os pfs orr

PFS is considered an indication of disease control and stabilization. Rochester (NY): Disease-free survival as a surrogate for overall survival in adjuvant trials of gastric cancer: a meta-analysis. Nineteen trials involving 4571 patients were included in the analysis. Delayed Response After Confirmed Progression (DR) and Other Unique Immunotherapy-Related Treatment Concepts in Cutaneous Squamous Cell Carcinoma. Identification of biomarkers is important in early phase trials. Median PFS and OS across all trials were 4.5 months and 11.5 months and median ORR and DCR were 11.4% and 65%, respectively. Unable to load your collection due to an error, Unable to load your delegates due to an error. Trial-level associations between modified PFS and OS ranged between 0.07 and 0.1, and individual-level correlations were approximately 0.6. Intermediate endpoints based on tumor measurement, such as ORR and PFS, have been routinely used to evaluate new therapies in oncology trials and have served as the endpoints likely to predict clinical benefit for the consideration of accelerated approval of drugs. Nie RC, Chen FP, Yuan SQ, Luo YS, Chen S, Chen YM, Chen XJ, Chen YB, Li YF, Zhou ZW. Eur J Cancer. It is unclear what impact, if any, the nontarget and new lesion progressions played in contributing to the lack of association between PFS and OS; however, >45% of progressions were based on these types of response. Due to the nature of this modification, the impact on assessment of PD and the number of PFS events decreased as the threshold values increased. There have been multiple attempts to modify the RECIST algorithm, from the Immune-Related Response Criteria (irRC 2009; ref. eCollection 2021. The trial-level association between OS and the traditional PFS endpoint, derived using investigator-evaluated tumor assessments to define progression based on standard RECIST criteria, was R2 = 0.0559. The OR for ORR in one study was an outlier (13.56; Table 1), and excluding this from the analysis resulted in an R2 value of 0.1213. Patient-level responder analysis was performed for PFS and OS. Associations between treatment effects of ORR, PFS, modified PFS, and OS were evaluated at individual and trial levels. PFS and OS were primary endpoints; ORR was a secondary endpoint. The line represents the regression line fitted using the HR of PFS as a predictor of OS HR on a logarithmic scale. Epub 2018 Aug 21. An example in oncology is the use of objective response rate (ORR) and progression-free survival (PFS). The search for surrogate endpoints for immunotherapy trials. This suggests that, although responders lived longer without disease progression and death, both PFS and ORR are not good surrogate endpoints for OS. The challenges noted in using RECIST to evaluate immunotherapies have not gone unnoticed in the oncology community. The odds ratio (OR) was considered when assessing the relative effect of ORR. 2017 Nov;86:257-265. doi: 10.1016/j.ejca.2017.09.018. No potential conflicts of interest were disclosed. Disease progression (PD) was determined using criteria as described by RECIST v1.1, where a significant increase (≥20%) in size of target lesions as compared with nadir with an absolute increase in size of at least 5 mm, development of new lesion(s), or unequivocal progression in an existing nontarget tumor was defined as progression. a ORR defined as CR+PR per RECIST v1.1 in the ITT population as evaluated by ICR. At the individual level, the Spearman rank correlation coefficient between PFS and OS was 0.61. Results: The coefficient of determination (R²) measured the strength of associations, where values near 1 imply surrogacy and values close to 0 suggest no association. Although every cancer type is unique, immunotherapies have demonstrated various levels of clinical benefit across different cancer types. Avelumab is also indicated for Merkel cell carcinoma. The differences that were observed in number of PFS events by varying the cutoff values were due solely to the target tumor response. PFS showed good correlation with OS (squared Spearman rank correlation coefficient [r s 2] = 0.54; P < 0.001), while ORR and DCR illustrated moderate association with OS (r s 2 = 0.29 and 0.28, respectively; both P < 0.001). No statistically significant difference was observed between the two groups in terms of OS, PFS, and ORR. It is important to note that many of these trials allowed for treatment beyond initial RECIST-defined progression; thus, there is the potential for a patient whose initial value was between the 20% and 25% cut points to appear as a progression at a later date if his or her tumor burden increased to that higher threshold value. In cases such as this, promising products may not have been approved if PFS was the primary endpoint of the study evaluating the product. These endpoints are primarily defined by changes in tumor burden and are assessable earlier, require shorter study durations and follow-up time, and may not need the larger sample sizes required in studies with OS as the primary endpoint. We aimed to assess whether the Response Evaluation Criteria in Solid Tumors (RECIST) criteria–based objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) could be valid surrogate end-points for overall survival (OS) in anti–programmed death-1 (PD-1)/programmed death … PFS2 (time from randomization to objective tumor progression on next-line treatment/death), was an exploratory endpoint. Purpose: With the approval of immunotherapies for a variety of indications, methods to assess treatment benefit addressing the response patterns observed are important. ISSN: 1078-0432. 这四个终点指标分为近期疗效治疗和远期疗效指标，近期疗效指标主要评估药物对肿瘤的直接影响（包括导致肿瘤消失或退缩等），其中以ORR … However, the RECIST criteria were developed based on experience with cytotoxic agents, and it has been observed that the mechanisms of action of immunotherapeutic agents are markedly different from cytotoxic drugs. It is due to these limitations of the OS endpoint and the intent to provide patients with access to promising agents as early as possible that surrogate endpoints such as ORR and progression-free survival (PFS) have been useful in evaluating new treatments. The individual-level association based on rank correlation between PFS and OS was not strong (Ρ = 0.61). Reason for progression (using RECIST criteria of 20% for target tumors) in each treatment group. The primary component of tumor progression was further characterized based on target, nontarget, new lesion, or progression based on new and nontarget lesions together at the same assessment. Taking into account that there may be delayed response preceded by actual disease progression, modifying the burden level at which we determine progression could potentially address this issue. 2019 Feb;128:113-119. doi: 10.1016/j.lungcan.2018.12.023. Pembrolizumab and nivolumab, both checkpoint inhibitors that block the interaction between PD-1 and its ligands PD-L1 and PD-L2, received accelerated approval (1, 2) from the FDA in the last quarter of 2014 based on overall response rate (ORR). Modifications to PFS did not improve associations. HRs of PFS and OS for responders versus nonresponders were 0.129 [95% confidence interval (CI), 0.11–0.15] and 0.118 (95% CI, 0.11–0.13), respectively. Thus, using a more stringent criterion to define PFS did not result in a better association between PFS and OS. ©2018 American Association for Cancer Research. Table 1 summarizes the trials included in the analyses (16–28). OS, defined as the time from random assignment to the date of death from any cause, is a precise, objectively measured, and easy-to-interpret clinical outcome, and has been considered the most reliable and clinically meaningful endpoint for evaluating drug efficacy in oncology trials. The HRs ranged between 0.42 and 0.86 for OS and 0.41 and 0.93 for PFS, and the minimum OR for ORR was 1.67. The coefficient of determination (R²) value computed from the weighted linear regression model was used to measure the strength of association between PFS/ORR and OS. Evaluation of objective response, disease control and progression-free survival as surrogate end-points for overall survival in anti-programmed death-1 and anti-programmed death ligand 1 trials. Cramer-van der Welle CM, Verschueren MV, Tonn M, Peters BJM, Schramel FMNH, Klungel OH, Groen HJM, van de Garde EMW; Santeon NSCLC Study Group. NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. For example, when applying the 20% cutoff criteria (PFS_20), almost 52% of the progressions were based on target tumors, as shown in Table 2. doi: 10.1136/jitc-2020-002114. eISSN: 1557-3265 At the trial level, the association between hazard ratios (HR) of PFS and OS was R2 = 0.1303, and between the odds ratio (OR) of ORR and HR of OS was R2 = 0.1277. At the individual level, the Spearman rank correlation coefficient between PFS and OS was 0.61. Mushti, F. Mulkey, R. Sridhara, Study supervision: S.L. In part 2 of the analysis, a consistent approach was implemented using investigator-evaluated tumor assessments to define progression using the standard RECIST v1.1 criteria across all trials. The lack of association could be due to a subgroup of patients benefitting from the therapy. 2018 Jun;6(11):231. doi: 10.21037/atm.2018.05.16. Ito K, Miura S, Sakaguchi T, Murotani K, Horita N, Akamatsu H, Uemura K, Morita S, Yamamoto N. Lung Cancer. Atypical response patterns in patients receiving immunotherapies have led to challenges in evaluating clinical benefit using the traditional RECIST criteria. The primary endpoint was OS, and the secondary endpoints were progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). Adherence to this new model of data collection will give an opportunity to make potential changes to RECIST, which was not possible before due to the nonavailability of assessments. Select secondary endpoints include objective response rate (ORR) by BICR per RECIST v1.1 and safety/tolerability. At the individual level, the Spearman rank correlation coefficient between PFS and OS was 0.61. PSA response rate). The outcome measures considered in this analysis were OS, PFS, and ORR. 2021 Apr 7;19(1):144. doi: 10.1186/s12967-021-02811-8. The Spearman rank correlation coefficient was used to assess individual-level associations between PFS and OS considering the individual patient data from all the clinical trials. This site needs JavaScript to work properly. 2 c Patients with inactive (asymptomatic and previously treated) brain metastases. OS was defined as the time since randomization to death. Enter multiple addresses on separate lines or separate them with commas. The associations can be characterized using a simple Spearman method when censoring is not an issue or evaluated using multitrial joint modeling methods, such as a copula bivariate survival model (13). Second, in some studies, the appearance of new lesions in the patients treated with immunotherapeutic agents were no longer considered as unequivocal progression, and hence the therapy was continued for a longer duration and patients were followed past initial progression. In oncology, PFS usually refers to situations in which a tumor is present, as demonstrated by laboratory testing, radiologic testing, or clinically.Similarly, … Early PFS is a robust surrogate endpoint for OS in immunotherapy trials, while the surrogacy relationship between ORR and OS is weak. Patient-level responder analysis was performed for PFS and OS.Results: The coefficient of determination (R²) measured the strength of associations, where values near 1 imply surrogacy and values close to 0 suggest no association. Prevention and treatment information (HHS). Response duration is measured from the time of initial response until documented tumor progression. We propose that the selection of the right drug for the right patient population makes the most sense; the selection of an endpoint should not be predicated on … Mushti, F. Mulkey, R. Sridhara, Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): S.L. For our analysis, we selected randomized, multicenter, active-controlled trials that were designed with head-to-head comparisons or add-on designs. Future clinical trials (CT) may take much longer to complete in order to demonstrate incremental improvement in survival, and OS may not be a feasible endpoint for the evaluation of new drug products seeking marketing approval. OS was censored at the last follow-up date for patients who were alive at the time of data cutoff. Immunotherapies, which utilize and enhance the distinctive powers of the immune system to fight cancer, are proving to be the most promising cancer treatments today. 2021 Apr;9(4):e002501. Roviello G, Andre F, Venturini S, Pistilli B, Curigliano G, Cristofanilli M, Rosellini P, Generali D. Eur J Cancer. Mushti, R. Sridhara, Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc. 3. ©2018 AACRSee related commentary by Korn and Freidlin, p. 2239. In this modified PFS analysis, the date of unequivocal progression of nontarget tumors and existence of new lesions were utilized as recorded in the database to indicate progression. Sci Rep. 2021 Mar 18;11(1):6306. doi: 10.1038/s41598-021-85696-3. For each study, the disease indication, primary or coprimary and secondary endpoints, total number of randomized patients and corresponding randomization allocation ratio, unstratified HR of OS, PFS as defined by RECIST criteria v1.1, unstratified OR for ORR, and response rates in the experimental versus control arm are listed. Surrogate endpoints in clinical trials: definition and operational criteria, Progression-free survival is a surrogate for survival in advanced colorectal cancer, Criteria for the validation of surrogate endpoints in randomized experiments, The validation of surrogate endpoints in meta-analyses of randomized experiments, Objective response to chemotherapy as a potential surrogate end point of survival in metastatic breast cancer patients, Progression-free survival as a surrogate endpoint in advanced breast cancer, Progression-free survival, post-progression survival, and tumor response as surrogate markers for overall survival in patients with extensive small cell lung cancer Ann Thorac Med. Of note, the endpoints based on tumor response may not always capture the drug's effect on OS and hence may result in weak associations. Study Design The threshold percentage for defining PD due to target lesions, based on percent increase in sum of the longest diameters of all target lesions from nadir, was modified to range from the RECIST definition of 20% up to 45% in 5% increments. Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland. PFS results are typically available earlier in a trial than OS data. In this figure, each dot in the plot represents a single trial, with the size of each dot proportional to the size of the trial and color of the dot referring to the disease indication. The analysis was repeated in predefined data cuts based on crossover and balance of … 肿瘤治疗的四大终点指标分别是客观缓解率（Objective Response Rate； ORR）、疾病控制率（Disease Control Rate； DCR）、无进展生存期（ progression-free survival； PFS）和总生存期（ overall survival；OS）。. Purpose: With the approval of immunotherapies for a variety of indications, methods to assess treatment benefit addressing the response patterns observed are important. These trials included both head-to-head (treatment A vs. treatment B) comparisons, where an experimental monotherapy (treatment A) is compared directly against an active control (treatment B), and add-on (treatment A vs. treatment A + B) treatment comparisons, where an experimental agent is added to a standard-of-care background. Epub 2018 Dec 26. In the exploratory analysis, when assessed separately, associations between PFS and OS in patients with melanoma were weaker than associations in patients with NSCLC (at PFS_45 R2 = 0.08 in melanoma studies vs. R2 = 0.59 in NSCLC studies), although sample sizes among specific disease types are small for these methods and both values are still below any that would indicate surrogacy-level association (34). In evaluating efficacy, overall survival (OS) provides one of the most direct measures of true clinical benefit. Ann Transl Med. The treatment effects based on PFS and OS were measured by the log of HR estimated using an unstratified Cox proportional hazards model with treatment as the covariate. On the other hand, if PFS and OS are not strongly correlated, the use of PFS as a surrogate for OS may lead to treatments with … Patients may exhibit delay in response, immediate reduction to target tumor burden accompanied by presence of a new lesion, or even an initial increase in tumor burden (tumor flare or pseudo-progression) followed by a decrease in tumor burden. Defining the Most Appropriate Primary End Point in Phase 2 Trials of Immune Checkpoint Inhibitors for Advanced Solid Cancers: A Systematic Review and Meta-analysis. Trial-level associations between modified PFS and OS ranged between 0.07 and 0.1, and individual-level correlations were approximately 0.6. Clipboard, Search History, and several other advanced features are temporarily unavailable. 4 Osimertinib (TAGRISSO) is the first and only EGFR TKI recommended by NCCN as adjuvant treatment for … The median PFS was 4.0 months versus 2.8 months (HR, 0.70; 95% CI, 0.45-1.08), and the ORR was 22% versus 18% for MPDL3280A and docetaxel, respectively. In addition, the experience and length of follow-up in these studies are limited, as some of the trial level results included in this study are based on interim analyses. over use of PFS or ORR as a primary outcome measure. Experimental Design: Thirteen randomized, multicenter, active-control trials containing immunotherapeutic agents submitted to the FDA were analyzed. Exploration of modified progression-free survival as a novel surrogate endpoint for overall survival in immuno-oncology trials. Privacy, Help 2021 Apr;9(4):e002114. In recent immunotherapy studies, such as in nonsquamous NSCLC (23), despite a weak-to-moderate PFS treatment effect, significant improvement in the OS treatment effect was observed. The rank correlations between the observed values of PFS at different thresholds for progression and survival times of each patient were calculated to assess the individual-level associations and are presented in Fig. We evaluated RECIST criteria-based overall response rate (ORR) and progression-free survival (PFS) as potential surrogate endpoints of overall survival (OS), and explored a modified definition of PFS by altering the threshold percentage determining disease progression to assess the association with survival benefit in immunotherapy trials.Experimental Design: Thirteen randomized, multicenter, active-control trials containing immunotherapeutic agents submitted to the FDA were analyzed. Diseases represented in these trials include melanoma (6), NSCLC (5; 1 for squamous and 4 for nonsquamous), renal cell carcinoma (1), and head and neck cancer (1). Bethesda, MD 20894, Copyright However, at this time, a well-defined subgroup of patients based on molecular biomarkers or clinical features who are more likely to respond has not been identified. The "Great Debate" at Immunotherapy Bridge 2020, December 3rd, 2020. Given the uncertainty that surrounds the use of PFS as an endpoint to assess survival benefit (35, 36) and the weak associations of PFS, ORR, and modified PFS endpoints with OS, as shown in this analysis, there is a need to further explore novel intermediate endpoints (37) that would better serve as a surrogate endpoint for OS in assessing the clinical benefit of immunotherapeutic agents and accelerate the drug approval process. At the individual level, the Spearman rank correlation coefficient between PFS and OS was 0.61. The FDA has generally defined ORR as the sum of partial responses (PRs) and CRs. The PFS events calculated using a higher threshold value were a subset of the PFS events calculated using a lower threshold value, because the criteria for PD due to target tumors were defined to meet a “minimum” percentage increase in the sum of target lesions. Each of these treatments differ in their mechanism of action, and immune checkpoint inhibitors in particular represent a strong future for cancer treatment. Available from: Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial, Pembrolizumab versus ipilimumab in advanced melanoma, Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial, Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer, Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer, Nivolumab versus everolimus in advanced renal-cell carcinoma, Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial, Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer, Nivolumab in previously untreated melanoma without BRAF mutation, Combined nivolumab and ipilimumab or monotherapy in untreated melanoma, Nivolumab and ipilimumab versus ipilimumab in untreated melanoma, Nivolumab for recurrent squamous-cell carcinoma of the head and neck, Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial, Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria, Developing a common language for tumor response to immunotherapy: immune-related response criteria using unidimensional measurements, Adaptation of the immune-related response criteria: irRECIST, iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics, Non-classical response patterns, immune-modified RECIST and immune-modified PFS: potential optimization of radiographic endpoints for immnotherapies [workshop presentation]. Mushti, R. Sridhara, Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): S.L. NCI CPTC Antibody Characterization Program. Because achieving R² = 1 is nearly impossible, we prospectively chose R² = 0.80 as the cutoff value to establish PFS and ORR as a validated surrogate endpoint for OS in this specific context. Overall Response Rate (ORR) or reduction of a tumour marker (e.g. Similarly, atezolizumab was approved in 2016 under accelerated approval regulation (3) based on ORR for both urothelial carcinoma and non–small cell lung cancer (NSCLC). Surrogate and Intermediate Endpoints in Randomized Trials: What's the Goal? See related commentary by Korn and Freidlin, p. 2239. The impact of high PD-L1 expression on the surrogate endpoints and clinical outcomes of anti-PD-1/PD-L1 antibodies in non-small cell lung cancer. Tumor assessments were made using RECIST v1.1 criteria for patients in the intent-to-treat population (as randomized) who had measurable lesions at baseline and at least one post-baseline visit. Careers. Please enable it to take advantage of the complete set of features! 8600 Rockville Pike As a class, immunotherapies encompass several different types of treatments, such as checkpoint inhibitors and cancer therapeutic vaccines. New guidelines to evaluate the response to treatment in solid tumors (RECIST guidelines). We identified 13 randomized clinical trials consisting of 6,722 patient records. 29) to immune-related RECIST (irRECIST 2013–2014; refs. In recent times, many immunotherapies, in particular checkpoint inhibitors, have demonstrated superior overall survival (OS) compared with existing standard of care. Challenges in interpreting results based on traditional endpoints. doi: 10.1136/jitc-2021-002501. One of the first immunotherapies, ipilimumab, approved by the FDA in 2011, was the first checkpoint inhibitor to block the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) pathway and was shown to extend survival among patients with advanced melanoma. Clin Cancer Res. Mushti, F. Mulkey, R. Sridhara, Writing, review, and/or revision of the manuscript: S.L. A flexible copula model for bivariate survival data [dissertation]. OS historically is an endpoint most appropriate for the phase III clinical trial, and PFS was used as a screening endpoint best fitted to the phase II setting. Evaluation of classical clinical endpoints as surrogates for overall survival in patients treated with immune checkpoint blockers: a systematic review and meta-analysis. The trial-level R2 value computed using the weighted linear regression model was 0.1303, demonstrating a weak association between PFS and OS. Brain lesions were non-target lesions. “In the study, lenvatinib plus everolimus significantly improved PFS and ORR, but not OS, vs sunitinib,” said investigator Dr Robert Motzer of the Memorial Sloan Kettering Cancer Center, New York, US, at ASCO GU 2021. Progression-free survival (PFS) or percent without progression at a given time are also appropriate endpoints in phase II trials, especially if they are randomised.

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