Anti-VEGF and anti-EGFR monoclonal antibodies (Mabs) in the first-line therapy for metastatic colorectal cancer: A meta-analysis

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15012-e15012
Author(s):  
Z. Zhou ◽  
W. V. Walsh ◽  
V. G. Bathini ◽  
B. Piperdi
Keyword(s):  
Disease Progression ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Wild Type ◽  
First Line ◽  
First Line Therapy ◽  
Anti Vegf ◽  
Increased Risk ◽  
Risk Of Progression ◽  
Ras Status

e15012 Background: Anti-VEGF (VEGFi) and anti-EGFR (EGFRi) Mabs have increased options for patients with metastatic colorectal cancers (mCRC). The optimal class of antibody to combine with chemotherapy (Ctx) in the first-line treatment for mCRC remains less well defined. Results from randomized controlled trials (RCTs) are variable. Methods: Systematic review and meta-analysis were performed on the basis of previously released RCTs results. We searched the MEDLINE, Cochrane registry, proceedings from ASCO, ECCO, ESMO until 12/ 2008 for RCTs of Mabs in first-line mCRC. Summary statistics were pooled hazard ratio (HR) of progression-free survival (PFS), overall survival (OS) and odds ratio (OR) of Response rate (RR) and 60 day mortality (60d-M). Effect of k-ras wild type and mutation were stratified in trials involving EGFRi. Results: 7 trials with complete data were identified, including 3 Ctx ± VEGFi (AVF2107g, NO16966, JCO2005.05.122), n=2422; 2 Ctx±EGFRi (CRYSTAL, OPUS), n=1554; 2 Ctx/VEGFi ± EGFRi (PACCE, CAIRO-2), n=1789. Addition of VEGFi to Ctx offered 20–30% risk reduction in disease progression and overall mortality, a 30% higher RR and nonsignificant 60d-M. Benefit of EGFRi in addition to Ctx was seen only in k-ras wild type patients with 36% reduction in disease progression and doubling in RR. However, addition of EGFRi to Ctx+VEGFi caused increased risk of progression and death with no significant increase in RR and 60d-M. Conclusions: Benefit of VEGFi in addition to Ctx in first-line mCRC is well pronounced and persistent. In k-ras wild type patients, addition of EGFRi to Ctx results in significant increase in RR and PFS. Addition of EGFRi to Ctx+VEGFi appeared harmful regardless of k- ras status. [Table: see text] [Table: see text]

RECORD-4 phase 2 trial of second-line everolimus (EVE) in patients (pts) with metastatic renal cell carcinoma (mRCC): Final OS analysis.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 560-560
Author(s):  
Thomas Cosgriff ◽  
Lin Yang ◽  
Anna Alyasova ◽  
Dingwei Ye ◽  
Andrey Karpenko ◽  
...  
Keyword(s):  
Disease Progression ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Second Line ◽  
Phase 2 ◽  
First Line ◽  
Primary Analysis ◽  
First Line Therapy ◽  
Phase 2 Trial ◽  
Anti Vegf

560 Background: The phase 2 RECORD-4 study assessed EVE in pts with mRCC who progressed after 1 prior anti-VEGF or cytokine (J Clin Oncol 2015;abstr 4518). At primary analysis, median progression-free survival (PFS, primary end point) in the overall population was 7.8 months (95% CI, 5.7-11.0). Here we present results of the final updated primary PFS and final overall survival (OS) analysis. Methods: RECORD-4 enrolled 134 pts with clear cell mRCC into 1 of 3 cohorts based on prior first-line therapy: sunitinib (cohort 1, n=58), other anti-VEGF (cohort 2, n=62: 23 sorafenib, 16 bevacizumab, 13 pazopanib, 10 other), or cytokines (cohort 3, n=14). Pts received EVE 10 mg/d until progression of disease (PD; RECIST, v1.0) or intolerance. Database lock for final analysis was June 26, 2015. Results: Demographics were balanced among cohorts; overall most pts were men (68%) and most had good/intermediate MSKCC prognosis (90%); median age was 59 yrs. Median duration of exposure was 5.8 mo. At the time of final analysis, study discontinuation was primarily due to disease progression (61%). In the overall population, median PFS (95% CI) was 7.4 (5.6-10.5) mo and median OS (95% CI) was 23.8 (17.0-not evaluable [NE]) mo (Table). Overall rate of grade 3 or 4 adverse events (AEs) was 56%. There were 13 on-treatment deaths; primary causes were disease progression, multi-organ failure, and respiratory failure (2.3% each). Conclusions: RECORD-4 final OS analysis supports EVE as a second-line option after sunitinib and other first-line therapies. EVE safety profile was consistent with previous experience. Clinical trial information: NCT01491672. [Table: see text]

Pharmacoeconomic analysis for K-Ras status–based decisions for first-line therapy of metastatic colorectal cancer (mCRC) in Spain.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 438-438
Author(s):  
Cristobal Belda
Keyword(s):  
Randomized Clinical Trials ◽  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
Wild Type ◽  
First Line ◽  
Free Survival ◽  
First Line Therapy ◽  
Line Therapy ◽  
Ras Status

438 Background: Personalized medicine is a challenge for current oncology practice. Nowadays there are no pharmacoeconomic analyses in Spain dealing with the clinical and financial impact secondary to K-Ras based decisions for first-line therapy in mCRC patients. So, this study was aimed to assess the cost- effectiveness of K-Ras status based decisions in first- line therapy of mCRC patients in comparison with non- K-Ras based selection of available therapies. Methods: K-Ras mutation prevalence and efficacy of available therapies (measured as response rate and progression free survival) were extracted from randomized clinical trials (RCT) that allowed on-label use of accessible drugs in Spain. Then, we have simulated all possibilities of combination therapies for first-line mCRC based on K-Ras status (wild- type vs mutated) and confronted with all therapies that could be chosen in absence of K-Ras analysis. Prices for all drugs in Spain were used to assume the best- value for each drug including all possibilities to reduce pharmacy costs. For first line, median duration of therapy reported by RCT was used to calculate the final budget. 70 kg and 1.7 m were used as reference for patients dose calculations. Results: First-line therapy that includes a biological drug in absence of K-Ras status based decisions implies an incremental cost per 1% of increased response rate of 1,237 euros for irinotecan based doublets and 3,193 euros for oxaliplatin based doublets. On the opposite, K-Ras based decisions reduce costs per objective response by 69% and 35% for irinotecan and oxaliplatin- based schedules in K-Ras wild-type population incorporating cetuximab as biological agent. These data mimic all calculi based on incremental costs secondary to improved progression free survival measured as HR when all scenarios without prior determination of K-Ras status were confronted with K-Ras based decisions. Conclusions: K-Ras based decisions reduces costs per objective response as well as per improved progression free survival. The most cost- effective scenario among all simulated was cetuximab in combination with chemotherapy for patients that harbor wt K-Ras mCRC.

scholarly journals The benefits and risks of pembrolizumab in combination with chemotherapy as first-line therapy in small-cell lung cancer: a single-arm meta-analysis of noncomparative clinical studies and randomized control trials

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Qiangyun Liu ◽  
Yixuan Zhang ◽  
Miaowen Liu ◽  
Ruoxin Xu ◽  
Fengming Yi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line ◽  
Conventional Chemotherapy ◽  
Free Survival ◽  
First Line Therapy ◽  
Line Therapy

Abstract Background Although pembrolizumab has shown clinical benefit in patients with small-cell lung cancer (SCLC), its actual efficacy in combination with a conventional chemotherapy drug has not been determined. We performed this study to discern the efficacy and risk of pembrolizumab in combination with chemotherapy as first-line therapy in SCLC patients. Methods We systematically searched the PubMed, ScienceDirect, Cochrane Library, Scopus, Ovid MEDLINE, Embase, Web of Science, and Google Scholar databases for relevant studies. The main outcomes were overall survival (OS) and progression-free survival (PFS). Results We identified 2980 articles and included 6 studies (5 were noncomparative open-label studies and 1 was a randomized controlled trial [RCT]) involving 396 patients in our meta-analysis. The pooled median OS (mOS) was 9.6 months (95% CI, 8.0-11.2), and the pooled median PFS (mPFS) was 4.2 months (95% CI, 2.2-6.1). The 1-year overall survival rate (OSR-1y) and 6-month progression-free survival rate (PFSR-6m) were 45.1% (95% CI, 33-57.2%) and 41.6% (95% CI, 24.3-59%), respectively. The objective response rate (ORR) was 38.8% (95% CI, 11.9-65.67%), disease control rate (DCR) was 69.30% (95% CI, 51.6-87.0%), complete response (CR) was 2.20% (95% CI, 0.8-3.7%), partial response (PR) was 34.70% (95% CI, 7.8-61.5%), and stable disease (SD) was 20.90% (95% CI, 9.1-32.6%). The grade 3-4 adverse effect (AE) rate was 20.88% (95% CI, 1.22-54.85%). The most common AEs were neutropenia (90.16%), anemia (53.21%), dysphagia (41.96%), platelet count decrease (34.87%), and esophagitis (32.89%); severe AEs included neutropenia, respiratory failure, pneumonitis, acute coronary syndrome, and colitis/intestinal ischemia. Conclusions The combination of pembrolizumab with conventional chemotherapy is an effective therapeutic schedule with acceptable and manageable efficacy and toxicity in patients with SCLC. More high-quality and well-designed RCTs with large sample sizes are warranted to further validate our findings.

scholarly journals Comparison of Poly (ADP-ribose) Polymerase Inhibitors (PARPis) as Maintenance Therapy for Platinum-Sensitive Ovarian Cancer: Systematic Review and Network Meta-Analysis

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3026
Author(s):  
Amos Stemmer ◽  
Inbal Shafran ◽  
Salomon M. Stemmer ◽  
Daliah Tsoref
Keyword(s):  
Ovarian Cancer ◽  
Maintenance Therapy ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Wild Type ◽  
Brca Mutations ◽  
Increased Risk ◽  
Significant Difference ◽  
Indirect Comparisons

Background: Three PARPis (olaparib, niraparib and rucaparib) are currently FDA-approved as maintenance therapy in newly diagnosed and recurrent ovarian cancer. However, thus far, no trial has compared the three approved PARPis in the overall population, in patients with BRCA mutations, or in those with wild-type BRCA. Methods: A frequentist network meta-analysis was used for indirect comparisons between the different PARPis with respect to progression free survival (PFS), overall survival (OS), and adverse events. Results: Overall, six randomized clinical trials involving 2,770 patients, were included in the analysis. Results from the indirect comparisons revealed no statistically significant differences between the three PARPis with respect to PFS or OS in the entire population and in patients with mutated and wild-type BRCA, separately. Niraparib showed a statistically significant increased risk for grade 3 and 4 thrombocytopenia (risk-difference [RD] from placebo: 0.3; 95% confidence interval [CI], 0.27‒0.34) and any grade neutropenia (RD from placebo: 0.22; 95% CI, 0.18‒0.25) as compared with the other PARPis. Conclusion: No statistically significant difference was found between the three PARPis with respect to PFS or OS (overall and in subpopulations by BRCA status). There is, however, a statistical difference in toxicity as niraparib is associated with a greater risk for thrombocytopenia and neutropenia.

EVERSUN: A phase II trial of everolimus alternating with sunitinib as first-line therapy for advanced renal cell carcinoma (RCC) (ANZUP trial 0901).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4681-TPS4681 ◽  
Author(s):  
Ian D. Davis ◽  
Val Gebski ◽  
Mark D. Chatfield ◽  
Peter S. Grimison ◽  
George Kannourakis ◽  
...  
Keyword(s):  
Disease Progression ◽  
Phase Ii ◽  
Prognostic Score ◽  
Single Agent ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
First Line ◽  
Free Survival ◽  
First Line Therapy ◽  
Line Therapy

TPS4681 Background: Treatment of RCC has improved due to better understanding of its biology. New targeted therapies have improved time to progression and overall survival but the optimal sequencing of agents is unknown. Currently drugs are given sequentially, usually starting with sunitinib and often followed by an mTOR inhibitor or another VEGFR-targeted therapy, but resistance to both drugs eventually occurs probably due to host adaptive responses. We hypothesize that resistance might be delayed by planned alternation of treatments. Methods: EVERSUN is a single-arm, two-stage, multicenter, phase II clinical trial aiming to determine the activity and safety of an alternating regimen of two therapies with different targets (sunitinib and everolimus) in patients with advanced RCC. Key eligibility criteria: RCC with a clear cell component; metastatic or locally advanced disease not suitable for resection; ECOG performance status 0-1; low or intermediate MSKCC prognostic score. The primary endpoint is the status of being alive and progression-free (RECIST 1.1) 6 months after registration. Target accrual of 55 subjects gives 95% power and 95% confidence to distinguish between 6-month progression free survival rates of 64% or lower vs 84% or higher using a Simon 2-stage minimax design. The criteria for further evaluation come from the pivotal trial of single agent sunitinib as first line therapy for RCC, in which the 6-month progression free survival rate was 74%. Trial treatment is administered in 12-week (wk) cycles consisting of 4 wks of sunitinib (50 mg daily) followed by 2 wks rest, followed by 5 wks of everolimus (10 mg daily) followed by 1 wk rest. Disease progression is interpreted as failure of the most recent drug taken. Participants who stop one drug because of toxicity or disease progression, on or before the 6 month assessment, will continue the other drug until subsequent progression or prohibitive toxicity on the second drug. EVERSUN is an ANZUP Cancer Trials Group Ltd. trial coordinated by the NHMRC Clinical Trials Centre. Accrual commenced in September 2010 with 38/55 participants recruited as of the 31-Jan-12 from 17 Australian sites (ACTRN12609000643279).

Whether mCRC patients with other RAS mutations benefit from the addition of bevacizumab as first-line therapy.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 579-579
Author(s):  
Mingyi Zhou ◽  
Ping Yu ◽  
Kezuo Hou ◽  
Xiujuan Qu ◽  
Yunpeng Liu ◽  
...  
Keyword(s):  
Meta Analysis ◽  
Large Sample Size ◽  
First Line ◽  
Exon 2 ◽  
Ras Mutations ◽  
First Line Therapy ◽  
Line Therapy ◽  
Significant Difference ◽  
Ras Status ◽  
Kras Exon

579 Background: It is not clear whether Bevacizumab plus chemotherapy could improve the prognosis of mCRC patients with other RAS mutations beyond KRAS exon 2. Methods: The MEDLINE, EMBASE, Cochrane databases, and Clinical Trials databases were reviewed to September 2015. The data of patients with KRAS exon 2 mutations was only available in FIRE3 study. So we could not perform the meta-analysis by KRAS exon 2 mutations. The data of patients with other RAS mutations beyond KRAS exon 2 were available in PEAK and FIRE3 studies. Hazard ratio (HR) was used to analyze the progressive-free survival (PFS) and overall survival (OS). Relative risk (RR) was used to analyze overall response rate (ORR). Results: Patients with other RAS mutations beyond KRAS exon 2 benefited from the addition of Bevacizumab. Bevacizumab + chemotherapy significantly improved the PFS compared with anti-EGFR moAb + chemotherapy (HR: 1.82, CI: 1.20–2.77, P =.005). The addition of Bevacizumab tended to improve ORR, though there is no significant difference (RR: 0.83, CI: 0.58–1.18, P =.288). But the OS tended to be shorter in Bevacizumab + chemotherapy arm than anti-EGFR moAb + chemotherapy arm without significant difference (HR: 0.72, CI: 0.25–2.05, P =.534). Conclusions: Patients with other RAS mutations beyond KRAS exon 2 could choose Bevacizumab plus chemotherapy as first-line therapy. But there is still no adequate evidence to reject or support the predictive value of RAS status in the effect of the addition of Bevacizumab. Moreover, which is the better primary endpoint, PFS or OS? Which is the better consequence of strategy, anti-EGFR moAb followed by Bevacizumab or Bevacizumab followed by anti-EGFR moAb? RCTs with large sample size comparing the efficacy of anti-VEGF moAb + chemotherapy and chemotherapy alone by RAS status as the first-line therapy in mCRC patients are required in the future.

Withholding anti-EGFR, the impact on outcome in RAS wild-type metastatic colorectal tumors (WAIT or ACT trial).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 626-626
Author(s):  
Lola-Jade Palmieri ◽  
Laurent Mineur ◽  
David Tougeron ◽  
Benoit Rousseau ◽  
Victoire Granger ◽  
...  
Keyword(s):  
Growth Factor ◽  
Propensity Score ◽  
Cohort Analysis ◽  
Wild Type ◽  
First Line ◽  
Anti Vegf ◽  
Ras Status ◽  
Metastatic Sites ◽  
The Impact ◽  
Doublet Chemotherapy

626 Background: First line of RAS wild-type (WT) unresectable metastatic colorectal cancer (mCRC) can be doublet chemotherapy with an anti-VEGF (Vascular Endothelial Growth Factor), or an anti-EGFR (Epidermal Growth Factor Receptor). Waiting for RAS status, many oncologists initiate chemotherapy and add the anti-EGFR secondly. The objective was to compare the delayed introduction of the anti-EGFR to the immediate introduction of the anti-VEGF in first-line treatment of RAS WT mCRC. Methods: This was a retrospective cohort analysis from 2013 to 2016, multicentric with 28 health care centers. We included patients with RAS WT unresectable mCRC treated between 2013 and 2016 by a doublet chemotherapy with the anti-VEGF introduced immediately or with the anti-EGFR introduced at C2 or C3. Progression free survival (PFS), overall survival (OS) and response rate (RR) for the two cohorts were compared. Hazard ratios (HR) with 95% confidence interval (95%CI) were estimated with cox regression models weighted on propensity score to deal with potential confounders. Results: A total of 262 patients were included, 129 in the immediate anti-VEGF group and 133 in the delayed anti-EGFR group. Median follow-up was 37.9 months. Ninety-two patients had the anti-EGFR introduced at C2, 40 at C3. The median delay of RAS analysis was 19 days (q1-q3: 13-26). Patients treated with anti-VEGFs were more likely men (68% versus 56%), with more metastatic sites ( > 2 sites: 15% versus 9%). A propensity score including the number of metastatic sites and a possible previous treatment was built. Delayed anti-EGFRs were associated with longer PFS compared to immediate anti-VEGFs: 13.8 versus 11.0 months, p = 0.0244. After weighting, delayed anti-EGFRs were still associated with better PFS: HR 0.74, 95%CI [0.61 – 0.90], p = 0.0024. OS was not different between the two arms (30.5 for anti-VEGF versus 29.9 months, p = 0.3934), even after weighting (HR 0.86, 95%CI [0.69 – 1.08], p = 0.2024). There was a better RR with delayed anti-EGFRs: 66.7% versus 45.6%, p = 0.0007. Conclusions: Our findings suggest that, while waiting for RAS status, the delayed introduction of the anti-EGFR is a valid option, compared to the immediate introduction of the anti-VEGF.

scholarly journals Taxanes Alone or in Combination With Anthracyclines As First-Line Therapy of Patients With Metastatic Breast Cancer

2008 ◽  
Vol 26 (12) ◽  
pp. 1980-1986 ◽  
Author(s):  
Martine J. Piccart-Gebhart ◽  
Tomasz Burzykowski ◽  
Marc Buyse ◽  
George Sledge ◽  
James Carmichael ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Meta Analysis ◽  
Single Agent ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Response Rates ◽  
First Line ◽  
First Line Therapy ◽  
Hazard Ratios

Purpose Taxanes (paclitaxel or docetaxel) have been sequenced or combined with anthracyclines (doxorubicin or epirubicin) for the first-line treatment of advanced breast cancer. This meta-analysis uses data from all relevant trials to detect any advantages of taxanes in terms of tumor response, progression-free survival (PFS), and survival. Patients and Methods Individual patient data were collected on eight randomized combination trials comparing anthracyclines + taxanes (+ cyclophosphamide in one trial) with anthracyclines + cyclophosphamide (+ fluorouracil in four trials), and on three single-agent trials comparing taxanes with anthracyclines. Combination trials included 3,034 patients; single-agent trials included 919 patients. Results Median follow-up of living patients was 43 months, median survival was 19.3 months, and median PFS was 7.1 months. In single-agent trials, response rates were similar in the taxanes (38%) and in the anthracyclines (33%) arms (P = .08). The hazard ratios for taxanes compared with anthracyclines were 1.19 (95% CI, 1.04 to 1.36; P = .011) for PFS and 1.01 (95% CI, 0.88 to 1.16; P = .90) for survival. In combination trials, response rates were 57% (10% complete) in taxane-based combinations and 46% (6% complete) in control arms (P < .001). The hazard ratios for taxane-based combinations compared with control arms were 0.92 (95% CI, 0.85 to 0.99; P = .031) for PFS and 0.95 (95% CI, 0.88 to 1.03; P = .24) for survival. Conclusion Taxanes were significantly worse than single-agent anthracyclines in terms of PFS, but not in terms of response rates or survival. Taxane-based combinations were significantly better than anthracycline-based combinations in terms of response rates and PFS, but not in terms of survival.

scholarly journals Optimal Sequence and Second-Line Systemic Treatment of Patients with RAS Wild-Type Metastatic Colorectal Cancer: A Meta-Analysis

2021 ◽  
Vol 10 (21) ◽  
pp. 5166
Author(s):  
Chih-Chien Wu ◽  
Chao-Wen Hsu ◽  
Meng-Che Hsieh ◽  
Jui-Ho Wang ◽  
Min-Chi Chang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Meta Analysis ◽  
Second Line ◽  
Wild Type ◽  
First Line ◽  
Second Line Therapy ◽  
Optimal Sequence ◽  
First Line Therapy ◽  
Line Therapy

Although several sequential therapy options are available for treating patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC), the optimal sequence of these therapies is not well established. A systematic review and meta-analysis of 13 randomized controlled trials and 4 observational studies were performed, resulting from a search of the Cochrane Library, PubMed, and Embase databases. Overall survival (OS) did not differ significantly in patients with RAS-WT failure who were administered a second-line regimen of changed chemotherapy (CT) plus anti-epidermal growth factor receptor (EGFR) versus only changed CT, changed CT plus bevacizumab versus changed CT plus anti-EGFR, or changed CT versus maintaining CT plus anti-EGFR after first-line therapy with CT, plus bevacizumab. However, OS was significantly different with a second-line regimen that included changed CT plus bevacizumab, versus only changing CT. Analysis of first-line therapy with CT plus anti-EGFR for treatment of RAS-WT mCRC indicated that second-line therapy of changed CT plus an anti-EGFR agent resulted in better outcomes than changing CT without targeted agents. The pooled data study demonstrated that the optimal choice of second-line treatment for improved OS was an altered CT regimen with retention of bevacizumab after first-line bevacizumab failure. The best sequence for first-to-second-line therapy of patients with RAS-WT mCRC was cetuximab-based therapy, followed by a bevacizumab-based regimen.

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