Multicenter Phase II study of FOLFOX or biweekly XELOX and Erbitux (cetuximab) as first-line therapy in patients with wild-type KRAS/BRAF metastatic colorectal cancer: The FLEET study

Background:The efficacy of oxaliplatin-based chemotherapy combined with anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) remains controversial in metastatic colorectal cancer (mCRC). This meta-analysis aims to estimate the effect of adding panitumumab or cetuximab to oxaliplatin-based chemotherapy in RAS wild type mCRC patients for the first-line treatment. The primary tumor location is also considered into this meta-analysis.Methods:RCT studies were identified by a search of MEDLINE, EMBASE, Cochrane library to October 2017, supplemented by manually retrieving ASCO, ESMO conference abstracts. The pooled hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS), and pooled odds ratios (OR) for the overall response rate (ORR) were calculated by Review Manager 5.3.Results:The results indicated that the addition of anti-EGFR mAbs to FOLFOX regimen in RAS wild-type mCRC patients for the first-line treatment resulted in considerable improvements in PFS (HR = 0.70; 95% confidence interval [CI]: 0.59–0.82; P < .0001), OS (HR = 0.79; 95%CI: 0.67–0.92; P = .003), and ORR (OR = 2.56; 95% CI: 1.77–3.70; P < .00001) compared with chemotherapy alone. However, in RAS/BRAF wild patients, no significant differences were observed when anti-EGFR mAb was added to FLOX or XELOX regimen compared with chemotherapy alone with regard to OS and PFS, whereas FOLFOX+anti-EGFR mAb showed a marked superior OS and PFS (OS, HR = 0.77; 95% CI: 0.61–0.98; P = .03; PFS, HR = 0.68; 95% CI: 0.57–0.82; P < .00001). A meta-analysis including TAILOR and PRIME study suggests that primary tumor location (PTL) predicted a survival benefit when adding the EGFR antibody to FOLFOX regimen in RAS-wild mCRC patients (OS, HR for left-sided: 0.71; 95% CI: 0.59–0.85; P = .0002 and HR for right-sided: 0.90; 95% CI: 0.65–1.25; P = .53). However, the HR for PFS and ORR still suggests a benefit from the addition of anti-EGFR mAb in right-sided mCRC patients.Conclusion:So these results suggest anti-EGFR mAb and oxaliplatin are good partners in the FOLFOX regimen. The addition of EGFR antibody to FOLFOX markedly improved efficacy in RAS-wild patients with left-sided mCRC. In RAS/BRAF-wild patients, the efficacy is similar. For patients with right-sided tumor, a benefit showing a trendency in favor of anti-EGFR mAb can still seen. The molecular characteristics behind the tumor location need to be more explored urgently.

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“…[ 37 ] In fact, some clinical studies demonstrated cetuximab plus XELOX is a effective and tolerable treatment regimen. [ 38 – 40 ]…”

Section: Discussionmentioning

confidence: 99%

FOLFOX plus anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) is an effective first-line treatment for patients with RAS-wild left-sided metastatic colorectal cancer

Chen

Zhang

et al. 2018

Medicine

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“…In this study, only one of the 53 patients was converted from unresectable to resectable. Chemotherapy regimens were chosen according to the IRB‐approved clinical studies, which have been ongoing during the study period . Recently, our first‐line regimens have been oxaliplatin‐based regimens such as mFOLFOX (bolus/infusional fluorouracil and leucovorin with oxaliplatin) or XELOX (capecitabine and oxaliplatin) in combination with anti‐VEGF antibody or anti‐EGFR antibody .…”

Section: Methodsmentioning

confidence: 99%

“…Chemotherapy regimens were chosen according to the IRB‐approved clinical studies, which have been ongoing during the study period . Recently, our first‐line regimens have been oxaliplatin‐based regimens such as mFOLFOX (bolus/infusional fluorouracil and leucovorin with oxaliplatin) or XELOX (capecitabine and oxaliplatin) in combination with anti‐VEGF antibody or anti‐EGFR antibody . In particular, we selected cetuximab as the anti‐EGFR antibody rather than panitumumab, in combination with standard chemotherapy for KRAS wild‐type metastatic colorectal cancer based on our previous clinical study …”

Section: Methodsmentioning

confidence: 99%

“…(33)(34)(35)(36)(37)(38)(39)(40) Recently, our first-line regimens have been oxaliplatin-based regimens such as mFOLFOX (bolus/infusional fluorouracil and leucovorin with oxaliplatin) or XELOX (capecitabine and oxaliplatin) in combination with anti-VEGF antibody or anti-EGFR antibody. (40) In particular, we selected cetuximab as the anti-EGFR antibody rather than panitumumab, in combination with standard chemotherapy for KRAS wild-type metastatic colorectal cancer based on our previous clinical study. (41) The cases with a complete response (CR) to chemotherapy before operation were excluded from this study.…”

Section: Methodsmentioning

confidence: 99%

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Cetuximab strongly enhances immune cell infiltration into liver metastatic sites in colorectal cancer

et al. 2017

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Cetuximab has activity against colorectal cancers. Recent studies demonstrated that cetuximab induces antibody‐dependent cell‐mediated cytotoxicity via immune cells, and a new immune‐related mechanism of inducing immunogenic cell death. This study aimed to evaluate the immune responses induced by cetuximab in tumor microenvironments at liver metastasis sites of metastatic colorectal cancer patients. We assessed immune cell infiltration in the liver metastatic sites of 53 colorectal cancer patients. These patients were divided into three groups according to the treatment before operation: chemotherapy with cetuximab, chemotherapy without cetuximab, and no chemotherapy. The inflammatory cells in the liver metastatic sites were assessed by hematoxylin–eosin staining, focusing on the invasive margin. The overall inflammatory reaction and number of lymphoid cells were assessed with a four‐point scoring system. We then assessed immune cell infiltration (CD3, CD8 and CD56) in 15 liver metastatic sites. Hematoxylin–eosin staining demonstrated more inflammatory cells in the chemotherapy with cetuximab group than in the other groups (P < 0.001). Of note, inflammatory cells were found in intratumoral areas, and the destruction of cancer cell foci was observed in the chemotherapy with cetuximab group. Moreover, a higher infiltration of CD3+ (P = 0.003), CD8+ (P = 0.003) and CD56+ (P = 0.001) cells was observed in the chemotherapy with cetuximab group than in the other groups. These results suggest that cetuximab might have an immune‐enhancing effect. As such, the immune‐related mechanism of action of cetuximab may enhance the efficacy of combination therapy, such as chemotherapy and immunotherapy using therapeutic peptides.

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“…Paronychia is one of the most common cutaneous adverse event during treatment with cetuximab seen in approximately 10% of the patients. [ 7 8 ]…”

Section: Epidermal Growth Factor-receptor Inhibitorsmentioning

confidence: 99%

Systemic drug-induced chronic paronychia and periungual pyogenic granuloma

Wollina

2018

Indian Dermatol Online J

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Multicenter Phase II study of FOLFOX or biweekly XELOX and Erbitux (cetuximab) as first-line therapy in patients with wild-type KRAS/BRAF metastatic colorectal cancer: The FLEET study

Cited by 24 publications

References 28 publications

FOLFOX plus anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) is an effective first-line treatment for patients with RAS-wild left-sided metastatic colorectal cancer

FOLFOX plus anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) is an effective first-line treatment for patients with RAS-wild left-sided metastatic colorectal cancer

Cetuximab strongly enhances immune cell infiltration into liver metastatic sites in colorectal cancer

Systemic drug-induced chronic paronychia and periungual pyogenic granuloma

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