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Harry JM Groen
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OA04 - Immuno Combinations and the Role of TMB (ID 126)
- Event: WCLC 2019
- Type: Oral Session
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:Solange Peters, Martin Reck
- Coordinates: 9/08/2019, 15:15 - 16:45, Copenhagen (1980)
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OA04.02 - CheckMate 817: First-Line Nivolumab + Ipilimumab in Patients with ECOG PS 2 and Other Special Populations with Advanced NSCLC (Now Available) (ID 1876)
15:15 - 16:45 | Author(s): Harry JM Groen
- Abstract
- Presentation
Background
Data are limited for immunotherapy in patients with advanced NSCLC and poor performance status or other comorbidities. CheckMate 817 is a multi-cohort, open-label phase 3b/4 study investigating safety and efficacy of flat-dose nivolumab plus weight-based low-dose ipilimumab in advanced NSCLC. Here we evaluate this regimen as first-line treatment in special populations (cohort A1) and a reference population (cohort A; previously reported).
Method
Patients had previously untreated advanced NSCLC. Cohort A1 (n=198) had ECOG PS 2 or ECOG PS 0–1 with 1 of: asymptomatic untreated brain metastases, hepatic or renal impairment, or HIV. Cohort A (n=391) had ECOG PS 0–1. Patients with known EGFR mutations or ALK translocations sensitive to available targeted therapy were excluded from both cohorts. Nivolumab 240 mg Q2W plus ipilimumab 1 mg/kg Q6W was administered for two years or until disease progression/unacceptable toxicity. Safety and efficacy endpoints were assessed; cohort A1 analyses were exploratory.
Result
Cohort A1 patients were grouped as: ECOG PS 2 (n=139) and all other special populations (AOSP; n=59). Baseline characteristics were generally balanced between cohorts. Rates of grade 3–4 treatment-related adverse events (TRAEs) were similar between cohorts; within cohort A1, grade 3–4 TRAEs were numerically higher in AOSP versus the ECOG PS 2 subgroup; TRAEs leading to discontinuation were similar across populations (Table). ORR was 25% in cohort A1 (patients with ECOG PS 2, 20%; AOSP, 37%) and 35% in cohort A. PFS was numerically shorter in cohort A1 than cohort A; high TMB (≥10 mut/Mb) and higher PD-L1 expression (≥1% or ≥50%) were associated with numerically longer PFS in both cohorts (Table).
Conclusion
First-line flat-dose nivolumab plus weight-based ipilimumab showed a consistent safety profile in special populations with advanced NSCLC, including those with ECOG PS 2. Patients with either high TMB or higher tumor PD-L1 expression appeared to exhibit improved efficacy.
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OA12 - Profiling the Multidisciplinary Management of Stage III NSCLC (ID 144)
- Event: WCLC 2019
- Type: Oral Session
- Track: Treatment of Locoregional Disease - NSCLC
- Presentations: 1
- Now Available
- Moderators:Dirk De Ruysscher, Bartomeu Massuti
- Coordinates: 9/09/2019, 15:45 - 17:15, Seoul (2007)
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OA12.01 - PCI for Radically Treated Non-Small Cell Lung Cancer: A Meta-Analysis Using Updated Individual Patient Data of Randomized Trials (Now Available) (ID 2624)
15:45 - 17:15 | Author(s): Harry JM Groen
- Abstract
- Presentation
Background
In localized non-small cell lung cancer (NSCLC), prophylactic cranial irradiation (PCI) reduced the incidence of brain metastases (BM) (relative risk 0.35), but without a demonstrated effect on overall survival (OS). This may be due to the small sample size in these individual randomized clinical trials (RCTs).
Therefore, we aimed to assess the impact of PCI on long term OS for radically treated stage III NSCLC patients compared to observation using updated individual patient data (IPD) from RCTs.
Method
The main endpoint was OS and secondary endpoints were progression-free survival (PFS), BM-free survival (BMFS) and toxicity. All analyses were performed based on the intention-to-treat principle. The median follow-up was estimated using the inverse Kaplan-Meier method. The log-rank observed minus expected number of events and its variance were used to calculate individual and overall pooled hazard ratios (HRs) and 95% confidence intervals (95% CIs) with a fixed effects model. Heterogeneity was studied using the Cochrane test and I2. Survival curves and 5-year difference between arms were estimated using the Peto method. Interaction between prognostic factors (age, performance status, and histology) and treatment allocation were assessed using Cox proportional hazards models. Toxicities grade ≥ 3 were reported descriptively.
Result
Data on four of the seven eligible trials (SWOG 8300, RTOG 0214, Guangzhou 2005 and NVALT-11) were available for this IPD meta-analysis. In total, 924 patients were analyzed of which 68% was male, median age was 61 years, 94% of the patients had a performance status ≤ 1 and 37% had squamous histology. The median follow-up was 8.1 years. All trials provided sufficient IPD for the three endpoints, except for the SWOG 8300 trial (OS only). This trial explained inter-trial heterogeneity. Because of the qualitative interaction with the other trials (p=0.0062) it was separately analyzed (N=254). Compared to observation, OS was significantly lower for PCI in the SWOG 8300 trial (HR 1.38, 95% CI [1.07 to 1.79] p=0.013, 5-year absolute difference -0.9%, 95% CI [-5.9 to 4.1]). However, for the other trials (N=670) no significant OS difference was observed (HR 0.90, 95% CI [0.76 to 1.07] p=0.228, 5-year absolute difference 1.8%, 95% CI [-5.2 to 8.8]). PFS (HR 0.78, 95% CI [0.65 to 0.92] p=0.004, 5-year absolute difference 4.8%, 95% CI [-1.2 to 10.8]) and BMFS (0.38, 95% CI [0.27 to 0.53] p<0.001, 5-year absolute difference 20.7%, 95% CI [12.2 to 29.2]) were significantly higher in the PCI arm. There was no interaction between prognostic factors and treatment allocation for OS. Toxicity data for the PCI arm was available in all trials except the SWOG 8300 trial. The total number of patients with at least one grade ≥3 toxicity (for the adverse events pre-specified in the protocol) in the PCI arm was 19/456, including 11/86 in the NVALT-11 trial. Toxicity for the observation arm was only available in the NVALT-11 trial, including 4/88 patients with at least one grade ≥3 toxicity.
Conclusion
Although PFS and BM-free survival were improved for patients who received PCI, no significant PCI benefit for OS was observed.
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P1.11 - Screening and Early Detection (ID 177)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.11-27 - Computed Tomography Screening for Early Lung Cancer, COPD and Cardiovascular Disease in Shanghai: Rationale and Design of a Population-Based Comparative Study (ID 1863)
09:45 - 18:00 | Author(s): Harry JM Groen
- Abstract
Background
Volume-based management for lung nodules is associated with a lower rate of unnecessary referral for further work up as compared to diameter-based management in European population. Screening for chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD), in addition to lung cancer, may significantly increase the benefits of lung cancer low-dose computed tomography (CT) screening. While this is unclear in Chinese population. The aim of this study is to assess the diagnostic performance of volume-based lung nodule management for lung cancer CT screening as compared to diameter-based management, and to improve the effectiveness of CT screening for COPD and CVD based on quantitative measurement of CT imaging biomarkers in a Chinese screening setting.
Method
A comparative population-based study is ongoing, that will include 10,000 asymptomatic participants between 40 and 74 years old from Shanghai urban population in China.
Result
Participants will be randomized into the intervention and control groups and will undergo a low-dose chest CT scan at baseline and one year after baseline. NELCIN-B3 protocol will be applied in the intervention group. It recommends management of detected solid and part-solid lung nodules based on the volume and volume doubling time (VDT) of a lung nodule. The imaging biomarkers for COPD and CVD, such as emphysema score, bronchial wall thickness from inspiratory and expiratory chest CT scan, and coronary calcium score from ECG-triggered cardiac CT scan will be evaluated. In addition data on laboratory parameters and lung function test will be collected. The participants in the control group will be managed according to the standard hospital protocol based on visual assessment of the CT images. It recommends management of detected lung nodules based on the diameter according to the NCCN Clinical Practice Guideline in Oncology for Lung Cancer Screening. Epidemiological data (eg., risk factors) will be collected through questionnaires for all participants. Four years after the initial assessment the incidence of the three diseases will be evaluated. The design is shown in Figure 1.
The unnecessary referral rate will be compared between the NELCIN-B3 and standard protocol for early detected lung nodules management. The effectiveness of quantitative measurement of CT imaging biomarkers for early detection of lung cancer, COPD and CVD will be evaluated.
Conclusion
We expect that the quantitative assessment of the CT imaging biomarkers will reduce the number of unnecessary referrals for early detected lung nodules and improve the early detection of COPD and CVD in Chinese urban populations.
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P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-63 - Evaluation of Combined Biomarkers for Tumor Response to Immunotherapy (I/O) in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) (Now Available) (ID 1708)
10:15 - 18:15 | Author(s): Harry JM Groen
- Abstract
Background
Immune checkpoint inhibitors have revolutionized NSCLC treatment. At present, the only established predictive biomarker for I/O-therapy stratification are PD-L1 expression and MSI status. However, the expression of PD-L1 is limited by heterogeneous expression and even high expressors not always respond to I/O therapy. The aim of the study is to evaluate the value of combinations of positive (Tumor Mutational Burden, PD-L1) and negative (a.o. CD73 expression and inactivating STK11 mutations) predictive markers in patients (pts) with advanced NSCLC on I/O therapy.
Method
A retrospective study was performed on a cohort of 54 pts with advanced NSCLC that have been treated with I/O between 2015 and 2018. Pts were selected by the availability of tumor tissue and based on tumor response evaluated by RECIST v1.1 criteria: only patients with durable tumor response (CR,PR > 6 months) and patients with no tumor response (PD as best response) were analyzed for biomarkers: hybrid capture NGS assay for TMB (New Oncology) including STK11 mutations and IHC tests for PD-L1, CD73 and VISTA. Adjusted Cox regression and ROC analysis will be performed to evaluate the predictive value of the different biomarkers.
Result
43/54 pts received nivolumab, 11/54 pembrolizumab in different therapy lines (from 1st to 5th line). 24 pts were defined as having a durable tumor response (median PFS 20 months, median OS not reached) 30 pts as primary progressors (median PFS 2 months, p<0.0001), median OS 12 months, p<0.0001). In 30/54 pts enough material was available for TMB testing. The median TMB-value is 11.42 mutations/Mb. In 13 durable responders median TMB-value was 13.28 mutations/Mb versus 11.00 mutations/Mb in 17 primary non-responders. STK11 mutations were observed in 3/17 primary non-responders (10%) vs. 0/13 in durable responders (0%). Additional analyses of PD-L1, CD73, and VISTA will be presented at the meeting as well as correlative data of the parameters analysed.
Conclusion
Our results suggest that integrating several biomarkers including positive and negative predictive markers may correlate better with responses to I/O than PD-L1 and TMB alone.
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P2.10 - Prevention and Tobacco Control (ID 176)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Prevention and Tobacco Control
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.10-16 - Lung Cancer Occurrence Attributable to Passive Smoking Among Never Smokers in China: A Systematic Review and Meta-Analysis (ID 1946)
10:15 - 18:15 | Author(s): Harry JM Groen
- Abstract
Background
Quantifying lung cancer occurrence due to passive smoking is a necessary step for policy makers. The aim of this study is to estimate the proportion of lung cancer cases attributable to passive smoking among never smokers in China.
Method
A systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. We comprehensively searched six databases up to July 2019 for original observational studies in both English and Chinese languages. Studies that reported relative risks (RR) or odds ratios (OR) for lung cancer occurrence associated with passive smoking in Chinese never smokers were included. For each selected publication, two reviewers assessed publications in English and Chinese independently and assessed the quality of included studies using the Newcastle-Ottawa Scale (NOS). Any disagreements encountered were settled through a consensus. The population attributable fraction (PAF) was calculated using the combined proportion of lung cancer cases exposed to passive smoking and the pooled OR yielded from meta-analysis under the assumption of homogeneity.
Result
Thirty-one studies (all designed as case-control) were identified, comprising 9,614 cases and 13,093 controls. The overall proportion of lung cancer cases among never smokers attributable to passive smoking was estimated at 20.5% (95% CI: 16.0% - 24.7%), based on the proportion of lung cancer cases exposed to passive smoking (61.6%) and the pooled OR for passive smoking and lung cancer risk of 1.50 (95% CI: 1.35-1.76). ). The PAF was 15.5% (95%CI: 9.3%-21.0%) based on population-based studies and was 22.7% (95%CI: 16.6%-28.0%) based on hospital-based studies. The subgroup analysis (Table 1) showed that the PAF was similar in non-smoking men (20.9%) and women (21.3%). The proportion of lung cancer cases attributable to household passive smoking was much higher than workplace passive smoking (19.2% vs 10.5%).
Table 1 Population attributable fraction (PAF) of lung cancer caused by passive smoking among never smokers in subgroups subgroup
No. of studies
NOS score
cases
cases_
exposed
cases-exposed(%)
Pooled OR
95%CI
I2
P
PAF
95%CI
Study year
before 2000
13
6.23
2600
1639
63.04%
1.70
1.43-2.03
48.40%
0.025
25.96%
18.96% - 31.99%
after 2000
20
5.57
7000
4348
62.11%
1.50
1.31-1.72
67.60%
<0.001
20.70%
14.70% - 26.00%
Gender
men
9
6.22
809
473
58.47%
1.55
1.10-2.19
62.00%
0.007
20.75%
5.32% - 31.77%
women
26
5.77
7248
4803
66.27%
1.49
1.34-1.66
47.80%
0.004
21.79%
16.81% - 26.35%
Region
mainland
23
5.83
6468
3925
60.68%
1.55
1.35-1.79
67.60%
<0.001
21.53%
15.73% - 26.78%
non-mainland*
10
5.80
3132
2062
65.84%
1.61
1.36-1.90
49.00%
0.039
24.94%
17.43% - 31.19%
Exposure age
childhood/adulthood
5
6.40
1219
972
79.74%
1.50
1.14-1.96
52.70%
0.078
26.58%
9.79% - 39.06%
childhood
4
6.50
654
315
48.17%
1.50
1.08-2.10
43.30%
0.152
16.06%
3.57% - 25.23%
adulthood
5
6.60
835
517
61.92%
1.65
1.05-2.58
69.70%
0.010
24.39%
2.95% - 37.92%
Cancer type
all types
28
5.89
7642
4759
62.27%
1.62
1.44-1.82
59.80%
<0.001
23.83%
19.03% - 28.06%
adenocarcinoma
10
6.10
2485
1627
65.47%
1.52
1.20-1.91
67.80%
0.001
22.40%
10.91% - 31.19%
squamous cell carcinoma
3
6.67
101
57
56.44%
1.36
0.80-2.32
0.00%
0.400
14.94%
-14.11% - 32.11%
Publication language
EN
22
5.87
7082
4633
65.42%
1.40
1.27-1.54
35.40%
0.049
18.69%
13.91% - 22.94%
CN
11
5.72
2518
1354
53.77%
1.99
1.63-2.42
55.90%
0.012
26.75%
20.78% - 31.55%
Source of passive smoking
household/workplace
19
5.73
5183
3668
70.77%
1.70
1.46-1.99
72.20%
<0.001
29.14%
22.30% - 35.21%
household
7
6.14
1170
595
50.85%
1.67
1.32-2.10
41.40%
0.115
20.40%
12.33% - 26.64%
workplace
5
6.40
1178
245
20.80%
2.01
1.62-2.50
0.00%
0.514
10.45%
7.96% - 12.48%
Study setting
hospital-based
24
5.60
7428
4767
64.18%
1.67
1.47-1.9
68.50%
<0.001
25.75%
20.52% - 30.40%
population-based
9
6.44
2172
1220
56.17%
1.31
1.14-1.51
0.00%
0.464
13.29%
6.90% - 18.97%
Conclusion
Around 20% of lung cancer cases in never smokers, both men and women, are potentially attributable to passive smoking in China. These lung cancer cases in never smokers might be potentially prevented by eliminating exposure to passive smoking, in particular with regards to household passive smoking.
