Comprehensive Kras and Nras Mutation Analysis: Predictive Biomarkers in a Phase 3 Panitumumab Monotherapy Study of Metastatic Colorectal Cancer (Mcrc)

The discovery of predictive biomarkers in metastatic colorectal cancer (mCRC) is essential to improve clinical outcomes. Recent data suggest a potential role of circulating tumor cells (CTCs) as prognostic indicators. We conducted a follow-on analysis from a prospective study of consecutive patients with mCRC. CTC analysis was conducted at two timepoints: baseline (CTC1; before starting chemotherapy), and two months after starting treatment (CTC2). CTC isolation/quantification were completed by ISET® (Rarecells, France). CTC expressions of drug resistance-associated proteins were evaluated. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan–Meier method. Seventy-five patients were enrolled from May 2012 to May 2014. A CTC1 cut-off of >1.5 CTCs/mL was associated with an inferior median OS compared to lower values. A difference of CTC2−CTC1 > 5.5 CTCs/mL was associated with a reduced median PFS. By multivariate analysis, CTC1 > 1.5 CTCs/mL was an independent prognostic factor for worse OS. Multi-drug resistance protein-1 (MRP-1) expression was associated with poor median OS. CTC baseline counts, kinetics, and MRP-1 expression were predictive of clinical outcomes. Larger studies are warranted to explore the potential clinical benefit of treating mCRC patients with targeted therapeutic regimens guided by CTC findings.

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Impact of tumor epidermal growth factor receptor (EGFR) status on the outcomes of first-line FOLFOX-4 ± cetuximab in patients (pts) with RAS-wild-type (wt) metastatic colorectal cancer (mCRC) in the randomized phase 3 TAILOR trial

Annals of Oncology ◽

10.1093/annonc/mdw370.75 ◽

2016 ◽

Vol 27 ◽

pp. vi174 ◽

Cited By ~ 2

Author(s):

S. Qin ◽

J. Xu ◽

L. Wang ◽

Y. Cheng ◽

T. Liu ◽

...

Keyword(s):

Colorectal Cancer ◽

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Metastatic Colorectal Cancer ◽

Growth Factor Receptor ◽

Wild Type ◽

First Line ◽

Phase 3 ◽

Epidermal Growth

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Exploratory biomarker findings from cohort 2 of MODUL: An adaptable, phase 2, signal-seeking trial of fluoropyrimidine + bevacizumab ± atezolizumab maintenance therapy for BRAFwt metastatic colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3570 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3570-3570

Author(s):

Josep Tabernero ◽

Axel Grothey ◽

Dirk Arnold ◽

Michel Ducreux ◽

Peter J. O'Dwyer ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Maintenance Treatment ◽

Predictive Biomarkers ◽

Experimental Treatment ◽

Progression Free Survival ◽

Phase 2 ◽

First Line ◽

Tissue Samples ◽

First Line Therapy

3570 Background: MODUL is an adaptable, phase 2, signal-seeking trial testing novel agents as first-line therapy for predefined subgroups of patients with metastatic colorectal cancer (mCRC). Previously reported findings demonstrated that adding atezolizumab to fluoropyrimidine (FP)/bevacizumab as first-line maintenance treatment after induction with FOLFOX + bevacizumab did not improve efficacy outcomes in BRAFwt mCRC. Given these efficacy results, exploratory assessments on tumour samples were conducted to provide insights into factors that might affect efficacy of maintenance treatment and provide guidance on appropriate therapeutic strategies for BRAFwt mCRC. Methods: In patients with BRAFwt tumours (Cohort 2), experimental treatment was FP/bevacizumab + atezolizumab. Primary efficacy endpoint: progression-free survival (PFS). Overall survival (OS) was a secondary endpoint. Archival tissue samples from 104 patients were analysed by immunohistochemistry (IHC) at HistoGeneX (PD-L1; CD8/GrB/FoxP3). SP142 antibody was used for PD-L1 IHC analysis, which evaluated PD-L1low (IC 0–1) vs PD-L1high (IC > 1) in correlation with PFS and OS in the control and experimental arms. CD8/GrB/FoxP3 triplex staining was also performed to evaluate potential correlations with efficacy. Results: 445 patients with BRAFwt mCRC were randomised (2:1 ratio) to maintenance treatment in Cohort 2. Archival samples from 104 patients were analysed: FP/bevacizumab + atezolizumab (n = 82); FP/bevacizumab (n = 22). The biomarker evaluable population (BEP) for PD-L1 was n = 81 for FP/bevacizumab + atezolizumab [PD-L1low n = 35 (43%); PD-L1high n = 46 (57%)] and n = 22 for FP/bevacizumab [PD-L1low n = 16 (72%); PD-L1high n = 6 (28%)]. The BEP for CD8/GrB was n = 50 for FP/bevacizumab + atezolizumab and n = 16 for FP/bevacizumab. No difference in PFS or OS was observed in the FP/bevacizumab + atezolizumab vs FP/bevacizumab arms for PD-L1high [PFS: HR = 1.5 (95% CI 0.45−4.8), p = 0.51; OS: HR = 1.3 (95% CI 0.38−4.1), p = 0.71] or PD-L1low [PFS: HR = 0.92 (95% CI 0.47−1.8), p = 0.81; OS: HR = 0.78 (95% CI 0.4−1.5), p = 0.48]. Similar results were observed with CD8/GrBhigh [PFS: HR = 0.73 (95% CI 0.27−2.0), p = 0.55; OS: HR = 0.66 (95% CI 0.24−1.8), p = 0.44], CD8/GrBlow [PFS: HR = 1.0 (95% CI 0.42–2.5), p = 0.96; OS: HR = 0.73 (95% CI 0.3–1.8), p = 0.5], FoxP3high [PFS: HR = 0.97 (95% CI 0.37−2.5), p = 0.95; OS: HR = 0.95 (95% CI 0.36−2.5), p = 0.91] and FoxP3low [PFS: HR = 0.73 (95% CI 0.29−1.9), p = 0.53; OS: HR = 0.5 (95% CI 0.19−1.3), p = 0.18]. Conclusions: These findings suggest that PD-L1, CD8/GrB and FoxP3 might not be predictive biomarkers in BRAFwt mCRC. Further analyses are needed to further evaluate potential predictive and prognostic factors of response in this setting. Clinical trial information: NCT02291289.

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KRAS mutation analysis of single circulating tumor cells from patients with metastatic colorectal cancer

BMC Cancer ◽

10.1186/s12885-017-3305-6 ◽

2017 ◽

Vol 17 (1) ◽

Cited By ~ 23

Author(s):

Yuurin Kondo ◽

Kazuhiko Hayashi ◽

Kazuyuki Kawakami ◽

Yukari Miwa ◽

Hiroshi Hayashi ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Mutation Analysis ◽

Kras Mutation

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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

The Lancet Oncology ◽

10.1016/s1470-2045(14)70330-4 ◽

2014 ◽

Vol 15 (10) ◽

pp. 1065-1075 ◽

Cited By ~ 881

Author(s):

Volker Heinemann ◽

Ludwig Fischer von Weikersthal ◽

Thomas Decker ◽

Alexander Kiani ◽

Ursula Vehling-Kaiser ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Line Treatment ◽

First Line ◽

Open Label ◽

Phase 3 ◽

Open Label Phase ◽

First Line Treatment

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Phase Ib/II trial evaluating the safety, tolerability and immunological activity of durvalumab (MEDI4736) (anti-PD-L1) plus tremelimumab (anti-CTLA-4) combined with FOLFOX in patients with metastatic colorectal cancer

ESMO Open ◽

10.1136/esmoopen-2018-000375 ◽

2018 ◽

Vol 3 (4) ◽

pp. e000375 ◽

Cited By ~ 21

Author(s):

Jean-David Fumet ◽

Nicolas Isambert ◽

Alice Hervieu ◽

Sylvie Zanetta ◽

Jean-Florian Guion ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Checkpoint Inhibitors ◽

Target Therapy ◽

Performance Status ◽

Human Monoclonal Antibody ◽

Eastern Cooperative Oncology Group ◽

Predictive Biomarkers ◽

Progression Free Survival ◽

Mutational Status

Background5-Fluorouracil plus irinotecan or oxaliplatin alone or in association with target therapy are standard first-line therapy for metastatic colorectal cancer (mCRC). Checkpoint inhibitors targeting PD-1/PD-L1 demonstrated efficacy on mCRC with microsatellite instability but remain ineffective alone in microsatellite stable tumour. 5-Fluorouracil and oxaliplatin were known to present immunogenic properties. Durvalumab (D) is a human monoclonal antibody (mAb) that inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor. Tremelimumab (T) is a mAb directed against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). This study is designed to evaluate whether the addition of PD-L1 and CTLA-4 inhibition to oxaliplatin, fluorouracil and leucovorin (FOLFOX) increases treatment efficacy.MethodsThis phase II study (ClinicalTrials.gov NCT03202758) will assess the efficacy and safety of FOLFOX/D/T association in patients with mCRC (n=48). Good performance status patients (Eastern Cooperative Oncology Group <2) with untreated, RAS mutational status mCRC will be eligible. Prior adjuvant therapy is allowed provided recurrence is >6 months postcompletion. There is a safety lead in nine patients receiving FOLFOX/D/T. Assuming no safety concerns the study will go on to include 39 additional patients. Patients will receive folinic acid (400 mg/m²)/5-fluorouracil (400 mg/m² as bolus followed by 2400 mg/m2 as a 46-hour infusion)/oxaliplatin (85 mg/m2) every 14 days with D (750 mg) D1 every 14 days and T (75 mg) D1 every 28 days. After six cycles of FOLFOX only D/T will continue until disease progression, death, intolerable toxicity, or patient/investigator decision to stop. Primary endpoint is safety and efficacy according to progression-free survival (PFS); secondary endpoints include overall response rate and quality of life. Hypothesis is that a PFS of 50% at 6 months is insufficient and a PFS of 70.7% is expected (with α=10%, β=10%). Blood, plasma and tumour tissue will be collected and assessed for potential prognostic and predictive biomarkers.

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