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.
Quality of life outcomes for cabozantinib versus everolimus in patients with metastatic renal cell carcinoma: METEOR phase III randomized trial. Cella D, Escudier B, Tannir NM, et al. J Clin Oncol. 2018 Mar 10;36(8):757-764.
Summary: In the phase III METEOR trial, 658 previously treated patients with advanced renal cell carcinoma were randomly assigned 1:1 to receive cabozantinib or everolimus. The cabozantinib arm had improved progression-free survival, overall survival, and objective response rate compared with everolimus. Changes in quality of life (QoL), an exploratory end point, are reported here. Patients completed functional assessment questionnaires. Data were summarized descriptively and by repeated-measures analysis (for which a clinically relevant difference was an effect size ≥ 0.3). Time to deterioration (TTD) was defined as the earlier of date of death, radiographic progressive disease, or ≥ 4-point decrease from There wasno difference over time in data gathered between the cabozantinib and everolimus arms. Cabozantinib improved TTD overall, with a marked improvement in patients with bone metastases at baseline.
Conclusion: In patients with advanced RCC, relative to everolimus, cabozantinib generally maintained QoL to a similar extent. Compared with everolimus, cabozantinib extended TTD overall and markedly improved TTD in patients with bone metastases.
Cabozantinib, a new standard of care for patients with advanced renal cell carcinoma and bone metastases? Subgroup analysis of the METEOR Trial. Escudier B, Powles T, Motzer RJ, et al. J Clin Oncol. 2018 Mar 10;36(8):765-772.
Summary: Six hundred fifty-eight patients were randomly assigned 1:1 to receive 60 mg cabozantinib or 10 mg everolimus. Prespecified subgroup analyses of PFS, OS, and ORR were conducted in patients grouped by baseline bone metastases status per independent radiology committee (IRC). Additional end points included bone scan response per IRC, skeletal-related events, and changes in bone biomarkers. For patients with bone metastases at baseline (cabozantinib [n = 77]; everolimus [n = 65]), median PFS was 7.4 months for cabozantinib versus 2.7 months for everolimus. Median OS was also longer with cabozantinib (20.1 months v 12.1 months), and ORR per IRC was higher (17% v 0%). The rate of skeletal-related events was 23% with cabozantinib and 29% with everolimus, and bone scan response per IRC was 20% versus 10%, respectively. PFS, OS, and ORR were also improved with cabozantinib in patients without bone metastases. Changes in bone biomarkers were greater with cabozantinib than with everolimus. The overall safety profiles of cabozantinib and everolimus in patients with bone metastases were consistent with those observed in patients without bone metastases.
Conclusion: Cabozantinib treatment was associated with improved PFS, OS, and ORR when compared with everolimus treatment in patients with advanced RCC and bone metastases and represents a good treatment option for these patients.
Pooled analysis of stereotactic ablative radiotherapy for primary renal cell carcinoma: A report from the International Radiosurgery Oncology Consortium for Kidney (IROCK). Siva S, Louie AV, Warner A, et al. Cancer. 2018 Mar 1;124(5):934-942.
Summary: Individual patient data sets from 9 International Radiosurgery Oncology Consortium for Kidney institutions across Germany, Australia, the United States, Canada, and Japan were pooled. Of 223 patients, 118 received single-fraction SABR, and 105 received multifraction SABR. The mean patient age was 72 years, and 69.5% of patients were men. There were 83 patients with grade 1 and 2 toxicity (35.6%) and 3 with grade 3 and 4 toxicities (1.3%). The rates of local control, cancer-specific survival, and progression-free survival were 97.8%, 95.7%, and 77.4%, respectively, at 2 years; and they were 97.8%, 91.9%, and 65.4%, respectively, at 4 years. Tumors with a larger maximum dimension and the receipt of multifraction SABR were associated with poorer progression-free survival (hazard ratio, 1.16 [P< .01] and 1.13 [P= .02], respectively) and poorer cancer-specific survival (hazard ratio, 1.28 [P< .01] and 1.33 [P= .01], respectively). There were no differences in local failure between the singlefraction cohort (n = 1) and the multifraction cohort (n = 2; P= .60).
Conclusion: SABR is well tolerated and locally effective for treating patients who have primary renal cell carcinoma and has an acceptable impact on renal function. An interesting observation is that patients who receive single-fraction SABR appear to be less likely to progress distantly or to die of cancer.
Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial. Atkins MB, Plimack ER, Puzanov I, et al. Lancet Oncol. 2018 Mar;19(3):405-415.
Summary: This ongoing, open-label, phase 1b study, which was done at 10 centers in the US, enrolled patients aged 18 years or older who had advanced RCC (predominantly clear cell) with their primary tumor resected, and at least one measureable lesion, Eastern Cooperative Oncology Group performance status 0-1, controlled hypertension, and no previous systemic therapy for renal cell carcinoma. Axitinib 5 mg was administered orally twice per day with pembrolizumab 2 mg/kg given intravenously every 3 weeks. The primary endpoint was investigator assessed dose-limiting toxicity during the first two cycles (6 weeks) to estimate the maximum tolerated dose and recommended phase 2 dose. Between Sept 23, 2014, and March 25, 2015, we enrolled 11 patients with previously untreated advanced renal cell carcinoma to the dose-finding phase and between June 3, 2015, and Oct 13, 2015, we enrolled 41 patients to the dose-expansion phase. All 52 patients were analyzed together. No unexpected toxicities were observed. Three dose-limiting toxicities were reported in the 11 patients treated during the 6-week observation period (dose-finding phase): one patient had a transient ischaemic attack and two patients were only able to complete less than 75% of the planned axitinib dose because of treatment-related toxicity. At the data cutoff date (March 31, 2017), 25 (48%) patients were still receiving study treatment. Grade 3 or worse treatment- elated adverse events occurred in 34 (65%) patients; the most common included hypertension (n=12 [23%]), diarrhea (n=5 [10%]), fatigue (n=5 [10%]), and increased alanine aminotransferase concentration (n=4 [8%]). The most common potentially immune-related adverse events (probably related to pembrolizumab) included diarrhea (n=15 [29%]), increased alanine aminotransferase concentration (n=9 [17%]) or aspartate aminotransferase concentration (n=7 [13%]), hypothyroidism (n=7 [13%]), and fatigue (n=6 [12%]). 28 (54%) patients had treatment-related serious adverse events. At data cutoff, 38 (73%; 95% CI 59·0-84·4) patients achieved an objective response (complete or partial response).
Conclusion: The treatment combination of axitinib plus pembrolizumab is tolerable and shows promising antitumor activity in patients with treatment-naive advanced RCC. Whether or not the combination works better than a sequence of VEGF pathway inhibition followed by an anti-PD-1 therapy awaits the completion of a phase 3 trial comparing axitinib plus pembrolizumab with sunitinib monotherapy.
A genetic polymorphism in CTLA-4 is associated with overall survival in sunitinib-treated patients with clear cell metastatic renal cell carcinoma. Liu X, Swen JJ, Diekstra MHM, et al. Clin Cancer Res. 2018 Feb 28. pii: clincanres. 2815.2017. doi: 10.1158/1078-0432.CCR-17-2815.
Summary: With the fact that TKIs interact with immune responses, this report investigated whether polymorphisms of genes involved in immune checkpoints are related to the clinical outcome of cc-mRCC patients treated with sunitinib as first TKI; 27 single nucleotide polymorphisms (SNPs) in CD274 (PD-L1), PDCD1 (PD-1) and CTLA-4 were tested for a possible association with progression-free survival (PFS) and overall survival (OS) in a discovery cohort of 550 sunitinib-treated cc-mRCC patients. SNPs with a significant association (P<0.05) were tested in an independent validation cohort of 138 sunitinib-treated cc-mRCC patients. Finally, data of the discovery and validation cohort were pooled for meta-analysis. CTLA-4rs231775 and CD274 rs7866740 showed significant associations with OS in the discovery cohort after correction for age, gender and Heng prognostic risk group (HR=0.84,95%CI: 0.72-0.98, P=0.028 and HR=0.73, 95%CI: 0.54-0.99, P=0.047, respectively). In the validation cohort, the associations of both SNPs with OS did not meet the significance threshold of p<0.05. After meta-analysis, CTLA-4 rs231775 showed a significant association with OS (HR=0.83, 95%CI: 0.72-0.95, P=0.008). Patients with the GG-genotype had longer OS (35.1 months) compared to patients with an AG (30.3 months) or AA genotype (24.3 months). No significant associations with PFS were found.
Conclusion: The G-allele of rs231775 in the CTLA-4 gene is associated with improved OS in sunitinib-treated cc-mRCC patients and could potentially be used as a prognostic biomarker.
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 F, et al. J Clin Oncol. 2017 Dec 10;35(35):3916-3923. doi: 10.1200/JCO.2017.73.5324. Epub 2017 Sep 13.
Summary: This phase III trial evaluated the efficacy and safety of pazopanib vs placebo in patients with locally advanced 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 (95% CI, 0.51 to 0.94). 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. KCJ