治疗结肠直肠癌的靶向药物帕尼单抗临床评价

帕尼单抗是靶向表皮生长因子受体(EGFR)的第一个完全人源化单克隆抗体,主要用于实体瘤治疗,其可直接拮抗受体细胞外配体结合区,阻断下游信号通道.体内外试验及Ⅰ～Ⅲ期临床研究证明,其一般耐受良好,几无输液反应,是治疗转移性结肠直肠癌(mCRC)很有希望的药物.帕尼单抗是继贝伐单抗和西妥昔单抗之后获美国FDA批准治疗耐药mCRC的靶向药物,其单用或与标准化疗药物联合应用均有效,为mCRC患者提供了更多的治疗选择并可改善患者预后.     

KRAS基因检测干预西妥昔单抗治疗转移性结直肠癌的成本-效果探讨

目的：通过评价KRAS基因检测用于西妥昔单抗治疗转移性结直肠癌（metastatic colorectal cancer,mCRC）的国内外药物经济学研究,探讨其临床疗效及成本效果。方法：从Pubmed、CNKI等大型数据库对2006—2016年期间国内外公开发表的有关KRAS基因检测干预西妥昔单抗治疗的药物经济学评价文献进行检索,对研究内容及结果进行分析及综述。结果：纳入分析的7篇文献表明,与西妥昔单抗（无KRAS检测）相比,KRAS基因检测干预西妥昔单抗治疗mCRC可显著降低成本或提高质量调整生命年（quality adjusted life year,QALY）,改善成本效果,具有优势;且额外进行BRAF及RAS基因检测可进一步改善KRAS检测干预西妥昔单抗治疗的成本效果。结论：KRAS等基因突变检测干预西妥昔单抗治疗相比无KRAS检测为具有优势,且对于指导西妥昔单抗治疗方案的合理选择及实现肿瘤精准医疗有重大实践意义,或将成为未来肿瘤学研究趋势。     

西妥昔单抗治疗不同性别大肠癌患者的疗效观察

目的:观察西妥昔单抗治疗不同性别大肠癌患者的疗效。方法:回顾性分析我院2013年1月-2014年3月住院手术治疗的表皮生长因子受体(EGFR)阳性的KRAS野生型的大肠癌患者92例,以性别分成男、女两组,均采用FOLFIRI+西妥昔单抗方案治疗,临床病理学特征、治疗效果及不良反应与性别之间的关系。结果:大肠癌患者中男女比例1.42∶1;高分化腺癌男组33例(61.11%)、女组9例(23.68%),中分化腺癌男组9例(16.67%)、女组19例(50.00%),两组间差异均有统计学意义(P<0.05);女组客观有效率(ORR)为34.21%,较男组(14.81%)高(P=0.029),女组疾病控制率(DCR)为73.68%,较男组(50.00%)高(P=0.023),两组间差异均有统计学意义(P<0.05);女组患者治疗后皮疹发生率(57.89%)明显高于男组(33.33%),差异有统计学意义(P=0.019),而其他不良反应在患者性别间的差异均无统计学意义(P>0.05)。结论:大肠癌以男性多见,男组病理学分型高分化腺癌明显高于女组;女性患者在接受FOLFIRI标准化疗+西妥昔单抗治疗后获益更明显;女性大肠癌患者使用西妥昔单抗后更易发生皮疹。     

台疗结肠直肠癌的靶向药物帕尼单抗临床评价

帕尼单抗是靶向表皮生长因子受体（EGFR）的第一个完全人源化单克隆抗体，主要用于实体瘤治疗，其可直接拮抗受体细胞外配体结合区，阻断下游信号通道。体内外试验及Ⅰ-Ⅲ期临床研究证明，其一般耐受良好，几无输液反应，是治疗转移性结肠直肠癌（mCRC）很有希望的药物。帕尼单抗是继贝伐单抗和西妥昔单抗之后获美国FDA批；住治疗耐药mCRC的靶向药物，其单用或与标准化疗药物联合应用均有效，为mCRC患者提供了更多的治疗选择并可改善患者预后。     

西妥昔单抗联合化疗治疗转移性结直肠癌的临床观察

目的观察西妥昔单抗与奥沙利铂/5-FU/FA联合治疗转移性结直肠癌的近期疗效及毒性反应。方法对11例转移性结直肠癌(MCRC)患者采用西妥昔单抗与奥沙利铂/5-FU/FA化疗联合方案,应用2周期后评价近期疗效及毒性反应。西妥昔单抗首次推荐剂量为400 mg/m~2,以后每周剂量为250 mg/m~2,奥沙利铂/5-FU/FA化疗剂量采用FOLFOX4方案。结果11例患者均完成西妥昔单抗连续6周用药,奥沙利铂/5-FU/FA化疗2周期(每2周重复1次),无CR病例,2例PR(18.18%),4例SD(36.36%),5例PD(45.45%),疾病控制(PR SD)率54.55%。治疗过程中出现的毒性反应为3～4度的痤疮样皮疹,另外有恶心、呕吐、腹痛和虚弱,2～3度白细胞下降。全组患者无过敏反应。结论西妥昔单抗可提高肿瘤对放化疗的敏感性。采用西妥昔单抗与奥沙利铂联合治疗11例转移性结直肠癌患者,取得初步疗效和安全性观察,且不因联合化疗而增加毒性反应,耐受性良好。     

西妥昔单抗治疗中晚期恶性肿瘤的疗效和安全性评价

目的:观察西妥昔单抗治疗中晚期恶性肿瘤的疗效及不良反应,研究影响疗效的主要因素。方法:回顾性分析2007年1月—2009年3月使用西妥昔单抗治疗中晚期恶性肿瘤的41例患者资料,对疗效和安全性进行评价。采用相关性和回归分析方法对可能影响药物治疗效果的因素进行统计。结果:西妥昔单抗的总有效为41.2%、疾病控制率为85.3%,对大肠癌治疗效果优于其他肿瘤,联用其他化疗药物的效果优于单用。肿瘤病理分型、HER-1受体表达和Kras基因突变与患者的药物治疗效果相关。治疗过程中共观察到36例次药品不良反应,包括皮肤毒性(29例次)、过敏反应(4例次)和低镁血症(3例次)。结论:西妥昔单抗联用其他化疗药物治疗一线化疗方案失败的大肠癌疗效确切,建议在用药前明确肿瘤病理分型、检测HER-1受体表达和Kras基因突变以预测治疗效果,治疗过程中应妥善处理严重的药品不良反应。     

西妥昔单抗联合化疗方案治疗晚期结直肠癌的临床疗效

目的评价西妥昔单抗联合化疗方案治疗晚期结直肠癌的疗效及不良反应。方法选择我院2007年1月-2010年6月单用或联合化疗使用西妥昔单抗治疗晚期或转移性结直肠癌患者35例,采用RF,cISr 1.1版实体肿瘤客观疗效评定标准进行临床疗效评价。并采用美国毒性反应评价标准(CIE 3.0)进行不良反应评价。结果共有31例纳入疗效评价。其中完全缓解l例,部分缓解9例,疾病稳定14例,疾病进展7例,有效率32.3%,疾病控制率75.O%;K-RAS基因野生型的患者有效率(40.0%)明显高于未检测组(18.2%)。33例发生了不良反应,发生率94.3%,主要为I～Ⅱ级(占74.1%)。结论西妥昔单抗联合放化疗方案治疗晚期结直肠癌可获得较高有效率,延长了疾病进展时间。     

西妥昔单抗与放化疗联合治疗方案对进展期鼻咽癌患者预后的影响

目的:探讨西妥昔单抗与放化疗联合治疗方案对进展期鼻咽癌患者预后的影响。方法:收集2009年5月—2011年2月间诊治的进展期鼻咽癌患者64例,根据治疗方案将其分为观察组(n=36)和对照组(n=28),观察组患者给予西妥昔单抗与放化疗联合治疗方案治疗,对照组患者给予单纯放化疗治疗,分析两组患者的近期疗效、不良反应及3年内生存情况。结果:观察组患者治疗的总有效率66.67%高于对照组42.86%(P<0.05);两组患者不良反应发生情况经比较其差异无统计学意义(P>0.05);观察组患者3年内总生存率88.88%高于对照组67.86%(P<0.05)。结论:西妥昔单抗与放化疗联合治疗对进展期鼻咽癌患者的疗效较显著,未增加与放化疗相关的不良反应,安全性良好,有利于延长患者生存期。     

转移性结肠直肠癌抗体药物研究

对比贝伐单抗单用或联合IFL化疗方案、西妥昔单抗单用或分别与伊立替康、IFL方案联合应用的治疗效果,评价转移性结肠直肠癌(mCRC)靶向抗体药物的疗效和安全性,提示靶向药物治疗mCRC疗效较好,但尚需进一步临床研究证实。     

西妥昔单抗联合化疗治疗晚期结直肠癌临床疗效观察

目的 观察西妥昔单抗联合化疗治疗晚期结直肠癌的疗效及毒副反应.方法 25例晚期结直肠癌,给予西妥昔单抗联合化疗治疗.结果 全组有效率56.0%,疾病控制率(DCR)88.0%.中位肿瘤进展时间(TTP)10.5个月.主要毒副反应为痤疮样皮疹.结论 西妥昔单抗联合化疗治疗晚期结直肠癌疗效较好,毒副反应可耐受.     

Review article: panitumumab - a fully human anti-EGFR monoclonal antibody for treatment of metastatic colorectal cancer

Background  Panitumumab is a fully human monoclonal IgG2 antibody targeting the epidermal growth factor receptor (EGFR).
Aim  To review the efficacy of panitumumab in the treatment of metastatic colorectal cancer (mCRC).
Methods  Available literature identified from PubMed and conference websites was reviewed.
Results  In phase 2–3 studies, panitumumab monotherapy achieved objective response rates (ORRs) of 8–13% in relapsed/refractory EGFR-expressing mCRC. In a randomized phase 3 study (463 patients), panitumumab almost halved the risk of disease progression/death vs. a control group receiving only best supportive care (hazard ratio 0.54; 95% CI: 0.44–0.66; P  <   0.0001). Objective response was achieved in 22/231 (10%) patients randomized to panitumumab – and also in 20/176 (11%) patients assigned to the control group who received panitumumab in a separate crossover protocol after disease progression. Response was confined to patients with tumours harbouring wild-type KRAS (ORR ≈20%). Panitumumab is also being evaluated in earlier lines of treatment. Panitumumab monotherapy is generally well tolerated; the most common toxicities are skin toxicity (≈90%) and diarrhoea (<30%). Development of anti-panitumumab antibodies (0.3% by ELISA) and grade 3–4 infusion reactions (<1%) are rare.
Conclusion  Panitumumab is an effective monotherapy option for patients with relapsed/refractory EGFR-expressing mCRC harbouring wild-type KRAS .     

Clinical characterization of patients with metastatic colorectal cancer depending on the KRAS status

This retrospective study investigated the clinical characteristics of patients with metastatic colorectal cancer (mCRC) depending on the KRAS status, thereby differentiating KRAS exon 2 mutations in codon 12 versus codon 13. In total, 273 patients with mCRC receiving first-line therapy were analyzed. One hundred patients were treated within the FIRE-3 trial (FOLFIRI plus cetuximab or bevacizumab), 147 patients within the AIO KRK-0104 trial (cetuximab plus CAPIRI or CAPOX), and further 26 patients received therapy outside the study. Thirty-eight tumors with KRAS mutation in codon 13, 140 tumors with mutation in codon 12, and 95 tumors with KRAS wild type as a comparison were included in this analysis. Bivariate analyses demonstrated significant differences between KRAS wild-type, codon 12-mutated, and codon 13-mutated tumors with regard to synchronous lymph node metastasis (P=0.018), organ metastasis (76.8% vs. 65.9% vs. 89.5%, P=0.009), liver metastasis (89.5% vs. 78.2% vs. 92.1%, P=0.025), lung metastasis (29.5% vs. 42.9% vs. 50%, P=0.041), liver-only metastasis (48.4% vs. 28.8% vs. 28.9%, P=0.006), and metastases in two or more organs (49.5, 61.4, 71.1, P=0.047). Regression models indicated a significant impact of KRAS mutations in codon 12 versus codon 13 for synchronous organ and nodal metastasis (P=0.01, 0.03). This pooled analysis indicates that mCRC is a heterogeneous disease, which seems to be defined by KRAS mutations of the tumor. Compared with KRAS codon 12 mutations, codon 13-mutated mCRC presents as a more aggressive disease frequently associated with local and distant metastases at first diagnosis.     

Phase II study of combination chemotherapy with biweekly cetuximab and irinotecan for wild-type KRAS metastatic colorectal cancer refractory to irinotecan, oxaliplatin, and fluoropyrimidines

The aim of this study is to prospectively evaluate the efficacy of combination chemotherapy with every second week cetuximab and irinotecan in patients with pretreated metastatic colorectal cancer harboring wild-type KRAS. Patients with wild-type KRAS metastatic colorectal cancer that had progressed after chemotherapy with irinotecan, oxaliplatin, and fluoropyrimidine were included. Cetuximab was administered at 500 mg/m(2) biweekly with irinotecan. The primary endpoint was response rate. The pharmacokinetics of cetuximab was also evaluated in 5 patients. From May 2009 to February 2010, a total of 31 patients were enrolled from five institutions. One patient was not eligible. Among the 30 patients who were treated with biweekly cetuximab plus irinotecan, partial response was observed in 9 patients. The objective response rate was 30.0% (95% confidence interval [CI], 14.7%-49.4%) and the disease control rate (complete response, partial response, or stable disease) was 76.7% (95% CI, 57.7%-90.0%). The median progression-free survival was 5.3 months and median overall survival was 10.8 months. Grade 3 skin toxicity was observed in 3 patients (10.0%) and one treatment related death due to pneumonia was observed. Combination chemotherapy with biweekly cetuximab and irinotecan was effective for pretreated metastatic colorectal cancer with wild-type KRAS.     

The safety of monoclonal antibodies for treatment of colorectal cancer

ABSTRACT

Introduction: Monoclonal antibodies such as bevacizumab, ramucirumab, cetuximab and panitumumab play an important role in the treatment of metastatic colorectal cancer (mCRC). With the introduction of these drugs considerable improvements in both progression-free survival (PFS) and overall survival (OS) were achieved. However these antibodies are associated with a unique side effect profile.

Areas covered: This review provides an overview about drug efficacy of bevacizumab, cetuximab, panitumumab and ramucirumab in the treatment algorithm of mCRC. Additionally, we discuss the most common toxicites of these monoclonal antibodies.

Expert opinion: The most common toxicities associated with the VEGF-A directed antibody bevacizumab are hypertension, proteinuria, thromboembolism, bleeding, gastrointestinal perforation and prolonged wound healing. Similarly, the rate of hypertension and proteinuria is increased during treatment with the VEGFR2 antibody ramucirumab.

On the other hand the most frequent side effects of EGFR targeted antibodies are skin rash, hypersensitivity reactions and hypomagnesemia. Due to the murine portions of cetuximab the incidence of infusion reactions is more frequent compared to panitumumab which is a pure human monoclonal antibody.     

Cetuximab: a review of its use in squamous cell carcinoma of the head and neck and metastatic colorectal cancer

Cetuximab (Erbitux) is a human-mouse chimeric monoclonal antibody, which competitively binds to the accessible extracellular domain of the epidermal growth factor receptor (EGFR) to inhibit dimerisation and, subsequently, inhibit tumour growth and metastasis. In the EU and the US, cetuximab has been approved for use with concomitant radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) and in combination with irinotecan for the treatment of metastatic colorectal cancer (mCRC) in patients with EGFR-expressing tumours who are refractory to irinotecan-based therapy. In the US, cetuximab has also been approved as monotherapy in patients with recurrent or metastatic SCCHN for whom platinum-based therapy has failed and in patients with mCRC who are intolerant of irinotecan-based regimens.In treatment-naive patients with locoregionally advanced SCCHN, cetuximab plus radiotherapy was more effective than radiation therapy alone in prolonging locoregional disease control. In addition, more limited noncomparative data from a large trial indicated a 13% overall objective response rate (ORR) in platinum-refractory patients with SCCHN. In patients with EGFR-expressing mCRC, cetuximab plus irinotecan improved ORR more than cetuximab monotherapy in a trial in irinotecan-refractory patients; however, there was no difference in overall survival (OS) between cetuximab plus irinotecan and cetuximab monotherapy in oxaliplatin-refractory recipients in another trial. In an ongoing trial, progression-free survival (PFS) exceeded 50% after 12 weeks in irinotecan-refractory patients receiving three different dosages of cetuximab plus irinotecan. In another large trial, cetuximab monotherapy prolonged OS compared with best supportive care (BSC) in heavily pretreated patients. Overall, cetuximab treatment had an acceptable tolerability profile, with the majority of adverse events being mild or moderate in severity and clinically manageable. In particular, cetuximab therapy did not exacerbate toxicities commonly associated with chemo- or radiotherapeutic regimens. Albeit occurring with high incidence, adverse cutaneous reactions appear to be a marker for response. Results of ongoing head-to-head comparative trials comparing cetuximab with other biological agents will help to establish definitively the role of cetuximab in the management of SCCHN and mCRC. In the meantime, cetuximab, with its highly targeted mechanism of action and synergistic activity with current treatment modalities, is a valuable treatment option in patients with SCCHN and mCRC.     

A phase II,multicenter study of cetuximab monotherapy in patients with refractory,metastatic colorectal carcinoma with absent epidermal growth factor receptor immunostaining

Purpose To determine antitumor activity of cetuximab monotherapy in patients with refractory metastatic colorectal carcinoma (mCRC) with lack of specific membrane immunostaining for the epidermal growth factor receptor (EGFR). Patients and methods Patients had immunohistochemical (IHC)-determined mCRC with absent EGFR immunostaining that progressed after receiving at least one standard, fluoropyrimidine-containing chemotherapeutic regimen. Absent EGFR immunostaining was defined as the IHC absence of specific membrane staining in ≥500 cancer cells examined in well-preserved tissue. The study was performed prior to results of studies linking cetuximab sensitivity to K-ras mutation status. Patients received 400 mg/m² of intravenous (i.v.) cetuximab followed by once-weekly i.v. cetuximab 250 mg/m² until disease progression or unacceptable toxicity. Patients were evaluated for objective response at least every 6 weeks. Kaplan-Meier estimates were calculated for duration of response, time to progression (TTP), and overall survival (OS). Results Seven (8.2%) of 85 mCRC patients whose tumors lacked EGFR immunostaining had major responses following cetuximab treatment. The median duration of response was 5.1 months. Median TTP and OS were 2.5 months and 10.0 months, respectively; the 1-year survival rate was 39.6%. The most frequently reported cetuximab-related adverse events were acneiform dermatitis, fatigue, headache, and dry skin. Conclusion Cetuximab monotherapy produces objective antitumor activity in patients with mCRC that does not express EGFR as determined by IHC. The activity and safety profiles of cetuximab monotherapy in mCRC lacking EGFR immunostaining are similar to previous observations in EGFR IHC-positive disease that was not selected based on K-ras mutation status.     

Cetuximab-based or bevacizumab-based first-line treatment in patients with KRAS p.G13D-mutated metastatic colorectal cancer: a pooled analysis

KRAS p.G13D mutant metastatic colorectal cancer (mCRC) has been identified as representing a cetuximab-sensitive subtype of KRAS mutant mCRC. This analysis aims to answer the question of whether first-line treatment of p.G13D mCRCs should include cetuximab or bevacizumab. Fifty-four patients with p.G13D mutant mCRC were pooled in this analysis. All patients underwent systemic first-line treatment with a fluoropyrimidine and oxaliplatin/irinotecan that was combined with either cetuximab or bevacizumab. The analysis of cetuximab-based and bevacizumab-based regimens in mCRC patients with p.G13D-mutated tumours indicated comparable data for the overall response rate (58 vs. 57%) and progression-free survival (8.0 vs. 8.7 months; hazard ratio: 0.96, P=0.9). Overall survival (OS) was 20.1 months in patients treated with cetuximab-based first-line therapy compared with 14.9 months in patients receiving bevacizumab-containing regimens (hazard ratio: 0.70, P=0.29). Logistic regressions modelling OS revealed oxaliplatin-based first-line treatment to correlate with a poor outcome (P=0.03). Moreover, a strong trend in favour of capecitabine compared with infusional 5-FU (P=0.06) was observed. Response to treatment correlated with OS in patients receiving cetuximab-based, but not bevacizumab-based regimens. This retrospective pooled analysis suggests comparable efficacy of cetuximab-based and bevacizumab-based first-line therapy in patients with p.G13D mutant mCRC. The combination with capecitabine and irinotecan was associated with a more favourable outcome compared with infusional 5-FU and oxaliplatin.     

Advanced therapies on BRAF-mutated and KRAS-mutated metastatic colorectal cancer

Colorectal cancer(CRC) is one of the most-diagnosed cancer worldwide, and 30% of patients with CRC have showed a metastatic situation. Monoclonal antibodies(mAbs) that target vascular endothelial growth factor(VEGF) and the epidermal growth factor receptor(EGFR) can achieveantitumor efficacy via antivascular and anticellular effects respectively and have been added into first-line chemotherapy for patients with metastatic colorectal cancer(mCRC). Investigations found that unlike VEGF inhibitors, the efficacy of EGFR inhibitors,such as Cetuximab and panitumumab, is limited to patients with wild-type-KRAS tumors without BRAF mutant. Studies revealed that resistance to EGFR inhibitors result in the poor response to anti-EGFR therapiesthrough acquired mutations of KRAS and BRAF.Considering this situation, in this review, we will focus onresistance mechanism to anti-EGFR therapies and advanced therapies for BRAF-mutated and KRAS-mutated mCRC patients.