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Denis Moro-Sibilot
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EP1.14 - Targeted Therapy (ID 204)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.14-01 - Major Therapeutic Response to T-DM1 in Metastatic Lung Adenocarcinoma with HER2 Mutation (Now Available) (ID 1105)
08:00 - 18:00 | Author(s): Denis Moro-Sibilot
- Abstract
Background
The HER2 exon 20 mutation is described in 1-5% of patients with Non-small cell Lung cancer, and at the moment no targeted agents are approved in Europe. However, the use of conjugated antibodies such as trastuzumab and ado-trastuzumab emtansine (T-DM1) has shown promising results.
Method
We describe the case of a major response to T-DM1 in fourth line treatment in a patient with metastatic adenocarcinoma and HER2 mutation.
Result
A 60-year-old male, former smoker (3 packs/year), presented to the emergency room in 2016 for dyspnoea. A bilateral pleural and compressive pericardial effusion with tamponade requiring pericardial drainage were discovered. A lung adenocarcinoma with HER2 mutations was diagnosed. He benefited from two successive treatment lines between September 2016 and September 2017 (carboplatin- paclitaxel and bevacizumab followed by bevacizumab maintenance until progression, then pemetrexed for two cycles). At this time, he developed a new disease progression as a recurrence of tamponade requiring surgical drainage and a third line with docetaxel and trastuzumab was started for twelve cycles. After eight months, he presented an acute respiratory failure due to the recurrence of pericardial and pleural effusions, requiring a pleural drainage (Fig.1A). After discussion at the multidisciplinary meeting, a fourth line of treatment with T-DM1 in compassionate has been proposed. After three cycles, we observed an excellent clinical response, with disappearance of dyspnoea, resumption of normal daily activity. The radiological evolution was also very favourable (Fig.1B). The patient benefited from other six months of treatment before getting a new progression.
Conclusion
In this case T-DM1 showed a major clinical and radiological benefit despite its use in fourth line. Other clinical reports and phase II trials confirmed promising results with targeted agents already used in breast cancer. Several studies are exploring the efficacy of these agents, opening up new hopes.
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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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MA05.05 - Post-Discontinuation Treatments in IFCT-GFPC-0701 MAPS Trial: Real-World Effectiveness of 2nd-Line (2L) Treatments for Mesothelioma (Now Available) (ID 815)
13:30 - 15:00 | Author(s): Denis Moro-Sibilot
- Abstract
- Presentation
Background
MAPS phase 3 trial assessing the addition of bevacizumab to pemetrexed-cisplatin doublet set a new standard of care in malignant pleural mesothelioma (MPM) patients, showing 18.8 months median overall survival (OS) with triplet combo. While both arms were well balanced in terms of 2L treatments, the size of the OS benefit from second-line treatments remains controversial.
Method
Long-term survival data were collected in the 342 MAPS patients alive at the end of the first-line (1L) treatments, in both arms. Median OS and 2-year survivals were calculated from the initiation of 2L. Multivariate analysis using Cox model included the stratification variables of the MAPS trial, along with the treatment arm (with or without bevacizumab).
Result
342/442(77.4%) patients received 2L treatment for disease progression after MAPS trial, of which 324 received chemotherapy (CT), 18 palliative radiotherapy (RT), while 100/442 (22.6%) remained untreated. 160/342 patients (46.8%) had a platinum-based doublet CT. 163 patients (47.7%) received a single-drug CT. 172/324 (53.1%) received a pemetrexed-containing regimen (alone or with platinum), 84 (25.9%) a gemcitabine-based CT, 16 (4.9%) vinorelbin alone, 48 (14.8%) gemcitabine alone, while in 12 (3.7%) single-agent bevacizumab was resumed. Median age was lower in patients with doublet CT (64.4 years, IQR 60.2-68.9) vs. single-drug CT patients (66.3 years, IQR 61.5-70.3), patients receiving RT (68.5 years, IQR 63.3-70.5) or untreated patients (67.8 years, IQR 63.4-71) (p=0.007). There were more PS=2 patients (10%) in the untreated group, compared with 0.6%, 1.8% and 5.6% in those receiving doublet, monotherapy or radiotherapy, respectively (p<0.001). A lower proportion of patients receiving 2L doublet CT had sarcomatoid/biphasic MPM (11.2%) compared with 21.5%, 38.9% and 25% in those with single-arm agent, RT or untreated, respectively (p=0.002). When compared with those treated with 2L single-agent, patients with 2L doublet had more frequently objective response (11.9 vs. 3.1%, p=0.005) and disease control (60.3 vs. 34.6%, p<0.0001). From the date of 2L therapy initiation, median OS was 3.2 months, 95%CI [1.7-5.0] for RT vs. 7.0 months 95%CI[5.6-7.8] for single-agent CT, or 12.2 months 95%CI [9.5-14.1] for doublet CT. HRs were adjusted for 1L treatment type (bevacizumab-containing or not), PS, smoking, and histology. Adj.HR (single-agent vs. doublet) was 1.21, 95% CI(0.96-1.53), p=0.11. Adj.HR (monotherapy vs. RT) was 0.39, 95%CI[0.24-0.65], p=0.0003. Adj.HR (combination CT vs. RT) was 0.32 95%CI[0.19-0.54], p<0.0001. 1-year OS was 11.8%, 95%CI [0.0-27.1], 48.7%, 95%CI [39.9-57.5], and 32.9%, 95%CI [25.1-40.6], in patients with RT alone, single agent CT or combination CT, while 2-year OS was 0%, 14.2%, and 20.0% respectively.
Conclusion
Second-line monotherapy only gave a 7-months median OS in MPM patients, comparing unfavorably to 11.9 and 15.9-months median OS with 2nd/3rd-line nivolumab or nivolumab+ipilimumab respectively, in the IFCT-1501 MAPS-2 randomized phase 2 trial. Conversely, 2L platinum-based chemo, in younger fit patients, still gave a 12.2-months median OS, not statistically different from monotherapy in the multivariate analysis, as a consequence of PS influence, although clinically meaningful. Based on these results, immunotherapy might be preferred for 2L/3L MPM patients, while monotherapy CT shows limited survival benefit.
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MA07 - Clinical Questions and Potential Blood Markers for Immunotherapy (ID 125)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:David R Spigel, Roberto Ferrara
- Coordinates: 9/08/2019, 13:30 - 15:00, Vancouver (2003)
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MA07.05 - Immune Checkpoint Inhibitor (ICPi) Re-Challenge: Outcomes Analysis in a French National Cohort of Non-Small-Cell Lung Cancer (NSCLC) Patients (Now Available) (ID 1903)
13:30 - 15:00 | Author(s): Denis Moro-Sibilot
- Abstract
- Presentation
Background
Anti-PD1/PDL1 deeply changed the NSCLC therapeutic algorithm in the past few years. Unfortunately, a majority of patients experiences disease progression. ICPis re-challenge could be an attractive option but no data supporting this strategy are available. Here we report outcomes of a large cohort of NSCLC patients treated with anti-PD1/PDL1 re-challenge.
Method
We retrospectively collected data about 144 advanced NSCLC patients (diagnosis between 2010 and 2018) from 26 French centers. Patients were re-challenged with ICPis after at least 12 weeks of discontinuation for toxicity, disease progression or clinical decision. Progression Free Survival (PFS) and Overall Survival (OS) were calculated from the start of first or second ICPi to disease progression (PFS1;PFSR) and death or last follow-up (OS1;OS2) respectively.
Result
Median age was 63 year [39 –83], most of patients were male (67%), smokers (87%), adenocarcinomas (62%) and stage IV at diagnosis (66%). Most of patients received the first ICPi round in first or second line (66%) and the second ICPi round in third line or later (79%). In both settings patients received preferentially an anti-PD1 (87%) and no differences were detected regarding brain metastasis or ECOG PS (P = 1.10-1 and P = 1.10-1 respectively). The Best Response during the re-challenge was not associated to that one achieved to the first ICPi (P = 1.10-1). The median PFS1 and PFSR were 13 months [95% CI 10-16.5] and 4.4 months [95% CI 3-6.5] respectively. PFSR was longer in patients discontinued because of clinical decision (6.5 months [95% CI 2.5-11.9]) or toxicity (5.8 months [95%CI 3.5-18]) compared to disease progression (2.9 months [95% CI 2.0-4.4]) (P = 2.10-2) and in those not receiving chemotherapy between the two ICPis (5.8 months [95%CI 4.1-10.5]) compared to those who did (3.0 months [95% CI 2.0-4.4])(P = 2.10-3). Median OS1 was 3.3 years [95% CI 2.9-3.9] without differences according to the discontinuation reason (P =2.10-1). Median OS2 was 1.5 y [95%CI 1.0-2.1] and was longer in patients discontinuing the first ICPi due to toxicity (2.1y [95%CI 1.4-NR]) compared to disease progression (1.0y [95%CI 0.4-1.5]) or clinical decision (1.5y [95%CI 0.4-NR]) (P = 3.10-2). Neither OS1 nor OS2 were affected by treatments received between the two ICPis (P = 3.10-1 and P = 1.10-1 respectively).
Conclusion
ICPis re-challenge might be a useful option mainly in patients discontinuing the first ICPi because of toxicity or clinical decision and in those able to keep a treatment-free period between the two ICPis.
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P1.18 - Treatment of Locoregional Disease - NSCLC (ID 190)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment of Locoregional Disease - NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.18-01 - RELAY EU/US Subset: Ramucirumab Plus Erlotinib Improves Progression-Free Survival in First-Line EGFR Mutation-Positive NSCLC (Now Available) (ID 356)
09:45 - 18:00 | Author(s): Denis Moro-Sibilot
- Abstract
Background
Dual blockade of EGFR and VEGFR pathways in EGFR mutation-positive NSCLC augments anti-tumor efficacy versus EGFR inhibition alone. The RELAY (NCT02411448) phase 3 study demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for erlotinib plus ramucirumab versus erlotinib plus placebo in patients with previously untreated EGFR mutation-positive metastatic NSCLC (median PFS 19.4 vs 12.4mo, HR 0.591 (95% CI 0.461–0.760), p<0.0001). Here we report efficacy and safety data of the EU/US subset.
Method
Eligible patients (untreated, metastatic NSCLC with an EGFR exon 19 deletion or exon 21 (L858R) substitution mutation and no CNS metastasis) were randomized (1:1) to receive 150 mg daily oral erlotinib plus 10 mg/kg intravenous ramucirumab (RAM+ERL) or placebo (PL+ERL) Q2W until progressive disease or unacceptable toxicity. Patients were stratified by geographic region (East Asia vs ‘other’, i.e. EU/US). Primary endpoint was investigator-assessed PFS. Other key objectives included safety, ORR, DoR, PFS2, and OS.
Result
In the EU/US, 113 (25.2%) of 449 total patients (58 RAM+ERL, 55 PL+ERL) were randomized between Feb 2016-Feb 2018. Baseline characteristics were balanced between treatment arms: ~60% female, ~52% never-smokers and ~66% Ex19del. RAM+ERL improved PFS and had a longer DoR (Table). PFS2 and OS data were immature. Grade≥3 TEAEs occurring in >5% of patients included (RAM+ERL vs PL+ERL): hypertension (29.8% vs 7.3%), diarrhea (12.3% vs 1.8%), AST increased (7.0% vs 3.6%), ALT increased (7.0% vs 1.8%), dermatitis acneiform (5.3% vs 9.1%), fatigue (5.3% vs 0%), and rash (0% vs 5.5%).
Abbreviations: CI=confidence interval; DoR=duration of response; ERL=erlotinib; HR=hazard ratio; N=total population; n=total responders; NR=no response; ORR=overall response rate; OS=overall survival; PFS=progression-free survival; PL=placebo; RAM=ramucirumab RAM + ERL (N=58) PL + ERL (N=55) Unstratified HR (95% CI) p-value PFS Median, months (95% CI) 20.6 (14.7-26.0) 10.9 (8.3-19.4) 0.605 (0.362-1.010) 0.0523 Censoring rate
52% 38% ORR, % (95% CI)
74.1 (62.9-85.4) 76.4 (65.1-87.6) NA 0.8319 DoR, for responders only n=43 n=42 Median, months (95% CI) 18.0 (12.7-22.0) 10.0 (7.1-17.7) 0.527 (0.296-0.939) 0.0274 Censoring rate
54% 33% PFS2 Median, months (95% CI) NR NR 0.632 (0.304-1.313) 0.2143 Censoring rate 79% 67% OS Median, months (95% CI) NR NR 1.096 (0.465-2.582) 0.8344 Censoring rate 81% 82%
Conclusion
The EU/US subset analysis was consistent with the full ITT population where RAM+ERL demonstrated a statistically significant improvement in PFS over PL+ERL. Efficacy and tolerability were similar to that of the overall RELAY study population. Ramucirumab is an effective and safe addition to standard-of-care EGFR-TKI for treating EGFR mutation-positive metastatic NSCLC.
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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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P2.14-53 - High MET Overexpression Does Not Predict the Presence of MET Exon 14 Splice Mutations in NSCLC: Results from the IFCT Predict.amm Study (ID 2324)
10:15 - 18:15 | Author(s): Denis Moro-Sibilot
- Abstract
Background
MET exon 14 splice site (METex14) mutations were recently described in Non Small Cell Lung Cancer (NSCLC) and reported to correlate with efficacy of MET tyrosine kinase inhibitors. High diversity of these alterations make them hard to detect by DNA sequencing in clinical practice. Because METex14 mutations induce increased stabilization of the MET receptor, it is anticipated that these mutations are associated with MET overexpression. We aim to determine whether NSCLC with high MET overexpression could define a subset of patients with a high rate of METex14 mutations.
Method
From the IFCT Predict.amm cohort of 843 consecutive patients with a treatment-naïve advanced NSCLC who were eligible for a first-line therapy, 108 NSCLC samples with high MET overexpression defined by an immunochemistry (IHC) score 3+ were tested for METex14 mutations using fragment length analysis combined with optimized targeted next generation sequencing (NGS). MET copy number analysis was also derived from the sequencing data.
Result
METex14 mutations were detected in two patients (2.2%) who also displayed a TP53 mutation and a PIK3CA mutation, respectively. A MET gene copy number increase was observed in 7 additional patients (7.7%). NGS analysis revealed inactivating mutations in TP53 (52.7%) and PTEN (1.1%) and oncogenic mutations in KRAS (28.6%), EGFR (7.7%), PIK3CA (4.4%), BRAF (4.4%), NRAS (2.2%), GNAS (1.1%) and IDH1 (1.1%).
Conclusion
The rate of METex14 mutations in NSCLC with high MET overexpression was similar to that found in unselected NSCLC. Moreover, we observed a high frequency of driver alterations in other oncogenes. Consequently these findings do not support the use of MET IHC as a surrogate marker for METex14 mutations.
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P2.18 - Treatment of Locoregional Disease - NSCLC (ID 191)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment of Locoregional Disease - NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.18-10 - Importance of the Multidisciplinary Tumor Board in the Treatment Strategy of Stage III Non-Small Cell Lung Cancer (NSCLC) (Now Available) (ID 1107)
10:15 - 18:15 | Author(s): Denis Moro-Sibilot
- Abstract
Background
Stage III Non-Small Cell Lung Cancer (NSCLC) represents a heterogeneous population with different treatment strategies, often in combination. The PACIFIC trial is changing practices. It is therefore necessary to evaluate our current practices in order to identify the patients that should most likely receive this treatment after chemoradiotherapy
Method
A database constructed from our weekly multidisciplinary thoracic oncology meetings was retrospectively screened from 01/2010 to 01/2017. Consecutive patients with stages III NSCLC were included. We aimed to describe proposed treatment strategies and those really performed
Result
Of the 411 patients studied, 249 had a stage IIIA NSCLC and 162 a stage IIIB NSCLC. Median age was 65 years [IQR 25%-75%, 58-72], 309 (75%) patients were male. The majority of the patients (n=270, 69%, 20 missing data) had an ECOG-Performance status of 0 or 1. Regarding histology, 199 (48%) patients had an adenocarcinoma and 199 (48%) a squamous cell carcinoma. Treatment strategies are described in Table 1. Sixty-nine (17%) patients received exclusive chemoradiotherapy, and 60 (15%) were planned for neoadjuvant chemotherapy for subsequent surgery. Among these 60 patients, after the first cycles of the initial chemotherapy, only 37 (62%) received surgery in accordance with the multidisciplinary meeting decision; 6 (10%) received concurrent chemoradiotherapy and 6 (10%) sequential chemoradiotherapy.
Conclusion
In our cohort, 8% (32/411) of the stage III patients benefited from a chemoradiotherapy upfront. According to the PACIFIC study, these patients could receive adjuvant immunotherapy. We could ask if the patients planned for surgery after neoadjuvant chemotherapy should not be initially proposed for a concurrent chemoradiotherapy to give them the opportunity to receive adjuvant immunotherapy. Survival analyses according to treatment strategy are ongoing
