Up-front Targeted Therapy Prior to Cytoreductive Nephrectomy in Treatment-Naive Patients With Metastatic Renal Cell Carcinoma

Reports of spontaneous resolution of pulmonarymetastasis after nephrectomy in patients with metastatic renal cell carcinoma (mRCC) provided the rationale for surgical debulking because systemic treatment options were limited. This ultimately led to 2 randomized clinical trials evaluating cytoreductive nephrectomy (CN) in the immunotherapyera. In the first trial led by the Southwest Oncology Group (SWOG),1 246 patientswithmRCCwere randomized to undergo radical nephrectomy followedby treatmentwith interferonalfa-2bor up-front treatmentwith interferon alfa-2b alone. Overall survival (OS), the primary end point, was significantly improved in the nephrectomy group (11.1 vs 8.1 months; P = .05). In the second randomized study by the European Organization for Research andTreatmentofCancer (EORTC),2 83patientswere randomized to similar treatment arms. There was a significant improvement in both progression-free survival (PFS) (5 vs 3months; P = .04) and OS (17 vs 7months; P = .03). A subsequent combined analysis of survival outcomes in patients in both studies revealed an improved OS favoring CN prior to immunotherapy (13.6 vs 7.8 months), representing a 31% decrease in the risk of death (P = .002).3 These results established CN as standard of care in patients with synchronous mRCC, who are candidates for surgery. Over the lastdecade, the treatmentofmRCChasbeenrevolutionizedby theapprovalof several targeted therapies, largely replacing frontline immunotherapy. Although, the use of CN may have declined in the era of targeted therapies, it continues to play an important role in the management of many of these patients.4 However, the survival benefit of CN in conjunctionwith the current systemic agents is less defined. In a systematic review of published randomized trials of targeted agents formRCC,priornephrectomywasnot essential forbenefit from targeted therapy, with the caveat that patient and disease characteristicsmaydiffer in patients deemed tobe ineligible for surgical resection.5 On the contrary, in a multiinstitutional retrospective study published by the InternationalMetastaticDatabaseConsortium (IMDC),6 patientswho had CN (n = 201) had improved OS comparedwith thosewho did not (n = 113) (19.8 vs 9.4months; hazard ratio [HR], 0.68). Furthermore, this survival advantage favoringCNpersisted in amultivariable analysis adjusting for established IMDC prognostic risk factors.6 In the subgroup analysis of these patients, patients in the poor prognosis category and thosewith poorperformancestatusderivedmarginal survivalbenefitwith CN, suggesting the need for tools for better characterization of patients for CN in the era of targeted therapies. Often such patients have limited postoperative treatment options owing to either rapid progression or delayed initiation of systemic therapy.Thebenefit of analternativeapproachofup-front systemic therapy prior to CN has not been tested yet. As reported elsewhere in JAMA Oncology, Powles and colleagues7 conducted a phase 2 single-arm study to establish the safety andefficacyofup-front therapywithpazopanib (800 mg daily) prior to CN in patients with previously untreated clear cell variant mRCC, presenting with a synchronous renal mass and metastasis. A total of 104 patients were accrued, ofwhich 100were assessable for clinical benefit. The primary objective of the trial was defined as patientswho did not experience clinical or imagingprogressionofdiseaseat the time of surgery. Four patients were not assessable for the primaryobjectivebecause theyhad todiscontinuepazopanibowing to toxic effects prior to radiologic assessment. The median duration of pazopanib therapy was 13 weeks, with all patients stopping therapy at least 48 hours prior to surgery. Pazopanib was resumed after a 14-day break following surgery. The studymet the primary objective with 84% (n = 84 of 100) patients achieving clinical benefit. The median PFS and OS of 104 enrolled patientswere 7.1months and 22.7months, respectively, which are in line with data reported in the firstline therapy setting with this class of drugs. Notably, the patients who failed to achieve clinical benefit had a significantly shorterOScomparedwith thosewithclinicalbenefit (3.9 vs 24 months; HR, 3.92). Eighteen out of 100 assessable patients (18%) belonged to the Memorial Sloan-Kettering Cancer Center (MSKCC) poor risk category and had amedian PFS and OS of 3.9months and 5.7 months, respectively. From the perspectiveof safetyofup-front therapywithpazopanibprior to surgery, only 65 of 104 patients (63%) eventually underwent surgery. The 3 most common reasons cited for not undergoing nephrectomywere disease progression prior to surgery (n = 13), patient choice (mostly in those who were responding) (n = 9), and inadequate fitness for surgery (n = 5). Overall, surgery-related morbidities were low. Several biomarkers were analyzed at baseline and at the time of surgery. Notably, there was a significant decrease of expression of VEGFR2, HIF1 alpha, c-met, VHL, and CD8, and a significant increase in the expression of programmed cell death 1 ligand Related article Opinion