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Joachim G.J.V. Aerts
Moderator of
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ES24 - Diagnosis and Management of Side Effects of Immunotherapy (ID 363)
- Event: WCLC 2019
- Type: Educational Session
- Track: Immuno-oncology
- Presentations: 3
- Now Available
- Moderators:Daniel SW Tan, Joachim G.J.V. Aerts
- Coordinates: 9/10/2019, 11:30 - 13:00, Amsterdam (2011)
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ES24.01 - Recognizing Toxicities in an Early Phase in PDL1 Treatment (Now Available) (ID 3905)
11:30 - 13:00 | Presenting Author(s): Hossein Borghaei
- Abstract
- Presentation
Abstract not provided
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ES24.02 - Renal Toxicities in Combination I/O Chemotherapy Treatment (Now Available) (ID 3906)
11:30 - 13:00 | Presenting Author(s): Joachim G.J.V. Aerts
- Abstract
- Presentation
Abstract not provided
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ES24.03 - Management of Immunerelated Toxicities Unresponsive to Steroids (Now Available) (ID 3907)
11:30 - 13:00 | Presenting Author(s): Anne Tsao
- Abstract
- Presentation
Abstract not provided
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Author of
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ES24 - Diagnosis and Management of Side Effects of Immunotherapy (ID 363)
- Event: WCLC 2019
- Type: Educational Session
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:Daniel SW Tan, Joachim G.J.V. Aerts
- Coordinates: 9/10/2019, 11:30 - 13:00, Amsterdam (2011)
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ES24.02 - Renal Toxicities in Combination I/O Chemotherapy Treatment (Now Available) (ID 3906)
11:30 - 13:00 | Presenting Author(s): Joachim G.J.V. Aerts
- Abstract
- Presentation
Abstract not provided
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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): Joachim G.J.V. Aerts
- 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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MA05 - Update on Clinical Trials and Treatments (ID 123)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Mesothelioma
- Presentations: 1
- Now Available
- Moderators:Seiki Hasegawa, Enrico Ruffini, Angel Artal
- Coordinates: 9/08/2019, 13:30 - 15:00, Melbourne (1991)
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MA05.09 - Real-World Data of Nivolumab and Pembrolizumab in Chemotherapy Pre-Treated Mesothelioma Patients (Now Available) (ID 1918)
13:30 - 15:00 | Author(s): Joachim G.J.V. Aerts
- Abstract
- Presentation
Background
Both nivolumab and pembrolizumab have shown positive results in phase II studies in patients following chemotherapy in mesothelioma patients. However, these studies were done in a limited number of patients with strict inclusion criteria, while reports show a difference between real life and study setting.
Method
In our mesothelioma center, we treated patients that progressed during or after chemotherapy treatment with nivolumab 3mg/kg once every 2 weeks independent of PD-L1 expression or with pembrolizumab 200mg once every 3 weeks when PD-L1 expression was ³1%, both in Early Patient Access programs. All patients were pre-treated with at least one cycle of platinum/folate treatment. CT scan evaluation was done using modified RECIST every 6 weeks.
Result
In total, we treated 78 patients with nivolumab and 13 patients with pembrolizumab. Median age of the patients was 71 years (29-85) at start of the checkpoint inhibitor treatment, 80 (88%) were male. Performance status was ECOG 0 in 19 patients, ECOG 1 in 57 patients, ECOG 2 in 9 patients. Data analysis thus far showed 9 partial responses (10%) and 31 patients with stable disease (29%) and therefore a disease control rate of 39% at twelve weeks of treatment. Median progression free survival is 2.4 months and median overall survival 6,3 months. Median duration of response had not been reached yet. These data will be updated for the meeting. Two cases of pseudoprogression were seen on checkpoint inhibition therapy where progression according to modified RECIST was followed by response during continuation of PD-1 therapy. Toxicity was in line with historical data.
Conclusion
We believe that this large dataset, using real-world data, can truly give an insight in the clinical benefit of these immune checkpoint inhibitors. In comparison with the published phase I and II trials on nivolumab and pembrolizumab, the response rates appear to be lower in a real-life setting. However, clinically meaningful and durable responses are seen in a population that has no other proven therapy options.
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MA12 - New Frontiers from Pathology to Genomics (ID 138)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Mesothelioma
- Presentations: 1
- Now Available
- Moderators:Prasad S Adusumilli, Francisco Perez Ochoa
- Coordinates: 9/09/2019, 14:00 - 15:30, Melbourne (1991)
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MA12.09 - Checkpoint Inhibitors Synergize with Dendritic Cell-Therapy in Pre-Clinical Models and Mesothelioma Patients (Now Available) (ID 2425)
14:00 - 15:30 | Author(s): Joachim G.J.V. Aerts
- Abstract
- Presentation
Background
Malignant Pleural Mesothelioma (MPM) is a lethal, treatment resistant neoplasm. Checkpoint inhibitors (CI) have shown promising clinical effects in a minority of patients. It is hypothesized that low response rates to CI are correlated to low numbers of tumor-infiltrating T-cells in MPM patients. Dendritic cell (DC) therapy instigates an immune response and activates tumor-specific T-cells. DC therapy has proven to be effective in pre-clinical models and in a subset of MPM patients. Upregulation of PD-L1 and PD-1 co-inhibitory checkpoints may suppress DC-therapy induced anti-tumor immune response and limit clinical efficacy. To investigate this, we conducted a preclinical and clinical study to evaluate the clinical and immunological effects of DC therapy combined with CI.
Method
Immune competent CBA/J mice were orthotopically injected with a syngeneic mesothelioma cell line. Mice were treated with DC-therapy alone or in combination anti-PD-L1 antibodies at high tumor load when DC-monotherapy was found to be ineffective. Peripheral blood and tumors were obtained for flow cytometric analysis and survival was monitored.
Result
In a clinical setting, nine patients that received DC therapy were sequentially treated with CI. Progression free survival (PFS) was determined from start of CI, using the modified RECIST criteria.
Tumors of mice treated with DC-therapy exhibited a three-fold increase in CD8+ T-cell infiltration which was paralleled by heightened expression of PD-L1 on tumor cells (r2=0.69, p=0.0015). Whereas both anti-PD-L1 and DC-monotherapies were ineffective in prolonging survival in our model, combination immunotherapy did (median OS: 24 vs 35 days, p=0.0063). Immune monitoring analyses demonstrated a synergistic increase in proliferation and activation of circulating T-cell following combination therapy. In the clinical trial 3 patients had partial response, 5 patients had stable disease and 1 patient had progressive disease. Median PFS was 5,2 months and median OS was 17,5 months. Currently 3 patients are still alive and two patients are still progression free. There were no grade 3/4 adverse events. PD-L1 expression in tumor biopsies was increased after DC therapy in two of the three responders to CI.
Conclusion
In a murine model the synergy between DC therapy and CI was proven and efficacy was driven by activation of CD4+ and CD8+ positive cells. In humans, CI after DC therapy is safe and feasible. Disease control was seen in 8 out of 9 patients treated with CI after DC therapy. DC therapy induces tumor-specific CD8+ T-cell proliferation which is correlated to PD-L1 expression on tumor cells and possibly synergizes with CI treatment.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-115 - Long-Term Effects of Concurrent Chemoradiotherapy on Quality of Life in Locally Advanced Non-Small Cell Lung Cancer Patients (ID 1780)
09:45 - 18:00 | Author(s): Joachim G.J.V. Aerts
- Abstract
Background
Concurrent chemoradiotherapy imposes beneficial effects on overall survival (OS) in patients with locally advanced non-small cell lung cancer (NSCLC). Currently, it is unknown what the effects on long-term health-related quality of life (HRQOL) are. Therefore, we investigated long-term HRQOL in locally advanced NSCLC patients treated with concurrent chemoradiotherapy, using an accelerated fractionation scheme of 24 x 2.75 Gy +/- Cetuximab.
Method
A 2-armed phase II, multi-center study (NTR2230) was performed with the initial aim to assess the effect of additional Cetuximab to concurrent chemoradiotherapy in locally advanced NSCLC patients. Arm A received high dose accelerated radiotherapy (24 x 2.75 Gy) and concurrent daily low-dose cisplatin (6 mg/m2). Arm B additionally received weekly Cetuximab (400 mg/m2 one-week pre-treatment followed by weekly 250 mg/m2). HRQOL was assessed using the EORTC QLQ-C30 at baseline, 3 months post treatment and after 1 year. The primary endpoints included dyspnea, pain, physical functioning, cognitive functioning and the QLQ-C30 summary score. Following the EORTC guidelines, the scores of the endpoints were linearly transformed to 0–100 scales. Higher scores correspond to improved functioning for the functioning scales and for the summary score while for symptom scales (pain and dyspnea), higher scores indicate more symptoms. Linear mixed-modeling was used to assess differences over time. Standardized effect sizes based on the t-test statistic were calculated: (2*t)/(√degrees of freedom). Effect sizes of 0.2 were considered small, 0.5 moderate and clinically relevant, and 0.8 large.
Result
Between February 2009 and May 2011, 102 patients were randomly allocated in two arms; 51 patients (50%) in arm A and 51 patients (50%) in arm B. Of those, 79 (77%) patients had at least one evaluable questionnaire. Figure 1 shows the development of the HRQOL endpoints over time. Over time, physical functioning (ES 0.48, P-value 0.003), cognitive functioning (ES 0.37, P-value 0.020), dyspnea complaints (ES 0.67, P-value <0.001) and the summary score (ES 0.44, P-value 0.006) significantly worsened. Only pain showed a reversing pattern in which pain was less present at 1 year (ES 0.37, P-value 0.021). No differences between the two arms were found.
Conclusion
In this randomized study of locally advanced NSCLC patients treated with concurrent chemoradiotherapy with or without Cetuximab, a clinically meaningful and long-term decline for all HRQOL endpoints except pain was observed. This analysis suggests that although concurrent chemoradiotherapy improves OS in NSCLC patients, efforts should also be taken to improve long-term HRQOL.
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P1.01-73 - An Explorative Analysis of Pemetrexed +/- Pembrolizumab Maintenance from KEYNOTE-189 Versus PARAMOUNT, PRONOUNCE, and JVBL (ID 756)
09:45 - 18:00 | Author(s): Joachim G.J.V. Aerts
- Abstract
Background
Recently, the phase 3 KEYNOTE-189 study demonstrated improved progression-free survival (PFS) and overall survival (OS) when pemetrexed/platinum doublet was combined with pembrolizumab as first-line treatment in patients with non-squamous NSCLC. The specific benefits of maintaining pemetrexed in combination with pembrolizumab after the triplet with platinum has not been previously assessed.
Method
Using patient level data, we selected patients who had ≥5 cycles of pemetrexed (including the induction phase with platinum) from 3 randomized non-pembrolizumab clinical trials (PARAMOUNT, PRONOUNCE, and JVBL; N=486). As such, patients in the KEYNOTE-189 trial who had ≥5 cycles of pemetrexed in both arms (placebo arm; N=135, versus pembrolizumab arm; N=310) were analyzed. PFS and OS were evaluated by Kaplan-Meier estimator and Cox proportional hazard model; treatment emergent adverse events (TEAEs) were compared by descriptive statistics.
Result
Baseline characteristics of the selected population with ≥5 cycles of pemetrexed were comparable between the pooled trials and KEYNOTE-189. Median PFS for patients with ≥5 cycles of pemetrexed was 5.6 months (95% CI: 4.6-5.8) from the pooled non-pembrolizumab trials and 6.6 months (95% CI: 5.4-7.1) in the placebo plus pemetrexed/platinum arm in KEYNOTE-189 (un-stratified HR: 1.29; 95% CI: 1.02-1.62). Median PFS in the selected population with ≥5 cycles of pemetrexed in KEYNOTE-189 was 9.3 months (95% CI: 9.0-11.1) in the pembrolizumab plus pemetrexed/platinum arm, and when compared with the placebo plus pemetrexed/platinum arm in KEYNOTE-189, resulted in an un-stratified HR of 0.53 (95% CI: 0.42-0.68). Incidence rates of TEAEs were similar in those 3 selected populations (Table 1).
Conclusion
In a selected population with pemetrexed maintenance in KEYNOTE-189, the placebo arm showed numerically comparable efficacy with historical data on pemetrexed maintenance. Pemetrexed/platinum in combination with pembrolizumab proved consistent clinical benefit in the same population with ≥5 cycles of pemetrexed, compared to the placebo arm in KEYNOTE-189 and historical controls.
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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): Joachim G.J.V. Aerts
- 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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P1.09 - Pathology (ID 173)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Pathology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.09-21 - Tumor Responses Based on Tumor Growth Rate During PD-1 Inhibitor Therapy in Advanced Non-Small-Cell Lung Cancer Patients (ID 1906)
09:45 - 18:00 | Author(s): Joachim G.J.V. Aerts
- Abstract
Background
Immune checkpoint inhibitors have emerged as a standard of care treatment for non-small cell lung cancer (NSCLC). However, there remains debate about the tumor growth kinetics during treatment, for instance the incidence of rapid disease progression, described as hyperprogressive disease (HPD). To get insight into variations in tumor growth kinetics and their potential predictive values for outcome we evaluated tumor growth rate (TGR) in patients receiving PD-1 checkpoint inhibitors.
Method
An analysis and radiological review of all Nivolumab treated NSCLC patients (n=196) between 06-2015 and 09-2017 in an early access program and as standard of care was performed. Differences in TGR before and after the start of treatment were calculated by entering the sum of the longest diameters from CT-scans before and after the initiation of therapy into a formula that assumes a volumetric exponential tumor growth. TGR variations, possible predictors for TGR changes and its relationship to overall survival (OS) were studied. For comparison tumor response was assessed using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST1.1).
Result
Among the 58 evaluable patients, 37 patients (64%) showed deceleration of TGR and 16 patients (27%) showed acceleration of TGR after initiation of therapy, with a significant difference in median OS of 18.0 versus 6.0 months (HR=0.35; 95%CI:0.18-0.71) between these groups. Four patients (7%) were defined as having HPD. In 5 patients (9%), the tumor growth remained stable. These TGR categories were not significantly different according to age, gender, histology, smoking or previous radiotherapy. Of the patients defined as having progressive disease by RECIST1.1 at first follow up 40% showed response to CPI by a decrease in tumor growth rate. (Figure 1)
Conclusion
Tumor growth kinetics can be used as a clinically relevant predictor for OS in anti-PD1 treated NSCLC patients, and may provide additional information to RECIST measurements.
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-23 - Resistance Mechanisms to Osimertinib Treatment in EGFR-Mutated Lung Cancer in a Real Life Cohort (Now Available) (ID 1657)
09:45 - 18:00 | Author(s): Joachim G.J.V. Aerts
- Abstract
Background
Targeted therapies in Epidermal Growth Factor Receptor (EGFR)-mutated advanced lung cancer are developing rapidly, with registration for third generation EGFR-tyrosine kinase inhibitor (TKI) osimertinib for first line treatment recently. The resistance mechanisms that develop during first line treatment with osimertinib seem to differ from resistance developing during treatment for p.T790M mutation after first- or second generation EGFR-TKI based on current limited knowledge. We investigated the resistance mechanisms at progression on osimertinib treatment in a real life cohort.
Method
In the START-TKI study, patients with EGFR-mutated lung cancer were pospectively sampled for plasma analysis during TKI treatment. We analysed the included osimertinib cohort until March 1, 2019, which included both first line and second line (based on p.T790M positivity) treated patients. Exclusion criteria were lack of subsequent samples until progression, double gene/TKI treatment or switch to other treatment because of toxicity. Next-generation sequencing (NGS) analysis was performed at progression on plasma and tissue specimens (when available).
Result
A total of 42 patients was included, which consisted of N=27 in the p.T790M positive (second line treatment) and N=15 in the p.T790M negative (first line treatment) subgroup. We excluded 4 patients in the first, and 5 patients in the second line treatment group. Evaluable progression was reached by N=11 and N=3 patients respectively.
In the second line (p.T790M positive) subgroup, resistance mechanisms were identified in 7 patients, and comprised MET amplification (N=2), small-cell transformation (N=2), EGFR p.C797S mutation (N=2) and BRAF mutation (N=1). In the p.T790M negative (first line) subgroup, resistance mechanisms were not identified.
Conclusion
Tissue specimen can provide important additional information on resistance mechanisms to EGFR-TKI treatment next to plasma analysis due to morphological information and in situ analyses (immunohistochemistry and in situ hybridization).
Resistance mechanisms to osimertinib in EGFR-mutated lung cancer are still under investigation, and may differ in a p.T790M positive and p.T790M negative setting.
This study was partly funded by a grant from AstraZeneca.
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P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 2
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-06 - Blood-Based Multiplex Kinase Activity Profiling as a Predictive Marker for Clinical Response to Checkpoint Blockade in Advanced NSCLC (ID 1322)
10:15 - 18:15 | Author(s): Joachim G.J.V. Aerts
- Abstract
Background
Only a minority of non-small-cell lung cancer (NSCLC) patients benefit from treatment with immune checkpoint inhibitors (ICIs), therefore, there is an urgent need for response prediction. Previously, the potential of using tyrosine kinase activity profiling of baseline peripheral blood mononuclear cells (PBMC) was demonstrated in an analysis with ICI treated advanced melanoma patients [1]. Here, we apply this methodology to evaluate the predictive value for response to ICIs in NSCLC.
Method
59 ICI naïve advanced NSCLC patients treated with PD-1 blockade were included in this exploratory analysis of the prospective immuno-monitoring study (MULTOMAB; NTR7015). PBMC were isolated from patient blood samples obtained prior to treatment with ICIs. Kinase phosphorylation signatures of PBMC lysates were measured using a micro-array, comprising of 144 different peptides derived from sites that are substrates for protein tyrosine kinases. Correlation of the profiles with progression free survival (PFS) and overall survival (OS) was analyzed using univariate cox-regression. Predictive multivariate (GLMnet) analysis was performed by binary survival grouping of patients with a cut-off at 140 days for PFS and 365 days for OS. The predictive performance of the models was estimated using cross validation. Multiplex flow cytometry, enumerating 18 immune cell subsets and assessing expression for 28 T cell markers, was performed for a selection of patients to gain additional insight in the immune profile [2].
Result
Univariate Cox regression showed significant correlation of phosphorylation signal with PFS for 7 peptides (p < 0.01, False Discovery Rate [FDR] = 10%), and with OS for 34 peptides (p < 0.01, FDR = 2%). Evaluation of the predictive value of GLMnet models resulted in estimates for the Correct Classification rate (CCR) of 67-70% for PFS and 67-73% for OS. When the cross validated predictions of the models were used to categorize the patients in a predicted-high-risk and a predicted-low-risk group, this resulted in a significant difference in survival between these groups. The predicted-low-risk group displayed significant better median PFS and OS than the predicted-high-risk group ([246 vs. 56 days; HR 2.3, 95%CI 1.2-4.7, p=0.02] and [488 vs. 171 days; HR 2.7, 95%CI 1.1-6.6, p=0.03], respectively).
Conclusion
Similar to melanoma, kinase activity profiles of baseline PBMC samples of advanced NSCLC patients can predict the response to PD-1 blockade. This assay may serve as a predictive biomarker for response to anti-PD-1 therapy. Involvement of immune receptor kinases is being investigated. An independent validation study is underway.
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P2.04-47 - Tumor Mutational Load, CD8+ T Cells, Expression of PD-L1 and HLA Class I to Guide Immunotherapy Decisions (ID 1259)
10:15 - 18:15 | Author(s): Joachim G.J.V. Aerts
- Abstract
Background
A minority of NSCLC patients benefit from anti-PD1 immune checkpoint inhibitor therapy. A rational combination of biomarkers is needed. The value of using a series of mechanism-of-action based parameters was studied for response prediction of immunotherapy: tumor mutational load (TML), CD8+ T cell infiltration, HLA class I expression and the currently used PD-L1 tumor proportion score.
Method
Patients were prospectively included between April 2016 and August 2017, and retrospectively analyzed. Metastatic NSCLC patients (n=30) with sufficient archival tissue, obtained prior to the first nivolumab administration, were selected. Response was assessed by RECIST v1.1. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier methodology. TML was determined using a next-genome sequencing panel (409 cancer-related genes). Immunohistochemistry was performed to score PD-L1, total CD8+ T cell infiltration and HLA class I.
Result
In 30 patients with adenocarcinoma (67%) or squamous cell carcinoma (33%), high TML was significantly associated with better PFS (p=0.004) and OS (p=0.025). Interaction analyses revealed that patients with both high TML and high total CD8+ T cell infiltrate (p=0.023) or no loss of HLA class I (p=0.026), patients with high total CD8+ T cell infiltrate and no loss of HLA class I (p=0.041) or patients with both high PD-L1 and high TML (p=0.003) or no loss of HLA class I (p=0.032) were significantly associated with better PFS. Unsupervised cluster analysis based on the four markers revealed three sub-clusters, of which cluster 1A was overrepresented by patients with progressive disease (15 out of 16), with significant effect on PFS (p=0.007).
Conclusion
This proof-of-concept study suggests that a combination of PD-L1 expression, TML, CD8+ T cell infiltration and HLA class I expression function as a better predictive biomarker for the response to anti-PD-1 immunotherapy and PFS. Consequently, refinement of this proposed set of biomarkers and validation in a larger set of patients is warranted.
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P2.06 - Mesothelioma (ID 170)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.06-01 - STELLAR Trial: Radiological Response Patterns of TTFields Plus Chemotherapy in First-Line Treatment of Malignant Pleural Mesothelioma (ID 2533)
10:15 - 18:15 | Author(s): Joachim G.J.V. Aerts
- Abstract
Background
Tumor Treating Fields (TTFields) are an anti-mitotic, regional treatment modality, utilizing low intensity alternating electric fields delivered non-invasively to the tumor using a portable, medical device. TTFields have significantly extended survival of glioblastoma patients. In-vitro, human malignant pleural mesothelioma (MPM) cells were highly susceptible to TTFields. In the STELLAR trial [NCT02397928], patients with unresectable MPM treated with first-line chemotherapy in combination with TTFields had a significantly higher median overall survival compared to historical controls (18.2 Vs. 12.1 months). We analyzed radiological data from STELLAR patients whose tumors responded while receiving the combined therapy.
Method
The trial accrued 80 patients with unresectable, previously untreated mesothelioma who were treated with continuous 150 kHz TTFields (>18h/day) in combination with pemetrexed and cisplatin or carboplatin (at standard dosing). Inclusion criteria: ECOG PS of 0-1, pathologically proven mesothelioma and at least one measurable lesion according to modified RECIST criteria. Patients were followed q3w (CT scan q6w) until disease progression. Radiological assessments were done at each study site. EOCG status and cancer-related pain were assessed until disease progression using a visual analog scale.
Result
Partial responses (PRs) were seen in 40.3% of evaluable patients and clinical benefit (PR+SD) was seen in 97.2% of patients. The median time between treatment start and PR was 1.8 (1.4-4.4) months). All patients presenting with PR during the STELLAR study had continuous reduction in the total sum of lesion diameters, suggesting no initial/pseudo-progression. 83% of the patients who responded to the combined therapy finally had disease progression within median response duration of 5.7 (1.4-13) months, per Kaplan-Meier Estimator. One patient did not progress for more than 27 months. Median time to deterioration in performance status was 13.1 months. Average pain score was lower compared to baseline during the first 7 months of treatment and higher later with a median time to a clinical significant 33% increase in pain of 8.4 months. Compliance with TTFields was 68% (16.3 hours/day) during the first 3 months of therapy. No TTFields-related other than expected dermatitis below the arrays were reported.
Conclusion
The STELLAR study showed significant survival extension in previously untreated MPM patients. Response rates were similar to that of current SOC treatment, but lasted longer with the addition of TTFields. TTFields was not associated with a decrease in performance status or an increase in pain. TTFields in combination with chemotherapy are efficacious in MPM vs chemotherapy alone reported in historical data.
