A study-level meta-analysis of efficacy data from head-to-head first-line trials of epidermal growth factor receptor inhibitors versus bevacizumab in patients with RAS wild-type metastatic colorectal cancer

Heinemann, Volker; Rivera, Fernando; O’Neil, Bert H.; Stintzing, Sebastian; Koukakis, Reija; Terwey, Jan-Henrik; Douillard, Jean-Yves

doi:10.1016/j.ejca.2016.07.019

Cited by 58 publications

(39 citation statements)

References 28 publications

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“…Because EGFR signaling has been recognized as an important player in CRC initiation and progression, EGFR inhibitors, which are effective in CRC harboring wild‐type RAS , have been used as one of the important molecular targeted therapies for CRC . Hence, RAS mutation analysis using plasma sample is expected to be applicable for the prediction of response to EGFR inhibitors and monitoring the change in RAS status of mCRC.…”

Section: Discussionmentioning

confidence: 99%

Clinical relevance of circulating tumor DNA assessed through deep sequencing in patients with metastatic colorectal cancer

et al. 2018

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Because circulating tumor DNA (ctDNA) studies focusing on only one or a few genes to monitor the disease progress or treatment response are unlikely to find its clinical significance, the development of cell‐free DNA (cfDNA) panel covering hundreds of mutation hot spots is important for the establishment of clinically practical ctDNA detection system. We enrolled 101 patients with metastatic colorectal cancer (mCRC) who received chemotherapy. Amplicon‐based genomic profiling of 14 genes, which are commonly mutated in CRC, in plasma by next‐generation sequencing (NGS) was carried out to evaluate the feasibility of this assay and was compared with their clinical parameters and RAS status in matched tissue samples. Somatic mutations of the 14 genes in plasma cfDNA were detected in 88 patients (87.1%) with mCRC. Mutations in TP53, KRAS, and APC genes were detected in 70 (69.3%), 39 (38.6%), and 24 (23.7%) patients, respectively. Mutant allele frequencies in plasma were significantly associated with metastasis (liver, P = 0.00004, lymph node, P = 0.008, number of metastatic organs, P = 0.0006), tumor markers (CEA, P = 0.000007, CA19‐9, P = 0.006, LDH, P = 0.00001), and tumor diameter (maximum, P = 0.00002, sum of diameter, P = 0.00009). The overall concordance rate of RAS status between ctDNA and matched tissue was 77.2% (78/101). Our data confirmed that mutant allele in cfDNA can be sensitively detected by amplicon‐based NGS system. These results suggest that ctDNA could be a novel diagnostic biomarker to monitor changes in mutational status and tumor burden in patients with mCRC.

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Section: Discussionmentioning

confidence: 99%

Clinical relevance of circulating tumor DNA assessed through deep sequencing in patients with metastatic colorectal cancer

et al. 2018

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“…This is also in line with results from two recent meta-analyses of these trials, which included primary analysis data from PEAK. Both meta-analyses demonstrated significantly improved ORR and OS with first-line anti-EGFR compared with anti-VEGF therapy in patients with RAS WT mCRC [18, 19]. The HR (95% CI) for OS was 0.77 (0.63–0.95) in favour of the EGFRI in both analyses.…”

Section: Discussionmentioning

confidence: 99%

Final analysis of the randomised PEAK trial: overall survival and tumour responses during first-line treatment with mFOLFOX6 plus either panitumumab or bevacizumab in patients with metastatic colorectal carcinoma

Rivera

Karthaus

Hecht

et al. 2017

Int J Colorectal Dis

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100

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PurposeTo report planned final overall (OS) and progression-free survival (PFS) analyses from the phase II PEAK trial (NCT00819780).MethodsPatients with previously untreated, KRAS exon 2 wild-type (WT) metastatic colorectal cancer (mCRC) were randomised to mFOLFOX6 plus panitumumab or bevacizumab. The primary endpoint was PFS; secondary endpoints included OS, objective response rate, duration of response (DoR), time to response, resection and safety. Treatment effect by tumour RAS status was a prespecified objective. Exploratory analyses included early tumour shrinkage (ETS) and depth of response (DpR).ResultsOne hundred seventy patients had RAS WT and 156 had RAS WT/BRAF WT mCRC. Median PFS was longer for panitumumab versus bevacizumab in the RAS WT (12.8 vs 10.1 months; hazard ratio (HR) = 0.68 [95% confidence intervals (CI) = 0.48–0.96]; p = 0.029) and RAS WT/BRAF WT (13.1 vs 10.1 months; HR = 0.61 [95% CI = 0.42–0.88]; p = 0.0075) populations. Median OS (68% OS events) for panitumumab versus bevacizumab was 36.9 versus 28.9 months (HR = 0.76 [95% CI = 0.53–1.11]; p = 0.15) and 41.3 versus 28.9 months (HR = 0.70 [95% CI = 0.48–1.04]; p = 0.08), in the RAS WT and RAS WT/BRAF WT populations, respectively. Median DoR (11.4 vs 9.0 months; HR = 0.59 [95% CI = 0.39–0.88]; p = 0.011) and DpR (65.0 vs 46.3%; p = 0.0018) were improved in the panitumumab group. More panitumumab patients experienced ≥30% ETS at week 8 (64 vs 45%; p = 0.052); ETS was associated with improved PFS/OS. No new safety signals occurred.ConclusionsFirst-line panitumumab + mFOLFOX6 increases PFS versus bevacizumab + mFOLFOX6 in patients with RAS WT mCRC.Electronic supplementary materialThe online version of this article (doi:10.1007/s00384-017-2800-1) contains supplementary material, which is available to authorized users.

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“…A meta-analysis showed that first-line cetuximab/panitumumab plus chemotherapy increased ORR and OS compared with Bev plus chemotherapy in mCRC patients with RAS wild-type. However, there was no difference in resection rate and PFS between the two regimens [40]. Given that epidermal growth factor receptor (EGFR) inhibitors are less effective in mCRC patients with RAS or BRAF mutations [41][42][43], FOLFOXIRI-Bev could be a viable option in conversion therapy for mCRC patients with RAS or BRAF mutations [37,44].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

Triplet Chemotherapy (FOLFOXIRI) Plus Bevacizumab Versus Doublet Chemotherapy (FOLFOX/FOLFIRI) Plus Bevacizumab in Conversion Therapy for Metastatic Colorectal Cancer: a Meta-Analysis

Lin

et al. 2018

Cell Physiol Biochem

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Background/Aims: Conversion therapy can convert unresectable metastatic colorectal cancer (mCRC) into resectable. However, the optimal conversion regimen was not yet defined. This meta-analysis aimed to compare the efficacy and safety of the triplet chemotherapy (FOLFOXIRI) plus bevacizumab (Bev) with doublet chemotherapy (FOLFOX/FOLFIRI) plus Bev in conversion therapy. Methods: Randomized controlled trials (RCTs) from databases, including Pubmed, EMBASE, Cochrane clinical trials, clinicaltrial.gov and some conferences, were searched from the inception to November 2017. The R0 resection, objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and the incidence of adverse events were pooled with the use of hazard ratio (HR) or risk ratio (RR). Results: Four RCTs with 1013 patients were included. FOLFOXIRI plus Bev regimen significantly improved the overall R0 resection rate (RR 1.41, 95% confidence interval (CI) 1.07-1.85, I²=37%), liver R0 resection rate (RR 2.28, 95% CI 1.34-3.89, I²=0%), ORR (RR 1.20, 95% CI 1.09-1.32, I²=0%), PFS (HR 0.72, 95% CI 0.62-0.84, I²=36%) and OS (HR 0.80, 95% CI 0.66-0.97, I²=0%). There was no significant difference in any Grade≥3 adverse event (RR 1.08, 95% CI 0.99-1.17, I²=0%) between two regimens. FOLFOXIRI-Bev was associated with a higher risk of neutropenia (RR 1.77, 95% CI 1.13-2.79, I²=68%) and diarrhea (RR 1.65, 95% CI 1.17-2.32, I²=0%). Conclusions: Triplet chemotherapy plus Bev significantly improved the R0 resection rates, ORR, PFS and OS in comparison with doublet chemotherapy plus Bev in conversion therapy for mCRC patients, with a higher risk of neutropenia and diarrhea.

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A study-level meta-analysis of efficacy data from head-to-head first-line trials of epidermal growth factor receptor inhibitors versus bevacizumab in patients with RAS wild-type metastatic colorectal cancer

Abstract: This meta-analysis supports a potential benefit for first-line EGFRI plus chemotherapy versus bevacizumab plus chemotherapy with respect to OS, ORR and ETS in patients with RAS WT mCRC. A patient-level meta-analysis is awaited.

Cited by 58 publications

References 28 publications

Clinical relevance of circulating tumor DNA assessed through deep sequencing in patients with metastatic colorectal cancer

Clinical relevance of circulating tumor DNA assessed through deep sequencing in patients with metastatic colorectal cancer

Final analysis of the randomised PEAK trial: overall survival and tumour responses during first-line treatment with mFOLFOX6 plus either panitumumab or bevacizumab in patients with metastatic colorectal carcinoma

Triplet Chemotherapy (FOLFOXIRI) Plus Bevacizumab Versus Doublet Chemotherapy (FOLFOX/FOLFIRI) Plus Bevacizumab in Conversion Therapy for Metastatic Colorectal Cancer: a Meta-Analysis

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