Tumor Response and Symptom Palliation from RAINBOW,a Phase III Trial of Ramucirumab Plus Paclitaxel in Previously Treated Advanced Gastric Cancer

BackgroundIn the intent‐to‐treat (ITT) population of the RAINBOW study, objective response rate (ORR) was 28% and 16% in the ramucirumab and control arms, respectively. To further characterize tumor response, we present details on timing and extent of tumor shrinkage, as well as associations with symptom palliation.Materials and MethodsTumor response was assessed with RECIST v1.1, and quality of life (QoL) was assessed with the European Organization for Research and Treatment of Cancer Quality‐of‐Life Questionnaire‐Core 30 (EORTC QLQ‐C30) v3.0. Prespecified and post hoc analyses were conducted in the ITT population, patients with measurable disease, or responders, and included best overall response (BOR), ORR, disease control rate (DCR), duration of response, time to response (TtR), change in tumor size, and associations of QoL with tumor shrinkage and BOR.ResultsIn both treatment arms, median TtR was 1.5 months. Responses were more durable in the ramucirumab versus control arm (median 4.4 vs. 2.8 months). In patients with measurable disease (78% of ITT), ORR was 36% versus 20%; DCR was 81% versus 61% in the ramucirumab versus control arms. Waterfall plots demonstrated more tumor shrinkage in the ramucirumab versus control arm. Regardless of treatment, tumor response and stable disease were associated with improved or stable QoL, with more tumor shrinkage associated with greater symptom palliation.ConclusionTreatment with ramucirumab plus paclitaxel yielded the highest ORR reported to date for patients with previously treated advanced gastric or gastroesophageal junction adenocarcinoma. Additional details demonstrate robustness of tumor response results. The extent of tumor shrinkage is directly associated with symptom palliation and should be considered when evaluating patient needs and treatment selection. Clinical trial identification number. {"type":"clinical-trial","attrs":{"text":"NCT01170663","term_id":"NCT01170663"}}NCT01170663.Implications for PracticeRamucirumab plus paclitaxel is a recognized standard of care as it improves survival for patients with advanced gastric or gastroesophageal junction adenocarcinoma who have been previously treated with recommended first‐line therapy. These additional data on tumor response demonstrate a positive association between tumor shrinkage and symptom palliation in a patient population that is often symptomatic. These observations included patients with nonmeasurable disease, a group of patients often underrepresented in clinical trials. This knowledge can inform treatment decisions, which align individual patient characteristics and needs with demonstrated benefits.     

Simplified FOLFIRI in pre-treated patients with metastatic gastric cancer

Purpose  Second-line chemotherapy in patients with metastatic gastric cancer (MGC) pre-treated with cisplatin is not a standard option. We studied a combination of irinotecan, fluorouracil and folates. Methods  Patients progressive to cisplatin-based chemotherapy were enrolled. Irinotecan 180 mg/m², folinic acid 200 mg/m², and fluorouracil 400 mg/m² were given on day 1, immediately followed by fluorouracil 2,400 mg/m² 46 h continuous infusion (simplified FOLFIRI), every 2 weeks. Results  Between June 2002 and May 2003, 28 patients were treated. Median age was 57 years (range 38–68). Most patients had a distal primary (90%), and metastatic disease (71%). Partial response was obtained in six patients (21%, 95% CI 8–41) and stable disease in eight (21%, 95% CI 13–41). Among the six responsive patients three were refractory to docetaxel. At a median follow-up of 2.9 years median time to progression was 4 months (95% CI: 2–5), and median overall survival was 5 months (95% CI 4–9). Toxicity was mild, without treatment-related deaths or life-treating adverse events. Conclusions  Simplified FOLFIRI was moderately active and well tolerated in unselected patients with MGC pre-treated with cisplatin-based chemotherapy. Its role in patients refractory to taxanes is promising and warrants further investigation.     

FOLFIRI as a second-line therapy in patients with docetaxel-pretreated gastric cancer: a historical cohort

Background

The role of second-line therapy in gastric cancer patients mostly stemmed from clinical trials with monochemotherapy carried out in Asian countries. Nevertheless, these results cannot be broadly generalized as molecular studies suggested the existence of different sets of deregulated gene networks correlated with ethnicity. In the present study, we investigated the activity and safety of FOLFIRI given as a second-line therapy in metastatic gastric or gastro-esophageal junction cancer patients who experienced disease progression on or after first-line docetaxel-containing chemotherapy.

Methods

Patients with histologically confirmed metastatic gastric cancer who failed docetaxel-containing first-line therapy and who received FOLFIRI in second line were eligible for the study. Seventy patients treated at three Italian cancer centers between 2005 and 2012 entered the study. Patients received every 2 weeks irinotecan 180 mg/m² as 1 h infusion on day 1, folinic acid 100 mg/m² intravenously days 1–2, and fluorouracil as a 400 mg/m² bolus and then 600 mg/m² continuous infusion over 22 hours days 1–2.

Results

We observed 1(1.4%) complete response, 15 (21.4%) partial response, for an overall response rate of 22.8% (95% confidence interval (CI): 13.4-32.3). Stable disease was recorded in 21 (30%) patients. Median progression-free survival and overall survival were 3.8 months (95% CI: 3.3-4.4) and 6.2 months (95% CI: 5.3-7.1), respectively. The treatment was well tolerated, as the most common G3-4 toxicities were neutropenia (28.5%) and diarrhea (14.5%).

Conclusions

FOLFIRI appears an effective and safe treatment option for pretreated metastatic gastric cancer patients, and deserves further investigation in randomized clinical trials.     

Long-term survival in an advanced gastric cancer patient treated with cetuximab in association with FOLFIRI: a case report

In December 2004, a 52-year-old woman with metastatic gastric cancer was enrolled in the phase II clinical trial FOLCETUX, receiving cetuximab at an initial dose of 400 mg/m² i.v. followed by weekly doses of 250 mg/m², irinotecan 180 mg/m² i.v. on day 1, LFA 100 mg/m² i.v. followed by 5-FU 400 mg/m² i.v. bolus and 600 mg/m² i.v. 22-h continuous infusion on days 1 and 2 every two weeks, to a total of 17 cycles. CT and PET-CT performed after six weeks treatment failed to show any residual disease, with complete radiological response in accord to RECIST criteria and complete metabolic response. A total of 24 maintenance administrations with cetuximab alone (250 mg/m² weekly) were performed, as foreseen by the protocol in responders. In November 2012 a clinical, radiological (CT) and metabolic (PET-CT) patient examination proved negative for recurrent disease, signifying 95 months’ progression free survival.     

Phase II Study of Ramucirumab Plus Irinotecan Combination Therapy as Second-Line Treatment in Patients with Advanced Gastric Cancer: HGCSG1603

BackgroundRamucirumab is a human IgG1 monoclonal vascular endothelial growth factor receptor-2 antibody that inhibits tumor cell growth and affects the tumor cell microenvironment. We assessed the efficacy and safety of ramucirumab plus irinotecan combination therapy as second-line treatment in patients with previously treated advanced gastric cancer.Materials and MethodsPatients with advanced gastric cancer refractory or intolerant to primary chemotherapy were included. Ramucirumab 8 mg/kg plus irinotecan 150 mg/m² combination therapy was administered every 2 weeks. The primary endpoint was progression-free survival rate at 6 months and secondary endpoints were overall survival, progression-free survival, response rate, safety, and dose intensity for each drug.ResultsThirty-five patients were enrolled between January 2018 and September 2019. The progression-free survival rate at 6 months was 26.5% [95%CI, 13.2%–41.8%, P = .1353)]. Median progression-free and overall survivals were 4.2 months (95%CI, 2.5-5.4 months) and 9.6 months (95%CI, 6.4-16.6 months), respectively. The overall response rate was 25.9% (95%CI, 11.1-36.3%) and disease control rate was 85.2% (95%CI, 66.3-95.8%). Grade ≥3 adverse events that occurred in >10% of patients included neutropenia, leucopenia, anemia, anorexia, and febrile neutropenia. No death or new safety signals with a causal relation to the study treatment were observed.ConclusionAlthough the primary endpoint was not achieved statistically, combination therapy of ramucirumab plus irinotecan showed anticancer activity and a manageable safety profile for second-line treatment of patients with advanced gastric cancer.     

Phase 1 Expansion Cohort of Ramucirumab Plus Pembrolizumab in Advanced Treatment-Naive NSCLC

IntroductionData of first-line ramucirumab plus pembrolizumab treatment of programmed death-ligand 1 (PD-L1)–positive NSCLC (cohort E) are reported (NCT02443324).MethodsIn this multicenter, open-label phase 1a/b trial, patients received ramucirumab 10 mg/kg and pembrolizumab 200 mg every 21 days for up to 35 cycles. PD-L1 positivity was defined as tumor proportion score (TPS) greater than or equal to 1%. Exploratory NanoString biomarker analyses included three T-cell signatures (T-cell–inflamed, Gajewski, and effector T cells) and CD274 gene expression.ResultsCohort E included 26 patients. Treatment-related adverse events of any grade occurred in 22 patients (84.6%). Treatment-related adverse events of grade greater than or equal to 3 were reported in 11 patients (42.3%); the most frequent was hypertension (n = 4, 15.4%). Objective response rate was 42.3% in the treated population and 56.3% and 22.2% for patients with high (TPS ≥ 50%) and lower levels (TPS 1%–49%) of PD-L1 expression, respectively. Median progression-free survival (PFS) in the treated population was 9.3 months, and 12-month and 18-month PFS rates were 45% each. Median PFS was not reached in patients with PD-L1 TPS greater than or equal to 50% and was 4.2 months in patients with PD-L1 TPS 1% to 49%. Median overall survival was not reached in the treated population, and 12-month and 18-month overall survival rates were 73% and 64%, respectively. Biomarker data suggested a positive association among clinical response, three T-cell signatures, CD274 gene expression, and PD-L1 immunohistochemistry.ConclusionsFirst-line therapy with ramucirumab plus pembrolizumab has a manageable safety profile in patients with NSCLC, and the efficacy signal seems to be strongest in tumors with high PD-L1 expression.     

Second-line chemotherapy with fluorouracil, leucovorin, and irinotecan (FOLFIRI regimen) in patients with advanced small bowel adenocarcinoma after failure of first-line platinum-based chemotherapy: a multicenter AGEO study

BACKGROUND:

Small bowel adenocarcinoma (SBA) is a rare tumor with poor prognosis. First‐line platinum‐based chemotherapy is active in patients with advanced SBA, but data regarding second‐line chemotherapy are lacking. The aim of this study was to evaluate the efficacy and tolerability of fluorouracil, leucovorin, and irinotecan (FOLFIRI regimen) as second‐line chemotherapy in patients with advanced SBA.

METHODS:

We analyzed all consecutive patients who received second‐line chemotherapy with FOLFIRI among 93 patients with advanced SBA included from 1996 to 2008 in a previous retrospective multicenter study. Progression‐free survival (PFS) and overall survival (OS) were estimated from the start of second‐line chemotherapy using the Kaplan‐Meier method. Cox models were applied for multivariate analyses.

RESULTS:

Among 51 patients who received second‐line chemotherapy, 28 patients (male, 57%; median age, 54 years; metastatic disease, 96%) were treated with FOLFIRI after progression (n = 24) or limiting toxicity (n = 4) to first‐line FOLFOX (n = 19) or LV5FU2‐cisplatin (n = 9). Grade 3‐4 toxicity was observed in 48% of patients (grade 3‐4 neutropenia, 37%). After a median follow‐up of 21.5 months, all patients had tumor progression, and 22 patients died. Objective response rate was 20%, and disease control rate was 52%. Median PFS and OS were 3.2 and 10.5 months, respectively. No clinical, biological, or tumor characteristics were associated with PFS or OS by multivariate analysis.

CONCLUSIONS:

Second‐line chemotherapy with FOLFIRI produced disease control in half of patients with advanced SBA after failure with first‐line platinum‐based chemotherapy. Nevertheless, the short median PFS warrants the evaluation of other treatments including targeted therapies. Cancer 2011. © 2010 American Cancer Society.     

Vandetanib with FOLFIRI in patients with advanced colorectal adenocarcinoma: results from an open-label, multicentre Phase I study

Purpose  The safety and tolerability of vandetanib (ZACTIMA™; ZD6474) plus FOLFIRI was investigated in patients with advanced colorectal cancer (CRC). Methods  Patients eligible for first- or second-line chemotherapy received once-daily oral doses of vandetanib (100 or 300 mg) plus 14-day treatment cycles of FOLFIRI. Results  A total of 21 patients received vandetanib 100 mg (n = 11) or 300 mg (n = 10) + FOLFIRI. Combination therapy was well tolerated at both vandetanib dose levels. There were no DLTs in the vandetanib 100 mg cohort and one DLT of hypertension (CTCAE grade 3) in the 300 mg cohort. The most common adverse events were diarrhoea (n = 20), nausea (n = 12) and fatigue (n = 10). Two patients (one in each cohort) discontinued vandetanib due to adverse events (rash, 100 mg cohort; hypertension, 300 mg cohort). There was no apparent pharmacokinetic interaction between vandetanib and FOLFIRI. Preliminary efficacy results included two confirmed partial responses in the 100 mg cohort and 9 patients with stable disease ≥8 weeks (100 mg, n = 7; 300 mg, n = 2). Conclusions  Once-daily vandetanib (100 or 300 mg) in combination with a standard FOLFIRI regimen was generally well tolerated in patients with advanced CRC.     

A Phase Ib Study of Safety and Pharmacokinetics of Ramucirumab in Combination With Paclitaxel in Patients With Advanced Gastric Adenocarcinomas

Lessons Learned

• The pharmacokinetic results of this phase Ib study of ramucirumab combined with paclitaxel as second-line therapy in Japanese patients with metastatic gastric or gastro-esophageal junction adenocarcinoma are in line with previous ramucirumab studies.
• This combination at the doses and schedule given did not result in any dose-limiting toxicities and appeared to be safe and well tolerated.

Background.

This phase Ib study evaluated the tolerability and pharmacokinetics of ramucirumab, an anti-VEGFR-2 antibody, combined with paclitaxel as second-line therapy in Japanese patients with metastatic gastric or gastroesophageal junction adenocarcinoma after first-line therapy with fluoropyrimidines and/or platinum.

Methods.

Patients received ramucirumab 8 mg/kg on days 1 and 15 and paclitaxel 80 mg/m² on days 1, 8, and 15 of a 28-day cycle. Safety analyses included all patients (n = 6).

Results.

No dose-limiting toxicities occurred in the first cycle. All patients experienced ≥1 treatment-emergent adverse event (TEAE); 5 patients experienced grade ≥3 TEAEs. There were two deaths caused by disease progression. The best overall responses were stable disease (n = 5) and partial response (n = 1). Patients received ramucirumab and paclitaxel for a median of 12.5 weeks (range: 11.4–42.7 weeks) and 12.2 weeks (range: 11.0–41.0 weeks), respectively. Following a single dose of ramucirumab IV infusion 8 mg/kg, clearance was ∼0.017 L/hour, half-life (t_1/2) was 138 to 225 hours, and steady-state volume of distribution (V_ss) was ∼3 L.

Conclusion.

The ramucirumab/paclitaxel combination appears to be well-tolerated in Japanese patients with advanced gastric adenocarcinomas. These results are in line with previous ramucirumab pharmacokinetic studies as anticipated.     

A retrospective observational study on the safety and efficacy of first-line treatment with bevacizumab combined with FOLFIRI in metastatic colorectal cancer

Background:

Combination of bevacizumab and FOLFIRI has currently become one of the standard therapeutic regimens. However, published information is still limited. The objective of the present retrospective observational study is to analyse the response and toxicity of first-line treatment with FOLFIRI+bevacizumab in patients with metastatic colorectal cancer (mCRC).

Methods:

Data were collected from patients from nine Spanish sites diagnosed with mCRC, ECOG⩽2, whose first treatment for advanced disease was at least three cycles of FOLFIRI+bevacizumab.

Results:

A total of 95 patients were enrolled into the study: 64.2% males, median age of 59 years (53.2–67.1 years), ECOG=0–1 in 96.9% of patients. The main site of primary tumour was the colon (69.7%), and most metastases occurred in the liver (71.6%). Clinical benefit was detected in 67.4% (57.0–76.6; 95% confidence interval (CI)), with 8.4% of CR and 42.1% of PR. Median TTP was 10.6 months (10.0–11.3; 95% CI), PFS was 10.6 months (9.8–11.3; 95% CI), and OS was 20.7 months (17.1–24.2; 95% CI). Main grade I–II toxicities included haematological toxicity (35.8%), diarrhea (27.3%), mucositis (25.3%), asthenia (19.0%), haemorrhages (11.6%), and emesis (10.6%). Toxicities reaching grades III–IV were haematological toxicity (9.5%), diarrhea (8.5%), mucositis (5.3%), hepatic toxicity (2.1%), asthenia (2.1%), proteinuria (1.1%), emesis (1.1%), pain (1.1%), and colics (1.1%).

Conclusion:

Results of this study support the beneficial effect of adding bevacizumab to FOLFIRI regimen in terms of efficacy and show a favourable tolerability profile.     

mEOX与FOLFIRI方案二线治疗晚期胃癌疗效对照观察

目的 晚期胃癌至今仍缺乏最佳二线治疗方案,如何选择高效低毒的化疗方案是临床函待解决的问题.比较mEOX(表柔比星,奥沙利铂和卡培他滨)与FOLFIRI(伊立替康,5-氟尿嘧啶和亚叶酸钙)在晚期胃癌二线治疗中的疗效及毒副作用.方法 选取2010-01-01-2014-06-30在海口市人民医院肿瘤内科住院治疗患者105例,且均经病理明确诊断为胃腺癌,一线DCF化疗后进展.采用简单随机化分配,A组55例患者行mEOX方案化疗,B组50例患者行FOL-FIRI方案化疗.收集所有患者的临床病理学特征.无进展生存期(progression-free survival,PFS)及总生存期(overall survival,OS)使用Kaplan-meier进行生存分析.结果 两组患者均一线接受mDCF方案治疗.二线使用mEOX和FOLFIRI方案各完成3.5(2～8个周期)和3个周期(1～5个周期),P=0.38.mEOX和FOLFIRI组客观缓解率(objective response rate,ORR)分别为21.8％和18.0％,x2 =0.239,P=0.625.mEOX和FOLFIRI组中位PFS分别为5.3和6.4个月(x2=4.01,P=0.045),2组患者从二线化疗开始后计算OS分别为7.0和7.2个月,组间比较差异无统计学意义,x2 =0.255,P=0.64. mEOX组较FOLFIRI组出现更少的粒细胞减少、腹泻等不良反应.而FOLFIRI组较mEOX组因不良反应至化疗药物减量或延期使用的患者更多,P＜0.001.结论 mEOX方案与FOLFIRI方案二线化疗晚期胃癌疗效相似,但mEOX方案不良反应更低,均值得临床推广使用.     

重组人血管内皮抑素联合FOLFIRI方案治疗结直肠癌肝转移的临床观察

目的 探讨重组人血管内皮抑素（恩度）联合FOLFIRI方案治疗结直肠癌肝转移的疗效和安全性。方法 收集2006年9月至2011年1月29例结直肠癌肝转移患者,给予恩度联合FOLFIRI方案治疗。恩度15mg静滴,d1～d10,14天为1周期。FOLFIRI方案：伊立替康180mg／m2静滴,d1;亚叶酸钙400mg／m2静滴,d1;氟尿嘧啶400mg／m2静推,d1,2400mg／m2持续静滴46～48h,14天为1周期。每周期评价不良反应,3～4个周期评价疗效。结果 29例患者中有27例可评价疗效,获CR 1 例,PR 10例,SD 9例,PD 7例,有效率为40.7％,疾病控制率为741％,14例患者生活质量改善;全组有27例获随访,中位无进展生存期为7.8个月（95％CI：5.3～10.2个月）。毒副反应主要为血液学毒性、恶心呕吐和迟发性腹泻,以1～2级为主,未出现严重的心血管系统毒副反应。结论 恩度联合FOLFIRI方案治疗结直肠癌肝转移疗效较好,毒副反应可耐受。     

FOLFIRI方案治疗常规化疗失败晚期大肠癌的疗效分析

目的：探讨FOLFIRI方案治疗常规化疗失败晚期大肠癌患者的临床疗效和不良反应。方法：常规化疗失败的晚期大肠癌患者25例,开普拓（Irinotecan,CPT-11）180mg／m^2,静脉滴注,d1;FA200mg／m^2,静脉滴注,d1-2;5-FU400mg／m^2静脉推注,然后5-FU 600mg／m^2持续静脉滴注22h,d1-2,每2周重复,2次为1个周期,共行1—6个周期,中位周期1．5个。结果：25例患者,PR9例,SD10例,PD6例,总缓解率36．0％,中位缓解时间3．0—13．5个月。主要不良反应为迟发性腹泻和中性粒细胞减少,Ⅲ-Ⅳ度发生率分别为25．6％（11／43）和41．9％（18／43）。结论：FOLFIRI方案是治疗常规化疗失败晚期大肠癌的有效化疗方案,缓解率较高,迟发性腹泻和中性粒细胞减少为其主要不良反应。     

Exploration of potential prognostic biomarkers in aflibercept plus FOLFIRI in Japanese patients with metastatic colorectal cancer

Aflibercept plus 5‐fluorouracil/levofolinate/irinotecan (FOLFIRI) is a second‐line treatment for metastatic colorectal cancer. This ancillary exploratory analysis of data in Japanese people was aimed at exploring the relationship between a set of potential prognostic biomarkers and efficacy endpoints following aflibercept plus FOLFIRI therapy. Sixty‐two patients with metastatic colorectal cancer received aflibercept (4 mg/kg) plus FOLFIRI every 2 weeks. Seventy‐eight potential protein biomarkers were chosen for analysis based on their roles in angiogenesis, tumor progression, and tumor‐stroma interaction. Plasma levels of biomarkers at baseline and at pre‐dose 3 (day 1 of treatment cycle 3) were measured in all patients by ELISA. Relationships between these levels and efficacy endpoints were assessed. Ten potential biomarkers had a ±30% change from baseline to pre‐dose 3 (adjusted P < .001), with the greatest changes occurring in placental growth factor (median: +4716%) and vascular endothelial growth factor receptor 1 (+2171%). Baseline levels of eight potential biomarkers correlated with overall survival in a univariate Cox regression analysis: extracellular newly identified receptor for advanced glycation end‐products binding protein, insulin‐like growth factor‐binding protein 1, interleukin‐8, kallikrein 5, pulmonary surfactant‐associated protein D, tissue inhibitor of metalloproteinases 1, tenascin‐C, and tumor necrosis factor receptor 2. None correlated with progression‐free survival or maximum tumor shrinkage. Pre‐dose 3 levels did not correlate with any efficacy endpoints. Preliminary data show that these eight biomarkers could be associated with overall survival. ClinicalTrials.gov identifier: NCT01882868.     

XELOX Plus Bevacizumab vs. FOLFIRI Plus Bevacizumab Treatment for First-line Chemotherapy in Metastatic Colon Cancer: a Retrospective Study of the Anatolian Society of Medical Oncology

Background: XELOX plus bevacizumab (XELOX-Bev) and FOLFIRI plus Bevacizumab (FOLFIRI - Bev)treatments are an effective strategies patients with metastatic colorectal cancer (mCRC).The aim of this studywas to compare efficacy of first-line XELOX-Bev treatment vs FOLFIRI-Bev treatment for mCRC. Materialsand Methods: A total of 409 patients with mCRC who received chemotherapy were included and divided into 2groups. Group 1 (n=298) received XELOX-Bev and Group 2 (n=111) FOLFIRI-Bev. Comparisons were made interms of overall (OS) and progression-free (PFS) survival, response rate (RR), and grade 3-4 toxicity. Results:Median follow-up was 11 months in Group 1 and 15 months for Group 2. Complete remission was observed in29 (9.7%) and 2 (1.8%) patients, partial remission in 139 (46.6%) and 27 (24.5%) , stable disease in 88 (29.5%)and 49 (44.1%) and progressive disease in 42 (14.1%) and 33 (30.0%) patients in Group 1 and 2, respectively.Median OS was 25 months (range 2-57 months, 95%CI; 22.2-27.7) for Group 1 and 20 months (range 1-67 months,95%CI; 16.8-23.1) for Group 2 (p=0.036). Median PFS was 9.6 months (range 2-36 months, 95%CI; 8.8-10.4) forGroup 1 and 9 months (range 1-44 months, 95%CI; 7.4-10.5) for Group 2 (p=0.019). Objective RR was 56.4%in Group 1 and 26.1% in Group 2 (p<0.001). Conclusions: First-line XELOX-Bev is more effective with a betterresponse rate, prolongation of median PFS/OS, and a superior safety profile compared with FOLFIRI-Bev.