Surrogate Endpoints in Second-Line Trials of Targeted Agents in Metastatic Colorectal Cancer: A Literature-Based Systematic Review and Meta-Analysis

Cremolini, Chiara; Antoniotti, Carlotta; Pietrantonio, Filippo; Berenato, Rosa; Tampellini, Marco; Baratelli, Chiara; Salvatore, Lisa; Marmorino, Federica; Borelli, Beatrice; Nichetti, Federico; Bironzo, Paolo; Sonetto, Cristina; Bartolomeo, Maria Di; Braud, Filippo de; Loupakis, Fotios; Falcone, Alfredo; Maïo, Massimo Di

doi:10.4143/crt.2016.249

Cited by 13 publications

(17 citation statements)

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“…On the one hand, response rates could be a sensitive measure of benefit in the context of pediatric malignancies, given their rapid progression. On the other hand, the relationship between response rates and patient-centered outcomes like quality of life or survival is variable [ 33 – 37 ]. Moreover, eventual drug approvals are usually based on survival data from randomized controlled trials, and only about 6.7% to 9.6% of drugs tested in oncology will eventually be registered [ 50 , 51 ].…”

Section: Discussionmentioning

confidence: 99%

“…From each study, we extracted data related to study design, funding, reason for stopping the trial, patient characteristics, intervention, outcomes, and the timing of pediatric testing relative to adult testing. Because Phase I cancer studies do not generally have comparator arms or measure survival endpoints, we used objective response rate and the number of patients receiving recommended dose as proxies for therapeutic benefit [ 33 – 37 ].…”

Section: Methodsmentioning

confidence: 99%

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Risk and surrogate benefit for pediatric Phase I trials in oncology: A systematic review with meta-analysis

et al. 2018

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BackgroundPediatric Phase I cancer trials are critical for establishing the safety and dosing of anti-cancer treatments in children. Their implementation, however, must contend with the rarity of many pediatric cancers and limits on allowable risk in minors. The aim of this study is to describe the risk and benefit for pediatric cancer Phase I trials.Methods and findingsOur protocol was prospectively registered in PROSPERO (CRD42015015961). We systematically searched Embase and PubMed for solid and hematological malignancy Phase I pediatric trials published between 1 January 2004 and 1 March 2015. We included pediatric cancer Phase I studies, defined as “small sample size, non‑randomized, dose escalation studies that defined the recommended dose for subsequent study of a new drug in each schedule tested.” We measured risk using grade 3, 4, and 5 (fatal) drug-related adverse events (AEs) and benefit using objective response rates. When possible, data were meta-analyzed. We identified 170 studies meeting our eligibility criteria, accounting for 4,604 patients. The pooled overall objective response rate was 10.29% (95% CI 8.33% to 12.25%), and was lower in solid tumors, 3.17% (95% CI 2.62% to 3.72%), compared with hematological malignancies, 27.90% (95% CI 20.53% to 35.27%); p < 0.001. The overall fatal (grade 5) AE rate was 2.09% (95% CI 1.45% to 2.72%). Across the 4,604 evaluated patients, there were 4,675 grade 3 and 4 drug-related AEs, with an average grade 3/4 AE rate per person equal to 1.32. Our study had the following limitations: trials included in our review were heterogeneous (to minimize heterogeneity, we separated types of therapy and cancer types), and we relied on published data only and encountered challenges with the quality of reporting.ConclusionsOur meta-analysis suggests that, on the whole, AE and response rates in pediatric Phase I trials are similar to those in adult Phase I trials. Our findings provide an empirical basis for the refinement and review of pediatric Phase I trials, and for communication about their risk and benefit.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Risk and surrogate benefit for pediatric Phase I trials in oncology: A systematic review with meta-analysis

et al. 2018

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“…The observatory main objective was to assess PFS and related predictive factors in routine clinical practice. PFS was chosen as the primary endpoint based on the results of several published analyses, demonstrating that PFS can act as a surrogate for OS in the first-line treatment metastatic colorectal cancer [ 9 , 10 ]. PFS is often chosen over OS in clinical trials as OS is impacted by the outcomes of subsequent therapeutic lines and does not directly evaluate the benefit of a given therapy [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

“…OS in the first-line treatment metastatic colorectal cancer [9,10]. PFS is often chosen over OS in clinical trials as OS is impacted by the outcomes of subsequent therapeutic lines and does not directly evaluate the benefit of a given therapy [11].…”

Section: Plos Onementioning

confidence: 99%

PREMIUM: A French prospective multicenter observational study of factors impacting on efficacy and compliance to cetuximab treatment in first-line KRAS wild-type metastatic colorectal cancer

et al. 2020

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Background Cetuximab improves progression-free survival (PFS) and overall survival (OS) in patients with KRAS wild type (wt) metastatic colorectal cancer (mCRC). Few data are available on factors impacting both efficacy and compliance to cetuximab treatment, which is, in combination with chemotherapy, a standard-of-care first-line treatment regimen for patients with KRAS wt mCRC. Patients and methods PREMIUM is a prospective, French multicenter, observational study that recruited patients with KRAS wt mCRC scheduled to receive cetuximab, with or without first-line chemotherapy, as part of routine clinical practice, between October 28, 2009 and April 5, 2012 (ClinicalTrials.gov Identifier: NCT01756625). The main endpoints were the factors impacting on efficacy and compliance to cetuximab treatment. Predefined efficacy endpoints were PFS and safety. Results A total of 493 patients were recruited by 94 physicians. Median follow-up was 12.9 months. Median progression-free survival was 11 months [9.6–12]. In univariate analyses, ECOG performance status (PS), smoking status, primary tumor location, number of metastatic organs, metastasis resectability, surgery, folliculitis, xerosis and paronychia maximum grade, and acne preventive treatment were statistically significant. In multivariate analysis (Hazard Ratios of multivariate stepwise Cox models), ECOG PS, surgery, xerosis and folliculitis were positive prognostics factors for longer PFS. Among all patients, 69 (14%) were non-compliant. In multivariate analysis, no variables were statistically significant. The safety profile of cetuximab was consistent with previous studies. Conclusions ECOG PS <2, surgical treatment performed, and maximum grade xerosis or folliculitis developed were predictive factors of cetuximab efficacy on KRAS wt mCRC patients. Unfortunately, we failed in identifying predictive factors for compliance in these patients.

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“…In their meta-analysis, Cremolini et al 7 confirmed the role of progression-free survival (PFS) as a reliable surrogate for OS, thus justifying the surrogacy of PFS as a primary endpoint in first-line studies in MCRC. Furthermore, the PFS has also been tested in second- and further-lines of treatment of several targeted agents producing significant results.…”

Section: Introductionmentioning

confidence: 99%

Progression-free survival as a surrogate endpoint of overall survival in patients with metastatic colorectal cancer

Cicero¹,

Luca²,

Dieli³

2018

OTT

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BackgroundIn many clinical trials designed to assess the efficacy of anticancer treatments, overall survival (OS) is often used as a primary endpoint despite its several points of weakness.MethodsThis study evaluated the role of progression-free survival (PFS) in the first three lines of treatment as a potential surrogate endpoint of OS in patients with metastatic colorectal cancer (MCRC). One hundred and twenty patients with MCRC were enrolled in this study. The median PFS of the first-, second-, and third-lines of treatment and the OS were evaluated. The correlation between the time to progression and the OS was analyzed. The median PFS of the three lines of treatment were 8.5, 5, and 3 months, respectively.ResultsThe median OS was 32.4 months. A modest correlation was found between the PFS to the first-line treatment with Folfox–avastin and OS. Similar data were obtained with the second-line treatment. However, no correlation was found between the PFS and OS during the third-line treatment. The regression analysis revealed that PFS is predictive of OS.ConclusionIn brief, the PFS of the first- and second-lines of treatment could be a good candidate as a surrogate endpoint of OS in patients with MCRC.

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Surrogate Endpoints in Second-Line Trials of Targeted Agents in Metastatic Colorectal Cancer: A Literature-Based Systematic Review and Meta-Analysis

Cited by 13 publications

References 35 publications

Risk and surrogate benefit for pediatric Phase I trials in oncology: A systematic review with meta-analysis

Risk and surrogate benefit for pediatric Phase I trials in oncology: A systematic review with meta-analysis

PREMIUM: A French prospective multicenter observational study of factors impacting on efficacy and compliance to cetuximab treatment in first-line KRAS wild-type metastatic colorectal cancer

Progression-free survival as a surrogate endpoint of overall survival in patients with metastatic colorectal cancer

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