Essential Peer-Reviewed Reading in Kidney Cancer
The peer-reviewed articles summarized in this section were selected by the Guest Editor, James Brugarolas, MD, PhD, for their timeliness, importance, relevance, and potential impact on clinical practice or translational research. Updated April 2017.
CheckMate 025 Randomized Phase 3 Study: Outcomes by Key Baseline Factors and Prior Therapy for Nivolumab Versus Everolimus in Advanced Renal Cell Carcinoma. Escudier B, Sharma P, McDermott DF, et al. Eur Urol. 2017 Mar 2; pii: S0302-2838(17)30099-4. doi: 10.1016/j.eururo.2017.02.010.
Summary: The randomized, phase 3 CheckMate 025 study of nivolumab (n=410) versus everolimus (n=411) in previously treated adults (75% male; 88% white) with advanced renal cell carcinoma (aRCC) demonstrated significantly improved overall survival (OS) and objective response rate (ORR). The minimum follow-up was 14 mo. Baseline subgroup distributions were balanced between nivolumab and everolimus arms. Nivolumab demonstrated an OS improvement versus everolimus across subgroups, including Memorial Sloan Kettering Cancer Center (MSKCC) and international Metastatic Renal Cell Carcinoma Database Consortium risk groups; age <65 and ³65 yr; one and two or more sites of metastases; bone, liver, and lung metastases; number of prior therapies; duration of prior therapy; and prior sunitinib, pazopanib, or interleukin-2 therapy. The benefit with nivolumab versus everolimus was noteworthy for patients with poor MSKCC risk. The mortality rate at 12 moths for all subgroups was lower with nivolu-mab compared with everolimus. ORR also favored nivolu-mab. The incidence of grade 3 or 4 treatment-related adverse events across subgroups was lower with nivolumab.
Conclusion: The trend for OS and ORR benefit with nivolumab for multiple subgroups, without notable safety concerns, may help to guide treatment decisions, and further supports nivolumab as the standard of care in previously treated patients with aRCC.
Discontinuing VEGF-targeted Therapy for Progression Versus Toxicity Affects Outcomes of Second-line Therapies in Metastatic Renal Cell Carcinoma. De Velasco, G, Xie W, Donskov F, et al. Clin Genitourin Cancer. 2017 Jan 12. pii: S1558-7673(17)30005-8. doi:10.1016/j.clgc. 2017.01.005.
Summary: A significant subgroup of metastatic renal cell carcinoma (mRCC) patients discontinue vascular endothelial growth factor-targeted therapies (VEGF-TT) because of toxicity. Whether clinical outcomes differ in patients who receive second-line (2L) targeted therapy on the basis of reason for discontinuation of first-line (1L) therapy is unknown. In total, 1124 patients were identified: 866 patients (77%) discontinued 1L VEGF-TT because of disease progression, and 208 patients (19%) because of toxicity. The reason for discontinuation of 1L therapy did not differ according to IMDC risk group. Compared with patients who stopped 1L VEGF-TT because of disease progression, patients who stopped because of toxicity had greater clinical benefit (nonprogressive disease as best response) in 2L treatment (68% vs. 56%; P = .023) and longer OS (17.4 vs. 11.2 months; P = .0002) adjusted for type of therapy, time to initiation of 2L treatment, IMDC risk group, and number of metastases at initiation of 2L treatment.
Conclusion: mRCC patients who discontinue 1L VEGF-TT because of toxicity have better outcomes with 2L therapy than patients who stop therapy because of disease progression. These findings should be taken into consideration when designing clinical trials for 2L therapies in mRCC.
Adjuvant Treatment for High-Risk Clear Cell Renal Cancer: Updated Results of a High-Risk Subset of the ASSURE Randomized Trial. Haas NB, Manola J, Dutcher JP, et al. JAMA Oncol. 2017 Mar 9. doi:10.1001/jamaoncol. 2017.0076.
Summary: Given recently published results of a 750-patient adjuvant sunitinib trial showing improved disease-free survival (DFS), the appropriate strategy for treating high-risk patients is unclear. This study determined whether there is improved disease-free survival benefit to taking the active drug in patients with high-risk (pT3, pT4, node-positive) clear cell renal cancer (ccRCC) in the ASSURE trial (adjuvant sunitinib or sorafenib vs placebo in resected unfavorable renal cell carcinoma [RCC]), the largest adjuvant trial published to date.
To evaluate DFS and overall survival (OS) in ccRCC high-risk patients were randomized to sunitinib or sorafenib vs placebo. Patients received 1 year of adjuvant sunitinib (50 mg), sorafenib (800 mg) daily, or equivalent placebo. The study was amended for patient intolerance to sunitinib (37.5 mg), sorafenib (400 mg) daily, or equivalent placebo with mandatory dose escalation if no serious adverse effects were experienced. Of 1069 patients, 358 (243 [67.9%] men, 115 [32.1%] women) received sunitinib, 355 (248 [69.9%] men, 107 [30.1%] women) received sorafenib, and 356 (254 [71.3%] men, 102 [28.7%] women) received placebo as adjuvant therapy. Five-year DFS rates were 47.7%, 49.9%, and 50.0%, respectively for sunitinib, sorafenib, and placebo with 5-year OS of 75.2%, 80.2%, and 76.5% There was no difference by dose quartile.
Conclusion: Neither prognostic category of the tumor nor dose intensity of therapy altered the lack of difference in DFS or OS in this population of patients with high-risk ccRCC.
Renal Cell Carcinoma With Pulmonary Metastasis and Metachronous Non-Small Cell Lung Cancer. Bowman IA, Pedrosa I, Kapur P, et al. Clin Genitorurin Cancer. 2017 Feb 6. pii: S1558-7673(17)30042-3. doi: 10.1016/ j.clgc. 2017.01.026.
Summary: The development of a second primary malignancy in a patient with a preexisting diagnosis of metastatic cancer may be easily overlooked or misattributed to progression of disease. This report includes 3 patients with clear-cell renal cell carcinoma (RCC) metastatic to the lungs who were subsequently diagnosed with non-small-cell lung cancer (NSCLC). The authors examined the frequency of this occurrence within their institution and report on the radiographic findings that may help distinguish between metastatic RCC and primary lung cancers. Patients who received systemic targeted therapy for metastatic RCC between January 2006 and October 2013 were identified, and the proportion and incidence rate for developing NSCLC with preexisting metastatic RCC were calculated.
Conclusion: The subsequent diagnosis of a primary lung cancer in metastatic RCC patients occurred in 2% of patients and is underreported in the literature. Primary NSCLC may be underdiagnosed in patients with metastatic RCC. Both the radiographic appearance and clinical behavior of a lesion may hold clues that can help distinguish between a new primary and progression of metastatic disease.
Outcome of Patients with Renal Cell Carcinoma and Multiple Glandular Metastases Treated with Targeted Agents. Grassi P, Doucet L, Giglione P, et al. Oncology. 2017 Feb 17. doi:10.1159/000455970
Summary: This study evaluated the outcome of RCC patients with multiple glandular metastases (MGM) treated with targeted therapies (TTs). Sixty-four MGM patients treated between 1993 and 2014 were retrospectively identified from a database of 274 RCC patients with pancreatic metastases (PM) from 11 European centers. The survival of MGM patients was compared with that of both patients with PM only and a cohort of 325 RCC patients with non-GM (control group) treated with TTs. Survival was estimated using the Kaplan-Meier method and was statistically compared using the log-rank test. Fifty-six patients (88%) had at least 2 MGM, 7 patients (11%) had 3 MGM and 1 patient had 4 MGM, while non-GM were present in the remaining patients. The median overall survival (OS) was 54.2 months for MGM and 73.4 months for patients with PM only. The median OS in the control group was 22.7 months and statistically inferior to both MGM (P < 0.001) and PM patients (P < 0.001).
Conclusion: MGM from RCC are associated with a remarkable survival. Despite some limitations, these findings suggest that GM might be considered a predictor of a favorable prognosis.
Transarterial Yttrium-90 Radioembolization Treatment of Patients with Liver-Dominant Metastatic Renal Cell Carcinoma. Kis B, Shah J, Choi J, et al. J Vasc Interv Radiol. 2017 Feb;28(2):254-259. doi: 10.1016/j.jvir. 2016.09.025.
Summary: From July 2010 to December 2014, 18 patients with liver-dominant metastatic RCC were treated with yttrium-90 glass microsphere radioembolization. Retrospective review of medical records and imaging studies was performed to evaluate toxicities, treatment response, and overall survival. The median follow-up period from radioembolization treatment was 17.8 months. Median overall survival from RCC diagnosis was 64 months, from diagnosis of liver metastasis was 29 months, and from radioembolization treatment was 22.8 months. After treatment, 10 patients reported grade 1 clinical toxicities, and 8 patients had grade 1 or 2 biochemical toxicities. The best radiographic responses of 17 patients who underwent contrast-enhanced cross-sectional imaging showed complete response in 16 patients and partial response in 1 patient evaluated by modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. The last available imaging of these 17 patients demonstrated complete response in 14 patients, partial response in 1 patient, and progression of disease in 2 patients. Images of a patient who underwent noncontrast CT showed stable disease as best response and stable disease on the last available imaging evaluated by RECIST.
Conclusion: Radioembolization is safe and effective and led to improved hepatic disease control and overall survival in patients with liver-dominant metastatic RCC.
Axitinib Versus Sorafenib in First-Line Metastatic Renal Cell Carcinoma: Overall Survival From a Randomized Phase III Trial. Hutson TE, Al-Shukri S, Stus VP, et al. Clin Genitourin Cancer. 2017 Feb; 15(1):72-76. doi: 10.1016/j.clgc.2016.05.008.
Summary: In a randomized phase 3 trial in treatment-naive patients with metastatic renal cell carcinoma (RCC), axitinib vs sorafenib yielded numerically longer progression-free survival (median, 10.1 vs. 6.5 months; P = .038) and significantly higher objective response rate (32% vs. 15%; P = .0006). This report updates results. Previously untreated patients with metastatic RCC (n = 288), stratified according to Eastern Cooperative Oncology Group performance status (ECOG PS; 0 vs. 1), were randomized 2:1 to receive axitinib 5 mg twice per day (b.i.d.; n = 192) or sorafenib 400 mg b.i.d. (n = 96). Median OS was 21.7 months (18.0-31.7) with axitinib versus 23.3 months (18.1-33.2) with sorafenib. Among patients with ECOG PS of 0, median OS was numerically longer with axitinib than with sorafenib (41.2 vs. 31.9 months; whereas among patients with ECOG PS 1, median OS was shorter with axitinib than with sorafenib (14.2 vs. 19.8 months; HR, 1.203; 1-sided; P = .7973). Incidence and severity of common adverse events were consistent with previous reports.
Conclusion: OS was similar between axitinib and sorafenib in treatment-naive patients with metastatic RCC, and no new safety signals emerged.
Inhibiting Histone Deacetylase as Means to Reverse Resistance to Angiogenesis Inhibitors: Phase I Study of Abexinostat Plus Pazopanib in Advanced Solid Tumor Malignancies. Aggarwal R, Thomas S, Pawlowska N, et al. J Clin Oncol. 2017 Feb 21:JCO2016705350. doi: 10.1200/JCO.2016.70.5350.
Summary: This phase 1 trial evaluated epigenetic modulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor by using a histone deacetylase abexinostat in combination with pazopanib to enhance response and reverse resistance. Pazopanib was administered once a day on days 1 to 28 and abexinostat was administered orally twice a day on days 1 to 5, 8 to 12, and 15 to 19 (schedule A) or on days 1 to 4, 8 to 11, and 15 to 18 (schedule B). Dose escalation (3 + 3 design) in all solid tumors was followed by dose expansion in renal cell carcinoma (RCC). Fifty-one patients with RCC were enrolled, including 30 (59%) with one or more lines of prior VEGF-targeting therapy. Five dose-limiting toxicities, including fatigue (n = 2), thrombocytopenia (n = 2), and elevated AST/ALT (n = 1), were observed with schedule A; one dose-limiting toxicity was observed (elevated AST/ALT) was observed with schedule B. Grade ³ 3 related adverse events included fatigue (16%), thrombocytopenia (16%), and neutropenia (10%). The recommended phase 2 dose was established as abexinostat 45 mg/m2 twice a day administered per schedule B plus pazopanib 800 mg/d. Objective response rate was 21% overall and 27% in the RCC subset. Median duration of response was 9.1 months (1.2 to > 49 months). Eight patients (16%) had durable control of disease for > 12 months. Durable tumor regressions were observed in seven (70%) of 10 patients with pazopanibrefractory disease, including one patients with RCC with ongoing response > 3.5 years. Peripheral blood histone acetylation and HDAC2 gene expression were associated with durable response to treatment.
Conclusion: Abexinostat is well tolerated in combination with pazopanib, allowing prolonged exposure and promising durable responses in pazopanib- and other VEGF inhibitor-refractory tumors, which supports epigenetically mediated reversal of treatment resistance. KCJ