Review Surrogate End Points and Postprogression Survival in Renal Cell Carcinoma: A Trials With Targ Fausto Petrelli, t n p ) (R the in te ic S .0 re sti ely em 1558-7673/$ - see frontmatter ª 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2013.07.012 Clinical Genitourinary Cancer December 2013 - 385 Clinical Genitourinary Cancer, Vol. 11, No. 4, 385-9 ª 2013 Elsevier Inc. All rights reserved. Keywords: Overall survival, Phase III trials, Postprogression survival, Progression-free survival, Renal cell carcinoma Surrogate end points, Targeted therapies Introduction The standard of care for advanced renal cell carcinoma (RCC) are agents targeting the vascular endothelial growth factor (VEGF) pathway. These agents have replaced cytokines as upfront treatment because they are more effective than older agents such as interferon.1 Oral multitarget tyrosine kinase inhibitors such as sunitinib or pazopanib, the mammalian target of rapamycin (mTOR) inhibitor temsirolimus, and the anti-VEGFmonoclonal antibody bevacizumab led to amedian overall survival (OS) in first-line trials covering about 2 years.However, because of the high crossover rate to other anti-VEGF agents after first-line failure in control arms, the differences in median OS were not observed as in the 2 bevacizumab phase III trials.2,3 Several agents have been approved for previously treated patients after cytokine or oral tyrosine kinase inhibitor failure. Among them are everolimus and axitinib. Sorafenib is also currently approved in this setting for patients unsuitable for cytokines. This continuum of care permits a sequential strategy in which patients with RCC are exposed to several molecularly targeted agents so that outcome has dramatically improved in comparison with older cytokine trials. However, the best sequence (or combination) of agents is currently unknown. This scenario makes the observed effect of study treatment on OS more diluted and often influenced mostly by postprogression sur- vival (PPS). Therefore, other end points such as progression-free survival (PFS) or time to progression (TTP) could potentially become acceptable surrogate end points of RCC trials with targeted agents, as in other solid tumors. However, in lung, breast, and colorectal cancer trials, PPS more than PFS is associated with OS as described in a recent analysis.4-6 When there is a short PPS or limited crossover is present, PFS becomes strongly correlated with OS in lung and breast cancer. Even in RCC, PPS in fact depends on the availability of active agents subsequently offered to patients (lines or sequence of treatment after first-line failure) rather than the biological characteristics and aggressiveness of the cancer itself. In the RCC setting, the correlation between treatment effects on PFS/TTP and on OS is in fact greater in studies that did not allow/ require crossover, in studies in which PFS rather than TTP was the Oncology Department, Medical Oncology Unit, Azienda Ospedaliera Treviglio, Treviglio, Italy Submitted: Apr 19, 2013; Revised: Jul 22, 2013; Accepted: Jul 31, 2013; Epub: Oct 2, 2013 Address for correspondence: Fausto Petrelli, MD, Piazzale Ospedale 1, 24047 Treviglio (BG), Italy Fax: þ39-0363424380; e-mail contact:
[email protected] Abs Our end point was to determine the correlations betwee (PPS), response rate (RR), and disease control rate (DCR trials of renal cell carcinoma (RCC) treated with targeted were collected from first-line phase III randomized trials correlations between end points and a potential surroga containing a total of 7 treatment arms. The nonparametr PPS, and RR/DCR and OS are 0.869, and 1, 0.96/1 (all P < differences (D) in DCR and DOS (rs ¼ 1). The slope of the drug producing a 10% increase for DCR will yield an e including novel targeted agents for RCC, PFS is a relativ Improvement in DCR is strongly associated with improv appropriate surrogate for OS. n Analysis of First-Line eted Therapies Sandro Barni ract rogression-free survival (PFS), postprogression survival R þ stable disease) and overall survival (OS) in first-line rapies and to identify a potential surrogate for OS. Data RCC. Linear regression was undertaken to evaluate the end point for OS. Six randomized trials were identified pearman rank correlation coefficients (rs) between PFS, 001), respectively. There is a strong relationship between gression line is 0.3963 � 0.0019, indicating that a novel mated absolute 3.9% increase in OS. In first-line trials flawed surrogate end point because of PPS influence. ent in median OS. In this population, DCR may be an e Se End Points in RCC With Targeted Therapies 386 - Figure 1 Flow Chart Showing the Progress of Trials Through th primary end point, and in studies published before 2005 when less active agents were available. Conversely, there is no significant as- sociation between the treatment effects on PFS/TTP and OS in the trials of VEGF inhibitors.7 Although several first-line phase III trials have been reported for patients with advanced RCC, little is known about the value of PPS. We partitioned OS into PFS and PPS and then assessed, through a regression analysis, association and correlation of each with OS in phase III trials for previously untreated patients with advanced RCC. The analysis of PPS could have the potential to clarify the appropriate end point of the trials designed in the first-line setting. An evaluation of PFS surrogacy of OS was also performed. Patients and Methods Search Strategy and Selection of Trials An independent review of PubMed and EMBASE citations up to April 31, 2011 was performed to identify trials. Keywords included in the search were renal cell carcinoma and (sunitinib or sorafenib or pazopanib or temsirolimus or axitinib or bevacizumab). The query translation was (“carcinoma, renal cell”[MeSH Terms] OR (“car- cinoma”[All Fields] AND “renal”[All Fields] AND “cell”[All Fields]) OR “renal cell carcinoma”[All Fields] OR (“renal”[All Clinical Genitourinary Cancer December 2013 lection Process Fields] AND “cell”[All Fields] AND “carcinoma”[All Fields])) AND ((“sunitinib”[Supplementary Concept] OR “sunitinib”[All Fields]) OR (“sorafenib”[Supplementary Concept] OR “sorafenib”[All Fields]) OR (“pazopanib”[Supplementary Concept] OR “pazopa- nib”[All Fields]) OR (“temsirolimus”[Supplementary Concept] OR “temsirolimus”[All Fields]) OR (“axitinib”[Supplementary Concept] OR “axitinib”[All Fields]) OR (“bevacizumab”[Supple- mentary Concept] OR “bevacizumab”[All Fields])) AND Ran- domized Controlled Trial[ptyp]. The search was limited to randomized controlled phase III trials and articles published in English. We reviewed each publication, and phase III studies that compared 2 or more accepted systemic therapies (including at least 1 treatment with molecularly targeted agents) in patients with metastatic RCC were selected. We also checked for further publi- cations through the EMBASE platform to find any additional trials. We included trials that provided data for both OS and either PFS or TTP, whether or not these parameters were explicitly defined. Trials were excluded if they investigated only immunotherapy regimens or other experimental agents and were not in the English language. Trials that were designed to assess combined-modality treatments only, including radiation therapy and cytoreductive surgery, were also excluded. Fausto Petrelli, Sandro Barni To avoid bias, the 2 authors independently abstracted the data from the trials. Data Extraction We analyzed in detail the primary and secondary efficacy end points, following definitions of the authors of each trial. When not specifically stated by the authors, we considered the primary end point to be that used for calculation of sample size. For simplicity, 2 end points (PFS and TTP) based on tumor assessment are collec- tively referred to as PFS in the present study, similar to the approach adopted in a recent report.6 Median OS and median PFS were extracted from all trials that provided data for each treatment group. Table 1 Characteristics of 8 Phase III Trials for Advanced RCC Included in Present Analysis Trial Characteristics Number of trials/arms/total randomized patients 6/7/3188 Median number of patients 417 (range, 77-750) Number of trial arms 2 5 3 1 Median age (years) 60 Median of previous nephrectomies (%) 76 Arms including bevacizumabþ IFN 2 Arms including sunitinib 1 Arms including sorafenib 1 Arms including pazopanib 1 Arms including temsirolimus 2 Primary end point OS 4 Primary end point PFS 2 Abbreviations: IFN ¼ interferon; OS ¼ overall survival; PFS ¼ progression-free survival. Median PPS was defined as median OS minus median PFS for each trial. When available, the proportion of patients who received second-line agents after study conclusion was recorded for each treatment arm. We also obtained the following information from each report: author, year of publication, number of patients ran- domized, number of patients in each treatment arm, number of treatment arms in each trial, proportion of patients who had pre- vious nephrectomy, rate of poor-risk patients, rate of clear cell histologic type, and median age of the patients. Data Analysis We summarized the efficacy and survival data (response rate [RR], disease control rate [DCR] [RR þ stable disease rate], median OS, median PFS, and median PPS) as the average and standard error for trial arms. To assess the association between median OS and RR/DCR, median PFS, or median PPS and between PFS and either RR or DCR, we used the Spearman rank correlation coeffi- cient (rs). We investigated the percentage of OS accounted for by PFS and PPS for each trial arm through a linear regression analysis (R2) to confirm to the goodness-of-fit of the regression model. We also calculated the incremental gains (D) in median OS, median PFS, RR, and DCR from the difference between the experimental and control arms as previously described,8 and we performed correlation analysis to examine whether a treatment benefit for PFS or DCR represents a surrogate of OS benefit through the rs correlation coefficient and Pearson correlation coef- ficient (r). A specific independent variable would be claimed as an acceptable surrogate end point for OS if (1) Spearman correlation coefficient was close to 1, indicating a strong correlation between PFS and OS and (2) r was close to 1, indicating a strong correlation between treatment effects on PFS and OS. To account for differences in sample size among trial arms, we weighted analyses that treated each trial arm as a unit by the number of patients in each arm. All reported P values correspond to 2-sided tests, and those of < .05 were considered statistically significant. Analyses were performed with NCSS 2007 software (version 07.1.21, released June 1, 2011; NCSS, LLC, Kaysville, UT). Results Characteristics of the Trials Figure 2 Correlation of Overall Survival (OS) With Postprogression Survival (PPS) (rs [ 0.939) 5.0 11.3 17.5 23.8 30.0 2.0 5.5 9.0 12.5 16.0 O S vs PPS PPS O S Our search yielded a total of 346 potentially relevant publica- tions. The selection process for the randomized controlled trials is shown in Figure 1. Initially, 319 studies were excluded for at least 1 of the following reasons: they examined other malignancies or combined modality treatments; they were not randomized; they were phase I or II trials; they were reviews, letters, or commentaries; they represented subgroup analyses; or they were duplicates. The review of the remaining 27 studies yielded 12 publications1-3,9-17 (n ¼ 8 trials) that were considered to be highly relevant for the present study (Fig. 1). Because the 2 more recent studies were presented only in abstract form from a 2012 European Society for Medical Oncology meeting,16,17 they were finally excluded by statistical analysis. Seven treatment arms in first-line settings were detected. The main char- acteristics of the 8 phase III trials included in the analysis are listed in Table 1. Data from a total of 3188 patients with advanced RCC were collected, with a median number of patients per study of 417 (range, 77-750). Most of the trials had a high proportion of patients previously treated with cytoreductive nephrectomy (median, 76%). Clinical Genitourinary Cancer December 2013 - 387 End Points in RCC With Targeted Therapies 388 - Two trials used a primary end point based on tumor assessment (PFS), whereas OS was assessed as the primary end point in 4 trials. Association Between Median PFS, OS, and RR/DCR, Median PFS and Median PPS (Outcome Surrogacy) The average median OS, median PFS, and median PPS in the present analysis are 22.9, 8.5 and 11.8, respectively. Median RR and DCR are 25.5% and 77%, respectively. We found that median PPS was strongly associated with median OS (rs ¼ 1; P < .0001) (Fig. 2) on the basis of the Spearman rank correlation coefficient; similarly median PFS was highly correlated with median OS (rs ¼ 0.869; P < .0001). The average proportion of median OS 2 Figure 3 Correlation Between Differences in Progression-Free Survival (DPFS) and Differences in Overall Survival (DOS). The Middle Line is the Regression Line; the 95% Confidence Intervals are Indicated by the Outside Lines -1.0 0.5 2.0 3.5 5.0 0.0 2.5 5.0 7.5 10.0 Δ_O S vs Δ_PFS Δ_PFS Δ _ O S accounted for by median PPS and PFS (R ) were 99% and 97%, respectively. Conversely, RR and DCR were highly correlated with OS (rs ¼ 0.96 and rs ¼ 1; P < .0001 for both associations). Median PFS was strongly correlated with RR (rs ¼ 0.96; P < .0001) and with DCR (rs ¼ 0.96; P < .0001). Correlation Between the DOS and DPFS or DRR/DCR (Effect Surrogacy) To further investigate the relation of surrogacy between OS and PFS or RR/DCR, we analyzed the DOS and DPFS or DRR/DCR for each trial. There was a weak correlation between DPFS and DOS (rs ¼ 0.36; P < .0001) (Fig. 3), whereas the corresponding corre- lation r was 0.26, and R2 was 0.07. The corresponding correlations between DOS and DRR/DDCR were rs ¼ 0.49 (P < .0001) and rs ¼ 1 (P< .00001) (Fig. 4). The corresponding Pearson correlation coefficients r and R2 were 0.52 (P < .0001) and 0.27 for DRR and 0.97 (P < .0001) and 0.95 for DDCR. The y-intercept, the estimated value of DOS when DDCR is 0, is �3.5655 with a standard error of 0.0323. The slope, the esti- mated change in DOS per unit change in DDCR is 0.3963 with a standard error of 0.0019. This means that a 10% increase in DCR led to an absolute OS gain of 3.9% þ 0.019%. Clinical Genitourinary Cancer December 2013 Discussion Our analysis shows that PPS, rather than PFS, is more strongly correlated with OS and could be responsible for up to 99% of the change in OS. Recently, some active second-line agents have shown extended outcome in RCC after first-line progression, therefore extending the PPS. Among these, everolimus and axitinib have demonstrated significant benefits in PFS compared with the comparator agents.18,19 The best sequence of treatment, currently unknown, has extended OS in patients with metastatic RCC and has made OS a more frail end point of first-line trials.20,21 With the advent of several active molecularly targeted agents, the most appropriate end point of phase III first-line trials remains a Figure 4 Correlation Between Differences in Disease Control Rate (DDCR) and Differences in Overall Survival (DOS). The Middle Line is the Regression Line; the 95% Confidence Intervals are Indicated by the Outside Lines 1.0 2.0 3.0 4.0 5.0 12.0 14.5 17.0 19.5 22.0 Δ_O S vs Δ_D CR Δ_DCR Δ _ O S matter of debate. We have calculated that improvement in DCR is strongly associated with an improvement in OS in randomized controlled trials of first-line chemotherapy for RCC. The strongest correlation was obtained between DDCR and DOS. This is the first time, to our knowledge, that such an end point has been observed as a surrogate end point in solid tumors. In fact, PFS is commonly described as a surrogate of survival in colorectal, breast, and lung cancer.4-6 Conversely, RR and DCR were not extensively investi- gated as potential end points. Heng et al analyzed 1158 patients treated with targeted agents and showed that PFS at 3 months and 6 months predicted OS.22 This indicates that PFS may be a meaningful intermediate end point for OS in patients with RCC who receive active treatments. The authors, however, did not analyze the effect of DCR or RR as a surrogate of survival. Recently, Delea et al calculated the correlation between PFS and TTP with OS in 31 randomized trials including older cytokines studies and second-line trials.7 They found that treatment effects on PFS/TTP (hazard ratios) are strongly associated with treatment effects on OS. However, there was no significant association between the treatment effects on PFS/TTP and OS in the subset of trials with VEGF inhibitors. Nevertheless, the article did not evaluate the surrogacy of RR or disease control. In this analysis, among potential surrogate end points, we observed a greater correlation of OS with DCR than with PFS. The corresponding rs values of linear regression analysis were 1 and 0.869, respectively. Similarly, correlation of treatment effect of DCR with treatment effect on OS are highly correlated. These re- sults depict, as hypothesis generating, DCR as a valid surrogate end point for OS. In the included trials, median RR and median DCR are 25.5% and 77%, and this confirms that not only tumor shrinkage but also disease stabilization is paramount with anti- 2. Rini BI, Halabi S, Rosenberg JE, et al. Phase III trial of bevacizumab plus inter- feron alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol 2010; 28:2137-43. 3. Escudier B, Bellmunt J, Négrier S, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol 2010; 28:2144-50. 4. Hotta K, Suzuki E, Di Maio M, et al. Progression-free survival and overall survival in phase III trials of molecular-targeted agents in advanced non-small-cell lung cancer. Lung Cancer 2013; 79:20-6. 5. Broglio KR, Berry DA. Detecting an overall survival benefit that is derived from progression-free survival. J Natl Cancer Inst 2009; 101:1642-9. 6. Petrelli F, Barni S. Correlation of progression-free and post-progression survival with overall survival in advanced colorectal cancer. Ann Oncol 2013; 24:186-92. 7. Delea TE, Khuu A, Heng DY, et al. Association between treatment effects on disease progression end points and overall survival in clinical studies of patients Fausto Petrelli, Sandro Barni bias in individual patients, and the quality of measurement for end points based on tumor assessment can vary between centers and trials. Finally, the evaluation of RR and DCR performed by in- vestigators could lead to potential biases. Confounding effects of second- and third-line therapies, commonly observed in RCC trials, have led to a debate about the value of PPS. Stage IV RCC has been transformed into a chronic disease by new agents, with a median OS of about 2 years. Thus, for ethical reasons it is not possible to renounce treatment and proceed to active second or third lines, and this has to be considered for adequate statistical adjustment and weight. It is reasonable to consider DCR an acceptable end point for exploring the benefit of agents in first-line trials. Conclusion In summary, we found a strong association between PPS and OS because of the efficacy of further lines of treatment after first pro- gression. This association makes PFS a flawed surrogate end point for OS. Second, we observed a strong correlation between im- provements in DCR and OS with first-line targeted agents. Thus, using DCR as a surrogate end point in randomized controlled trials in first-line chemotherapy for metastatic RCC may be appropriate. Disclosure The authors have stated that they have no conflicts of interest. References 1. Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009; 27:3584-90. stabilization and minimal decrease in tumor size could represent indicators of activity and outcome.23,24 The present study, as well as many literature-based reviews, has several limitations. First, our analysis included only published data. Second, the results of our study potentially have confounders because of selection of many heterogeneous trials for analysis (comparing placebo with active agents). Third, the assessment of disease progression is potentially subject to measurement error and with metastatic renal cell carcinoma. Br J Cancer 2012; 107:1059-68. 8. Johnson KR, Ringland C, Stokes BJ, et al. Response rate or time to progression as predictors of survival in trials of metastatic colorectal cancer or non-small-cell lung cancer: a meta-analysis. Lancet Oncol 2006; 7:741-6. 9. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010; 28:1061-8. 10. Sternberg CN, Hawkins RE, Szczylik C, et al. Randomized, double- blind phase III study of pazopanib in patients with advanced/metastatic renal cell carcinoma (MRCC): final overall survival (OS) results. Ann Oncol 2010; 21(suppl 8):abstract LBA22. 11. Negrier S, Jäger E, Porta C, et al. Efficacy and safety of sorafenib in patients with advanced renal cell carcinoma with and without prior cytokine therapy, a sub- analysis of TARGET. Med Oncol 2010; 27:899-906. 12. Rini BI, Halabi S, Rosenberg JE, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 2008; 26:5422-8. 13. Escudier B, Pluzanska A, Koralewski P, et al. AVOREN Trial investigators. Bev- acizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007; 370:2103-11. 14. Hudes G, Carducci M, Tomczak P, et al. Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007; 356: 2271-81. 15. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356:115-24. 16. Rini BI, Bellmunt J, Clancy J, et al. Randomized phase IIIb trial of temsirolimus and bevacizumab versus interferon and bevacizumab in metastatic renal cell car- cinoma: results from INTERACT. Ann Oncol 2012; 23(suppl 9):abstract LBA21_PR. 17. Motzer R, Hutson TE, Reeves J, et al. Randomized, open-label, phase III trial of pazopanib versus sunitinib in first-line treatment of patients with metastatic renal cell carcinoma (MRCC): results of the COMPARZ trial. Ann Oncol 2012; 23(suppl 9):abstract LBA8_PR. 18. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011; 378:1931-9. 19. Motzer RJ, Escudier B, Oudard S, et al. RECORD-1 Study Group. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prog- nostic factors. Cancer 2010; 116:4256-65. 20. Sonpavde G, Choueiri TK, Escudier B, et al. Sequencing of agents for metastatic renal cell carcinoma: can we customize therapy? Eur Urol 2012; 61:307-16. 21. Procopio G, Verzoni E, Iacovelli R, et al. Targeted therapies used sequentially in metastatic renal cell cancer: overall results from a large experience. Expert Rev Anticancer Ther 2011; 11:1631-40. 22. Heng DY, Xie W, Bjarnason GA, et al. Progression-free survival as a predictor of overall survival in metastatic renal cell carcinoma treated with contemporary tar- geted therapy. Cancer 2011; 117:2637-42. 23. Krajewski KM, Guo M, Van den Abbeele AD, et al. Comparison of four early posttherapy imaging changes (EPTIC; RECIST 1.0, tumor shrinkage, computed tomography tumor density, Choi criteria) in assessing outcome to vascular endo- thelial growth factor-targeted therapy in patients with advanced renal cell carci- noma. Eur Urol 2011; 59:856-62. 24. Agostino NM, Gingrich R, Drabick JJ. Bevacizumab demonstrates prolonged disease stabilization in patients with heavily pretreated metastatic renal cell carci- noma: a case series and review of the literature. Adv Urol 2010. Pii: 687043. http:// dx.doi.org/10.1155/2010/687043. Epub 2010 Jul 20. angiogenic agents. In fact, in anti-VEGF trials, long-lasting disease Clinical Genitourinary Cancer December 2013 - 389 Surrogate End Points and Postprogression Survival in Renal Cell Carcinoma: An Analysis of First-Line Trials With Targeted T ... Introduction Patients and Methods Search Strategy and Selection of Trials Data Extraction Data Analysis Results Characteristics of the Trials Association Between Median PFS, OS, and RR/DCR, Median PFS and Median PPS (Outcome Surrogacy) Correlation Between the ΔOS and ΔPFS or ΔRR/DCR (Effect Surrogacy) Discussion Conclusion Disclosures References