2013年第15届世界肺癌大会（WCLC）靶向治疗相关信息

2013年第15届世界肺癌大会（WCLC）靶向治疗相关信息
国际肺癌研究协会(IASLC)主办的第15届世界肺癌大会(WCLC)于2013年10月27-30日在澳大利亚悉尼召开,来自全球93个国家的5000多名代表参加了本次盛会。
会议摘要全集下载：
http://www.2013worldlungcancer.o ... 13-AbstractBook.pdf
本次会议报道了AZD9291、CO-1686、阿法替尼、PF00299804等药物的临床进展情况。

P2.11-010 PHASE I STUDY OF HM61713, A NOVEL EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) MUTANT SELECTIVE INHIBITOR, IN NON-SMALL CELL LUNG CANCER (NSCLC) PATIENTS HAVING AN ACTIVATING EGFR MUTATION BUT FAILED TO PRIOR EGFR TYROSINE KINASE INHIBITOR (TKI) THERAPY.
Dong-Wan Kim1, Sang-We Kim2, Tae Min Kim1, Se-Hoon Lee1, Chang-Min Choi2, Bhumsuk Keam1, Jae Cheol Lee2, Dae-Seog Heo1, Jungshin Lee2, Kyung-Sang Yu3, In-Jin Jang3, Kyung Joon Lim4, Jeewoong Son4, Dae Ho Lee21
Department Of Internal Medicine, Seoul National University Hospital/Korea, 2
Department Of Oncology, University Of Ulsan College Of Medicine, Asan Medical Center/Korea, 3
Department Of Clinical Pharmacology, Seoul National University Hospital/Korea, 4
Hanmi Pharmaceutical Co., Ltd./Korea
Background: NSCLC patients having an activating EGFR mutation initially responded well to EGFR TKI but most of them experienced progressive disease due to various resistance mechanisms including T790M (~50% of cases) mutation. HM61713 is an orally active, novel EGFR mutant selective inhibitor showing a strong anticancer activity in many lung cancer cell lines including T790M mutation harboring cell line. Therefore, HM61713 might provide the potential clinical benefit to those who have an activating EGFR mutation but have failed previous EGFR TKI treatment.
Methods: This is a phase I study using a standard 3+3 dose escalation scheme. NSCLC Patients with activating EGFR mutation and progressed after at least 2 prior chemotherapy regimens including EGFR TKI were eligible. The objective of this study is to determine the recommended phase II dose as well as to assess the preliminarily efficacy.
Results: To date, a total of 23 patients were treated with at doses of 75-250 mg/day. One patient at a dose of 200 mg/day experienced grade 3 drug induced idiosyncrasy and grade 4 elevation of amylase. The drug induced idiosyncrasy was skin rash of non-EGFR TKI type. The most common drug-related adverse events were desquamation, diarrhea, pruritus, and nausea; most were grade 1 or 2. The maximum tolerated dose (MTD) and recommended phase II dose were not determined yet. Plasma concentration of HM61713 reached the peak 2-4 hr after administration and declined with the half-life of 8-12 hr. Among 21 evaluable patients, 2 patients achieved partial response (PR) and one of them had confirmed T790M mutation while 12 patients had stable disease (SD) including 11 patients showed tumor shrinkage. Accrual to this study is ongoing and updated data will be presented at the meeting.
Conclusion: HM61713 showed good safety profile and promising anticancer activity in NSCLC patients with EGFR mutation who failed to prior EGFR TKI therapy. These results support the therapeutic potential of HM61713 for NSCLC patients with activating EGFR mutations after development of resistance to EGFR TKI therapy.

P2.11-011 A PHASE IB STUDY OF HIGH-DOSE INTERMITTENT (HDI) AFATINIB IN EGFR T790M MUTATION-POSITIVE NON-SMALL CELL LUNG CANCER PATIENTS WITH ACQUIRED RESISTANCE TO REVERSIBLE EGFR TKIS
D Ross Camidge1, Pasi A. Jänne2, Lecia V. Sequist3, Vikram Chand4, Elizabeth Dowling5, Yu Gu6
, David Schnell7, Geoffrey R. Oxnard8
Background: Afatinib, an irreversible ErbB Family Blocker, displayed nanomolar inhibitory activity in proliferation assays using lung adenocarcinoma cell lines expressing mutant EGFRL858R/T790M(NCI-H1975 EC50 92 nM).1 In NSCLC patients with prior erlotinib/gefitinib failure and one/two previous lines of chemotherapy, 50mg afatinib once daily produced confirmed objective responses in 7% of patients and a median PFS of 3.3 months.2 Preclinical models suggested that administering afatinib using a high-dose intermittent (HDI) schedule, leading to higher maximal plasma concentrations, may provide an alternative means to block T790Mharbouring cells effectively. It may also potentially reduce wildtype EGFR-mediated adverse events noted with continuous dosing of EGFR TKIs. In this ongoing open-label study, the maximum tolerated dose (MTD), safety and pharmacokinetics (PKs) of HDI afatinib are being assessed in Part A in patients with advanced solid tumours. The MTD of HDI afatinib will be evaluated in Part B in patients with T790M-mutated advanced NSCLC following prior EGFR TKI therapy. Preliminary results from Part A are presented.
Methods: In Part A, patients with metastatic/unresectable solid tumours and adequate organ function were administered 90–200mg afatinib on Days 1–3 every 14 days in each 28-day cycle using a 3+3 dose-escalation design. Doses are escalated until MTD (primary endpoint), defined as the dose at which less than two of up to six patients develop dose-limiting toxicities (DLTs) in Cycle 1. PK sampling was conducted on Days 1–3, 8, 15–17, 29, 43 and 57, with Cmax of afatinib on Day 3 of Cycle 1 being the secondary endpoint. In Part B, the MTD cohort will be expanded to specifically include EGFR TKI-pretreated advanced NSCLC patients with T790M mutations. Exploration of baseline and on-therapy plasma levels of detectable T790M is planned.
Results: To date, 16 patients have been recruited in Part A (90mg n=6; 120mg n=3; 150mg n=4; 200mg n=3; male/female n=8/8; median age 65 years; never smokers/ex-smokers n=10/6; primary
tumour site lung n=9; known T790M mutation n=7). The most common drug-related adverse events (DRAEs) were diarrhoea, rash, dermatitis acneiform and nausea. DRAEs of Grade ≥3 were seen in one patient at 90mg (Grade 3 worsening cellulitis [Cycle 1; DLT] and urosepsis [Cycle 2]) and one patient at 150mg (Grade 3 dehydration, hypokalaemia, hypophosphataemia, diarrhoea [Cycle 2]). Preliminary response data on evaluable T790M-mutated NSCLC patients will be presented as available. Preliminary PK analyses suggest 150mg afatinib once daily for 3 days is sufficient to achieve total plasma Cmax concentrations at or above the predicted IC50 value for T790M. Afatinib trough plasma concentrations will also be presented.
Conclusion: HDI afatinib elicited a manageable safety profile up to 200mg on Days 1–3 every 14 days. Total plasma Cmax concentrations at or above the predicted efficacious threshold for T790M inhibition were already achieved in the 150mg cohort. Treatment in the 200mg cohort is ongoing. Additional cohorts may be included to explore shorter drug-free dosing periods. 1. Solca F, et al. JPET2012;343:342–50. 2. Miller V, et al. Lancet Oncol 2012;13:528–38.

P2.11-031 RADIOFREQUENCY ABLATION OF LIVER METASTASES MAY PROLONG THE SURVIVAL OF PULMONARY ADENOCARCINOMA PATIENTS WITH LIVER METASTASIS
Shih-En Tseng1, Yi-You Chiou2, Yu-Chin Lee3, Reury-Perng Perng4 Yuh-Min Chen5
1Internal Medicine, Zhongxing Branch, Taipei City Hospital/Taiwan,2Radiology, Taipei Veterans General Hospital/Taiwan, 3Department Of Chest Medicine, Taipei Veterans General Hospital/Taiwan, 4Department Of Chest Medicine, Taipei Veteran General Hospital/Taiwan, 5Division Of Thoracic Oncology, Department Of Chest Medicine, Taipei Veterans General Hospital/Taiwan
Background: In patients with non-small cell lung cancer (NSCLC), the development of liver metastasis (LM) is a poor prognostic factor that compromises survival time. Whether combine systemic treatment with local treatment for liver metastases has benefit for NSCLC patients with LM is unknown. How to select a suitable patient for receiving local treatment is also unclear.
Methods: We retrospectively reviewed 713 pulmonary adenocarcinoma patients and 85 patients that developed LM at any time point in the course of the disease were identified for analysis. We
use radiofrequency ablation (RFA) for local treatment of liver metastases. The indication of RFA were liver metastases number less than three with maximal size less than 5cm. RFA was performed with real-time ultrasonography guidance. Dynamic computed tomography (CT) scan was done 1 month after RFA for evaluating local therapeutic efficacy. An SPSS version 19 statistical software package (SPSS INC, Chicago, IL, USA) was used for data analysis.
Results: The independent prognostic factors after LM were Performance status, epidermal growth factor receptor (EGFR) mutation and LM numbers. There were 47 patients (54.7%) have LM nodules number less than three. The median overall survival (OS) in patients with LM nodules number less than three was 7.9 months comparing with 2.9 months in patients with nodules number over three ( P < 0.001). The independent prognostic factors for LM nodules number less than three patients were performance status and presence of brain metastasis. There were total six patients received RFA. Patients who received RFA treatment had better median OS after LM than those not ( 19.1 v.s 6.0 months, P = 0.04)
Conclusion: We recommend patients with better performance status (ECOG <2) without brain metastasis can consider RFA for liver metastases.

P2.11-044 PHASE IB STUDY TO EVALUATE THE EFFICACY AND TOLERABILITY OF OLAPARIB (AZD2281) PLUS GEFITINIB IN PATIENTS (P) WITH EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) MUTATION POSITIVE ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC) PATIENTS (P). (NCT=1513174/GECP-GOAL)
Rosario Garcia Campelo1, Enriqueta Felip2, Bartomeu Massuti3Margarita Majem4, Enric Carcereny5, Ramon Palmero5, Miguel Angel Molina-Vila6, Rosana Cajal7, Maria Sanchez-Ronco8
, Rafael Rosell5
1Medical Oncology, Complejo Hospitalario Universitario A Coru&ntilde;a/Spain,
2Hospital Universitario De La Vall D‘hebron/Spain,
3Medical Oncology, Hospital General De Alicante/Spain,
4Medical Oncology, Hospital De La Santa Creu I Sant Pau/Spain,
5Medical Oncology, Catalan Institute Of Oncology/Spain,
6Quiron-Dexeus University Hospital, Pangaea Biotech/Spain,
7Astra Zeneca/Spain,
8Statistics, University Of Alcala De Henares/Spain
Background: Progression-free survival (PFS) and response rate (RR) to EGFR tyrosine kinase inhibitors (TKIs) vary in P with NSCLC driven by EGFR mutations, suggesting that other genetic alterations may influence oncogene addiction. In our experience, high BRCA1 mRNA expression negatively influenced PFS among EGFR mutant P treated with erlotinib. We hypothesiszed that since olaparib can attenuate and/or prevent BRCA1 expression, the addition of olaparib to gefitinib could improve PFS in these P.
Methods: This is a Phase IB dose escalation study to identify the maximum tolerated dose (MTD), dose limiting toxicity (DLT), pharmacokinetics (PK), and clinical activity of orally administered olaparib in combination with gefitinib in EGFR mutant advanced NSCLC. In a standard 3+3 design based on toxicity, P were treated with gefitinib 250mg once daily plus olaparib tablets at escalating doses ranging from 100mg BID to 250mg TDS during a 28-day cycle. Steady state Cmax and AUC (AUC0-12) were determined following dosing on Day 7 and 14 of the study and the Day 14: Day 7 treatment ratio calculated to assess the impact on olaparib steady state exposure of dosing in combination with gefitinib
Results: 22P have been included across four dose levels of olaparib: 100mg BID (3), 200mg BID (6), 200mg TDS (6) and 250mg TDS (7). Median age, 65 (range 39-84); male, 6P; PS 0-1, 20P; EGFR TKI
treatment-na&iuml;ve, 13P; Most toxicities were G1-2, including anemia, leucopenia, nausea, diarrhea, asthenia, rash and anorexia; G3 drug-related events included lymphopenia (1) and anemia (3). No
DLT at dose levels 1, 2, and 3; 3 DLT at dose level 4 (G3 anemia and repeated blood transfusion within 4-6 weeks). Few dose reductions or interruptions for both drugs were needed. 1P died due
to pulmonary embolism unrelated to study treatment. 19P were evaluated for response: For those not previously treated P, partial responses (PR) were observed in 8P (72,2%), stable disease (SD) in 3P (27,27%) and no progressive disease (PD) (0%). In previously TKI treated P, 3 (37,5%) PR were observed, 3 (37,5%) SD, and 2 (25,5%) PD. Durable PR and SD were observed in both EGFR TKI-na&iuml;ve and previously treated P.10P are still on treatment. The derived PK parameters were the following: 100mg bid: Olaparib Cmaxss(ug/ml): Day 7:4.60; Day 14:3.53; TR(range) 0.77. AUCss(ug.h/ml) Day 7:24.4; Day 14:18.9; TR:0.79. 200mg bid: Cmaxss(ug/ml): Day 7:7.68; Day
14:6.60; TR:0.89. AUCss(ug.h/ml) Day 7:48.6; Day 14:40.0; TR:0.85; 200mg tds: Cmaxss(ug/ml): Day 7:8.35; Day 14:8.01; TR:0.96. AUCss(ug.h/ml) Day 7: 34.9*; Day 14: 32.7*; TR: 0.94; 250mg tds: Cmaxss(ug/ml): Day 7:9.85; Day 14:9.46; TR:0.97. AUCss(ug.h/ml) Day 7: 44.2*; Day 14: 43.3*; TR: 0.99. *AUC quoted is AUC0-6 not AUCss.
Conclusion: This phase IB trial of gefitinib plus olaparib, confirms the tolerability of the combination and the anti-tumor activity seen warrants further exploration in treatment-na&iuml;ve patients. MTD of olaparib was 200mg TDS. Co-administration of gefitinib does not appear to have altered steady state exposure to olaparib. A phase II randomized trial in treatment-na&iuml;ve EGFR-mutant advanced NSCLC is planned to start in 2013. The final recommended dose of olaparib will be 200 mg TDS.

阿斯利康（AstraZeneca）的Olaparib是一种创新的、潜在首创口服多聚ADP核糖聚合酶（PARP）抑制剂，在临床前模型中已被证明，能够利用DNA修复途径的缺陷，优先杀死癌细胞。这种作用模式，赋予olaparib治疗具有DNA修复缺陷的广泛肿瘤类型的潜力。PARP与广泛的肿瘤类型相关，尤其是乳腺癌和卵巢癌。

沙发楼的翻译：

P2.11-010 HM61713临床一期试验。（HM61713是一种NOVEL研制的能选择性结合于发生突变的表皮生长因子受体的抑制剂，主要用于有EGFR突变但先前用EGFR-TKI治疗无效的患者）

试验人员略过，反正是棒子

背景：部分NSCLC患者有EGFR突变，一开始对EGFR TKI治疗敏感有效，但他们中的绝大数后续会经历病情进展，原因是各种复杂的耐药机制的产生，其中50%产生了T790M。HM61713是一种由NOVEL生产的口服的特异性作用于突变的EGFR的抑制剂。其在很多肺癌细胞上表现出强大的抗癌能力，包括T790M突变的癌细胞。因此HM61713可能会在临床上使一些具备EGFR突变但先前用其他EGFR TKI治疗无效的患者受益。

方法：此次一期临床试验使用标准的3+3计量递增模式。经历过至少两周期化疗含用EGFR TKI治疗且病情进展的NSCLC患者符合入组条件。本次研究的目的是为第二阶段试验找到适合的计量并且希望能观察到确切的疗效。

结果：截止目前，有23位病人接受了每日计量75-250毫克不等的治疗。其中一位接受每日200毫克治疗的患者发生了3级药物副作用和4级淀粉酶升高。药物引起的副作用主要是皮疹（和其他EGFR-TKI引起的皮疹不同）。和药物有关的不良事件主要是脱皮，腹泻，皮肤瘙痒和恶心，大多数是1-2级。2期试验所能耐受的最大剂量未在此次试验中有定论。HM61713的血浆浓度在用药后2-4小时达到峰值，半衰期是8-12小时。在21位可评价的病人中，2位病人部分有效（PR），而这其中一位病人确诊有T790M突变。其他12位病人病情稳定，11位病人显示肿瘤缩小。本次研究正在进行中最新的数据将在会议中提交。

结论：对于先前使用EGFR-tki治疗失败的NSCLC患者，HM61713表现出良好的安全性和抗癌潜力。本次研究支持HM61713作为一线使用EGFR-TKI治疗后产生抗药的患者的治疗手段

{:soso_e160:} 谢谢马老师分享

{:soso_e160:} 谢LS童鞋翻译