Improved post-surgical management of the 70% of all renal cell cancer (RCC) patients who present to urological surgeons with initially localised RCC, to prevent subsequent progression, is an area of great need within uro-oncology.GD Stewart has received educational grants from Pfizer and Intuitive Surgical; consultancy fees from Pfizer, EUSA Pharma and Cambridge Medical Robotics; Travel expenses from Pfizer and Speaker fees from Pfizer. RA Figlin has received research funding from Peloton, BMS, Argos Therapeutics, Exilexis, and Cerulean; consulting fees from Novartis, Pfizer, Nektar, Peloton, Calithera, and Acceleron.  S Negrier reports honoraria from Pfizer, Novartis, EUSA Pharma, Ipsen Biotech and Bristol-Myers Squibb.  BC Leibovich declares no conflicts of interest

Figlin, RA

Leibovick, BC

Negrier, S

Stewart, GD

Apollo (Cambridge)

JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A LAdjuvant Pazopanib Does Not PROTECT AgainstRecurrence of High-Risk, Initially Localized Renal CellCancer but Does Provide Novel InsightsGrant D. Stewart, University of Cambridge, Cambridge, United KingdomBradley C. Leibovich, Mayo Clinic, Rochester, MNSylvie Negrier, University of Lyon, Lyon, FranceRobert A. Figlin, Cedars-Sinai Medical Center, Los Angeles, CASee accompanying article on page 3916Improved postsurgical management to prevent subsequentprogression among the 70% of patients with renal cell cancer(RCC) who present to urologic surgeons with initially localizedRCC is an area of great need in urologic oncology. When con-sidering all comers, 50% of patients with initially localized RCCwill develop recurrent disease in the 10 years after nephrectomy.1This rate of recurrence rises to. 75% for patients deemed at highrisk for recurrence,2 at which point the disease is rarely curable.Postsurgery, patients with RCC are often surprised to hear that,unlike in other cancers, there is no evidence that adjuvant therapyimproves survival. As such, the urologic oncology clinical andpatient communities have been closely following the rapidlyemerging evidence around use of targeted therapy as an adjuvantstrategy for initially localized RCC. The assumption that agentsthat have proven successful in treating metastatic RCC will also beefﬁcacious in micrometastatic RCC led to the development ofa series of RCC adjuvant tyrosine kinase inhibitor (TKI) trials,recruitment for which started in 2007.3 The results of the PROTECT(Pazopanib As Adjuvant Therapy in Localized/Locally AdvancedRCC After Nephrectomy) trial,4 published in the article that ac-companies this editorial, represent the third report of a double-blind,placebo-controlled, randomized phase III trial of adjuvant vascularendothelial growth factor receptor (VEGFR) TKIs. PROTECT isreported at a fascinating juncture with our existing evidence baseconsisting of one large negative study of adjuvant sunitinib or soraﬁnib(ASSURE [Adjuvant Sorafenib or Sunitinib for Unfavorable RenalCarcinoma])5 and one smaller positive study of adjuvant sunitinib (S-TRAC [Sunitinib as Adjuvant Treatment for Patients at High Risk ofRecurrence of Renal Cell Carcinoma Following Nephrectomy])demonstrating a hazard ratio (HR) of 0.76 (P5 .03), providing a 1.2-year delay in disease-free survival (DFS) versus placebo.6In the PROTECT trial, patients with Karnofsky PerformanceStatus of $ 80% and pT2, G3-G4, N0; pT3, Gany, N0; pT4, Gany,N0; or pTany, Gany, N1 disease were randomly assigned at a one-to-one ratio to placebo or pazopanib for 1 year. Initially, patientswere treated with a starting dose of pazopanib 800 mg once daily(403 randomly assigned patients). However, because of a higher-than-expected trial discontinuation rate, a decision was made by thesponsor and study steering committee (rather than being mandatedby the independent data monitoring committee) to reduce thisstarting dose to 600 mg once daily (1,135 randomly assigned pa-tients). Critically, the primary analysis, which originally includedall patients, was also altered, to analysis of DFS only in those pa-tients receiving the 600-mg starting dose of pazopanib, effectivelyrestarting the study. Methodologically, this would seem to be thepurest way in which to assess the outcome of PROTECT. However, itis interesting to note that trial-level starting-dose reductions arecommon in adjuvant trials. In ASSURE, the starting dose ofsunitinib was reduced from 50 to 37.5 mg and of sorafenib from400 mg twice per day to once daily, with the aim of dose esca-lation; however, the primary analysis remained DFS of the entirecohort.5 The intended beneﬁt in PROTECT of reducing thepazopanib starting dose was to reduce toxicity and trial dis-continuation. However, despite a comparable toxicity proﬁle ofpazopanib in this localized RCC cohort relative to metastatic RCCstudies, this aim did not come to fruition, with the discontin-uation rate remaining similar after the dose reduction (39% ofintention-to-treat (ITT) patients receiving 800 mg discontinuedpazopanib v 35% of ITT patients receiving 600 mg, comparedwith a maximum of 24% in metastatic RCC pazopanib trials7). Inretrospect, had the PROTECT trial management group followedthe lead of previous RCC adjuvant studies and analyzed the DFSof the entire cohort, PROTECT may well have been a positivestudy. One of the key learning points from PROTECT is howdifferent patient tolerance of toxicity is among patients with non-metastatic disease versus those with metastatic disease, for whomdrug therapy is usually the sole treatment. Thus, successful directtranslation of drug dosing and administration schedules from themetastatic setting is not guaranteed. However, a related ﬁnding fromPROTECTwas that quality of life returned to baseline levels as soonas treatment was stopped; indeed, the only clinically relevant re-duction in quality of life was at 8 weeks after starting the drug,suggesting that good counseling, especially early in the study, may beessential in preventing patient discontinuation of the study drug.On initial inspection of the survival curves and HRs of the ITT800-mg versus placebo cohorts, it seems there might be beneﬁt inJournal of Clinical Oncology, Vol 35, No 35 (December 10), 2017: pp 3895-3897 © 2017 by American Society of Clinical Oncology 3895VOLUME 35 • NUMBER 35 • DECEMBER 10, 2017Downloaded from ascopubs.org by 109.145.205.213 on February 2, 2018 from 109.145.205.213Copyright © 2018 American Society of Clinical Oncology. All rights reserved.this adjuvant pazopanib dose, with a signiﬁcant improvement inDFS (HR, 0.69; P 5 .02), which in turn pushed the ITT all-patientcohort to a signiﬁcantly improved DFS with pazopanib overplacebo (HR, 0.80; P5 .01). However, the ITT 800-mg cohort wasan underpowered and nondeﬁnitive secondary end point, whichincluded only 198 patients receiving pazopanib and 205 receivingplacebo versus 571 and 564 patients, respectively, in the primaryend point ITT 600-mg cohort. Although one cannot be deﬁnitive,there seems to be a marked difference in DFS rate in the placebogroup between ITT patients receiving 600 versus 800 mg (3-yearsDFS rate, 64% v 56%, respectively; whereas DFS rates for pazopanib-treated ITT patients were similar at 67% and 66% for 600 v 800 mg,respectively). The reason for such a difference in sequentiallyrecruited patients in a randomized controlled trial is unclear; theauthors believe it may have resulted from missing demographicdata; nonetheless, this difference may account for the signiﬁcantimprovement in DFS at the ITT 800-mg dose.How should we interpret PROTECT in the context of ASSUREand S-TRAC? The PROTECT authors suggest that all three ad-juvant studies reported to date enrolled a similar population ofpatients. However, the level of interstudy heterogeneity appears tomake cross-study comparisons even more invalid than usual. Keyeligibility criteria differed across the three studies. First, PROTECTand S-TRAC recruited patients with clear cell or predominantlyclear cell RCC, whereas in ASSURE, 20% of patients had non–clearcell RCC. Second, there was limited uniformity in patient prog-nostic risk inclusion criteria. PROTECT claimed to risk stratifyusing stage, size, grade and necrosis, but the scores were not tab-ulated, and necrosis was not included8; similarly, S-TRAC andASSURE inclusion criteria were based on the University ofCalifornia Los Angeles Integrated Staging System (UISS), but thestudies did not adhere rigidly to the deﬁned criteria.9 Whenmapped onto the UISS, all three studies included intermediate- andhigh-risk patients,9 but of the three trials, ASSURE had the leastaggressive proﬁle (setting lower end of inclusion criteria at pT1b,G3/4, N0 disease), followed by PROTECT (including patients withpT2, G3/4, N0 disease) and S-TRAC, with the highest risk proﬁle(including patients with pT3, Gany, N0 disease). S-TRAC also in-cluded a modiﬁed very high-risk UISS group as a preplannedsecondary analysis, where a 2.2-year delay in DFS after sunitinibtherapy was seen (HR, 0.74; P 5 .04).6 In all three studies, . 80%of included patients had pT3 disease, the majority of whom willhave had pT3a disease; this is a heterogeneous group of patientswhen considering sinus fat versus perirenal fat versus renal veininvasion, with markedly different outcomes, also dependent ontumor size.10,11 These concepts emphasize that more advancedand uniﬁed prognostic scores, potentially including molecularstratiﬁers such as the RNA-based recurrence score,12,13 are neededfor the design of future adjuvant studies. In the meantime, access topatient-level, rather than trial-level, data from the three adjuvanttrials is necessary to allow accurate meta-analysis.Putting aside these issues and the possibility that PROTECTmight have been positive using the original planned analysis,PROTECT follows ASSURE in representing another large negativestudy of an adjuvant VEGFR TKI in initially localized RCC. As inboth S-TRAC and ASSURE, overall survival, which would seem tobe of key importance to patients in deciding whether to beginadjuvant therapy, was a secondary end point in PROTECT. As inthe other studies, PROTECT did not show a signiﬁcant survivaladvantage for pazopanib after a median of 30 months of follow-up,although the data are currently immature.The only positive RCC adjuvant study to date, S-TRAC, was alsothe only one that did not require a protocol amendment for the startingdose. All patients began sunitinib treatment at 50 mg once daily (dosereduction rate, 34%; discontinuation rate, 28%).6 Taken together withthe information from PROTECT (ie, ITT patients receiving 800 mgseemed to have signiﬁcantly improved DFS), these data indicate thatcumulative dose of VEGFR TKI might be key in delaying recurrence.Another difference in the S-TRAC study was that it was theonly study with central imaging review for both baseline andprimary end point. There was no central imaging review in ASSURE,and there was only baseline review in PROTECT. It is impossible toconclude that this was a deﬁning factor in the results of ASSURE orPROTECT, but it was a differentiating feature of the S-TRAC design.On the basis of these data, should central imaging review at baselineand primary end point now be standard?We now have one positive study, one negative study, and onenegative study with tantalizing secondary end points. There area series of other RCC adjuvant TKI studies due to report over thenext few years3: SORCE (a phase III randomised double-blindstudy comparing SOrafenib with placebo in patients with Resectedprimary renal CEll carcinoma at high or intermediate risk ofrelapse; patients randomly assigned at a three-to-three-to-two ratioto sorafenib for 1 year followed by placebo for 2 years, sorafenibfor 3 years, or placebo for 3 years; ClinicalTrials.gov identiﬁer:NCT00492258), EVEREST (EVErolimus for Renal Cancer EnsuingSurgical Therapy; everolimus v placebo in nine courses of 6 weeks;ClinicalTrials.gov identiﬁer: NCT01120249), and ATLAS (Adju-vant Axitinib Therapy of Renal Cell Cancer in High Risk Patients;axitinib v placebo for 3 years; ClinicalTrials.gov identiﬁer:NCT01599754). On the basis of our now greater understanding ofhow patients with nonmetastatic disease respond to treatment withtargeted therapy, there will be several unique points on which eachupcoming trial will provide information. First, we will gain the ﬁrstdata on axitinib and everolimus in the adjuvant setting. In all threepublished adjuvant trials, there was a perceptible separation of theDFS Kaplan-Meier curve during receipt of therapy; furthermore, theDFS advantage in S-TRAC was 1.2 years, suggesting that the studydrug may extend DFS for the duration of treatment. As such,secondly, we will also further deﬁne the role of more chronictreatment based on the SORCE and ATLAS trials, where patientsreceive 3 years of therapy. Third, the strategies of different ad-juvant studies for keeping patients on higher doses of drug forlonger will be scrutinized in more detail, because cumulative doseseems to be critical in the adjuvant setting. It does seem that thedosing tolerated by metastatic patients is not tolerated in thesame proportion of patients postnephrectomy for localized disease.Fourth, a better understanding of how to counsel patients on whatthey can expect is needed fromprevious and ongoing adjuvant studies.Finally, and perhaps most importantly, none of the adjuvant studieshave shown any overall survival beneﬁt (S-TRAC showed a delay inprogression only), placing a focus on what exactly patients wouldexpect to gain from a period of adjuvant therapy with its concomitanttoxicity. In particular, is deferment of potentially symptomatic me-tastases (and for how long), without prolongation of life, desired bypatients? It is for reasons such as this that patients must be involved in3896 © 2017 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGYEditorialDownloaded from ascopubs.org by 109.145.205.213 on February 2, 2018 from 109.145.205.213Copyright © 2018 American Society of Clinical Oncology. All rights reserved.the design of clinical trials, especially in a setting where approximately50% patients will not develop relapse without systemic therapy aftersurgery but would be exposed to associated drug toxicity.As we shift focus back to our current clinical practice, adjuvanttherapy is not standard of care after surgery for initially localizedRCC, and PROTECT does not provide further evidence alteringthis viewpoint. As such, we are now starting to recruit patients tothe next era of adjuvant RCC trials using immunooncologyagents.3 However, PROTECT has provided a greater understandingof the nuances of the effect of VEGFRTKIs in pT21 clear cell RCCafter surgery and, importantly for ongoing immunooncologyadjuvant trials, has not provided any suggestion that the controlarm of these studies needs to be altered, at least not yet.AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTDisclosures provided by the authors are available with this article atjco.org.AUTHOR CONTRIBUTIONSManuscript writing: All authorsFinal approval of manuscript: All authorsREFERENCES1. Cancer Research UK: Kidney cancer statistics. http://www.cancerresearchuk.org/cancer-info/cancerstats/types/kidney/?script5true2. Leibovich BC, Blute ML, Cheville JC, et al: Prediction of progression afterradical nephrectomy for patients with clear cell renal cell carcinoma: A stratiﬁcationtool for prospective clinical trials. Cancer 97:1663-1671, 20033. Blick C, Ritchie AWS, Eisen T, et al: Improving outcomes in high-risk,nonmetastatic renal cancer: new data and ongoing trials. Nat Rev Urol [epubahead of print on August 1, 2017] doi:10.1038/nrurol.2017.1234. Motzer RJ, Haas NB, Donskov F, et al: Randomized phase III trial of adjuvantpazopanib versus placebo after nephrectomy in patients with localized or locallyadvanced renal cell carcinoma. J Clin Oncol 35:3916-3923, 20175. Haas NB, Manola J, Uzzo RG, et al: Adjuvant sunitinib or sorafenib forhigh-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): A double-blind, placebo-controlled, randomised, phase 3 trial. Lancet 387:2008-2016,20166. Ravaud A, Motzer RJ, Pandha HS, et al: Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med 375:2246-2254, 20167. Motzer RJ, Hutson TE, Cella D, et al: Pazopanib versus sunitinib in meta-static renal-cell carcinoma. N Engl J Med 369:722-731, 20138. Parker WP, Cheville JC, Frank I, et al: Application of the stage, size, grade,and necrosis (SSIGN) score for clear cell renal cell carcinoma in contemporarypatients. Eur Urol 71:665-673, 20179. Zisman A, Pantuck AJ, Dorey F, et al: Improved prognostication of renalcell carcinoma using an integrated staging system. J Clin Oncol 19:1649-1657,200110. Klatte T, Pantuck AJ, Riggs SB, et al: Prognostic factors for renal cellcarcinoma with tumor thrombus extension. J Urol 178:1189-1195, discussion1195, 200711. Lam JS, Klatte T, Patard J-J, et al: Prognostic relevance of tumour size in T3arenal cell carcinoma: A multicentre experience. Eur Urol 52:155-162, 200712. Rini B, Goddard A, Knezevic D, et al: A 16-gene assay to predict recurrenceafter surgery in localised renal cell carcinoma: Development and validation studies.Lancet Oncol 16:676-685, 201513. Escudier BJ, Rini BI, Martini J-F, et al: Phase III trial of adjuvantsunitinib in patients with high-risk renal cell carcinoma (RCC): Validation ofthe 16-gene recurrence score in stage III patients. J Clin Oncol 35, 2017(suppl; abstr 4508)DOI: https://doi.org/10.1200/JCO.2017.75.4242; published at jco.org onOctober 25, 2017.n n njco.org © 2017 by American Society of Clinical Oncology 3897EditorialDownloaded from ascopubs.org by 109.145.205.213 on February 2, 2018 from 109.145.205.213Copyright © 2018 American Society of Clinical Oncology. All rights reserved.AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTAdjuvant Pazopanib Does Not PROTECT Against Recurrence of High-Risk, Initially Localized Renal Cell Cancer but Does Provide Novel InsightsThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships areself-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For moreinformation about ASCO’s conﬂict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.Grant D. StewartHonoraria: PﬁzerConsulting or Advisory Role: EUSA Pharma, Cambridge MedicalRoboticsSpeakers’ Bureau: PﬁzerResearch Funding: PﬁzerTravel, Accommodations, Expenses: Pﬁzer, Intuitive SurgicalBradley C. LeibovichNo relationship to discloseSylvie NegrierHonoraria: Pﬁzer, Novartis, EUSA Pharma, Ipsen, Bristol-Myers SquibbRobert A. FiglinConsulting or Advisory Role: Pﬁzer, Cerulean, Calithera, Novartis,Nektar, Peloton Therapeutics, AcceleronResearch Funding: Pﬁzer, Novartis, Cerulean, Peloton Therapeutics,Bristol-Myers Squibb, Argos, Exelixis© 2017 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGYEditorialDownloaded from ascopubs.org by 109.145.205.213 on February 2, 2018 from 109.145.205.213Copyright © 2018 American Society of Clinical Oncology. All rights reserved.

Adjuvant pazopanib does not PROTECT against recurrence of high risk initially localised renal cell cancer, but does provide novel insights

https://www.repository.cam.ac.uk/bitstream/1810/271606/3/jco.2017.75.4242-2.pdf

Adjuvant pazopanib does not PROTECT against recurrence of high risk initially localised renal cell cancer, but does provide novel insights

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