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Nicolas Girard
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FP05 - Mesothelioma, Thymoma and Other Thoracic Malignancies (ID 135)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Mesothelioma, Thymoma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP05.04 - Outcomes of Resected Thymic Epithelial Tumors (TET), insights from RYTHMIC (ID 3693)
00:00 - 00:00 | Author(s): Nicolas Girard
- Abstract
Introduction
TET are rare malignancies, with an annual incidence of 350 cases in France. The main prognostic factors are Masaoka-koga stage and quality of the resection. However, no large cohorts have been published concerning resection outcomes. RYTHMIC (Réseau tumeurs THYMiques et Cancer) is a French network mandated to systematically discuss every case of TET. We aimed to describe the resected tumor outcomes in a large French population.
Methods
RYTHMIC database, hosted by IFCT (Intergroupe Francophone de Cancérologie Thoracique), prospectively includes all consecutive pts with a diagnosis of TET discussed in French national or regional tumor boards. We analyzed epidemiologic, clinical and pathological characteristics of 1045 pts operated of a TET.
Results
From January 2012 to December 2019, 2909 pts were included in the database. Overall, the median age at diagnosis of TET was 60 (range 9-90) and 52% (n=1513) were male. Of them, 1082 (37,2%) pts were operated. 304/1045 (29%) pts reported autoimmune disorders and Myasthenia Gravis was the most common (250 pts, 82,2%). Masaoka-Koga stages (MK) were well balanced with 23% (n=240) stage I, 17.2% (n=180) stage IIa, 18.2% (n=190) stage IIb, 19.6% (n=205) stage III with lung as a main invaded organ (37%), 8% (n=85) stage IVa and 4.9% (n=51) stage IVb. Among resected tumors, B2 and AB were the most common subtypes (n=247, 23.6% and n=237, 22.7% respectively).
Sternotomy was the most used approach for resection (n=735, 70.3%). In addition to TET, surgery was extended to lung (35%), pericardium (24%), pleura (13%), recurrent nerve or great vessels (10%) and lymph nodes (46%). Complete resection was assessed in 71% of procedures with a median tumor size of 55mm (1-260) and a range of 0-28 resected pleural metastasis. Intrapleural chemotherapy was used as an associated technique during the first-line surgery (6/17 pts) or after recurrence (9/17 pts, 53%) shrinking the hazard for progression (PD) (OR= 0.5 95%CI [0.29 to 0.84], p<0.00). Induction chemotherapy and adjuvant radiotherapy was administered in 119/182 (65,3%) and 357/1045 (34.2%) pts, respectively. Principal location for progression was the pleura (119/223 pts, 53%) with surgery as the main treatment (31%).
Median-OS was 263 months (95%CI[NotR-NotR]) and median-PFS was 111 months (95%CI[97,4-124,5]). The Cox proportional Hazard’s model showed a statistically significant greater risk for PD of MK III comparing with other localized tumors (HR=10,618 95%CI[1,172-96,224], p=0,036). Patients presenting thymoma B3 and epidermoid thymic carcinoma assessed risk for PD (HR=1,357 95%[0,531-3,462]; p=0,524 and HR= 1,982 95%CI[0,774-5,073]; p=0,154, respectively). Patients who needed lung or phrenic nerve resection showed higher risk for PD (HR=1,643 95%CI[1,181-2,286]; p=0,003 and HR=1,829 95%CI[1,217-2,748]; p=0,003, respectively). Bigger tumors and those with no complete resection (R1) were more likely to progress (HR=1,009 95%CI[1,004-1,013]; p<0,00 and HR=1,821 95%CI[1,058-3,133]; p=0,03, respectively).
Conclusion
Up to 37% of RYTHMIC cohort were resected. MK I and III were the most common resected tumors with 71% of complete resection with impact on survival. Thymic carcinoma and thymoma B3 were more likely to progress. Pleura was the main site for recurrence and surgery the most used treatment, in addition with intrapleural chemotherapy in some cases.
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FP07 - Pathology (ID 109)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP07.12 - Underdiagnosis of EGFR Exon 20 Insertion Mutation Variants: Estimates from NGS-based Real-World Datasets (ID 3399)
00:00 - 00:00 | Author(s): Nicolas Girard
- Abstract
- Presentation
Introduction
Exon 20 insertion mutations (Exon20ins) account for up to 10% of all mutations in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancers (NSCLCs). Exon20ins specific drugs are in development. Because Exon20ins are molecularly heterogenous, the ability to identify the range of variants is dependent on the test methods used. Real-time polymerase chain reaction (PCR) and next-generation sequencing (NGS) are two molecular tests widely used to identify mutations in the EGFR. We analyzed real-world genomic data to determine the frequency of Exon20ins variants and to assess the ability of PCR and NGS to comprehensively identify them.
Methods
Two US-based genomic databases were utilized for this analysis. NGS data from US institutions were extracted from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database, version 8.5 (The AACR Project GENIE Consortium. Cancer Discov. 2017;7(8):818-831). The FoundationInsights™ database (Foundation Medicine, Cambridge, MA) was used to obtain EGFR Exon20ins variants in real-world NSCLC samples. Coverage of Exon20ins from commercially available PCR tests (therascreen® and cobas®) was obtained from their instructions for use.
Results
The GENIE database included 12,497 patients with NSCLC. A total of 2,316 patients with EGFR mutant lung adenocarcinoma were identified and of these patients, 175 (7.6%) harbored Exon20ins. A total of 40 unique Exon20ins variants were identified. Of the 9 most common Exon20ins variants (≥5 patients), only 4 would have been identified at the protein level using commercially available PCR tests. PCR tests would have identified only 89 (50.9%) of the 175 patients with Exon20ins identified by NGS (Figure). The FoundationInsights™ database included 627 patients with lung adenocarcinomas who harbored Exon20ins and identified 102 unique Exon20ins variants. Of the 17 most common variants (≥5 patients), only 4 would have been identified at the protein level with commercially available PCR tests. PCR tests would have identified just 305 (48.6%) of the 627 patients with Exon20ins identified by NGS (Figure).
Conclusion
PCR methods are projected to miss 50% or more of Exon20ins. Reliance on commercially available PCR kit methods may provide insufficient information to support appropriate decision-making for emergent Exon20ins-directed therapies. The large number of insertion variants suggests that NGS platforms, academic or commercially available, would also improve their detection rate by capturing the full breadth of variants that have been identified.
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IS10 - Industry Symposium Sponsored by Bristol Myers Squibb: Thoracic Cancers, New Developments with IO (ID 287)
- Event: WCLC 2020
- Type: Industry Symposium
- Track:
- Presentations: 2
- Moderators:
- Coordinates: 1/29/2021, 13:00 - 14:00, Industry Symposia Auditorium (via Industry Hub)
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IS10.05 - What Is I-O’s Impact on the Treatment Paradigm for Mesothelioma Patients? (ID 4353)
13:00 - 14:00 | Presenting Author(s): Nicolas Girard
- Abstract
Abstract not provided
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IS10.06 - Mesothelioma Q&A and Closing Remarks (ID 4354)
13:00 - 14:00 | Presenting Author(s): Nicolas Girard
- Abstract
Abstract not provided
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MA04 - Health Policy and the Real World (ID 217)
- Event: WCLC 2020
- Type: Mini Oral
- Track: Health Services Research/Health Economics
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 16:45 - 17:45, Scientific Program Auditorium
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MA04.07 - Comparative Clinical Outcomes for Patients with NSCLC Harboring EGFR Exon 20 Insertion Mutations and Common EGFR Mutations (ID 3390)
16:45 - 17:45 | Presenting Author(s): Nicolas Girard
- Abstract
- Presentation
Introduction
Approximately 85–90% of the mutations seen in EGFR-mutant non-small cell lung cancers (NSCLCs) are common mutations (cEGFR), Exon 19 deletions and Exon 21 L858R. Up to 10% of EGFR-mutant NSCLC harbors Exon 20 insertion mutations (Exon20ins). We conducted a retrospective cohort study using real-world data to compare clinical outcomes between patients harboring Exon20ins and cEGFR.
Methods
This retrospective cohort study included patients from the Flatiron Health database (1 January 2011 through 31 May 2020) who had advanced NSCLC. The objectives of the study were to assess the prognostic value of Exon20ins compared with cEGFR (start date of first-line therapy as the index date) and the effect of tyrosine kinase inhibitor (TKI) treatment between the groups (start date of first TKI line as the index date). Analysis was stratified by line of TKI use. Endpoints included real-world overall survival (rwOS), progression-free survival (rwPFS), and time to next therapy (rwTTNT) and were analyzed using multivariable Cox proportional hazards model and summarized by Kaplan-Meier method.
Results
Among 62,464 patients with advanced NSCLC, 181 with Exon20ins and 2833 with cEGFR met eligibility criteria. Population demographics between the groups were comparable with minor exceptions. With median 34-month follow-up, Exon20ins was associated with a 75% increased risk of death (adjusted hazard ratio [adjHR] of 1.75 [95%CI, 1.45–2.13]; p˂0.0001); median rwOS was 16.23 (95%CI, 11.04–19.38) for Exon20ins and 25.49 months (95%CI, 24.48–27.04) for cEGFR (Table). The estimated 5-year survival rate for Exon20ins is 8% compared with 19% for cEGFR.
The predictive value of TKI treatment, stratified by line, was assessed in 76 Exon20ins and 2749 cEGFR patients who were treated with TKIs. With median 20.6-month follow-up, there was a 170% increase in risk of progression or death associated with Exon20ins (adjHR of 2.7 [95% CI, 2.06–3.55]; p˂0.0001); median rwPFS was 2.86 months (95%CI, 2.14–3.91) compared with 10.45 months (95%CI: 10.05–10.94) for cEGFR. Furthermore, there was a 170% increased risk of death (adjHR of 2.70 [95% CI, 2.04–3.57]; p˂0.0001) associated with Exon20ins; median rwOS was 7.46 months (95%CI, 5.45–13.34) for Exon20ins and 25.49 months (95%CI, 24.28–26.81) for cEGFR (Table).
Conclusion
Patients with Exon20ins have a worse prognosis compared with patients with cEGFR. Furthermore, EGFR TKI treatment was substantially less effective for patients with Exon20ins, as the risk of disease progression and mortality was higher compared with patients with cEGFR. These findings highlight the need for new treatment options for Exon20ins.
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OA04 - New Data from Rare EGFR Alterations (ID 223)
- Event: WCLC 2020
- Type: Oral
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 11:45 - 12:45, Scientific Program Auditorium
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OA04.04 - Amivantamab in Post-platinum EGFR Exon 20 Insertion Mutant Non-small Cell Lung Cancer (ID 3031)
11:45 - 12:45 | Author(s): Nicolas Girard
- Abstract
- Presentation
Introduction
Despite sharing similar tumor biology to other epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) tumors, no targeted therapies have been approved for NSCLC harboring EGFR Exon 20 insertion mutations (Exon20ins). The standard of care remains platinum-based chemotherapy for the front-line, with no clear subsequent options available. Amivantamab (JNJ-61186372) is a novel, fully human EGFR-MET bispecific antibody with immune cell-directing activity that targets activating and resistance EGFR mutations, as well as MET mutations and amplifications, and has received FDA Breakthrough Therapy Designation for the treatment of patients with EGFR Exon20ins NSCLC after platinum-based chemotherapy. Here we present updated results on the Exon20ins cohort from the CHRYSALIS study (NCT02609776).
Methods
The dose escalation phase enrolled patients with advanced NSCLC to determine the recommended phase 2 dose (RP2D) of 1050 mg (1400 mg for ≥80 kg) amivantamab. The dose expansion phase assessed the safety and efficacy of amivantamab in patients with EGFR- and MET-mutant NSCLC treated at the RP2D. Disease response was assessed by the investigator per RECIST v1.1 and is presented for those patients with Exon20ins NSCLC who had progressed on prior platinum-based chemotherapy, were treated at the RP2D, and had at least 3 post-baseline disease assessments (18 weeks) or discontinued, progressed, or died prior to the 3rd assessment (the Post-Platinum Cohort). The data cutoff date was 8 Jun 2020.
Results
In the Post-Platinum Cohort (n=81), median age was 62 (42 – 84), 59% were women, 49% were Asian, median prior lines of therapy was 2 (1 – 7), and 53% were never-smokers. At a median follow-up of 6.5 months (1.1 – 29.3), investigator-assessed overall response rate (ORR) was 36% (29/81; 95% CI, 25 – 47), with all responders achieving partial response (PR). The clinical benefit rate (≥PR or stable disease ≥11 weeks) was 73% (59/81; 95% CI, 62 – 82). Responses were durable at a median of 6.8 months (95% CI, 5.0 – not reached) with ongoing responses in 18/29 (longest at 16+ months). Median progression-free survival was 8.3 months (95% CI, 5.5 – 12.7) and median overall survival was 22.8 months (95% CI, 14.0 – not reached).
Among all phase 1 patients, across a variety of EGFR genomic alterations and lines of therapy, treated with amivantamab monotherapy at the RP2D (n=258), the most common adverse events (AEs) were rash (78%), infusion related reaction (IRR; 65%), and paronychia (40%). Additional EGFR-related AEs were stomatitis (19%), pruritus (19%), and diarrhea (11%). Grade ≥3 AEs were reported in 39% of patients; 14% were considered treatment-related, with rash (3%) and IRR (2%) being most frequent. No treatment-related deaths were reported. The incidence of treatment-related AEs leading to dose reduction and discontinuation was 10% and 3%, respectively.
Conclusion
Amivantamab treatment led to promising efficacy with durable responses in patients with EGFR Exon20ins NSCLC post-platinum doublet and continues to demonstrate a manageable safety profile in over 250 patients treated at the RP2D. A phase 3 study, PAPILLON, evaluating amivantamab in combination with chemotherapy in the front-line setting is in planning stages.
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OA09 - Mesothelioma from Pathogenesis to Therapy (ID 132)
- Event: WCLC 2020
- Type: Oral
- Track: Mesothelioma, Thymoma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 1/30/2021, 15:30 - 16:30, Scientific Program Auditorium
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OA09.03 - MESOMICS Project: Molecular Characterization of Malignant Pleural Mesothelioma Using a Multi-Omic Approach (ID 2235)
15:30 - 16:30 | Author(s): Nicolas Girard
- Abstract
- Presentation
Introduction
The MESOMICS project for the multi-omic characterization of Malignant Pleural Mesothelioma (MPM) belongs to the Rare Cancers Genomics initiative (www.rarecancersgenomics.com) aiming at providing a better understanding of the molecular characteristics of rare cancers, such as MPM. Taking advantage of the expertise provided by a multidisciplinary team, and by means of state-of-the-art computational analyses as well as exceptional bio-repositories, our research is focused on: (1) identifying the molecular characteristics that may inform the carcinogenesis and aetiology of MPM; (2) providing the necessary data to generate a more clinically relevant classification of tumours; and (3) improving clinical management by identifying and validating novel candidate diagnostic, prognostic, and predictive biomarkers.
Methods
We have generated whole-genome sequencing, RNA sequencing data, and EPIC 850k methylation arrays data for 124 MPM of the three main histological types (epithelioid, sarcomatoid, and biphasic) and subtypes (epithelioid morphological subtypes). In addition, we have generated multi-regional multi-omic data for 12 of the MPM epithelioid samples. We have performed in-depth characterization of genomes (single nucleotide variants, indels, copy number variants, and structural variants), transcriptomes (genes, transcripts, and fusion genes), and methylomes (methylation levels), as well as integrative analyses of the three 'omic layers, including unsupervised molecular classifications and supervised analyses of molecular subtypes.
Results
Analyses of whole-genome sequencing data for our series of 124 MPM samples uncovered frequent genomic rearrangements affecting, among others, BAP1 (Mangiante et al. In preparation). This suggests that BAP1 inactivation might be more frequent than initially estimated based on published whole-exome sequencing data (Bueno et al. Nat Genet 2016; TCGA Cancer Discov 2019). We also provide the first continuous integrative multi-omic classification of MPM, extending the continuous classifications recently proposed using expression data (Alcala et al. Ebiomedicine 2019; Blum et al. Nat Commun 2019); this classification reveals novel, specific copy number and methylation profiles associated with expression profiles and histological types. In addition, leveraging the information from whole-genome sequencing data, we provide the first large scale assessment of mutational signatures in MPM. We also perform the first fine-scale reconstruction of tumor evolution in MPM, shedding light into the events occurring during the long latency period of the disease by revealing the timing of alterations in MPM, and showing that histological type, survival, and molecular profiles are associated with the strength of natural selection acting on hallmarks of cancer genes. Finally, multi-omic integrative analyses of multi-region samples from 12 MPMs detected significant intra-tumour heterogeneity in the expression of immune checkpoints and pro-angiogenic genes, providing some biological insight on the modest and variable response to immunotherapy and anti-angiogenic drugs, respectively, observed in recent clinical trials.
Conclusion
Considerable progress has been made in recent years in the molecular characterization of MPM. However, the assumptions made in the analyses of the data and the limited whole-genome sequencing data generated have hampered the discovery of important findings for the clinical management of MPM. The MESOMICS project aims to fill these gaps to provide the missing pieces needed to tackle this aggressive disease.
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P84 - Targeted Therapy - Clinically Focused - ALK (ID 261)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P84.06 - Alectinib in ALK-Rearranged NSCLC Patients Following Crizotinib. Final Results and Biological Outcomes - Phase II ATALK Study (ID 3361)
00:00 - 00:00 | Author(s): Nicolas Girard
- Abstract
Introduction
Patients (pts) with advanced Anaplastic Lymphoma Kinase (ALK+) Non-Small Cell Lung Cancer (NSCLC) treated with crizotinib as first ALK inhibitor often develop acquired resistance during the 1st year of treatment. The ATALK study aimed at evaluating the efficacy and safety of alectinib, a 2nd generation ALK inhibitor, in selected pts with ALK-rearranged NSCLC, having progressed on prior treatment with crizotinib, without any supposed resistance mechanism to alectinib.
Methods
ATALK is an open-label, multicenter, single-arm, phase II study. Pts with ALK+ advanced or metastatic NSCLC progressing after crizotinib, whatever the line of treatment, received alectinib 600 mg twice daily until progressive disease (PD). Pts harbouring a mechanism suspected to confer resistance to alectinib (including selected ALK mutations, loss of ALK rearrangement, histological transformation) on a liquid or solid biopsy performed at inclusion were excluded. Pts were followed-up for 12 months.
The primary endpoint was the objective response rate (ORR) per investigator assessed from the Best Overall Response (BOR) using RECIST 1.1 within the 12 months following the first intake of alectinib.
Major secondary objectives were Progression-Free Survival (PFS), Overall Survival (OS), Disease Control Rate (DCR) and safety.
Results
Sixty four (64) pts were screened and 4 were excluded due to suspected resistance mechanisms to alectinib. A total of 44 pts were included (ITT/Safety population) and 39 pts had measurable disease at baseline (mITT population).
In the ITT population, 21 contributive fresh tumor tissue biopsies were obtained, all showed ALK rearrangement and absence of resistance mechanism to alectinib. Recruited pts were mostly men (57%), with a median age of 57 and an ECOG PS of 0-1 (89%)). Central nervous system (CNS) metastases were identified in 61% pts, of whom 16% had already been treated mainly with radiotherapy. All pts had ≥ 1 prior NSCLC therapy and 52% had received a 2nd therapy line; 11% had undergone ≥1 prior lung cancer surgery and 27 % ≥1 prior cancer radiotherapy.
In the mITT population, ORR was 51% (CI95%:34.8-67.6) and only 2 pts experienced a PD. The disease control rate was 94.9% (CI95%:82.7-99.4). In 11 pts with measurable CNS metastases at baseline, the CNS-ORR was 91% (CI95%:58.7-99.8).
In the ITT population, the median PFS was 14.4 months (9.2-NR). The OS rate at 12 months was 87.1% (71.6-94.4), median OS was not reached.
Efficacy outcomes regarding single nucleotide variants, ALK variants and ALK amplification are ongoing and will be presented later.
Grade ≥ 3 adverse events occurred in 34.1% pts, mainly respiratory disorders (13.6%) and cardiac disorders (6.8%). Death was reported in 11.4% pts, none was related to the treatment (pneumonia, stroke, general health deterioration, suffocation and ventricular dysfunction).
Conclusion
Alectinib efficacy and safety profile in this study align with known alectinib results in post-crizotinib setting. Identification of mechanisms of resistance emerging from exposure to previous ALK inhibitor was feasible and helped selecting subsequent treatment options.
