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Jin-Hyoung Kang
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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OA 05 - Next Generation TKI (ID 657)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:James Chih-Hsin Yang, Fiona Blackhall
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 301 + 302
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OA 05.03 - Clinical Activity of ASP8273 in Asian Non-Small Cell Lung Cancer Patients with EGFR Activating and T790M Mutations (ID 7889)
16:05 - 16:15 | Author(s): Jin-Hyoung Kang
- Abstract
- Presentation
Background:
Epidermal growth factor receptor (EGFR) activating mutations confer sensitivity to tyrosine kinase inhibitor (TKI) treatment for non-small cell lung cancer (NSCLC) and occur in ~50% of East Asian patients with NSCLC. While initial TKI treatment can be effective, acquired resistance inevitably develops with a secondary mutation (T790M). ASP8273 is a highly specific, irreversible, once-daily, oral, EGFR TKI which inhibits both activating (eg, exon 19 deletions, L858R) and resistance (eg T790M) mutations.
Method:
This dose-escalation/dose-expansion study (NCT02192697) was conducted in two phases. In Phase 1, adult Japanese patients (≥20 yr) with NSCLC previously treated with ≥1 EGFR TKI were enrolled and received escalating ASP8273 doses (25–600mg) to assess safety/tolerability as well as to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). In phase 2, adult T790M-positive NSCLC patients in Japan, Korea, and Taiwan were enrolled to further define the ASP8273 safety/tolerability profile at RP2D and determine antitumor activity (assessed using RECIST v1.1). Antitumor activity in phase 2 was evaluated according to Simon’s 2-stage design (uninteresting response=0.3, desired response=0.5, α=0.05, β=0.1). If ≥9 of 24 ASP8273-treated patients achieved a desired response in the first stage, then 39 additional patients would be enrolled. If ≥ 25 of the 63 total patients achieved response, ASP8273 would be considered to have antitumor effects.
Result:
A total of 123 patients (n=47 phase 1; n=76 phase 2) were enrolled. In both phases, more women were enrolled. The median age was 65 years in phase 1 and 63 years in phase 2. Based on phase 1 findings, MTD and RP2D were 400mg and 300mg, respectively. As 27 of the 63 patients treated with ASP8273 300mg in the first and second stages combined achieved a clinical response (based on independent central review), ASP8273 was determined to have antitumor activity (ORR=42.9%; 95% CI: 30.5–56.0). The ORR at week 24 in all patients in the full analysis set was 42.1% (n=32/76; 95% CI: 30.9, 54.0). The median duration of PFS (central review) was 8.1 months (95%CI: 5.6,--). The most commonly reported treatment-emergent AEs (TEAE) in phase 2 were diarrhea (n=50/76), nausea (n=31/76), increased alanine aminotransferase (n=27/76), decreased appetite and vomiting (n=26/76 each), and hyponatremia (n=25/76). Drug-related TEAEs were reported in 93.4% (n=71/76) of patients, the most common of which was diarrhea (n=43/76).
Conclusion:
ASP8273 was generally well tolerated and demonstrated antitumor activity in Asian patients with both EGFR activating and T790M mutations.
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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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P1.01-070 - BIW-8962, an Anti-GM2 Ganglioside Monoclonal Antibody, in Advanced/Recurrent Lung Cancer: A Phase I/II Study (ID 10421)
09:30 - 09:30 | Author(s): Jin-Hyoung Kang
- Abstract
Background:
GM2 ganglioside is a tumor-associated antigen that is overexpressed in a high proportion of several malignancies, e.g. SCLC, NSCLC, mesothelioma, melanoma, neuroblastoma, multiple myeloma. BIW-8962 is a recombinant, humanized, non-fucosylated immunoglobulin G1 monoclonal antibody to GM2 ganglioside that shows pre-clinical activity towards lung cancer cell lines and in an animal model bearing SCLC xenografts. The aim of this study was to determine the safety and preliminary clinical efficacy of BIW-8962 administered as monotherapy in patients with previously treated lung cancer.
Method:
In phase I, patients (N=16) with advanced, recurrent lung cancer (8 each with SCLC and NSCLC) received increasing doses of BIW-8962 (1–10 mg/kg) intravenously every 3 weeks using a standard 3+3 design to determine the maximum tolerated dose (MTD). The highest dose (10 mg/kg) was administered to patients with advanced, recurrent SCLC (N=21) in phase II.
Result:
It was only possible to obtain pre-study biopsy samples for two patients, both of which showed cell surface GM2 overexpression of moderate intensity on immunohistochemistry testing. In phase I and II, all patients received the total planned dose. There were no dose-limiting toxicities in phase I and the MTD was not established. BIW-8982 10 mg/kg therefore used as the recommended phase II dose. The phase II study was prematurely terminated due to lack of efficacy. The objective response rate was 5.0% (95% CI, 0.1%–24.9%) in the efficacy evaluable population (N=20). Median overall survival was 304.0 days (95% CI, 70.0–406 days) and median progression free survival (PFS) was 43.0 days (95% CI, 38.0–43.0 days). One patient showed a durable partial response with PFS of 463 days and response duration of 382 days. There were a few patients with stable disease, which was generally not durable. No pattern of consistent toxicity was observed across the phases: there were no treatment-related adverse events (AEs) Grade ≥3, serious AEs, AEs leading to discontinuation of BIW-8962, or deaths. No unexpected trends or safety concerns were identified from laboratory parameter, vital sign, or electrocardiogram assessments. Anti-BIW-8962 antibodies were not detected in serum of any patient before or following treatment. Exploratory analysis of circulating tumor cells and other potentially predictive or pharmacodynamic markers did not reveal any results consistent with an effect from BIW-8962.
Conclusion:
This study was prematurely terminated due to lack of efficacy, for which the reason is unknown. Clinical development of BIW-8962 has been discontinued.
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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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P2.03-022 - Impact of EGFR Mutation on Clinical Outcome of Nintedanib plus Docetaxel in Previously Treated Non- Small Cell Lung Cancer (NSCLC) (ID 8720)
09:30 - 09:30 | Presenting Author(s): Jin-Hyoung Kang
- Abstract
Background:
Anti-angiogenic agents have been reported to have clinical activity EGFR mutant NSCLC with/without EGFR Tyrosine kinase inhibitor (TKI). We reported clinical outcomes of nintedanib plus docetaxel in refractory NSCLC according to EGFR mutation status during a Korean nintedanib NPU program.
Method:
Patients with NSCLC were eligible if they failed at least one prior systemic treatment. Docetaxel was administered either 75mg/m[2] or 37.5mg/m[2] on D1, D8 q every 3weeks plus nintedanib 200mg orally twice daily. Nintedanib treatment was continued until disease progression or unacceptable toxicity after 4-6 cycles of combination therapy.
Result:
62 patients were enrolled. 28 patients with activating EGFR mutation (17 in exon19 deletion, 8 exon21 L858R/L861Q, 1 exon 18 G719X, 1 in exon20 duplication, 1 in exon19 deletion and exon20 T790M) progressed after EGFR-TKI, 25/28 patient also progressed after platinum doublet chemotherapy were enrolled. Only for 2 patients EGFR mutation status were unknown. Patients were heavily pretreated, with 38.7% patients receiving nintedanib plus docetaxel as ≥ 4[th] line therapy. 5 patients had received bevacizumab. For patients with response assessment reported objective response rate was 30.6% and median PFS and OS were 3.9 months (95% CI 3.4-4.4) and 11.7months (95% CI 5.2-18.1) respectively in overall patients. Based on EGFR mutation status, objective response rate was 52.1% vs 24.1% (EGFR mut(+) vs EGFR mut (-), p=0.47) and median PFS was 5.9 vs 3.6 months (EGFR mt(+) vs EGFR mt(-), p=0.031). No treatment related death was reported. Common grade 3/4 adverse event were neutropenia (33.8 %), and reversible elevated liver enzyme(9.7%). 10 patients in 150mg twice daily and 2 patients with 100mg twice daily administered grade 3 adverse events. Figure 1
Conclusion:
Nintedanib plus docetaxel was well-tolerated and had clinical activity in refractory NSCLC. Specifically, EGFR TKI resistant EGFR mutant NSCLC may be a good candidate for nintedanib plus docetaxel.
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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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P3.01-050 - A Real World Treatment Study of Osimertinib: ASTRIS Study Korean Subgroup Analysis (ID 9678)
09:30 - 09:30 | Author(s): Jin-Hyoung Kang
- Abstract
Background:
ASTRIS (NCT02474355) is an open-label, single-arm, multination, real world treatment study, investigating the safety and efficacy of osimertinib in patients with T790M-positive advanced non-small cell lung cancer (NSCLC), who have previously received EGFR-TKI. We report the first results of Korean subset from ASTRIS which is the largest real world treatment study of osimertinib to date.
Method:
Eligible patients had advanced NSCLC harbouring a T790M mutation determined by local validated molecular tests, received prior EGFR-TKI therapy, acceptable organ and bone marrow function and no history of interstitial lung disease (ILD) or QTc prolongation. Enrollment of patients with asymptomatic, stable CNS metastases were permitted. Patients received osimertinib 80 mg once daily. The primary efficacy outcome was overall survival; other outcomes included investigator-assessed response rate (RR), progression-free survival (PFS) and time to treatment discontinuation (TTD). Safety assessment was also conducted. Data cut-off (DCO) was 3 November 2016; results from 1,217 patients in the global study have been presented previously (ASCO 2017 Abstract 9036).
Result:
A total of 371 patients received at least one dose of osimertinib from 30 Korean sites (full analysis set); at DCO, 319 patients (81.4%) were ongoing and median follow-up time was of 3.1 (0–8) months. Baseline patients’ characteristics were median age 61.1 (27–85) years old, female 65.5%, PS 0/1 88%, prior chemotherapy 47%, prior radiotherapy 48%. Tissue was the most common specimen source to test T790M mutation as well as other EGFR mutations (287/371, 77.4%) and plasma was the next (39/371, 13.1%). Fifty two patients (13.3%) had discontinued treatment; median duration of exposure 3.3 (0–7) months, 30 pts (7.7%) had disease progression and 24 patients (6.5%) died. In patients evaluable for response, defined as at least one dose of osimertinib and one response assessment, the investigator-assessed RR was 72.1% (212/294; 95% CI 66.6 – 77.2). Due to limited follow-up period, OS, PFS, and TTD were immature to analyze. Adverse events (AEs) leading to dose modification and treatment discontinuation were reported in 26 patients (7%) and 14 patients (3.8%), respectively. Serious AEs were reported in 50 patients (13.5%) and AEs leading to death in 8 patients (2.2%). ILD/pneumonitis-like events were reported in 9 patients (2.4%), and QTc prolongation (>470ms) in 5 patients (1.3%).
Conclusion:
At DCO for the 1[st] interim analysis of ASTRIS, Korean subgroup results demonstrated similar clinical activities (RR) to that observed in the osimertinib clinical trial program with no new safety signals.
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P3.08 - Locally Advanced Nsclc (ID 724)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.08-003 - Multimodal Treatment in the Initially Inoperable Stage III N2 Non-Small Cell Lung Cancer Patients (ID 10088)
09:30 - 09:30 | Author(s): Jin-Hyoung Kang
- Abstract
Background:
A multimodal treatment is frequently performed in many initially inoperable stage III N2 non-small cell lung cancer. However, selection of the best treatment for these patients is controversial issue. This study was conducted to explore the benefit of neoadjuvant chemotherapy and adjuvant therapy in these patients.
Method:
Between Jan. 2008 and Dec. 2015, patients with stage III N2 NSCLC enrolled. All of them were treated with induction chemotherapy and surgical resection. Some of them who had high risk factors for disease recurrence underwent adjuvant treatment including chemothearpy, radiothearpy or concurrent chemoradiotherapy.We reviewed medical record including clinicopathologic characteristics and the survival outcome.
Result:
The median age was 65 (range 43-77), and male was more common (M:F, 3.8:1). Median follow-up period was 23.6 months (Range: 3.0-23.6 months). 32 patients (59.%) presented with squamous cell cancer (SqCC), and 20 patients (37.0%) were presented as adenocarcinoma. Docetaxel/cisplatin in 52 patients (96.3%) and gemcitabine/cisplatin in 2 patients (3.7%) were selected as neoadjuvant chemotherapy regimen. The overall clinical response rate to induction chemotherapy was 70.4%. After surgical resection, 27 patients (50.0%) underwent adjuvant chemotherapy alone and 20 patients (37.0%) underwent adjuvant radiotherapy with or without chemotherapy. Median OS was 56.4 months (range 33.5-79.3 months) and median PFS was 24.4 months (ranage 26.6-43.0 months). In multivariable analysis, the adjuvant treatment group showed better survival than the no adjuvant treatment group. Among them, median OS was not reached in adjuvant radiotherapy with or without chemotherapy group and 53.9 months in the adjuvnat chemotherapy alone group (p=0.016).
Conclusion:
Neoadjuvant chemotherapy is active in patients with stage III N2 NSCLC and adjuvant multimodal therapy including chemotherapy or radiotherapy demonstrated favorable survival outcomes. Based on our data, active multimodal neoadjuvant and postadjuvant treatment should be considered for the initially unoperable stage III N2 NSCLC patients.
