Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials

Arnold, Dirk; Lueza, Béranger; Douillard, Jean Yves; Peeters, Marc; Lenz, Heinz Josef; Venook, Alan P.; Heinemann, Volker; Cutsem, Éric Van; Pignon, Jean-Pierre; Tabernero, Josep; Cervantes, Andrés; Ciardiello, Fortunato

doi:10.1093/annonc/mdx175

Cited by 714 publications

(630 citation statements)

References 50 publications

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“…The analysis by tumour location did not uncover a significant difference in os duration between treatments for either lcc or rcc (lcc hr: 0.96; 95% ci: 0.74 to 1.23; rcc hr: 1.14; 95% ci: 0.68 to 1.89). Similar results were observed for pfs 28 . Exclusion of patients with BRAFmutant tumours did not significantly affect those results.…”

Section: Second Linesupporting

confidence: 88%

“…In contrast to the differential benefits associated with egfr mAbs by sidedness for os duration, egfr mAbs appear to produce a superior orr in both lcc and rcc, as shown in the Holch et al 12 meta-analysis and the Arnold et al 28 pooled analysis. That observation could suggest that, if tumour shrinkage is the primary initial goal of treatment (for example, in patients with high-bulk, symptomatic, unresectable disease), an egfr mAb combined with chemotherapy might be more effective than bevacizumab combined with doublet chemotherapy.…”

Section: Tumour Responsementioning

confidence: 94%

“…A retrospective analysis of ptl in that trial was first presented at the 2016 American Society of Clinical Oncology annual meeting 36 and updated in a recently published meta-analysis 28 . Those analyses showed that, in patients with lcc, treatment with cetuximab was associated with a median os duration of 39.3 months; treatment with bevacizumab was associated with a median os duration of 32.6 months (hr: 0.77; p = 0.04).…”

Section: Impact Of Ptl On Therapy With Either Egfr Mabs or Bevacizumabmentioning

confidence: 99%

“…Arnold and colleagues 28 recently published the results of summary data from six randomized trials of tumour sidedness and egfr mAb treatment in patients with advanced crc. They used a standard fixed-effects model to calculate the hrs for os duration and pfs, and the or for orr.…”

Section: Meta-analyses Of the Effect Of Ptlmentioning

confidence: 99%

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The Predictive Effect of Primary Tumour Location in the Treatment of Metastatic Colorectal Cancer: A Canadian Consensus Statement

et al. 2017

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In recently published data, the predictive value of primary tumour location for the treatment of metastatic colorectal cancer with available biologic therapies has been explored. Recognizing the potential effect of those data on clinical practice, we convened a meeting of Canadian experts who treat metastatic colorectal cancer to develop a set of national, evidence-based treatment guidelines based on primary tumour location. This report summarizes the relevant evidence and presents the consensus recommendations of those experts.

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Section: Second Linesupporting

confidence: 88%

Section: Tumour Responsementioning

confidence: 94%

Section: Impact Of Ptl On Therapy With Either Egfr Mabs or Bevacizumabmentioning

confidence: 99%

Section: Meta-analyses Of the Effect Of Ptlmentioning

confidence: 99%

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The Predictive Effect of Primary Tumour Location in the Treatment of Metastatic Colorectal Cancer: A Canadian Consensus Statement

et al. 2017

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“…24 , 25 Several studies also demonstrate the importance of taking PTL into account when evaluating treatment response, 26-28 and retrospective analyses from large phase III trials have demonstrated that patients with right-sided tumours have less benefit from the addition of EGFR-targeted therapy. 29 …”

Section: Discussionmentioning

confidence: 99%

Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer: Relationship with sidedness and prognosis

et al. 2018

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Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 has been demonstrated to confer a prognostic value in colorectal cancer (CRC), but no studies have investigated whether this association differs according to tumour location. In this study, immunohistochemical expression of PD-1 and PD-L1 was analysed in tissue microarrays with primary tumours from 557 incident CRC cases from a prospective population-based cohort. Univariable and multivariable Cox regression analyses, adjusted for age, sex, TNM stage, differentiation grade and vascular invasion, were applied to determine the impact of biomarker expression on 5-year overall survival (OS), in the entire cohort and in subgroup analysis of right colon, left colon, and rectum. High PD-L1 expression on tumour-infiltrating immune cells was an independent factor of a prolonged OS in the entire cohort (hazard ratio [HR] = 0.49; 95% confidence interval [CI] CI 0.35 – 0.68), and in tumours of the right colon (HR = 0.43; 95% CI 0.25 – 0.74) and the left colon (HR = 0.28; 95% CI 0.13 – 0.61), but not in rectal cancer. Tumour-specific PD-L1-expression was not prognostic, neither in the full cohort nor according to tumour location. High immune cell-specific PD-1 expression was associated with a prolonged OS in the entire cohort and in tumours of the right colon, but not in the left colon or rectum, and only in univariable analysis. In conclusion, these results demonstrate that immune cell-specific PD-L1 and PD-1 expression is prognostic in a site-dependent manner, whereas tumour-specific PD-L1-expression is not prognostic in CRC.

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Panitumumab vs Bevacizumab Added to Standard First-line Chemotherapy and Overall Survival Among Patients With RAS Wild-type, Left-Sided Metastatic Colorectal Cancer

Watanabe

Muro

Shitara

et al. 2023

JAMA

102

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ImportanceFor patients with RAS wild-type metastatic colorectal cancer, adding anti–epidermal growth factor receptor (anti-EGFR) or anti–vascular endothelial growth factor (anti-VEGF) monoclonal antibodies to first-line doublet chemotherapy is routine, but the optimal targeted therapy has not been defined.ObjectiveTo evaluate the effect of adding panitumumab (an anti-EGFR monoclonal antibody) vs bevacizumab (an anti-VEGF monoclonal antibody) to standard first-line chemotherapy for treatment of RAS wild-type, left-sided, metastatic colorectal cancer.Design, Setting, and ParticipantsRandomized, open-label, phase 3 clinical trial at 197 sites in Japan in May 2015–January 2022 among 823 patients with chemotherapy-naive RAS wild-type, unresectable metastatic colorectal cancer (final follow-up, January 14, 2022).InterventionsPanitumumab (n = 411) or bevacizumab (n = 412) plus modified fluorouracil, l-leucovorin, and oxaliplatin (mFOLFOX6) every 14 days.Main Outcomes and MeasuresThe primary end point, overall survival, was tested first in participants with left-sided tumors, then in the overall population. Secondary end points were progression-free survival, response rate, duration of response, and curative (defined as R0 status) resection rate.ResultsIn the as-treated population (n = 802; median age, 66 years; 282 [35.2%] women), 604 (75.3%) had left-sided tumors. Median follow-up was 61 months. Median overall survival was 37.9 months with panitumumab vs 34.3 months with bevacizumab in participants with left-sided tumors (hazard ratio [HR] for death, 0.82; 95.798% CI, 0.68-0.99; P = .03) and 36.2 vs 31.3 months, respectively, in the overall population (HR, 0.84; 95% CI, 0.72-0.98; P = .03). Median progression-free survival for panitumumab vs bevacizumab was 13.1 vs 11.9 months, respectively, for those with left-sided tumors (HR, 1.00; 95% CI, 0.83-1.20) and 12.2 vs 11.4 months overall (HR, 1.05; 95% CI, 0.90-1.24). Response rates with panitumumab vs bevacizumab were 80.2% vs 68.6%, respectively, for left-sided tumors (difference, 11.2%; 95% CI, 4.4%-17.9%) and 74.9% vs 67.3% overall (difference, 7.7%; 95% CI, 1.5%-13.8%). Median duration of response with panitumumab vs bevacizumab was 13.1 vs 11.2 months for left-sided tumors (HR, 0.86; 95% CI, 0.70-1.10) and 11.9 vs 10.7 months overall (HR, 0.89; 95% CI, 0.74-1.06). Curative resection rates with panitumumab vs bevacizumab were 18.3% vs 11.6% for left-sided tumors; (difference, 6.6%; 95% CI, 1.0%-12.3%) and 16.5% vs 10.9% overall (difference, 5.6%; 95% CI, 1.0%-10.3%). Common treatment-emergent adverse events were acneiform rash (panitumumab: 74.8%; bevacizumab: 3.2%), peripheral sensory neuropathy (panitumumab: 70.8%; bevacizumab: 73.7%), and stomatitis (panitumumab: 61.6%; bevacizumab: 40.5%).Conclusions and RelevanceAmong patients with RAS wild-type metastatic colorectal cancer, adding panitumumab, compared with bevacizumab, to standard first-line chemotherapy significantly improved overall survival in those with left-sided tumors and in the overall population.Trial RegistrationClinicalTrials.gov Identifier: NCT02394795

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Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials

Cited by 714 publications

References 50 publications

The Predictive Effect of Primary Tumour Location in the Treatment of Metastatic Colorectal Cancer: A Canadian Consensus Statement

The Predictive Effect of Primary Tumour Location in the Treatment of Metastatic Colorectal Cancer: A Canadian Consensus Statement

Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer: Relationship with sidedness and prognosis

Panitumumab vs Bevacizumab Added to Standard First-line Chemotherapy and Overall Survival Among Patients With RAS Wild-type, Left-Sided Metastatic Colorectal Cancer

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