2013年第15届世界肺癌大会（WCLC）靶向治疗相关信息

好药越来越多了，真好。

非常感谢翻译者，这个药物到来给我们新的曙光

谢谢老马，更希望看到世界各路专家们能加快PD-1，PD-L1等免疫治疗方面脚步，并早出结果！

活着就有希望

P2.11-035 ASSOCIATION OF TUMOR PD-L1 EXPRESSION AND IMMUNE BIOMARKERS WITH CLINICAL ACTIVITY IN PATIENTS WITH NON-SMALL CELL LUNG CANCER (NSCLC) TREATED WITH NIVOLUMAB (ANTI-PD-1; BMS-936558; ONO-4538)

肿瘤PD-L1表达和免疫标志物与nivolumab在NSCLC患者中的临床活性相关

Background: The immune checkpoint receptor programmed death-1 (PD-1) negatively regulates T-cell activation upon interaction with its ligands, PD-L1 and PD-L2. In a Phase 1 dose-escalation/cohort expansion study (CA209-003; NCT00730639), nivolumab, a fully human PD-1 receptor blocking antibody, delivered durable responses in patients with solid tumors, including advanced NSCLC. Immunohistochemistry (IHC) analysis of tumor samples from this study suggested an association between pre-treatment tumor PD-L1 expression and clinical response to nivolumab in patients with melanoma (Grosso JF J Clin Oncol. 2013;31(suppl):abs 3016; Topalian SL NEJM 2012;366:2443-54). Here we investigate the association between PD-L1 expression by IHC and response to nivolumab in patients with NSCLC, and patient response with pre-/post-dose absolute lymphocyte counts (ALC) and selected lymphocyte cell subsets.

Methods: 129 patients with NSCLC from the CA209-003 trial received nivolumab between 2008 and 2012 (1ｨC10 mg/kg IV every 2 weeks) during dose escalation and/or cohort expansion. Archived formalin-fixed paraffin-embedded pre-treatment tumor tissue and pre-treatment and on-treatment peripheral whole blood samples were analyzed to explore potential pharmacodynamic/predictive biomarkers associated with nivolumab therapy. Pre-treatment tumor PD-L1 expression was evaluated by IHC using an automated assay developed by Dako based on a sensitive and specific anti-PD-L1 monoclonal antibody (28-8). Tumors were defined as PD-L1 positive (PD-L1+) when ≥5% of the tumor cells had membrane staining
at any intensity. Lymphocyte subsets in the periphery were measured using flow cytometry.

Results: Tumor membrane PD-L1 expression was measured in 63 patients with NSCLC (29 squamous; 34 non-squamous). 31/63 (49%) NSCLC biopsies were PD-L1+. There was no apparent association between PD-L1 protein expression and NSCLC histology: for squamous and non-squamous tumors, 52% (15/29) and 47% (16/34) were PD-L1+, respective. Objective response rates for PD-L1+ and PD-L1- NSCLC patients with non-squamous and squamous histology are shown in the Table. Objective responses were observed in patients with squamous and non-squamous NSCLC who were negative for PD-L1 expression. Since increases in on-treatment ALC and activated T-cell phenotypes have been shown to positively associate with favorable clinical outcomes in ipilimumab monotherapy (Ku GY Cancer 2010;116:1767-75; Carthon BC Clin Cancer Res 2010;16:2861-71), results from an analysis correlating patient response with pre-/post-dose ALC and T-cell populations in patients with NSCLC receiving nivolumab will be presented.

结果：我们测量了63位NSCLC患者（鳞癌29位，非鳞癌34位）的肿瘤细胞膜PD-L1表达水平。49%（31/63）的患者活检样本显示PD-L1阳性（PD-L1+）。PD-L1蛋白表达与NSCLC病理组织学特征没有明显的关联：对于鳞癌和非鳞癌来说，分别有52%（15/29）和47（16/34）表现为PD-L1阳性。下表给出了在鳞癌和非鳞癌患者中观察到的客观响应率（ORR）。因为在ipilimumab单药治疗中，绝对淋巴细胞计数（ALC）和激活的T细胞表型的增加显示出与有效的临床收益具有正相关性，所以我们会展示接受nivolumab治疗的NSCLC患者的给药前和给药后的ALC和T细胞亚群数量分析。



（请重点关注这个表，此表显示即使PD-L1阴性的患者，仍然有一定的客观响应率，特别是对于鳞癌患者来说，但这个临床的病例数太少，搞得阴性反而比阳性的收益更大，还需更大样本的验证）

Conclusion: Further evaluation of PD-L1 as a molecular marker of nivolumab therapy is required. Association of PD-L1 protein expression with clinical outcome is currently being prospectively assessed in ongoing Phase 3 trials. Clinical Trial Registration Number: NCT00730639

P2.05-010 SEVERAL RECEPTOR TYROSINE KINASE IS ACTIVATED BUT ORCHESTRATED BY EGFR IN EGFR-TKI ACQUIRED RESISTANT LUNG ADENOCARCINOMA CELLS WITH EGFR MUTATION
Background: Lung adenocarcinomas with EGFR mutation initially show good responses to EGFR- tyrosine kinase inhibitors (TKIs). However, emergence of acquired resistance is almost inevitable.
To analyze molecular mechanisms underlying acquired resistance, we established a cell line from a patient who acquired resistance to geftinib/erlotinib.
Methods: A 64-year-old woman underwent a pulmonary resection for lung adenocarcinoma in February 2009 (pT2aN0M0, EGFR L858R mutation). In April 2010, pulmonary metastases, mediastinal lymph node metastases, and right pleural effusion were identifed. Geftinib was started and this led to a complete response. However, despite continuous treatment with geftinib, pleural effusion and serum carcinoembryonic antigen (CEA) levels gradually increased. In December 2010, geftinib was switched to erlotinib but the serum CEA level continued to increase, and erlotinib was stopped on March, 2011. Even though she received no treatment after erlotinib withdrawal, interestingly, the serum CEA level was decreased signifcantly (from 89.5ng/ml on March 2011 to 19.2ng/ml on April 2011), and erlotinib was re-started on April 2011. The serum CEA level increased after re-administration of erlotinib (55.7ng/ml on May 2011). Therefore the regimen was switched to cisplatin/pemetrexed and she responded to this combination chemotherapy (CEA 9.1ng/ml on July 2011). This clinical experience may be an actual case of “drug addiction phenomenon” that we and others have observed in preclinical acquired resistance models (Suda K, et al. Lung Cancer 2012; Das Thakur M, et al. Nature 2013). We established a cell line from her pleural effusion obtained on March 2011 in drug-free condition (designated as ACC-GR1 cells). We analyzed this cell line to evaluate the effcacy of erlotinib and dacomitinib, an irreversible EGFR-TKI. In addition, we examined phosphorylation status of 42 receptor tyrosine kinase (RTK) of ACC-GR1 cells using Human Phospho-RTK Array Kit (R&D Systems) with/without erlotinib or dacomitinib. We also examined PC9 lung adenocarcinoma cell line for phosphorylation status of RTKs with/without erlotinib.
Results: ACC-GR1 cells harbored the T790M mutation, in addition to the original L858R mutation in the EGFR gene. ACC-GR1 cells do not have amplifcation of MET proto-oncogene. IC50 values for erlotinib and dacomitinib were 2.9 uM and 0.05 uM, respectively. Phospho-RTK array analysis revealed marked activation of EGFR and MET, in addition, activation of ERBB2, ERBB3, RET, and AXL in a culture condition without EGFR-TKI. Treatment with 1 uM of erlotinib led to mild inhibition of EGFR and MET phosphorylation (71% and 58%, respectively, compared with control), and phosphorylation of other RTKs fell below detectable limits. Treatment with 1 uM of dacomitinib led to further inhibition of EGFR phosphorylation (35% compared with control). In PC9 cells, phosphorylation of EGFR and MET were also observed in drug-free condition, and remarkably inhibited by 1 uM erlotinib treatment (10% and 64%, respectively, compared with control).
Conclusion: A cell line model established from pleural effusion of a patient who acquired resistance to geftinib/erlotinib harbored T790M mutation and responded to dacomitinib in vitro. The acquired resistant cells showed activation of several RTKs in drug free condition, and these are remarkably inhibited by EGFR-TKI treatment.

Das Thakur, M. et al. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature 494, 251–255 (2013).
This phenomenon has also been reported in a study of patient-derived mouse xenografts of BRAF V600E melanoma, which demonstrated that discontinuous dosing strategies may prolong the duration of vemurafenib response as a result of drug dependency in resistant cells133.
http://www.nature.com/nature/jou ... ll/nature11814.html
Mutational activation of BRAF is the most prevalent genetic alteration in human melanoma, with ≥50% of tumours expressing the BRAF(V600E) oncoprotein1, 2. Moreover, the marked tumour regression and improved survival of late-stage BRAF-mutated melanoma patients in response to treatment with vemurafenib demonstrates the essential role of oncogenic BRAF in melanoma maintenance3, 4. However, as most patients relapse with lethal drug-resistant disease, understanding and preventing mechanism(s) of resistance is critical to providing improved therapy5. Here we investigate the cause and consequences of vemurafenib resistance using two independently derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumours show continued dependency on BRAF(V600E)MEKERK signalling owing to elevated BRAF(V600E) expression. Most importantly, we demonstrate that vemurafenib-resistant melanomas become drug dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumours. We further demonstrate that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. These data highlight the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. Such observations may contribute to sustaining the durability of the vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations.
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Unintentional weakness of cancers: the MEK/ERK pathway as a double-edged sword
Kenichi Suda, and Tetsuya Mitsudomi
http://mcr.aacrjournals.org/cont ... CR-13-0228.abstract
Abstract
Recent advances in molecular target therapy have greatly improved treatment outcomes for cancers driven by oncogenic mutations. However despite initial dramatic responses, cancer cells eventually acquire resistance to these drugs, showing flexible and diverse responses. Interestingly, cancer cells may sometimes over-adapt to the environment with the drug, leading to a state in which cancer cells cannot survive without the drug. This interesting phenomenon, which can be termed as "drug dependency" or "drug addiction," is exemplified in preclinical acquired resistance models of BRAF-mutated melanoma treated with vemurafenib and EGFR-mutated lung cancer treated with EGFR tyrosine kinase inhibitors. By comparing these two preclinical models, we noticed intriguing parallels of "drug addicted" cancers: (a) overexpression of driver oncogenes as causes of acquired resistance; (b) overexpression of driver oncogenes causing MEK-ERK hyperactivation under drug free conditions; (c) hyperactivation of the MEK-ERK pathway as critical to this "drug addiction" phenomenon; (d) ongoing dependence on the driver oncogene; and (e) morphological changes in resistant cells under drug-free conditions. In this perspective article, we focus on this interesting and weird phenomenon and discuss treatment strategies to utilize this unintentional weakness of cancers.

谢谢老马，感激。

3楼的翻译

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

Afatinib在对可逆性EGFR TKIs耐药的具有T790M突变的患者的高剂量间歇性给药（HDI）的Phase IB研究

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.

背景：Afatinib，作为一种ErbB家族不可逆抑制剂，在表达EGFR突变（L858R/T790M）的肺腺癌细胞系增殖实验中展现出了纳摩尔级的抑制活性（NCI-H1975 EC50=92nM）。1. 在前期接受erlotinib/gefitinib治疗失败且已经经过1-2个疗程的化疗的NSCLC患者中，给予每天50mg的afatinib后显示客观响应率达7%，中位PFS为3.3个月。2. 根据临床前建模得知，给予高剂量间隙性（HDI）afatinib，能产生更高的血药浓度，从而能有效抑制含有T790M突变的细胞。同时，此方法也能减少在连续剂量TKI给药后，由于野生型EGFR抑制而导致的副作用。 在目前进行的这个开放标签的研究中，我们在Part A中评估了将HDI应用于晚期实体瘤患者中的最大耐受剂量（MTD），安全性和药代动力学（PKs）。在Part B中，我们估算出了接受过EGFR TKI治疗后含有T790M突变晚期NSCLC患者的HDI afatinib的MTD。

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.

方法：在Part A中， 对于有转移或者不可手术切除但有足够器官功能的实体瘤患者，我们在每14天的第1-3天给予90-200mg afatinib，每个治疗周期为28天，采用3+3的剂量递增设计。剂量逐渐增加至MTD（主要终点），MTD定义为在此剂量下，在第一个治疗周期中，多达6位患者中的2位或者更少的患者显示出了剂量限制毒性（DLT）。分别于第1-3天，第8天，第15-17天，第29天，第43天和第57天作药代动力学抽样，第二终点为afatinib在第一个周期中第三天的Cmax。 在Part B中，MTD队列将会扩展至包括前期接受过EGFR TKI治疗的含有T790M的NSCLC患者，同时按计划研究可检测的T790M在血浆中的基线表达水平和治疗中的表达水平。

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.

结果：截止到目前，16位患者入组Part A（90mg n=6; 120mg n=3; 150mg n=4; 200mg n=3; 男性/女性 n=8/8; 中位年龄为65岁; 非吸烟者/戒烟者 n=10/6; 原发肿瘤病灶为肺部 n=9; 已知T790M患者 n=7）。最常见的药物相关不良事件（DRAEs）为腹泻、皮疹、痤疮型药疹和恶心。3级以上的DRAEs出现在1位接受90mg的患者（3级进展性蜂窝组织炎[第1周期，DLT]和尿脓毒病[第2周期]）和1位接受150mg的患者（3级脱水，低血钾症，低磷酸盐血症和腹泻[第2周期]）。已经得到了在可测量的T790M突变的NSCLC患者中的初步的响应数据。初步动力学分析表示每日150mg持续3日的afatinib给药，能有效的达到总血药Cmax浓度，并且具有不低于预期的对T790M的半数抑制浓度（IC50）。我们也将会展示Afatnib的血药谷浓度。

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.

总结：HDI afatnib给出了一种可控制的安全的给药模式：在每14天中的第1-3天最高给药至200mg每天。已经在150mg的队列中达到了抑制T790M所需要的总血药Cmax浓度。200mg队列的研究还在进行中。其他队列可能被用于研究更短的药物空窗剂量周期。1. Solca F, et al. JPET2012;343:342–50. 2. Miller V, et al. Lancet Oncol 2012;13:528–38.

这篇HDI的大致方法就是以28天为一个周期，在第1-3天和15-17天每天给药150mg，然后第4-14天和第18-28天空窗，之后再重复给药，这样可以达到有效抑制T790M的血药浓度，又能避免出现太大的副作用。（注意：从摘要中看出，研究者仅仅检测到使用HDI后血药浓度已达抑制T790M所需要的水平，并未作影像学评价，该研究还在进一步进行中，请病友不要擅自尝试此方法）