ESMO2014摘要汇总

ESMO2014 摘要汇总（晚期及转移性肺癌部分）

2楼：克唑替尼对比基于铂类的化疗对患者自诉症状以及全局生活质量(quality of life, QoL)的影响，一项对未经治疗的ALK阳性的晚期NSCLC患者的三期临床研究

3楼：日本在晚期EGFR阴性的NSCLC患者中出现RET融合突变的全国范围内的基因组筛查，以及对应分子靶向药物的研发情况:\LC-SCRUM-Japan研究

4楼：EGFR抑制剂在具有G719X/L861Q/S768I突变的晚期NSCLC患者中的治疗响应

5楼：口服PI3K/mTOR双靶点抑制剂GDC-0908联合卡铂/紫杉醇±贝伐单抗和顺铂/培美曲塞在晚期实体瘤和NSCLC患者的1b期临床研究

6楼：HSP90抑制剂AT13387单药和联合克唑替尼(CZT)对NSCLC的临床研究

7楼：1199PD-MET蛋白表达在欧洲NSCLC患者中的发生率及其临床结局: 来自欧洲胸部肿瘤学平台Lungscape项目的研究结果

8楼：一项随机、开放标签的对比阿法替尼和厄洛替尼作为晚期肺鳞癌患者一线接受基于铂类的化疗之后的二线治疗的三期临床试验：LUX-Lung 8(LL8)

9楼：ASPIRATION: 在EGFR阳性的亚洲患者中一线采用厄洛替尼(E)治疗至疾病进展后继续使用的研究

10楼：alectinib在接受克唑替尼治疗后的ALK重排NSCLC患者中的抗肿瘤活性：JP28927研究

1226PD - Impact of crizotinib on patient-reported symptoms and global quality of life (QOL) compared with platinum based chemotherapy in phase III study of treatment naïve advanced ALK-positive non-small cell lung cancer (NSCLC)
1226PD - 克唑替尼对比基于铂类的化疗对患者自诉症状以及全局生活质量(quality of life, QoL)的影响，一项对未经治疗的ALK阳性的晚期NSCLC患者的三期临床研究

Aim 目标
The main objective of our analysis was to compare patient-reported symptom and global QOL improvement and worsening rates between crizotinib and platinum based chemotherapy in treatment naïve patients with advanced ALK-positive NSCLC in PROFILE 1014 study (Pfizer; NCT01154140).
我们分析的主要目的是在PROFILE 1014研究(Pfizer, NCT01154140)中未经治疗的ALK阳性晚期NSCLC患者中，对比克唑替尼和基于铂类的化疗对患者自诉症状和全局QoL的改善和恶化程度的影响

Methods 方法
Patients in the ongoing PROFILE 1014 study were randomized to crizotinib (250 mg PO bid; n= 172) or chemotherapy (pemetrexed 500 mg/m2 + either cisplatin 75 mg/m2 or carboplatin AUC 5–6; all IV q3w for ≤6 cycles; n= 171). Patient-reported outcomes were assessed at baseline, day 7 and day 15 of cycle 1, day 1 of subsequent 3-week cycles and end of treatment using EORTC QLQ-C30 and lung can¬cer module QLQ-LC13. Higher scores (range 0 − 100) indicated higher symptom severity or better functioning/QOL. A clinically meaningful change was defined as a ≥10-point change from baseline. The percentage of patients classified as having improved (≥10-point increase for functioning/QOL scales / ≥ 10-point reduction for symptoms in average of change from baseline scores across cycles for a patient) or worsened (≥10-point reduction for functioning / ≥ 10-point increase for symptoms in average of change from baseline scores across cycles) was examined and compared between treatment groups using chi-square tests.

Results 结果
Completion rates at baseline were ≥95% in each group and scores were balanced. A significantly (p < 0.05) greater percentage of patients on crizotinib versus chemotherapy arm showed improvement for global QOL (36 % vs. 19.6%), physical functioning (31.3% vs. 15.3%), fatigue (42.2% vs. 28.2%), cough (57.8% vs. 44.2%) and dyspnea (39.8% vs. 23.3%). Worsening rates were significantly (p < 0.05) higher with crizotinib for diarrhea (44% vs. 19.0%) and lower for alopecia (14.5% vs. 34.4%) and sore mouth (13.3% vs. 25.8%) compared to chemotherapy. No significant difference was observed for cognitive functioning, dysphagia and constipation.

Conclusions 总结
Treatment with crizotinib led to higher improvement rates in global QOL, physical functioning and key lung cancer symptoms compared with chemotherapy.

1227PD - Nationwide genomic screening for RET fusion in advanced EGFR mutation-negative non-squamous lung cancer and development of molecular targeted therapy in Japan: LC-SCRUM-Japan
1227PD - 日本在晚期EGFR阴性的NSCLC患者中出现RET融合突变的全国范围内的基因组筛查，以及对应分子靶向药物的研发情况:\LC-SCRUM-Japan研究

Aim 目标
EGFR mutations and ALK fusions have emerged as important oncogenic drivers in non–small cell lung cancer (NSCLC). RET fusion have identified as new drivers of lung adenocarcinomas and these fusions are reported to be promising druggable targets. However, RET fusion is encountered rather rarely, that is observed in only 1-2% of all lung adenocarcinomas.

Methods
This study was established in February 2013 as a new nationwide genomic screening project for developing individualized medicine of advanced NSCLC patients in Japan. Tumor samples of advanced EGFR mutation-negative non-squamous lung cancer patients were eligible for submission. The specimens were screened for RET, ROS1 and ALK fusions by RT-PCR and FISH methods.

Results
As of March 28th in 2014, The LC-SCRUM-Japan is under way with the participation of 161 institutions in Japan, under aid from the public research fund of the Ministry of Health, Labour and Welfare of Japan. 667 patients were enrolled to this study and 581 tumor samples of enrolled patients (87%) were screened. RET fusion was detected in 23 (4%) of the 581 patients. Seventeen (74%) patients were women, and all patients had adenocarcinoma. Median age was 61 years (range, 41-79). The majority of the patients (78%) were never-smoker. We have synchronously initiated a phase II trial of vandetanib for advanced RET fusion-positive NSCLC patients (LURET study) (UMIN000010095). 12 of 23 patients with positive for RET fusion determined in the LC-SCRUM-Japan have been already enrolled and just treated with vandetanib in the LURET study.

Conclusions
The prevalence of RET fusion in our enriched population was relatively higher compared with that reported in non-selected NSCLC population. This innovative screening project in Japan leads to the activation of screening for lung cancer with rare driver mutations and developing targeted therapy trials.

1228PD - Epidermal growth factor receptor tyrosine kinase inhibitor treatment response in advanced non-small cell lung cancer with G719X/L861Q/S768I mutations
1228PD - EGFR抑制剂在具有G719X/L861Q/S768I突变的晚期NSCLC患者中的治疗响应

Aim
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are very effective for lung cancers with classical sensitive EGFR mutations; however, their role in tumors with uncommon mutations, such as G719X, L861Q and S768I, is still not clear. Previous studies are limited by their small sample size. Taiwan Lung Cancer Society, in conjunction with Taiwan Lung Cancer Clinical Trial Consortium, initiated a study to evaluate the clinical effectiveness of EGFR-TKI in patients with advanced non-small cell lung carcinoma (NSCLC) bearing EGFR G719X, L861Q and/or S768I mutations.

Methods
Patients were eligible if they had stage IIIB or IV NSCLC bearing G719X, L861Q or S768I mutations, had been treated by gefitinib or erlotinib, and did not receive other anti-tumor therapy during EGFR-TKI treatment. Patients with tumors that had concomittant classical sensitive (exon 19 deletions and L858R mutation) or resistant (T790M and exon 20 insertions) mutations were excluded.

Results
Totally 226 cases were screened from 18 institutes throughout Taiwan. One hundred and sixty-one cases were eligible and all were adenocarcinomas. Among them, 56.5% were female, 68.8% were never smokers, 95.7% were stage IV, 76.4% were PS 0-1, and 78.9% were treatment-naive. EGFR mutation status were G719X of 78 cases, L861Q of 58, S768I of 7, G719X + L861Q of 8, and G719X + S768I of 10. One hundred and twenty-seven patients were treated by gefitinib and 34 by erlotinib. Four hundred and eighty-three patients who had classical sensitive EGFR mutations and were treated by EGFR-TKI were served as the control. EGFR-TKI treatment outcomes are summarized in the Table. Patients with G719X/L861Q/S768I mutations had inferior response rate and shorter progression free survival than patients with exon 19 deletions or L858R mutations (both P< 0.001).

	ORR	DCR	PFS
G719X/L861Q/S768I (n = 161)	40.5%	75.8%	7.7m
L858R mutations (n = 253)	67.6%	95.7%	10.4m
exon 19 deletions (n = 223)	64.5%	94.6%	14.1m

Conclusions
Patients with advanced lung adenocarcinomas of EGFR G719X/L861Q/S768I mutations had suboptimal treatment outcome to EGFR-TKI. Prospective randomized trials are warranted to decide the most appropriate therapy for patients with these uncommon mutations.

1230PD - Phase 1b study of oral dual-PI3K/mTOR inhibitor GDC-0980 in combination with carboplatin (Carbo)/paclitaxel (Pac) ± bevacizumab (Bev) and cisplatin (Cis)/pemetrexed (Pem) in patients (pts) with advanced solid tumors and NSCLC
1230PD - 口服PI3K/mTOR双靶点抑制剂GDC-0908联合卡铂/紫杉醇±贝伐单抗和顺铂/培美曲塞在晚期实体瘤和NSCLC患者中的1b期临床研究

Aim
The PI3K signaling pathway is altered in many tumor types, including NSCLC. GDC-0980 has single-agent activity as well as preclinical cytotoxic synergy with taxane and platinum agents and antiangiogenic synergy with anti-VEGF agents.

Methods
This Phase 1b study evaluated the safety and tolerability of GDC-0980 in combination with platinum-based chemotherapy (CT) and Bev in pts with advanced solid tumors (AST) or first-line advanced NSCLC: Arm A – Carbo (AUC 6) + Pac (200&#8195;mg/m2); Arm B – Carbo/Pac + Bev (15&#8195;mg/kg); Arm C - Cis (75&#8195;mg/m2) + Pem (500&#8195;mg/m2). On a 21-day cycle, CT regimens were administered on Day 1, and GDC-0980 PO QD on Days 1-14. Pharmacokinetic (PK) analyses were performed. Archival tumor tissue and blood samples for pharmacogenetic and ctDNA analyses were collected.

Results
Sixty-five pts (28 in Arm A [17 NSCLC]; 18 in Arm B [10 NSCLC]; 19 in Arm C [12 NSCLC]) were treated with GDC-0980 20 to 40&#8195;mg. For AST cohorts in Arms A and B, the MTD of GDC-0980 was 25&#8195;mg (DLTs were febrile neutropenia, rash, and fatigue). For NSCLC cohorts in Arms A and C, the maximum administered dose (MAD) was 30&#8195;mg GDC-0980. At this dose, Grade 3/4 adverse events (AEs) in >10% of all treated pts were neutropenia (59%), rash (24%), febrile neutropenia and anemia (12%) in Arm A and neutropenia (33%), anemia and fatigue (25%), hypertension, infection, and pneumonitis (17%) in Arm C. Other high-grade AEs of interest were less common: hyperglycemia in Arm A (6%) and Arm C (8%) and rash (8%) in Arm C. Among NSCLC pts treated with 30&#8195;mg GDC-0980, objective responses were observed in 9 of 14 (64%) pts in Arm A and 4 of 12 (33%) pts in Arm C. Other pts with follicular thyroid, ovarian, and urothelial cancers (Arm A) and angiosarcoma (Arm B) also had objective responses. There were no apparent PK interactions. Biomarker analysis is ongoing.

Conclusions
The safety profile of GDC-0980 30&#8195;mg in combination with Carbo/Pac or Cis/Pem is consistent with that of the individual agents, and AEs were manageable and reversible. These GDC-0980 combinations have demonstrated preliminary activity in first-line NSCLC

1231PD - A study of Hsp90 inhibitor AT13387 alone and in combination with crizotinib (CZT) in the treatment of non-small cell lung cancer (NSCLC)
1231PD - HSP90抑制剂AT13387单药和与克唑替尼(CZT)的联合用药对NSCLC的临床研究

Aim
Hsp90 is a molecular chaperone required for the proper folding and function of the anaplastic lymphoma kinase (ALK) protein. AT13387 (AT), a synthetic Hsp90 inhibitor displays potent antitumor activity and delays the onset of crizotinib (CZT) resistance in ALK-driven lung cancer xenograft models. A 3-Part, Phase 1/2, randomized study was initiated to investigate AT alone or in combination with CZT in patients with NSCLC receiving CZT. Here we present the Phase 1 results.

Methods
The primary objectives were the safety and tolerability of CZT/AT and to select the AT dose for the Phase 2 parts of the study based on assessment of safety and antitumor activity. Secondary endpoints included pharmacokinetics (PK), pharmacodynamics (PD) and anti-tumor activity. Part A utilized a rolling six design to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of the combination. Patients who previously tolerated 8 weeks of CZT at 250&#8195;mg BID continued to receive oral CZT at 250&#8195;mg BID plus IV AT dosed Days 1, 8, and 15 of a 28 day dosing cycle (dosing cohorts of 150, 180, or 220&#8195;mg/m2).

Results
In Part A, 32 patients (median age 59 years, range 29-75 years) were treated in 3 dosing cohorts. All subjects had prior CZT treatment (best prior response being 2 CR, 10 PR, 13 SD, 4 PD, and 3 unknown). AT was escalated up to 220&#8195;mg/m2 without DLTs. Among the 32 patients, the mean number of AT cycles was 4.2 (range 1-11+). The combination was generally well tolerated with only diarrhea (19%) occurring in more than 5% of subjects as an AT-related AE ≥ Grade 3. PK analysis showed AT exposures were similar to that observed in previous AT phase 1 studies at the same dose levels. CZT exposures were not affected when co-administered with AT. In 24 evaluable pts, 4 RECIST PR were observed and 15/24 subjects had a best response of decrease in tumor size.

Conclusions
Our study represents the first clinical trial of an Hsp90 inhibitor in combination with CZT. CZT/AT doses of 250&#8195;mg BID/220&#8195;mg/m2 were well tolerated with multiple objective responses observed, including in patients progressing on prior CZT, so was selected as the RP2D. Phase 2 studies of CZT/AT in patients prior to or after progression on CZT are ongoing.

1199PD - Prevalence and clinical outcomes for patients with MET protein expression in patients with non-small cell lung cancer in Europe: Results from the European Thoracic Oncology Platform Lungscape Project
1199PD - MET蛋白表达在欧洲NSCLC患者中的发生率及其临床结局: 来自欧洲胸部肿瘤学平台Lungscape项目的研究结果

Aim
The reported prevalence of MET overexpression varies from 25-55% in non-small cell lung cancer (NSCLC) and clinical correlations are emerging slowly. In a well-defined NSCLC cohort of the Lungscape program, we explore the epidemiology, the natural history of IHC MET positivity and its association to OS, RFS and TTR.

Methods
Resected stage I-III NSCLC identified based on the quality of clinical data and FFPE tissue availability were assessed for MET expression using immunohistochemistry (IHC) on TMAs (CONFIRM anti total c-MET assay, clone SP44, Ventana BenchMark platform). All cases were analysed at participating pathology laboratories using the same protocol, after passing an external quality assurance program. MET positive status is defined as ≥ 50% of tumor cells staining with 2+ or 3+ intensity.

Results
A total of 2709 cases are included in the iBiobank and will be analysed. IHC MET expression is currently available for 1552 patients, with positive MET IHC staining in 380 cases [24.5%; IHC 3+ in 157 cases (41.3%) and 2+ in 223 cases (58.7%)]. The cohort of 1552 patients includes 48.2%, 44.7% and 4.4% cases of adenocarcinoma, squamous and large cell histologies, respectively. IHC MET status was independent of stage, age and smoking history. Significant differences in MET positivity were associated with gender (32% vs. 21% for female vs. male, p < 0.001), with performance status (25% vs. 18% for 0 vs. 1-3, p = 0.006), and histology (34%, 14% and 24% for adenocarcinoma, squamous and large cell carcinoma, p < 0.001). IHC MET positivity was independent of the IHC ALK status (p = 0.08). At last FU, 52% of patients were still alive, with a median FU of 4.8 yrs. No association of IHC MET was found with OS, RFS or TTR.

Conclusions
The preliminary results for this large multicentre European cohort describe a prevalence of MET overexpression that seems lower than previous observations in NSCLC, such as reported for the OAM4971g trial, suggesting potential biological differences between surgically resected and metastatic disease. Analysis for the full cohort is ongoing and results will be presented.

1222O - A randomized, open-label, phase III trial of afatinib (A) vs erlotinib (E) as second-line treatment of patients (pts) with advanced squamous cell carcinoma (SCC) of the lung following first-line platinum-based chemotherapy: LUX-Lung 8 (LL8)
1222O - 一项随机、开放标签的对比阿法替尼和厄洛替尼作为晚期肺鳞癌患者一线接受基于铂类的化疗之后的二线治疗的三期临床试验：LUX-Lung 8(LL8)

Aim
A is an irreversible ErbB family blocker that has shown promising clinical activity in pts with SCC of the head/neck and lung. Here, we report results of LL8, a phase III trial that prospectively compared A and E in pts with SCC of the lung following failure of first-line chemotherapy.

Methods
Eligible pts with stage IIIB/IV SCC were randomized 1:1 to receive A (40&#8195;mg/day; 50&#8195;mg/day from Cycle 2 for pts meeting AE criteria) or E (150&#8195;mg/day) until disease progression. All pts had progressed after ≥4 cycles of platinum-based doublet chemotherapy and had not received prior EGFR TKIs. Pts were stratified based on race (eastern Asian vs other). The trial was powered for PFS and OS. The primary endpoint was PFS (RECIST 1.1) as assessed by independent radiological review (IRR). Secondary endpoints included overall survival (OS; planned at 632 events), objective response rate (ORR), disease control rate (DCR) and safety. Overall 795 pts were recruited between March 2012 and January 2014. Planned primary analysis was based on 414 PFS events by IRR in the first 669 patients randomized (A: 335, E: 334) while recruitment was ongoing.

Results
Baseline characteristics were well balanced between arms: median age 65y; male 85%; eastern Asian 22%; never smoker 5%. Median PFS was significantly higher for A than E, both by IRR (2.4 vs 1.9 months; HR [95% CI]: 0.82 [0.68–1.00]; p = 0.043) and investigator review (2.7 vs 1.9 months; HR [95% CI]: 0.78 [0.65–0.93]; p = 0.005). Furthermore, ORR (4.8% vs 3.0%; p = 0.233) and DCR (45.7% vs 36.8%; p = 0.020) were higher with A vs E. Overall AE profile was comparable (pts with ≥G3 AEs: 50.2 and 49.1% for A and E) with higher incidence of drug-related ≥G3 diarrhoea (9.7 vs 2.4%) and G3 stomatitis (3.3 vs 0.0%) with A and higher incidence of G3 rash/acne with E (5.5 vs 9.0%).

Conclusions
LL8 is the largest prospective trial to compare EGFR TKIs in pts with relapsed/refractory SCC. PFS and DCR were significantly better for A than E. AEs were comparable and consistent with the mechanistic profile of EGFR inhibition.

1223O - ASPIRATION: first-line erlotinib (E) until and beyond RECIST progression (PD) in Asian patients (pts) with EGFR mutation-positive (mut+) NSCLC
1223O - ASPIRATION: 在EGFR阳性的亚洲患者中一线采用厄洛替尼(E)治疗至疾病进展后继续使用的研究

Aim
E has proven efficacy as first-line therapy for pts with EGFR mut+ NSCLC. The phase 2, open-label, single-arm ASPIRATION study assessed the efficacy of first-line E until RECIST PD, efficacy beyond PD if E was continued by the investigator, and safety in pts with EGFR mut+ NSCLC in Asia.

Methods
Pts ≥18 yrs with stage IV, EGFR mut+ NSCLC received E 150mg/day orally. Primary endpoint: PFS1 (time to RECIST PD/death). Secondary endpoints: PFS2 (time to off-E PD if E was extended beyond RECIST PD) in all pts and in pts with exon 19 deletion/L858R mutations, objective response rate (ORR), disease control rate (DCR), best objective response (BOR), PFS1 in the exon 19 deletion/L858R subset, OS and safety.

Results
ITT population: 207 pts; 150 had a RECIST PD event at data cut-off, 46 had no PFS1, 11 withdrew, 81 continued post-PD E. Median follow-up: 213 days. PFS1: median 10.8 mo (95% CI 9.2–11.1). For pts with a RECIST PD event, data from pts receiving post-PD E vs pts not receiving post-PD E are shown in the Table. Median PFS2 (n = 81; 67 PD events): 13.0 mo (95% CI 11.5–14.8). In pts receiving post-PD E the difference between PFS1 and PFS2 was 3.7 mo. In pts with centrally confirmed exon 19 deletion/L858R mutations, median PFS1 (n = 144): 11.0 mo; median PFS2 (n = 54): 13.1 mo. ORR: 65.2%, DCR: 82.6%. OS data are immature. In the safety population (n = 207), 94 pts (45.4%) had grade ≥3 AEs, 7 (3.4%) had grade 5 AEs and 49 (23.7%) had a serious AE. The most common treatment-related AEs (grade ≥3) were skin disorders (15.9%) and GI disorders (2.9%); these were more common (all grades) in post-PD E pts vs pts not receiving post-PD E. More non-post-PD E pts (11%) had new lung lesions at PFS1 than post-PD E pts (5%).

	Post-PD E N = 81	No post-PD E N = 69
PFS1*, mos	9.3 (95% CI 9.1–11.0)	7.2 (95% CI 5.4–9.2)
Depth of response*, %	-49.6†	-38.9‡
Baseline to BOR*, days	55	59
BOR to PFS1*, days	140	105
ECOG 0/1§, %	95.1	78.3§§
Grade 4 AEs§, %	2.5	2.7

*Median, &#8224;n = 79, &#8225;n = 61, §at PFS1, §§n = 62.

Conclusions

The ASPIRATION data show that continuing E beyond RECIST PD is feasible, with a difference between PFS1 and PFS2 of 3.7 mo in post-PD E pts. However, validation of the optimal pt subset to benefit from post-PD E needs further research.

1224O - Anti-tumor activity of alectinib in crizotinib pre-treated ALK-rearranged NSCLC in JP28927 study
1224O - alectinib在接受克唑替尼治疗后的ALK重排NSCLC患者中的抗肿瘤活性：JP28927研究

Aim
Alectinib is a CNS-penentrant, highly selective ALK inhibitor with a novel scaffold. JP28927 is a clinical pharmacological study to evaluate the bioequivalence of alectinib 300&#8195;mg b.i.d. with 20 and 40&#8195;mg capsules (caps) vs. 150&#8195;mg caps and food effect with 150mg caps in ALK-rearranged NSCLC patients (pts), regardless of history of previous ALK inhibitor treatment. Results for bioequivalence, food effect, efficacy and safety were reported at ASCO2014. ALK-rearranged NSCLC pts had to discontinue treatment from crizotinib, a first generation ALK inhibitor, because of drug resistance or intolerance.

Methods
35 ALK-rearranged NSCLC pts were enrolled into JP28927 study. Pts continued alectinib 300&#8195;mg b.i.d. with 150&#8195;mg caps until the investigator determined lack of clinical benefit. This report describes the updated efficacy and safety data for alectinib in 28 crizotinib pre-treated NSCLC pts included in JP28927.

Results
As of Jan 11, 2014, median follow-up duration was 141 days (range: 35-166) and 21 pts continued treatment with alectinib without progressive disease (PD). Among 24 pts with target lesions, tumor shrinkage of more than 30 % was observed in 18 pts. Confirmed response rate was 58.3% (95%CI: 36.6-77.9) and disease control rate was 83.3 % (95%CI: 62.6-95.3) by investigator assessment. 19 of 28 pts had brain metastases at baseline, and 6 pts had no prior brain irradiation. 13 pts with brain metastases, including 4 pts without prior brain irradiation, were still on study treatment without PD. The safety profile was favorable, and continued the same trend previously reported. No pts discontinued study treatment for a safety reason. Gastrointestinal and visual disorders, characteristic of crizotinib treatment, were mild and not so frequent with alectinib.

Conclusions
Alectinib showed promising response, including in brain metastases, and good tolerability in crizotinib pre-treated pts. These findings suggest that alectinib is a novel therapeutic option for crizotinib pre-treated ALK-rearranged NSCLC.