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Yun Fan
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OA 06 - Global Tobacco Control and Epidemiology I (ID 662)
- Event: WCLC 2017
- Type: Oral
- Track: Epidemiology/Primary Prevention/Tobacco Control and Cessation
- Presentations: 9
- Moderators:G. Kovács, Yun Fan
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 511 + 512
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OA 06.01 - Costs and Cost-Effectiveness of Smoking Cessation Within an Organized CT Lung Cancer (LC) Screening Program (ID 9642)
15:45 - 15:55 | Presenting Author(s): William Kenneth Evans | Author(s): C. Gauvreau, W. Flanagan, S. Memon, N. Fitzgerald, John R Goffin, A. Miller
- Abstract
- Presentation
Background:
Low-dose CT (LDCT) screening of smokers at high risk of developing lung cancer has been shown to reduce LC-specific and overall mortality. A retrospective analysis of the National Lung Screening Trial (NLST) data suggests that smoking cessation contributed to the mortality reduction. Pilot LDCT screening programs are being implemented in Ontario with smoking cessation integrated. The Canadian Partnership Against Cancer with Statistics Canada have developed a microsimulation model (OncoSim-LC, version 2.5) that projects the impact of cancer control measures on LC incidence, mortality and cost. Assuming that each annual visit for LDCT is a teachable moment to promote smoking cessation, we have modelled the potential cost and cost-effectiveness of integrating cessation into an organized screening program.
Method:
OncoSim-LC incorporates Canadian demographic characteristics, risk factors, cancer management approaches and outcomes and resource utilization to assess clinical, economic and healthcare system impacts. We compare a base case of organized screening with no cessation to various scenarios of screening with cessation. Modelling assumptions included: annual screening of 55-74 year olds with 30+ pack year smoking history, target participation rate reached over 10 years; one cessation intervention (nicotine replacement therapy + varenicline + 12 weeks of counselling) costs $490; up to 10 cessation attempts per eligible individual dependent on screening encounters; a permanent quit rate of 5% per cessation attempt. Cost-effectiveness was estimated with a lifetime horizon, health system perspective and 1.5% discount rate. Costs are in 2016 CAD.
Result:
Cessation within a screening program with 60% recruitment and 70% rescreening (adherence) would cost approximately $76 million (undiscounted) per year for 2017-2036 or 8% of the total cost of screening, treatment and cessation. Compared to screening with no cessation, approximately 110 fewer incident cases and 50 fewer lung cancer deaths would occur on average per year for 2017-2036 and cost $14,000/QALY (lifetime horizon). 90% recruitment and 80% rescreening would result in 260 fewer deaths and cost of $24,000/QALY. At a doubled permanent quit rate of 10%, screening with cessation would cost $6,000/QALY. A 50% increase in the cost of the cessation intervention would decrease cost-effectiveness to $22,000/QALY.
Conclusion:
Based on the OncoSim-LC model, a cessation program within an organized LDCT screening program would cost well under $50,000/QALY even over multiple quit attempts. Integrating robust smoking cession initiatives within a LDCT screening program could save lives and be relatively cost-effective.
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OA 06.02 - Final Report of the INHERIT EGFR Study - 33 Unrelated Kindreds Carrying Germline EGFR Mutations (ID 9370)
15:55 - 16:05 | Presenting Author(s): Geoffrey R. Oxnard | Author(s): J.C. Heng, R. Chen, D.R. Koeller, K. Shane-Carson, R.H. Morgan, G.L. Wiesner, J.E. Garber
- Abstract
- Presentation
Background:
Anecdotal reports of families carrying germline EGFR mutations force us to reconsider our understanding of inherited lung cancer risk in non-smokers. We launched this prospective trial (NCT01754025; ALCMI-002) to remotely enroll and characterize these rare families.
Method:
Eligible subjects were recruited at participating cancer centers or through an online referral system. Following consent (in person or by phone), subjects received genetic counseling and sequencing of saliva or blood for germline EGFR mutations. Cancer specimens and CT scans were additionally analyzed when available.
Result:
Between 12/2012-6/2017, 105 participants were enrolled from 30 US states. Germline EGFR mutations were found in 63% of patients (31 of 49) with EGFR T790M in their lung cancer at diagnosis, and in 62% (16 of 27) and 44% (4 of 9) of first- and second-degree relatives of germline carriers. Pedigrees were available for 32 unrelated kindreds (31 germline T790M, 1 germline R776H): 4 with no family history of lung cancer, 8 with a family history of lung cancer in non-smokers, 18 with multiple relatives with lung cancer. Characteristics of 31 lung cancer probands: median age of lung cancer diagnosis was 57 (range 28-82); 81% white, 19% black; 52% never-smokers; 65% stage IV at diagnosis; 65% were from states in or bordering the US Southeast. Tumor genotyping revealed somatic EGFR co-mutations in 29 (94%) of probands: 6 exon 19 del, 12 L858R, 6 G719X, 1 exon 19 del & G719R, 1 L861Q, 2 H773R, 1 V774M. Imaging analysis suggests a unique pattern of cancer evolution including an indolent multi-focal nodular phase which then progresses to lymph nodes and then remote metastatic disease. Of 8 probands with sensitizing EGFR co-mutations treated with osimertinib, no unexpected toxicities were seen, and 4 have had durable benefit exceeding 12 months. Of 9 relatives with germline EGFR mutations and CT imaging available, 2 have a lung cancer diagnosis and 6 others have lung nodules.
Conclusion:
This study confirms the high likelihood of a germline mutation in lung cancer patients with EGFR T790M detected at diagnosis, and suggests a risk of lung nodules and lung cancer in germline carriers. The regional enrichment in the US Southeast suggests a possible founder effect; haplotyping is planned. A registry is under development to continue follow-up of these rare individuals. Further investigation of germline risk alleles associated with lung cancer risk in non-smokers is needed. Funding: Bonnie J. Addario Lung Cancer Foundation, Conquer Cancer Foundation of ASCO.
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OA 06.03 - Comorbidity and Competing Causes of Death attenuate outcomes in the NLST. (ID 8606)
16:05 - 16:15 | Presenting Author(s): Robert P Young | Author(s): Raewyn J Hopkins, G.D. Gamble
- Abstract
- Presentation
Background:
In the National Lung Screening Trial (NLST), annual CT screening reduced lung cancer-specific mortality by 20% and all-cause mortality by 7% relative to chest x-ray (CXR) screening. However, in contrast to other screening approaches, recommendations for CT screening for lung cancer is limited to older heavy smokers, where the risk of death from all smoking-related complications is high, relative to the unscreened population. In the NLST, airflow limitation affects 35% of screening participants and is associated with a 2-4 fold increase risk of lung cancer. We have recently shown that for screening participants with COPD, the reduction in lung cancer-specific mortality with CT screening is only half that seen in those with no COPD (15% vs 28%). We hypothesise that this reduction is due in part to a “competing cause of death” effect.
Method:
Using 10,054 subjects from the ACRIN-NLST sub-study, the current study aimed to compare disease-specific mortality according to the severity of airflow limitation at baseline to better understand it’s relationship with dying of lung cancer and dying of other smoking-related diseases. We also examined this relationship according to baseline risk of lung cancer, using the Brock (Lung cancer risk) Model, and outcomes from screening.
Result:
After 6.4 years of follow-up, there were 699 deaths; 189 (27%) attributed to lung cancer, 166 (24%) to cardiovascular disease, 61 (9%) to respiratory disease and 150 (21%) to other cancers. After stratifying the 10,054 subjects according to severity of airflow limitation (baseline FEV1%predicted and GOLD grade), we found that the risk of dying of lung cancer and risk of dying of other diseases diverged favouring a stronger relationship with non-lung cancer causes. After stratifying the 10,054 subjects according to their risk of lung cancer (tertiles), we found that CT screening in those at highest risk (highest tertile) had only a 12% reduction in lung cancer-specific deaths compared to 23-24% in other lower risk tertiles. This was associated with higher deaths from cardiovascular disease, respiratory disease and other cancers.
Conclusion:
In a CT screening study, where smokers were followed for a mean of 6.4 years, we found worsening lung function and higher underlying risk for lung cancer was associated with a greater tendency to die of causes other than lung cancer. We suggest smokers at the greatest risk for lung cancer, and those with worse lung function, benefit less from CT screening due to a “competing cause of death” effect.
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OA 06.04 - Discussant - OA 06.01, OA 06.02, OA 06.03 (ID 10787)
16:15 - 16:30 | Presenting Author(s): Anthonie Van Der Wekken
- Abstract
- Presentation
Abstract not provided
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OA 06.05 - Socioeconomic Factors Affecting Outcomes in Non-Small Cell Lung Cancer (NSCLC): A Large Population-Based Analysis (ID 9049)
16:30 - 16:40 | Presenting Author(s): Yanyan Lou | Author(s): Bhagirathbhai Dholaria, A.E. Soyano, D. Hodge, S. Ailawadhi
- Abstract
- Presentation
Background:
Disparities exist in cancer outcomes. NSCLC outcomes have improved in recent years but effects of socioeconomic factors have not been reported.
Method:
The National Cancer Database with NSCLC incident cases between 2004-2013 was analyzed. Overall survival (OS) was explored by several available factors with a focus on race and socioeconomic factors.
Result:
A total of 1,150,722 NSCLC patients were included with majority White (86.4%) followed by Black (10.6%) and a smaller proportion of Asians and Hispanics. Patients were evenly distributed among income quartiles and majority were insured (96.7%), lived in a metro area (81.7%) and treated at non-academic facilities (68.5%). Overall median OS was 13.1 months and significantly better for Asians (18.2 months) and Hispanics (16.6 months) as compared to Whites (13.2 months) and Blacks (11.5 months). (Figure 1, p<0.001) Outcomes were worse with higher comorbidity score, TNM stage and treatment at community or high-volume facility. Socioeconomic factors other than race associated with worse outcome included lower education and median income, uninsured status and Central geographic region. (Table 1) Figure 1 Figure 2
Conclusion:
In this largest analysis thus far, patient race and socioeconomic factors were found to significantly influence NSCLC survival. These must be addressed for equitable healthcare benefit and outcomes.
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OA 06.06 - Chr15q25 Locus Confers Risk of Lung Cancer, COPD and Smoking: Triple Whammy Effect in the ACRIN NLST Sub-Study (N=9,270) (ID 8611)
16:40 - 16:50 | Presenting Author(s): Raewyn J Hopkins | Author(s): F. Duan, E. Greco, C. Chiles, G.D. Gamble, D.R. Aberle, Robert P Young
- Abstract
- Presentation
Background:
Several large genetic studies have consistently linked the cholinergic nicotinic receptor polymorphism (CHRNA3/5, rs 16969968) to lung cancer and smoking addiction. However, we have shown that this genetic variant was also independently associated with susceptibility to chronic obstructive pulmonary disease (COPD). To date this observation, independently linking CHRNA3/5 polymorphism to both COPD and lung cancer, has not been tested prospectively in a cohort study. Using 10,054 subjects from the ACRIN-NLST cohort, a sub-study of the NLST that recruited high risk smokers and followed them for an average of 6.4 years, we examined the association between the CHRNA3/5 variant in the development of lung cancer relative to its role in COPD and lifelong smoking exposure.
Method:
We compared the frequency of the high risk AA genotype in our cohort of 10,054 high risk smokers according to their smoking status, lung function and COPD status. We also compared the lung cancer incidence rate according to the CHRNA3/5 genotype. Lastly we used stepwise logistic regression and mediation analysis to examine the role of the AA genotype of the CHRNA3/5 variant in smoking exposure, COPD and lung cancer.
Result:
Relative to healthy smoking controls, the AA genotype was associated with the presence of COPD (OR=1.3, P<0.001) and the development of lung cancer overall (OR=1.5, P<0.01), lung cancer with pre-existing COPD (OR=1.5, P=0.04), lung cancer with no COPD (OR=1.5, P=0.04). Compared to the GG and AG genotypes, the AA genotype was associated with (a) lower FEV1%pred, lower FEV1/FVC and a 19% increase in risk of COPD; and (b) greater cigs/day, pack years exposure and a 47% increased risk of lung cancer. No differences were found for age, gender, smoking duration, years since quitting and current smoking status. In stepwise logistic regression, we found that age, BMI, AA genotype, smoking exposure and lung function were independently associated with getting lung cancer. In the mediation analyses we found that the AA genotype was independently associated with smoking (OR=1.42,P<0.05), COPD (OR=1.25,P<0.05) and getting lung cancer (OR=1.37, P<0.05).
Conclusion:
This is the first prospective study to confirm that while the CHRNA3/5 variant is associated with lung cancer, more importantly this variant is also independently associated with airflow limitation (COPD). It is also the first cohort study to show that while this genetic variant is also associated with smoking exposure (triple whammy effect), this is independent of its effects on predisposition to both COPD and lung cancer.
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OA 06.07 - Survival Trends Among Non-Small Cell Lung Cancer (NSCLC) Patients Over A Decade: Impact of Initial Therapy at Academic Centers (ID 10149)
16:50 - 17:00 | Presenting Author(s): Yanyan Lou | Author(s): Bhagirathbhai Dholaria, S. Ailawadhi, A.E. Soyano, D. Hodge, R. Manochakian, M.E. Menefee, E. Johnson, M. Thomas, S. Ko, R.C. Miller, M. Johnson, N. Patel, K. Mody, R. Joseph
- Abstract
- Presentation
Background:
Treatment of NSCLC is rapidly advancing and academic centers are considered equipped with better expertise. NSCLC outcome trends in novel therapeutic era and impact of initial treatment at academic centers have not been reported.
Method:
The National Cancer Database (NCDB) with NSCLC incident cases between 2004-2013 was used. Overall survival (OS) was plotted by year of diagnosis and type of treatment facility, accounting for several available factors in NCDB.
Result:
A total of 1,150,722 NSCLC patients were included and separated by initial treatment facility type (academic: 31.5%, non-academic: 68.5%). Several characteristics were significantly different between the two cohorts (Table 1). Median OS for all patients was 13.1 months and improved significantly for those diagnosed in 2010-2013 (14.8 months) as compared to 2004-2009 (12.4 months) (p<0.001). Treatment at academic centers was associated with reduced risk of death [Multivariate HR=0.91 (95% CI 0.906-0.919), P<0.001]. Four-year OS for academic and non-academic cohorts was 25% and 19%, respectively (p<0.001), the difference more pronounced in stage 1-3. (Figure 1) Figure 1 Figure 2
Conclusion:
In this largest analysis thus far, NSCLC survival has improved over time and type of treatment facility significantly influences survival. Factors influencing treatment facility choice should be addressed for easier access to academic centers.
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OA 06.08 - Is Lung Cancer Screening Associated with a Negative Psychological Impact? (ID 9879)
17:00 - 17:10 | Presenting Author(s): Ben Young | Author(s): M. Clark, L. Bedford, R. Das Nair, J. Robertson, K. Vedhara, D. Kendrick
- Abstract
- Presentation
Background:
Lung cancer screening can reduce lung cancer mortality by 20%. It is currently recommended in the USA, but not in the UK and ensuring any potential psychological harm is minimised is important. Current evidence is limited to the psychological impact of CT lung cancer screening. This study assesses psychological responses in the Early Cancer Detection Test - Lung Cancer Scotland Study (ECLS Study), whose participants have a tumour antibody blood test (Early CDT®-Lung test) and CT scans only for those with positive blood tests.
Method:
ECLS study participants were randomised to an Early CDT®-Lung test group or a control group. A sample (n=1032) participated in a nested psychological outcomes study. Questionnaires measured psychological responses (positive and negative affect scale (PANAS), lung cancer worry scale (LCWS) and impact of events scale (IES)) at baseline and 1, 3, 6 and 12 months post-trial recruitment. Psychological responses over time were assessed using multilevel modelling and compared between those in the control group, the test-positive group and the test‑negative group.
Result:
In total, 350, 361 and 321 participants were in the control, test-negative and test-positive groups respectively. Follow-up questionnaire completion rates were ≥90% at all time-points. Baseline psychological measures did not differ significantly between groups. Significant differences were found between PANAS scores, but absolute differences between the groups were very small and unlikely to be clinically significant. The IES avoidance and intrusion scores were significantly higher in the positive than the negative group at all time-points and at 1, 3 and 6 months respectively. However, median scores for both subscales at all the time-points were in the subclinical range. Anxiety about future tests and treatment at 1 month was significantly higher in the test-positive group than the control (OR (95%CI) 3.55 (1.70, 7.41)), or the negative group (OR (95%CI) 5.74 (2.69, 12.2)). Worry about getting lung cancer in the future was significantly higher in the test-positive than the test-negative group at 1 month (OR (95%CI) 2.61 (1.35, 5.02)), 3 months (OR (95%CI) 2.52 (1.30, 4.87)) and 6 months ((OR (95%CI) 2.98 (1.53, 5.82)).
Conclusion:
Lung cancer screening using a blood test followed by CT scanning for test-positive individuals does not appear to impact on affect, intrusive thoughts or avoidant behaviour to a clinically important degree. However, anxiety about future tests and treatment and future worry about lung cancer needs to be addressed if lung cancer screening is implemented in the UK.
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OA 06.09 - Discussant - OA 06.05, OA 06.06, OA 06.07, OA 06.08 (ID 10788)
17:10 - 17:25 | Presenting Author(s): Norihiko Ikeda
- Abstract
- Presentation
Abstract not provided
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JCSE 01 - Joint IASLC/CSCO/CAALC Session: Immunotherapy for Management of Lung Cancer: Ongoing Research from East and West (ID 630)
- Event: WCLC 2017
- Type: Joint Session IASLC/CSCO/CAALC
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:C. Bai, Fred R. Hirsch, Tony SK Mok, Yi-Long Wu
- Coordinates: 10/15/2017, 07:30 - 11:30, F203 (Annex Hall)
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JCSE 01.18 - Uncommon Mutation Types of EGFR and Response to EGFR Tyrosine Kinase Inhibitors in Chinese Non-Small Cell Lung Cancer Patients (ID 10914)
11:30 - 11:30 | Presenting Author(s): Yun Fan
- Abstract
Background:
Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the standard therapy for advanced lung adenocarcinomas with common EGFR mutations. However, the efficacy of EGFR-TKIs in patients with these uncommon EGFR mutations (other than exon 19 deletions or exon 21 L858R mutation) remains undetermined.
Method:
Seven hundred and fifty-five non-small cell lung cancer (NSCLC) patients with EGFR mutation analyses for TKI therapy were identified between October 2010 and December 2015 in East of China. And 66 patients bearing uncommon EGFR mutations were included to collect data from TKI response and prognosis.
Result:
Rare sensitive mutations (G719X, L861Q, S768I), primary resistant mutation (Ex20 ins), and complex mutations (G719X + L861Q, G719X+S768I, 19 del+T790M, 19 del+L858R, L858R+S768I, and L858R+T790M) of EGFR were identified in 37 (56.1%), 9 (13.6%), and 20 (33.3%) patients, respectively. TKI treatment in patients harboring uncommon EGFR mutations exhibited a tumor response rate of 28.8% and a median progression-free survival (PFS) of 4.8 months. Importantly, patients with complex EGFR mutations had significantly longer PFS when compared with the remaining sensitizing rare mutations or Ex20 ins (8.6 versus 4.1 versus 3.1 months; p=0.041). Furthermore, complex EGFR mutations were independent predictors of increased overall survival in NSCLC patients (Hazard Ratios=0.31; 95% confidence intervals: 0.11-0.90; p=0.031). Among them, patients harboring Del-19 compound L858R mutations showed a tendency to have higher response rate and improved median PFS than those regarding patients with other complex mutations patterns (66.7% verse14.3%, p=0.021; 10.1 verse 8.6 months, p=0.232).
Conclusion:
Personalized treatment should be evolving in different types of uncommon EGFR mutations. And complex mutations of EGFR may benefit more from EGFR-TKIs than other uncommon mutations in Chinese NSCLC patients.
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MA 03 - Chemotherapy (ID 651)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Jin-Hyoung Kang, W. Su
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 502
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MA 03.03 - Nedaplatin plus Docetaxel versus Cisplatin plus Docetaxel as First-Line Chemotherapy for Advanced Squamous Cell Carcinoma of the Lung (ID 8154)
11:10 - 11:15 | Author(s): Yun Fan
- Abstract
- Presentation
Background:
A previous phase III randomized trial improved overall survival of patients with advanced or relapsed squamous cell lung carcinoma, compared with cisplatin plus docetaxel. However, evaluation of nedaplatin plus docetaxel’s effect on progression free survival (PFS) and time to progression (TTP) was limited.
Method:
To compare the efficacy and safety of nedaplatin plus docetaxel and cisplatin plus docetaxel. In this randomized, open-label, multicenter trial, patients diagnosed with advanced or relapsed squamous cell carcinoma pathologically or cytologically were enrolled in China. All the patients have no previous oncology medication. Patients were randomly assigned (1:1) to 80 mg/m² nedaplatin and 75 mg/m² docetaxel intravenously, or 75 mg/m² cisplatin and 75 mg/m² docetaxel, every 3 weeks for four cycles. The primary end points was PFS. Secondary endpoints included TTP and best overall response. The efficacy endpoint were analyzed in the intention-to-treat set and in the per protocol set. （Clinical trial number: NCT02088515; Funding:Jiangsu Simcere Pharmaceutical Co., Ltd.）
Result:
From December 2013 to December 2015, 286 patients were randomly assigned. Two hundred and eighty patients were included in the modified intention-to-treat analysis (141 in the nedaplatin group and 139 in the cisplatin group). In the intention-to-treat analysis set, median PFS was 4.63 months (95% confidence interval (CI), 4.43-5.10) in the nedaplatin group and 4.23 months (95% CI, 3.37-4.53) in the cisplatin group. PFS did not differ significantly between two groups (log-rank test, p =0.056). In per protocol set, PFS was significantly longer in the nedaplatin group (median 4.63 months, 95% CI, 4.43-5.10) than in the cisplatin group (median 4.27 months, 95% CI, 3.37-4.53; hazard ratio 0.760, 95% CI 0.585-0.989; p=0.039, log-rank test). Best overall response and TTP were improved in nedaplatin group than in cisplatin group (p= 0.002, median 4.57(4.30-4.80) vs 3.67(3.13-4.43) p= 0.020, respectively) in the intention-to-treat analysis set. Grade III or IV adverse events was more frequent in the cisplatin group than in the nedaplatin group (46 of 141 patients in the nedaplatin group and 62 of 139 in the cisplatin group, p=0.039). Grade 3 or worse nausea (0 vs 7) and fatigue (1 vs 3) were more frequent in the cisplatin group than in the nedaplatin group.
Conclusion:
There was no significant difference of PFS between cisplatin group and nedaplatin group. However, more adverse events was observed in the cisplatin group than in the nedaplatin group. Nedaplatin plus docetaxel could be a new treatment option for advanced or relapsed squamous cell lung cancer.
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P2.01 - Advanced NSCLC (ID 618)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:00 - 16:00, Exhibit Hall (Hall B + C)
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P2.01-057 - Activity of Pemetrexed on Wild-Type and Unknown Status EGFR Genes with Brain Metastases from Non-Small Cell Lung Cancer (ID 10612)
09:00 - 09:00 | Presenting Author(s): Yun Fan
- Abstract
Background:
Brain metastases (BM) are a common cause of morbidity and mortality in patients with non-small-cell lung cancer (NSCLC). For patients with wild-type EGFR genes, therapeutic options for BM are even limited. Besides local therapy, pemetrexed is the preferred chemotherapy in NSCLC, but the efficacy of this treatment is uncertain. This study evaluated the efficacy of wild-type and unknown status EGFR patients with BM receiving pemetrexed based chemotherapy and analyze the prognostic factors.
Method:
We retrospectively studied 138 EGFR wild-type and unknown EGFR status patients with BM, who had received first line pemetrexed based chemotherapy between 2010 and 2015 at Zhejiang Cancer Hospital. Unknown EGFR status patients were treated with EGFR TKIs after progression. Patient follow-up by telephone was done until January 2016. Treatment response was evaluated and survival data were collected and analyzed.
Result:
Among the 138 patients, 49(35.5%) were EGFR wild type and 89(64.5%) were unknown EGFR status. And 80(58.0%) received whole-brain radiotherapy (WBRT), 19(13.8%) received stereotactic radiosurgery (SRS)/surgery, 10(7.2%) were treated with WBRT plus SRS/surgery, 29(21.0%) didn’t receive any local therapy. The median overall survival (OS) from diagnosis of BM was 21.0 months for the whole cohort (95% CI, 17.2-24.8 months), the intracranial progression-free survival (iPFS) was 9.5 months (95% CI, 6.6-12.4 months) and extracranial PFS was 8.3 months (95% CI, 6.9-9.7 months). Patients with unknown EGFR status had a longer iPFS and OS than EGFR wild-type (11.7 vs. 7.6 months, P=0.23; 24.0 vs. 17.7 months, P=0.24). The combination of pemetrexed and platinum showed better iPFS than single agent of pemetrexed in patients, although it did not reach statistical significance (10.7 vs. 7.2 months, P=0.27). Patients with more than 6 cycles of chemotherapy tend to have longer iPFS and OS than those who received less than 6 cycles or 4 cycles (12.6 vs. 10.3 vs. 8.3 months, P=0.52; 47.9 vs. 27.9 vs. 19.2 months, P=0.18).
Conclusion:
Pemetrexed shows good tolerability and efficiency in EGFR wild-type and unknown EGFR status patients with brain metastases from advanced NSCLC, and have a good control of activity on brain localizations.
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P2.03 - Chemotherapy/Targeted Therapy (ID 704)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.03-013 - Uncommon Mutation Types of EGFR and Response to EGFR Tyrosine Kinase Inhibitors in Chinese Non-Small Cell Lung Cancer Patients (ID 8076)
09:30 - 09:30 | Presenting Author(s): Yun Fan
- Abstract
Background:
Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the standard therapy for advanced lung adenocarcinomas with common EGFR mutations. However, the efficacy of EGFR-TKIs in patients with these uncommon EGFR mutations (other than exon 19 deletions or exon 21 L858R mutation) remains undetermined.
Method:
Seven hundred and fifty-five non-small cell lung cancer (NSCLC) patients with EGFR mutation analyses for TKI therapy were identified between October 2010 and December 2015 in East of China. And 66 patients bearing uncommon EGFR mutations were included to collect data from TKI response and prognosis.
Result:
Rare sensitive mutations (G719X, L861Q, S768I), primary resistant mutation (Ex20 ins), and complex mutations (G719X + L861Q, G719X+S768I, 19 del+T790M, 19 del+L858R, L858R+S768I, and L858R+T790M) of EGFR were identified in 37 (56.1%), 9 (13.6%), and 20 (33.3%) patients, respectively. TKI treatment in patients harboring uncommon EGFR mutations exhibited a tumor response rate of 28.8% and a median progression-free survival (PFS) of 4.8 months. Importantly, patients with complex EGFR mutations had significantly longer PFS when compared with the remaining sensitizing rare mutations or Ex20 ins (8.6 versus 4.1 versus 3.1 months; p=0.041). Furthermore, complex EGFR mutations were independent predictors of increased overall survival in NSCLC patients (Hazard Ratios=0.31; 95% confidence intervals: 0.11-0.90; p=0.031). Among them, patients harboring Del-19 compound L858R mutations showed a tendency to have higher response rate and improved median PFS than those regarding patients with other complex mutations patterns (66.7% verse14.3%, p=0.021; 10.1 verse 8.6 months, p=0.232).
Conclusion:
Personalized treatment should be evolving in different types of uncommon EGFR mutations. And complex mutations of EGFR may benefit more from EGFR-TKIs than other uncommon mutations in Chinese NSCLC patients.
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P2.04 - Clinical Design, Statistics and Clinical Trials (ID 705)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.04-003 - Phase II Trial of X-396 (Ensartinib) for Chinese Patients with ALK (+) Non–Small-Cell Lung Cancer Who Progressed on Crizotinib (ID 8849)
09:30 - 09:30 | Author(s): Yun Fan
- Abstract
Background:
Crizotinib has been established as the standard first-line treatment for patients with ALK-rearranged non-small-cell lung cancer. However, despite its superiority to chemotherapy, resistance occurs within approximately 12 months. New ALK-inhibitors are needed to overcome the resistance to crizotinib and to increase drug penetration to CNS. X-396 (ensartinib) is a novel, potent ALK tyrosine kinase inhibitor (TKI). Its phase I/II study showed X-396 is well-tolerated with favorable anti-tumor activities in both ALK TKI-naïve and crizotinib-resistant NSCLC patients, as well as patients with CNS metastases. The recommended phase II dose (RP2D) was established at 225 mg, once daily.
Method:
A phase II, multi-center study is evaluating the efficacy and safety of single-agent X-396 in Chinese patients with ALK (+) non–small-cell lung cancer after progression on crizotinib. Eligible patients will have documentation of a positive ALK rearrangement and progression on crizotinib. X-396 225 mg is orally administered until disease progression or intolerable toxicity. The primary endpoint is RECIST 1.1 response rate. Secondary endpoints include PFS, duration of response, and safety. The sample size is calculated using the test for inequality method, assuming that X396 have an ORR of 50% in patients with ALK-positive NSCLC, 15% higher than that from existing second-line therapy. Therefore, up to 144 patients will be enrolled with a significance level and power of 5% and 90%, respectively. Recruitment will be started on September, 2017.
Result:
Section not applicable
Conclusion:
Section not applicable
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P2.07 - Immunology and Immunotherapy (ID 708)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.07-057 - Anti-PD-1/PD-L1 Antibodies Combine with Chemotherapy or CTLA4 Antibodies for First-Line Treatment of Advanced Lung Cancer (ID 9289)
09:30 - 09:30 | Presenting Author(s): Yun Fan
- Abstract
Background:
Checkpoint inhibitors showed satisfactory efficacy in treating lung cancer. We conducted this meta-analysis to explore the therapeutic efficacy and safety of anti-PD-1/PD-L1 antibodies combine with chemotherapy or CTLA4 antibodies as first-line treatment on advanced lung cancer.
Method:
A quantitative meta-analysis was performed through a systematic search in PubMed, Web of Science, the conference abstracts and so on. The pooled ORR, 6-month progression-free survival rate (PFSR6m), and 1-year overall survival rate (OSR1y) were calculated and compared. 9 trials were included in this meta-analysis.
Result:
Our analyses demonstrated the pooled ORR and DCR of anti-PD-1/PD-L1 antibodies combine with chemotherapy for non-small-cell lung cancer were 48.0% (40.2–56.0 %) and 84.8 % (78.1– 89.7%), respectively. The pooled OR and DCR of anti-PD-1/PD-L1 antibodies combine with chemotherapy for small-cell lung cancer were 42.9% (18.5–71.2 %) and 73.6 % (32.8–94.1%), respectively. The pooled PFSR6m of anti-PD-1/PD-L1 antibodies combine with chemotherapy for NSCLC and SCLC were 62.9% (46.3–79.6%) and 27.6 % (18.9–36.2 %), respectively. The OSR1y of anti-PD-1/PD-L1 antibodies combine with chemotherapy for NSCLC and SCLC were 70.1 % (57.4%-82.8 %) and 32.0 % (25.2–38.9 %). In addition, the pooled ORR and DCR for anti-PD-1/PD-L1 antibodies plus CTL4 antibodies treatment group was 29.6% (11.4%-657.8%) and 48.7% (16.8%-81.7%), respectively.
Conclusion:
Anti-PD-1/PD-L1 antibody plus chemotherapy can serve as a promising treatment option for lung cancer. While patients treated anti-PD-1/PD-L1 antibodies plus CTLA4 antibodies may benefit less compare with anti-PD-1/PD-L1 antibodies combine with chemotherapy. Encouraging activity with tolerable adverse effect was observed.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-069 - Three Treatments for EGFR-Mutant Non-Small-Cell Lung Cancer with Brain Metastases (ID 10610)
09:30 - 09:30 | Presenting Author(s): Yun Fan
- Abstract
Background:
Brain metastases (BM) are a common cause of morbidity and mortality in patients with non-smallcell lung cancer (NSCLC). EGFR-TKIs, whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS) and chemotherapy are treatment options available. But the optimal management, the combination or sequence, remains undefined. This study evaluated the efficacy of EGFR-mutant NSCLC patients with BM receiving multiple regimens and analyze the prognostic factors.
Method:
We retrospectively studied 45 EGFR-mutated NSCLC patients with BM, who had received EGFR TKIs、radiation therapies (WBRT or SRS) and pemetrexed based chemotherapy successively between 2010 and 2015 at Zhejiang Cancer Hospital. Patient follow-up by telephone was done until January 2016. Treatment response was evaluated and survival data were collected and analyzed.
Result:
Among the 45 patients, 22(48.9%) had an EGFR exon 19 deletion and 23(51.1%) had an EGFR exon 21 L858R mutation. Thirty (66.7%) patients received upfront radiation therapies (RT). 28 patients (62.2%) were treated with pemetrexed based chemotherapy as the first line treatment while 17 (37.8%) received first line EGFR TKIs instead. The median overall survival (OS) from diagnosis of BM was 28.0 months for the whole cohort (95% CI, 17.3-38.7 months). Patients with the exon 19 deletion had a longer median OS than patients with the exon 21 L858R mutation (not reached vs. 23.2 months, P=0.031). There was no difference in OS between the upfront RT group and the deferral group (26.5 vs. 28.0 months, P=0.57), and similar results were found between the first line chemotherapy group and the TKIs group (28.0 vs. 23.2 months, P=0.499). Patients with a higher GPA score showed better survival. In multivariate analysis, the prognosis was correlated with EGFR mutation type (P=0.017). Patients with extracranial metastases showed the strongest trend toward decreased OS, although it did not reach statistical significance (P = 0.070).
Conclusion:
Applying three treatments can significantly improve OS of patients, especially those with EGFR exon 19 deletion. Different sequences of treatments and timing of RT need further studies to identify the optimal treatment model.
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P3.03 - Chemotherapy/Targeted Therapy (ID 719)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 2
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.03-030 - TP53 Alteration, a Potential Primary Cause of Early Progression in EGFR-Mutated NSCLC Patients Treated with First-Line TKIs (ID 9426)
09:30 - 09:30 | Presenting Author(s): Yun Fan
- Abstract
Background:
EGFR-TKIs are recommended first-line treatment for patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC). Most patients develop resistance after an average of approximately 12 months. Among various mechanisms, about half are acquired with T790M in EGFR exon 20. Little is known about the mechanisms in patients progressed within 6 months after first-line treatment of EGFR-TKIs. Therefore, we prospectively designed this study to investigate the possible mechanisms of resistance in this group of patients.
Method:
NSCLC patients with sensitive EGFR mutations who treated with first-line EGFR-TKI in Zhejiang Cancer Hospital from Jun 2014 to Jan 2017 were screened prospectively. Tissue samples pre-TKI and after disease progression (RECIST1.1) were collected. Blood samples were collected after disease progression. The study was approved by hospital research ethics committees. Of the total 50 patients enrolled for the study, 21 patients were included and further divided into two groups: patients suffered disease progression within six months after taking EGFR-TKI were classified as Group A (rapid progress group, n=13); patients took EGFR-TKI more than two years were classified as Group B (long term survival group, n=8). Patients with a PFS between 6 months to two years were excluded. We performed NGS of ~416 cancer related genes from the primary cancer samples collected before TKI treatment. Differences of gene alterations between two groups were analyzed.
Result:
The median age was 55 years old (range: 34-75 years). There were 47.6% female and 53.8% non-smokers. All patients in Group A carried TP53 mutation before treatment, none was found in Group B. The average cancer-related genetic mutations is 6.46 (range 3-16, 6 in Group A, 5.6 in Group B, P>0.05). There was enrichment for co-alterations in TP53 (100%), RB1 (38%), NKX2-1 (31%), BIM (30.8%) in pre-treated tissues from Group A. ERCC2 (38%), JAK3 (38%), BRCA2 (25%) were enriched in pre-treated tissues from Group B. Mutation rate of EGFR T790M after resistance was lower in Group A (2/13,15.4%) than in Group B (2/5, 40%). Three patients (3/8) are still benefit from first-line EGFR-TKI without disease progression in Group B. The median PFS was 3 months for Group A (range 1-5 months) and 26.5 months for Group B (range 24-52 months).
Conclusion:
This data highlights a model of genetic collectives as potential mechanisms of rapid progression in first-line EGFR-TKIs treatment. TP53 mutation reduced responsiveness to TKIs and worsen prognosis in EGFR-mutated NSCLC patients, contributing to rapid disease progression. EGFR T790M mutation seems uncommon in rapid progression patients.
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P3.03-031 - Response to Crizotinib Can Occur in C-MET Overexpression NSCLC Independent of MET exon14 Alterations After First-Line EGFR-TKI Resistance (ID 9463)
09:30 - 09:30 | Presenting Author(s): Yun Fan
- Abstract
Background:
Although non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations are responsive to EGFR-tyrosine kinase inhibitors (EGFR-TKIs), drug resistances are always inevitable. Concurrent multiple mutations and bypass mechanisms both can contribute to development of resistance to EGFR-TKIs. Preclinical and clinical evidences suggest a role for MET activation as a secondary driver of resistance to targeted therapy. Activation of the MET pathway can occur through a diverse set of mechanisms including MET amplification, MET exon 14 alterations, MET overexpression. As partial overlap of these biomarkers occurs, whether one is purely a surrogate for the other, or if both can represent true oncogenic driver states continues to be explored. Cases of MET inhibitor sensitive NSCLC harboring exon 14 alterations without co-incident amplification have already been described. But concurrent EGFR-mutation and MET overexpression in one case is rare. Whether MET overexpression can be served as a driver alteration in NSCLC and its cut-off value need to be explored.
Method:
A NSCLC patient with EGFR mutation who took first line EGFR-TKI therapy was described in this report. The chest enhanced CT examination, whole-body PET/CT, coarse needle biopsy on right clavicle and bronchoscopy were taken to assess the disease condition before treatment. ARMS, IHC, FISH, ddPCR and NGS were used to detect gene alterations including gene mutation, overexpression and amplification, in cancer tissue samples obtained before TKI and after disease progression.
Result:
In this case, we described a 56-year-old male NSCLC patient with EGFR Ex21 L858R mutation who underwent refractory after first line EGFR-TKI therapy and was confirmed having concurrent c-MET overexpression (ICH: +++, 95%) before treatment. Disease progression was occurred after taking first-line EGFR-TKI for 4 months. Patient was then further confirmed having c-MET overexpression (ICH: +++, 90%) but without EGFR T790M mutation, c-MET amplification and MET exon 14 alterations in progressed cancer samples. Crizotinib was added to the treatment from Aug 8, 2016 after disease progression. And the recent chest enhanced CT examination on May 5, 2017 confirmed complete response (CR) to crizotinib in this patient.
Conclusion:
Our case report uncovered the underling mechanism of c-MET overexpression in EGFR-TKI resistance, and crizotinib may assist to overcome this resistance to EGFR-TKI. In this case, MET overexpression and EGFR mutation were concurrent before treatment. Thus, whether simultaneously applied EGFR-TKI and MET inhibitor in first-line treatment could result a better outcome was needed to be further demonstrated. The ideal cut-off value of MET overexpression is also waiting for determination.
