关于这个药，2011年ASCO有这样几个报告：
Cediranib, a VEGF receptor 1, 2, and 3 inhibitor, and pemetrexed in patients (pts) with recurrent non-small cell lung cancer (NSCLC).
Background: The role of anti-VEGF therapy in recurrent NSCLC is unclear. We are currently conducting a phase II trial evaluating cediranib, an oral inhibitor of VEGFR 1, 2 and 3, and pemetrexed in recurrent NSCLC pts who may or may not have previously received bevacizumab. Methods: Pts with progressive NSCLC following 1 or 2 prior regimens and with any histologic sub-type were eligible. Pts on anti-coagulants and with treated brain mets were allowed. Pts received cediranib 30mg daily. 1 week after starting cediranib, pts received pemetrexed 500 mg/m2 every 21 days. The study consists of two cohorts- A (no prior bevacizumab) and B (prior bevacizumab). Planned accrual is 37 pts each cohort. Accrual to cohort A is completed. Consenting pts underwent blood draw for circulating tumor cells (CTCs) and circulating endothelial cells (CECs) before therapy, 1 week after cediranib was commenced, and after 1 cycle of the combination. Results: 38 pts were enrolled in cohort A. Median age- 62, males- 50%, ever smokers- 92%, squamous- 18% (7 patients), brain mets- 34%, 2 prior regimens- 42%. Median cycles- 4 (range: 0-26). Grade 3/4 toxicities- neutropenia- 14%, febrile neutropenia- 5%, fatigue-22%, diarrhea- 14%, infection- 8%. One patient each developed pulmonary hemorrhage, cardiac ischemia and cerebrovascular event. Three deaths were deemed related to drug related toxicities. Response rate is 29% (95% CI: 17%-45%) and disease control rate (response+stable disease) is 74% (58%-85%). Median PFS is 5.6 (4.4-6.8) months and median survival is 11 (5.8-16.6) months. Efficacy parameters for squamous versus non-squamous were- Response rate- 0% vs. 35%, PFS- 3.7 vs. 5.7 months, survival 5.2 vs. 11.5 months. Among 18 pts with available data, 60% had decrease in CTCs and 31% of the patients had declines in CECs. There was no significant association between declines in CTCs or CECs and PFS. Conclusions: 1.The combination of cediranib and pemetrexed is tolerable. 2. The response rate of 29% (35%-non-squamous) and the median PFS of 5.6 (5.7-non-squamous) months are very promising. 3. Though the numbers are small, this combination is ineffective in recurrent squamous cell patients. 4. Enrollment to cohort B is ongoing.
简单而言，西地(30mg)加培美曲赛(500mg, 21天）在38名非小患者中有效率29%（非鳞癌患者有效率35%), 总控制率74%（有效加稳定），中位无进展5.6月，中位生存期11个月。数字还可以，但这种组合的副作用不可小觑，有三起死亡事件可能和副作用有关。
[一直不太明白各种有效率，中位生存期的数字后括号里数字的意思，还请哪位高手解释一下。]
Dual inhibition of VEGF pathway: Phase I trial of bevacizumab and cediranib in advanced solid tumors.
Background: We evaluated the safety of a combination of bevacizumab (B) and a TKI against VEGFR-cediranib (C). Methods: This was a phase I study with 3+3 design in patients (pts) with advanced solid tumors. C was given po daily for 21 days and B i.v. every two weeks (days 1 and 15). We measured changes in serum total nitrate in response to therapy. Results: 51 pts were dosed. 2 pts at DL4 had DLT of hypertension (HTN) grade 3 and 4. DL3 was initially deemed the MTD (C30 mg/day and B5mg/kg/2weeks). However at the DL3 dose-expansion of the initial 18 pts, 2 pts had a CNS bleed with HTN, 1 pt had grade 5 hemoptysis and 3 pts had thrombopenia (grade 3 and 4) DLTs. Although DL3 did not exceed the >33% definition of MTD (7 DLTs/24 pts), given the severe adverse events (AEs), DL3 was deemed too toxic and all remaining pts at DL3 were reduced to DL2 (C20mg/day and B5mg/kg/2weeks) and additional 8 pts were enrolled at DL2. No DLT was observed at DL2 and was deemed the RP2D dose. PKs on patients at DL3 based on C mean drug exposure showed a 50-75% increase in AUC (0-24h) on cycle 1day 1 when compared to historical controls from single agent studies. The most common drug related AEs were HTN (54%), fatigue (42%), anorexia (38%), diarrhea and proteinuria (27%). The most common grade 3-4 AEs were CNS bleed (8%), HTN and nausea (6% each). 42 pts were evaluable by RECIST.17 pts had SD for >4 months (including 9 pts with soft tissue sarcomas). 2 sarcoma pt had PR : alveolar soft tissue part sarcoma (ASPS) (-43%, +16months [m]) and synovial (-32%, +10m). Other SD sarcoma pts included: ASPS (17%, -27%, -16%) of 4, 7, +24 months, spindle cell (-9%, 8m), leiomyosarcoma (-17%, 6m) and 2 synovial sarcoma pts (-8%,-18%) of 10,+5m. PRs were also seen in basal cell ca (-33%, +13m), inflammatory breast (-54%, 3m). Median PFS was > in pts with decreases in total nitrate by day 14 but not statistically significant (4.2 months vs. 1.9, p=0.25). Conclusions: The combination of C 20mg/day and B 5mg/kg/2weeks was well tolerated and is the RP2D/MTD. At doses above the MTD, dual targeting of the VEGF pathway led to increased exposure to C and increased toxicity, specifically CNS bleeds and HTN. Activity in soft tissue sarcomas and other tumor types were seen. This study was supported by U01CA62461 (RK).
上面这个说西地(20mg)加阿瓦(5mg/kg/14天)对各种实体瘤的效果。42个病人中17个（9个是软组织肉瘤患者）稳定超过4个月。两药联用效果和副作用都增大。
Use of KRAS mutation status to predict clinical outcomes in patients with metastatic colorectal cancer (mCRC) treated with the VEGF signaling inhibitor cediranib.
Background: The value of KRAS mutations as predictive markers of clinical benefit of anti-EGFR antibody therapy in patients with mCRC has been shown in randomized trials. Less is known of the influence of KRAS mutations in patients with mCRC treated with VEGF signaling inhibitors and literature on the prognostic value of KRAS mutations in this setting is inconsistent. The Phase III HORIZON II (HZII) study evaluated the efficacy of cediranib 20 mg + FOLFOX (FF) or XELOX (X) vs placebo + FF or X in patients with mCRC; cediranib 20 mg met the co-primary endpoint of progression-free survival (PFS; HR=0.84) but not overall survival (OS; HR=0.94). A retrospective analysis of KRAS mutation status and correlation with PFS and OS in patients was performed to evaluate its prognostic and predictive value. Methods: Analysis of KRAS codon 12 and 13 mutations was performed at a central laboratory using a commercially available, allele-specific, ARMS-based polymerase chain reaction assay. Results: KRAS mutation status was determined in 489/860 patients (cediranib 20 mg arm, n=285/502; placebo arm, n=204/358); of these 489 patients, 42.3% had mutant KRAS and 57.7% were wild-type. Baseline characteristics were similar in the KRAS mutant, KRAS wild-type and KRAS status unknown groups. There was a trend towards improved PFS and OS in the KRAS wild-type subgroup compared with the KRAS mutant subgroup, which was independent of treatment arm (PFS: HR=0.85, 95% CI: 0.70,1.03, median 8.5 vs 8.3 months; OS: HR=0.71, 95% CI: 0.57,0.88, median 20.9 vs 16.9 months). There were no statistically significant differences in treatment effect between KRAS subgroups for the cediranib vs placebo arm (PFS: wild-type HR=0.78, mutant HR=0.82; OS: wild-type HR=0.92; mutant HR=1.01). Conclusions: This is the first reported analysis of KRAS mutation status in a randomized Phase III clinical study with a VEGFR-TKI. KRAS mutation status did not influence the PFS or OS treatment effect and therefore cannot be used as a predictive marker for outcome. These data show that KRAS codon 12 or 13 mutations have prognostic value in mCRC independent of treatment.
这个临床针对直肠癌，结论KRAS突变与西地疗效无关，但是预后不好的征兆。 |
显身卡
