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)

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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%

“…Because EGFR signaling has been recognized as an important player in CRC initiation and progression, [38][39][40] EGFR inhibitors, which are effective in CRC harboring wild-type RAS, have been used as one of the important molecular targeted therapies for CRC. [41][42][43] 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. Although the timing of liquid biopsy (blood collection) after tissue biopsy in each patient was inconsistent in this study, the concordance rate of RAS status between tissue and matched plasma was 77.2% (78/101).…”

Section: Discussionmentioning

confidence: 99%

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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%

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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“…However, there was a higher response rate achieved in the cetuximab arm (68.6% versus 53.6%, p < 0.01). A meta-analysis of these randomized controlled trials supports a potential benefit of first-line EGFR inhibitors plus chemotherapy versus bevacizumab plus chemotherapy with respect to OS (HR = 0.8, 95% CI = 0.68–0.93, p = 0.004) and ORR (OR = 0.57, 95% CI = 0.42–0.76) in patients with wild-type RAS mCRC [44]. Another phase III trial currently in progress, PARADIGM [45], is comparing panitumumab versus bevacizumab in combination with FOLFOX.…”

Section: Anti-egfr Therapies Versus Bevacizumab In First Line Chemmentioning

confidence: 99%

Recent Advances in Targeting the EGFR Signaling Pathway for the Treatment of Metastatic Colorectal Cancer

Miyamoto

Suyama

Baba

2017

IJMS

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Outcomes for metastatic colorectal cancer (mCRC) patients have been improved by treatment with anti-epidermal growth factor receptor (anti-EGFR) antibodies, particularly when combined with predictive biomarkers to select patients lacking RAS mutations. New technologies such as liquid biopsy and next-generation sequencing have revealed that potential mechanisms of resistance to anti-EGFR therapies act through acquired mutations of KRAS and the EGFR ectodomain. Mutations in cross-talking molecular effectors that participate in downstream EGFR signaling are also negative predictors for anti-EGFR therapy. In the current review, we describe recent advances in anti-EGFR therapy and discuss new treatment strategies to target downstream RAS-MAPK signaling in mCRC.

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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

Recent Advances in Targeting the EGFR Signaling Pathway for the Treatment of Metastatic Colorectal Cancer

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