Essential Peer-Reviewed Reading in Kidney Cancer


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.

Metastatic clear-cell renal cell carcinoma with a long-term response to sunitinib: a distinct pheno­type independently associated with low PD-L1 ex­pression. Kammerer-Jacquet SF, Brunot A, Lefort M, at al. Clin Genitorurin Cancer. 2019 Feb 4; pii: S1558-7673(18)30716-X. doi: 10.1016/j.clgc.2019.01.014. Summary: Long-term responders (LTRs) are defined by at least 18 months of response to sunitinib in metasta­tic clear-cell renal cell carcinoma (ccRCC). The pheno­type of these tumors has never been explored. In a retrospective and multicenter study, 90 ccRCCs of pa­tients with metastatic disease were analyzed. Immuno­histochemistry (carbonic anhydrase IX, vascular endothelial growth factor, c-MET, programmed death-ligand 1 [PD-L1], and PD-1) and VHL status were per­formed. Progression-free survival and overall survival were calculated from sunitinib introduction and from progression. LTRs and their corresponding tumors were compared with others using univariate and multivariate analysis. Twenty-eight patients were LTRs. They had a median progression-free survival of 28 months vs 4 months for other patients. Similarly, LTRs had a median overall sur­vival of 49 months vs 14 months, even from progres­sion (median, 21 vs. 7 months). They were associated with a favorable or intermediate risk (International Metastatic Renal Cell Carcinoma Database Consortium model) and less liver metastasis. They experienced more frequent complete or partial responses at the first radio­logic evaluation. The corresponding ccRCCs were asso­ciated with less nucleolar International Society for Urological Pathology grade 4 and hilar fat infiltration. They were also associated with low PD-L1 expression.
Conclusion: Primary tumor characteristics of LTRs were studied for the first time and demonstrated a different phenotype. Interestingly, they were characterized by low expression of PD-L1, suggesting a potentially lower impact of targeted immunotherapy in these patients.

Cabozantinib in advanced non-clear-cell renal cell carcinoma: a multicentre, retrospective, cohort study. Martinez Chanzá N, Xie W, Asim Bilen M, et al. Lancet Oncol. 2019 Feb 28. pii: S1470-2045(18)30907-0. doi: 10.1016/S1470-2045(18)30907-0. Summary: This study analyzed the antitumor activity and toxicity of cabozantinib in advanced non-clear-cell renal cell carcinoma. This was a multicenter, interna­tional, retrospective cohort study of patients with metastatic nccRCC treated with oral cabozantinib dur­ing any treatment line at 22 centers: 21 in the US and one in Belgium. The main objectives were to estimate the proportion of patients who achieved an objective response, time to treatment failure, and overall survival after treatment. Of 112 identified patients with nc­cRCC, 66 (59%) had papillary histology, 17 (15%) had Xp11.2 translocation histology, 15 (13%) had unclassi­fied histology, ten (9%) had chromophobe histology, and four (4%) had collecting duct histology. The pro­portion of patients who achieved an objective response across all histologies was 30 of 112 patients. At a me­dian follow-up of 11 months (IQR 6-18), median time to treatment failure was 6·7 months, median progres­sion-free survival was 7·0 months (5·7-9·0), and median overall survival was 12·0 months (9·2-17·0). The most common adverse events of any grade were fatigue (58 [52%]), and diarrhea (38 [34%]). The most common grade 3 events were skin toxicity (rash and palmar-plan­tar erythrodysesthesia; five [4%]) and hypertension (four [4%]). No treatment-related deaths were observed. Across 54 patients with available next-generation se­quencing data, the most frequently altered somatic genes were CDKN2A (12 [22%]) and MET (11 [20%]) with responses seen irrespective of mutational status.
Conclusion: This real-world study provides evidence supporting the antitumor activity and safety of cabozantinib across non-clear-cell renal cell carcinomas. Continued support of international collaborations and prospective ongoing studies targeting nccRCC carci­noma subtypes and specific molecular alterations are warranted to improve outcomes across these rare dis­eases with few evidence-based treatment options.

Sarcomatoid renal cell carcinoma: population-based study of 879 patients. Alevizakos M, Gaitanidis A, Na­sioudis D, et al. Clin Genitourin Cancer. 2019 Jan 17. pii: S1558-7673(19)30014-X. doi:10.1016/j.clgc.2019. 01.005.
This study accessed the National Cancer In­stitute’s Surveillance, Epidemiology, and End Results database (2010-2015) and extracted data on patients with sRCC. Median, 1-, 3-, and 5-year disease-specific survival (DSS) probabilities were estimated to evaluate variables associated with nephrectomy and DSS. A total of 879 patients with sRCC were identified; 60.9% pa­tients had stage IV disease at diagnosis, and the median tumor size was 8.3 cm (interquartile range, 5.5-12 cm). The 5-year DSS were 77.7%, 67.8%, 35.4%, and 3.5% for patients with stage I, II, III, and IV disease at diagnosis, respectively; median DSS was 9 months (interquartile range, 4-42 months) for the entire cohort. Older age higher tumor stage and performance of nephrectomy were found to independently affect DSS.
Conclusion: In the largest sRCC cohort to date, the re­sults showed that most patients present with metastatic disease, and prognosis remains extremely poor. Neph-rectomy should be considered in all patients with acceptable surgical risk, including cytoreductive nephrectomy in carefully selected patients with metastatic disease.

Overweight and obesity during adolescence in­creases the risk of renal cell carcinoma. Landberg A, Fält A, Montgomery S, et al. Int J Cancer. 2019 Feb 20. doi: 10.1002/ijc.32147.
Summary: While overweight among adults has been linked with renal cell carcinoma (RCC) risk, little is known about the potential influence of overweight and obesity during adolescence. To ascertain if adolescent body mass index is associated with subsequent risk of RCC, we identified a cohort of 238,788 Swedish men who underwent mandatory military conscription as­sessment between 1969 and 1976 at a mean age of 18.5 years. At the time of conscription assessment, physical and psychological tests were performed including meas­urements of height and weight. Participants were fol­lowed through linkage to the Swedish Cancer Registry to identify incident diagnoses of RCC. The association between body mass index (BMI, kg/m2 ) at conscription assessment and subsequent RCC was evaluated using multivariable Cox regression. During a follow-up of up to 37 years, 266 men were diagnosed with RCC. We ob­served a trend for higher RCC risk with increasing BMI during adolescence, where one-unit increase in BMI conferred a 6% increased risk of RCC (95% CI 1.01-1.10) compared to normal weight men (BMI 18.5- < 25), men with overweight (BMI 25- < 30) or obesity (BMI ≥30) had hazard ratios for RCC of 1.76 and 2.87, respec­tively.
Conclusion: The link between overweight/obesity and RCC appears to be already established during late ado­lescence. Prevention of unhealthy weight gain during childhood and adolescence may thus be a target in ef­forts to decrease the burden of RCC in the adult popula­tion.

First-line nivolumab plus ipilimumab vs sunitinib for metastatic renal cell carcinoma: a cost-effective­ness analysis. Wan X, Zhang Y, Tan C, et al. JAMA Oncol. 2019 Feb 21. doi: 10.1001/jamaoncol.2018.7086.
Summary: Considering the high cost of nivolumab plus ipilimumab, there is a need to assess its value by considering both efficacy and cost. A Markov model was developed to compare the lifetime cost and effec­tiveness of nivolumab plus ipilimumab vs sunitinib in the first-line treatment of mRCC using outcomes data from the CheckMate 214 phase 3 randomized clinical trial, which included 1096 patients with mRCC (me­dian age, 62 years) and compared nivolumab plus ipili­mumab vs sunitinib as first-line treatment of mRCC. In the analysis, patients were modeled to receive sunitinib or nivolumab plus ipilimumab for 4 doses followed by nivolumab monotherapy. Life-years, quality-adjusted life-years (QALYs), and lifetime costs were estimated, at a willingness-to-pay threshold of $100,000 to $150,000 per QALY. Nivolumab plus ipilimumab provided an ad­ditional 0.96 QALYs, at a cost of $108,363 per QALY. Re­sults were most sensitive to overall survival hazard ratio and mean patient weight (70 kg). Other variables, such as the cost of nivolumab plus ipilimumab (mean, $32,213.44; range, $25,770.75-$38,656.13), utility val­ues for nivolumab plus ipilimumab (mean, 0.82), and proportion receiving nivolumab in sunitinib arm (mean, 0.27), had a moderate or minor influence on model results. Subgroup analyses demonstrated that nivolumab plus ipilimumab was most cost-effective for patients with programmed cell death 1 ligand 1 expres­sion of at least 1% ($86,390 per QALY).
Conclusion: In this model, nivolumab plus ipilimumab was estimated to be cost-effective compared with suni­tinib for intermediate- and poor-risk patients with mRCC at a willingness-to-pay threshold from $100,000 to $150,000 per QALY.

Avelumab plus axitinib versus sunitinib for ad­vanced renal-cell carcinoma. Motzer RJ, Penkov K, Haanen J, et al. N Engl J Med. 2019 Feb 16. doi: 10.1056/NEJMoa1816047
Summary: This phase 3 trial involving previously un­treated patients with advanced RCC compared avelumab plus axitinib with sunitinib. Patients were randomly assigned in a 1:1 ratio to receive avelumab (10 mg per kg) intravenously every 2 weeks plus axi­tinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). Primary end points were progression-free survival and overall survival among patients with programmed death ligand 1 (PD-L1)-positive tumors. A key secondary end point was progression-free survival in the overall population; other end points included objective response and safety. A total of 886 patients were assigned to receive avelumab plus axitinib (442 patients) or sunitinib (444 patients). Among the 560 patients with PD-L1-positive tumors (63.2%), the median progression-free survival was 13.8 months with avelumab plus axitinib, as com­pared with 7.2 months with sunitinib (hazard ratio for disease progression or death, 0.61; in the overall popu­lation, the median progression-free survival was 13.8 months, as compared with 8.4 months (hazard ratio, 0.69; 95% CI, 0.56 to 0.84; P<0.001). Among the pa­tients with PD-L1-positive tumors, the objective re­sponse rate was 55.2% with avelumab plus axitinib and 25.5% with sunitinib; at a median follow-up for overall survival of 11.6 months and 10.7 months in the two groups, 37 patients and 44 patients had died, respec­tively. Adverse events during treatment occurred in 99.5% of patients in the avelumab-plus-axitinib group and in 99.3% of patients in the sunitinib group; these events were grade 3 or higher in 71.2% and 71.5% of the patients in the respective groups.
Conclusion: Progression-free survival was significantly longer with avelumab plus axitinib than with sunitinib among patients who received these agents as first-line treatment for advanced renal-cell carcinoma.

Pembrolizumab plus axitinib versus sunitinib for ad­vanced renal-cell carcinoma. Rini BI, Plimack ER, Stus V, et al. N Engl J Med. 2019 Feb 16. doi: 10.1056/NEJ­Moa1816714.
Summary: The combination of pembrolizumab and ax­itinib showed antitumor activity in a phase 1b trial in­volving patients with previously untreated advanced renal-cell carcinoma. Whether pembrolizumab plus axi­tinib would result in better outcomes than sunitinib in such patients was unclear. This open-label, phase 3 trial randomly assigned 861 patients with previously un­treated advanced clear-cell renal-cell carcinoma to re­ceive pembrolizumab (200 mg) intravenously once every 3 weeks plus axitinib (5 mg) orally twice daily (432 patients) or sunitinib (50 mg) orally once daily for the first 4 weeks of each 6-week cycle (429 patients). Pri­mary end points were overall survival and progression-free survival in the intention-to-treat population. The key secondary end point was the objective response rate. All reported results are from the protocol-specified first interim analysis. After a median follow-up of 12.8 months, the estimated percentage of patients who were alive at 12 months was 89.9% in the pembrolizumab-axitinib group and 78.3% in the sunitinib group. Me­dian progression-free survival was 15.1 months in the pembrolizumab-axitinib group and 11.1 months in the sunitinib group. The objective response rate was 59.3% in the pembrolizumab-axitinib group and 35.7%in the sunitinib group (P<0.001). The benefit of pem­brolizumab plus axitinib was observed across the Inter­national Metastatic Renal Cell Carcinoma Database Consortium risk groups (i.e., favorable, intermediate, and poor risk) and regardless of programmed death lig­and 1 expression. Grade 3 or higher adverse events of any cause occurred in 75.8% of patients in the pem­brolizumab-axitinib group and in 70.6% in the suni­tinib group.
Conclusion: Among patients with previously untreated advanced RCC, treatment with pembrolizumab plus ax­itinib resulted in significantly longer overall survival and progression-free survival, as well as a higher objec­tive response rate, than treatment with sunitinib. KCJ