies, only seven used methods to balance patient characteristics across treatments. Of these seven, relative effect estimates trended toward improved overall survival (OS) and progression-free survival (PFS) associated with chemotherapy doublets involving pemetrexed, nab-paclitaxel, or the addition of bevacizumab, relative to older platinum-based chemotherapy doublets (Figure 1). Significantly higher objective response rates (ORR) were observed for pemetrexed-based doublets relative to paclitaxel- and gemcitabine-based doublets reported in one multi-group study. There were no significant differences in non-hematologic and few significant differences in hematologic adverse event rates.
Conclusion
This SLR provides complementary evidence showing relative effect sizes of 1L chemotherapies in the RW setting, which were broadly consistent with those observed in clinical trials. Comparative RW evidence for immunotherapies in 1L aNSCLC is lacking and is expected to emerge in the future; however, this research provides a benchmark against which new evidence can be compared.
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P1.04 - Immuno-oncology (ID 164)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.04-32 - Ki67+ PD-1+ Central Memory CD8 T-Cell Frequencies Predict Response Upon Nivolumab+Ipilimumab in Malignant Pleural Mesothelioma (ID 2270)
09:45 - 18:00 | Author(s): Paul Baas
- Abstract
Background
New treatment options for malignant pleural mesothelioma (MPM) are urgently needed, as the only standard treatment, chemotherapy, has only modest activity in the majority of the patients. Recent clinical trials with checkpoint inhibitors have shown promising results in MPM patients who progressed after first line platinum-based chemotherapy. We reported on 2 phase II clinical trials which assessed nivolumab (aPD-1) monotherapy (NIVOMES) and the combination of nivolumab + ipilimumab (INITIATE). At the 12-week time point, the disease control was 47% for nivolumab and 68% for the combination. Here we report on differences in T cell subsets present in the peripheral blood at baseline and during treatment in both trials.
Method
Peripheral blood of 31 MPM patients enrolled in NIVOMES and 38 MPM patients enrolled in INITIATE was collected at baseline and 6-weeks after start of treatment. T-cell subsets frequencies and the expression of Ki67 and PD-1 on these subsets were determined by flow cytometry.
Result
An increased proportion of proliferating Ki67+ T-cells was found after 6-weeks of combination treatment with nivolumab/ipilimumab, which was not observed 6-weeks after treatment with nivolumab monotherapy. Increased proliferation was particularly observed in the effector memory (EM) and central memory (CM) CD4+ T-cells and EM CD8+ T-cells. Additionally, patients with a clinical response on combination therapy had a significantly higher frequency of PD-1+ Ki67+ CM CD8+ T-cells and effector memory re-expressing RA (EMRA) CD8+ T-cells compared to non-responders at baseline. These differences were not seen in patients that responded to nivolumab monotherapy. No alterations in the frequencies of either activated or naïve regulatory T cells (Tregs) were found in both treatment groups comparing baseline to 6 weeks.
Conclusion
Our results indicate that specifically in patients that respond to combination therapy the frequency of PD-1+Ki67+ CM CD8 T-cells at baseline was significantly increased, whereas combination therapy in both responding and non-responding patients increased proliferation of memory T-cell subsets. This indicates that addition of ipilimumab to nivolumab treatment reinvigorates T-cell responses in general, whereas responding patients present with elevated immune activation already at baseline. In conclusion, we were able to select MPM patients that are most likely to benefit from combination therapy of nivolumab and ipilimumab at baseline.
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P1.06 - Mesothelioma (ID 169)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.06-06 - EORTC 1205: Randomized Study of Pleurectomy/Decortication (P/D) Preceded or Followed by Chemotherapy in Malignant Pleural Mesothelioma (ID 2511)
09:45 - 18:00 | Author(s): Paul Baas
- Abstract
Background
P/D is considered a valid surgical approach in selected pts with resectable MPM with less morbidity than extrapleural pneumonectomy. The procedure is however, poorly standardized and never radical, and is hence preferably preceded or followed by systemic chemotherapy.
EORTC 1205 aims at comparing the optimal sequencing of chemotherapy with P/D with regard to overall treatment time and feasibility.
Method
Functionally operable treatment-naïve pts with T1-3 N0-2 epithelial or biphasic mesothelioma and PS 0-1 are randomized between adjuvant (arm A) and neo-adjuvant chemotherapy (arm B). Chemotherapy in both arms consists of 3 cycles of cisplatin and pemetrexed at standard dosage and with premedication. P/D is performed by experienced thoracic surgeons in credentialed centers. Strict timelines between both procedures apply and surgical quality is audited with intra-operative mapping and imaging and comprehensive registration of complications. Primary endpoint in the intention-to-treat population is successful completion of the multimodality treatment within 20 weeks of randomisation and being alive with no signs of PD and/or persistent grade III-IV toxicity.
Result
As of April 10, 2019, 30 pts of the required sample size of 64 have been randomized and 17 operated. Baseline patient and tumor characteristics appear well balanced sofar (table).
Characteristics and treatment results as per 1/04/2019 Table
Arm A
Arm B
All
N
16
14
30
Male gender (%)
56
71
63
Median age (y)
62
66
64
WHO PS 0/1
10/6
7/7
17/13
TNM Stage 1/2/3 at presentation
6/6/4
9/2/3
15/8/7
% administered 3 cycles of chemotherapy
88
100
94
N operated
9
8
17
Median time between randomization and 1st treatment modality (weeks)
2.9
1.6
2.0
Median time between 1st and 2nd treatment modality
5.7
11.0
10.1
N completed treatment
9
8
17
Median overall treatment time in those completing treatment
23.7
18.7
21.3
Conclusion
Trial accrual proceeds on schedule and last patient will be included in 2020. A protocol amendment will allow carboplatin/pemetrexed as induction regimen. An updated analysis on all included patients as per 1/08/2019 will be presented at the meeting.
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P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-83 - Long-Term Follow-Up Compassionate Use Program Nivolumab in NSCLC (ID 904)
10:15 - 18:15 | Presenting Author(s): Paul Baas
- Abstract
Background
Background: From August 2015 until March 2016, patients with NSCLC were treated in the Early Access Program (EAP) or commercially available nivolumab. Here, we report the long term survival figures for this Real Life treatment (early data were presented at WCLC in 2016). Currently, the median follow-up is 3 years for the patients treated in the EAP, and 2.5 years for the patients that have been treated with commercially available nivolumab. We address open questions of the efficacy of nivolumab in real life on special subgroups (brain mets, elderly, ECOG, smoking, platinum sensitivity) with regards to OS.
Method
Methods: A prospective follow up of 248 pts was performed with respect to the above mentioned subgroups using Kaplan Meier curves and Cox proportional hazards regression.
Result
Results: Median age 63 (29-84); 55% male; 81% (ex)-smoker; 67% adeno, 22% squamous and 11% mixed type carcinoma; PS 0-1: 84%; PS 2-3: 16%; brain mets 23%.
Overall survival in the whole group was 17% at 3 years. For the subgroups, the PS 2-3 vs 0-1 showed a HR of 1.77 (p=0.0023); Platinum sensitive vs resistant showed a HR of 0.55 (p=0.00032): (Ex) Smoker vs never smoker showed a HR of 0.62 (p=0.007) and no difference was observed between Squamous vs Non-squamous or for patients who initially presented with or without brain mets.
Conclusion
Conclusions: These data confirm the activity of nivolumab in second line treatment outside of a reported study. The 17% 3 yrs survival is exactly in line with the pooled data from the Checkmate 017/057 study (Vokes et al. Ann Oncol 32018, 29;9590-65). Long term efficacy of this checkpoint inhibitor is confirmed. Good performance status, smoking, non-squamous carcinoma and platinum sensitive tumors are positive predictive factors.
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WS02 - Mesothelioma Workshop (Ticketed Session) (ID 102)
- Event: WCLC 2019
- Type: Workshop
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2019, 08:00 - 11:30, Interlaken (1988)
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WS02.10 - Immunotherapy and Novel Targets - Biomarker Driven MPM Treatment (ID 3839)
08:00 - 11:30 | Presenting Author(s): Paul Baas
- Abstract
Abstract not provided
