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      Exploratory analyses assessing the impact of early tumour shrinkage and depth of response on survival outcomes in patients with RAS wild-type metastatic colorectal cancer receiving treatment in three randomised panitumumab trials

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          Abstract

          Purpose

          To report exploratory analyses of early tumour shrinkage (ETS) and depth of response (DpR) in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC), receiving the first-line treatment in three randomised panitumumab trials.

          Methods

          Data from the PRIME (NCT00364013), PEAK (NCT00819780) and PLANET (NCT00885885) studies were included. Median DpR, the proportion of patients achieving ETS ≥ 20% or ≥ 30% at week 8, and the impact of ETS and DpR (including by category) on outcome were analysed. Factors associated with ETS and DpR and the optimal ETS/DpR cut-off values for predicting improved overall survival (OS) were assessed.

          Results

          Overall, 505, 170 and 53 patients had RAS WT mCRC in PRIME, PEAK and PLANET, respectively. Patients receiving panitumumab had higher ETS rates (≥ 30%: PRIME 59% vs. 38%; PEAK 64% vs. 45%) and greater DpR (PRIME: 54% vs. 46%; PEAK: 65% vs. 46%) than those receiving treatment without panitumumab. In multiple regression analyses, panitumumab treatment, liver-only metastases and WT BRAF status were consistently associated with improved ETS and DpR outcomes. Irrespective of treatment, ETS and DpR were associated with improved progression-free survival, overall survival and resection rates; most resections occurred in patients in the two highest DpR categories. In PRIME and PEAK, respectively, the optimal cut-offs for predicting improved OS were 32 and 34% for ETS, and 59 and 70% for DpR.

          Conclusions

          These exploratory analyses suggest that panitumumab is associated ETS and DpR benefits in patients with RAS WT mCRC and that achieving these endpoints during first-line treatment is linked with favourable outcomes.

          Electronic supplementary material

          The online version of this article (doi:10.1007/s00432-017-2534-z) contains supplementary material, which is available to authorized users.

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          Most cited references23

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          Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study.

          Panitumumab, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS), is approved as monotherapy for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). The Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) was designed to evaluate the efficacy and safety of panitumumab plus infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as initial treatment for mCRC. In this multicenter, phase III trial, patients with no prior chemotherapy for mCRC, Eastern Cooperative Oncology Group performance status of 0 to 2, and available tissue for biomarker testing were randomly assigned 1:1 to receive panitumumab-FOLFOX4 versus FOLFOX4. The primary end point was PFS; overall survival (OS) was a secondary end point. Results were prospectively analyzed on an intent-to-treat basis by tumor KRAS status. KRAS results were available for 93% of the 1,183 patients randomly assigned. In the wild-type (WT) KRAS stratum, panitumumab-FOLFOX4 significantly improved PFS compared with FOLFOX4 (median PFS, 9.6 v 8.0 months, respectively; hazard ratio [HR], 0.80; 95% CI, 0.66 to 0.97; P = .02). A nonsignificant increase in OS was also observed for panitumumab-FOLFOX4 versus FOLFOX4 (median OS, 23.9 v 19.7 months, respectively; HR, 0.83; 95% CI, 0.67 to 1.02; P = .072). In the mutant KRAS stratum, PFS was significantly reduced in the panitumumab-FOLFOX4 arm versus the FOLFOX4 arm (HR, 1.29; 95% CI, 1.04 to 1.62; P = .02), and median OS was 15.5 months versus 19.3 months, respectively (HR, 1.24; 95% CI, 0.98 to 1.57; P = .068). Adverse event rates were generally comparable across arms with the exception of toxicities known to be associated with anti-EGFR therapy. This study demonstrated that panitumumab-FOLFOX4 was well tolerated and significantly improved PFS in patients with WT KRAS tumors and underscores the importance of KRAS testing for patients with mCRC.
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            PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer.

            To evaluate panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated wild-type (WT) KRAS exon 2 (codons 12 and 13) metastatic colorectal cancer (mCRC). A prespecified secondary objective was to assess treatment effects in an extended RAS analysis that included exons 2, 3, and 4 of KRAS and NRAS.
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              An application of changepoint methods in studying the effect of age on survival in breast cancer

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                Author and article information

                Contributors
                +33 1 5609351 , julien.taieb@egp.aphp.fr , jtaieb75@gmail.com
                Journal
                J Cancer Res Clin Oncol
                J. Cancer Res. Clin. Oncol
                Journal of Cancer Research and Clinical Oncology
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0171-5216
                1432-1335
                28 October 2017
                28 October 2017
                2018
                : 144
                : 2
                : 321-335
                Affiliations
                [1 ]GRID grid.414093.b, Department of Hepatogastroenterology and GI Oncology, , Georges Pompidou European Hospital and Sorbonne Paris Cité / Université Paris Descartes, ; 20 rue Leblanc, 75015 Paris, France
                [2 ]ISNI 0000 0001 0627 4262, GRID grid.411325.0, Hospital Universitario Marqués de Valdecilla, ; Santander, Spain
                [3 ]ISNI 0000 0004 1757 2822, GRID grid.4708.b, Grande Ospedale Metropolitano Niguarda and Dipartimento di Oncologia e Emato-Oncologia, Niguarda Cancer Center, , Università degli Studi di Milano, ; Milan, Italy
                [4 ]ISNI 0000 0000 8788 1541, GRID grid.419595.5, Städtisches Klinikum München, ; Klinikum Neuperlach, Munich, Germany
                [5 ]ISNI 0000 0000 9542 1158, GRID grid.411109.c, Virgen del Rocio Hospital, ; Seville, Spain
                [6 ]ISNI 0000 0004 0399 7977, GRID grid.411093.e, Hospital General Universitario de Elche, ; Elche, Spain
                [7 ]Klinikum Esslingen, Esslingen, Germany
                [8 ]GRID grid.476413.3, Biostatistics, , Amgen Ltd, ; Uxbridge, UK
                [9 ]ISNI 0000 0004 0476 2707, GRID grid.476152.3, Amgen (Europe) GmbH, Medical Development, ; Zug, Switzerland
                [10 ]ISNI 0000 0004 0626 3418, GRID grid.411414.5, Antwerp University Hospital, ; Antwerp, Belgium
                Author information
                http://orcid.org/0000-0002-9955-4753
                Article
                2534
                10.1007/s00432-017-2534-z
                5794806
                29080924
                d08bc651-fcb2-4be2-ac90-016168f4edc9
                © The Author(s) 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 29 August 2017
                : 13 October 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100002429, Amgen;
                Categories
                Original Article – Clinical Oncology
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2018

                Oncology & Radiotherapy
                depth of response,early tumour shrinkage,metastatic colorectal cancer,panitumumab,survival

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