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Essential Peer-Reviewed Reading in Kidney Cancer

The peer-reviewed articles summarized in this section were selected by the
Guest Editor, Bernard J. Escudier, MD
, for their timeliness, importance,
relevance, and potential impact on clinical practice or translational research.

Updated October 2017.

 

Randomized Phase III Trial of Adjuvant Pazopanib Versus Placebo After Nephrectomy in Patients With Localized or Locally Advanced Renal Cell Carcinoma. Motzer RJ, Haas NB, Donskov, et al. J Clin Oncol. 2017 Sep 13; JCO2017735324. doi: 10.1200/JCO.2017.73. 5324.
Summary: This phase III trial evaluated the efficacy and safety of pazopanib versus placebo in patients with locally advanced renal cell carcinoma (RCC) at high risk for relapse after nephrectomy. A total of 1,538 patients with resected pT2 (high grade) or ≥ pT3, including N1, clear cell RCC were randomly assigned to pazopanib or placebo for 1 year; 403 patients received a starting dose of 800 mg or placebo. To address toxicity attrition, the 800-mg starting dose was lowered to 600 mg, and the primary end point analysis was changed to disease-free survival (DFS) for pazopanib 600 mg versus placebo (n = 1,135). Primary analysis was performed after 350 DFS events in the intent-to-treat (ITT) pazopanib 600 mg group (ITT600mg), and DFS follow-up analysis was performed 12 months later. Secondary end point analyses included DFS with ITT pazopanib 800 mg (ITT800mg) and safety. The primary analysis results of DFS ITT600mg favored pazopanib but did not show a significant improvement over placebo (P = .165). The secondary analysis of DFS in ITT800mg (n = 403) yielded an HR of 0.69. Follow-up analysis in ITT600mg yielded an HR of 0.94 (95% CI, 0.77 to 1.14). Increased ALT and AST were common adverse events leading to treatment discontinuation in the pazopanib 600 mg (ALT, 16%; AST, 5%) and 800 mg (ALT, 18%; AST, 7%) groups.
Conclusion: The results of the primary DFS analysis of pazopanib 600 mg showed no benefit over placebo in the adjuvant setting.

Long-Term Response to Sunitinib Treatment in Metastatic Renal Cell Carcinoma: A Pooled Analysis of Clinical Trials. Tannir NM, Figlin RA, Gore ME, et al. EClin Genitourin Cancer. 2017 Jun 20. S1558-7673(17) 30171-4.
Summary: We characterized clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib who were long-term responders (LTRs), defined as patients having progression-free survival (PFS) > 18 months. A retrospective analysis of data from 5714 patients with mRCC treated with sunitinib in 8 phase II/III clinical trials and the expanded access program. Duration on-study and objective response rate (ORR) were compared between LTRs and patients with PFS ≤ 18 months (“others”). PFS and overall survival (OS) were summarized using Kaplan-Meier methodology. Overall, 898 (15.7%) patients achieved a long-term response and 4816 (84.3%) patients did not achieve long-term response. The median (range) duration on-study was 28.6 (16.8-70.7) months in LTRs and 5.5 (0-68.8) months in others. ORR was 51% in LTRs versus 14% in others (P < .0001). Median PFS in LTRs was 32.11 months and median OS was not reached. LTRs had higher percentage of early tumor shrinkage ≥ 10% at the first scan (67.1% vs. 51.2%; P = .0018) and greater median maximum on-study tumor shrinkage from baseline (-56.9 vs. -27.1; P < .0001) versus others.
Conclusion: White race, Eastern Cooperative Oncology Group performance status 0, time from diagnosis to treatment ≥ 1 year, clear cell histology, no liver metastasis, lactate dehydrogenase ≤ 1.5 upper limit of normal (ULN), corrected calcium ≤ 10 mg/dL, hemoglobin greater than the lower limit of normal, platelets less than or equal to ULN, body mass index ≥ 25 kg/m2, and low neutrophil-to-lymphocyte ratio were associated with LTR. A subset of patients with mRCC treated with sunitinib achieved long-term response. LTRs had improved ORR, PFS, and OS.

Biomarker-Based Phase II Trial of Savolitinib in Patients With Advanced Papillary Renal Cell Cancer. Choueiri TK, Plimack E, Arkenau HT, et al. J Clin Oncol. 2017 Sep 10;35(26):2993-3001. doi: 10.1200/JCO.2017.72.2967
Summary: Patients with advanced papillary renal cell carcinoma (PRCC) have limited therapeutic options. PRCC may involve activation of the MET pathway, for example, through gene amplification or mutations. Savolitinib (AZD6094, HMPL-504, volitinib) is a highly selective MET tyrosine kinase inhibitor. We report results of a single-arm, multicenter, phase II study evaluating the safety and efficacy of savolitinib in patients with PRCC according to MET status. Patients and Methods Patients with histologically confirmed locally advanced or metastatic PRCC were enrolled and received savolitinib 600 mg orally once daily. MET-driven PRCC was defined as any of the following: chromosome 7 copy gain, focal MET or HGF gene amplification, or MET kinase domain mutations. Efficacy was assessed according to MET status. Safety, toxicity, and patient-reported health-related quality-of-life outcomes were assessed in all patients. Results Of 109 patients treated, PRCC was MET driven in 44 (40%) and MET independent in 46 (42%); MET status was unknown in 19 (17%). MET-driven PRCC was strongly associated with response; there were eight confirmed partial responders with MET-driven disease (18%), but none with MET-independent disease (P = .002). Median progression-free survival for patients with MET-driven and MET-independent PRCC was 6.2 months  and 1.4 months, respectively (hazard ratio, 0.33; 95% CI, 0.20 to 0.52; log-rank P < .001). The most frequent adverse events associated with savolitinib were nausea, fatigue, vomiting, and peripheral edema.
Conclusion: These data show activity and tolerability of savolitinib in the subgroup of patients with MET-driven PRCC. Furthermore, molecular characterization of MET status was more predictive of response to savolitinib than a classification based on pathology. These findings justify investigating savolitinib in MET-driven PRCC.

Safety and Efficacy of Nivolumab in Combination With Ipilimumab in Metastatic Renal Cell Carcinoma: The CheckMate 016 Study. Hammers HJ, Plimack ER, Infante JR, et al. J Clin Oncol. 2017 Jul 5;JCO20167219 85. doi: 10.1200.
Summary: Combination treatment with immune checkpoint inhibitors has shown enhanced antitumor activity compared with monotherapy in tumor types such as melanoma. The open-label, parallel-cohort, dose-escalation, phase I CheckMate 016 study evaluated the efficacy and safety of nivolumab plus ipilimumab in combination, and nivolumab plus a tyrosine kinase inhibitor in metastatic renal cell carcinoma (mRCC). Safety and efficacy results from the nivolumab plus ipilimumab arms of the study are presented. Patients with mRCC received intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3I1), nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1I3), or nivolumab 3 mg/kg plus ipilimumab 3 mg/kg (N3I3) every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks until progression or toxicity. End points included safety (primary), objective response rate, and overall survival (OS). All patients in the N3I3 arm (n = 6) were censored at the time of analysis as a result of dose-limiting toxicity or other reasons. Forty-seven patients were treated in both the N3I1 and the N1I3 arm, and baseline patient characteristics were balanced between arms. Grade 3 to 4 treatment-related adverse events were reported in 38.3% and 61.7% of the patients in the N3I1 and N1I3 arms, respectively. At a median follow-up of 22.3 months, the confirmed objective response rate was 40.4% in both arms, with ongoing responses in 42.1% and 36.8% of patients in the N3I1 and N1I3 arms, respectively. The 2-year OS was 67.3% and 69.6% in the N3I1 and N1I3 arms, respectively.
Conclusion: Nivolumab plus ipilimumab therapy demonstrated manageable safety, notable antitumor activity, and durable responses with promising OS in patients with mRCC.

Correlation of c-MET Expression with PD-L1 Expression in Metastatic Clear Cell Renal Cell Carcinoma Treated by Sunitinib First-Line Therapy. Kammerer-Jacquet SF, Medane S, Bensalah K, et al. Target Oncol. 2017 Aug; 12(4):487-494.
Summary:  Cabozantinib, an anti-angiogenic tyrosine kinase inhibitor that targets c-MET, provided interesting results in metastatic ccRCC treatment. To understand better the role of c-MET in ccRCC, we assessed its status in a population of patients with metastatic ccRCC. For this purpose, tumor samples were analyzed for c-MET expression by immunohistochemistry (IHC), for c-MET copy number alterations by fluorescence in situ hybridization (FISH), and for c-MET mutations by next generation sequencing (NGS) in a retrospective cohort of 90 primary ccRCC of patients with metastases treated by first-line sunitinib. The expression of c-MET was correlated with pathological, immunohistochemical (VEGFA, CAIX, PD-L1), clinical, and molecular criteria (VHL status) by univariate and multivariate analyses and to clinical outcome using Kaplan-Meier curves compared by log-rank test. Of ccRCC, 31.1% had low c-MET expression (absent to weak intensity by IHC) versus 68.9% with high expression (moderate to strong intensity). High expression of c-MET was associated with a gain in FISH analysis (P = 0.0284) without amplification. No mutations were detected in NGS. Moreover, high c-MET expression was associated with lymph node metastases (P = 0.004), sarcomatoid component (P = 0.029), VEGFA (P = 0.037), and PD-L1 (P = 0.001) overexpression, the only factor that remained independently associated (P < 0.001) after logistic regression. No difference was observed in clinical outcomes.
Conclusion: This study is the first to analyze c-MET status in metastatic ccRCC. The high expression of c-MET in the majority of ccRCC and its independent association with PD-L1 expression, may suggest a potential benefit from combining c-MET inhibitors and targeted immunotherapy.

New Insights into Adjuvant Renal Cell Carcinoma Treatment with Vascular Endothelial Growth Factor Inhibitors: What Have We Learned So Far? Escudier B, Staehler M. Eur Urol. 2017 Sep 7; pii: S0302-2838(17) 30713-3. doi: 10.1016
Summary: Adjuvant treatment of renal cell carcinoma with vascular endothelial growth factor inhibitors is feasible and effective with careful patient selection and standard dosing levels.  KCJ