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W. Su
Moderator of
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MA 03 - Chemotherapy (ID 651)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 12
- Moderators:Jin-Hyoung Kang, W. Su
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 502
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MA 03.01 - Nab-Paclitaxel ± CC-486 as Second-Line Treatment of Advanced NSCLC: Results from the ABOUND.2L+ Study (ID 8676)
11:00 - 11:05 | Presenting Author(s): Ramaswamy Govindan | Author(s): D. Morgensztern, Manuel Cobo Dols, S. Ponce Aix, Pieter E. Postmus, Jaafar Bennouna, J.R. Fischer, O.J. Vidal, D.J. Stewart, G. Fasola, J. Weaver, M. Wolfsteiner, T.J. Ong
- Abstract
- Presentation
Background:
CC-486 (oral azacitidine) is an epigenetic modifier with potential effect as a priming agent for chemotherapy in patients with NSCLC. Outcomes of nab-paclitaxel+CC-486 vs nab-paclitaxel as second-line treatment of advanced NSCLC are reported.
Method:
Patients with advanced nonsquamous NSCLC and no more than 1 prior chemotherapy line (including platinum doublet combination) were randomized (1:1) to nab-paclitaxel 100 mg/m[2] d8, 15 + CC-486 200 mg qd d1-14 or nab-paclitaxel 100 mg/m[2] d1, 8, both administered q3w until progressive disease/unacceptable toxicity. Primary endpoint was PFS. Secondary endpoints: DCR, ORR, OS, and safety. QoL, an exploratory endpoint, was assessed on d1 of each cycle.
Result:
The nab-paclitaxel+CC-486 arm was discontinued in October 2016 due to demonstrated futility vs nab-paclitaxel monotherapy upon completion of a protocol-specified interim analysis. Overall, 161 patients were randomized (nab-paclitaxel+CC-486, 81; nab-paclitaxel, 80). Baseline characteristics were balanced between arms. The median number of cycles was 4 for each arm, and the median nab-paclitaxel cumulative dose was 600 mg/m[2] and 800 mg/m[2] in the nab-paclitaxel+CC-486 and nab-paclitaxel arms, respectively. Rates of grade 3/4 (G3/4) treatment-emergent AEs were 59.5% and 54.4% for the combination and monotherapy arms, respectively. The most frequent hematologic G3/4 AEs were neutropenia (16.5% vs 10.1%) and anemia (1.3% vs 7.6%). G3/4 peripheral neuropathy was reported in 2.5% and 7.6% of patients, respectively. The addition of CC-486 to nab-paclitaxel did not improve ORR, DCR, PFS, or OS (Table). When assessed by Lung Cancer Symptom Scale, nab-paclitaxel monotherapy was associated with improvement in the global QoL, average symptom burden index, and lung cancer symptoms except for hemoptysis.
Conclusion:
The addition of CC-486 to nab-paclitaxel did not clinically benefit patients with previously treated NSCLC. However, single-agent nab-paclitaxel appears to be a promising therapy based on safety, efficacy, and QoL data. Updated efficacy and safety data will be presented. NCT02250326nab-Paclitaxel + CC-486 n = 81 nab-Paclitaxel n = 80 Median PFS, months 3.2 4.2 HR (95% CI) 1.3 (0.9 - 2.0) 1-year PFS, % 4.1 18.3 Median OS, months 8.4 12.7 HR (95% CI) 1.4 (0.88 - 2.31) 1-year OS, % 39.2 54.3 ORR, n (%)[a] 11 (13.6) 11 (13.8) Response rate ratio (95% CI) 0.99 (0.45 - 2.15) CR PR SD PD DCR (≥ SD) 0 11 (13.6) 41 (50.6) 22 (27.2) 52 (64.2) 0 11 (13.8) 43 (53.8) 19 (23.8) 54 (67.5) CR, complete response; DCR, disease control rate; HR, hazard ratio; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease. [a] Response rate was based on the intent-to-treat population; however, 14 patients did not have a response assessment.
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MA 03.02 - Timing of B12/Folate Supplementation in NSCLC Patients on Pemetrexed Based Chemotherapy: Final Results of the PEMVITASTART Randomized Trial (ID 7957)
11:05 - 11:10 | Presenting Author(s): Navneet Singh | Author(s): M. Baldi, J. Kaur, Kuruswamy Thurai Prasad, R. Kapoor, Digambar Behera
- Abstract
- Presentation
Background:
Vitamin B12 and folic acid supplementation(B12-FAS) reduces the incidence and severity of hematological toxicity[HTox] in pemetrexed-based chemotherapy. It is recommended to initiate B12-FAS 5-7 days before the first cycle. Observational and prospective single-arm studies have not shown any increase in HTox when pemetrexed was started earlier than the recommended duration of B12-FAS.
Method:
An open-label, randomized trial (PEMVITASTART; NCT02679443) was conducted to evaluate differences in HTox between patients initiated on pemetrexed-platinum chemotherapy following 5-7 days of B12-FAS (Delayed Arm; DA) versus those receiving B12-FAS simultaneously(≤24 hours) with chemotherapy initiation (Immediate Arm; IA). Eligible patients had locally advanced/metastatic non-squamous NSCLC AND ECOG PS=0-2. Block randomization was 1:1 into DA and IA. All enrolled patients received 3-weekly pemetrexed-platinum doublet [500mg/m[2] AND cisplatin(65mg/m[2]) OR carboplatin(AUC 5.0mg/mL/min) each on D1] for maximum of six cycles. Supplementation was 1000µgm FA PO daily and 3-weekly 1000µgm i/m vitamin B12. Primary outcome was any grade HTox while secondary outcomes were grade 3/4 HTox, relative dose intensity(RDI) delivered, inter-cycle delays(ICDs), supportive therapies usage (ESA/G-CSF/PRBC transfusions) and changes in serum levels of B12/FA/homocysteine.
Result:
Of 161 patients recruited (81 IA, 80 DA), 150 patients (77 IA, 73 DA) received ≥1 cycle and were included in modified ITT analysis. Baseline parameters were matched except for gender (IA=10.4%, DA=23.3%, p=0.03) and baseline thrombocytopenia (IA=7.8%, DA=0%, p=0.03). Baseline anemia(Hb<12gm/dL) was present in 34.7% (IA=32.5%, DA=37.0%; p=0.56). Incidence of any grade anemia, leukopenia, neutropenia and thrombocytopenia was 87.0% vs. 87.7%(p=0.90), 37.7% vs. 28.8%(p=0.25), 20.8% vs. 15.1%(p=0.36) and 31.2% vs. 16.4%(p=0.04) in IA and DA respectively. Grade 3/4 anemia was 18.2% vs. 12.3%(p=0.32) in IA and DA respectively while other cytopenias were similar (<5% in each arm). Supportive therapies usage in IA vs. DA were 22.1% vs. 12.3% for PRBC transfusions (p=0.12), 3.9% vs. 6.8% for G-CSF (p=0.49) and 10.4% vs. 1.4% for ESAs (p=0.03). ICDs occurred in 14.3% of IA vs. 8.2% in DA (p=0.24). RDI delivered (median 93.5% for pemetrexed and 91.0% for platinum) was similar in both arms. Following continued B12-FAS, after C3(compared to baseline), serum homocysteine was lower (median 10.0µmol/L vs. 17.6µmol/L;p<0.001) while FA (median 17.9ng/ml vs. 5.7ng/ml;p<0.001) and B12 levels (mean 1926.3pg/ml vs. 880.2pg/ml;p<0.001) were higher. In DA, serum FA and B12 on Day1 of C1(following 5-7days of B12-FAS) were significantly higher than baseline but homocysteine levels were similar.
Conclusion:
Simultaneous B12-FAS initiation with pemetrexed-based chemotherapy is feasible with acceptable HTox profile. Serum homocysteine levels are unaffected by 5-7 days of B12-FAS.
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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 | Presenting Author(s): Shun Lu | Author(s): Z. Chen, C.P. Hu, R. Xin-Ling, Y. Chen, Yong Song, Z. Qiong, Yun Fan, W. Gang, M. Zhi-Yong, Jian Fang, Y. Qi-Tao, Z. Liu
- 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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MA 03.04 - Discussant - MA 03.01, MA 03.02, MA 03.03 (ID 10808)
11:15 - 11:30 | Presenting Author(s): Adrian G. Sacher
- Abstract
- Presentation
Abstract not provided
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MA 03.05 - Bevacizumab Combined with Chemotherapy for Patients with Advanced NSCLC and Brain Metastasis. A French Cohort Study (ID 8188)
11:30 - 11:35 | Presenting Author(s): Jaafar Bennouna | Author(s): L. Falchero, R. Schott, F. Bonnetain, M. Coudert, B. Ben Hadj Yahia, C. Chouaid
- Abstract
- Presentation
Background:
Although brain metastases (BM) are a very common and clinically challenging for NSCLC progression, there are few prospective studies addressing the safety and efficacy of bevacizumab in combination with chemotherapy in patients with BM. This study aimed to describe the characteristics of patients receiving bevacizumab in combination with first-line metastatic chemotherapy for advanced NSCLC (aNSCLC), with BM or not, in routine clinical practice.
Method:
For this French non-interventional, prospective, and multicenter study, data were collected every 3 months over an 18-month period, from bevacizumab initiation. End points were progression-free survival (PFS), overall survival (OS), treatment use, and safety.
Result:
Amongst the 407 aNSCLC patients analyzed, the 84 patients (21%) with BM at bevacizumab initiation had poorer general health than patients without BM (ECOG 2: 16% versus 11%). All except for 2 patients received bevacizumab (7.5 or 5 mg/kg/3 weeks in 99% of patients) in combination with doublet chemotherapy. After a median follow-up of 10.8 months (range: 0.2-34.1), median PFS and OS were not significantly different between patients with or without BM. BM was not found as PFS prognosis factor in multivariate analysis (HR=1.03; 95% CI=[0.79; 1.33], p=0.85). At least one serious adverse event (SAE) was reported in 30% of aNSCLC patients with BM (n=25) and in 32% of patients without BM (n=106); 13% (n=11) and 12% (n=40) of patients experienced at least one bevacizumab-related SAE, respectively. Three patients in each group died from bevacizumab-related events.aNSCLC patients with brain metastasis - N=84 (months, [CI 95%]) aNSCLC patients without brain metastasis - N=423 (months, [CI 95%]) Logrank test p value Median PFS 6.5 [5.7; 8.1] 6.9 [5.9; 7.6] 0.57 Median OS 14.5 [10.0; -] 12.5 [10.1; 14.7] 0.33
Conclusion:
In this study, no differences were observed between advanced NSCLC patients with and without brain metastasis in terms of clinical benefit (survival and safety) from first-line chemotherapy combined with bevacizumab. Nature, severity and outcome of AEs were consistent with the known safety profile of bevazicumab.
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MA 03.06 - Effect of 2L Ramucirumab after Rapid Time to Progression on 1L Therapy: Subgroup Analysis of REVEL in Advanced NSCLC (ID 7947)
11:35 - 11:40 | Presenting Author(s): Martin Reck | Author(s): Frances A Shepherd, Maurice Pérol, Frederico Cappuzzo, J. Shih, Keunchil Park, K.B. Winfree, E. Alexandris, P. Lee, A. Sashegyi, Edward Brian Garon
- Abstract
- Presentation
Background:
In REVEL, ramucirumab+docetaxel in the second-line (2L) treatment of patients with advanced NSCLC led to improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR), independent of histology. This exploratory, post-hoc analysis focuses on patients who progressed rapidly on first-line (1L), and who traditionally have a poor prognosis in the 2L setting. In REVEL, treatment benefit was observed in patients with progressive disease as their best overall response to 1L and in patients who were on 1L for only a short time (Reck M, ASCO 2017, Abstr 9079). Here, we report outcomes from patients who participated in REVEL according to their time to tumor progression (TTP) on 1L (ClinicalTrials.gov, NCT01168973).
Method:
Patients with advanced NSCLC of squamous or nonsquamous histology with disease progression during or after 1L platinum-based chemotherapy were randomized (1:1) to receive docetaxel 75 mg/m[2] and either ramucirumab 10 mg/kg or placebo on day 1 of a 21-day cycle. OS was the primary endpoint. Secondary endpoints included PFS, ORR, safety, and patient-reported quality-of-life (QoL). Response was assessed according to RECIST v1.1. QoL was assessed with the Lung Cancer Symptom Scale. TTP on 1L, defined as the time from start of 1L until progressive disease, was assessed for the REVEL intent-to-treat population.
Result:
Of 1253 patients in REVEL, 11% had TTP ≤9 weeks, 17% had TTP ≤12 weeks, and 28% had TTP ≤18 weeks on 1L therapy. Baseline characteristics of each subgroup generally were balanced between treatment arms. Efficacy, safety, and QoL outcomes by TTP are shown in the table.Outcomes in Patients From the REVEL Study by Time to Tumor Progression on First-Line Therapy
≤9 Weeks ≤12 Weeks ≤18 Weeks INTENT-TO-TREAT POPULATION Ramucirumab+Docetaxel N = 71 Placebo+Docetaxel N = 62 Ramucirumab+Docetaxel N = 111 Placebo+Docetaxel N = 98 Ramucirumab+Docetaxel N = 182 Placebo+Docetaxel N = 172 Median OS, months (95% Confidence Interval [CI]) 8.28 (5.19, 10.84) 4.83 (3.09, 6.90) 9.10 (6.70, 10.84) 5.78 (4.30, 7.49) 8.51 (6.97, 9.95) 5.95 (4.44, 6.97) Unstratified Hazard Ratio (HR) (95% CI) 0.69 (0.47, 1.01) 0.74 (0.54, 1.00) 0.80 (0.63, 1.01) 12-month survival rate, % (95% CI) 47 (35, 58) 32 (20, 44) 34 (25, 43) 23 (15, 32) 30 (23, 37) 24 (18, 31) 18-month survival rate, % (95% CI) 20 (11, 31) 12 (5, 24) 17 (10, 26) 13 (6, 22) 17 (11, 23) 13 (8, 20) Median PFS, months (95% CI) 3.01 (2.66, 4.07) 1.48 (1.41, 1.87) 3.61 (2.76, 4.21) 1.61 (1.45, 2.60) 3.22 (2.79, 4.14) 1.61 (1.48, 2.60) Unstratified HR (95% CI) 0.69 (0.48, 0.98) 0.73 (0.55, 0.97) 0.72 (0.58, 0.89) ORR (complete response [CR]+partial response [PR]), %, (95% CI) 18.3 (10.1,29.3) 3.2 (0.4, 11.2) 18.9 (12.1, 27.5) 9.2 (4.3, 16.7) 19.2 (13.8, 25.7) 10.5 (6.3, 16.0) Disease Control Rate (CR+PR+stable disease), % (95% CI) 50.7 (38.6, 62.8) 30.6 (19.6, 43.7) 49.5 (39.9, 59.2) 37.8 (28.2, 48.1) 50.5 (43.1, 58.0) 36.0 (28.9, 43.7) Average Symptom Burden Index, time to deterioration HR (95% CI) 0.60 (0.30, 1.22) 0.49 (0.27, 0.88) 0.74 (0.49, 1.12) Total Score Lung Cancer Symptom Scale, time to deterioration HR (95% CI) 0.89 (0.45, 1.78) 0.71 (0.41, 1.23) 0.90 (0.60, 1.36) SAFETY POPULATION Ramucirumab+Docetaxel N = 70 Placebo+Docetaxel N = 61 Ramucirumab+Docetaxel N = 109 Placebo+Docetaxel N = 97 Ramucirumab+Docetaxel N = 179 Placebo+Docetaxel N = 171 Any Treatment-Emergent Adverse Event (TEAE), n (%) 67 (95.7) 58 (95.1) 105 (96.3) 92 (94.8) 173 (96.6) 159 (93.0) Grade ≥3 50 (71.4) 46 (75.4) 80 (73.4) 69 (71.1) 134 (74.9) 113 (66.1) TEAE leading to discontinuation 4 (5.7) 2 (3.3) 5 (4.6) 3 (3.1) 13 (7.3) 6 (3.5) TEAE leading to dose adjustment 24 (34.3) 19 (31.1) 39 (35.8) 28 (28.9) 70 (39.1) 47 (27.5) TEAE leading to death 5 (7.1) 4 (6.6) 7 (6.4) 6 (6.2) 9 (5.0) 8 (4.7) TESAE 25 (35.7) 30 (49.2) 46 (42.2) 46 (47.4) 80 (44.7) 71 (41.5)
Conclusion:
Efficacy, toxicity, and QoL outcomes among ramucirumab+docetaxel patients who have aggressive disease with rapid TTP on 1L therapy appear consistent with the intent-to-treat population. The benefit/risk profile for these rapid progressors suggests that such patients may derive meaningful benefit from ramucirumab+docetaxel in the 2L setting.
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- Abstract
- Presentation
Background:
Background: INF-γ had recently been known to take part in cancer immunology and its interactions with chemotherapy were also described. Our previous study had showed that impaired PHA-stimulated INF-γ (PSIG) response from peripheral lymphocytes was associated with lower one-year overall survival in advanced non-small cell lung cancer (NSCLC) patients. In this study, we aimed to evaluate the correlation between PSIG and chemotherapy response.
Method:
Form January 2011 to August 2012, 340 newly-diagnosed lung cancer patients from 4 referral centers in Taiwan were enrolled in a prospective latent TB observational study. Patients who had advanced NSCLC and had been treated with chemotherapy were included in this study. The pretreatment PSIG levels were evaluated by Interferon-Gamma Release Assay (IGRA) with QuantiFERON-TB In-Tube (Qiagen, Germany). Patients were grouped into high PHA response group if their PSIG levels were above the median level; the others were grouped into low PHA response group. Their demographic characteristics, tumor response, and survival were investigated and correlated with PSIG levels.
Result:
Eighty-four patients were enrolled in this study. The response rate in high PHA response group was 45.2%, versus 35.7% in lower PHA response group (p=0.999190). The disease control rate in high PHA response group was 76.2%, versus 52.4% in low PHA response group (p=0. 023999). In multivariate analysis, PSIG response was an independent predictor for disease control rate (OR=3.017, 95% CI= 1.115-8.165). Also, the Kaplan-Meier curves and estimates survival analysis demonstrated both longer progression-free survival (p=0.008) and overall survival (p=0.003) in high PHA response group.
Conclusion:
Higher pre-treatment PSIG response, assayed by IGRA testing, was associated with better disease control rate and survival among advanced NSCLC patients treated with chemotherapy.
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MA 03.08 - Discussant - MA 03.05, MA 03.06, MA 03.07 (ID 10809)
11:45 - 12:00 | Presenting Author(s): Ikuo Sekine
- Abstract
- Presentation
Abstract not provided
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MA 03.09 - The Cost and the Benefit: Front-Line Immunotherapy for Non-Small Cell Lung Cancer (ID 9645)
12:00 - 12:05 | Presenting Author(s): Christine M Bestvina | Author(s): Everett E Vokes, P.C. Hoffman, J. Patel
- Abstract
- Presentation
Background:
The U.S. Food and Drug Administration approved pembrolizumab in combination with carboplatin/pemetrexed for patients with untreated, metastatic, non-squamous, non-small cell lung cancer based on KEYNOTE 021G. This trial randomized 123 patients to carboplatin/pemetrexed versus carboplatin/pemetrexed/pembrolizumab with maintenance pembrolizumab. Maintenance pemetrexed was optional in both arms. Progression-free survival (PFS) was longer for carboplatin/pemetrexed/pembrolizumab (not reached vs. 8.9 months, HR 0.49, 95% CI 0.29-0.83, p=0.0035). No statistically significant improvement in overall survival (OS) has yet been demonstrated (HR 0.69, 95% CI 0.36-1.31, p=0.13), with neither arm reaching median OS. Frontline pembrolizumab improves PFS and OS in comparison to chemotherapy in patients with high PD-L1 expression. Drug cost information should be available to providers to better inform decision-making and assess value.
Method:
Dose calculations were based on the following: GFR 125, BSA 2.00 m2, carboplatin AUC 5, pemetrexed 500mg/m2, and pembrolizumab 200mg. Drug costs were obtained via the Centers for Medicare & Medicaid Services Pricing File.
Result:
Four cycles of carboplatin/pemetrexed/pembrolizumab followed by maintenance pembrolizumab and pemetrexed cost $618,889. Four cycles of carboplatin/pemetrexed followed by pemetrexed maintenance cost $249,972. Pembrolizumab alone for an equivalent number of cycles cost $368,917. Table 1: Regimen Cost Calculations Figure 1
Conclusion:
While the addition of pembrolizumab to front-line therapy resulted in an improvement in PFS in a phase II study of 123 patients, it increased medication costs 2.4 fold, from $249,972 to $618,889. Phase III trials are underway to more definitively assess the benefit of immunotherapy administered with chemotherapy in a broad population of patients. Treatment with carboplatin/pemetrexed/pembrolizumab cost 1.7 times that of pembrolizumab alone, and the addition of chemotherapy is of unclear benefit for patients with high PD-L1 expression. Further defining patient subsets who will benefit the most from this costly regimen should be undertaken. It is crucial healthcare professionals and patients understand the cost implications of front line therapy options.
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MA 03.10 - Prognostic Factors in NSCLC Patients Treated with a Fourth-Line Therapy (ID 7455)
12:05 - 12:10 | Presenting Author(s): Vincent Leroy | Author(s): J. Labreuche, T. Gey, G. Terce, M.C. Willemin, X. Dhalluin, E. Wasielewski, A. Scherpereel, Alexis B Cortot
- Abstract
- Presentation
Background:
Emergence of new active drugs and improvement in supportive care make it more likely for patients with advanced NSCLC to receive a fourth-line therapy.However, no survival benefit of such treatment has ever been demonstrated yet, although some studies suggest that it may be effective in selected patients. A better selection could avoid exposing patients to futile and toxic treatments. We conducted a study aiming at identifying prognostic factors in patients with advanced NSCLC treated with a fourth-line therapy.
Method:
In this retrospective, multicentric study, patients with advanced NSCLC receiving a fourth-line therapy were included. Factors associated with prolonged overall survival (OS, defined as OS >6 months) were identified by univariate and multivariate analysis using a Forward method.
Result:
151 patients were included in this study between Jan 2015 and Dec 2016. Median age was 60 (range 55-64). Most patients were male (70%) and had adenocarcinoma (72%). Most common prior treatments included platinum-based chemotherapy (92%), single-agent chemotherapy (81%), targeted therapies (46%) and immunotherapy (9%). Median OS was 7.39 months (6.7-9.43). Nine factors were significantly associated with OS >6 months: current smoker (Hazard Ratio (HR) 1.99, 95% confidence interval[1.16-3.41]), former smoker (HR 0.51[0.30-0.98]), Karnofsky Index (KI) ≥ 90% at the start of fourth-line therapy (HR 0.35[0.19-0.65]), weight loss since first-line therapy (HR 1.85[1.06-3.23]), early stage at diagnosis (HR 0.48[0.24-0.96]), number of cycles and delay since first-line therapy (HR 0.94[0,89-0,99]and 0.99[0.99-1]), Progressive Disease (PD) as Best Objective Response (BOR) in the first 3 lines of treatment (HR 2.92[1.9-5.37]), absence of grade ≥ 3 Adverse Events (AEs) during first-line therapy(HR 0.54[0.31-0.94]). Among them, 4 independent variables were found to be statistically significant by multivariate analysis, including early stage at diagnosis (HR 0.37[0.16-0.58]), absence of grade ≥ 3 AEs during first-line therapy (HR 0.56[0.32-0.98]), PD as BOR in the first 3 lines of treatment (HR 3.06[1.64 -5.73]) and KI ≥ 90% at the start of fourth-line therapy (HR 0.31[0.16-0.58]).
Conclusion:
We highlighted 4 factors significantly associated with OS >6 months in patients treated with fourth-line advanced NSCLC. These factors need to be prospectively assessed to confirm if they could help identifying patients who may benefit from fourth-line therapy.
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MA 03.11 - Targeting CDCA3 Enhances Sensitivity to Platinum-Based Chemotherapy in Non-Small Cell Lung Cancer (ID 9607)
12:10 - 12:15 | Presenting Author(s): Mark N Adams | Author(s): J. Burgess, D. Richard, Kenneth Obyrne
- Abstract
- Presentation
Background:
Lung cancer is the leading cause of cancer-related mortality worldwide with a 5 year survival rate of 15%. Non-small cell lung cancer (NSCLC) is the most commonly diagnosed form of lung cancer. Cisplatin-based regimens are currently the most effective chemotherapy for NSCLC, however, chemoresistance poses a major therapeutic problem. New and reliable strategies are required to avoid drug resistance in NSCLC. Cell division cycle associated 3 (CDCA3) is a key regulator of the cell cycle. CDCA3 modulates this process by enabling cell entry into mitosis through degradation of the mitosis-inhibitory factor WEE1. Herein, we describe CDCA3 as a novel prognostic target to delay or prevent cisplatin resistance in NSCLC.
Method:
CDCA3 expression was investigated using bioinformatic analysis, tissue microarray immunohistochemistry and western blot analysis of matched NSCLC tumour and normal tissue. CDCA3 function in NSCLC was determined using several in vitro assays by siRNA depleting CDCA3 in a panel of three immortalized bronchial epithelial cell lines (HBEC) and seven NSCLC cell lines. To determine strategies to suppress CDCA3 activity the phosphorylation status of CDCA3 was assessed using mass spectrometry analysis. Kinases that phosphorylate CDCA3 were identified using a siRNA screen and high content immunofluorescence and microscopy approaches.
Result:
We have previously shown that CDCA3 transcripts and protein levels are elevated in resected NSCLC patient tissue, high mRNA levels being associated with poor survival. CDCA3 depletion markedly impairs proliferation in seven NSCLC cell lines by inducing a G2 cell cycle arrest. Silencing of CDCA3 also greatly sensitises NSCLC cell lines to cisplatin. Consistently, NSCLC patients with elevated CDCA3 levels and treated with cisplatin have a poorer outcome than patients with reduced CDCA3 levels. To aid patient response to cisplatin, we have been looking at strategies to suppress CDCA3 expression in tumour cells. Accordingly, in response to cisplatin, CDCA3 is phosphorylated (S[222]) via casein kinase 2 (CK2) which prevents CDCA3 degradation in NSCLC cells. Moreover, the CK2 inhibitor CX-4945 reduces CDCA3 levels in cisplatin treated cells. CX-4945 increased cisplatin-induced cell death in control cells. The efficacy was further enhanced in CDCA3 depleted NSCLC cells.
Conclusion:
Our data highlight CDCA3 as a novel factor in the pathogenesis of NSCLC. We propose that preventing cisplatin-induced CDCA3 phosphorylation by targeting CK2 is a worthwhile and novel strategy in treating NSCLC and may ultimately benefit patient outcome by preventing cisplatin resistance.
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MA 03.12 - Discussant - MA 03.09, MA 03.10, MA 03.11 (ID 10810)
12:15 - 12:30 | Presenting Author(s): Mary Obrien
- Abstract
- Presentation
Abstract not provided
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Author of
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MA 16 - Mediastinal, Tracheal and Esophageal Tumor: Multimodality Approaches (ID 675)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:K. Shibuya, Francoise Mornex
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 313 + 314
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MA 16.02 - Different Pattern and Prognostic Role of PD-L1, IDO, and Foxp3 Treg Expression in Thymoma and Thymic Carcinoma (ID 8796)
15:50 - 15:55 | Author(s): W. Su
- Abstract
- Presentation
Background:
The immune checkpoint ligand programmed cell death 1 ligand (PD-L1) is expressed in various tumors, and the expression of indoleamine 2,3-dioxygenase (IDO) and Foxp3 Tregs are associated with tumor-induced tolerance and reported to be responsible for worse survival. Their prognostic role in thymoma and thymic carcinoma, however, has not been investigated.
Method:
A tissue microarray comprised of 100 surgically treated thymomas and 69 surgically treated thymic carcinomas was evaluated. PD-L1, IDO, and Foxp3 Treg staining was scored based on intensity as follows: 0 = none, 1 = equivocal/uninterpretable, 2 = weak, and 3 = intermediate-strong. The PD-L1, IDO, and Foxp3 Treg expression score was calculated using a semiquantitive method by multiplying the intensity [0-3] by the staining area [0-100%]. Those cases with all cores scoring three and 2 in more than 50% in the staining area were categorized as PD-L1, IDO, and Foxp3 Treg high expression and the remaining as low expression. Clinical information was also collected on age, sex, Masaoka staging, tumor histology, surgical radicality, and locoregional invasion. Statistical associations were evaluated using χ[2] test and Fisher’s exact test. Progression-free survival and overall survival curves were established by the Kaplan-Meier method and compared using a log-rank test.
Result:
Figure 1Figure 2Thirty-six (36%) thymoma and 25 (36%) thymic carcinoma cases revealed high expression of PD-L1. PD-L1 expression in thymoma is significantly associated with Masaoka staging (p<0.001), tumor histology (p<0.001). Although there was a trend toward worse progression-free and overall survival in thymoma and thymic carcinoma with high-expression of PD-L1, only the progression-free survival in thymoma was significantly worse (p=0.024). High expression of IDO was detected in 13 (13%) thymoma and 10 (14%) thymic carcinoma cases, whereas Foxp3 Treg was detected in 16 thymoma (16%) and 20 (29%) thymic carcinoma cases. The expressions of IDO and Foxp3 Treg were significantly associated with tumor histology in thymoma (p=0.002 and 0.016, respectively), but not in thymic carcinoma. Thymic carcinoma with high expression of IDO had a trend toward worse progression-free and overall survival trend (p=0.109 and 0.053, respectively). High expression of Foxp3 Treg, however, was significantly associated with better progression-free survival (p=0.006) and overall survival (p=0.007) in thymic carcinoma.
Conclusion:
This is the largest-scale study to evaluate PD-L1 expression in thymic epithelial tumors. Although high expression of PD-L1 might be associated with worse prognosis in thymoma and thymic carcinoma, further investigation into PD-L1, IDO, and Foxp3 Treg should be conducted to benefit anti-PD-L1 immunotherapy for thymic epithelial tumor.
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OA 09 - EGFR TKI Resistance (ID 663)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Thanyanan Reungwetwattana, Lecia V Sequist
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 301 + 302
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OA 09.03 - TATTON Ph Ib Expansion Cohort: Osimertinib plus Savolitinib for Pts with EGFR-Mutant MET-Amplified NSCLC after Progression on Prior EGFR-TKI (ID 8985)
11:20 - 11:30 | Author(s): W. Su
- Abstract
- Presentation
Background:
MET amplification is a well described mechanism of acquired resistance to EGFR inhibition in EGFR-mutant NSCLC, making combined MET/EGFR inhibition a compelling therapeutic approach. We previously reported tolerability of the oral, CNS active, third-generation EGFR-TKI osimertinib, which is selective for both EGFR-TKI sensitizing and EGFR T790M resistance mutations, combined with the highly selective MET-TKI savolitinib (volitinib, HMPL-504, AZD6094). Here we assess safety and preliminary activity of this combination in a cohort of patients (pts) with EGFR-mutant NSCLC and MET-positive acquired resistance in the multi-arm, Phase Ib TATTON study (NCT02143466).
Method:
Eligible pts were aged ≥18 years (WHO performance status 0/1) with locally advanced or metastatic EGFR-mutant NSCLC who progressed on at least one prior EGFR-TKI with centrally confirmed MET-amplification (fluorescence in-situ hybridisation, MET gene copy ≥5 or MET/CEP7 ratio ≥2). Pts received osimertinib 80 mg QD plus savolitinib 600 mg QD. Primary objective was safety and tolerability; secondary objectives included preliminary assessment of anti-tumour activity and pharmacokinetics.
Result:
As of data-cut off (15 April 2017), 45 pts with centrally confirmed MET-amplification (FISH) were enrolled and received treatment, including 25 pts previously treated with a third-generation EGFR-TKI and 20 without prior third-generation EGFR-TKI treatment (T790M negative n=13; T790M positive n=7). At baseline, median age was 58 years (range 38–76), 24 (53%) were female, 36 (80%) were Asian. The most frequent adverse events (AEs) were nausea (n=21, 47%), decreased appetite (n=15, 33%), fatigue (n=13, 29%) vomiting (n=13, 29%), rash (n=11, 24%), myalgia (n=8, 18%), pyrexia (n=7, 16%), ALT/AST increased (n=6, 13%), and WBC decreased (n=6, 13%), consistent with the known safety profiles. Serious AEs were reported in 15 (33%) pts; events reported in >1 patient were pneumonia, dyspnoea, acute kidney injury and pyrexia (all n=2). Four pts died due to AEs, none were considered related to study drugs. At data cut-off, confirmed partial responses were reported in 5/25 (20%) pts previously treated with a third-generation EGFR-TKI; 5/12 (42%) T790M negative pts without prior third-generation EGFR-TKI and 3/7 (43%) T790M positive pts without prior third-generation EGFR‑TKI. Twenty-eight (62%) pts are ongoing treatment. Preliminary steady-state exposures and pharmacokinetic parameters of savolitinib and osimertinib were consistent with historical data.
Conclusion:
These findings demonstrate promising safety, tolerability, and preliminary activity of osimertinib plus savolitinib and support further investigation of this combination for the treatment of pts with locally advanced or metastatic EGFR-mutant NSCLC and MET-amplification. Updated data will be presented.
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-048 - Clinical Impact of EGFR Mutation on Brain Metastasis in NSCLC Patients: A Meta-Regression Analysis (ID 7312)
09:30 - 09:30 | Author(s): W. Su
- Abstract
Background:
Though target agents like epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) have shown activity in patients with brain metastasis, the impact of EGFR mutation on incidence of non-small cell lung cancer (NSCLC) with brain metastasis and treatment outcome remain inconclusive.
Method:
MEDLINE, PubMed, and EBSCO Libraries were systematically searched until August 31, 2015. Retrospective studies including investigating the correlation between EGFR mutation status with brain metastasis from NSCLC were included.
Result:
The result of the fourteen studies including 4432 patients indicated NSCLC patients with EGFR mutation have higher incidence of brain metastasis (Figure 1, odd ratio = 2.09, 95% CI: 1.72–2.53). And, EGFR mutations were associated with better survival in patients with brain metastasis from five studies though not statistically significant (Figure 2, hazard ratio = 0.47, 95% CI: 0.16–1.35). Figure 1. Meta-analysis of the association between EGFR mutation status and the risk of brain metastasis. Figure 1 Figure 2. Meta-analysis on mean overall survival among NSCLC patients with brain metastasis according to EGFR mutation status. Figure 2
Conclusion:
We found that EGFR mutation increased risk of brain metastasis but EGFR mutation might predict better survival with appropriate treatments.
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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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P2.03-058 - Tiger-3: A Phase 3 Randomized Study of Rociletinib Vs Chemotherapy in EGFR-mutated Non-small Cell Lung Cancer (NSCLC) (ID 8395)
09:30 - 09:30 | Author(s): W. Su
- Abstract
Background:
Rociletinib, an oral, irreversible tyrosine kinase inhibitor (TKI), selectively targets activating mutations in EGFR and the acquired resistance mutation T790M and demonstrated antitumor activity in the phase 1/2 TIGER-X study (NCT01526928). Initial results are reported from the TIGER-3 study (NCT02322281) of rociletinib vs chemotherapy in EGFR TKI-resistant patients with EGFR-mutated NSCLC.
Method:
Eligibility criteria included: metastatic or unresectable, locally advanced, EGFR-mutated NSCLC; radiological progression on most recent TKI therapy; ≥1 line of platinum doublet chemotherapy. Patients were not selected based on T790M status. Patients (N=900) were to be randomized (1:1:1) to rociletinib 500 or 625 mg BID or investigator’s choice of chemotherapy (pemetrexed, gemcitabine, docetaxel, or paclitaxel). The primary endpoint was investigator-assessed progression-free survival (PFS) (RECIST v1.1); objective response rate (ORR) was a secondary endpoint. The rociletinib dosing groups were combined and compared with chemotherapy in a step-down procedure (patients with a centrally confirmed T790M mutation, followed by all randomized patients).
Result:
TIGER-3 enrollment was halted upon discontinuation of rociletinib development in NSCLC in 2016; therefore, target enrollment was not achieved. TIGER-3 enrolled 75 patients in the rociletinib groups [500 mg BID, n=53; 625 mg BID, n=22] and 74 in the chemotherapy group. Median age was 62 years, 69.1% had ECOG Performance Status of 1, 39.6% were Asian, 58.4% were female, and median number of prior therapies was 3. PFS and ORR data are presented in the Table. The most common adverse events (all grade; grade ≥3) in the rociletinib group were diarrhea (62.7%; 2.7%), hyperglycemia (58.7%; 24.0%), nausea (37.3%; 4.0%), fatigue (37.3%; 8.0%), and decreased appetite (37.3%; 0%) and in the chemotherapy group were nausea (27.4%; 5.5%), anemia (24.7%; 2.7%), and fatigue (24.7%; 9.6%).Outcome Centrally Confirmed T790MPositive Centrally Confirmed T790MNegative Intent-to-Treat Population* Rociletinib[†] (n=25) Chemotherapy (n=20) Rociletinib[†] (n=36) Chemotherapy (n=41) Rociletinib[†] (n=75) Chemotherapy (n=73) Median PFS, mo (95% CI) 6.8 (3.7–12.2) 2.7 (1.3–7.0) 4.1 (2.5–4.6) 1.4 (1.3–2.7) 4.1 (2.8–5.5) 2.5 (1.4–2.9) HR (95% CI) 0.570 (0.285–1.140); P=0.105 0.532 (0.322–0.878); P=0.011 0.609 (0.423–0.875); P=0.006 Confirmed ORR, n (%) [95% CI] 9 (36.0) [18.0%–57.5%] 3 (15.0) [3.2%–37.9%] 3 (8.3) [1.8%–22.5%] 2 (4.9) [0.6%–16.5%] 13 (17.3) [9.6%–27.8%] 6 (8.2) [3.1%–17.0%] *Includes patients with undetermined T790M mutation status. [†]Rociletinib 500 mg BID and 625 mg BID dose groups were pooled for the analysis. CI, confidence interval; HR, hazard ratio.
Conclusion:
Incomplete enrollment precluded hypothesis testing. However, the data show a trend toward longer PFS and higher ORR with rociletinib.
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P2.10 - Nursing/Palliative Care/Ethics (ID 711)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Nursing/Palliative Care/Ethics
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.10-001 - Factors Associated with Quality of Life among Patients with Lung Cancer (ID 8710)
09:30 - 09:30 | Author(s): W. Su
- Abstract
Background:
Lung cancer is the third incidence and first mortality of cancer disease in Taiwan. The survival time of lung cancer patients was extended. The overall 2 year survival rate from 29% to 49.8% at National Cheng Kung University Hospital (NCKUH). Factors associated with quality of life have become the issues of focus and need to be elucidated as the improvements of medical science prolong the survival of patients with lung cancer.The purpose of this study was to describe the long-term trend on the quality of life of patients with lung cancer, and to understand the related factors.
Method:
This was a retrospective study with secondary data analysis and chart review. The study samples were lung cancer patients who were diagnosed from 2005 to 2012 at NCKUH and joined WHOQOL interview research program. We assessed personal characteristic, health status, lung cancer disease status and treatment. The authors analyzed secondary databases included the NCKUH cancer registration database and the NCKUH Cancer QoL Study database. The analyzing protocol was also approved by the institutional ethics committee. Using SAS 9.3 software, the regression models and mixed-models were constructed to explore related factors and the time trend of QoL.
Result:
Total 1887 questionnaires were included in research. The proportion of female subject was 47.7%. Figure 1
Conclusion:
The physical, psychological, environment domains and global QoL among lung cancer patients was improved over time, which showed the promising quality of treatment and care in NCKUH. The factors associated with QoL among patients with lung cancer include gender, age, married status, employment status, income, and with chronic kidney disease or brain metastasis. More resources are to be explored for patients who are single or have lower income, and special attention should be paid to patients who are unemployed, female, elder, or to under radiotherapy that would improve their QoL.
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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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P3.01-036 - A Phase IIIb Open-Label, Single-Arm Study of Afatinib in EGFR TKI-Naïve Patients with EGFRm+ NSCLC: An Interim Analysis (ID 9251)
09:30 - 09:30 | Author(s): W. Su
- Abstract
Background:
In the Phase III LUX-Lung (LL) 3 and LL6 trials, first-line afatinib significantly improved PFS vs platinum-doublet chemotherapy in patients with EGFRm+ NSCLC (independent review; LL3: 11.1 vs 6.9 months, HR=0.58; p=0.001; LL6: 11.0 vs 5.6 months, HR=0.28; p<0.0001). In the Phase IIb LL7 trial, afatinib significantly improved PFS and TTF vs gefitinib in patients with EGFRm+ NSCLC harboring common EGFR mutations (PFS, independent review: 11.0 vs 10.9 months, HR=0.73; p=0.017; TTF: 13.7 vs 11.5 months, HR=0.73, p=0.0073). Here we report interim analysis results of a large Phase IIIb study of afatinib in a broad population of EGFR TKI-naïve patients with EGFRm+ NSCLC.
Method:
In this Phase IIIb trial with a similar setting to ‘real-world’ practice, EGFR TKI-naïve patients with locally advanced/metastatic EGFRm+ NSCLC were recruited from centers in China, Hong Kong, India, Singapore and Taiwan and received afatinib 40mg/day until investigator-assessed progression or lack of tolerability. Primary endpoint: number of patients with serious adverse events (SAEs). Secondary endpoints included: number of patients with afatinib-related AEs; time to symptomatic progression (TTSP). Other assessments included PFS (investigator review).
Result:
At data cut-off (13 Feb 2017) 479 patients were treated with afatinib (median age: 59.0 years; female: 52.4%; common [(Del19 and/or L858R) with or without uncommon]/uncommon only EGFR mutations: 86.0%/14.0%; ECOG PS 0/1: 19.8%/78.1%; brain metastases: 19.2%; 0/1/≥2 lines of prior chemotherapy: 59.7%/30.1%/10.2%. 24.8% of patients required dose reductions to 30mg; 6.1% had further reductions to 20mg. Median (range) treatment time was 9.7 months (0.2–38.6). SAEs were reported in 115 (24.0%) patients and afatinib-related SAEs in 29 (6.1%) patients. Grade ≥3 afatinib-related AEs occurred in 122 (25.5%) patients; diarrhea (n=50; 10.4%) and rash/acne (n=38; 7.9%) were the most common (≥5%). 18 (3.8%) patients discontinued treatment due to afatinib-related AEs. Median TTSP (15.3 months [95% CI: 13.4–17.5]) was 3 months longer than PFS (12.1 months [10.8–13.7]), suggesting afatinib may be continued beyond progression, and both were longer in patients with common (with/without uncommon) vs uncommon only EGFR mutations (PFS: 12.6 vs 9.1; TTSP: 15.8 vs 10.0 months).
Conclusion:
The safety data of afatinib from this interim analysis of a large-scale population of EGFR TKI-naïve EGFRm+ NSCLC patients are consistent with LL3/6/7 and confirm that most afatinib-related AEs are manageable and result in few treatment discontinuations. Afatinib also demonstrated encouraging efficacy in patients with common and uncommon EGFR mutations. Data from larger patient populations will be evaluated in further analyses of this trial.
