Essential Peer-Reviewed Reading in Kidney Cancer

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Essential Peer-Reviewed Reading in Kidney Cancer

The peer-reviewed articles summarized in this section were selected by the Editor-in-Chief, Robert A. Figlin, MD, for their timeliness, importance, relevance, and potential impact on clinical practice or translational research.

Emerging role of combination immunotherapy in the first-line treatment of advanced renal cell carcinoma: a review. George S, Rini BI, Hammers HJ. JAMA Oncol. 2018 Nov 21; doi: 10.1001/jamaoncol.2018.4604
Summary: Novel immunotherapies, notably the immune checkpoint inhibitors, have been shown to be efficacious in patients with advanced renal cell carcinoma (RCC), but innate or adaptive resistance is observed with single-agent immunotherapy. New combination treatment strategies are needed that can improve efficacy in a broader patient population, without exacerbating the toxic effects. Numerous late-phase trials are ongoing to investigate (1) dual immune checkpoint inhibition or (2) combined inhibition of immune checkpoints and vascular endo- thelial growth factor. Initial results from studies of the nivolumab plus ipilimumab and atezolizumab plus beva­cizumab combinations have demonstrated efficacy com­pared with sunitinib malate in treatment-naïve patients with advanced renal cell carcinoma; moreover, the safety profile of these combinations compare favorably with sunitinib. Nevertheless, immune checkpoint inhibition is associated with unique immune-related adverse events.
Conclusion: Evidence suggests that immunotherapy-based combination regimens will be an important addition to the treatment of advanced renal cell carcinoma in both the first- and later-line setting; however, clinical study data and clinical practice experience indicate that optimizing the management of the associated immune- related adverse events is essential to maximizing the advantages of these therapies.

Cost-effectiveness of nivolumab plus ipilimumab as first-line therapy in advanced renal-cell carcinoma. Wu B, Zhang Q, Sun J. J Immunother Cancer. 2018 Nov 20;6(1):124. doi: 10.1186/s40425-018-0440-9.
Summary: The current study aimed to assess the cost- effectiveness of nivolumab plus ipilimumab for first-line treatment of advanced RCC from the payer perspectives high- and middle-income regions. A decision-analytic model was constructed to evaluate the health and eco­nomic outcomes of first-line sunitinib and nivolumab plus ipilimumab treatment associated with advanced RCC. The clinical and utility data were obtained from published reports. The cost data were acquired for the payer perspectives of the United States (US), United King­dom (UK), and China. Sensitivity analyses were performed to test the uncertainties of the results. Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) were used. Nivolumab plus ipilimumab gained 0.70-0.76 QALYs compared with sunitinib. The analysis determined the following ICERs for nivolumab plus ipilimumab over sunitinib in first-line advanced RCC treatment: US $ 85,506 /QALY; UK $ 126,499/QALY; and China $ 4682/QALY. Sensitivity analyses found the model outputs to be most affected for body weight and for the prices of nivolumab, sunitinib and ipilimumab.
Conclusion: Nivolumab plus ipilimumab as first-line treatment could gain more health benefits for advanced RCC in comparison with standard sunitinib, which is considered to be cost-effective in the US and China but not in the UK.

The identification of immunological biomarkers in kidney cancers. Lopez-Beltran A, Henriques V, Cimadamore A, et al. Front Oncol. 2018 Nov 2;8:456. doi: 10.3389/fonc.2018.00456
Summary: RCC includes a large group of tumor entities, each of them with different genetic and mutational alter­ations, but also showing different clinical behavior; a reason behind the need for a subtype specific personalized approach to therapy of RCC. Due to the combination of potent treatment success and potentially deadly adverse effects from immune checkpoint inhibitors (ICI), gather­ing prognostic and predictive information about FDA- indicated tumors seems to be prudent. Robust and reliable biomarkers are crucial for patient’s selection of treatments with immunomodulatory drugs. PD-L1 expression is a poor prognostic factor and predictive of better responses from both PD-1 and PD-L1 inhibitors in a variety of tumor types including RCC. Each FDA approved PD-1/PD-L1 drug is paired with a PD-L1 Immunohistochemistry (IHC) assay. Thus, there is need for improved knowledge and application of PD-1/PD-L1 IHC biomarkers in daily practice. IHC staining appears in membranous fashion.
Conclusion: The atezolizumab approved IHC assay is unique in that only immune cell staining is quantified for the use of this assay in RCC. A single biomarker for patient selection may not be feasible, given that immune responses are dynamic and evolve over time. Biomarker development for ICI drugs will likely require integration of multiple biologic components like PD-L1 expression, TILs and mutational load. New methodological ap­proaches based on digital pathology may be relevant since they will allow recognition of the biomarker and to objec­tively quantitate its expression, and therefore might pro­duce objective and reproducible cut-off assessment. Multidisciplinary approach is very much needed to fully develop the current and future value of ICI in clinical practice.

Genomically annotated risk model for advanced renal-cell carcinoma: a retrospective cohort study. Voss MH, Reising A, Cheng Y, et al. Lancet Oncol. 2018 Nov 8. pii: S1470-2045(18)30648-X.
Summary: Several mutations, including BAP1 and PBRM1, have prognostic value in renal-cell carcinoma. Using two independent clinical trial datasets of patients with metastatic renal-cell carcinoma, this study aimed to determine whether the addition of the mutation status for several candidate prognostic genes to the MSKCC model could improve the model’s prognostic performance. This retrospective cohort study used available formalin-fixed paraffin-embedded tumor tissue and clinical outcome data from patients with metastatic renal-cell carcinoma assigned to treatment with tyrosine kinase inhibitors in the COMPARZ trial (training cohort; n=357) and RECORD-3 trial (validation cohort; n=258). Eligible patients in both trials were treatment-naive; had histolog­ically confirmed, advanced, or metastatic renal-cell carci­noma; and a Karnofsky performance status score of at least 70. For each cohort, data from patients in all treat­ment groups (sunitinib and pazopanib in the training cohort, and everolimus and sunitinib in the validation co­hort) were pooled for this analysis. In the training cohort, tumor tissue was used to evaluate somatic mutations by next-generation sequencing, and the association between cancer-specific outcomes (overall survival, progression-free survival, and overall response) and the mutation status of six genes of interest (BAP1, PBRM1, TP53, TERT, KDM5C, and SETD2) was tested. Only those genes with prognostic value in this setting were added to the MSKCC risk model to create a genomically annotated version. In the training cohort, the presence of any mutation in BAP1 or TP53, or both, and absence of any mutation in PBRM1 were prognostic in terms of overall survival (TP53wt/ BAP1mut, TP53mut/BAP1wt o TP53mut BAP1mut vs TP53wt/BAP1wt hazard ratio [HR] 1·57, 95% CI 1·21-2·04; P=0·0008; PBRM1wt vs PBRMmut, HR 1·58, 1·16-2·14; P=0·0035). The mutation status for these three prognostic genes were added to the original MSKCC risk model to create a genomically annotated version. Distribution of participants in the training cohort into the three risk groups of the original MSKCC model changed from 87 (24%) of 357 patients deemed at favorable risk, 217 (61%) at intermediate risk, and 53 (15%) at poor risk, to distribu­tion across four risk groups in the genomically annotated risk model, with 36 (10%) of 357 deemed at favourable risk, 77 (22%) at good risk, 108 (30%) at intermediate risk, and 136 (38%) at poor risk. Addition of genomic informa­tion improved model performance for predicting overall survival (C-index: original model, 0·595 [95% CI 0·557-0·634] vs new model, 0·637 [0·595-0·679]) and progres­sion-free survival (0·567 [95% CI 0·529-0·604] vs 0·602 [0·560-0·643]) with adequate discrimination of the pro­portion of patients who achieved an objective response (Cochran-Armitage one-sided P=0·0014). Analyses in the validation cohort confirmed the superiority of the genom­ically annotated risk model over the original version.
Conclusion: The mutation status of BAP1, PBRM1, and TP53 has independent prognostic value in patients with advanced or metastatic renal-cell carcinoma treated with first-line tyrosine kinase inhibitors. Improved stratifica­tion of patients across risk groups by use of a genomically annotated model including the mutational status of these three genes warrants further investigation in prospective trials and could be of use as a model to stratify patients with metastatic RCC in clinical trials.

Adjuvant sunitinib in patients with high-risk renal cell carcinoma: safety, therapy management, and patient-reported outcomes in the S-TRAC trial. Staehler M, Motzer RJ, George DJ, et al. Ann Oncol. 2018 Oct 1;29(10): 2098-2104.
Summary: Adjuvant sunitinib has significantly improved disease-free survival versus placebo in patients with renal cell carcinoma at high risk of recurrence post-nephrec­tomy. This study reported safety, therapy management, and patient-reported outcomes for patients receiving suni­tinib and placebo in the S-TRAC trial. Patients were ran­domized (1:1) to receive sunitinib (50 mg/day) or placebo. Single dose reductions to 37.5 mg, dose delays, and dose interruptions were used to manage adverse events (AEs). Patients’ health-related quality of life, including key symptoms typically associated with sunitinib, were evalu­ated with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Patients maintained treatment for 9.5 (mean, SD 4.4) and 10.3 (mean, SD 3.7) months in the sunitinib and placebo arms, respectively. In the sunitinib arm, key AEs occurred 1 month (median) after start of treatment and resolved within 3.5 weeks (median). Many (40.6%) AEs leading to permanent discontinuation were grade 1/2, and most (87.2%) resolved or were resolving by 28 days after last treatment. Patients reported symptoms typically related to sunitinib treatment with diarrhea and loss of appetite showing clinically meaningful increases.
Conclusion: In S-TRAC, AEs were predictable, manage­able, and reversible via dose interruptions, dose reduc­tions, and/or standard supportive medical therapy. Patients on sunitinib did report increased symptoms and reduced HRQoL, but these changes were generally not clinically meaningful, apart from appetite loss and diarrhea, and were expected in the context of known sunitinib effects.

Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. Méjean A, Ravaud A, Thezenas S, et al. N Engl J Med. 2018 Aug 2;379(5):417-427.
Summary: This phase 3 trial randomly assigned, in a 1:1 ratio, patients with confirmed metastatic clear-cell RCC at presentation who were suitable candidates for nephrec­tomy to undergo nephrectomy and then receive sunitinib (standard therapy) or to receive sunitinib alone. Random­ization was stratified according to prognostic risk (inter­mediate or poor) in the Memorial Sloan Kettering Cancer Center prognostic model. Patients received sunitinib at a dose of 50 mg daily in cycles of 28 days on and 14 days off every 6 weeks. The primary end point was overall survival. A total of 450 patients were enrolled from Sep­tember 2009 to September 2017. At this planned interim analysis, the median follow-up was 50.9 months, with 326 deaths observed. The results in the sunitinib-alone group were noninferior to those in the nephrectomy- sunitinib group with regard to overall survival. The me­dian overall survival was 18.4 months in the sunitinib-alone group and 13.9 months in the nephrectomy-suni- tinib group. No significant differences in response rate or progression-free survival were observed. Adverse events were as anticipated in each group. Conclusion: Sunitinib alone was not inferior to nephrec­tomy followed by sunitinib in patients with metastatic RCC who were classified as having intermediate-risk or poor risk disease poor-risk disease. KCJ