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Sebastian Stintzing - One of the best experts on this subject based on the ideXlab platform.

  • relation of cetuximab induced skin toxicity and early tumor shrinkage in metastatic colorectal cancer patients results of the randomized phase 3 trial fire 3 aio krk0306
    Annals of Oncology, 2020
    Co-Authors: Julian Walter Holch, Swantje Held, Sebastian Stintzing, Fischer L Von Weikersthal, T Decker, Alexander Kiani, Florian Kaiser, Tobias Heintges, Christoph Kahl, Frank Kullmann
    Abstract:

    Background Cetuximab-induced skin toxicity (Cet-ST) is positively associated with outcome in metastatic colorectal cancer (mCRC). Besides its predictive relevance for targeted therapy, we investigated its prognostic impact with early tumor shrinkage (ETS) ≥20%, another on-treatment surrogate for clinical outcome in FIRE-3. Patients and methods FIRE-3 evaluated first-line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab (FOLFIRI/Cet) versus FOLFIRI plus bevacizumab (FOLFIRI/Bev) in mCRC patients with RAS-WT tumors (i.e. wild-type in KRAS and NRAS exons 2–4). Retrospective data on Cet-ST that occurred during cycles 1–3 of treatment were correlated with efficacy endpoints, including ETS. To control for guarantee-time bias, only patients who had completed three or more treatment cycles were considered. Results Of 199 patients treated with FOLFIRI/Cet, 181 (91.0%) completed three or more treatment cycles. A significant survival benefit of FOLFIRI/Cet over FOLFIRI/Bev was only evident in patients developing Cet-ST grade 2–3 [41.0 versus 26.6 months; hazard ratio (HR) = 0.73; 95% confidence interval (CI): 0.61–0.87; P Conclusions In FIRE-3, the addition of cetuximab to FOLFIRI was associated with superior OS compared with FOLFIRI/Bev only in patients developing Cet-ST grade ≥2. Regarding prognostic relevance, both Cet-ST and ETS were independent and early predictors of survival. The present analysis supports that a combined evaluation of on-treatment parameters such as Cet-ST and ETS may help to guide treatment of mCRC.

  • relevance of liver limited disease in metastatic colorectal cancer subgroup findings of the fire 3 aio krk0306 trial
    International Journal of Cancer, 2018
    Co-Authors: Julian Walter Holch, Sebastian Stintzing, Alexander Kiani, Tobias Heintges, Salaheddin Albatran, Thomas Decker, Ursula Vehlingkaiser, Ludwig Fischer Von Weikersthal, Ingrid Ricard, Christian Lerchenmuller
    Abstract:

    In metastatic colorectal cancer (mCRC), liver-limited disease (LLD) is associated with a higher chance of metastectomy leading to long-term survival. However, limited data describes the prognostic and predictive relevance of initially unresectable LLD with regard to targeted first-line therapy. The present analysis investigated the relevance of initially unresectable LLD in mCRC patients treated with targeted therapy against either the epidermal growth factor receptor (EGFR) or vascular epithelial growth factor (VEGF). The analysis was performed based on FIRE-3, a randomized phase III trial comparing first-line chemotherapy with FOLFIRI plus either cetuximab (anti-EGFR) or bevacizumab (anti-VEGF) in RAS wild-type (WT) mCRC. Of 400 patients, 133 (33.3%) had LLD and 267 (66.8%) had non-LLD. Median overall survival (OS) was significantly longer in LLD compared to non-LLD patients (36.0 vs. 25.4 months; hazard ratio [HR] = 0.66; 95% confidence interval [CI]: 0.51-0.87; p = 0.002). In a multivariate analysis also including secondary hepatic resection as time-dependent variable, LLD status was independently prognostic for OS (HR = 0.67; 95% CI: 0.50-0.91; p = 0.01). As assessed by interaction tests, treatment benefit from FOLFIRI plus cetuximab compared to FOLFIRI plus bevacizumab was independent of LLD status with regard to objective response rate (ORR), early tumour shrinkage ≥20% (ETS), depth of response (DpR) and OS (all p > 0.05). In conclusion, LLD could be identified as a prognostic factor in RAS-WT mCRC, which was independent of hepatic resection in patients treated with targeted therapy. LLD had no predictive relevance since benefit from FOLFIRI plus cetuximab over bevacizumab was independent of LLD status.

  • impact of genetic variations in the mapk signaling pathway on outcome in metastatic colorectal cancer patients treated with first line FOLFIRI and bevacizumab data from fire 3 and tribe trials
    Annals of Oncology, 2017
    Co-Authors: Martin D Berger, Sebastian Stintzing, Volker Heinemann, D Yang, Shu Cao, Yu Sunakawa, Yan Ning, Satoshi Matsusaka, Satoshi Okazaki, Yuji Miyamoto
    Abstract:

    Background The MAPK-interacting kinase 1 (MKNK1) is localized downstream of the RAS/RAF/ERK and the MAP3K1/MKK/p38 signaling pathway. Through phosphorylation MKNK1 regulates the function of eukaryotic translation initiation factor 4E, a key player in translational control, whose expression is often upregulated in metastatic colorectal cancer patients (mCRC). Preclinical data suggest that MKNK1 increases angiogenesis by upregulating angiogenic factors. We therefore hypothesize that variations in the MKNK1 gene predict outcome in mCRC patients treated with first-line FOLFIRI and bevacizumab (bev). Patients and methods A total of 567 patients with KRAS wild-type mCRC in the randomized phase III FIRE-3 and TRIBE trials treated with first-line FOLFIRI/bev (discovery and validation cohorts) or FOLFIRI and cetuximab (cet) (control cohort) were included in this study. Five single-nucleotide polymorphisms in the MAPK signaling pathway were analyzed. Results AA genotype carriers of the MKNK1 rs8602 single-nucleotide polymorphism treated with FOLFIRI/bev in the discovery cohort (FIRE-3) had a shorter progression-free survival (PFS) than those harboring any C (7.9 versus 10.3 months, Hazard ratio (HR) 1.73, P = 0.038). This association could be confirmed in the validation cohort (TRIBE) in multivariable analysis (PFS 9.0 versus 11.0 months, HR 3.04, P = 0.029). Furthermore, AA carriers in the validation cohort had a decreased overall response rate (25% versus 66%, P = 0.049). Conversely, AA genotype carriers in the control group receiving FOLFIRI/cet did not show a shorter PFS. By combining both FOLFIRI/bev cohorts the worse outcome among AA carriers became more significant (PFS 9.0 versus 10.5 months) in univariable (HR 1.74, P = 0.015) and multivariable analysis (HR 1.76, P = 0.022). Accordingly, AA carriers did also exhibit an inferior overall response rate compared with those harboring any C (36% versus 65%, P = 0.005). Conclusion MKNK1 polymorphism rs8602 might serve as a predictive marker in KRAS wild-type mCRC patients treated with FOLFIRI/bev in the first-line setting. Additionally, MKNK1 might be a promising target for drug development.

  • prognostic and predictive relevance of primary tumor location in patients with ras wild type metastatic colorectal cancer retrospective analyses of the crystal and fire 3 trials
    JAMA Oncology, 2017
    Co-Authors: Sabine Tejpar, Eric Van Cutsem, Josep Tabernero, Sebastian Stintzing, Fortunato Ciardiello, Frank Beier, Regina Esser, Heinzjosef Lenz, Volker Heinemann
    Abstract:

    Importance Metastatic colorectal cancer (mCRC) is heterogeneous, and primary tumors arising from different regions of the colon are clinically and molecularly distinct. Objective To examine the prognostic and predictive value of primary tumor location in patients withRAS wild-type (wt) mCRC treated with first-line fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus cetuximab in the Cetuximab Combined With Irinotecan in First-line Therapy for Metastatic Colorectal Cancer (CRYSTAL) trial and FOLFIRI Plus Cetuximab Versus FOLFIRI Plus Bevacizumab as First-Line Treatment For Patients With Metastatic Colorectal Cancer (FIRE-3) trial. Design, Setting, and Participants In this retrospective analysis patients withRASwt metastatic colorectal cancer from the CRYSTAL and FIRE-3 trials were classified as having left-sided or right-sided mCRC, defined, respectively, as patients whose tumors originated in the splenic flexure, descending colon, sigmoid colon, or rectum vs appendix, cecum, ascending colon, hepatic flexure, or transverse colon. Main Outcomes and Measures Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were assessed according to tumor location and treatment arm. Results In theRASwt populations of the CRYSTAL and FIRE-3 trials, patients with left-sided tumors (n = 142 and n = 157, respectively) had markedly superior PFS, OS, and ORR compared with patients with right-sided tumors (n = 33 and n = 38, respectively). Among CRYSTAL and FIRE-3 study patients withRASwt left-sided tumors, FOLFIRI plus cetuximab significantly improved OS relative to the respective comparators (FOLFIRI and FOLFIRI plus bevacizumab); in contrast, inRASwt patients with poor-prognosis right-sided tumors, limited efficacy benefits were observed upon the addition of cetuximab to FOLFIRI in CRYSTAL, and comparable outcomes were observed between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab arms of FIRE-3. A significant interaction was observed between primary tumor location and treatment for OS (CRYSTAL: hazard ratio [HR], 1.95; 95% CI, 1.09-3.48 and FIRE-3: HR, 0.40; 95% CI, 0.23-0.70) within theRASwt populations of both studies in multivariable models that also included sex, prior adjuvant therapy, andBRAFmutational status. Conclusions and Relevance In theRAS wt populations of CRYSTAL and FIRE-3, patients with left-sided tumors had a markedly better prognosis than those with right-sided tumors. First-line FOLFIRI plus cetuximab clearly benefitted patients with left-sided tumors (vs FOLFIRI or FOLFIRI plus bevacizumab, respectively), whereas patients with right-sided tumors derived limited benefit from standard treatments. Trial Registration clinicaltrials.gov Identifiers: CRYSTAL,NCT00154102, and FIRE-3,NCT00433927

  • FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer fire 3 a post hoc analysis of tumour dynamics in the final ras wild type subgroup of this randomised open label phase 3 trial
    Lancet Oncology, 2016
    Co-Authors: Sebastian Stintzing, Alexander Kiani, Salaheddin Albatran, Lisa Rossius, Dominik Paul Modest, Ludwig Fischer Von Weikersthal, Thomas Decker, Ursula Vehlingkaiser, Markus M Lerch, Tobias Heintges
    Abstract:

    Summary Background FIRE-3 compared first-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus cetuximab with FOLFIRI plus bevacizumab in patients with KRAS exon 2 wild-type metastatic colorectal cancer. The same study also reported an exploratory analysis of a subgroup of patients with tumours that were wild-type at other RAS genes ( KRAS and NRAS exons 2–4). We report here efficacy results for the FIRE-3 final RAS ( KRAS/NRAS , exons 2–4) wild-type subgroup. Moreover, new metrics of tumour dynamics were explored during a centralised radiological review to investigate how FOLFIRI plus cetuximab conferred overall survival benefit in the absence of differences in investigator-assessed objective responses and progression-free survival. Methods FIRE-3 was a randomised phase 3 trial comparing FOLFIRI plus cetuximab with FOLFIRI plus bevacizumab in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer. The primary endpoint of the FIRE-3 study was the proportion of patients achieving an objective response according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.0 in the intention-to-treat population. A centralised radiological review of CT scans was done in a post-hoc analysis to assess objective response according to RECIST 1.1, early tumour shrinkage, depth of response, duration of response, and time to response in the final RAS wild-type subgroup. Comparisons between treatment groups with respect to objective response rate and early tumour shrinkage were made using Fisher's exact test (two-sided), while differences in depth of response were investigated with a two-sided Wilcoxon test. This trial is registered at ClinicalTrials.gov, number NCT00433927. Findings In the final RAS wild-type population (n=400), median overall survival was better in the FOLFIRI plus cetuximab group than the FOLFIRI plus bevacizumab group (33·1 months [95% CI 24·5–39·4] vs 25·0 months [23·0–28·1]; hazard ratio 0·70 [0·54–0·90]; p=0·0059), although investigator-assessed objective response and progression-free survival were comparable between treatment groups. Centralised radiological review of CT-assessable patients (n=330) showed that the proportion of patients achieving an objective response (113 of 157, 72·0% [95% CI 64·3–78·8] vs 97 of 173, 56·1% [48·3–63·6]; p=0·0029), frequency of early tumour shrinkage (107 of 157, 68·2% [60·3–75·4] vs 85 of 173, 49·1% [41·5–56·8]; p=0·0005), and median depth of response (–48·9% [–54·3 to −42·0] vs −32·3% [–38·2 to −29·2]; p RAS wild-type patients receiving FOLFIRI plus cetuximab versus those receiving FOLFIRI plus bevacizumab. No differences in duration of response and time to response were observed between treatment groups. Interpretation This analysis provides a new framework that connects alternative metrics of response to overall survival. Superior response-related outcome parameters, such as early tumour shrinkage and depth of response, obtained by centralised radiological review correlated with the overall survival benefit conferred by FOLFIRI plus cetuximab compared with FOLFIRI plus bevacizumab in the extended RAS wild-type subgroup. Funding Merck KGaA and Pfizer.

Claus Henning Kohne - One of the best experts on this subject based on the ideXlab platform.

  • FOLFIRI plus cetuximab in patients with liver limited or non liver limited ras wild type metastatic colorectal cancer a retrospective subgroup analysis of the crystal study
    Ejso, 2016
    Co-Authors: Claus Henning Kohne, Gunnar Folprecht, Fortunato Ciardiello, Frank Beier, G Poston, P Ronga, E Van Cutsem
    Abstract:

    Abstract Background Adding cetuximab to first-line FOLFIRI in the phase 3 CRYSTAL trial significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) in patients with KRAS wild-type (wt) or RAS wt metastatic colorectal cancer (mCRC). In this retrospective subgroup analysis of CRYSTAL, we investigated benefit of treatment in patients with KRAS wt or RAS wt tumors according to whether patients had liver-limited disease (LLD) or non-LLD, including assessing the role of cetuximab in downsizing metastases and conversion rates from initially unresectable to resectable disease. Methods PFS, OS, ORR, and R0 resection rates were analyzed according to treatment arm for the LLD and non-LLD subgroups. Results Of the 367 patients with RAS wt tumors, 89 (24%) had LLD and 278 (76%) had non-LLD. Within the RAS wt LLD and non-LLD subpopulations, demographic and baseline characteristics were comparable between treatment arms. In patients with RAS wt LLD, adding cetuximab to FOLFIRI significantly improved PFS (hazard ratio [HR][95% CI] = 0.21[0.09–0.49]) and ORR (odds ratio [OR][95% CI] = 8.99[3.17–25.52]), and numerically improved OS (HR[95% CI] = 0.65[0.38–1.10]) and R0 resection rate (OR[95% CI] = 2.68[0.63–11.43]) relative to FOLFIRI alone. In patients with RAS wt non-LLD, adding cetuximab to FOLFIRI significantly improved PFS (HR[95% CI] = 0.65[0.46–0.93]), OS (HR[95% CI] = 0.71[0.54–0.93]), ORR (OR[95% CI] = 2.44[1.49–3.98]), and—numerically—R0 resection rate (OR[95% CI] = 5.94[0.79–44.88]). Similar results were obtained from the KRAS wt population. Conclusions Adding cetuximab to first-line FOLFIRI appears to improve clinical outcomes and R0 resection rates in KRAS wt and RAS wt mCRC patients with LLD as well as in those with non-LLD.

  • effect of kras and nras mutational status on first line treatment with FOLFIRI plus cetuximab in patients with metastatic colorectal cancer mcrc new results from the crystal trial
    Journal of Clinical Oncology, 2014
    Co-Authors: Fortunato Ciardiello, Claus Henning Kohne, Sabine Tejpar, Frank Beier, Regina Esser, Heinzjosef Lenz, Volker Heinemann, Christopher Stroh, Klaus Duecker, Eric Van Cutsem
    Abstract:

    LBA443 Background: The phase III CRYSTAL study showed patients with unresectable KRAS exon 2, codon 12 and 13, wild-type (wt) mCRC (n = 666) to benefit from the addition of cetuximab to FOLFIRI first-line. Progression-free survival (PFS), overall survival (OS) times and response rate (RR) were significantly better in patients who received FOLFIRI plus cetuximab, compared with FOLFIRI alone. Recent retrospective analyses of studies involving EGFR-targeted monoclonal antibody therapy have suggested that patients with KRAS and NRAS mutations in other codons were unlikely to benefit from the addition of an EGFR-targeted agent. Thus, the impact of these additional KRAS and NRAS mutations on the efficacy and safety of FOLFIRI plus cetuximab treatment is under investigation in patients from the CRYSTAL study. Methods: KRAS (eight mutations on exons 3 [codons 59 and 61] and 4 [codons 117 and 146]) and NRAS (18 mutations on exons 2 [codons 12 and 13], 3 [codons 59 and 61] and 4 [codons 117 and 146]) mutation detec...

  • first line panitumumab plus irinotecan 5 fluorouracil leucovorin treatment in patients with metastatic colorectal cancer
    Journal of Cancer Research and Clinical Oncology, 2012
    Co-Authors: Claus Henning Kohne, Ralf Hofheinz, Laurent Mineur, H Letocha, Richard Greil, Josef Thaler, Eva Fernebro, Erick Gamelin, Lucy Decosta, Meinolf Karthaus
    Abstract:

    Purpose Panitumumab monotherapy is approved for KRAS wild-type (WT) metastatic colorectal cancer (mCRC) progressing after standard chemotherapy. This study evaluated first-line panitumumab plus FOLFIRI in patients with mCRC.

  • cetuximab plus irinotecan fluorouracil and leucovorin as first line treatment for metastatic colorectal cancer updated analysis of overall survival according to tumor kras and braf mutation status
    Journal of Clinical Oncology, 2011
    Co-Authors: Eric Van Cutsem, Claus Henning Kohne, Gunnar Folprecht, Joan Maurel, Istvan Lang, M Nowacki, Stefano Cascinu, I Shchepotin, David Cunningham, Sabine Tejpar
    Abstract:

    Purpose The addition of cetuximab to irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer (mCRC) was shown to reduce the risk of disease progression and increase the chance of response in patients with KRAS wild-type disease. An updated survival analysis, including additional patients analyzed for tumor mutation status, was undertaken. Patients and Methods Patients were randomly assigned to receive FOLFIRI with or without cetuximab. DNA was extracted from additional slide-mounted tumor samples previously used to assess epidermal growth factor receptor expression. Clinical outcome according to the tumor mutation status of KRAS and BRAF was assessed in the expanded patient series. Results The ascertainment rate of patients analyzed for tumor KRAS status was increased from 45% to 89%, with mutations detected in 37% of tumors. The addition of cetuximab to FOLFIRI in patients with KRAS wild-type disease resulted in significant improvements in overall survival (median, 23.5 v 20.0 months; hazard ratio [HR], 0.796; P .0093), progression-free survival (median, 9.9 v 8.4 months; HR, 0.696; P .0012), and response (rate 57.3% v 39.7%; odds ratio, 2.069; P .001) compared with FOLFIRI alone. Significant interactions between KRAS status and treatment effect were noted for all key efficacy end points. KRAS mutation status was confirmed as a powerful predictive biomarker for the efficacy of cetuximab plus FOLFIRI. BRAF tumor mutation was a strong indicator of poor prognosis. Conclusion The addition of cetuximab to FOLFIRI as first-line therapy improves survival in patients with KRAS wild-type mCRC. BRAF tumor mutation is an indicator of poor prognosis.

  • cetuximab plus FOLFIRI final data from the crystal study on the association of kras and braf biomarker status with treatment outcome
    Journal of Clinical Oncology, 2010
    Co-Authors: E Van Cutsem, Carlo Barone, Istvan Lang, M Nowacki, I Shchepotin, David Cunningham, G Folprecht, J Maurel, Ilhan Celik, Claus Henning Kohne
    Abstract:

    3570 Background: The phase III CRYSTAL study showed that patients (pts) with KRAS wild-type (wt) tumors benefit from the addition of cetuximab to FOLFIRI as first-line treatment for metastatic colorectal cancer (mCRC). BRAF is a downstream effector of KRAS. Methods: Tumor KRAS and BRAF mutation status (wt or mutant [mt]) was determined for an expanded patient population using polymerase chain reaction and melting curve assays. Treatment arms were compared according to mutation status (log rank and Cochran-Mantel-Haenszel tests). Results: Of 1,198 pts in the primary analysis population, 1,063 (89%) were evaluable for KRAS mutation status; double the previous ascertainment rate. In pts with KRAS wt tumors, all efficacy endpoints were significantly improved in pts receiving cetuximab + FOLFIRI compared with FOLFIRI alone. Tumor BRAF status was evaluable in 625/666 pts with KRAS wt tumors. BRAF mutation was a marker of poor prognosis in both treatment arms (see Table). Conclusions: For all efficacy endpoints,...

Tobias Heintges - One of the best experts on this subject based on the ideXlab platform.

  • relation of cetuximab induced skin toxicity and early tumor shrinkage in metastatic colorectal cancer patients results of the randomized phase 3 trial fire 3 aio krk0306
    Annals of Oncology, 2020
    Co-Authors: Julian Walter Holch, Swantje Held, Sebastian Stintzing, Fischer L Von Weikersthal, T Decker, Alexander Kiani, Florian Kaiser, Tobias Heintges, Christoph Kahl, Frank Kullmann
    Abstract:

    Background Cetuximab-induced skin toxicity (Cet-ST) is positively associated with outcome in metastatic colorectal cancer (mCRC). Besides its predictive relevance for targeted therapy, we investigated its prognostic impact with early tumor shrinkage (ETS) ≥20%, another on-treatment surrogate for clinical outcome in FIRE-3. Patients and methods FIRE-3 evaluated first-line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab (FOLFIRI/Cet) versus FOLFIRI plus bevacizumab (FOLFIRI/Bev) in mCRC patients with RAS-WT tumors (i.e. wild-type in KRAS and NRAS exons 2–4). Retrospective data on Cet-ST that occurred during cycles 1–3 of treatment were correlated with efficacy endpoints, including ETS. To control for guarantee-time bias, only patients who had completed three or more treatment cycles were considered. Results Of 199 patients treated with FOLFIRI/Cet, 181 (91.0%) completed three or more treatment cycles. A significant survival benefit of FOLFIRI/Cet over FOLFIRI/Bev was only evident in patients developing Cet-ST grade 2–3 [41.0 versus 26.6 months; hazard ratio (HR) = 0.73; 95% confidence interval (CI): 0.61–0.87; P Conclusions In FIRE-3, the addition of cetuximab to FOLFIRI was associated with superior OS compared with FOLFIRI/Bev only in patients developing Cet-ST grade ≥2. Regarding prognostic relevance, both Cet-ST and ETS were independent and early predictors of survival. The present analysis supports that a combined evaluation of on-treatment parameters such as Cet-ST and ETS may help to guide treatment of mCRC.

  • relevance of liver limited disease in metastatic colorectal cancer subgroup findings of the fire 3 aio krk0306 trial
    International Journal of Cancer, 2018
    Co-Authors: Julian Walter Holch, Sebastian Stintzing, Alexander Kiani, Tobias Heintges, Salaheddin Albatran, Thomas Decker, Ursula Vehlingkaiser, Ludwig Fischer Von Weikersthal, Ingrid Ricard, Christian Lerchenmuller
    Abstract:

    In metastatic colorectal cancer (mCRC), liver-limited disease (LLD) is associated with a higher chance of metastectomy leading to long-term survival. However, limited data describes the prognostic and predictive relevance of initially unresectable LLD with regard to targeted first-line therapy. The present analysis investigated the relevance of initially unresectable LLD in mCRC patients treated with targeted therapy against either the epidermal growth factor receptor (EGFR) or vascular epithelial growth factor (VEGF). The analysis was performed based on FIRE-3, a randomized phase III trial comparing first-line chemotherapy with FOLFIRI plus either cetuximab (anti-EGFR) or bevacizumab (anti-VEGF) in RAS wild-type (WT) mCRC. Of 400 patients, 133 (33.3%) had LLD and 267 (66.8%) had non-LLD. Median overall survival (OS) was significantly longer in LLD compared to non-LLD patients (36.0 vs. 25.4 months; hazard ratio [HR] = 0.66; 95% confidence interval [CI]: 0.51-0.87; p = 0.002). In a multivariate analysis also including secondary hepatic resection as time-dependent variable, LLD status was independently prognostic for OS (HR = 0.67; 95% CI: 0.50-0.91; p = 0.01). As assessed by interaction tests, treatment benefit from FOLFIRI plus cetuximab compared to FOLFIRI plus bevacizumab was independent of LLD status with regard to objective response rate (ORR), early tumour shrinkage ≥20% (ETS), depth of response (DpR) and OS (all p > 0.05). In conclusion, LLD could be identified as a prognostic factor in RAS-WT mCRC, which was independent of hepatic resection in patients treated with targeted therapy. LLD had no predictive relevance since benefit from FOLFIRI plus cetuximab over bevacizumab was independent of LLD status.

  • FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer fire 3 a post hoc analysis of tumour dynamics in the final ras wild type subgroup of this randomised open label phase 3 trial
    Lancet Oncology, 2016
    Co-Authors: Sebastian Stintzing, Alexander Kiani, Salaheddin Albatran, Lisa Rossius, Dominik Paul Modest, Ludwig Fischer Von Weikersthal, Thomas Decker, Ursula Vehlingkaiser, Markus M Lerch, Tobias Heintges
    Abstract:

    Summary Background FIRE-3 compared first-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus cetuximab with FOLFIRI plus bevacizumab in patients with KRAS exon 2 wild-type metastatic colorectal cancer. The same study also reported an exploratory analysis of a subgroup of patients with tumours that were wild-type at other RAS genes ( KRAS and NRAS exons 2–4). We report here efficacy results for the FIRE-3 final RAS ( KRAS/NRAS , exons 2–4) wild-type subgroup. Moreover, new metrics of tumour dynamics were explored during a centralised radiological review to investigate how FOLFIRI plus cetuximab conferred overall survival benefit in the absence of differences in investigator-assessed objective responses and progression-free survival. Methods FIRE-3 was a randomised phase 3 trial comparing FOLFIRI plus cetuximab with FOLFIRI plus bevacizumab in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer. The primary endpoint of the FIRE-3 study was the proportion of patients achieving an objective response according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.0 in the intention-to-treat population. A centralised radiological review of CT scans was done in a post-hoc analysis to assess objective response according to RECIST 1.1, early tumour shrinkage, depth of response, duration of response, and time to response in the final RAS wild-type subgroup. Comparisons between treatment groups with respect to objective response rate and early tumour shrinkage were made using Fisher's exact test (two-sided), while differences in depth of response were investigated with a two-sided Wilcoxon test. This trial is registered at ClinicalTrials.gov, number NCT00433927. Findings In the final RAS wild-type population (n=400), median overall survival was better in the FOLFIRI plus cetuximab group than the FOLFIRI plus bevacizumab group (33·1 months [95% CI 24·5–39·4] vs 25·0 months [23·0–28·1]; hazard ratio 0·70 [0·54–0·90]; p=0·0059), although investigator-assessed objective response and progression-free survival were comparable between treatment groups. Centralised radiological review of CT-assessable patients (n=330) showed that the proportion of patients achieving an objective response (113 of 157, 72·0% [95% CI 64·3–78·8] vs 97 of 173, 56·1% [48·3–63·6]; p=0·0029), frequency of early tumour shrinkage (107 of 157, 68·2% [60·3–75·4] vs 85 of 173, 49·1% [41·5–56·8]; p=0·0005), and median depth of response (–48·9% [–54·3 to −42·0] vs −32·3% [–38·2 to −29·2]; p RAS wild-type patients receiving FOLFIRI plus cetuximab versus those receiving FOLFIRI plus bevacizumab. No differences in duration of response and time to response were observed between treatment groups. Interpretation This analysis provides a new framework that connects alternative metrics of response to overall survival. Superior response-related outcome parameters, such as early tumour shrinkage and depth of response, obtained by centralised radiological review correlated with the overall survival benefit conferred by FOLFIRI plus cetuximab compared with FOLFIRI plus bevacizumab in the extended RAS wild-type subgroup. Funding Merck KGaA and Pfizer.

  • cea response is associated with tumor response and survival in patients with kras exon 2 wild type and extended ras wild type metastatic colorectal cancer receiving first line FOLFIRI plus cetuximab or bevacizumab fire 3 trial
    Annals of Oncology, 2016
    Co-Authors: Marlies Michl, Sebastian Stintzing, Fischer L Von Weikersthal, T Decker, Alexander Kiani, Tobias Heintges, Ursula Vehlingkaiser, S E Albatran, Christian Lerchenmueller
    Abstract:

    Carcinoembryonic antigen (CEA) response may be a surrogate for response and long-term outcome in (K)RAS wild-type mCRC receiving first-line targeted therapy. FOLFIRI and cetuximab induced a greater CEA response than FOLFIRI and bevacizumab. CEA response correlated with longer survival. Hypothesizing that CEA reflects tumor burden, greater CEA response may indicate greater antitumor efficacy.To examine the relation of carcinoembryonic antigen (CEA) response with tumor response and survival in patients with (K)RAS wild-type metastatic colorectal cancer receiving first-line chemotherapy in the FIRE-3 trial comparing FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab. CEA response assessed as the percentage of CEA decrease from baseline to nadir was evaluated for its association with tumor response and survival. Receiver operating characteristic analysis revealed an optimal cut-off value of 75% using the maximum of sensitivity and specificity for CEA response to discriminate CEA responders from non-responders. In addition, the time to CEA nadir was calculated. Of 592 patients in the intent-to-treat population, 472 were eligible for analysis of CEA (cetuximab arm: 230 and bevacizumab arm: 242). Maximal relative CEA decrease (%) significantly (P = 0.003) differed between the cetuximab arm (median 83.0%;IQR 40.9%-94.7%) and the bevacizumab arm (median 72.3%;IQR 26.3%-91.0%). In a longitudinal analysis, the CEA decrease occurred faster in the cetuximab arm and was greater than in the bevacizumab arm at all evaluated time points until 56 weeks after treatment start. CEA nadir occurred after 3.3 months (cetuximab arm) and 3.5 months (bevacizumab arm), (P = 0.49). In the cetuximab arm, CEA responders showed a significantly longer progression-free survival [11.8 versus 7.4 months;hazard ratio (HR) 1.53;95% Cl, 1.15-2.04;P = 0.004] and longer overall survival (36.6 versus 21.3 months;HR 1.73;95% Cl, 1.24-2.43;P = 0.001) than CEA non-responders. Analysis of extended RAS wild-type patients revealed similar results. In the FIRE-3 trial, CEA decrease was significantly faster and greater in the cetuximab arm than in the bevacizumab arm and correlated with the prolonged survival observed in patients receiving FOLFIRI plus cetuximab. NCT00433927 (ClinicalTrials.gov);AIO KRK0306 FIRE-3.

  • FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first line treatment for patients with metastatic colorectal cancer fire 3 a randomised open label phase 3 trial
    Lancet Oncology, 2014
    Co-Authors: Volker Heinemann, Alexander Kiani, Tobias Heintges, Christoph Kahl, Salaheddin Albatran, Ludwig Fischer Von Weikersthal, Thomas Decker, Ursula Vehlingkaiser, Christian A Lerchenmuller, G Seipelt
    Abstract:

    Summary Background Cetuximab and bevacizumab have both been shown to improve outcomes in patients with metastatic colorectal cancer when added to chemotherapy regimens; however, their comparative effectiveness when partnered with first-line fluorouracil, folinic acid, and irinotecan (FOLFIRI) is unknown. We aimed to compare these agents in patients with KRAS (exon 2) codon 12/13 wild-type metastatic colorectal cancer. Methods In this open-label, randomised, phase 3 trial, we recruited patients aged 18–75 years with stage IV, histologically confirmed colorectal cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, an estimated life expectancy of greater than 3 months, and adequate organ function, from centres in Germany and Austria. Patients were centrally randomised by fax (1:1) to FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab (using permuted blocks of randomly varying size), stratified according to ECOG performance status, number of metastatic sites, white blood cell count, and alkaline phosphatase concentration. The primary endpoint was objective response analysed by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov, number NCT00433927. Findings Between Jan 23, 2007, and Sept 19, 2012, 592 patients with KRAS exon 2 wild-type tumours were randomly assigned and received treatment (297 in the FOLFIRI plus cetuximab group and 295 in the FOLFIRI plus bevacizumab group). 184 (62·0%, 95% CI 56·2–67·5) patients in the cetuximab group achieved an objective response compared with 171 (58·0%, 52·1–63·7) in the bevacizumab group (odds ratio 1·18, 95% CI 0·85–1·64; p=0·18). Median progression-free survival was 10·0 months (95% CI 8·8–10·8) in the cetuximab group and 10·3 months (9·8–11·3) in the bevacizumab group (hazard ratio [HR] 1·06, 95% CI 0·88–1·26; p=0·55); however, median overall survival was 28·7 months (95% CI 24·0–36·6) in the cetuximab group compared with 25·0 months (22·7–27·6) in the bevacizumab group (HR 0·77, 95% CI 0·62–0·96; p=0·017). Safety profiles were consistent with the known side-effects of the study drugs. The most common grade 3 or worse adverse events in both treatment groups were haematotoxicity (73 [25%] of 297 patients in the cetuximab group vs 62 [21%] of 295 patients in the bevacizumab group), skin reactions (77 [26%] vs six [2%]), and diarrhoea (34 [11%] vs 40 [14%]). Interpretation Although the proportion of patients who achieved an objective response did not significantly differ between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab groups, the association with longer overall survival suggests that FOLFIRI plus cetuximab could be the preferred first-line regimen for patients with KRAS exon 2 wild-type metastatic colorectal cancer. Funding Merck KGaA.

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  • impact of genetic variations in the mapk signaling pathway on outcome in metastatic colorectal cancer patients treated with first line FOLFIRI and bevacizumab data from fire 3 and tribe trials
    Annals of Oncology, 2017
    Co-Authors: Martin D Berger, Sebastian Stintzing, Volker Heinemann, D Yang, Shu Cao, Yu Sunakawa, Yan Ning, Satoshi Matsusaka, Satoshi Okazaki, Yuji Miyamoto
    Abstract:

    Background The MAPK-interacting kinase 1 (MKNK1) is localized downstream of the RAS/RAF/ERK and the MAP3K1/MKK/p38 signaling pathway. Through phosphorylation MKNK1 regulates the function of eukaryotic translation initiation factor 4E, a key player in translational control, whose expression is often upregulated in metastatic colorectal cancer patients (mCRC). Preclinical data suggest that MKNK1 increases angiogenesis by upregulating angiogenic factors. We therefore hypothesize that variations in the MKNK1 gene predict outcome in mCRC patients treated with first-line FOLFIRI and bevacizumab (bev). Patients and methods A total of 567 patients with KRAS wild-type mCRC in the randomized phase III FIRE-3 and TRIBE trials treated with first-line FOLFIRI/bev (discovery and validation cohorts) or FOLFIRI and cetuximab (cet) (control cohort) were included in this study. Five single-nucleotide polymorphisms in the MAPK signaling pathway were analyzed. Results AA genotype carriers of the MKNK1 rs8602 single-nucleotide polymorphism treated with FOLFIRI/bev in the discovery cohort (FIRE-3) had a shorter progression-free survival (PFS) than those harboring any C (7.9 versus 10.3 months, Hazard ratio (HR) 1.73, P = 0.038). This association could be confirmed in the validation cohort (TRIBE) in multivariable analysis (PFS 9.0 versus 11.0 months, HR 3.04, P = 0.029). Furthermore, AA carriers in the validation cohort had a decreased overall response rate (25% versus 66%, P = 0.049). Conversely, AA genotype carriers in the control group receiving FOLFIRI/cet did not show a shorter PFS. By combining both FOLFIRI/bev cohorts the worse outcome among AA carriers became more significant (PFS 9.0 versus 10.5 months) in univariable (HR 1.74, P = 0.015) and multivariable analysis (HR 1.76, P = 0.022). Accordingly, AA carriers did also exhibit an inferior overall response rate compared with those harboring any C (36% versus 65%, P = 0.005). Conclusion MKNK1 polymorphism rs8602 might serve as a predictive marker in KRAS wild-type mCRC patients treated with FOLFIRI/bev in the first-line setting. Additionally, MKNK1 might be a promising target for drug development.

  • prognostic and predictive relevance of primary tumor location in patients with ras wild type metastatic colorectal cancer retrospective analyses of the crystal and fire 3 trials
    JAMA Oncology, 2017
    Co-Authors: Sabine Tejpar, Eric Van Cutsem, Josep Tabernero, Sebastian Stintzing, Fortunato Ciardiello, Frank Beier, Regina Esser, Heinzjosef Lenz, Volker Heinemann
    Abstract:

    Importance Metastatic colorectal cancer (mCRC) is heterogeneous, and primary tumors arising from different regions of the colon are clinically and molecularly distinct. Objective To examine the prognostic and predictive value of primary tumor location in patients withRAS wild-type (wt) mCRC treated with first-line fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus cetuximab in the Cetuximab Combined With Irinotecan in First-line Therapy for Metastatic Colorectal Cancer (CRYSTAL) trial and FOLFIRI Plus Cetuximab Versus FOLFIRI Plus Bevacizumab as First-Line Treatment For Patients With Metastatic Colorectal Cancer (FIRE-3) trial. Design, Setting, and Participants In this retrospective analysis patients withRASwt metastatic colorectal cancer from the CRYSTAL and FIRE-3 trials were classified as having left-sided or right-sided mCRC, defined, respectively, as patients whose tumors originated in the splenic flexure, descending colon, sigmoid colon, or rectum vs appendix, cecum, ascending colon, hepatic flexure, or transverse colon. Main Outcomes and Measures Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were assessed according to tumor location and treatment arm. Results In theRASwt populations of the CRYSTAL and FIRE-3 trials, patients with left-sided tumors (n = 142 and n = 157, respectively) had markedly superior PFS, OS, and ORR compared with patients with right-sided tumors (n = 33 and n = 38, respectively). Among CRYSTAL and FIRE-3 study patients withRASwt left-sided tumors, FOLFIRI plus cetuximab significantly improved OS relative to the respective comparators (FOLFIRI and FOLFIRI plus bevacizumab); in contrast, inRASwt patients with poor-prognosis right-sided tumors, limited efficacy benefits were observed upon the addition of cetuximab to FOLFIRI in CRYSTAL, and comparable outcomes were observed between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab arms of FIRE-3. A significant interaction was observed between primary tumor location and treatment for OS (CRYSTAL: hazard ratio [HR], 1.95; 95% CI, 1.09-3.48 and FIRE-3: HR, 0.40; 95% CI, 0.23-0.70) within theRASwt populations of both studies in multivariable models that also included sex, prior adjuvant therapy, andBRAFmutational status. Conclusions and Relevance In theRAS wt populations of CRYSTAL and FIRE-3, patients with left-sided tumors had a markedly better prognosis than those with right-sided tumors. First-line FOLFIRI plus cetuximab clearly benefitted patients with left-sided tumors (vs FOLFIRI or FOLFIRI plus bevacizumab, respectively), whereas patients with right-sided tumors derived limited benefit from standard treatments. Trial Registration clinicaltrials.gov Identifiers: CRYSTAL,NCT00154102, and FIRE-3,NCT00433927

  • FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first line treatment for patients with metastatic colorectal cancer fire 3 a randomised open label phase 3 trial
    Lancet Oncology, 2014
    Co-Authors: Volker Heinemann, Alexander Kiani, Tobias Heintges, Christoph Kahl, Salaheddin Albatran, Ludwig Fischer Von Weikersthal, Thomas Decker, Ursula Vehlingkaiser, Christian A Lerchenmuller, G Seipelt
    Abstract:

    Summary Background Cetuximab and bevacizumab have both been shown to improve outcomes in patients with metastatic colorectal cancer when added to chemotherapy regimens; however, their comparative effectiveness when partnered with first-line fluorouracil, folinic acid, and irinotecan (FOLFIRI) is unknown. We aimed to compare these agents in patients with KRAS (exon 2) codon 12/13 wild-type metastatic colorectal cancer. Methods In this open-label, randomised, phase 3 trial, we recruited patients aged 18–75 years with stage IV, histologically confirmed colorectal cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, an estimated life expectancy of greater than 3 months, and adequate organ function, from centres in Germany and Austria. Patients were centrally randomised by fax (1:1) to FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab (using permuted blocks of randomly varying size), stratified according to ECOG performance status, number of metastatic sites, white blood cell count, and alkaline phosphatase concentration. The primary endpoint was objective response analysed by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov, number NCT00433927. Findings Between Jan 23, 2007, and Sept 19, 2012, 592 patients with KRAS exon 2 wild-type tumours were randomly assigned and received treatment (297 in the FOLFIRI plus cetuximab group and 295 in the FOLFIRI plus bevacizumab group). 184 (62·0%, 95% CI 56·2–67·5) patients in the cetuximab group achieved an objective response compared with 171 (58·0%, 52·1–63·7) in the bevacizumab group (odds ratio 1·18, 95% CI 0·85–1·64; p=0·18). Median progression-free survival was 10·0 months (95% CI 8·8–10·8) in the cetuximab group and 10·3 months (9·8–11·3) in the bevacizumab group (hazard ratio [HR] 1·06, 95% CI 0·88–1·26; p=0·55); however, median overall survival was 28·7 months (95% CI 24·0–36·6) in the cetuximab group compared with 25·0 months (22·7–27·6) in the bevacizumab group (HR 0·77, 95% CI 0·62–0·96; p=0·017). Safety profiles were consistent with the known side-effects of the study drugs. The most common grade 3 or worse adverse events in both treatment groups were haematotoxicity (73 [25%] of 297 patients in the cetuximab group vs 62 [21%] of 295 patients in the bevacizumab group), skin reactions (77 [26%] vs six [2%]), and diarrhoea (34 [11%] vs 40 [14%]). Interpretation Although the proportion of patients who achieved an objective response did not significantly differ between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab groups, the association with longer overall survival suggests that FOLFIRI plus cetuximab could be the preferred first-line regimen for patients with KRAS exon 2 wild-type metastatic colorectal cancer. Funding Merck KGaA.

  • 528paflibercept FOLFIRI for treatment of metastatic colorectal cancer after oxaliplatin failure 4th interim safety data from the global aflibercept safety and quality of life program asqop afeqt studies
    Annals of Oncology, 2014
    Co-Authors: L Frassineti, Volker Heinemann, Gerard Lledo, M Di Bartolomeo, Anne L Thomas, Julien Taieb, Yan Moore, Chiara Zilocchi, Sandrine Brette, A Sobrero
    Abstract:

    ABSTRACT Aim: In VELOUR, aflibercept (ziv-aflibercept in the US) + FOLFIRI demonstrated a statistically significant improvement in overall survival vs placebo + FOLFIRI in metastatic colorectal cancer (mCRC) patients (pts) previously treated with an oxaliplatin-containing regimen. Results supported initiation of the global Aflibercept Safety and Quality-of-Life (QoL) Program composed of 2 clinical studies (ASQoP; AFEQT) to capture utility values from QoL instruments and collect safety data from a population similar to that in VELOUR in a real-life setting. We report safety data from the 4th interim analysis of these ongoing studies. Methods: ASQoP and AFEQT are single-arm, open-label trials in mCRC pts previously treated with an oxaliplatin-containing regimen. Eligible pts received aflibercept 4 mg/kg every 2 weeks on day 1 of each cycle followed by FOLFIRI. FOLFIRI starting dose and subsequent additional dose modifications are at discretion of the treating physician. Results: At data cut-off for this interim analysis, the safety population (n = 688) was compared with VELOUR. In 44% of ASQoP vs 33.5% of VELOUR, pts were ≥65 years; 10.8% of ASQoP vs 5.4% of VELOUR were ≥75 years. ASQoP pts received a median of 6 treatment cycles while VELOUR pts received a median of 9. Grade (G) 3/4 adverse events (AEs) were experienced by 72.2% of ASQoP pts vs 83.5% in VELOUR. Most were G3. G4 hypertension or diarrhea was not reported. Table shows selected G3/4 AEs. ASQoP/AFEQT VELOUR Adverse Events, % Aflibercept + FOLFIRI (n = 688) Aflibercept + FOLFIRI (n = 611) Grade 3/4 (%) Grade 3/4 (%) Proteinuria 3.6 7.9 Stomatitis and ulceration (high level term) 9.6 13.8 Diarrhea (preferred term) 14.1 19.3 Infections and infestations (system organ class) 9.6 12.3 Hypertension 23.0 19.3 Arterial thromboembolic event 0.6 1.8 Venous thromboembolic event 4.4 7.9 Fistula (gastrointestinal [GI] origin) 0.6 0.3 GI perforation 1.3 0.5 Conclusions: Interim safety analysis from ASQoP/AFEQT has identified no new safety signals. Despite a greater % of elderly pts in ASQoP/AFEQT, reported incidence of toxicity is generally similar or less than VELOUR. Differences in AE incidence in ASQoP/AFEQT vs VELOUR may be related to the VELOUR protocol requirement of full-dose FOLFIRI initiation and current overall exposure differences. Disclosure: J. Taieb: has conflicts of interest related to advisory boards for Sanofi and for corporate-sponsored research for Sanofi; Y. Moore: formerly held a leadership position at Sanofi at the time this study was conducted and has stock ownership in Sanofi; C. Zilocchi: is an employee of Sanofi and has stock ownership; S. Brette: is an employee (biostatistician) of Lincoln, which is a consultant for Sanofi. A. Sobrero: has received honoraria for participating in advisory boards for Bayer, Roche, Sanofi, Celgene, Merck, and Amgen. All other authors have declared no conflicts of interest.

  • effect of kras and nras mutational status on first line treatment with FOLFIRI plus cetuximab in patients with metastatic colorectal cancer mcrc new results from the crystal trial
    Journal of Clinical Oncology, 2014
    Co-Authors: Fortunato Ciardiello, Claus Henning Kohne, Sabine Tejpar, Frank Beier, Regina Esser, Heinzjosef Lenz, Volker Heinemann, Christopher Stroh, Klaus Duecker, Eric Van Cutsem
    Abstract:

    LBA443 Background: The phase III CRYSTAL study showed patients with unresectable KRAS exon 2, codon 12 and 13, wild-type (wt) mCRC (n = 666) to benefit from the addition of cetuximab to FOLFIRI first-line. Progression-free survival (PFS), overall survival (OS) times and response rate (RR) were significantly better in patients who received FOLFIRI plus cetuximab, compared with FOLFIRI alone. Recent retrospective analyses of studies involving EGFR-targeted monoclonal antibody therapy have suggested that patients with KRAS and NRAS mutations in other codons were unlikely to benefit from the addition of an EGFR-targeted agent. Thus, the impact of these additional KRAS and NRAS mutations on the efficacy and safety of FOLFIRI plus cetuximab treatment is under investigation in patients from the CRYSTAL study. Methods: KRAS (eight mutations on exons 3 [codons 59 and 61] and 4 [codons 117 and 146]) and NRAS (18 mutations on exons 2 [codons 12 and 13], 3 [codons 59 and 61] and 4 [codons 117 and 146]) mutation detec...

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  • analysis of kras nras mutations in a phase iii study of panitumumab with FOLFIRI compared with FOLFIRI alone as second line treatment for metastatic colorectal cancer
    Clinical Cancer Research, 2015
    Co-Authors: Marc Peeters, Timothy J Price, Thierry Andre, Kelly S Oliner, Andres Cervantes, A Sobrero, Michel Ducreux, Yevhen Hotko, Emily Chan, Florian Lordick
    Abstract:

    Purpose: We evaluated the influence of RAS mutation status on the treatment effect of panitumumab in a prospective–retrospective analysis of a randomized, multicenter phase III study of panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) versus FOLFIRI alone as second-line therapy in patients with metastatic colorectal cancer (mCRC; ClinicalTrials.gov, NCT0039183). Experimental Design: Outcomes were from the study9s primary analysis. RAS mutations beyond KRAS exon 2 (KRAS exons 3, 4; NRAS exons 2, 3, 4; BRAF exon 15) were detected by bidirectional Sanger sequencing in wild-type KRAS exon 2 tumor specimens. Progression-free survival (PFS) and overall survival (OS) were coprimary endpoints. Results: The RAS ascertainment rate was 85%; 18% of wild-type KRAS exon 2 tumors harbored other RAS mutations. For PFS and OS, the hazard ratio (HR) for panitumumab plus FOLFIRI versus FOLFIRI alone more strongly favored panitumumab in the wild-type RAS population than in the wild-type KRAS exon 2 population [PFS HR, 0.70 (95% confidence interval [CI], 0.54–0.91); P = 0.007 vs. 0.73 (95% CI, 0.59–0.90); P = 0.004; OS HR, 0.81 (95% CI, 0.63–1.03); P = 0.08 vs. 0.85 (95% CI, 0.70–1.04); P = 0.12]. Patients with RAS mutations were unlikely to benefit from panitumumab. Among RAS wild-type patients, the objective response rate was 41% in the panitumumab–FOLFIRI group versus 10% in the FOLFIRI group. Conclusions: Patients with RAS mutations were unlikely to benefit from panitumumab–FOLFIRI and the benefit–risk of panitumumab–FOLFIRI was improved in the wild-type RAS population compared with the wild-type KRAS exon 2 population. These findings support RAS testing for patients with mCRC. Clin Cancer Res; 21(24); 5469–79. ©2015 AACR. See related commentary by Salazar and Ciardiello, p. 5415

  • updated analysis of kras nras and braf mutations in study 20050181 of panitumumab pmab plus FOLFIRI for second line treatment tx of metastatic colorectal cancer mcrc
    Journal of Clinical Oncology, 2014
    Co-Authors: Marc Peeters, Timothy J Price, Thierry Andre, Kelly S Oliner, Andres Cervantes, A Sobrero, Michel Ducreux, Yevhen Hotko, Emily Chan, Florian Lordick
    Abstract:

    3568 Background: Previously, extended RAS analysis from this study showed a trend toward improvements in HR on OS and PFS with pmab + FOLFIRI vs FOLFIRI in WT RAS group vs WT KRAS exon 2 group. Her...

  • analysis of kras nras mutations in phase 3 study 20050181 of panitumumab pmab plus FOLFIRI versus FOLFIRI for second line treatment tx of metastatic colorectal cancer mcrc
    Journal of Clinical Oncology, 2014
    Co-Authors: Marc Peeters, Timothy J Price, Thierry Andre, Kelly S Oliner, Andres Cervantes, A Sobrero, Michel Ducreux, Yevhen Hotko, Emily Chan, Florian Lordick
    Abstract:

    LBA387 Background: Previously, this study showed significant improvement in progression-free survival (PFS) in pmab + FOLFIRI vs FOLFIRI (HR=0.73; 95% CI: 0.59-0.90; p=0.004) and a trend toward improved overall survival (OS; HR=0.85; 95% CI: 0.70-1.04; P=0.12; Peeters et al. JCO 2010). Recently, analysis from 1st-line mCRC PRIME study showed that mutations in RAS genes (KRAS/NRAS exons 2/3/4) predicted a lack of response to pmab (Douillard et al. NEJM 2013). Methods: The primary objective was to assess the tx effect of pmab + FOLFIRI vs FOLFIRI on OS and PFS based on RAS mutation status in the primary analysis population. Bidirectional Sanger sequencing was used to detect mutations in KRAS exons 3, 4 and NRAS exons 2, 3, 4 in patients (pts) with known WT KRAS exon 2 mCRC. Results: In this prospective retrospective analysis, overall RAS ascertainment rate was 85% (n=1008/1186). 18% of the WT KRAS exon 2 pts harbored additional RAS mutations (n=107/597). Efficacy is shown (Table). Tx HR for pts with WT RAS ...

  • final results from a randomized phase 3 study of FOLFIRI panitumumab for second line treatment of metastatic colorectal cancer
    Annals of Oncology, 2014
    Co-Authors: Marc Peeters, Timothy J Price, Thierry Andre, Andres Cervantes, A Sobrero, Michel Ducreux, Yevhen Hotko, Emily Chan, Florian Lordick, C J A Punt
    Abstract:

    ABSTRACT Background The study 20050181 demonstrated significant improvements in progression-free survival (PFS), objective response, and a nonsignificant trend toward increased overall survival (OS) with panitumumab–FOLFIRI versus FOLFIRI alone for second-line wild-type (WT) KRAS metastatic colorectal cancer (mCRC). Updated long-term data from a prespecified descriptive analysis are reported. Patients and methods Patients receiving one prior mCRC treatment were randomly assigned (1:1) to panitumumab (6.0 mg/kg)–FOLFIRI versus FOLFIRI every 2 weeks. Co-primary end points (PFS and OS) were prospectively analyzed by tumor KRAS status. Results One thousand one hundred and eighty-six patients were randomly assigned. In patients with WT KRAS tumors, panitumumab–FOLFIRI significantly improved PFS versus FOLFIRI [median 6.7 versus 4.9 months; hazard ratio (HR) 0.82 [95% confidence interval (CI) 0.69, 0.97]; P = 0.023]. A trend toward longer OS was observed (median 14.5 versus 12.5 months; HR 0.92 [95% CI 0.78, 1.10]; P = 0.37). Response rates improved from 10% to 36% (P Conclusions These data confirm the primary efficacy and safety findings of this trial and support panitumumab–FOLFIRI as a second-line treatment of WT KRAS mCRC.

  • a randomised double blind placebo controlled phase 2 study of trebananib amg 386 in combination with FOLFIRI in patients with previously treated metastatic colorectal carcinoma
    British Journal of Cancer, 2013
    Co-Authors: Marc Peeters, Douglas Warner, Andrew Strickland, M Lichinitser, Attili Satya Suresh, G Manikhas, Jeremy Shapiro, W Rogowski, X Huang, Rakesh K Jain
    Abstract:

    A randomised, double-blind, placebo-controlled phase 2 study of trebananib (AMG 386) in combination with FOLFIRI in patients with previously treated metastatic colorectal carcinoma