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Clarisse Audigier-Valette
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MA08 - Clinical Trials in Brain Metastases (ID 906)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 15:15 - 16:45, Room 203 BD
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MA08.09 - Impact of Brain Metastases in Immune Checkpoint Inhibitors (ICI) Treated Advanced Non-Small Cell Lung Cancer (NSCLC) Patients (ID 12575)
16:10 - 16:15 | Author(s): Clarisse Audigier-Valette
- Abstract
- Presentation
Background
Brain metastases (BM) are frequent in NSCLC. Unfortunately, patients with (untreated) BM are often excluded from ICI trials so that their outcome on ICI is largely unknown..
a9ded1e5ce5d75814730bb4caaf49419 Method
Retrospective data collection of all consecutive advanced ICI treated NSCLC patients in 6 centers (5 French, 1 Dutch) (nov 2012 – march 2018). Active BM was defined as non-irradiated new and/or growing lesions on brain imaging < 6 weeks before ICI start. Progression free survival (PFS), overall survival (OS) and site of progression on ICI was collected.
4c3880bb027f159e801041b1021e88e8 Result
945 patients included: 63% male, 83% WHO PS 0-1, median age 64 years, 73% non-squamous, 4% targetable driver mutations, 33% known PD-L1 (65% ≥1% expression). ICI treatment was median 2nd line (range 1-12), 94% had monotherapy PD-(L)1 inhibition. 241 patients (26%) had BM, 68% had previous cranial irradiation, 40% had active BM. BM patients were significantly younger than others (61 vs 66 years), had more adenocarcinoma (78 vs 62%), more organs involved (median 3 vs 2), a poorer PS (0-1: 76 vs 85%) and more steroids at baseline (26 vs 9%). Median follow-up: 15 months. Median (95% CI) PFS and OS without and with BM were 2 (2-3) vs 2 (1-2) months and 13 (9-16) vs 9 (7-13) months, respectively. In multivariate analysis, > 2 metastatic sites, PS ≥2 and steroids use were associated with worse PFS and OS, BM were not (table 1). In univariate analysis of BM patients, active BM were not associated with worse outcome compared to stable BM (HR PFS 0.98 (p=0.66), HR OS 0.93 (p=0.92)). Progressing BM patients had more often brain PD and a dissociated response (not specifically brain dissociated) on ICI (40 vs 12% and 13 vs 7%, respectively).
Factor PFS HR (95% CI) p-value OS HR (95% CI) p-value Age > 65 vs ≤ 65 1.02 (0.87-1.20) 0.79 1.11 (0.92-1.34) 0.29 Smoking yes vs no 0.53 (0.41-0.69) <0.001 0.81 (0.59-1.12) 0.20 Histology squamous vs adeno 1.07 (0.89-1.28) 0.78 1.24 (0.99-1.55) 0.12 Nr of organs with metastases > 2 vs ≤ 2 1.28 (1.09-1.50) 0.003 1.48 (1.22-1.80) <0.001 Immuno line > 2 vs ≤ 2 1.11 (0.94-1.30) 0.22 1.10 (0.91-1.33) 0.34 WHO PS 0-1 vs ≥2 2.14 (1.75-2.62) <0.001 3.48 (2.78-4.36) <0.001 Use of corticosteroids yes vs no 1.36 (1.10-1.69) 0.005 1.31 (1.03-1.68) 0.03 BM yes vs no 1.05 (0.88-1.26) 0.58 0.96 (0.77-1.19) 0.70
8eea62084ca7e541d918e823422bd82e Conclusion
BM, treated or active, do not negatively impact outcome on ICI although BM failure is more common in these patients.
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P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 3
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.01-66 - Randomized Phase II Evaluating EGFR-TKI Associated with Anti-Estrogen in Women with Non-Squamous Advanced Stage NSCLC: IFCT-1003 LADIE Trial. (ID 13740)
16:45 - 18:00 | Author(s): Clarisse Audigier-Valette
- Abstract
Background
The incidence of lung cancer is increasing dramatically in women with recent findings as the preferential involvement of the EGFR pathway and the potential impact of hormonal factors in women. Preclinical data have shown that the combination of an EGFR-TKI with an anti-estrogen could overcome resistance to EGFR-TKI.
a9ded1e5ce5d75814730bb4caaf49419 Method
IFCT-1003 LADIE Trial was a 2x2 arms parallel open-label randomized phase II trial. PS 0-2 post-menopausal women with advanced stage lung adenocarcinoma were treated with gefitinib (G 250 mg/day) vs. G + fulvestrant 500 mg / month with a supplementary dose at day 15 (G+F) in the EGFR mutated group (EGFR+) in 1st or 2nd line setting or with erlotinib (E 150 mg/day) vs. E + fulvestrant (E+F) in the EGFR wild-type group (EGFR WT) in 2nd or 3rd line setting until progression or unacceptable toxicity. Primary objective was progression-free survival (PFS) at 3 and 9 months for EGFR WT and EGFR+ patients, respectively.
4c3880bb027f159e801041b1021e88e8 Result
From 02/2012 to 03/2017, 204 pts (G 104, G+F 100) and 175 (E 87, E+F 88) were enrolled in the EGFR+ and EGFR WT cohorts respectively. The median number of fulvestrant injections was 10 in the G+F group and 3 in the E+F group. The tolerance was correct (grade 3/4: 24.2% in the G+F group vs 21.3% in the G group, 16.0% in the E+F group vs 13.8% in the E group) and no treatment-related death. In the EGFR+ cohort, the primary endpoint was reached as 54 pts in the G+F group were non-progressive at 9 months. Nevertheless, addition of F to G was not associated with significant better PFS (9.9 vs 10.1 months) or OS (22.1 vs 29.9 months). In the EGFR WT cohort, the primary endpoint was not reached as 29 patients were non-progressive at 3 months. Here also, addition of F to E was not associated with better outcome (PFS 1.8 vs 2.0 and OS 10.0 vs 7.3 months). No PFS difference was observed in the subgroup of patients with positive staining for REα.
8eea62084ca7e541d918e823422bd82e Conclusion
Addition of fulvestrant to EGFR-TKI is feasible and is associated with good PFS in the EGFR mutated group. Nevertheless, the lack of benefit associated with the combination of fulvestrant to EGFR-TKI does not support its future development in a phase 3 trial in women with NSCLC.
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P1.01-68 - Correlation of the Lung Immune Prognostic Index (LIPI) and PDL1 Status with Outcomes for Immune Checkpoint Inhibitors in Advanced NSCLC Patients (ID 14256)
16:45 - 18:00 | Author(s): Clarisse Audigier-Valette
- Abstract
Background
Baseline LIPI, based on derived NLR (neutrophils/[leucocytes-neutrophils]) and lactate dehydrogenase (LDH) was associated with outcomes for immune checkpoint inhibitors in advanced NSCLC patients. We assessed the correlation between LIPI and PDL1 for ICI outcomes in NSCLC.
a9ded1e5ce5d75814730bb4caaf49419 Method
Baseline dNLR and LDH and clinical data were retrospectively collected in advanced NSCLC patients, treated with PD1/PDL1 +/- CTLA4 inhibitors from Nov. 2012 to Mar. 2018, in a multicentric cohort (N=794) from 11 centers. LIPI stratified 3 groups: good (dNLR<3+LDH<upper limit of normal (ULN), intermediate (dNLR>3 or LDH>ULN), poor risk (dNLR>3+LDH>ULN). PDL1 positivity was defined as ≥ 1% tumor cells expression by immunohistochemistry.
4c3880bb027f159e801041b1021e88e8 Result
476 patients (60%) were male, 693 (87%) smokers, 695 (88%) had PS ≤1, with median age 65; 576 (73%) had nonsquamous histology. PDL1 was ≥ 1% in 195 (70%) patients, negative in 82 (30%), and unknown in 517. The median of prior lines was 1 (0-11). The median PFS and OS were 4 months (m) [95% CI 4-5] and 12 m [10-15]. dNLR was>3 in 276 (35%) and LDH>ULN in 290 (37%) patients. LIPI stratified 349 patients as good (44%), 323 (41%) as intermediate and 121 (15%) as poor LIPI risk groups. LIPI was an independent factor for OS (table) and PFS (HR 2.58; CI 1.3-5.2, P=0.02). ≥ 1% PDL1 and ≥ 50% PDL1 were not correlated with OS and PFS. Median OS for good, intermediate, and poor LIPI risk groups were 21 m [17-23], 11 m [9-14] and 4 m [2-6], respectively (P=<0.0001). Median PFS for good, intermediate, and poor risk was 5 m [5-7], 4 m [3-5], and 2 m [1-3], respectively (P=0.0005). No differences were observed in LIPI groups according to the PDL1 expression.
8eea62084ca7e541d918e823422bd82e ConclusionMultivariate analysis for OS
HR
95% CI
P value
Immunotherapy line
>2
2.117
0.641
6.992
0.219
N# Metastasis sites
≥2
1.242
0.727
2.121
0.428
Performance status
≥2
2.141
1.059
4.332
0.034
Albumin
>35 g/dL
0.867
0.507
1.48
0.6
LIPI
Intermediate
Poor
1.697
4.178
0.917
1.956
3.142
8.925
0.001
PDL1 IHC
≥1%
0.713
0.406
1.252
0.239
Baseline LIPI is associated with ICI outcomes in advanced NSCLC, regardless the PDL1 expression. LIPI should be evaluated in prospective clinical trials.
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P1.01-79 - CheckMate 817: Safety of Flat-Dose Nivolumab Plus Weight-Based Ipilimumab for the First-line (1L) Treatment of Advanced NSCLC (ID 12004)
16:45 - 18:00 | Author(s): Clarisse Audigier-Valette
- Abstract
Background
CheckMate 227 demonstrated significant, clinically meaningful progression-free survival benefit with 1L nivolumab 3 mg/kg every 2 weeks (Q2W) plus low-dose ipilimumab 1 mg/kg Q6W vs chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) and tumor mutational burden (TMB) ≥10 mutations/megabase. The dose and schedule for this combination regimen were optimized for 1L NSCLC in CheckMate 012 and further validated in CheckMate 568 and CheckMate 227. Flat dosing of nivolumab (240 mg Q2W) may simplify treatment while providing comparable exposure, and was recently approved for previously treated NSCLC. CheckMate 817 (NCT02869789) is a multi-cohort, open-label phase 3b/4 study evaluating the safety and efficacy of flat-dose nivolumab plus weight-based low-dose ipilimumab in recurrent/metastatic NSCLC. We report safety results from Cohort A, which evaluated this regimen in the 1L setting; updated results will be presented.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with ECOG PS ≤1 and previously untreated NSCLC were eligible, regardless of tumor programmed death ligand 1 (PD-L1) expression and TMB. Nivolumab 240 mg Q2W plus ipilimumab 1 mg/kg Q6W were administered for 2 years or until disease progression/unacceptable toxicity. The primary endpoint was safety assessed by the incidence of grade ≥3 select treatment-related adverse events (TRAEs; defined as AEs of potential immunologic causes).
4c3880bb027f159e801041b1021e88e8 Result
Enrollment occurred between October 2016 and August 2017, with 391 patients initiating treatment at 68 academic and community-based centers in Europe and North America. Median age was 65 years and 27.9% of patients had squamous histology. PD-L1 expression was evaluable in 91% of patients; of these, 50% had ≥1% tumor PD-L1 expression. At database lock (March 1, 2018), minimum follow-up was 5.4 months and 34.5% of patients remained on treatment. The median (range) number of nivolumab and ipilimumab doses received were 9 (1–28) and 3 (1–10), respectively. Any grade and grade 3–4 TRAEs occurred in 74.4% and 27.6% of patients, respectively; 14.1% of patients discontinued treatment due to TRAEs. Rates of any grade select TRAEs by category ranged from 1.3% (renal) to 28.4% (skin). The most common grade 3–4 select TRAEs by category were hepatic (4.6%), pulmonary (3.1%), and gastrointestinal (3.1%). Two treatment-related deaths were reported; one due to Guillain-Barré syndrome and one due to rhabdomyolysis leading to heart failure.
8eea62084ca7e541d918e823422bd82e Conclusion
The safety profile of flat-dose nivolumab plus low-dose ipilimumab was consistent with previous reports of weight-based nivolumab plus low-dose ipilimumab optimized for NSCLC. Toxicities were manageable with no new safety signals identified.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P3.03 - Biology (Not CME Accredited Session) (ID 969)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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P3.03-27 - Somatic BRCA1/2 Mutations in Advanced NSCLC Patients: Description of a Sub-Population from the Ongoing Unicancer SAFIR02-Lung / IFCT-1301 Trial (ID 13332)
12:00 - 13:30 | Author(s): Clarisse Audigier-Valette
- Abstract
Background
Molecular profiling is considered standard of care in advanced NSCLC. Identification of druggable molecular alterations may enhance the percentage of patients suitable for personalized treatment.
a9ded1e5ce5d75814730bb4caaf49419 Method
From 04/2014 to 03/2017, 602 newly diagnosed,advanced NSCLC patients (pts) were enrolled in SAFIR02-Lung trial (NCT02117167). Molecular profile provided information on copy number alterations and mutations on 71 oncogenes and tumor suppressor genes. The profile was performed for 420 pts (70%) on archival tissue or frozen tissue collected from a new biopsy performed before the 3rd cycle (tissue or liquid) of chemotherapy. The frequency of BRCA mutation (mut) was assessed and clinicopathologic data collected. A homologous recombinant deficiency (HRD) score was performed on the copy number variations (CNV) data and the germline status was based on blood analysis. The BRCAshare database was the reference for the variants classification.
4c3880bb027f159e801041b1021e88e8 Result
18 pts were identified with BRCA alterations. BRCA variants of unknown significance were detected in 11 pts (2.6%). Response to chemotherapy according to RECIST 1.1 by investigator was: 6 stable disease (SD), 1 partial response, and 4 progressive disease (PD). CNV profile was evaluable for HRD in 6 out of 11 pts, with 50% positive.
Seven pts (1.7%) were identified with deleterious BRCA-mut. 2 pts (0.5%) harboured germline BRCA2-mut (1 with breast cancer familiar history). Both pts had SD to chemotherapy. Somatic BRCA-mut was identified in 5 pts (1.2%, 2 BRCA1- and 3 BRCA2-mut). All were male, 100% adenocarcinoma, 75% smokers of 40 pack/year, 1 pt with familial cancer history, and 80% of pts had bone metastases. Response to chemotherapy was: 4 SD, and 1 PD. Three of 7 corresponding CNV profiles were evaluable for HRD score analysis with 100% positive.
8eea62084ca7e541d918e823422bd82e ConclusionN=420
BRCA alterations (N=18)
BRCA VUS
N=11
BRCA deleterious
N=7
Somatic
6
5
Germline
5
2
HRD positive- Somatic
Germline
3/6*
2
1
3/3*
3
0
VUS: variants of unknown significance
*Amongst patients with available samples for analysis
Pathogenic BRCA1/2 mutations occur in 1.7% of advanced NSCLC with 71% of somatic mutations suggesting its value for exploring new therapeutic strategies in this population
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