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Thomas John
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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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MA12.11 - Analysis of Angiogenic and Stromal Biomarkers in a Large Malignant Mesothelioma Cohort (ID 12234)
11:40 - 11:45 | Author(s): Thomas John
- Abstract
- Presentation
Background
Malignant mesothelioma (MM) is an aggressive malignancy of the pleura and other mesothelium membranes. Agents targeting vascular endothelial growth factor (VEGF) receptor such as bevacizumab; and multi-kinase inhibitors like nintedanib [angiokinase inhibitor of VEGF, platelet-derived growth factor (PDGF) receptor and fibroblast growth factor receptor (FGFR)] have recently demonstrated efficacy in MM. In the setting of these new therapies, it is important to evaluate angiogenic and stromal markers in MM to assess their associated prognostic implications.
a9ded1e5ce5d75814730bb4caaf49419 Method
Tissue microarrays (TMAs) were created from formalin-fixed, paraffin-embedded tissue samples obtained from 326 patients who underwent surgical resection or biopsy for MM between 1988 and 2014. PDGF-CC, FGFR-1, VEGF and CD31 expression were analysed by immunohistochemical (IHC) staining. The H-score method assigned a score of 0–300 to each sample, based on the percentage of cells stained at different intensities. The discriminatory threshold was set for each IHC stain (usually the median score) and samples were classified as low (below median) or high expression (above median). CD31 was evaluated via Chalkley’s method to evaluate microvessel density. We evaluated the association between expression of the biomarkers, clinicopathological factors and outcomes, in patients with MM.
4c3880bb027f159e801041b1021e88e8 Result
The histological subtypes comprised of 203/325 (62.5%) epithelioid; 72/325 (22.2%) biphasic; 42/325 (12.9%) sarcomatoid, or indeterminate. The median age was 67 (range 24-88) with Male: Female ratio of 266: 53.
CD31 high (≥5) was seen in only 31/302 (10.3%) irrespective of histology (13/31 (42%) epithelioid; 10/31 (32%) sarcomatoid; 7/31 (23%) biphasic; 1/31 indeterminate).
PDGF-CC high (≥150) was seen in 203/310 (65%) of all samples but was higher in epithelioid subtype [129/203 (64%)]. VEGF high (≥80) was seen in 219/322 (68%) of all MM with 143/209 (68%) of epithelioid histology.
FGFR-1 high (≥40) was seen in 127/310 (41%) of all MM and 73/127 (57.5%) are of epithelioid histology.
There was no association of VEGF and FGFR-1 IHC with survival nor differences between histological subtypes.
There was a non-significant trend towards poorer survival in epithelioid tumours with increased PDGF-CC expression (OS 18.5 vs 13.2 months; HR 0.7928; 95%CI 0.5958 to 1.055, P=0.1110).
High CD31 score was associated with significantly poorer survival (OS 12 vs 8.6 months; HR 0.48; 95%CI 0.2873 to 0.7941, P=0.0044). Of the 31 patients with high CD31 scores; 23/31 (74%) were also high for PDGF-CC and 20/31 (64%) with high VEGF scores.
8eea62084ca7e541d918e823422bd82e Conclusion
High PDGF-CC expression and CD31 scores are associated with poor survival in MM. Abrogating these pathways may have prognostic implications.
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MA15 - Colliding Approaches - EGFR and Immunotherapy (ID 916)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 13:30 - 15:00, Room 107
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MA15.03 - PD-L1 Expression in Untreated EGFRm Advanced NSCLC and Response to Osimertinib and SoC EGFR-TKIs in the FLAURA Trial (ID 12989)
13:40 - 13:45 | Author(s): Thomas John
- Abstract
- Presentation
Background
In the Phase III FLAURA trial (NCT02296125), osimertinib significantly improved PFS relative to SoC EGFR-TKIs (gefitinib/erlotinib) in patients with untreated Ex19del/L858R positive (EGFRm) NSCLC. EGFRm NSCLC tumors can exhibit high PD-L1 expression, an important biomarker for immunotherapy treatment decisions. The frequency and clinical relevance of exhibiting both biomarkers prior to treatment are unclear. We report PD-L1 expression in patients with EGFRm advanced NSCLC and association with clinical outcomes following EGFR-TKI treatment.
a9ded1e5ce5d75814730bb4caaf49419 Method
Tissue samples from 994 patients with advanced NSCLC were screened for EGFR Ex19del/L858R mutations for enrolment in FLAURA; 556 were randomized to treatment. 197 tissue-blocks from the screened population (including EGFR mutation-positive and -negative samples) were tested for PD-L1 using the SP263 (Ventana) immunohistochemical assay; positive tumour cell (TC) staining PD-L1 TC≥25% and TC≥1% thresholds were applied. PFS was investigator-assessed, per RECIST 1.1, according to PD-L1-expressers (TC≥1%) or -negatives (TC<1%) in randomized patients.
4c3880bb027f159e801041b1021e88e8 Result
193/197 blocks had sufficient tumor tissue for staining. 65/193 patients were EGFR mutation-negative. 128/193 patients were EGFR mutation-positive: 106/128 were randomized to treatment (osimertinib: 54; SoC: 52). The table presents PD-L1 expression according to EGFR mutation status. For PD-L1-expressers (TC≥1%), median PFS was 18.4 months for osimertinib and 6.9 months for SoC (HR 0.30 [95% CI 0.15, 0.60]). For PD-L1-negative patients (TC<1%), median PFS was 18.9 months for osimertinib and 10.9 months for SoC (HR 0.37 [95% CI 0.17, 0.74]).
8eea62084ca7e541d918e823422bd82e ConclusionPD-L1 TC≥1%, n (%)
PD-L1 TC≥25%, n (%)
EGFR mutation-negative (n=65)
Screened population (n=65)
44 (68)
23 (35)
EGFR mutation-positive (n=128)
Screened population (n=128)
65 (51)
10 (8)
Randomized to treatment (n=106)
52 (49)
8 (8)
Randomized to osimertinib (n=54)
28 (52)
3 (6)
Randomized to SoC EGFR-TKI (n=52)
24 (46)
5 (10)
There was PFS benefit with osimertinib versus SoC regardless of whether tumors were PD-L1-expressers (TC≥1%) or -negatives (TC<1%). Using the TC≥25% threshold, PD-L1 prevalence was lower in EGFR mutation-positive than mutation-negative samples; there were insufficient patients with TC≥25% tumors for PFS assessment.
These results support the efficacy of EGFR-TKIs, including osimertinib, as first-line treatment of EGFRm advanced NSCLC, irrespective of PD-L1 expression.
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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MS25 - Genetic and Prognostic Markers in Mesothelioma; Going Beyond the Histology Subtypes (ID 803)
- Event: WCLC 2018
- Type: Mini Symposium
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 10:30 - 12:00, Room 206 AC
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MS25.03 - Impact of Innate and Adaptive Tumor Infiltrating Cells on Prognosis (ID 11508)
11:00 - 11:15 | Presenting Author(s): Thomas John
- Abstract
- Presentation
Abstract not provided
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OA08 - Mesothelioma: Immunotherapy and microRNA for Diagnosis and Treatment (ID 907)
- Event: WCLC 2018
- Type: Oral Abstract Session
- Track: Mesothelioma
- Presentations: 3
- Moderators:
- Coordinates: 9/24/2018, 15:15 - 16:45, Room 201 BD
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OA08.02 - DREAM - A Phase 2 Trial of Durvalumab with First Line Chemotherapy in Mesothelioma: Final Result (ID 12022)
15:25 - 15:35 | Author(s): Thomas John
- Abstract
- Presentation
Background
We report here the final results of a single-arm, phase 2 trial designed to determine the activity, safety and tolerability of durvalumab, cisplatin and pemetrexed as first line therapy in MPM. ANZ Clinical trial registry number: ACTRN12616001170415
a9ded1e5ce5d75814730bb4caaf49419 Method
Participants were considering first line chemotherapy for MPM, were unsuitable for radical surgery, had an un-irradiated target lesion, and had good performance status (ECOG PS 0-1). Objective tumour response (OTR) and progression free survival (PFS) were assessed primarily according to the modified Response Evaluation Criteria in Solid Tumors for MPM (mRECIST) and as secondary endpoints according to RECIST modified for immunotherapy (iRECIST). Study treatment was durvalumab 1125mg, cisplatin 75mg/m2, and pemetrexed 500mg/m2 all given intravenously on day 1, and repeated every 3 weeks for a maximum of 6 cycles, followed by durvalumab 1125 mg every 3 weeks until progression, unacceptable toxicity, or a maximum total of 12 months. The primary endpoint was PFS at 6 months (PFS6). The sample size of 54 provided 90% power to distinguish the observed proportion PFS6 from a null hypothesis of 45% versus an alternative of 65% with a 1-sided alpha of 5%. Tissue and blood samples were required and collected for translational correlative studies.
4c3880bb027f159e801041b1021e88e8 Result
We recruited 54 participants from Dec 2016 to Sep 2017. Median age was 68 (range 42-82), 82% were male, 60 had ECOG PS 0, and 82% had epithelioid histology. Dose intensities were 97% for cisplatin and 94% for durvalumab. The proportion PFS6 was 57% (31/54, 90% CI 45-68%); median PFS was 6.9 months (95% CI 5.5-9.0). The OTR rate was 48% (95% CI 35-61%) according to mRECIST and 50% (95% CI 37-63) according to iRECIST. The median duration of response was 6.5 months. Grade 3-5 adverse events occurred in 36 participants, including neutropenia in 13%, nausea in 11%, anaemia in 7%, fatigue in 6% and any grade peripheral neuropathy in 35%. There were 4 deaths on study, none attributed to durvalumab. Immune-related adverse events occurred in 17 participants, and were of grade 3 or worse in 8, including increased lipase (1), pancreatitis (1), and renal impairment (1).
8eea62084ca7e541d918e823422bd82e Conclusion
The combination of durvalumab, cisplatin, and pemetrexed has demonstrated sufficient activity, safety, and tolerability as first line therapy in MPM to warrant further evaluation in a large-scale, randomised phase 3 trial.
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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OA08.04 - Discussant - OA 08.01, OA 08.02, OA 08.03 (ID 14560)
15:45 - 16:00 | Presenting Author(s): Thomas John
- Abstract
- Presentation
Abstract not provided
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OA08.05 - Quantifying Tumour Infiltrating Lymphocytes (TILs) in Malignant Pleural Mesothelioma (MPM) -Defining the Hot, the Warm and the Cold Tumours. (ID 13326)
16:00 - 16:10 | Presenting Author(s): Thomas John
- Abstract
- Presentation
Background
Immunological infiltrates into tumor tissues have been associated with improved prognosis in many cancers including breast, colorectal, cervical, melanoma and lung. While most studies evaluating TILs have been based on evaluation of individual types of T lymphocytes, more recently, a morphological assessment of the TILs based on a simple hematoxylin & eosin (H&E) slide examination has been shown to be an independent positive prognostic factor in HER2 positive early stage breast cancer and lung cancer. We used similar methods to explore the immune microenvironment in a large mesothelioma cohort.
a9ded1e5ce5d75814730bb4caaf49419 Method
Using full face sections of MPM tumour samples, we assessed lymphocytes infiltrating tumour stroma.TILs score was calculated as a % of stromal area assessed to be covered by TILs by an experienced pathologist. Tissue microarrays (TMA) were constructed and stained with PD-L2, LAG3 and TIM3 antibodies. These data were combined with PD-L1 expression, CD4+ and CD8+ infiltration in the same cohort reported previously. We explored the clinical and pathological correlates of the level of TILs.
4c3880bb027f159e801041b1021e88e8 Result
Amongst 329 patients evaluated, 308 samples were evaluable for TILs characterisation. The scores ranged from 0-90 (median 30). Stratified using tertiles, 142 patients had low TILs, 68 had medium and 98 had high TILs. High TILs were seen in patients who were PD-L1 (Chi square test p = 0.002) and PD-L2 positive (Chi square test p <0.0001) and of non-epithelioid histological subtype (Fischer’s exact test p = 0.01). On univariate analysis, PD-L2 positivity (HR = 3.2; CI = 2.2-4.6; Log rank P < 0.0001), high TILs (HR = 2.03; CI = 1.5-2.6; Log rank P < 0.0001), and high TIM3+ lymphocytes (HR = 1.3; CI = 1.0-1.7; Log rank P < 0.04) were found to be related to poorer overall survival (OS). On multivariate analysis, higher TILS was found to remain significantly associated with poorer OS along with non-epithelioid histology and poor physiological status.
8eea62084ca7e541d918e823422bd82e Conclusion
High TILs correlated with non-epithelioid histology and greater expression of PD-L1 and PD-L2. In contrast to other tumor types, a high TIL infiltrate was negatively prognostic.
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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P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)
- 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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P2.01-50 - Thromboembolism in ROS1 Rearranged Non-Small Cell Lung Cancer (ID 12885)
16:45 - 18:00 | Author(s): Thomas John
- Abstract
Background
The risk of thromboembolism (TE) is estimated to be 0.001% per year and hereditary thrombophilia present in 0.2-5% of the general adult population.
It is estimated that 8-15% of patients with advanced non-small cell lung cancer (NSCLC) will develop thromboembolism throughout their disease course. In ALK rearranged NSCLC this incidence has been reported to be three to four fold higher at 36%.
We sought to investigate the incidence in TE in a cohort of the rare ROS1 rearranged molecular subgroup.
a9ded1e5ce5d75814730bb4caaf49419 Method
Electronic records were reviewed in six tertiary hospitals to identify all patients diagnosed with ROS1 NSCLC. Predefined data were analysed in STATA15 software for Kaplan-Meier (KM) plot and Cox-regression modelling.
4c3880bb027f159e801041b1021e88e8 Result
Forty-two patients were identified at data cut (31/1/2018). Median follow up was 10.9 months (mo); 38% had died. Median age was 53 years (31-80); 74% were female; 67% non-Asian and 88% non- smokers and 29% CNS disease during diagnosis.
Median overall survival (OS) overall was estimated 28.8mo (range: 0.1-180.4mo).
Thromboembolism incidence was 48% (n=20); 19 venous, 11 with pulmonary embolus (PE). One patient presented with fatal arterial TE (ROS1 diagnosed pre-mortem).
Median time to TE was 2.3mo. In four patients TE was the harbinger for their diagnosis and two had encountered unprovoked TE prior to diagnosis, one then recurrent TE throughout diagnosis.
Screening for a thrombophilia (TP) was not mandatory, and tested in n=9/20 cases with TE, one without. A co-occurring TP was identified in 15% (n=3/20); two factor V Leiden; one anti-thrombin III (ATIII) deficiency. Of interest, one patient with TE had factor XII deficiency; one thalassaemia minor and one acute-promyelocytic leukaemia without evidence of disseminated intravascular coagulation.
Age; race; baseline ECOG; smoking history; treatment received; brain metastases at diagnosis; hereditary thrombophilia and neutrophil to lymphocyte ratio were not predictive of TE in this small cohort.
Median OS in patients with TE was 21.3mo (0.1-180.4) versus 28.83mo (1.2-63.5) with no TE; hazard ratio 1.16 (95%CI 0.43-3.15, p=0.77).
The ROS-1 fusion partner was known in two cases, both CD74-ROS1, one encountering TE (PE). Twenty-five have archival tissue available to identify the fusion partner and explore an association with TE.
8eea62084ca7e541d918e823422bd82e Conclusion
To the best of our knowledge, this is the first report on the incidence of thrombotic events specifically in ROS1-rearranged NSCLC. In this small cohort intriguingly there was a high incidence of TE and a higher incidence than the general population of hereditary thrombophilia.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P2.06 - Mesothelioma (Not CME Accredited Session) (ID 955)
- 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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P2.06-08 - ABT-806 Derived Antibody Drug Conjugates (ADCs) Inhibit Growth of Malignant Mesothelioma In-Vivo (ID 12233)
16:45 - 18:00 | Author(s): Thomas John
- Abstract
Background
Malignant mesothelioma (MM) is an aggressive malignancy of the pleura with limited therapeutic options, and is associated with a poor prognosis. EGFR is known to be highly over-expressed in mesothelioma with reported EGFR overexpression between 44 to 97%.We have developed an anti-EGFR antibody (ABT-806), which is tumour specific and robustly inhibits EGFR-expressing tumours. We aimed to establish the validity and feasibility of targeting tumour expressed EGFR in MM using ABT-806 novel ADCs (ABT-414 and ABBV-221).
a9ded1e5ce5d75814730bb4caaf49419 Method
We evaluated EGFR and mAb 806 immunohistochemistry in 4 MM cell lines (MSTO-211H, NCI-H2052, NCI-H28, NCI-H2452) and performed in-vitro cell proliferation assays to evaluate the antineoplastic potential of mAb806-related ADCs. In-vivo therapeutic studies using the biphasic mesothelioma cell line (MSTO-211H) were conducted with treatment groups involving ABT-414, ABBV-221, ADC control, cisplatin chemotherapy. We also performed quantitative biodistribution and imaging of mAb806 ADC uptake (89Zr mAb806 ADC) to allow correlation of mAb806 ADC concentration in tumours.
4c3880bb027f159e801041b1021e88e8 Result
mAb806 to be bound strongly to three of four MM cell lines (MSTO-211H, NCI-H2052 and NCI-H28). Cell proliferation assays (CPA) also demonstrated ABT-414 and ABBV- 221 had significant cell growth inhibition demonstrated in the range between 1 to 10ug/ml for MM cell lines. In MSTO211H xenograft model significant anti-tumour response to both ABT-414 and ABBV-221 (p<0.01), was demonstrated. High, specific targeting of 89Zr-ch806 to MM tumour in-vivo was also shown.
8eea62084ca7e541d918e823422bd82e Conclusion
ABT-806 ADCs show potent anti-tumour activity in MM model, and warrant further exploration as a potential therapy for MM.
6f8b794f3246b0c1e1780bb4d4d5dc53
