新药讨论：Tarceva(特罗凯)

特罗凯不是新药，但其适应证目前只存在于肺癌中，这个贴子是介绍特罗凯在肠癌方面的临床和相关结论，供大家参考。

Avastin and Chemotherapy Followed by a KRAS Stratified Randomization to Maintenance Treatment for First Line Treatment of Metastatic Colorectal Cancer. (ACT2)

Patients with metastatic colorectal cancer will be treated with chemotherapy according to investigators choice. In addition to chemotherapy treatment, treatment with bevacizumab will be given concomitantly. This treatment will continue during 18 weeks. Meanwhile, the patients KRAS status will be tested. After having fulfilled these 18 weeks of induction treatment, patients who has responded (complete response/partial response versus stable disease) will be randomized to maintenance treatment. Patients with KRAS WT will be randomized to either bevacizumab alone, or to bevacizumab and erlotinib. Patient with KRAS mutation will be randomized to either bevacizumab, or metronomic capecitabine. Translational research is performed, with purpose to find predictive factors in blood and tumor tissue.

Arms                                                                                 Assigned Interventions
Active Comparator:                                                         Drug: bevacizumab, erlotinib
bevacizumab and erlotinib (KRAS WT)                             bevacizumab 7.5 mg/kg body  weight  
                                                                                       every third week, erlotinib 150 mg daily
                                                                                       Other Name: Avastin, Tarceva

Active Comparator: bevacizumab (KRAS WT)                  Drug: bevacizumab
                                                                                       bevacizumab 7.5 mg/kg body weight every third week
                                                                                       Other Name: Tarceva

Active Comparator: bevacizumab (KRAS mutated)           Drug: bevacizumab
                                                                                        bevacizumab 7.5 mg/kg body weight every third week.
                                                                                        Other Name: Avastin

Active Comparator: low dose capecitabine                        Drug: low dose capecitabine
(KRAS mutated)                                                               capecitabine 500 mg twice daily
                                                                                        Other Name: Xeloda

Estimated Enrollment: 181
Study Start Date: October 2010
Estimated Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)


这是一个三期的临床，主要用来研究肠癌化疗间歇期的维持性治疗方案。维持性治疗是目前的热点，这个临床的设计涵盖了当前肠癌的化疗与靶向药物做为维持治疗的可行性元素。设计考虑了Kras基因的状态并分别做了针对性方案。Kras野生型的方案有两个：一是阿瓦+特罗凯；另一个是单药阿瓦。Kras突变型也有两个方案：一是单药阿瓦；另一个是节拍式疗法的希罗达。

目前循证医学得到的结论是阿瓦的持续性运用（自转移发现伊始起且无法手术）会带来最大的生存受益。有没有在此基础上可以更上一层楼的方案？我想这就是这个临床中阿瓦+特方案的设计目的。另外，针对经济无法承受或是毒性无法耐受的患者，设计者也给出一个方案即希罗达节拍式疗法。

无论是哪种模式，都期望最终实验结果有一个好的数据，让患者有更多的选择，得到最大的受益。

相关临床实验的网站链接：http://clinicaltrials.gov/ct2/sh ... orectal&rank=15


A randomized phase III trial on maintenance treatment with bevacizumab (bev) alone or in combination with erlotinib (erlo) after chemotherapy and bev in metastatic colorectal cancer (mCRC).

Background: To improve the management of patients (pts) with mCRC, it is important to identify maintenance strategies that may contribute to prolonged survival with sustained QoL. The aim of the present study was to compare bev with bev + erlo following induction treatment with chemotherapy and bev. Progression free survival (PFS) was the primary end point. Methods: Pts with previously untreated mCRC, performance status (PS) 0-1, and adequate hepatic/renal/hematological function were included between May 2007 and Oct 2009 at 16 sites in Sweden and Denmark. Induction treatment consisted of XELOX, XELIRI, FOLFOX or FOLFIRI (investigator’s choice) + bev for 18 weeks. Pts without tumor progression were eligible for randomization to maintenance treatment with bev 7.5 mg/kg q3w +/- erlo 150 mg daily, until progression or unacceptable toxicity. Results: 249 pts were enrolled, median age 66 years (range 27-84), 58% male, 67% PS 0, primary site; colon/rectum/both: 60/34/6%, 35% had primary tumor in situ, 48% had liver metastases only. 73% received oxaliplatin-containing induction treatment. Response rate on induction treatment among 231 evaluable pts were PR/SD/PD: 48/43/9%. 161 pts were randomized. Reasons for non-randomization were PD in 23 pts and intended surgery in 19 pts. Median time on maintenance treatment was 15 weeks (range 0-102). Adverse events grade III-IV occurred in 44% of pts during induction phase. In the maintenance phase 31% experienced grade III-IV toxicity, with rash in 8%, hypertension in 4% and bleeding in 2% of pts. There were 3 toxic deaths; intestinal perforation (n=2) and abdominal bleeding (n=1). Conclusions: Maintenance treatment with bev +/- erlo after first-line chemotherapy in pts with mCRC seems to be a feasible strategy with limited side-effects. The primary study endpoint, PFS in the randomized population, will be reported at the meeting.

这是设计者就本临床在ASCO2011年年会上的一些相关阶段性结论，主要是针对阿瓦+特的维持性治疗方案。从数据上来看还是不错的。

Randomized phase II trial of capecitabine (X) versus X plus erlotinib (E) in patients (pts) with metastatic colorectal cancer (mCRC): Differential impact of KRAS.

Background: Palliative X monotherapy of mCRC is generally tolerated by elderly, and/or medically unfit pts. Epidermal growth factor receptor (EGFR) inhibitors improve efficacy when added to combination chemotherapy for mCRC. It is unknown whether biologic agents add benefit to alone in pts who either opt against, or are not candidate for, combination chemotherapy. We conducted a randomized phase II trial to investigate the novel “all-oral” combination of low-dose X and E in this pt population. Methods: Eligible pts with mCRC were either deemed unfit for, or chose against, 1st-line combination chemotherapy. Pts were randomized to X (1000 mg/m2 PO BID x 14 days) alone or in combination with E (150 mg PO OD) on a 3-week schedule. A 3rd arm (E alone) was ineffective, and discontinued after a preplanned interim analysis. Imaging was performed every 9 weeks until progression. Primary endpoint was time to disease progression (TTP); secondary endpoints included: objective response rate (ORR), overall survival (OS), safety and quality of life. Results: From June 2004 to June 2008, 95 pts [median age: 67; range 40-84; ECOG PS: 0 (45pts), 1 (38 pts), or 2 (22 pts)] were randomized to X alone (40 pts), XE (42 pts), or E alone (13 pts). KRAS status, where possible, was analyzed for pts in the first 2 arms only. As compared to X alone, XE was associated with significantly more Gr 3+ toxicity: (diarrhea: 29% vs 5%; fatigue: 12% vs 0%; anorexia 7% vs 0%; stomatitis 7% vs 0%). One pt discontinued treatment in the X arm vs 2 in XE. There was 1 toxic death in XE. TTP was not different for the whole trial (X=7.9 m, XE=9.2 m; p=0.8897), but exploratory subgroup differences emerged (below). Conclusions: The addition of E to X is associated with additional toxicity. E may benefit pts with KRAS-wild-type CRC and may harm those with KRAS-mutated CRC. Further study of XE in elderly/unfit pts with KRAS-wild-type CRC is warranted. Supported by grant from Roche.


--------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                              Median TTP (m)
                                                                           --------------------------------------------------------------------------------                                                                                                       X                    XE                       p  
--------------------------------------------------------------------------------------------------------------------------------------------
All pts (n = 40 / 42)                                                                    7.9                  9.2                    0.8897  
KRAS wt (n =18 / 24)                                                                 8.4                  11.7                      *  
KRAS mut (n = 18 / 12)                                                              7.4                  1.9                        *  
--------------------------------------------------------------------------------------------------------------------------------------------

*Cox regression p=0.0236 for interaction of study arm by Kras status.

这是在ASCO2011年年会上发布的关于特罗凯+希罗达在转移性结直肠癌治疗方面的二期临床报道。从最终数据TTP来看，如同EGFR大分子单抗一样，Kras基因的状态对最终的TTP影响很大。对于年纪较大、或是无法适应强度化疗而Kras基因又是野生型的病患来说，这不失为一种可能的合理选择。

Bevacizumab (Bev) with or without erlotinib as maintenance therapy, following induction first-line chemotherapy plus Bev, in patients (pts) with metastatic colorectal cancer (mCRC): Efficacy and safety results of the International GERCOR DREAM phase III trial.

Background: Therapy targeting VEGF or EGFR demonstrated clinical activity in combination with chemotherapy (CT) in mCRC but monoclonal antibodies cannot be associated. The DREAM trial compares a maintenance therapy (MT) with bev +/- EGFR tyrosine kinase inhibitor erlotinib (E) after a first-line Bev-based induction therapy (IT) in pts with mCRC. Methods: Pts with previously untreated and unresectable mCRC were eligible. After a Bev-based IT with FOLFOX or XELOX or FOLFIRI, pts without disease progression were randomized to MT between Bev alone (Bev 7.5 mg/kg q3w; arm A) or Bev+E (B 7.5 mg/kg q3w, E 150 mg/day continuously; arm B). Pts were treated until progression or unacceptable toxicity. The primary endpoint was PFS on MT. Results: The study enrolled 700 pts from 01/2007 to 11/2011 in 3 countries (France, Canada, Austria). 446 (63.7%) pts were randomized for MT (arm A, N=224; arm B, N=222). Among the 446 randomized pts, IT regimen was FOLFOX-Bev in 265 pts (59.4%), XELOX-Bev in 135 pts (30.3%), and FOLFIRI-Bev in 46 pts (10.3%). Baseline characteristics of randomized pts were (arm A/B): ECOG PS 0, 60% in both arms; normal LDH level 47%/49%; normal alkaline phosphatase level 48%/50%; synchronous metastasis 83%/82%. The median no of MT cycles was 6 in both arms. With a median follow-up of 31.0 months, 327 PFS events were observed. Median MT-PFS were 4.6 m in arm A vs 5.8 m in arm B (HR 0.73 [95%CI: 0.59-0.91], P=.005). Median PFS from inclusion were 9.2 m vs 10.2 m. During MT, in arm A vs arm B, grade 3-4 diarrhea (<1% vs 9%) and grade 3 skin toxicity (0% vs 19%) were the main differences in toxicity. Severe adverse events from randomization related to B or E were 6 in arm A and 7 in arm B. Overall survival is not mature. Conclusions: The addition of erlotinib to bevacizumab after induction therapy significantly improves the duration of maintenance PFS, following induction with first-line chemotherapy plus bevacizumab, in patients with unresectable metastatic colorectal cancer.

ASCO2012关于mCRC维持治疗模式的后续报道。从上文可看出，维持治疗采用阿瓦斯汀联合特罗凯的模式在PFS方面还是有一定优势的，OS方面的数据还没有出来。可惜的是报道中并没有做Kras基因亚组区分，因此并不知道野生型是否会有更多收益（虽然理论上会）。阿瓦联合特罗凯自然是一个豪华方案，我们不一定能用，但至少为我们提供了联合用药的思路，证明EGFR+VEGF靶点的联合有其可取之处。