Modified FOLFOXIRI With or Without Cetuximab as Conversion Therapy in Patients with RAS/BRAF Wild‐Type Unresectable Liver Metastases Colorectal Cancer: The FOCULM Multicenter Phase II Trial

PurposeThis trial evaluated the addition of cetuximab to a modified FOLFOXIRI (mFOLFOXIRI: 5‐fluorouracil/folinic acid, oxaliplatin, irinotecan) as conversion therapy in a two‐group, nonrandomized, multicenter, phase II trial in patients with initially technically unresectable colorectal liver‐limited metastases (CLM) and BRAF/RAS wild‐type.Patients and MethodsPatients were enrolled to receive cetuximab (500 mg/m²) plus mFOLFOXIRI (oxaliplatin 85 mg/m², irinotecan 165 mg/m², folinic acid 400 mg/m², 5‐fluorouracil 2,800 mg/m² 46‐hour infusion, every 2 weeks) (the cetuximab group) or the same regimen of mFOLFOXIRI alone (the control group), in a 2:1 ratio allocation. The primary endpoint was the rate of no evidence of disease (NED) achieved. Secondary endpoints included resection rate, objective response rate (ORR), survival, and safety.ResultsBetween February 2014 and July 2019, 117 patients were registered for screening at six centers in China, and 101 of these were enrolled (67 cetuximab group, 34 control group). The rate of NED achieved was 70.1% in the cetuximab group and 41.2% in the control group (difference 29.0%; 95% confidence interval [CI], 9.1%–48.8%; p = .005). Patients in the cetuximab group had improved ORR (95.5% vs. 76.5%; difference 19.1%; 95% CI, 17.4%–36.4%; p = .010) compared with those in control group. Progression‐free survival and overall survival showed the trend to favor the cetuximab group. The incidence of grade 3 and 4 adverse events was similar in the two groups.ConclusionAddition of cetuximab to mFOLFOXIRI improved the rate of NED achieved. This combination could be an option of conversion regimen for molecularly selected patients with initially technically unresectable CLM.Implications for PracticeThis trial evaluated the addition of cetuximab to a modified FOLFOXIRI as conversion therapy in a phase II trial in patients with initially technically unresectable colorectal liver‐limited metastases and BRAF/RAS wild‐type. The rate of no evidence of disease achieved was 70.1% in the cetuximab plus modified FOLFOXIRI group and 41.2% in the modified FOLFOXIRI group. Objective response rates, overall survival, and progression‐free survival were improved in the cetuximab group when compared with the modified FOLFOXIRI group. Addition of cetuximab to modified FOLFOXIRI increased the rate of no evidence of disease achieved, and this combination could be an option of conversion regimen for molecularly selected patients with initially technically unresectable colorectal liver‐limited metastasis.     

Phase II Study of Cetuximab,Docetaxel, and Gemcitabine in Patients With Previously Untreated Advanced Non–Small-Cell Lung Cancer

BackgroundTargeting epidermal growth factor receptors (EGFRs) has been a novel strategy in treating non–small-cell lung cancer (NSCLC). This multicenter, community-based trial was designed to examine the role of cetuximab in combination with a nonplatinum regimen.Patients and MethodsEligibility criteria were newly diagnosed unresectable stage III/IV NSCLC, all histologies, measurable disease, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2. Treatment premedication included dexamethasone 20 mg orally 12 and 6 hours before treatment, and 4 mg 12 hours following treatment; diphenhydramine 50 mg intravenously (I.V.) and cimetidine 300 mg I.V. before cetuximab. Treatment medication included docetaxel 30 mg/m² I.V. days 1 and 8; gemcitabine 1000 mg/m² I.V. days 1 and 8; and cetuximab 400 mg/m² I.V. day 1, then 250 mg/m² I.V. weekly. Patients received up to 6 cycles with restaging every 6 weeks. The primary endpoint was an overall response rate (ORR) ≥ 25%.ResultsSixty-nine patients enrolled from July 2005 to October 2007. Patients had a median age of 69 years; 70% were male and 30% were female; ECOG PS was 0 in 42%, 1 in 51%, and 2 in 7%; patients had adenocarcinoma (42%), squamous cell (30%), large cell (6%), mixed (1%), and not otherwise specified (20%) disease. The ORR was 17% (95% CI, 9%-29%). Thirty-five patients (54%) had stable disease; 14 patients (22%) had progressive disease. With a median follow-up of 17.8 months, the median progression-free and overall survivals were 4 months and 9.4 months, respectively. The most common (> 10%) grade 3/4 toxicities were neutropenia (25%), rash (22%), and fatigue (12%). Accrual in our middle Tennessee offices was temporarily suspended and ultimately stopped because of a higher-than-anticipated rate of cetuximab-related severe hypersensitivity reactions (HSRs) in 4 patients among the first 12 enrolled, including 1 fatal event.ConclusionCetuximab/docetaxel/gemcitabine was relatively well-tolerated and associated with efficacy similar to chemotherapy alone. Additional study with cetuximab/chemotherapy in NSCLC should focus on new potentially predictive biomarkers. Also, additional study is needed to better understand and prevent the severe HSRs that appear to be endemic to specific regions of the United States.     

Results of a Phase II Trial of Cetuximab plus Capecitabine/Irinotecan as First-Line Therapy for Patients with Advanced and/or Metastatic Colorectal Cancer

BackgroundXELIRI (capecitabine/irinotecan) is effective and well tolerated in metastatic colorectal cancer (mCRC). Cetuximab is active in mCRC alone or with chemotherapy. This study evaluated cetuximab plus XELIRI in first-line treatment of mCRC.Patients and MethodsSubjects had histologically confirmed unresectable colorectal adenocarcinoma (with T4 lesions) after preoperative chemoradiation and/or metastases. Treatment was capecitabine 1700 mg/m² (850 mg/m² orally twice a day on days 1-14 for 3 weeks), irinotecan 200 mg/m² intravenously (I.V.) on day 1 every 3 weeks, and weekly cetuximab (initially 400 mg/m² I.V. [120 minutes], subsequently 250 mg/m² [30 minutes]).ResultsBaseline characteristics (N = 70): 43 men (61%); median age, 61.5 years; Eastern Cooperative Oncology Group performance status 0/1 = 66%/34%; 94% adenocarcinoma. Previous therapy: surgery (91%), chemotherapy (14%), or radiation therapy (7%). Responses (patients completing ≥ 2 cycles): complete response (5.7%), partial response (37.7%), stable disease (43.4%), and progressive disease (PD; 13.2%); 16 patients discontinued early (n = 4 allergic reaction, n = 2 withdrew consent, n = 2 death, and n = 8 other adverse events [AEs]). The overall per-protocol response rate was 43.4% (34% intent to treat [ITT]; disease control rate, 86.8%; 69% ITT). The median time to progression was 8.1 months (range, < 1-27.0 months), and the median time to response was 1.6 months (range, 1.1-8.4 months). The median survival was 20.5 months, and 45.7% of patients remain alive. Of the 38 deaths, 84% were because of PD. No death was treatment related. The most frequent grade 3/4 treatment-related AEs included diarrhea, neutropenia, and nausea/vomiting; 32% of patients required dose reductions. All patients are off the study primarily because of PD (34.3%) or AEs (40.0%).ConclusionIn summary, XELIRI plus cetuximab is a promising regimen that merits further study for first-line mCRC.     

Cetuximab,docetaxel, and cisplatin as first-line treatment in patients with recurrent or metastatic head and neck squamous cell carcinoma: a multicenter,phase II GORTEC study

BackgroundCetuximab in combination with platinum and 5-fluorouracil is the standard of care in the first-line treatment of patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Cetuximab and taxane combinations have shown promising activity. This study evaluated the efficacy and safety of four cycles of docetaxel associated with cisplatin and cetuximab (TPEx), followed by maintenance with cetuximab every 2 weeks.Patients and methodsPatients with a histologically confirmed HNSCC with metastasis or recurrence unsuitable for locoregional curative treatment received docetaxel and cisplatin (75 mg/m² both) at day 1 and weekly cetuximab 250 mg/m² (loading dose of 400 mg/m²), repeated every 21 days for four cycles, followed by maintenance cetuximab 500 mg/m² every 2 weeks until progression or unacceptable toxicity. Prophylactic administration of granulocyte colony-stimulating factor was done systematically after each chemotherapy cycle. Patients had a good general status (performance status ≤1) and were under 71 years. Prior total doses of cisplatin exceeding 300 mg/m² were not allowed. The primary end point was objective response rate (ORR) after four cycles.ResultsFifty-four patients were enrolled. The primary end point was met with an ORR of 44.4% (95% CI 30.9–58.6). Median overall and progression-free survivals were, respectively, 14 months (95% CI 11.3–17.3) and 6.2 months (95% CI 5.4–7.2). The most common grade 3/4 adverse events were skin rash (16.6%) and non-febrile neutropenia (20.4%). There were one pulmonary embolism and two infectious events leading to death.ConclusionsThe TPEx regimen showed promising activity as first-line treatment in fit patients with recurrent/metastatic HNSCC. Further studies are needed to compare the TPEx versus EXTREME regimen in this population.ClinicalTrial.govNCT01289522.     

Phase II trial of capecitabine and oxaliplatin (CAPOX) plus cetuximab in patients with metastatic colorectal cancer who progressed after oxaliplatin-based chemotherapy.

BACKGROUND: Cetuximab is an IgG1 monoclonal antibody targeting the epidermal growth factor receptor and is able to reverse the resistance to irinotecan in patients with metastatic colorectal cancer (mCRC). This phase II trial evaluates the safety and efficacy of cetuximab combined with capecitabine and oxaliplatin (CAPOX) in the treatment of patients with mCRC progressing under oxaliplatin-based chemotherapy. Patients and treatment: Forty patients with mCRC were treated with cetuximab (loading dose 400 mg/m(2) and then 250 mg/m(2) i.v. weekly) in combination with CAPOX (d(1): L-OHP 85 mg/m(2) and d(1-7) capecitabine 2000 mg/m(2) every 2 weeks). Thirty-one (77.5%) and nine (22.5%) patients had oxaliplatin-refractory and -resistant disease, respectively; in addition, 32 (80%) patients had also progressed on prior irinotecan-based chemotherapy. RESULTS: One hundred and thirty-four cycles were administered (median of four cycles per patient). Main toxic effects included grade 3-4 neutropenia (12.5%), grade 3/4 diarrhea (7.5%), grade 3 fatigue (2.5%), and grade 2-3 neurotoxicity (22.5%). One (2.5%) complete and seven (17.5%) partial responses were achieved [overall objective response rate (ORR): 20%; 95% confidence interval (CI): 9% to 32%)], whereas 11 (27.5%) patients had stable disease [disease control rate (DCR): 47.5%; 95% CI: 30.2% to 64.5%]. The ORR and DCR were 18.7% and 46.8%, respectively, in patients with oxaliplatin-refractory disease. The median time to tumor progression was 3 months, the median survival 10.7 months and the probability of 1-year survival rate 53.4%. CONCLUSIONS: The combination of cetuximab plus CAPOX is safe and has a promising activity in patients with mCRC refractory or resistant to oxaliplatin.     

China special issue on gastrointestinal tumors-Cetuximab retreatment plus camrelizumab and liposomal irinotecan in patients with RAS wild-type metastatic colorectal cancer: Cohort B of the phase II CRACK study

Patients with metastatic colorectal cancer (mCRC) have poor long-term survival. Rechallenge with anti-epidermal growth factor receptor (anti-EGFR) based therapy has shown certain activity as late-line therapy. To further improve clinical outcomes, we evaluated the antitumor efficacy and safety of cetuximab in combination with camrelizumab and liposomal irinotecan in patients with RASwt mCRC pretreated with anti-EGFR-based therapy. Patients with RASwt mCRC who had received at least two prior systemic therapies, including anti-EGFR-based treatment in the metastatic or unresectable disease setting, were enrolled in cohort B. Patients were treated with cetuximab (500 mg/m²) and camrelizumab (200 mg) plus liposomal irinotecan (HR070803, 60 mg/m²) intravenously once every 2 weeks. The primary endpoint was the objective response rate (ORR) by RECIST v1.1. The secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. At the data cutoff (23 November 2022), 19 patients were enrolled in the two stages, and 16 were evaluable for efficacy analyses. The ORR was 25% (95% confidence interval [CI]: 10.2%-49.5%), and DCR was 75% (95% CI: 50.5%-89.8%). The median PFS and OS were 6.9 (95% CI: 2.6-11.2) and 15.1 (95% CI: 6.1-24.0) months, respectively. Grade 3 treatment-related adverse events (TRAEs) occurred in 15.8% (3/19) of patients. No grade ≥4 TRAEs were found in the safety population. Our study suggests that anti-EGFR retreatment therapy with cetuximab plus camrelizumab and liposomal irinotecan (HR070803) is a promising late-line treatment option with good antitumor activity and well-tolerated toxicity in RASwt mCRC patients.     

Predictive Value of Early Skin Rash in Cetuximab-Based Therapy of Advanced Biliary Tract Cancer

Randomized trials in advanced biliary tract cancer (BTC) did not show benefit of cetuximab addition over chemotherapy. This is probably due to the lack of predictive biomarkers. The aim of this study was to explore possible predictive factors. Between 2009 and 2014, 57 patients were treated in 3-week cycles with cetuximab (250 mg/m²/week, loading dose: 400 mg/m²), gemcitabine (1000 mg/m² on day 1 and 8), and capecitabine (1300 mg/m²/day on days 1–14). The objective response rate (ORR), progression-free (PFS) and overall survival (OS) and the adverse events (AEs) were evaluated. An exploratory analysis was performed to find possible predictive factors on clinicopathological characteristics, routine laboratory parameters and early AEs, which occurred within 2 months from the beginning of treatment. The ORR was 21%. The median PFS and OS were 34 (95% CI: 24–40) and 54 (43–67) weeks, respectively. The most frequent AEs were skin toxicities. In univariate analysis performance status, previous stent implantation, thrombocyte count at the start of therapy, early neutropenia and skin rash statistically significantly influenced the ORR, PFS and/or OS. In multivariate Cox regression analysis only normal thrombocyte count at treatment start and early acneiform rash were independent markers of longer survival. In patients showing early skin rash compared to the others the median PFS was 39 vs. 13 weeks and the median OS was 67 vs. 26 weeks, respectively. It is suggested that early skin rash can be used as a biomarker to select patients who would benefit from the treatment with cetuximab plus chemotherapy.     

Phase II study of low-dose paclitaxel with timed thoracic radiotherapy followed by adjuvant gemcitabine and carboplatin in unresectable stage III non-small cell lung cancer

Objectives

The purpose of the proposed study is to evaluate the effectiveness and safety of low-dose paclitaxel with timed thoracic radiotherapy (TTR) for local control by inducing maximum radiosensitization through G2-M phase cell cycle arrest, followed by full dose adjuvant chemotherapy with gemcitabine and carboplatin for eradication of possible micrometastasis in unresectable stage III non-small cell lung cancer (NSCLC).

Materials and methods

This is a single-center, non-randomized prospective phase II study. Patients with unresectable stage III NSCLC were treated with paclitaxel 15 mg/m² IV, followed by TTR 6 h later on Monday/Wednesday/Friday, and TTR only on Tuesday/Thursday mornings (total 55 Gy). Full dose adjuvant chemotherapy consisted of intravenous carboplatin (AUC 5) on day 1, gemcitabine 1000 mg/m² on days 1 and 8, every 21 days for 4 cycles. The primary endpoint was overall survival (OS). Secondary endpoints were overall response rate (ORR), and toxicities.

Results

Twenty-seven patients were eligible for the study. Patient characteristics were: 19 males (70%); median age 67 years (range 39–82); 15 (56%) stage IIIB; 89% with ECOG performance status ≥1. Three-year OS was 16.7% in all patients, and 27.3% in patients received three or more cycles of adjuvant chemotherapy, respectively. ORR was 63%. Grade 3 toxicities during paclitaxel plus concurrent TTR phase were radiation esophagitis (11%) and radiation pneumonitis (4%), no grade 4 toxicities occurred. One grade 5 hemoptysis. Grade 3/4 toxicities during adjuvant gemcitabine/carboplatin were pneumonitis (22%), anemia (30%), neutropenia (22%), and thrombocytopenia (33%), one grade 5 neutropenic fever.

Conclusion

Low-dose paclitaxel with concurrent TTR is an effective chemoradiotherapy regimen in unresectable stage III NSCLC. Improved survival benefit was observed in patients who have received three or more cycles of full dose adjuvant chemotherapy, yet, gemcitabine related radiation pneumonitis and hematological toxicities limited adjuvant chemotherapy delivery.     

西妥昔单抗联合化疗治疗K-Ras野生型转移性结直肠癌的疗效分析

目的 观察西妥昔单抗联合化疗治疗K-Ras野生型转移性结直肠癌的疗效及安全性,探讨可能影响疗效及预后的因素。方法 收集2007年5月至2012年5月解放军总医院收治的K Ras野生型转移性结直肠癌患者共90例,采用西妥昔单抗（400mg／m2,静滴,第1周,维持剂量每周250mg／m2或每2周500mg／m2）联合化疗方案,主要为含伊立替康为基础方案（FOLFIRI或XELIRI或单药CPT-11）、含奥沙利铂为基础方案（FOLFOX或XELOX）、5 FU／LV方案或单药卡培他滨。回顾性评估西妥昔单抗联合化疗在治疗中的疗效和安全性,分析患者临床病理特征,并探讨影响疗效的因素以及此类患者预后相关的因素。结果 西妥昔单抗中位治疗时间为16周（6～44周）,客观缓解率（ORR）为45.6％,疾病控制率（DCR）为87.8％。其中一线治疗ORR为51.6％,二线治疗ORR为40.0％,三线治疗ORR为18.2％。单因素分析显示,年龄、原发灶部位、西妥昔单抗治疗时间与疗效有关,差异具有统计学意义（P＜0.05）。90例患者中位随访时间为20.2个月,82例（91.1％）复发转移,60例（66.7％）死亡。患者中位无疾病进展时间（PFS）为7.8个月,中位总生存时间（OS）为22.5个月。其中一线中位PFS为9.1个月,中位OS为27.6个月;二线中位PFS为7.7个月,中位OS为14.5个月;三线中位PFS为2.9个月,中位OS为6.7个月。单因素分析显示：原发灶部位、早期肿瘤缓解者以及西妥昔单抗治疗时间与PFS有关;原发灶部位、早期肿瘤缓解者、西妥昔单抗治疗时间以及转移侵及范围与OS有关。Cox多因素生存分析显示：原发肿瘤病灶部位、早期肿瘤缓解是PFS的独立预后因素,转移侵及范围是OS的独立预后因素。西妥昔单抗相关治疗最常见的不良反应是痤疮样皮疹（78.0％）,化疗相关的不良反应主要为腹泻、恶心呕吐、骨髓抑制,经对症处理后,患者均可耐受。结论 西妥昔单抗联合多种方案化疗治疗晚期转移性结直肠癌患者,各线治疗均能取得较好的疗效,不良反应可耐受;原发灶部位可能是西妥昔单抗联合化疗的疗效预测因素,其与患者预后生存可能相关;早期肿瘤缓解可作为判断患者预后相关指标。     

A KRAS mutation status-stratified randomized phase II trial of gemcitabine and oxaliplatin alone or in combination with cetuximab in advanced biliary tract cancer

Addition of cetuximab showed trend, but not significantly, to improve the therapeutic effects of gemcitabine and oxaliplatin combination for advanced biliary tract cancer in current randomized phase II trial. The trend of improvement did not correlate with KRAS mutation status. Biomarkers finding for selecting patients who will benefit most from anti-EGFR targeted therapy is warranted.BackgroundPrevious clinical trials have not proved that adding epidermal growth factor receptor inhibitors to chemotherapy confers a survival benefit for patients with advanced biliary tract cancer (ABTC). Whether the KRAS mutation status of tumor cells confounded the results of past studies is unknown.Patients and methodsABTC patients stratified by KRAS status, Eastern Cooperative Oncology Group performance status, and primary tumor location were randomized 1 : 1 to receive GEMOX (800 mg/m² gemcitabine and 85 mg/m² oxaliplatin) or C-GEMOX (500 mg/m² cetuximab plus GEMOX) every 2 weeks. The primary end point was objective response rate (ORR).ResultsThe study enrolled 122 patients between December 2010 and May 2012 (62 treated with C-GEMOX and 60 with GEMOX). Compared with GEMOX alone, C-GEMOX was associated with trend to better ORR (27% versus 15%; P = 0.12) and progression-free survival (PFS, 6.7 versus 4.1 months; P = 0.05), but not overall survival (OS, 10.6 versus 9.8 months; P = 0.91). KRAS mutations, which were detected in 36% of tumor samples, did not affect the trends of difference in ORR and PFS between C-GEMOX and GEMOX. The two treatment arms had similar adverse events, except that more patients had skin rashes, allergic reactions, and neutropenia in the C-GEMOX arm. Of patients with C-GEMOX, the presence of a grade 2 or 3 skin rash was associated with significantly better ORR, PFS, and OS.ConclusionsAddition of cetuximab did not significantly improve the ORR of GEMOX chemotherapy in ABTC, although a trend of PFS improvement was observed. The trend of improvement did not correlate with KRAS mutation status.Clinical Trials numberThis study is registered at ClinicalTrials.gov (NCT01267344). All patients gave written informed consent.     

First-Line Nivolumab Plus Ipilimumab With Chemotherapy Versus Chemotherapy Alone for Metastatic NSCLC in CheckMate 9LA: 3-Year Clinical Update and Outcomes in Patients With Brain Metastases or Select Somatic Mutations

IntroductionIn the phase 3 CheckMate 9LA study, nivolumab plus ipilimumab with chemotherapy prolonged overall survival (OS) versus chemotherapy alone. We report updated efficacy and safety (≥3 y of follow-up), clinical outcomes in patients with baseline brain metastases, and exploratory somatic mutation analyses.MethodsAdults with stage IV or recurrent NSCLC, no known sensitizing EGFR or ALK alterations, and Eastern Cooperative Oncology Group performance status less than or equal to 1 were randomized 1:1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with chemotherapy (two cycles) or chemotherapy alone (four cycles). Assessments included OS, progression-free survival (PFS), and objective response rate. Exploratory analyses included systemic and intracranial efficacy in patients with or without baseline brain metastases, in addition to OS and PFS by KRAS, TP53, STK11, and KEAP1 somatic mutation status in patients with nonsquamous NSCLC.ResultsWith a minimum follow-up of 36.1 months, nivolumab plus ipilimumab with chemotherapy continued to prolong OS versus chemotherapy alone in the intent-to-treat population (median [hazard ratio; 95% confidence interval] OS: 15.8 versus 11.0 mo [0.74; 0.62–0.87]; 3-y OS: 27% versus 19%). Efficacy outcomes were improved in patients with pretreated baseline brain metastases (median [hazard ratio; 95% confidence interval] OS: 19.3 versus 6.8 mo [0.45; 0.29–0.70]; systemic PFS: 9.7 versus 4.1 mo [0.44; 0.28–0.69]; intracranial PFS: 11.4 versus 4.6 mo [0.42; 0.26–0.68]). A trend of OS benefit was observed in patients treated with nivolumab plus ipilimumab with chemotherapy versus chemotherapy alone, despite KRAS, TP53, and STK11 tumor mutations. Extended follow-up revealed no new safety signals.ConclusionsWith a 3-year minimum follow-up, nivolumab plus ipilimumab with two cycles of chemotherapy continued to have long-term, durable efficacy versus chemotherapy alone; a manageable safety profile; and survival benefit in patients with or without baseline brain metastases or select somatic mutations, further supporting the regimen as first-line treatment for patients with metastatic NSCLC.     

Modified biweekly cisplatin,docetaxel plus cetuximab (TPEx) as first-line treatment for patients with recurrent/metastatic head and neck cancer

Three weekly high-dose chemotherapy regimens in combination with weekly cetuximab are the treatment of choice for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (SCCHN), although the majority of patients suffer from severe side effects. Thus, we investigated the efficacy and safety of an alternative, more convenient and less toxic biweekly modified cisplatin, docetaxel plus cetuximab (TPEx) regimen in this retrospective analysis. Thirty-eight patients receiving off-protocol cisplatin (50 mg/m²) in combination with docetaxel (50 mg/m²) plus cetuximab (500 mg/m²) every other week were included. Data collection included baseline demographic, response rate (ORR) and toxicity data as well as disease control rate, overall survival (OS) and progression-free survival (PFS). The median age was 60 years, and the majority of patients suffered from oral cavity carcinomas (44.7%) followed by oropharyngeal (28.9%) and laryngeal (17.9%) carcinomas. The ORR was 50%, and four (10.5%) patients achieved a complete response, while 15 (39.5%) patients had a partial response. The OS and PFS were 10.8 months (95% CI 6.7–14.2) and 6.3 months (95% CI 5.7–6.8), respectively. The one-year survival rate was 44.7%. The therapy was well tolerated, and the most common grade 3/4 adverse events were myelosuppression (13.2%), hypomagnesaemia (23.7%) and acne-like rash (13.1%). In conclusion, modified biweekly TPEx is of comparable efficacy with conventional TPEx and represents a well-tolerated regimen in R/M SCCHN patients. Further evaluation of this protocol in prospective clinical trials is warranted.     

Short-term outcomes of cetuximab combined with standard chemotherapy as first line setting for Chinese patients with non-small cell lung cancer: a report of 12 cases

Cetuximab combined with chemotherapy has been used to treat Non-small cell lung cancer (NSCLC) in recent years, however, the data from China was rare. This study was to summarize our experiences in treating NSCLC patients with cetuximab in the first line setting. From October 1st 2006 to Jun 30th 2010, twelve NSCLC patients were treated with cetuximab combined standard chemotherapy as first line setting in Sun Yat-sen University Cancer Center entered the study and the short-term efficacy and safety were analyzed. A total of 132 cycles of cetuximab treatment, with a median of nine cycles in the whole group were administered. The ORR was 41.7% (5/12), DCR was 83.3% (10/12), median TTP was 5.5 months (2-23), and median OS was 9 months (2-48) in the whole group. There were 75% (9/12) patients occurred acne-like rash within first 3 weeks, their ORR was 55.6% (5/9), DCR was 100% (9/9), however, ORR and DCR in patients who didn't occurred acne-like rash within first 3 weeks were 0 and 33.3% (1/3), the difference ORR between two group was insignificant (P = 0.091), however, DCR was significant different (P = 0.007). There no treatment-associated death and no cetuximab-associated discontinuation. The incidence of acne-like rash was 83.3% (10/12) and 75% (9/12) occurred within first 3 weeks, there were eight patients suffered side effects associated with chemotherapy. So we can draw a conclusion that the short-term outcome of cetuximab application in first line setting for patients with NSCLC were promising since the higher ORR and DCR, especially those occurred acne-like rash within the first 3 weeks, and the addition of cetuximab in this population was safe.     

Prospective phase II study of neoadjuvant FOLFOX6 plus cetuximab in patients with colorectal cancer and unresectable liver-only metastasis

Purpose

Liver resection may offer the only chance of cure in patients with colorectal cancer with liver metastases. In the unresectable cases, neoadjuvant chemotherapy could render curability if resectability could be achieved.

Methods

Newly diagnosed K-RAS wild-type colorectal cancer patients with unresectable liver-only metastases were treated with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX6) plus cetuximab every 2 weeks for a maximum of 12 cycles. Clinical response was evaluated every 6 weeks, and surgery was performed at the physician’s discretion in patients with sufficient tumor shrinkage, followed by chemotherapy with the same regimen, to complete a total of 12 cycles. The primary endpoint was an overall R0 resection rate.

Results

Between July 2008 and December 2009, 73 patients were registered from 11 Korean centers. Among 53 (73 %) patients who showed at least partial response, surgery with curative intent was attempted in 36 (49 %) patients. Intention-to-treat analysis revealed a R0 resection rate of 27 % (20/73) including 8 patients whose unresectable liver metastases were successfully treated with radiofrequency ablation (RFA). The most common grade 3 and 4 toxicity was neutropenia (50/462 cycles, 10.7 %). Median time to progression (TTP) was 9.8 months (range 0.5–31.8) in all patients, but we observed TTP of 14.1 months (range 1.3 to ?30.8) in patients who received R0 resection and RFA + R0 resection.

Conclusions

Neoadjuvant chemotherapy with FOLFOX6 plus cetuximab showed high response rates and increased the resectability in colorectal patients with non-resectable liver-only metastases.     

Relevance of liver‐limited disease in metastatic colorectal cancer: Subgroup findings of the FIRE‐3/AIO KRK0306 trial

In metastatic colorectal cancer (mCRC), liver‐limited disease (LLD) is associated with a higher chance of metastectomy leading to long‐term survival. However, limited data describes the prognostic and predictive relevance of initially unresectable LLD with regard to targeted first‐line therapy. The present analysis investigated the relevance of initially unresectable LLD in mCRC patients treated with targeted therapy against either the epidermal growth factor receptor (EGFR) or vascular epithelial growth factor (VEGF). The analysis was performed based on FIRE‐3, a randomized phase III trial comparing first‐line chemotherapy with FOLFIRI plus either cetuximab (anti‐EGFR) or bevacizumab (anti‐VEGF) in RAS wild‐type (WT) mCRC. Of 400 patients, 133 (33.3%) had LLD and 267 (66.8%) had non‐LLD. Median overall survival (OS) was significantly longer in LLD compared to non‐LLD patients (36.0 vs. 25.4 months; hazard ratio [HR] = 0.66; 95% confidence interval [CI]: 0.51–0.87; p = 0.002). In a multivariate analysis also including secondary hepatic resection as time‐dependent variable, LLD status was independently prognostic for OS (HR = 0.67; 95% CI: 0.50–0.91; p = 0.01). As assessed by interaction tests, treatment benefit from FOLFIRI plus cetuximab compared to FOLFIRI plus bevacizumab was independent of LLD status with regard to objective response rate (ORR), early tumour shrinkage ≥20% (ETS), depth of response (DpR) and OS (all p > 0.05). In conclusion, LLD could be identified as a prognostic factor in RAS‐WT mCRC, which was independent of hepatic resection in patients treated with targeted therapy. LLD had no predictive relevance since benefit from FOLFIRI plus cetuximab over bevacizumab was independent of LLD status.     

Liver resection after irinotecan, 5-fluorouracil, and folinic acid for patients with unresectable colorectal liver metastases

The main objectives of this study were to assess the use of irinotecan, 5-fluorouracil (5-FU), and leucovorin (FA) as neoadjuvant chemotherapy for patients with unresectable colorectal liver metastases and to determine the response rate and proportion of patients that could be down-staged to resectable tumors. Forty patients were treated with irinotecan (180 mg/m2 over 30 min) on d 1, FA (200 mg/m2 over 30 min) followed by 5-FU (400 mg/m2 bolus and continuous infusion of 600 mg/m2 over 22 h) on d 1 and 2 every 2 wk. The overall response rate was 55% (95% CI: 39.5-70.4%). The progression-free survival was 12.1 mo (95% CI: 11.4-14.8 mo). The median overall survival was 20 mo (95% CI: 17.7-26.6 mo). Four patients (10%) have undergone liver resection after a median of eight cycles. Those patients remained alive with a median follow up period of 33 mo. The principal grade 3-4 toxicity was neutropenia in 20 patients (50%). We conclude that the regimen of irinotecan/5-FU/FA was highly active in patients with colorectal cancer and liver metastases with limited toxicity. In a subgroup of patients with initial inoperable liver metastases, this regimen was able to down-stage the disease to an operable stage.     

Conversion to resection of liver metastases from colorectal cancer with hepatic artery infusion of combined chemotherapy and systemic cetuximab in multicenter trial OPTILIV

BackgroundSystemic chemotherapy typically converts previously unresectable liver metastases (LM) from colorectal cancer to curative intent resection in ∼15% of patients. This European multicenter phase II trial tested whether hepatic artery infusion (HAI) with triplet chemotherapy and systemic cetuximab could increase this rate to 30% in previously treated patients.Patients and methodsParticipants had unresectable LM from wt KRAS colorectal cancer. Main non-inclusion criteria were advanced extra hepatic disease, prior HAI and grade 3 neuropathy. Irinotecan (180 mg/m²), oxaliplatin (85 mg/m²) and 5-fluorouracil (2800 mg/m²) were delivered via an implanted HAI access port and combined with i.v. cetuximab (500 mg/m²) every 14 days. Multidisciplinary decisions to resect LM were taken after every three courses. The rate of macroscopic complete resections (R0 + R1) of LM, progression-free survival (PFS) and overall survival (OS) were computed according to intent to treat.ResultsThe patient population consisted of 42 men and 22 women, aged 33–76 years, with a median of 10 LM involving a median of six segments. Up to 3 extrahepatic lesions of <1 cm were found in 41% of the patients. A median of six courses was delivered. The primary end point was met, with R0–R1 hepatectomy for 19 of the 64 previously treated patients, 29.7% (95% confidence interval 18.5–40.9). Grade 3–4 neutropenia (42.6%), abdominal pain (26.2%), fatigue (18%) and diarrhea (16.4%) were frequent. Objective response rate was 40.6% (28.6–52.3). Median PFS and OS reached 9.3 (7.8–10.9) and 25.5 months (18.8–32.1) respectively. Those with R0-R1 hepatectomy had a median OS of 35.2 months (32.6–37.8), with 37.4% (23.6–51.2) alive at 4 years.ConclusionThe coordination of liver-specific intensive chemotherapy and surgery had a high curative intent potential that deserves upfront randomized testing.Protocol numbersEUDRACT 2007-004632-24, NCT00852228.     

Concurrent cetuximab and radiotherapy after docetaxel-cisplatin induction chemotherapy in stage III NSCLC: Satellite—A phase II study from the Swedish Lung Cancer Study Group

Background

Several attempts to increase the locoregional control in locally advanced lung cancer including concurrent chemotherapy, accelerated fractionation and dose escalation have been made during the last years. As the EGFR directed antibody cetuximab has shown activity concurrent with radiotherapy in squamous cell carcinoma of the head and neck, as well as in stage IV NSCLC combined with chemotherapy, we wanted to investigate radiotherapy with concurrent cetuximab in locally advanced NSCLC, a tumour type often over expressing the EGF-receptor.

Methods

Between February 2006 and August 2007 75 patients in stage III NSCLC with good performance status (PS 0 or 1) and adequate lung function (FEV1 > 1.0) were enrolled in this phase II study at eight institutions. Treatment consisted of 2 cycles of induction chemotherapy, docetaxel 75 mg/m² and cisplatin 75 mg/m² with 3 weeks interval. An initial dose of cetuximab 400 mg/m² was given before start of 3D-CRT to 68 Gy with 2 Gy per fraction in 7 weeks concurrent with weekly cetuximab 250 mg/m². Toxicity was scored weekly during radiotherapy (CTC 3.0), and after treatment the patients were followed every third month with CT-scans, toxicity scoring and QLQ.

Results

Seventy-one patients were eligible for analysis as four were incorrectly enrolled. Histology: adenocarcinoma 49%, squamous cell carcinoma 39% and other NSCLC 12%. The majority had PS 0 (62.5%), median age 62.2 (42-81), 50% were women and 37% had a pre-treatment weight loss > 5%. Toxicity: esophagitis grade 1-2: 72%; grade 3: 1.4%. Hypersensitivity reactions grade 3-4: 5.6%. Febrile neutropenia grade 3-4: 15.4%. Skin reactions grade 1-2: 74%; grade 3: 4.2%. Diarrhoea grade 1-2: 38%; grade 3: 11.3%. Pneumonitis grade 1-2: 26.8%; grade 3: 4.2%; grade 5: 1.4%. The median follow-up was 39 months for patients alive and the median survival was 17 months with a 1-, 2- and 3-year OS of 66%, 37% and 29% respectively. Until now local or regional failure has occurred in 20 patients and 22 patients have developed distant metastases. Weight loss, PS and stage were predictive for survival in univariate as well as in multivariate analysis.

Conclusion

Induction chemotherapy followed by concurrent cetuximab and RT to 68 Gy is clearly feasible with promising survival. Toxicity, e.g. pneumonitis and esophagitis is low compared to most schedules with concurrent chemotherapy. This treatment strategy should be evaluated in a randomised manner vs. concurrent chemoradiotherapy to find out if it is a valid treatment option.     

Feasibility of cetuximab and chemoradiotherapy combination in Chinese patients with unresectable stage Ⅲ non-small cell lung cancer:a preliminary report

Objective:In recent years,the combination of cetuximab and chemoradiotherapy（CRT） has been used to treat stage III non-small cell lung cancer（NSCLC）;however,limited data are available for Chinese patients.Herein,we report preliminary data from a phase Ⅰ/Ⅱ study testing the combination of cetuximab with inductive chemotherapy,followed by concurrent CRT（CCRT） in Chinese patients with stage HI NSCLC.Methods:Eligibility criteria were Zubrod performance status（PS） 0-1,forced expiratory volume in 1 second（FEVl） >1.2 L and adequate organ function.Enrolled patients received weekly cetuximab（initial dose of400 mg/m² on day 1 of week 1 and a maintenance dose of 250 mg/m² on week 2 to the end of CCRT） with cisplatin/vinorelbine（NP） chemotherapy(every 3 weeks for 2 cycles from week 2,followed by two cycles of concomitant NP chemotherapy and intensity-modulated thoracic radiotherapy（TRT）（60-66 Gy/2 Gy）.The primary endpoints were toxicity and feasibility.All patients received positron emission tomographycomputerized tomography（PET-CT） scans within the 2 weeks prior to enrollment.Univariate analyses were used to assess the correlation between SUV-T,SUV-N,SUV-TOTAL,gender,age,histology,tumor-nodemetastasis（TNM） stage,PS and smoking status and survival.Survival curves were generated for different populations using the Kaplan-Meier method and compared using a log-rank test.Results:Seventeen patients were enrolled and 16 completed the full regime.The overall response rate（ORR）was 58.8%and 82.3%after the induction and CCRT phases,respectively.With a median follow-up duration of 27.6 months,the median survival was 27.6 months[95%confidence interval（CI）:11.3-43.9 months]with 1-and 2-year survival rates of 88.2%（95%CI,60.6-96.9%） and 58.8%（95%CI,60.6-77.8%）,respectively.Three patients remain progression-free to date,and the median progression-free survival（PFS） was 13.5 months（95%CI,6.8-20.2 months）.No treatment-related death occurred;however,76%of the patients experienced grade3+ adverse events（AEs）,including nausea/vomiting,intestinal obstruction,and esophagitis（<6%）,while other AEs were mostly of hematological nature（71%）.The cut-off values for SUV-T and SUV-TOTAL were 11 and20,respectively.Univariate analyses revealed SUV-TOTAL（P=0.027）,SUV-T（P=0.025）,and PS（P=0.006） as potential survival predictors,with a hazard ratio（HR） of 3.4,3.7,and 9.9,respectively.Conclusions:The combination of cetuximab with induction chemotherapy followed by CCRT appears feasible and promising.Local and locoregional maximal SUVs,defined by ¹⁸F-FDG PET-CT scanning,may represent a prognostic indicator for long-term survival for these patients,which warrants further study.     

A case of multiple lung and liver metastases from colon cancer treated with clinical benefit by hepatic arterial infusion chemotherapy plus cetuximab mono-therapy after standard chemotherapy failure

We report a case of multiple lung and liver metastases from colon cancer treated with clinical benefit by hepatic arterial infusion chemotherapy plus cetuximab mono-therapy after a standard chemotherapy was failed. A 61-year-old female who had sigmoid colon cancer with unresectable multiple lung and liver metastases underwent sigmoidectomy. Bevacizumab plus mFOLFOX6 was performed as first-line therapy. Partial response was obtained temporarily. After the first-line therapy failed, bevacizumab plus FOLFIRI as second-line, and cetuximab plus CPT-11 as third-line therapy were performed. Since these regimens did not work, her performance status got worse by cholangitis due to progressive liver metastases and anemia. Hepatic arterial infusion chemotherapy for liver metastases and cetuximab for lung metastases as fourth therapy were chosen because we thought her liver metastases should be critical for the maintenance of her QOL and diagnosis. After that, serum CEA was reduced from 14,715 to 6,940 ng/mL during the 3 month period. And her performance status got better as cholongitis and anemia were improved. Additionally, lung metastases were controlled by cetuximab.