Dataset Information

Identification of potential surrogate end points in randomized clinical trials of aggressive and indolent non-Hodgkin's lymphoma: correlation of complete response, time-to-event and overall survival end points.

ABSTRACT:

Background

The correlation between efficacy end points in randomized controlled trials (RCTs) of systemic therapy for non-Hodgkin's lymphoma (NHL) was investigated to identify an appropriate surrogate end point for overall survival (OS).

Methods

RCTs of previously untreated NHL published from 1990 to 2009 were identified. Associations between absolute differences in efficacy end points were determined using nonparametric Spearman's rank correlation coefficients (r(s)).

Results

Thirty-eight RCTs representing 85 treatment arms for aggressive NHL and 20 RCTs representing 42 arms for indolent NHL were included. For aggressive NHL, differences in 3-year progression-free survival (PFS)/event-free survival (EFS) were high correlated with differences in 5-year OS {r(s) of 0.90 [95% confidence interval (CI) 0.73-0.96]} and linear regression determined that a 10% improvement in 3-year EFS or PFS would predict for a 7% ± 1% improvement in 5-year OS. For indolent histology disease, differences in complete response were strongly correlated with differences in 3-year EFS [r(s) 0.86 (95% CI 0.35-0.97)], but there was no correlation between 3-year time-to-event end points and 5-year OS.

Conclusions

Improvements in 3-year EFS/PFS are highly correlated with improvements in 5-year OS in aggressive NHL and should be explored as a candidate surrogate end point. Definition of these relationships may inform future clinical trial design and interpretation of interim trial data.

SUBMITTER: Lee L

PROVIDER: S-EPMC3101365 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Identification of potential surrogate end points in randomized clinical trials of aggressive and indolent non-Hodgkin's lymphoma: correlation of complete response, time-to-event and overall survival end points.

Lee L L Wang L L Crump M M

Annals of oncology : official journal of the European Society for Medical Oncology 20110125 6

<h4>Background</h4>The correlation between efficacy end points in randomized controlled trials (RCTs) of systemic therapy for non-Hodgkin's lymphoma (NHL) was investigated to identify an appropriate surrogate end point for overall survival (OS).<h4>Methods</h4>RCTs of previously untreated NHL published from 1990 to 2009 were identified. Associations between absolute differences in efficacy end points were determined using nonparametric Spearman's rank correlation coefficients (r(s)).<h4>Results< ...[more]

PMID: 21266519

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Project description:Treatment of non-Hodgkin lymphoma (NHL) in general has improved over the years with the emergence of the monoclonal antibodies (MAB) therapy. NHL is divided into B cell NHL and T cell NHL. Treatment of NHL was based on the subtype of NHL and its staging. NHL is divided into aggressive and indolent NHL (iNHL). Subtypes of iNHL include: Follicular lymphoma (FL), Marginal zone lymphoma (MZL), Chronic lymphocytic leukemia/small-cell lymphocytic lymphoma (CLL/SLL), Gastric mucosa-associated lymphoid tissue (MALT) lymphoma, Lymphoplasmacytic lymphoma, Waldenström macroglobulinemia, Nodal marginal zone lymphoma (NMZL), Splenic marginal zone lymphoma (SMZL). Chemotherapy was the main stay treatment of iNHL until the emergence of Rituximab, anti-CD20 MAB targeting CD-20 surface cell antigens that are present on B-cells lymphoma and not on precursor cells, mainly efficacious in B cell iNHL, It became the mainstay treatment in follicular lymphoma (FL) as a single agent modality or in combination with chemotherapy. The anti-CD20 Rituximab played an important role in the development of the treatment of iNHL to become FDA approved in 1997. It was also proven effective in multiple other types of lymphoma. MAB through targeting the cell surface antigen leads to a direct or immune mediated cytotoxicity. This carries few side effects, including allergic reactions. Other than that, a resistance mechanism to rituximab emerged by inducing a failure in the apoptosis mechanism. Alternative mechanisms of resistance included the presence of soluble antigens that could act by binding to the antibody present before the drug itself can bind the lymphoma cell. Thus, the interest in immunotherapy grew further to explore the possibility of conjugating an immune mediated drug to a radio-sensitizing agent in order to enhance the selectivity of the drug. Here came the development of 90Y-ibritumomab tiuxetan and 131I-tositumomab. After it, humanized anti-CD20 emerged ofatumumab, IMMU106 (veltuzumab) in 2005, and ocrelizumab which are considered as second generation anti-CD20 and 3rd generation anti-CD20 include AME-133v (ocaratuzumab), PRO131921 and GA101 (obinutuzumab). Also multiple other agents emerged targeting different surface cell antigens like CD52 (alemtuzumab), CD22 (unconjugated epratuzumab and calicheamicin conjugated CMC-544 [inotuzumab ozogamicin]), CD80 (galiximab), CD2 (MEDI-507 [siplizumab]), CD30 (SGN-30 and MDX-060 [iratumumab], Brentuximab vedotin), CD40 (SGN-40), and CD79b (Polatuzumab). Other agents include MAB targeting T-Cells like mogamulizumab, Denileukin Diftitox and BiTEs or bispecific T cell engagers like Mosunetuzumab, Glofitamab, and Epcoritamab. Moreover, further studies came up to evaluate the role of immunotherapy in combination chemotherapy as a pathway to evade the resistance mechanisms. Side effects of the treatment were mainly infusion related adverse reactions, myelosuppression in conjugated forms leading to immunosuppression and subsequently to infectious complications. Another important aspect in immunotherapy is the half-lives of the medication which is an important factor that can influence the evaluation of the response. The MAB treatment showed important benefit in the treatment of iNHL and it continuously shows how rapidly it can develop to provide optimum care and benefit to patients with iNHL.

Project description:ImportanceContemporary observational cancer research requires associating genomic biomarkers with reproducible end points; overall survival (OS) is a key end point, but interpretation can be challenging when multiple lines of therapy and prolonged survival are common. Progression-free survival (PFS), time to treatment discontinuation (TTD), and time to next treatment (TTNT) are alternative end points, but their utility as surrogates for OS in real-world clinicogenomic data sets has not been well characterized.ObjectiveTo measure correlations between candidate surrogate end points and OS in a multi-institutional clinicogenomic data set.Design, setting, and participantsA retrospective cohort study was conducted of patients with non-small cell lung cancer (NSCLC) or colorectal cancer (CRC) whose tumors were genotyped at 4 academic centers from January 1, 2014, to December 31, 2017, and who initiated systemic therapy for advanced disease. Patients were followed up through August 31, 2020 (NSCLC), and October 31, 2020 (CRC). Statistical analyses were conducted on January 5, 2021.ExposuresCandidate surrogate end points included TTD; TTNT; PFS based on imaging reports only; PFS based on medical oncologist ascertainment only; PFS based on either imaging or medical oncologist ascertainment, whichever came first; and PFS defined by a requirement that both imaging and medical oncologist ascertainment have indicated progression.Main outcomes and measuresThe primary outcome was the correlation between candidate surrogate end points and OS.ResultsThere were 1161 patients with NSCLC (648 women [55.8%]; mean [SD] age, 63 [11] years) and 1150 with CRC (647 men [56.3%]; mean [SD] age, 54 [12] years) identified for analysis. Progression-free survival based on both imaging and medical oncologist documentation was most correlated with OS (NSCLC: ρ = 0.76; 95% CI, 0.73-0.79; CRC: ρ = 0.73; 95% CI, 0.69-0.75). Time to treatment discontinuation was least associated with OS (NSCLC: ρ = 0.45; 95% CI, 0.40-0.50; CRC: ρ = 0.13; 95% CI, 0.06-0.19). Time to next treatment was modestly associated with OS (NSCLC: ρ = 0.60; 0.55-0.64; CRC: ρ = 0.39; 95% CI, 0.32-0.46).Conclusions and relevanceThis cohort study suggests that PFS based on both a radiologist and a treating oncologist determining that a progression event has occurred was the surrogate end point most highly correlated with OS for analysis of observational clinicogenomic data.

Project description:Importance:Surrogate end points in oncology trade the advantage of reducing the time needed to conduct clinical trials for the disadvantage of greater uncertainty regarding the treatment effect on patient-centered end points, such as overall survival (OS) and quality of life. Objective:To quantify the amount of time saved through the acceptance of surrogate end points, including response rate (RR) and progression-free survival (PFS). Design, Setting, and Participants:This retrospective study of US Food and Drug Administration (FDA) oncology approvals and their drug registration trials based on actual publication analyzed the original and updated clinical trials data that led to FDA-approved drug indications in oncology from 2006 to 2017 by using existing publications, conference abstracts, and package inserts from the FDA. Data related to cancer type, line of therapy (first-line, second-line, and third- or later-line treatment of advanced or metastatic disease), FDA approval type, end point basis for approval (RR, PFS, or OS/quality of life), sample size, accrual rate, and drug RR were extracted by March 23, 2018. All data were analyzed by July 13, 2018. Main Outcomes and Measures:The main outcome was the study duration needed to complete the primary end point analysis used for each drug indication approval. This was estimated from reported enrollment dates, analysis cutoff dates, time to response, median duration of response, median PFS, and median OS. Results:In total, 188 distinct indications among 107 cancer drugs were identified. The RR was more often used for FDA approval in subsequent lines of therapy (17 of 71 drug indications [24%] in first-line therapy vs 34 of 77 drug indications [44%] in second-line therapy vs 19 of 24 drug indications [79%] in third- or later-line therapy, P < .001). Study duration for PFS (median, 31 [range, 10-104] months) was similar to that for OS (median, 33 [range, 12-117] months; P = .31), whereas study duration for RR (median, 25 [range, 11-54] months) was shorter than that for OS (P = .001). In multivariate analysis, compared with using OS, use of PFS as the end point was associated with study durations that were shorter by a mean of 11 months (95% CI, 5-17 months), and the use of RR as the end point was associated with study durations that were shorter by a mean of 19 months (95% CI, 13-25 months). Conclusions and Relevance:From the findings of this study, an estimated 11 months appeared to be needed (ie, approximately 12% longer in the drug development cycle) to assess the OS benefit of a cancer drug. This study's findings suggest that this must be weighed against the downside of increased uncertainty of clinical benefit arising from using surrogate end points.

Project description:BackgroundThe efficacy of autologous stem-cell transplantation during the first remission in patients with diffuse, aggressive non-Hodgkin's lymphoma classified as high-intermediate risk or high risk on the International Prognostic Index remains controversial and is untested in the rituximab era.MethodsWe treated 397 patients who had disease with an age-adjusted classification of high risk or high-intermediate risk with five cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP plus rituximab. Patients with a response were randomly assigned to receive three additional cycles of induction chemotherapy (control group) or one additional cycle of induction chemotherapy followed by autologous stem-cell transplantation (transplantation group). The primary efficacy end points were 2-year progression-free survival and overall survival.ResultsOf 370 induction-eligible patients, 253 were randomly assigned to the transplantation group (125) or the control group (128). Forty-six patients in the transplantation group and 68 in the control group had disease progression or died, with 2-year progression-free survival rates of 69 and 55%, respectively (hazard ratio in the control group vs. the transplantation group, 1.72; 95% confidence interval [CI], 1.18 to 2.51; P=0.005). Thirty-seven patients in the transplantation group and 47 in the control group died, with 2-year overall survival rates of 74 and 71%, respectively (hazard ratio, 1.26; 95% CI, 0.82 to 1.94; P=0.30). Exploratory analyses showed a differential treatment effect according to risk level for both progression-free survival (P=0.04 for interaction) and overall survival (P=0.01 for interaction). Among high-risk patients, the 2-year overall survival rate was 82% in the transplantation group and 64% in the control group.ConclusionsEarly autologous stem-cell transplantation improved progression-free survival among patients with high-intermediate-risk or high-risk disease who had a response to induction therapy. Overall survival after transplantation was not improved, probably because of the effectiveness of salvage transplantation. (Funded by the National Cancer Institute, Department of Health and Human Services, and others; SWOG-9704 ClinicalTrials.gov number, NCT00004031.).

Dataset Information

Identification of potential surrogate end points in randomized clinical trials of aggressive and indolent non-Hodgkin's lymphoma: correlation of complete response, time-to-event and overall survival end points.

Background

Methods

Results

Conclusions

Publications

Identification of potential surrogate end points in randomized clinical trials of aggressive and indolent non-Hodgkin's lymphoma: correlation of complete response, time-to-event and overall survival end points.

Similar Datasets

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