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Sanjay Popat
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IBS23 - Treatment of NSCLC OMD in Clinical Practice (Ticketed Session) (ID 54)
- Event: WCLC 2019
- Type: Interactive Breakfast Session
- Track: Oligometastatic NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/10/2019, 07:00 - 08:00, Toronto (1985)
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IBS23.02 - Oncological Treatment of Omd in Daily Clinical Practice (Now Available) (ID 3386)
07:00 - 08:00 | Presenting Author(s): Sanjay Popat
- Abstract
- Presentation
Abstract
The front line systemic treatment of metastatic non-small cell lung cancer (NSCLC) has changed rapidly over the past 10 years, from the establishment of histology-specific chemotherapy, the introduction of molecular targeted therapies for specific somatic sensitizing gene mutations/fusions, and now the routine use of immune checkpoint inhibitors either as monotherapy or in combination with chemotherapy. Current data suggests that oncogene addicted tumours have little benefit from checkpoint inhibitor monotherapy, and so advanced NSCLC can be functionally categorized into those that are oncogene addicted and ideally treated with molecular targeted therapy – either as monotherapy or in combination with other therapies- or immune sensitive, ideally treated with immune checkpoint inhibitors again as monotherapy or in combination with chemotherapy. At the same time, advances in radiotherapy delivery have meant that small volume metastatic disease can be treated at ablative doses of radiotherapy. How these two modalities should be integrated in patients with oligometastatic disease for optimal survival and minimal toxicities has been debated over recent months.
In parallel our understanding of the natural history of different types of NSCLC has become better understood, alongside the phenotypic and genotypic selection pressures put on them by systemic therapy. Thus, recognizing that patients with oncogene addicted disease such as ALK and ROS1 fusions or EGFR mutations have a high propensity to CNS metastases, and that next generation CNS-penetrant kinase inhibitors are optimally used up front, SRS to brain metastases may be deferred and used on demand in case of late progression, effectively withholding whole brain radiotherapy until much later in the patient care timeline. However, trial data to support this decision making is currently lacking and awaited. Understanding that patients with oncogene addicted disease now have a median survival quadrupled to that previously (now in excess of 4 years) with optimal sequencing of kinase inhibitors, allows a more thoughtful way to integrate a more radical approach into those with small volume oligometastatic disease.
We therefore now recognize several states of oligometastatic disease, with much of our information and treatment paradigms evolving from the treatment of patients with oncogene addicted disease. Patients may have the now well-known synchronous or metachronous oligometastatic disease state. Moreover, the integration of kinase inhibitors has identified an oligoprogressive disease occurring in around 30% of cases, and the ability to treat such cases with radical radiotherapy or a surgical approach. In such cases, tissue sampling may be required not only to plan the next steps of systemic therapy by tissue genotyping for acquired resistance mechanisms and new molecular target identification, but also for fiducial placement. Another less well defined disease entity is that of oligopersistent disease- defined as small volume radically treatable disease present after the bulk of oligo- or poly-metastatic disease has responded well to initial therapy, with patient series data suggesting a survival benefit for radically consolidating (oligo-consolidation) or optimally debulking in this approach.
The integration of immune checkpoint inhibitors has again changed patterns of disease response and progression. Certainly, major durable responders are observed with checkpoint inhibitors alone, and the role of radically consolidating such patients may be debatable given that around 30% of patients with 50%+ PDL1 expression treated with front-line pembrolizumab monotherapy survive 5 years. However, acquired checkpoint inhibitor resistance is common and single centre series have suggested a rate of 30% of patients progressing with oligoprogression, suitable for ablative therapy or resection.
In this presentation, I will discuss all these issues, including concerns about toxicities, and duration of therapy, arguing for a consensus on oligo-definitions, and molecular stratification within trials, encouraging enrolment into ongoing clinical trials to quantify the magnitude of benefit afforded by radically treating the oligometastatic state.
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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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MA05.01 - Second or Third Line Anti-PD-1 Therapy After Multimodality Therapy Including Total Pleurectomy in Malignant Pleural Mesothelioma (Now Available) (ID 1955)
13:30 - 15:00 | Author(s): Sanjay Popat
- Abstract
- Presentation
Background
Surgical resection plays an important role in the management of selected patients with malignant pleural mesothelioma (MPM). Early experience with anti-PD-1 immunotherapy showed promise in MPM, but it is yet uncertain if it can improve outcomes when tumour relapses following surgical resection, radiotherapy and chemotherapy. We reviewed our experience in patients who received Pembrolizumab or Nivolumab following multimodality therapy.
Method
Retrospective study including patients with histologically-proven MPM having completed multimodality therapy and received anti-PD-1 immunotherapy as 2nd or 3rd line treatment. Data were retrieved from a prospective mesothelioma database. Histopathology, BAP1, MTAP and PD-L1 (22C3) immunohistochemistry were performed on surgical specimens and reported by a senior pathologist. All patients had chest computed tomography and positron emission tomography (PET-CT) as part of their normal follow-up. Response evaluation was determined using RECIST 1.1 criteria.
Result
16 patients received anti-PD-1 immunotherapy between August 2015 and March 2019. All patients had total pleurectomy/decortication, prophylactic radiotherapy (21Gy/3) and systemic chemotherapy based on pemetrexed and platinum. Median age was 68.5 years, with male predominance (13/16). 56% had epithelioid type, 44% had biphasic type. Median time to starting immunotherapy was 20 months (range 11-42) following surgery. Median ECOG performance status was 0. Twelve patients received Pembrolizumab and 4 received Nivolumab. Median number of cycles of anti-PD-1 therapy received was 5 (range 1-33). Disease control rate at 12 weeks was 56.2% and 7 (43.7%) patients had disease progression. Adverse events were observed in 6 patients (one Grade 3). Eight patients were alive by 1st April 2019. Median OS from starting immunotherapy was 13.5 months. Three patients received treatment for 14 months or more. Five patients started further therapy after discontinuing immunotherapy.
Conclusion
In our cohort, second or third-line anti-PD-1 immunotherapy showed efficacy with DCR comparable to non-surgical setting. Further studies are warranted to validate our preliminary findings.
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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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MA12.02 - Growth Patterns in Epithelioid Malignant Pleural Mesothelioma: A Clinicopathological Review of 614 Cases Over 15 Years (Now Available) (ID 1595)
14:00 - 15:30 | Author(s): Sanjay Popat
- Abstract
- Presentation
Background
Nuclear grading system has been validated as a powerful prognostic tool for epithelioid malignant pleural mesothelioma (MPM) whilst growth patterns had demonstrated prognostic value in earlier studies. We aim to externally validate the previous findings and evaluate the utility of a composite architecture-nuclear grade scoring system.
Method
We retrospectively reviewed 614 consecutive cases of epithelioid MPM diagnosed at our institution over a 15-year period. Clinicopathological information including predominant growth pattern (Solid, Tubulo-papillary, Trabecular, Micropapillary, Microcystic, Discohesive, Pleomorphic) and 2-tier nuclear grade were retrieved from an institutional mesothelioma database. The tumours were categorised into High Grade (Solid, Micropapillary, Score=1) and Low Grade (All others, Score=0). A composite score (0-2) was generated based on growth pattern and 2-tier nuclear grade (0-1). Survival analysis was performed using Kaplan-Meier method.
Result
Pleomorphic epithelioid MPM was associated with the worst median overall survival (5.4 months), followed by micropapillary- (6.2 months), solid- (10.5 months), microcystic- (15.3 months), discohesive- (16.1 months), trabecular- (17.6 months) and tubulo-papillary- (18.6 months) patterns. The composite scoring system further improved stratification of overall survival based on 2-tier nuclear grade (19.8 vs. 13.4 vs. 8.1 months, p<0.001).
Conclusion
Epithelioid MPM growth patterns predicted survival in our cohort. Composite architecture-nuclear grade scoring system further improved prognostic stratification.
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MA23 - Preclinical Models and Genetics of Malignant Pleural Mesothelioma (ID 353)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Mesothelioma
- Presentations: 2
- Now Available
- Moderators:Ramon Palmero Sánchez, Raphael Bueno
- Coordinates: 9/10/2019, 14:30 - 16:00, Copenhagen (1980)
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MA23.10 - Low Number of Mutations and Frequent Co-Deletions of CDKN2A and IFN Type I Characterize Malignant Pleural Mesothelioma (Now Available) (ID 1627)
14:30 - 16:00 | Author(s): Sanjay Popat
- Abstract
- Presentation
Background
Malignant pleural mesothelioma (MPM) is an aggressive tumour with dismal prognosis and overall survival.
To expand our understanding of molecular background of MPM and to identify novel targetable aberrations we report an integrated genomic analysis of 121 tumour samples.
Method
Fresh-frozen tumour samples (obtained from Mesobank UK,the BLF funded Mick Knighton Mesothelioma Tissue Bank, Respiratory BRU Biobank Diagnostic Archive, Royal Brompton Hospital and an Imperial College London prospective study) were analysed by whole exome sequencing (WES, n=50), SNP genotyping (n=118) and targeted capture sequencing (n=119) for 57 genes.
Sequencing libraries were prepared using Target Enrichment Systems for the Illumina Multiplexed Sequencing platform. Somatic mutations were called using VarScan after recalibration of alignments by Genome Analysis Toolkit (GATK). SNP genotyping was performed with the Human Infinium Omni-Express-Exome v1.3/1.4 Bead Chips arrays. Segmentation and copy number calling was performed using a combination of Allelic specific copy number analysis of tumour (ASCAT), DNACopy and GISTIC softwares.
Result
Analysis of WES paired samples revealed a median of 31 non-synonymous somatic mutations per tumour, lower than melanoma (315 somatic mutations) or lung cancer (187.5 for squamous and 158 for adenocarcinoma), two types of tumours linked to known carcinogen exposure.
Investigation of copy number showed significant frequent deletion (q-value>0.05) of 9p21 locus where CDKN2A, MTAP and IFN type I genes are located. Deletion of CDKN2A was seen in 71/121 patients with homozygous deletion in 58/71 patients. Homozygous co-deletion of CDKN2A and IFN type I was seen in 38/58 patients, homozygous codeletion with MTAP in 49/58 patients while 37 patients showed all three as homozygous co-deleted.
Patients with CDKN2A and IFN type I deletions had worse overall survival compared with the CDKN2A wild type and patients CDKN2A only deleted patients (median 8.3 months vs 13.1 months, p-value=0.016).
Deletion of 3p21.1 locus and mutations in BAP1 were detected in 54.5% of the patients, making BAP1 the second most commonly altered gene. RB1 (13q14.2) was commonly altered mainly by deletion in 25.6% of the patients. NF2 and TP53 were affected by mutations in 19.8% and 7.4% of the patients, repectively. Patients with mutations in TP53 had worse overall survival compared with TP53 wild type patients (p-value=0.0005).
Conclusion
Co-deletion of CDKN2A, MTAP and IFN type I genes could have therapeutic implications for the patients. Deletion of IFN type I may have direct implications for patient responses to immunotherapy. In the contex of multiple vulnerabilities, the presence of both CDKN2A and RB1 loss might define an important group of patients susceptible to CDK4/6i targeted therapies.
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MA23.11 - Analysis of Immune Phenotype Composition in Malignant Pleural Mesothelioma (MPM) Using Bulk RNA Sequencing (Now Available) (ID 2326)
14:30 - 16:00 | Author(s): Sanjay Popat
- Abstract
- Presentation
Background
Exploiting the immune status of the tumour microenvironment (TME) is increasingly being adopted for many cancer types. Investigation into immune phenotype composition of the TME is at present lacking for malignant pleural mesothelioma (MPM) but critically important in light of the cancer’s overall poor prognosis and lack of targeted therapy as clinical standard of care. In this study, CD8+ve tumour infiltrating lymphocyte (TIL) level has been used as a starting point to compare differences in mutational patterns, histology and survival in MPM.
Method
Bulk RNA sequencing of tumour tissue from 35 MPM patients (in-house cohort) was performed. Sequencing read alignment and gene count estimation were performed using STAR (v.2.5.2b). To increase the sample size, raw data from Bueno et al. (n=211 subjects) was accessed and gene count estimations performed. In addition, the TCGA-MESO cohort (n=86 subjects) count data was included from the GDC (Genomic Data Commons) website. All count data were normalized cohort-wise using the ‘voom’ method implemented in limma package. Deconvolution of constituent immune phenotypes in the TME from the bulk RNA-sequencing data was performed by applying CIBERSORT (v.1.04) on normalized count data sets. For assessing the genetic context of observed immune phenotypes, somatic mutations were profiled using targeted sequencing of a custom gene panel for the in-house cohort. For the Bueno et al. and the TCGA-MESO cohorts, somatic mutations were either available from an overlap of whole-exome sequencing (WES) and targeted gene panel, or from WES only.
Result
A total of 27 samples (3 of 35 (8.6%), 21 of 211 (9.9%) and 3 of 86 (3.5%) from the in-house, Bueno et al. and TCGA-MESO cohorts respectively) were identified with immune phenotype enriched for CD8+ve TIL. Histological subtype distribution in the CD8+ve enriched samples was seen to be almost equivalently split between Epithelioid and Biphasic subtypes (51.85% and 48.15% respectively). Interestingly, BAP1 mutation was found to be present in only 7.7% of the samples. Considering in addition the genes NF2, SETD2, SETD6, SETDB1, TP53 and LATS1/2, mutations were only found to be present in 57.7% of the samples in total. As such >40% of samples with CD8+ve TIL do not have any mutations detected in known hotspot genes for MPM. Histological subtype is not significantly different between these ‘wild-type’ and hotspot gene(s) mutated samples. Median survival for the groups was found to be 1.85 and 0.73 years respectively.
Conclusion
In the present study, approximately 3-10% of MPM samples were found to have enrichment for CD8+ve TIL. Nonetheless on closer examination of the genetic context, mutation patterns emerge that warrant further investigation. For samples that have TP53 (n=3) mutation or mutations in multiple hotspot genes (BAP1, NF2, SETD2, LATS2; n=1), survival understandably is lowest (0.27 years average). This raises a number of further questions including what sustains a tumour despite high CD8+ve TIL population? And more importantly with lack of tumour mutational burden what other TME signals draw effector immune cells? Further investigations, by comparing additional immune markers with copy number changes that might be present in hotspot genes, are therefore required.
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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
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-124 - Health-Related Quality of Life (HRQoL) Data in a Phase 3 Study of First-Line Brigatinib vs Crizotinib in NSCLC (ALTA-1L) (ID 507)
09:45 - 18:00 | Author(s): Sanjay Popat
- Abstract
Background
Results from ALTA-1L (NCT02737501) showed that brigatinib vs crizotinib as first-line ALK therapy significantly improves progression-free survival (PFS; HR: 0.49, 95% CI, 0.33, 0.74) in advanced ALK+ NSCLC. HRQoL was evaluated as a secondary objective.
Method
ALK+ NSCLC patients were randomized 1:1 to brigatinib or crizotinib as first-line ALK therapy. HRQoL was assessed with the EORTC QLQ-C30 and LC13. Change from baseline, duration of improvement, and time to worsening were analyzed in the ITT-PRO population (n=131 for both groups).
Result
HRQoL compliance was >90% for both groups. Brigatinib substantially improved overall HRQoL vs crizotinib, as demonstrated by the estimated mean difference on change from baseline (4.1, P<0.05; Figure 1) and duration of improvement for GHS/QoL (HR=0.16, P<0.001; Figure 2), which was also supported by improvement in several functional domains and symptoms (Figure 1). No domains significantly favored crizotinib. Similar results were also observed in patients with baseline CNS metastases.
Conclusion
Consistent with the prolongation of PFS seen in first-line treatment of advanced ALK+ NSCLC, brigatinib improved HRQoL and prolonged the duration of improvement in GHS/QoL, and the majority of functional and symptom domains vs crizotinib.
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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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P1.04-63 - Correlation of Mutations in TP53, CDKN2A and PIK3CA with VISTA Expression in Pleomorphic Lung Carcinoma (ID 2248)
09:45 - 18:00 | Author(s): Sanjay Popat
- Abstract
Background
Pleomorphic Lung Carcinoma (PC) is a rare subtype of NSCLC poorly responsive to systemic therapy. VISTA is an immune checkpoint that negatively regulates T-cells and offers an alternative therapeutic approach to immune checkpoint manipulation. It has increased expression in the tumour microenvironment. We aimed to identify the genomic associations of PC with VISTA immunohistochemistry (IHC) expression and establish its correlation with PD-L1 IHC expression.
Method
Histopathological assessment and diagnosis was confirmed for 42 cases of resected PCs from the Royal Brompton Hospital histopathology diagnostic archive. DNA was isolated and a targeted capture panel for next generation sequencing performed. Samples were stained with H&E to confirm diagnosis, VISTA (D1L2G) and PD-L1 (28-8) and scored as the proportion of positively stained cells. Normal lung acted as control.
Result
VISTA was increased in tumour infiltrating immune cells compared to background lung and tumour (median: 33% (0-85) vs. 0% (0-15); vs. 0% (0-11); P<0.001). VISTA was upregulated on infiltrating immune cells of cases with variants in TP53 (n=25, median 52.5% vs. 24% P=0.008) and CDKN2A (n=4, median 57.5% vs. 30%; P=0.068) but was reduced in cases with PIK3CA mutations (n=4; median 7% vs. 35%; P=0.029). There was no association of VISTA with PD-L1 expression (spearman rank: -0.19; P=0.22).
Figure 1: Percent of VISTA staining of immune cells according to tumour mutation
Conclusion
VISTA is raised in infiltrating immune cells of tumours with TP53 and CDKN2A mutations. This may suggest dampening of the immune reaction to tumours defective in cell cycle control. Conversely, tumours with PIK3CA mutations had reduced VISTA expression by infiltrating immune cells. VISTA and PD-L1 exhibited no association in their levels of expression and therefore offers a therapeutic opportunity.
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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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P1.06-08 - WDPM-Like but Not Cribriform as Secondary Growth Patterns Modify Survival in Epithelioid Malignant Pleural Mesothelioma (ID 1609)
09:45 - 18:00 | Author(s): Sanjay Popat
- Abstract
Background
The presence of well differentiated papillary mesothelioma (WDPM)- like and cribriform growth patterns in otherwise unequivocally invasive, tubulo-papillary-predominant epithelioid malignant pleural mesothelioma (MPM) is recognised in clinical practice, but their prognostic impact is largely uncertain. We hypothesise they modify prognosis as secondary patterns.
Method
We retrospectively reviewed the tubulo-papillary-predominant, invasive epithelioid MPM (n=269) as a subset of 614 consecutive epithelioid MPM diagnosed at our institution over a 15-year period. The diagnostic criteria for WDPM-like and cribriform patterns were inferred from those of canonical WDPM and lung adenocarcinoma. Survival analysis was performed using Kaplan-Meier method.
Result
We identified 10 cases of tubulo-papillary-predominant epithelioid exhibiting WDPM-like pattern, and one case being predominantly WDPM-like (Estimated incidence 4.1%). They are associated with significantly prolonged median overall survival (78.7 months vs. 18.0 months, p=0.001). On the other hand cribriform neither as predominant (n=9, 3.3%, p=0.672) or secondary growth patterns (n=46, 17.1%, p=0.952) achieved statistical significance in univariate setting compared with tubulo-papillary epithelioid MPM without such pattern.
Conclusion
We propose tubulo-papillary-predominant epithelioid MPM with WDPM-like features as a rare and favourable prognostic group. Further molecular analysis is planned. Cribriform pattern does not appear to be prognostically relevant. We recommend external validation of our findings for both growth patterns.
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P2.06 - Mesothelioma (ID 170)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Mesothelioma
- Presentations: 2
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.06-02 - Mesothelioma Stratified Therapy (MiST): A Phase IIA Umbrella Trial for Accelerating the Development of Precision Medicines (ID 2465)
10:15 - 18:15 | Author(s): Sanjay Popat
- Abstract
Background
There are currently no approved therapies for the treatment of relapsed mesothelioma. Recent advances in our understanding of inter-patient genomic heterogeneity, identification of potential drivers, and application of high throughput -omic technologies to clinical trial samples , has created opportunities to explore novel treatments in prospectively biomarker-enriched cohorts.
Method
MiST is a British Lung Foundation funded, University of Leicester sponsored multicentre national clinical trial. Patients (Pts) harbouring either pleural (any histological subtype) or peritoneal mesothelioma are eligible. Pts must have ECOG performance status 1 or 0, received prior standard chemotherapy and progressed from their last treatment (in any line). The study is designed in three stages. Stage 1 comprises prospective molecular profiling of the tumour suppressors BAP1, BRCA1, p16ink4A and the immune checkpoint inhibitor PDL1 (22C3), using automated immunohistochemistry. Stage 2: Patients meeting eligibility criteria are presently stratified into Arm 1: Rucaparib (PARP inhibitor) for BAP1 inactivated (cytoplasmic or loss of expression) /BRCA1 negative mesothelioma. Arm 2: Abemaciclib (CDK4/6 inhibitor) for p16ink4a negative tumour, Arm 3, Pembrolizumab (anti-PD1) and Bemcentinib (AXL) to patients without biomarker specification. Arm 4, Atezolizumab (anti-PDL1) and Avastin (anti-VEGF) for PDL1 positive MM. Further arms are in development. The primary endpoint is 12 week disease control (12wDCR), with the secondary endpoints, 24wDCR, response rate (modified RECIST1.1) and safety/tolerability. 12wDCR>50% will be considered worthy of further investigation. Stage 3: Genome wide somatic copy number analysis and transcriptomic analysis with in-silico deconvolution of immune cell infiltrates will be used to refine molecular correlates of response. Gut microbiome 16RNA sequencing will be conducted in arms 3 and 4. Patients exhibiting a response to treatment who then progress, will be re-biopsied to facilitate molecular interrogation of acquired resistance mechanisms. MiST is coupled to our laboratory functional genomics programme, aimed at exploring co-clinical trial models, to robustly define or validate mechanisms that underpin drug responses.
Result
Section not applicable
Conclusion
In summary, MiST is a new clinical research platform that will support proof-of-concept studies capable of testing biomarker enrichment/efficacy hypotheses, with the aim of advancing personalised therapy for mesothelioma.
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P2.06-05 - Multimodality Therapy Using Total Pleurectomy in Malignant Pleural Mesothelioma: Long-Term Outcomes in 150 Consecutive Cases (Now Available) (ID 1441)
10:15 - 18:15 | Author(s): Sanjay Popat
- Abstract
Background
We wished to evaluate the long-term outcomes of patients receiving multimodality therapy including total pleurectomy/decortication, radiotherapy and systemic chemotherapy for malignant pleural mesothelioma.
Method
Retrospective analysis of patients treated between September 2004 and April 2019 by a specialised thoracic multidisciplinary team. Treatment involved total pleurectomy and decortication of lung, prophylactic radiotherapy (21 Gy in 3 fractions) and systemic chemotherapy based on pemetrexed and platinum. PET-CT was used routinely to diagnose disease recurrence or progression. Second or third-line therapies were administered when appropriate. Survival and prognostic factors were analysed by the Kaplan-Meier method and Cox regression analysis.
Result
150 patients had multimodality therapy over a 15-year period. Median age at operation was 62 years (range 32-82) and the male/female ratio was 122/28. Thirty-one patients (20.6%) had received chemotherapy before surgery. Thirty-three patients (22%) had extended resections. Sixty-two patients suffered a postoperative complication and 90-day mortality was nil. Eleven patients (7.3%) had reoperation within 30 days. Histological types were epithelioid in 105 patients and non-epithelioid in 45. Pathological stages were: I:86, II: 9, III: 54, and IV:1 (8th TNM classification). All patients but one received prophylactic radiotherapy. Six patients (4%) did not received systemic chemotherapy. Sixty-five patients (43.3%) received second-line or further systemic therapies. Five patients received stereotactic radiotherapy and three patients had late reoperation for focal tumour recurrence. Median survival was 30.5 months overall (95% CI 25.4-35.6), 34 months for epithelioid type (95% CI 25.8-42.2) and 18.3 months for non-epithelioid type (95% CI 14.2-22.4). Histological type and macroscopic complete resection were predictive of extended survival in our analysis.
Conclusion
Total Pleurectomy /Decortication is a safe and well-tolerated procedure associated with no mortality and acceptable morbidity. Most patients can receive prophylactic radiotherapy and systemic chemotherapy in due time. Many can receive second-line or further therapy on progression, resulting in prolonged survival.
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P2.14 - Targeted Therapy (ID 183)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.14-60 - Afatinib in EGFR Mutation-Positive NSCLC: Activity in Patients with Brain Metastases, and Impact on CNS Progression/Spread (ID 1664)
10:15 - 18:15 | Author(s): Sanjay Popat
- Abstract
Background
In the LUX-Lung 3 and 6 trials, first-line afatinib significantly improved progression-free survival (PFS) versus chemotherapy in patients with EGFR mutation-positive (EGFRm+) NSCLC and baseline brain metastases (hazard ratio [HR], 0.50; P=0.0297).1 In LUX-Lung 7, similar PFS improvement with afatinib versus gefitinib was observed in patients with, and without, brain metastases (HR, 0.76 and 0.74; Pint=0.93).2 The aims of this study were to assess: i) the impact of afatinib on central nervous system (CNS) progression or metastatic spread in LUX-Lung 3, 6, and 7; ii) efficacy of afatinib in patients with brain metastases in a similar setting to ‘real-world’ practice.
Method
Competing risk analysis of CNS/non-CNS progression or death was performed in patients who received afatinib in LUX-Lung 3, 6, and 7, based on the cumulative frequency of the event of interest versus the competing risk event. Separate analysis was performed of an Asian phase IIIb study, which assessed afatinib in a broad population of EGFR TKI-naïve patients with EGFRm+ NSCLC (NCT01953913).3 PFS and time-to-symptomatic progression (TTSP) in patients with baseline brain metastases were calculated by Kaplan–Meier methodology.
Result
In patients with baseline brain metastases receiving afatinib in LUX-Lung 3 and 6 (n=48; median follow-up: 10.3 months), the risk of CNS progression was 40% lower than the risk of extracranial progression; 31.3%/52.1% of patients had CNS/non-CNS progression, respectively. In patients without baseline brain metastases receiving afatinib in LUX-Lung 3, 6, and 7 (n=485; median follow-up: 13.0 months), the risk of de novo CNS/non-CNS progression was 6.4%/78.4%. Cumulative risk of CNS/non-CNS progression was 1.3%/17.2% at 6 months and 2.6%/41.2% at 12 months. In the Asian phase IIIb study, there was no difference in PFS (median 10.9 vs 12.4 months; P=0.18) or TTSP (median 14.8 vs 15.4 months; P=1.0) between patients with (n=92) or without (n=387) brain metastases.
Conclusion
Competing risk analyses of LUX-Lung 3, 6, and 7 suggest that afatinib delays the onset/progression of brain metastases. Real-world data are consistent with LUX-Lung 3, 6, and 7, and support the use of afatinib in patients with EGFRm+ NSCLC and baseline brain metastases.
1. Schuler, M. et al. J Thorac Oncol 2016;11:380‒90
2. Park, K. et al. Lancet Oncol 2016;17:577‒89
3. Wu YL, et al. J Thorac Oncol 2017;12(suppl 2):abstract P3.01-036
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PL02 - Presidential Symposium including Top 7 Rated Abstracts (ID 89)
- Event: WCLC 2019
- Type: Plenary Session
- Track:
- Presentations: 1
- Moderators:Giorgio Vittorio Scagliotti, Ramon Rami-Porta
- Coordinates: 9/09/2019, 08:00 - 10:15, Barcelona (2005)
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PL02.09 - National Lung Matrix Trial (NLMT): First Results from an Umbrella Phase II Trial in Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 2282)
08:00 - 10:15 | Author(s): Sanjay Popat
- Abstract
Background
Oncogene-addicted NSCLC can achieve substantial clinical benefit with single-agent targeted therapy. Seeking to extend this paradigm to other more genetically complex NSCLC, we report first results of NLMT, an umbrella phase II trial whereby a bespoke next-generation sequencing screening panel (Stratified Medicine Programme 2) stratifies NSCLC patients to rationally selected targeted therapies. Uniquely we present results across the entirety of the platform to enable an assessment of the potential to further stratify medicine in advanced NSCLC. Novel methodology is used to ensure that the integrity of this ongoing platform trial is not jeopardised.
Method
NLMT uses a Bayesian adaptive design to screen currently 8 targeted drugs for signals of activity in 22 molecularly defined cohorts. For single agents, pre-specified clinically relevant outcomes are either median progression-free survival (mPFS) >3 months or objective response rate (ORR) and/or durable clinical benefit rate at 24 weeks (DCBR) >30%. Target recruitment for each cohort is 30 with futility analyses at 15. Recruitment continues in 19 cohorts. We report posterior probabilities (PP) of a clinically relevant outcome for closed cohorts and Bayesian predictive probability of success (PPoS) given observed data for open cohorts. This novel approach provides insight into the drug-biomarker combinations that have the strongest potential for further research.
Result
Over a 4 year period to end of March 2019, NLMT has recruited 286 patients from >4000 screened. Of 6 palbociclib cohorts (all proficient Rb): mPFS in KRAS mutation (n=30) is 5.8 months (PP>0.99); CDKN2A loss/non-squamous (n=27) passed its interim analysis; we predict >75% PPoS, given current data, in CDKN2A loss/squamous (n=16) and CCND1 amplification (n=13). Data for crizotinib show >90% PPoS in ROS1 gene fusions (n=8) and MET exon 14 skipping mutation (n=8), with less clear signal for MET amplification (n=9). Responses to selumetinib/docetaxel in NF1 mutation (n=16) warrant continuation. Recruitment to vistusertib was halted at interim for LKB1 single mutation (ORR=0/15, PP=0.003; DCBR=1/15, PP=0.026), but DCBR in LKB1/KRAS double mutation (n=23) warrant continuation. 4 cohorts receive capivasertib (n=22): data in PIK3CA amplifications (n=9) indicate <15% PPoS.
Conclusion
These first results from the largest stratified medicine dataset in NSCLC indicate further molecular stratifications could benefit from targeted therapies. Reporting interim outputs for all cohorts will allow reappraisal of the global stratified medicine strategy in cancer.
