Effect of matched therapy in metastatic colorectal cancer on progression free survival in the phase I setting.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 619-619
Author(s):  
Michael Lam ◽  
Allan Andresson Lima Pereira ◽  
Jonathan M. Loree ◽  
Shailesh M Advani ◽  
Michael J. Overman ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Decision Support ◽  
Metastatic Colorectal Cancer ◽  
Phase 1 ◽  
Univariate Analysis ◽  
Pik3ca Mutation ◽  
Progression Free Survival ◽  
Precision Oncology ◽  
Free Survival ◽  
Significant Difference

619 Background: The benefits of matching targeted treatments to aberrations identified by molecular profiling (MP) is unclear. Outcomes in phase 1 settings have been traditionally reported across tumor histologies. We report outcomes based on a metastatic colorectal cancer (mCRC) population. Methods: Patients (pts) with mCRC receiving at least one dose of treatment on a phase 1 study were annotated for variants detected by MP. A precision oncology decision support (PODS) team determined variant function and actionability. A matched therapy (MT) was defined as allocation to a novel agent that targeted the aberration or predicted pathway deemed actionable by PODS. Progression-free survival (PFS) was estimated using the Kaplan-Meier method. A Cox proportional hazards model was used to estimate hazard ratios (HR). Results: A total of 370 patients enrolled onto 467 phase 1 trials were identified from January 2012 to April 2017. 106 enrolments were assigned to MT. Pts with microsatellite instability-high (MSI-H), BRAFV600E, PIK3CA mutation were more likely to be assigned a MT, while left-sided tumors and RAS mutant patients were less likely to be treated with a MT. Molecularly-targeted regimens (MTR) were utilized more frequently in MT while immune-targeting MTR was more common in non-MT. BRAFV600E mutations and HER2 amplification/overexpression made up 44.3% of MT. There was a significant difference in PFS between the MT vs non-MT group (HR 0.65, 95% CI 0.51-0.83, p = 0.016) in univariate analysis. The 6-month PFS probability was 31% (95% CI; 23-41%) versus 13% (95% CI; 10-17%) respectively. Other significant factors in univariate analysis associated with longer PFS were MSI-H, BRAFV600E and use of a regimen containing cytotoxic chemotherapy while RAS mutations were associated with shorter PFS. In multivariate analysis, after correcting for mutation status, allocation to a MT was associated with improved PFS (HR = 0.72, 95% CI 0.50-0.99, p = 0.043). Conclusions: Matching clinical trial enrollment to MP based on dedicated decision support is associated with improved outcomes in mCRC patients. The MT strategy is still hampered by a limited number of actionable variants, and is driven by a small number of active MTs.

scholarly journals ONCOGRAM: study protocol for the evaluation of therapeutic response and survival of metastatic colorectal cancer patients treated according to the guidelines of a chemosensitivity assay, the Oncogramme®

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Muriel Mathonnet ◽  
Mathieu Vanderstraete ◽  
Christophe Bounaix Morand du Puch ◽  
Stéphanie Giraud ◽  
Christophe Lautrette ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Decision Support ◽  
Metastatic Colorectal Cancer ◽  
Survival Rates ◽  
Prospective Trial ◽  
Progression Free Survival ◽  
Decision Support Tool ◽  
Chemosensitivity Assay ◽  
Free Survival ◽  
Support Tool

Abstract Background Colorectal cancer is a major public concern, being the second deadliest cancer in the world. Whereas survival is high for localized forms, metastatic colorectal cancer has showed poor prognosis, with a 5-year survival barely surpassing 11%. Conventional chemotherapies against this disease proved their efficiency and remain essential in first-line treatment. However, the large number of authorized protocols complexifies treatment decision. In common practice, such decision is made on an empirical basis, by assessing benefits and risks for the patient. In other words, there is currently no efficient means of predicting the efficacy of any chemotherapy protocol for metastatic colorectal cancer. Methods/design The use of a chemosensitivity assay, the Oncogramme®, should help clinicians administer the best chemotherapy regimen to their patients. We hypothesize it would ultimately improve their survival. In this multicentred, prospective trial (ONCOGRAM), eligible patients with metastatic colorectal cancer are randomized to determine whether they will receive an Oncogramme®. For clinicians whose patients benefited from the assay (arm A), results are used as a decision support tool. Patients not undergoing the Oncogramme® procedure are treated according to current practice, without the assistance of the assay (arm B). Primary outcome is 1-year progression-free survival. Secondary outcomes include response rates, as well as 6-month and 1-year survival rates. Discussion This study aims at investigating the clinical utility of the Oncogramme® as a decision support tool for the treatment of patients with metastatic colorectal cancer. If the Oncogramme® positively influenced patient overall survival and/or progression-free survival, it would be of great value for clinicians to implement this assay within the current landscape of personalized medicine tools, which include genomics and biomarker assays. Trial registration ClinicalTrials.gov identifier NCT03133273. Registered on April 28, 2017.

Retrospective cohort study on the safety and efficacy of panitumumab for patients with metastatic colorectal cancer: The HGCSG1002 study—Analysis of after cetuximab refractory.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 541-541
Author(s):  
Yoshimitsu Kobayashi ◽  
Hiraku Fukushima ◽  
Takahide Sasaki ◽  
Satoshi Yuki ◽  
Hiroyuki Okuda ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Progression Free Survival ◽  
Daily Practice ◽  
Free Survival ◽  
Naive Group ◽  
Significant Difference ◽  
Heavily Pretreated ◽  
Grade 3 ◽  
Egfr Antibody

541 Background: In the previous studies, panitumumab (Pmab) has been demonstrated the efficacy for patients with metastatic colorectal cancer (mCRC) in all treatment lines. It is still controversial about the efficacy of Pmab for patients that had progressed on prior cetuximab (Cmab), though there had been a few reports (from Metges et al. and Wadlow et al.) regarding the efficacy of Pmab after Cmab refractory or intolerance. To evaluate the efficacy and safety of Pmab in patients with cetuximab-refractory mCRC, in comparison with anti-EGFR antibody naïve patients (Cmab-naïve) and Cmab-refractory or intolerance patients (prior-Cmab). Methods: Two hundred patients with mCRC treated by Pmab contained chemotherapy were retrospectively registered from 20 centers in Japan (HGCSG 1002 study). Of these, the patients that were refractory to or intolerant for 5-FU/ irinotecan/ oxaliplatin, and were administered Pmab monotherapy were included in this analysis. Results: Of 93 patients (44 prior-Cmab and 49 Cmab-naïve) were evaluated. There were no significant differences in the baseline characteristics of the patients in each group. The incidence of Grade 3 or higher any skin toxicities were higher in the Cmab-naïve (26.5.%) than in the prior-Cmab (11.4%). The overall response rate (RR) was not significantly difference (prior-Cmab/ Cmab-naïve, 9.1%/ 10.2%), but the disease control rate (DCR) was slightly higher in Cmab-naïve group (38.6%/ 55.1%, p=0.15). Progression free survival (PFS) and overall survival (OS) were follows: prior-Cmab/ Cmab-naïve, 2.8m/ 3.1m, 6.8m / 9.5m. There was a significant difference between the two groups in OS curve (p=0.04). Conclusions: Pmab was safely administered to heavily pretreated mCRC patients in daily practice. Although there were no significant differences in RR, DCS and PFS between prior-Cmab and Cmab-naïve, but the median OS was longer for the Cmab-naïve group compared with the prior-Cmab group. Therapeutic efficacies of Pmab for prior-Cmab patients did not comparable to those for Cmab-naïve patients. We are now performing a phase II trial on the efficacy of Pmab for Cmab-refractory mCRC patients.

Genes involved in EGFR-degradation to predict for efficacy in metastatic colorectal cancer patients treated with cetuximab.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3557-3557
Author(s):  
Sebastian Stintzing ◽  
Wu Zhang ◽  
Takeru Wakatsuki ◽  
Yan Ning ◽  
Nico Benjamin Volz ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Metastatic Colorectal Cancer ◽  
Univariate Analysis ◽  
Resistance Mechanism ◽  
Progression Free Survival ◽  
P Value ◽  
Nucleotide Polymorphisms ◽  
Free Survival ◽  
Receptor Endocytosis

3557 Background: As many transmembrane receptors, the epithelial growth factor receptor (EGFR) has a highly regulated turnover leading to inactivation and recycling or degradation after activation. This process can be divided into four different phases: receptor endocytosis, ubiquitation/neddylation, recycling and degradation. We tested whether functional significant single nucleotide polymorphisms in genes involved in the degradation pathway will predict clinical outcome (response, PFS and OS) in 108 patients with metastatic colorectal cancer enrolled in clinical trials and treated with cetuximab. Methods: Genomic DNA was isolated from blood from 108 patients treated with cetuximab enrolled in one of two clinical trials. All patients were KRAS and BRAF wildtyp. 20 SNPs were selected based on the involvement in receptor endocytosis (CBL, CIN85, endophilin) ubiquitation/neddylation, recycling and degradation (CBL, EPS15, Ubc12, UbcH7). Minor allele frequency had to by higher than 10%. PCR and product sequencing were done using standard procedures. Uni- and multivariate analyses, adjusting for age, gender, rash and racial background, were carried out. Results: In univariate analysis, rs895374 (HR: 1.69; p= 0.03), which is located in the exome of UbcH7, was able to separate patient cohorts significantly in perspective of progression free survival (CC = 5.7mo, CA= 3.6mo, AA= 3.4mo). Using multivariate analysis, rs895375 stayed to be a significant predictor of progression free survival with a Hazard ratio of 2.08 (95% CI 1.24 – 3.48) and a p value of 0.005. UbcH7 plays a pivotal role in the process of neddylation (adding NEDD8 to the EGFR), which switch the balance between recycling and degradation of the EGFR towards degradation. Conclusions: The process of EGFR recycling is important mechanism of resistance of cetuximab in colorectal cancer. This is the first report suggesting that germline polymorphisms in the degradation process may predict efficacy of cetuximab in patients with metastatic colorectal cancer. Anti-EGFR antibody like Sym004 might overcome this resistance mechanism by preventing EGFR recycling.

Genetic variants in CCL5 and CCR5 genes and serum VEGF-A levels to predict efficacy of bevacizumab in metastatic colorectal cancer patients receiving first-line chemotherapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11564-11564
Author(s):  
Mitsukuni Suenaga ◽  
Shu Cao ◽  
Wu Zhang ◽  
Yan Ning ◽  
Satoshi Okazaki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Direct Sequencing ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Progression Free Survival ◽  
Nucleotide Polymorphisms ◽  
First Line ◽  
Significant Difference

11564 Background: Early VEGF-A reduction by targeting abundant VEGF-A is a potential predictive marker of bevacizumab (BV). CCL5/CCR5 axis modulates VEGF-A production via endothelial progenitor cells migration. We tested whether genetic polymorphisms in CCL5/CCR5 pathway will predict outcomes in metastatic colorectal cancer (mCRC) patients (pts) receiving BV in first-line setting. Methods: Genomic DNA was extracted from 215 samples of three independent cohorts: 61 pts receiving FOLFOX+BV (median age 60 yrs, median follow-up 39.2 mos); 83 pts receiving FOLFOX (median age 61 yrs, median follow-up 57.6 mos); 71 pts receiving FOLFOX/XELOX+BV as exploratory for serum biochemistry assay (median age 60 yrs, median follow-up 28.9 mos). Single nucleotide polymorphisms of genes in CCL5/CCR5 pathway were analyzed by PCR-based direct sequencing. Serum VEGF-A levels at baseline and day 14 were measured using ELISA. Results: In univariate analysis for the FOLFOX cohort, pts with the CCL5 rs2280789 G/G variant or any CCR5 rs1799988 T allele had shorter overall survival (OS) compared to the those with any A allele or the C/C variant (18.7 vs. 29.4 mos, HR 1.93, 95%CI: 1.05−3.53 P= 0.025; 22.0 vs. 31.2 mos, HR 1.74, 95%CI: 0.98-3.90, P= 0.055). The trend remained in multivariable analysis ( P= 0.090 and P= 0.026). The differences were not confirmed in the FOLFOX+BV cohort. Pts with any CCL5 rs2280789 G allele had longer progression-free survival (PFS) and OS when receiving FOLFOX+BV than FOLFOX (PFS: 19.8 vs. 11.0 mos, HR: 0.44, 95%CI: 0.25-0.78, P= 0.002; OS: 41.8 vs. 21.1 mos, HR: 0.43, 95%CI: 0.24-0.77, P= 0.002); pts carrying any CCR5 rs1799988 T allele had longer PFS and OS ( P= 0.025 and P= 0.008, respectively). No significant difference was shown in pts with either A/A or C/C variant. In the exploratory cohort, any CCL5 rs2280789 G allele was associated with higher VEGF-A levels at baseline and greater decrease of VEGF-A levels at day 14 compared with the A/A variant. Conclusions: CCL5 and CCR5 impact the angiogenic environment. Our data suggest the genotypes may identify specific populations who benefit from BV-based chemotherapy in first-line treatment for mCRC.

scholarly journals Bevacizumab plus capecitabine as later-line treatment for patients with metastatic colorectal cancer refractory to irinotecan, oxaliplatin, and fluoropyrimidines

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yeong Hak Bang ◽  
Jeong Eun Kim ◽  
Ji Sung Lee ◽  
Sun Young Kim ◽  
Kyu-Pyo Kim ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Median Overall Survival ◽  
Treatment Options ◽  
Multivariable Analysis ◽  
Progression Free Survival ◽  
Line Treatment ◽  
Free Survival ◽  
Medical Need ◽  
Significant Disease

AbstractThere is an unmet medical need for later-line treatment options for patients with metastatic colorectal cancer (mCRC). Considering that, beyond progression, co-treatment with bevacizumab and cytotoxic chemotherapy showed less toxicity and a significant disease control rate, we aimed to evaluate the efficacy of capecitabine and bevacizumab. This single-center retrospective study included 157 patients between May 2011 and February 2018, who received bevacizumab plus capecitabine as later-line chemotherapy after progressing with irinotecan, oxaliplatin, and fluoropyrimidines. The study treatment consisted of bevacizumab 7.5 mg/kg on day 1 and capecitabine 1,250 mg/m2 orally (PO) twice daily on day 1 to 14, repeated every 3 weeks. The primary endpoint was progression-free survival (PFS). The median PFS was 4.6 months (95% confidence interval [CI] 3.9–5.3). The median overall survival (OS) was 9.7 months (95% CI 8.3–11.1). The overall response rate was 14% (22/157). Patients who had not received prior targeted agents showed better survival outcomes in the multivariable analysis of OS (hazard ratio [HR] = 0.59, 95% CI 0.43–0.82, P = 0.002) and PFS (HR = 0.61, 95% CI 0.43–0.85, P = 0.004). Bevacizumab plus capecitabine could be a considerably efficacious option for patients with mCRC refractory to prior standard treatments.

scholarly journals Safety and efficacy of panitumumab in combination with trifluridine/tipiracil for pre-treated patients with unresectable, metastatic colorectal cancer with wild-type RAS: The phase 1/2 APOLLON study

2021 ◽  
Author(s):  
Takeshi Kato ◽  
Yoshinori Kagawa ◽  
Yasutoshi Kuboki ◽  
Makio Gamoh ◽  
Yoshito Komatsu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Therapeutic Option ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Wild Type ◽  
Open Label ◽  
Safety And Efficacy ◽  
Multicentre Phase

Abstract Background We aimed to assess the safety and efficacy of combination treatment with panitumumab plus trifluridine/tipiracil (FTD/TPI) in patients with wild-type RAS metastatic colorectal cancer (mCRC) who were refractory/intolerant to standard therapies other than anti-epidermal growth factor receptor therapy. Methods APOLLON was an open-label, multicentre, phase 1/2 trial. In the phase 1 part, 3 + 3 de-escalation design was used to investigate the recommended phase 2 dose (RP2D); all patients in the phase 2 part received the RP2D. The primary endpoint was investigator-assessed progression-free survival (PFS) rate at 6 months. Secondary endpoints included PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), time to treatment failure (TTF), and safety. Results Fifty-six patients were enrolled (phase 1, n = 7; phase 2, n = 49) at 25 Japanese centres. No dose-limiting toxicities were observed in patients receiving panitumumab (6 mg/kg every 2 weeks) plus FTD/TPI (35 mg/m2 twice daily; days 1–5 and 8–12 in a 28-day cycle), which became RP2D. PFS rate at 6 months was 33.3% (90% confidence interval [CI] 22.8–45.3). Median PFS, OS, ORR, DCR, and TTF were 5.8 months (95% CI 4.5–6.5), 14.1 months (95% CI 12.2–19.3), 37.0% (95% CI 24.3–51.3), 81.5% (95% CI 68.6–90.8), and 5.8 months (95% CI 4.29–6.21), respectively. Neutrophil count decreased (47.3%) was the most common Grade 3/4 treatment-emergent adverse event. No treatment-related deaths occurred. Conclusion Panitumumab plus FTD/TPI exhibited favourable anti-tumour activity with a manageable safety profile and may be a therapeutic option for pre-treated mCRC patients.

Lonsurf (trifluridine/tipiracil): Assessing the impact of dose related toxicities and progression free survival in (refractory) metastatic colorectal cancer

2021 ◽  
pp. 107815522110179
Author(s):  
Olivia R Court
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Dose Reduction ◽  
Progression Free Survival ◽  
Electronic Patient Records ◽  
Free Survival ◽  
Length Of Treatment ◽  
Common Grade ◽  
Grade 3 ◽  
The Impact

In the RECOURSE trial which lead to its accreditation, Lonsurf (trifluridine/tipiracil) was shown to extend progression free survival (PFS) by 1.8 months in metastatic colorectal cancer. This Trust audit aims to assess the average quantity of cycles of Lonsurf received by participants and the length of time it extends PFS. Similarly, to identify how many participants required a dose-reduction or experienced toxicities which necessitated supportive therapies. Quantitative data was collected retrospectively from all participants who had received ≥1 cycle of Lonsurf from The Clatterbridge Cancer Centre (CCC) from 2016 until June 2020. Participant electronic patient records were accessed to identify toxicity grading, length of treatment received, the date progression was identified, if dose reductions were applied and if supportive therapies were administered. Lonsurf extends PFS in patients with metastatic colorectal cancer at CCC by 3.0 months (95% CI: 2.73–3.27) and average treatment length was 2.4 months. However, 78 participants (41.5%) received a dose reduction due to toxicities. A total of 955 toxicities were recorded by participants; the most commonly reported toxicities irrespective of grade were fatigue (33.8%), diarrhoea (13.8%) and nausea (12.3%). The most common grade ≥3 toxicities were constipation and infection. The most frequently utilised supportive therapies were loperamide (49.6%) and domperidone (49.1%). Granulocyte colony stimulating factor (GCSF) was required by patients on 5 occasions (0.3%) in total. Lonsurf extends median PFS in patients with metastatic colorectal cancer by 3.0 months. The most common grade ≥3 toxicities which necessitated supportive therapies or a dose reduction were gastrointestinal and infection.

scholarly journals Population-Based Study of Docetaxel or Abiraterone Effectiveness and Predictive Markers of Progression Free Survival in Metastatic Castration-Sensitive Prostate Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Juan Briones ◽  
Maira Khan ◽  
Amanjot K. Sidhu ◽  
Liying Zhang ◽  
Martin Smoragiewicz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Predictive Factors ◽  
Real World ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Progression Free Survival ◽  
Predictive Markers ◽  
Age At Diagnosis ◽  
Free Survival ◽  
Significant Difference

BackgroundBoth Docetaxel (DOC) and Abiraterone (ABI) improve the survival of men with metastatic, castration sensitive prostate cancer (mCSPC). However, the outcome among mCSPC patients is highly variable, while there is a lack of predictive markers of therapeutic benefit. Furthermore, there is limited data on the comparative real-world effectiveness of adding DOC or ABI to androgen deprivation therapy (ADT).MethodsWe conducted a retrospective analysis of 121 mCSPC patients treated at Odette Cancer Centre (Toronto, ON, Canada) between Dec 2014 and Mar 2021 (DOC n = 79, ABI n = 42). The primary endpoint studied was progression free survival (PFS), defined as the interval from start of ADT to either (i) biochemical, radiological, or symptomatic progression, (ii) start of first-line systemic therapy for castration-resistant prostate cancer (CRPC), or (iii) death, whichever occurred first. To identify independent predictive factors for PFS in the entire cohort, a Cox proportional hazard model (stepwise selection) was applied. Overall survival (OS) was among secondary endpoints.ResultsAfter a median follow-up of 39.6 and 25.1 months in the DOC and ABI cohorts, respectively, 79.7% of men in the DOC and 40.5% in the ABI group experienced a progression event. PFS favored the ABI cohort (p = 0.0038, log-rank test), with 78.0% (95%CI 66.4–91.8%) of ABI versus 67.1% (57.5–78.3%) of DOC patients being free of progression at 12 months. In univariate analysis superior PFS was significantly related to older age at diagnosis of mCSPC, metachronous metastatic presentation, low-volume (CHAARTED), and low-risk (LATITUDE) disease, ≥90% PSA decrease at 3 months (PSA90), and PSA nadir ≤0.2 at 6 months. Age (HR = 0.955), PSA90 (HR = 0.462), and LATITUDE risk stratification (HR = 1.965) remained significantly associated with PFS in multivariable analysis. OS at 12 months was 98.7% (96.3–100%) and 92.7% (85.0–100%) in the DOC and ABI groups (p = 0.97), respectively.ConclusionsIn this real-world group of men undergoing treatment intensification with DOC or ABI for mCSPC, we did not find a significant difference in OS, but PFS was favoring ABI. Age at diagnosis of mCSPC, PSA90 at 3 months and LATITUDE risk classification are predictive factors of PFS in men with mCSPC.

scholarly journals Protocol of the EFFORT study: a prospective study of FOLFIRI plus aflibercept as second-line treatment after progression on FOLFOXIRI plus bevacizumab or during maintenance treatment in patients with unresectable/metastatic colorectal cancer

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Hironaga Satake ◽  
Koji Ando ◽  
Eiji Oki ◽  
Mototsugu Shimokawa ◽  
Akitaka Makiyama ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii Study ◽  
Progression Free Survival ◽  
Second Line ◽  
First Line ◽  
Second Line Therapy ◽  
Free Survival ◽  
First Line Therapy ◽  
Line Therapy

Abstract Background FOLFOXIRI plus bevacizumab is used as a first-line therapy for patients with unresectable or metastatic colorectal cancer. However, there are no clear recommendations for second-line therapy after FOLFOXIRI plus bevacizumab combination. Here, we describe our planning for the EFFORT study to investigate whether FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for mCRC. Methods EFFORT is an open-label, multicenter, single arm phase II study to evaluate whether a FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for mCRC. Patients with unresectable or metastatic colorectal cancer who received FOLFOXIRI plus bevacizumab as a first-line therapy will receive aflibercept and FOLFIRI (aflibercept 4 mg/kg, irinotecan 150 mg/m2 IV over 90 min, with levofolinate 200 mg/m2 IV over 2 h, followed by fluorouracil 400 mg/m2 bolus and fluorouracil 2400 mg/m2 continuous infusion over 46 h) every 2 weeks on day 1 of each cycle. The primary endpoint is progression-free survival (PFS). To achieve 80% power to show a significant response benefit with a one-sided alpha level of 0.10, assuming a threshold progression-free survival of 3 months and an expected value of at least 5.4 months, we estimated that 32 patients are necessary. Secondary endpoints include overall survival, overall response rate, safety, and exploratory biomarker analysis for differentiating anti-VEGF drug in 2nd-line chemotherapy for unresectable or metastatic colorectal cancer. Discussion This is the first study to investigate whether FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for unresectable or metastatic colorectal cancer. Switching to a different type of anti-VEGF drug in second-line therapy after FOLFOXIRI plus bevacizumab appears to be an attractive treatment strategy when considering survival benefit. It is expected that this phase II study will prove the efficacy of this strategy and that a biomarker for drug selection will be discovered. Trial registration Japan Registry of Clinical Trials jRCTs071190003. Registered April 18, 2019.

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