Predictive biomarkers to improve treatment of metastatic colorectal cancer (mCRC): Outcomes with cetuximab plus FOLFIRI in the CRYSTAL trial

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4068-4068 ◽  
Author(s):  
C. Kohne ◽  
D. Stroiakovski ◽  
C. Chang-chien ◽  
R. Lim ◽  
T. Pintér ◽  
...  
Keyword(s):  
Antibody Therapy ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Phase Iii ◽  
First Line ◽  
Braf Mutations ◽  
Mutation Status ◽  
Significance Level ◽  
Line Of Therapy ◽  
The Impact

4068 Background: KRAS oncogene mutation status is predictive of efficacy of cetuximab alone or combined with chemotherapy (CT) in mCRC. Previous data from the phase III CRYSTAL trial showed that adding cetuximab to FOLFIRI in first-line mCRC significantly improved the overall response rate (ORR) and progression-free survival (PFS) in pts with KRAS wild-type (wt) tumors. The serine-threonine kinase BRAF is a direct downstream effector of KRAS. Here, we report the influence of KRAS and BRAF status on mature overall survival (OS) data. Methods: DNA was extracted from archived tumor material where available from randomized pts. KRAS and BRAF mutation status (wt or mutant [mt]) was determined by quantitative PCR. Treatment arms were compared using two-sided log-rank tests (5% significance level) for PFS and OS, and the CMH test for best ORR. Results: The KRAS-evaluable cohort (n=540; 64.4% KRAS wt) was similar to the overall ITT group. In KRAS wt pts, adding cetuximab to FOLFIRI significantly increased the odds for tumor response nearly 2-fold, reduced the risk of progression by 32% and extended median OS from 21.0 months (mo) to 24.9 mo (details in Table ). KRAS mt pts did not benefit from cetuximab. Data on the impact of BRAF mutations on cetuximab activity will be presented at the meeting. In the FOLFIRI and cetuximab + FOLFIRI arms, 31.2% and 36.1% of pts, respectively, received no further line of therapy, while 25.4% and 6.2%, respectively, received EGFR antibody therapy. Conclusions: The benefits of adding cetuximab to CT were greater in KRAS wt pts than ITT pts for all clinically relevant endpoints. KRAS is a key biomarker for selecting a targeted therapy combined with standard CT in first-line mCRC. [Table: see text] [Table: see text]

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.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. LBA443-LBA443 ◽  
Author(s):  
Fortunato Ciardiello ◽  
Heinz-Josef Lenz ◽  
Claus-Henning Kohne ◽  
Volker Heinemann ◽  
Sabine Tejpar ◽  
...  
Keyword(s):  
Mutation Detection ◽  
Antibody Therapy ◽  
Progression Free Survival ◽  
Phase Iii ◽  
First Line ◽  
Exon 2 ◽  
Ras Mutation ◽  
Mutational Status ◽  
The Impact ◽  
Kras Exon

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 detection is ongoing using BEAMing (Beads, Emulsions, Amplification, and Magnetics) with a mutation detection cut-off of 0.1%. Tumor genomic DNA samples from 541 randomized patients with KRAS exon 2 wt disease (81% of KRAS wt patient population) and tumor material available are currently being screened. Treatment arms will be compared using two-sided log-rank tests for PFS and OS, and the Cochran–Mantel–Haenszel (CMH) test for response. Results: RAS mutation status is currently available from 192 patients (28.8% ascertainment) with further RAS assessment ongoing. Currently 63.5% of the samples are RAS wt and 36.5% are new RAS mutations. Conclusions: Updated information on the full RAS mutation dataset of up to 400 samples combined with the clinical data will be presented and implications for patient care discussed.

BRAF, PIK3CA, and PTEN status and benefit from cetuximab (CET) in the treatment of advanced colorectal cancer (CRC): Results from NCIC CTG/AGITG CO.17.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3515-3515 ◽  
Author(s):  
Derek J. Jonker ◽  
Christos Stelios Karapetis ◽  
Christopher J. O'Callaghan ◽  
Celia Marginean ◽  
John Raymond Zalcberg ◽  
...  
Keyword(s):  
Cox Model ◽  
Pik3ca Mutation ◽  
Progression Free Survival ◽  
Pten Expression ◽  
Phase Iii ◽  
Wild Type ◽  
Braf Mutations ◽  
Colorectal Tumour ◽  
Mutation Status ◽  
Pik3ca Mutations

3515 Background: CET, a monoclonal antibody targeting the epidermal growth factor receptor, improves overall survival (OS) and progression free survival (PFS) in patients (pts) with KRAS wild-type (WT) chemotherapy refractory CRC. BRAF and PIK3CA mutation status, and PTEN expression levels may further predict benefit from CET therapy. Methods: Available colorectal tumour samples were analyzed from a phase III trial of CET plus best supportive care (BSC) vs BSC alone (NEJM 2007; 357(20)). BRAF and PIK3CA mutations (MUT) identified in tumour-derived DNA using a high resolution melting analysis to identify amplicons with mutations were confirmed by sequencing. PTEN expression by immunohistochemistry (IHC) was performed on tissue microarrays constructed from available tumour blocks. For each biomarker, prognostic (treatment independent) effects were assessed in patients on the BSC alone arm. Predictive effects (benefit from CET) on OS and PFS among all patients and those in the KRAS wild-type subset were examined using a Cox model with tests for treatment-biomarker interaction, adjusting for covariates. Results: Of 401 pts assessed for BRAF status (70% of CO17 population), 13(3%) had mutations. Of 407 pts assessed for PIK3CA status (71% of CO17 population), 61(15%) had mutations. Of 205 pts assessed for PTEN (36% of CO17 population), 148(72%) were negative for IHC expression. No biomarker was prognostic for OS or PFS, and none were predictive of benefit from CET, either in the whole study population or the KRAS WT subset. Conclusions: In chemotherapy-refractory CRC, neither PIK3CA mutation status nor PTEN expression were predictive of benefit from CET therapy. BRAF mutations are uncommon in this setting. Larger sample sizes would be required to determine if BRAF status is predictive for CET benefit. [Table: see text]

Randomized phase II study on the influence of BRAF and PIK3CA mutations on the efficacy of FOLFIRI plus bevacizumab (Bev) or cetuximab (Cet), as first line therapy of patients (pts) with RAS wild-type metastatic colorectal carcinoma (mCRC) and <3 baseline circulating tumor cells (bCTCs).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3549-3549
Author(s):  
Enrique Aranda ◽  
Pilar Garcia-Alfonso ◽  
Jose María Vieitez ◽  
Maria Jose Ortiz ◽  
Carlos López-López ◽  
...  
Keyword(s):  
Phase Ii ◽  
Negative Impact ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Mutation Status ◽  
Pik3ca Mutations ◽  
First Line Therapy ◽  
Randomized Phase Ii ◽  
Group B ◽  
The Impact

3549 Background: The outcome for mCRC has changed since the introduction of new chemotherapy schedules and targeted therapies, however new predictive biomarkers are needed. bCTCs and BRAF / PIK3CA mutations have been studied as a potential predictive biomarkers. The primary endpoint was progression-free survival (PFS) in pts WT KRAS and <3 bCTCs, according to BRAF/ PIK3CA status. Methods: This is an open, multicentric, randomized phase II trial and included wildtype KRAS mCRC pts (RAS after approval of protocol amendment), younger than ≤70 with <3 bCTCs, ECOG 0-1 and available tissue for molecular analyses. Pts were stratified per number of metastatic organs involved (1 vs >1) and mutation status of BRAF and/or PIK3CA (WT vs MUT) and randomized to group A (FOLFIRI+Bev) or group B (FOLFIRI+Cet). Results: 240 pts (196 WT and 44 MUT: 6 BRAF, 12 PIK3CA and 6 BRAF + PIK3CA) were included. General characteristics per mutation status (WT vs MUT): Mean age (59 vs 61 years), gender (Male/Female 68/32 vs 70/30%), ECOG 0/1 (57/43 vs 66/34%), primary tumor unresected (48 vs 64%), RAS MUT in 12 pts (11 and 1 pts, respectively), previous chemotherapy (12 vs 9%). Overall response rate (ORR) was 52 and 41% in the WT and MUT groups, respectively. PFS and overall survival (OS) are presented in the table. Conclusions: In the low risk mCRC pts according to bCTCs, BRAF and/or PIK3CA MUT have a negative impact in OS and a trend to worse PFS in the ITT population. The impact of treatment is under evaluation and will be provided during the meeting. Clinical trial information: 2012-000840-90. [Table: see text]

Examining progression-free survival in first- and second-line treatment for BRAF-mutant metastatic colorectal cancer (CRC).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 728-728
Author(s):  
Belinda Lee ◽  
Angelyn Anton ◽  
Margaret Lee ◽  
Rachel Wong ◽  
Phillip Parente ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Rank Test ◽  
Second Line ◽  
First Line ◽  
Mutation Status ◽  
Kaplan Meier ◽  
The Impact ◽  
Line Chemotherapy

728 Background: BRAF mutated (BRAFm) CRC represents ~10% of all CRC and is associated with significantly poorer prognosis. However, responses to chemotherapy do still occur. Some data suggest that the poor prognosis associated with BRAFm CRC is dominated by substantially poorer second line PFS (PFS2), whereas first line PFS (PFS1) was similar for both BRAFm and BRAF wildtype (BRAFwt) CRC. Using a large multicenter dataset, our study aimed to examine PFS1 and PFS2 in BRAFm versus BRAFwt CRC. Methods: Prospectively collected data from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) database was interrogated. PFS was calculated and compared in patients with BRAFm versus BRAFwt CRC. Median survival was determined by the Kaplan-Meier method and compared using the log rank test. Results: TRACC identified 523 CRC patients with known BRAF mutation status, who received first-line chemotherapy: 53 (10%) were BRAFm, while 470 (90%) were BRAFwt. At the time of data analysis, only 231 (44%) CRC patients had received second-line chemotherapy, of which 21 (9%) were BRAFm and 210 (91%) were BRAFwt. PFS1 analyses demonstrated significantly poorer survival in the BRAFm population (Median 7.8mo versus 11.5mo, HR 1.72, p = 0.0026). PFS2 analyses revealed similar findings for the BRAFm population, albeit non-significant due to smaller numbers (Median 5.5mo versus 7.7mo, HR1.26, p = 0.44). Conclusions: Our study demonstrated that BRAFm CRC was associated with poorer PFS in both first- and second-line settings. Additional analyses will be performed to examine the impact of different treatment strategies and other clinicopathological features.

Polymorphisms in the dopamine (DA) signaling to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from TRIBE, MAVERICC, and FIRE-3 phase III trials.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3048-3048
Author(s):  
Francesca Battaglin ◽  
Shu Cao ◽  
Fotios Loupakis ◽  
Sebastian Stintzing ◽  
Aparna Raj Parikh ◽  
...  
Keyword(s):  
Multiple Testing ◽  
Meta Analysis ◽  
Critical Role ◽  
Progression Free Survival ◽  
Phase Iii ◽  
P Value ◽  
Nucleotide Polymorphisms ◽  
First Line ◽  
The Impact

3048 Background: Strong evidence supports the critical role of the gut-brain axis in modulating gastrointestinal function and homeostasis. Available data suggest an involvement of the dopaminergic pathway in CRC dynamics. DA could inhibit proliferation and migration of tumor endothelial cells and enhanced 5-fluorouracil efficacy in CRC preclinical models. Hence, we hypothesized that genetic variants in DA signaling may predict treatment outcomes in mCRC pts. Methods: The impact on outcome of 22 selected single nucleotide polymorphisms (SNPs) in 9 genes of the DA signaling pathway ( DRD1, DRD2, DRD3, DRD4, DRD5, TAAR1, SLC6A3, SLC18A2, PPP1R1B) was analyzed on a total of 884 pts enrolled in three independent randomized first-line trials: TRIBE (n = 324), MAVERICC (n = 324), and FIRE-3 (n = 236). Genomic DNA from blood samples of pts was genotyped through the OncoArray, a custom array manufactured by Illumina. A meta-analysis approach using the METASOFT software was used to quantify SNPs prognostic effects and heterogeneities across treatment arms. P values were adjusted for multiple testing using the false discovery rate (FDR) method. Results: Overall, DRD3 rs3732790, rs9817063 and rs2134655 showed a significant nominal p value ( P) in association with tumor response (TR) across trials ( P= 0.032, P= 0.021, P= 0.027, respectively). TAAR1 rs8192620 showed an association with both progression free survival (PFS) ( P= 0.01) and overall survival (OS) ( P= 0.033), similar to DA transporter SLC6A3 rs6347 ( P= 0.016 and P= 0.002, respectively). SLC6A3 rs6347 association with OS remained significant after FDR ( PFDR= 0.045). Subgroup analyses showed a significant association with PFS for DRD1 rs267410 and SLC6A3 rs2652510 in females ( PFDR= 0.056), and between SLC6A3 rs6347 and OS ( PFDR= 0.041) and SLC6A3 rs6876890 and TR ( PFDR= 0.05) in KRAS wild type. Conclusions: Our results suggest that SNPs in DA signaling may have a prognostic value in mCRC pts receiving first-line treatment. Upon validation, these findings may provide novel insight on the role of DA signaling in CRC and possibly contribute to open novel therapeutic perspectives.

Sex differences in efficacy and toxicity of first-line treatment of metastatic colorectal cancer (CRC): An analysis of 18,399 patients in the ARCAD database.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4029-4029
Author(s):  
Anna Dorothea Wagner ◽  
Manel Rakez ◽  
Benoist Chibaudel ◽  
Richard Adams ◽  
John Raymond Zalcberg ◽  
...  
Keyword(s):  
Sex Differences ◽  
Performance Status ◽  
Single Agent ◽  
Progression Free Survival ◽  
Tumor Location ◽  
Tumor Characteristics ◽  
First Line ◽  
Braf Mutations ◽  
Cox Models ◽  
The Impact

4029 Background: The clearance of 5-FU differs significantly between men (M) and women (W). Adjuvant chemotherapy (CT) for CRC has a higher toxicity in W. The impact of sex on efficacy and toxicity in first-line trials of metastatic CRC (mCRC) is unknown. Methods: We analyzed patient (pt) and tumor characteristics, toxicities (nausea (AE1), vomiting (AE2), diarrhea, neutropenia (AE3)) and efficacy (overall survival (OS), progression-free survival (PFS)) according to sex in the following treatment groups: A: CT alone, B: CT + bevacizumab, C: CT + EGFR-antibodies, with subgroup analyses in the CT alone group for single-agent, doublets and triplets, as well as irinotecan- and oxaliplatin-based regimens. Pts from trials with treatments still used today and all relevant data available were eligible. OS and PFS were assessed using Kaplan-Meier and Cox models adjusted for primary tumor location and performance status (PS). Results: We included 28 trials with 18.399 pts (11.352 M and 7.047 W). W were younger (61 vs. 63 years), had more often a PS of 1 (49 vs 45%), BRAF mutations (10 vs. 7%), right-sided tumors (42 vs. 35%) and less often rectal tumors (26 vs. 32%). Significant differences in toxicity are reported in table. Rates of diarrhea were similar. There was no sex disparity in OS in the predefined subgroups except for pts receiving triplets where OS was better in M (HRadj=1.39 (1.05 - 1.85)). Median (interquartile range) OS in months for M and W was 16.7 (9.2-27.4) and 16.2 (8.9-27.2) in group 1, 21.9 (12.7-37.5) and 22.3 (12.9 – 39.0) in group 2, and 26.8 (14.6-45.3) and 24.8 (12.3-49.2) in group 3. HRsadj (W vs M) (95% CI), p values for OS were 1.02 (0.96-1.09), .557, 0.92 (0.83-1.03), .142, 0.99 (0.85-1.14), .866. Conclusions: M and W with mCRC differ significantly regarding patient and tumor characteristics. The significant higher toxicity in W does not translate in a higher treatment efficacy. Apart from known sex differences in pharmacokinetics of 5-FU, differences in pharmacodynamics must be postulated. [Table: see text]

scholarly journals FOLFOXIRI plus bevacizumab versus FOLFOX plus bevacizumab for patients with metastatic colorectal cancer and ≥3 circulating tumour cells: the randomised phase III VISNÚ-1 trial

ESMO Open ◽  
2020 ◽  
Vol 5 (6) ◽  
pp. e000944 ◽  
Author(s):  
Enrique Aranda ◽  
Jose Maria Viéitez ◽  
Auxiliadora Gómez-España ◽  
Silvia Gil Calle ◽  
Antonieta Salud-Salvia ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Phase Iii ◽  
First Line ◽  
Open Label ◽  
Intention To Treat ◽  
First Line Therapy ◽  
Line Therapy

Purpose5-Fluorouracil/leucovorin, oxaliplatin, irinotecan (FOLFOXIRI) plus bevacizumab is more effective than doublets plus bevacizumab as first-line therapy for metastatic colorectal cancer, but is not widely used because of concerns about toxicity and lack of predictive biomarkers. This study was designed to explore the role of circulating tumour cell (CTC) count as a biomarker to select patients for therapy with FOLFOXIRI-bevacizumab.Patients and methodsVISNÚ-1 was a multicentre, open-label, randomised, phase III study in patients with previously untreated, unresectable, metastatic colorectal carcinoma and ≥3 CTC/7.5 mL blood. Patients received bevacizumab 5 mg/kg plus FOLFOXIRI (irinotecan 165 mg/m2, oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 and 5-fluorouracil 3200 mg/m2) or FOLFOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil 400 mg/m2 then 2400 mg/m2) by intravenous administration every 2 weeks. The primary outcome was progression-free survival (PFS).ResultsThe intention-to-treat population comprised 349 patients (FOLFOXIRI-bevacizumab, n=172; FOLFOX-bevacizumab, n=177). Median PFS was 12.4 months (95% CI 11.2 to 14.0) with FOLFOXIRI bevacizumab and 9.3 months (95% CI 8.5 to 10.7) with FOLFOX-bevacizumab (stratified HR, 0.64; 95% CI 0.49 to 0.82; p=0.0006). Grade≥3 adverse events were more common with FOLFOXIRI-bevacizumab 85.3% vs 75.1% with FOLFOX-bevacizumab (p=0.0178). Treatment-related deaths occurred in 8 (4.7%) and 6 (3.4%) patients, respectively.ConclusionsFirst-line FOLFOXIRI-bevacizumab significantly improved PFS compared with FOLFOX-bevacizumab in patients with metastatic colorectal cancer and ≥3 CTCs at baseline, which indicate a poor prognosis. CTC count may be a useful non-invasive biomarker to assist with the selection of patients for intensive first-line therapy.

Are BRAF mutated metastatic colorectal cancer (mCRC) tumors more responsive to VEGFR-2 blockage? Analysis of patient outcomes by RAS/RAF mutation status in the RAISE study—A global, randomized, double-blind, phase III study.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 622-622 ◽  
Author(s):  
Takayuki Yoshino ◽  
Radka Obermannova ◽  
Gyorgy Bodoky ◽  
Jana Prausová ◽  
Rocio Garcia-Carbonero ◽  
...  
Keyword(s):  
Patient Outcomes ◽  
Poor Prognosis ◽  
Proportional Hazards ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Phase Iii ◽  
Wild Type ◽  
Braf Mutations ◽  
Double Blind ◽  
Mutation Status

622 Background: The RAISE trial (NCT01183780) demonstrated that ramucirumab (RAM) plus leucovorin, fluorouracil, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo (PBO) plus FOLFIRI as second-line mCRC treatment. RAS/RAF mutations are associated with resistance to anti-EGFR therapies and poor prognosis, particularly BRAF mutations. The extensive RAISE biomarker program assessed the association of multiple candidate markers with efficacy outcomes. Here we present the results for RAS/ RAF mutations. Methods: Plasma and tumor tissue collection were mandatory. KRAS mutation status was determined locally before randomization. Further RAS and RAF mutations were assessed centrally by multiplex qPCR using the Modaplex system (Qiagen) only in samples that were initially reported as KRAS wild type. Thus, patients were classified into one of the 3 categories in the table. OS and PFS by RAS and RAF subgroups were evaluated by Kaplan-Meier and Cox proportional hazards analyses. Results: As with previously reported KRAS analyses, the favorable RAM treatment effect was similar between patients with expanded RAS mutations compared with patients with RAS/ RAF wild-type tumors. However, in the 41 patients with BRAF mutated tumors, the RAM benefit was even more notable for both OS (hazard ratio [HR] 0.54; 95% CI 0.25–1.13) and PFS (HR 0.55; 95% CI 0.28–1.08). Conclusions: RAISE demonstrated that the addition of RAM to FOLFIRI improved patient outcomes regardless of RAS mutation status. The noteworthy signal for patients with BRAF mutant tumors is encouraging due to their poor prognosis but requires further validation in other clinical trials. Clinical trial information: NCT01183780. [Table: see text]

scholarly journals Clinical impact of subclonal EGFR T790M mutations in advanced-stage EGFR-mutant non-small-cell lung cancers

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Tereza Vaclova ◽  
Ursula Grazini ◽  
Lewis Ward ◽  
Daniel O’Neill ◽  
Aleksandra Markovets ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Small Cell ◽  
Phase Iii ◽  
Advanced Stage ◽  
Small Cell Lung ◽  
Nsclc Patients ◽  
The Impact ◽  
Egfr T790m

AbstractAdvanced non-small-cell lung cancer (NSCLC) patients with EGFR T790M-positive tumours benefit from osimertinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). Here we show that the size of the EGFR T790M-positive clone impacts response to osimertinib. T790M subclonality, as assessed by a retrospective NGS analysis of 289 baseline plasma ctDNA samples from T790M‐positive advanced NSCLC patients from the AURA3 phase III trial, is associated with shorter progression-free survival (PFS), both in the osimertinib and the chemotherapy-treated patients. Both baseline and longitudinal ctDNA profiling indicate that the T790M subclonal tumours are enriched for PIK3CA alterations, which we demonstrate to confer resistance to osimertinib in vitro that can be partially reversed by PI3K pathway inhibitors. Overall, our results elucidate the impact of tumour heterogeneity on response to osimertinib in advanced stage NSCLC patients and could help define appropriate combination therapies in these patients.

scholarly journals Bevacizumab and Breast Cancer: A Meta-Analysis of First-Line Phase III Studies and a Critical Reappraisal of Available Evidence

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
José R. Rossari ◽  
Otto Metzger-Filho ◽  
Marianne Paesmans ◽  
Kamal S. Saini ◽  
Alessandra Gennari ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fixed Effects ◽  
Meta Analysis ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Phase Iii ◽  
First Line ◽  
Statistical Estimates ◽  
Treatment Indications ◽  
Phase Iii Studies

Background. Randomized studies have shown different magnitude of bevacizumab benefit in the treatment of advanced breast cancer. Regulatory agencies have modified bevacizumab treatment indications across different regions. In this study, we perform a meta-analysis of phase III studies aiming to interrogate the magnitude of bevacizumab benefit for the treatment of first-line HER2-negative metastatic breast cancer (MBC).Methods. Data from studies E2100, AVADO and RIBBON-1 were used to calculate the benefit of bevacizumab in terms of tumor overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and toxicities. Combined statistical estimates of hazard ratios (HR) and odds ratios were calculated using fixed-effects or random-effects models.Results. A total of 2,695 patients were evaluated. Combining bevacizumab with different chemotherapy backbones resulted in a 30% risk reduction of PFS events (HR = 0.70; 95% confidence interval [CI], 0.57–0.86) and increased ORR (odds ratio 1.81; 95% CI, 1.53–2.14). No OS benefit could be demonstrated (HR = 0.95; 95% CI, 0.85–1.06). Bevacizumab significantly increased the incidence of adverse events such as proteinuria, hypertension and cardiovascular events.Conclusions. Bevacizumab combined with chemotherapy in the first-line treatment of MBC significantly improved ORR and PFS, but also increased grade 3-4 toxicities. No significant OS advantage was observed.

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