The prognostic and predictive impact of BRAF mutations in deficient mismatch repair/microsatellite instability-high colorectal cancer: systematic review/meta-analysis

2021 ◽  
Author(s):  
Robin Park ◽  
Laercio Lopes ◽  
Sunggon Lee ◽  
Ivy Riano ◽  
Anwaar Saeed
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Response Rate ◽  
Meta Analysis ◽  
Objective Response ◽  
Wild Type ◽  
Braf Mutations ◽  
Deficient Mismatch Repair

Aims: The authors present a systematic review/meta-analysis of the impact of BRAF mutations on prognosis and immune checkpoint inhibitor (ICI) response in deficient mismatch repair/microsatellite instability-high colorectal cancer. Methods: Hazard ratios for overall survival and odds ratios for objective response rate to ICIs were calculated in BRAF-mutated versus BRAF wild-type patients. Results: After screening, nine and three studies, respectively, were included for analysis of prognosis (analysis A) and ICI response (analysis B). Analysis A showed worse overall survival in BRAF-mutated compared with BRAF wild-type stage I–IV patients (hazard ratio: 1.57; 95% CI: 1.23–1.99), and analysis B showed no difference in objective response rate (odds ratio: 1.04; 95% CI: 0.48–2.25). Conclusion: BRAF mutations are associated with worse overall survival but not differential response to ICIs in deficient mismatch repair/microsatellite instability-high colorectal cancer.

Efficacy and safety of PD-1/PD-L1 and CTLA-4 immune checkpoint inhibitors in colorectal cancer: a meta-analysis

2022 ◽  
Author(s):  
Chunhui Jin ◽  
Xiaodan Zhu ◽  
Xiaona Huang ◽  
Tingjie Gong ◽  
Zhipeng Wei ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Survival Rate ◽  
Mismatch Repair ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Objective Response ◽  
Progression Free Survival ◽  
Adverse Event Rate ◽  
Efficacy And Safety ◽  
Deficient Mismatch Repair

Aims: To evaluate the efficacy and safety of PD-1/PD-L1 and/or CTLA-4 inhibitors in the treatment of colorectal cancer (CRC) by meta-analysis. Methods: Electronic databases were searched. Eligible studies included investigations of efficacy and safety of anti-PD-1/PD-L1 or anti-CTLA-4 agents in patients with CRC. Corresponding indicators were calculated. Results: A total of 15 articles were included. The pooled objective response rate, overall survival rate, progression-free survival rate and adverse event rate were 33, 56, 46 and 59%, respectively. The objective response rates for CRC with deficient mismatch repair and CRC with proficient mismatch repair were 43 and 3%, respectively, in patients treated with PD-1 inhibitors. Conclusion: The authors' study indicates that PD-1/PD-L1 inhibitors manifest promising clinical responses in the treatment of CRC with deficient mismatch repair with acceptable treatment-related adverse events.

Efficacy of immunotherapy with PD-1 inhibitor in colorectal cancer: a meta-analysis

2020 ◽  
Vol 9 (18) ◽  
pp. 1285-1292
Author(s):  
Shengqi He ◽  
Dongqing Hu ◽  
Haixia Feng ◽  
Ye Xue ◽  
Jin Jin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Survival Rate ◽  
Objective Response Rate ◽  
Response Rate ◽  
Meta Analysis ◽  
Objective Response ◽  
Progression Free Survival ◽  
Overall Survival Rate ◽  
Free Survival

Aim: PD-1 inhibitors have a leading role among immunotherapy while its efficacy on colorectal cancer (CRC) patients did not reach consensus and the small sample size remains as a limitation. Therefore, we undertook a meta-analysis on the effects of the monotherapy anti-PD-1 inhibitors in treating metastatic colorectal cancer (mCRC). Materials & methods: We searched databases to identify studies on efficacy of anti-PD-1 inhibitor on CRC. Objectives were objective response rate, progression-free survival rate, disease control rate and overall survival rate with their 95% CI. Results: The overall survival rate at 1-year was 64.2% (95% CI: 0.46–0.83). Disease control rate was 56.5% (CI: 0.27–0.86) and the objective response rate as 19.7% (CI: 0.08–0.32). The 1-year-progression-free survival rate was 38.4% (CI: 0.12–0.66). Sensitivity analysis and subgroup analysis were also conducted. Conclusion: The monotherapy anti-PD-1 inhibitors are effective in treating mCRC and could be a new option for dMMR mCRC patient in first-line treatment.

scholarly journals Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability–High/Mismatch Repair–Deficient Metastatic Colorectal Cancer: KEYNOTE-164

2020 ◽  
Vol 38 (1) ◽  
pp. 11-19 ◽  
Author(s):  
Dung T. Le ◽  
Tae Won Kim ◽  
Eric Van Cutsem ◽  
Ravit Geva ◽  
Dirk Jäger ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Growth Factor ◽  
Mismatch Repair ◽  
Response Rate ◽  
Objective Response ◽  
Open Label ◽  
Open Label Study ◽  
Label Study ◽  
Duration Of Response

PURPOSE KEYNOTE-164 (NCT02460198) evaluated the antitumor activity of pembrolizumab in previously treated, metastatic, microsatellite instability–high/mismatch repair–deficient (MSI-H/dMMR) colorectal cancer (CRC). METHODS This phase II open-label study involved 128 centers worldwide. Eligible patients were age ≥ 18 years and had metastatic MSI-H/dMMR CRC treated with ≥ 2 prior lines of standard therapy, including fluoropyrimidine, oxaliplatin, and irinotecan with or without anti–vascular endothelial growth factor/epidermal growth factor receptor monoclonal antibody (cohort A) or ≥ 1 prior line of therapy (cohort B). MSI-H/dMMR status was assessed locally. Patients received pembrolizumab 200 mg every 3 weeks for up to 2 years until progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate by RECIST version 1.1 by independent central review. Secondary end points were duration of response, progression-free survival (PFS), overall survival, safety, and tolerability. RESULTS A total of 124 patients with MSI-H/dMMR CRC (61 in cohort A, 63 in cohort B) enrolled. At data cutoff, median follow-up was 31.3 months (range, 0.2-35.6 months) for cohort A and 24.2 months (range, 0.1-27.1 months) for cohort B. Objective response rate was 33% (95% CI, 21% to 46%) and 33% (95% CI, 22% to 46%), respectively, with median duration of response not reached in either cohort. Median PFS was 2.3 months (95% CI, 2.1 to 8.1 months) and 4.1 months (95% CI, 2.1 to 18.9 months). Median overall survival was 31.4 months (95% CI, 21.4 months to not reached) and not reached (95% CI, 19.2 months to not reached). Treatment-related grade 3-4 adverse events occurred in 10 patients (16%) in cohort A and 8 (13%) in cohort B, with the most common occurring in ≥ 2 patients being pancreatitis, fatigue, increased alanine aminotransferase, and increased lipase (2 patients each; 3%) in cohort A. CONCLUSION Pembrolizumab is effective with a manageable safety profile in patients with MSI-H/dMMR CRC.

Clinical and molecular features of responders to PD-1 blockade for patients with microsatellite instability high or mismatch repair deficient advanced gastrointestinal tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16550-e16550
Author(s):  
Keigo Chida ◽  
Akihito Kawazoe ◽  
Masahito Kawazu ◽  
Yoshiaki Nakamura ◽  
Toshihiro Suzuki ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Tumor Cells ◽  
Response Rate ◽  
Objective Response ◽  
Wild Type ◽  
Durable Response ◽  
Pten Mutation ◽  
Molecular Features ◽  
Biomarker Analysis

e16550 Background: An anti-PD-1 inhibitor pembrolizumab showed a durable response for patients with microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) advanced solid tumors. However, clinical and molecular features of responders to PD-1 blockade for MSI-H/dMMR advanced gastrointestinal (GI) tumors are not well understood. Methods: Patients with MSI-H/dMMR GI tumors who received anti‒PD-1 monotherapy were enrolled in this study. PD-L1 expression in tumor cells or immune cells as well as combined positive score (CPS) were assessed using the PDL1 IHC 22C3 pharmDx assay. Cancer genome alterations were evaluated by a next generation sequencing-based panel with Oncomine Comprehensive Assay for tumor tissue samples or Guardant360 ctDNA Assay for plasma samples. Results: A total of 43 patients with gastric cancer (n = 19), colorectal cancer (n = 16), cholangiocarcinoma (n = 4), small intestine cancer (n = 2) and pancreatic cancer (n = 2) were analyzed in this study. All patients had measurable lesions and objective response was observed in 20 patients (46%). Objective response rate (ORR) was significantly higher in patients with ECOG PS of 0 than in those with PS of 1 or 2 (64% vs. 22%, p = 0.01) and PD-L1+ in tumor cells than in those with PD-L1- in tumor cells (67% vs. 32%, p = 0.03). ORR was similar according to PD-L1 CPS; 45% in CPS < 1, 47% in CPS ≥1 and 56% in CPS ≥10, respectively. ORR was numerically lower in patients with PTEN mutation than in those with PTEN wild type (29% vs. 56%). Also, durable response rate (objective response lasting continuously ≥6 months) was significantly lower in patients with PTEN mutation than in those with PTEN wild type (0% vs. 52%, p = 0.03). In the overall population, median progression-free survival (PFS) was 10.0 months (95% CI, 4.0-not reached). In univariate analysis, PS (1 or 2 vs. 0) was the strongest clinical factor associated with PFS (3.9 months vs. not reached, HR 3.9; 95% CI 1.7-9.2, p = 0.002). After adjusted by PS, PTEN mutation was only molecular factor associated with shorter PFS (3.4 vs. 24.5 months, HR 3.0; 95% CI 1.1-8.4, p = 0.03). Conclusions: Some clinical and molecular factors were associated with response to PD-1 blockade for MSI-H/dMMR advanced GI tumors. Updated biomarker analysis with whole exome sequencing and multiplex IHC will be presented.

Effects of adding necitumumab to first-line chemotherapy in patients with stage IV non-small-cell lung cancer: Meta-analysis

2019 ◽  
Vol 26 (6) ◽  
pp. 1331-1342
Author(s):  
Irena Ilic ◽  
Sandra Sipetic ◽  
Jovan Grujicic ◽  
Milena Ilic
Keyword(s):  
Overall Survival ◽  
Objective Response Rate ◽  
Advanced Nsclc ◽  
Response Rate ◽  
Meta Analysis ◽  
Objective Response ◽  
Stage Iv ◽  
Progression Free Survival ◽  
First Line ◽  
Free Survival

Introduction Almost half of patients with non-small-cell lung cancer (NSCLC) are diagnosed at an advanced stage. Our aim was to assess the effects of adding necitumumab to chemotherapy in patients with stage IV NSCLC. Material and methods A comprehensive literature search was performed according to pre-specified inclusion and exclusion criteria. Data on overall survival, progression-free survival, objective response rate and adverse events were extracted. A meta-analysis was performed to obtain pooled hazard ratios (HR) and corresponding 95% confidence intervals (CI) for time-to-event data and pooled odds ratio (OR) with 95% CI for dichotomous outcomes. Results The meta-analysis included four randomized clinical trials with 2074 patients. The pooled results showed significant improvement for overall survival (HR = 0.87 (95% CI 0.79–0.95), p = 0.004) when necitumumab was added to chemotherapy in patients with advanced NSCLC. No statistically significant improvement was noted for progression-free survival and objective response rate (HR = 0.83 (95% CI 0.69–1.01), p = 0.06 and OR = 1.46 (95% CI 0.90–2.38), p = 0.13, respectively). Subgroup analysis showed that in patients with non-squamous NSCLC, there was no benefit in overall survival and objective response rate. Patients with advanced NSCLC who received necitumumab were at the highest odds of developing a skin rash (OR = 14.50 (95% CI 3.16–66.43), p = 0.0006) and hypomagnesaemia (OR = 2.77 (95% CI 2.23–3.45), p < 0.00001), while the OR for any grade ≥3 adverse event was 1.55 (95% CI 1.28–1.87, p < 0.00001). Conclusions The addition of necitumumab to standard chemotherapy in a first-line setting in patients with stage IV NSCLC results in a statistically significant improvement in overall survival, while the results were not significant for progression-free survival and objective response rate.

Phase II study of combination chemotherapy with biweekly cetuximab and irinotecan for wild-type KRAS metastatic colorectal cancer refractory to irinotecan, oxaliplatin, and fluoropyrimidines.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 561-561
Author(s):  
S. Yuki ◽  
K. Shitara ◽  
M. Yoshida ◽  
D. Takahari ◽  
S. Utsunomiya ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Combination Chemotherapy ◽  
Response Rate ◽  
Standard Dose ◽  
Objective Response ◽  
Progression Free Survival ◽  
Wild Type ◽  
Standard Regimen ◽  
Free Survival

561 Background: Weekly cetuximab and irinotecan is a standard regimen in heavily pretreated patients with metastatic colorectal cancer (MCRC). The aim of this study was to prospectively evaluate the efficacy of combination chemotherapy with biweekly cetuximab and irinotecan in patients with pretreated MCRC harboring wild-type KRAS. Methods: Patients with wild- type KRAS MCRC that had progressed after chemotherapy with irinotecan, oxaliplatin, and fluoropyrimidine were included in this study. Cetuximab was administered at 500 mg/m2 biweekly with irinotecan. The primary endpoint was response rate. The secondary endpoints included adverse events, progression-free survival, and overall survival. The pharmacokinetics of cetuximab was also evaluated in five patients. Results: From May, 2009 to February, 2010, a total of 31 patients were enrolled from five institutions. One patient was not eligible. Among the 30 assessable patients, ECOG PS was 0 in 12, 1 in 16, and 2 in two patients. The objective response rate was 30.0% (95% confidence interval [CI], 14.7-49.4), and the disease control rate (complete response, partial response, or stable disease) was 76.7% (95%CI, 61.4-92.3). The median progression-free survival was 5.3 months (95%CI, 3.4-7.3). Grade 3 skin toxicity was observed in 3 patients (10%), and treatment related death due to pneumonia occurred in one patient. Conclusions: The efficacy data are similar to those of standard dose of cetuximab plus irinotecan. Combination chemotherapy with biweekly cetuximab and irinotecan is effective for pretreated metastatic wild-type KRAS MCRC. No significant financial relationships to disclose.

Overall survival analysis of the FOXFIRE prospective randomized studies of first-line selective internal radiotherapy (SIRT) in patients with liver metastases from colorectal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3507-3507 ◽  
Author(s):  
Ricky A. Sharma ◽  
Harpreet Singh Wasan ◽  
Guy A. Van Hazel ◽  
Volker Heinemann ◽  
Navesh K. Sharma ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Liver Metastases ◽  
Response Rate ◽  
Objective Response ◽  
Hepatic Metastases ◽  
First Line ◽  
Selective Internal Radiotherapy ◽  
Internal Radiotherapy ◽  
Randomized Studies

3507 Background: The FOXFIRE, SIRFLOX and FOXFIRE-Global (FF-SF-FFG) randomized studies evaluated the efficacy of combining first-line chemotherapy for metastatic colorectal cancer (mCRC) with selective internal radiotherapy (SIRT) using yttrium-90 resin microspheres in patients with liver metastases. The studies were designed for prospective, combined analysis of overall survival (OS). Methods: FF-SF-FFG randomized (1:1) chemotherapy-naïve mCRC patients (performance status 0/1) with liver metastases not suitable for curative resection/ablation. Arm A was oxaliplatin-based chemotherapy (mFOLFOX6/ OxMdG) ± investigator-chosen biologically targeted agent. Arm B was the same systemic therapy (oxaliplatin dose modification) + single treatment SIRT with cycle 1/2 of chemotherapy. Primary tumor in situ and/or limited extra-hepatic metastases were permitted. Minimum sample size was 1075 patients (HR 0.8, 80% power, two-sided 5% significance). Secondary outcomes included PFS, liver-specific PFS and response rate. Apart from safety, outcomes were analysed on intention-to-treat population using meta-analytic methods of pooled individual patient data. Results: Between 2006 and 2014, 1103 patients were randomized in 14 countries. Median age was 63 years (range 23-89); median follow-up 43.3 months. There were 844 deaths. There was no difference in OS (HR 1.04; 95% CI 0.90-1.19, p= 0.609) or PFS (HR 0.90, CI 0.79-1.02, p= 0.108) between Arms. Objective response rate ( p= 0.001) and liver-specific progression (HR 0.51, CI 0.43-0.62, p< 0.001) were significantly more favorable in Arm B. Patients in Arm B had higher risk of non-liver progression as first event (HR 1.98, CI 1.53-2.58, p< 0.001). Grade 3-5 adverse events were more common in Arm B (74.0%) than A (66.5%), p= 0.009. In health status questionnaires, EQ-5D utility scores were not significantly different between Arms at 6, 12 or 24 months. Conclusion: Despite higher response rates and improved liver-specific PFS, the addition of SIRT to first-line oxaliplatin-fluorouracil chemotherapy for patients with liver-only and liver-dominant mCRC did not improve OS or PFS. Clinical trial information: 83867919.

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