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Joachim G.J.V. Aerts
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MA12 - Mesothelioma Surgery and Novel Targets for Prognosis and Therapy (ID 913)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 10:30 - 12:00, Room 202 BD
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MA12.06 - STELLAR – Final Results of a Phase 2 Trial of TTFields with Chemotherapy for First-Line Treatment of Malignant Pleural Mesothelioma (ID 13806)
11:05 - 11:10 | Author(s): Joachim G.J.V. Aerts
- Abstract
- Presentation
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. In-vitro, human mesothelioma cells were highly susceptible to TTFields. TTFields have been shown to significantly extend survival of patients with glioblastoma when added to chemotherapy.
a9ded1e5ce5d75814730bb4caaf49419 Method
The trial accrued 80 patients with unresectable, previously untreated mesothelioma. Patients were treated with continuous 150 kHz TTFields (>18h/day) in combination with pemetrexed and cisplatin or carboplatin (at standard dosing). Inclusion criteria included 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. The primary endpoint was overall survival (OS) and secondary endpoints were response rate, progression free survival (PFS) and toxicity. This prospective, single arm study assumed an historical control with a median survival of 12.1 months (Vogelzang et al. 2003). The sample size provides 80% power with a two-sided alpha of 0.05 to detect an increase in median OS of 5.5 months.
4c3880bb027f159e801041b1021e88e8 Result
All 80 patients were enrolled between 2016 and 2017, with a minimum follow up of 12 months. Median age was 67 (range 27-78), 84% were male and 56% smokers. 16% (13 patients) had metastatic disease and 44% (35 patients) had an ECOG PS of 1. 66% (53 patients) had epithelioid histology. Compliance with TTFields was 68% (16.3 hours/day) during the first 3 months of therapy and 63% (50 patients) received carboplatin.
Median OS was 18.2 months (95% CI 12.1-25.8) compared to 12.1 months in the historical control. Median PFS was 7.6 months (95% CI 6.7-8.6) compared to 5.7 months in the historical control. Partial responses were seen in 40.3% of patients and clinical benefit (PR+SD) was seen in 97.2% of patients. No device-related serious adverse events (AEs) were reported. Expected TTFields-related dermatitis was reported in 46% (37 patients). Only 4 patients (5%) had grade 3 dermatitis. The following grade 3-4 systemic AEs were reported in >3% of patients: hematological AEs (15%) and fatigue (4%).
8eea62084ca7e541d918e823422bd82e Conclusion
The study met its primary endpoint of significant extension of survival for previously untreated mesothelioma patients. Secondary efficacy endpoints were also improved compared to historical control. The study demonstrated no safety concerns for the combination of TTFields to the thorax together with standard chemotherapy. These results support the addition of TTFields to standard chemotherapy in the treatment of first-line malignant pleural mesothelioma.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MA19 - Genomic Markers of IO Response (ID 922)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Immunooncology
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 15:15 - 16:45, Room 201 BD
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MA19.08 - Detection of Primary Immunotherapy Resistance to PD-1 Checkpoint Inhibitors (PD1CI) in 2nd Line NSCLC (ID 13916)
16:05 - 16:10 | Presenting Author(s): Joachim G.J.V. Aerts
- Abstract
- Presentation
Background
PD1CI are capable of restoring immunity, but some patients do not benefit. While molecular tests like PD-L1 expression and TMB help in enriching response in respective subsets, a test identifying patients showing primary resistance to PD1CI which does not require tissue samples could help in optimizing treatment regimens.
a9ded1e5ce5d75814730bb4caaf49419 Method
Sophisticated mass spectrometry profiling data from a development set (S) of pre-treatment serum from 116 2nd line NSCLC patients treated with nivolumab were correlated with outcome data (PFS/OS)using multivariate machine learning techniques related to deep learning. The resulting test stratified patients into three groups: group A having very poor outcomes, group B having intermediate outcomes, and group C having very good outcomes. Development results were obtained using out-of-bag estimators. Two additional patient cohorts treated with nivolumab, V1(N=58) and V2(N=75), were used for validation.
4c3880bb027f159e801041b1021e88e8 Result
The proportions of patients in A, B, and C were 41:43:32 in S, 23:18:17 in V1, and 32:19:24 in V2. Median PFS/OS in the poor prognosis group A was 43/132 days in S, 105/189 days in V1, 90/278 days in V2, and in the good prognosis group C 276/528 days in S, 192/459 days in V1, and 155/not reached days in V2. In a comparison with historical controls treated with single agent chemotherapy and analyzed with the same technique, nivolumab appeared substantially superior in the good prognosis group C, while there was no evidence of superiority in the poor prognosis group A. In multivariate analysis including performance status, smoking history, and histology, the test remained an independent predictor of outcome. The patterns of protein expression related to poor prognosis in group A patients were associated with elevated complement, wound healing, and acute phase reactants.
8eea62084ca7e541d918e823422bd82e Conclusion
We developed and validated a test stratifying patients into three groups with significantly different outcomes on nivolumab. The poor prognosis group showed little benefit from nivolumab, and other treatments may be needed, while in the good prognosis group outcomes were very good for a 2nd line population. Our results emphasize the important role of the host immune response in the prediction of PD1CI efficacy. Data on PD-L1 IHC from these cohorts will be included in the multivariate analysis and presented at the meeting.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MS31 - Clinical Science in Mesothelioma (ID 809)
- Event: WCLC 2018
- Type: Mini Symposium
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 13:30 - 15:00, Room 205 AC
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MS31.05 - Vaccination and Antibody-Based Therapy in Mesothelioma (ID 11539)
14:30 - 14:45 | Presenting Author(s): Joachim G.J.V. Aerts
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.13-28 - Comparison of ddPCR and NGS in Liquid Biopsy to Pathology Results in EGFR-Mutated NSCLC (ID 13889)
16:45 - 18:00 | Author(s): Joachim G.J.V. Aerts
- Abstract
Background
In the blood of EGFR-mutated NSCLC patients, primary activating mutations as well as the resistance mutation T790M can be detected in ctDNA (liquid biopsy). Several methods have been developed for this purpose but techniques are still evolving. We compared two tests (BioRad digital droplet PCR (ddPCR) and IonTorrent/Oncomine next generation sequencing (NGS)) for ctDNA primary activating EGFR mutations and T790M to results of pathological investigation of a tissue biopsies or pleural fluid.
a9ded1e5ce5d75814730bb4caaf49419 Method
We collected the data on liquid biopsies performed on EGFRm+ NSCLC patients from November 2016 untill February 2018 at the Erasmus MC. In this study we analyzed all liquid biopsies from patients with EGFR mutations at baseline or after progression from whom also pathology results in the same time frame of treatment were available.
Liquid biopsy results obtained from the two methods were compared to each other as well as to the pathology results. Cohen’s kappa was calculated as measure of agreement.
4c3880bb027f159e801041b1021e88e8 Result
In total, 29 out of 123 patients (24%) did meet the criteria and were included in our study.
Concordance for the detection of the primary activating mutation between pathology results and blood was 66% for the BioRad ddPCR and 83% for the IonTorrent/Oncomine NGS (n=29). Concordance for the detection of p.T790M between pathology results and blood was 76% for both ddPCR and NGS (κ=0.51, n=29). In 5 patients (17%), p.T790M was detected by pathology results but not in cfDNA. In 2 patients (7%), p.T790M was detected in blood but not in the pathology specimen.
Concordance between ddPCR and NGS on blood for the primary activating EGFR mutation was 83% (κ=0.57, n=29) and for p.T790M detection 93% (κ=0.86, n=29).
8eea62084ca7e541d918e823422bd82e Conclusion
Detection of mutations in plasma show reasonable to high concordance with tissue biopsy. The method of testing defines the extent of the number of tested mutations and therefore the height of concordance. NGS seems to upscale the concordance of detection of the primary mutation due to examination of a broader panel of available mutations (in ddPCR only exon 19 deletions and exon 21 p.L858R are tested), but is comparable to ddPCR on the level of a specific mutation in the panel (p.T790M).
Discrepant results between pathology specimens and liquid biopsy remain a difficult issue for clinical practice.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P3.13 - Targeted Therapy (Not CME Accredited Session) (ID 979)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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P3.13-04 - Lorlatinib in Anaplastic Lymphoma Kinase and Proto-Oncogene Tyrosine-Protein Kinase ROS-Positive Non-Small Cell Lung Cancer (ID 14150)
12:00 - 13:30 | Author(s): Joachim G.J.V. Aerts
- Abstract
Background
In this case series we present ten patients with anaplastic lymphoma kinase (ALK)-rearranged or ROS proto-oncogene 1 (ROS1)-rearranged non-small-cell lung cancer (NSCLC) treated with lorlatinib.
a9ded1e5ce5d75814730bb4caaf49419 Method
Lorlatinib is highly potent and selective third generation ALK and ROS1 tyrosine kinase inhibitor (TKI) with known activity against most resistance mutations. In a phase 1 study, lorlatinib showed intracranial and systemic activity in ROS1-positive and ALK-positive patients with advanced NSCLC.
4c3880bb027f159e801041b1021e88e8 Result
Thus far, we treated 6 ALK- and 4 ROS1-positive stage IV NSCLC patients with lorlatinib in a compassionate use program. Best response was complete remission in two of our patients. One ROS1-positive patient with CNS metastases has now ongoing complete response for 27 months; the other patient with a ALK-positive NSCLC with CNS metastasis has now been treated with lorlatinib for 16 months. Three patients showed a partial response with an ongoing progression free survival of respectively 3, 5 and 8 months. Two of our patients (one ALK-positive and one ROS1-positive NSCLC) showed progressive disease as best response. In three patients response data is not (yet) available. There were no significant side effect apart from hypercholesterolemia, which occurred in four of our patients.
8eea62084ca7e541d918e823422bd82e Conclusion
Lorlatinib shows promise in the treatment of ROS1-positive and ALK-positive patients with advanced NSCLC.
6f8b794f3246b0c1e1780bb4d4d5dc53
