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.
Comparing the relative importance of attributes of metastatic renal cell carcinoma treatments to patients and physicians in the United States: A Discrete-Choice Experiment. González JM, Doan J, Gebben DJ, et al. Pharmacoeconomics. 2018 Jun 5; doi: 10.1007/s40273-018-0640-7.
Summary: Patients with RCC and physicians who treat RCC completed an online discrete-choice experiment survey. In a series of 12 questions, respondents chose between two hypothetical treatments defined in terms of six attributes: progression-free survival (PFS), probability of living ≥ 3 years (PL3Y), skin reactions, severity of fatigue, mode of administration, and monthly co-payment. Treatment choices were analyzed using a random-parameters logit model to estimate relative preference weights for the attribute levels and relative attribute importance. Overall, 201 patients and 142 physicians completed the survey.
For both patients and physicians, PL3Y was the attribute with the greatest and statistically significant conditional relative importance. Estimates of the conditional relative importance of PFS, skin reactions, and mode of administration for patients, and for PFS and mode of administration for physicians, were not statistically significant. The preferences for improvements in PFS were independent of the level of PL3Y for both patients and physicians. Conditional relative attribute importance varied by patient disease stage.
Conclusion: Patients and physicians indicated that PL3Y was the most important treatment attribute and was significantly more important than PFS. Importance rankings differed between physicians and patients and between all patients and those with advanced/metastatic disease.
Clinical activity and molecular correlates of response
to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma.
McDermott DF, Huseni MA, Atkins MB, et al. Nat Med. 2018 Jun; 24(6):749-757. doi: 10.1038/s41591-018-0053-3. Epub 2018 Jun 4.
Summary: Results are from IMmotion150, a randomized phase 2 study of atezolizumab (anti-PD-L1) alone or combined with bevacizumab versus sunitinib in 305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+ populations. Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively.
Conclusion: Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN-γ response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments. These molecular profiles suggest that prediction of outcomes with anti-VEGF and immunotherapy may be possible and offer mechanistic insights into how blocking VEGF may overcome resistance to immune checkpoint blockade.
Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. Méjean A, Ravaud A, Thezenas S, et al. N Engl J Med. 2018 Jun 3; doi: 10.1056/NEJMoa1803675.
Summary: this study assessed the role of nephrectomy in patients with metastatic renal-cell carcinoma who were receiving targeted therapies. The 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 non-inferior 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-sunitinib 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 renal-cell carcinoma who were classified as having intermediate-risk or poor-risk disease.
Sunitinib in patients with metastatic renal cell carcinoma: Clinical Outcome According to International Metastatic Renal Cell Carcinoma Database Consortium Risk Group. Rini BI, Hutson TE, Figlin RA, et al. Clin Genitourin Cancer. 2018 May 4; pii: S1558-7673(18)30136-8. doi: 10.1016/j.clgc.2018.04.005.
Summary: This analysis reported benchmarks for clinical outcomes on the basis of International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups for patients treated with sunitinib for mRCC in a first-line setting. A retrospective analysis was performed on data from sunitinib-treated patients (n = 375) in the pivotal phase III trial of sunitinib versus interferon-α as first-line treatment for mRCC. Objective response rates (ORRs) were determined from independently reviewed radiologic assessments. Median PFS (95% confidence interval [CI]) was 14.1 (13.4-17.1), 10.7 (10.5-12.5), 2.4 (1.1-4.7), and 10.6 (8.1-10.9) months in sunitinib-treated patients in the IMDC favorable (n = 134), intermediate (n = 205), poor (n = 34), and intermediate + poor (n = 239) risk groups, respectively. Median OS (95% CI) was 23.0 (19.8-27.8), 5.1 (4.3-9.9), and 20.3 (16.8-23.0) months in sunitinib-treated patients in IMDC intermediate, poor, and intermediate + poor risk groups, respectively, and was not reached in the favorable risk group (>50% of patients were alive at data cutoff). ORRs were 53.0%, 33.7%, 11.8%, and 30.5% in sunitinib-treated patients in IMDC favorable, intermediate, poor, and intermediate + poor risk groups, respectively.
Conclusion: This retrospective analysis showed differences in patient outcomes for PFS, OS, and ORR on the basis of IMDC prognostic risk group assignment for patients with mRCC.
Phase 1 trials of anti-ENPP3 antibody drug conjugates in advanced refractory renal cell carcinomas. Thompson JA, Motzer RJ, Molina AM, et al. Clin Cancer Res. 2018 May 30; pii: clincanres.0481.2018. doi: 10.1158/1078-0432.CCR-18-0481.
Summary: The study determined the safety, pharmacokinetics, and recommended phase 2 dose of an antibody drug conjugate (ADC) targeting ectonucleotide phosphodiesterases-pyrophosphatase 3 (ENPP3) conjugated to monomethyl auristatin F (MMAF) in subjects with advanced RCC. Two phase 1 studies were conducted sequentially with 2 ADCs considered equivalent, hybri-doma derived AGS-16M8F and Chinese Hamster Ovary derived AGS-16C3F. AGS-16M8F was administered intravenously every 3 weeks at 5 dose levels ranging from 0.6 to 4.8 mg/kg until unacceptable toxicity or progression. The study was terminated before reaching the maximum tolerated dose (MTD). A second study with AGS-16C3F started with the AGS-16M8F bridging dose of 4.8 mg/kg given every 3 weeks. The AGS-16M8F study (n=26) closed before reaching the MTD. The median duration of treatment was 12 weeks. One subject had durable partial remission (PR) (83 weeks) and 1 subject had prolonged stable disease (48 weeks). In the AGS-16C3F study (n=34), the protocol defined MTD as 3.6 mg/kg but this was not tolerated in multiple doses. Reversible keratopathy was dose limiting and required multiple dose de-escalations. The 1.8 mg/kg dose was determined to be safe and was associated with clinically relevant signs of antitumor response. Three of 13 subjects at 1.8 mg/kg had durable PRs (range 100-143 weeks). Eight (8) subjects at 2.7 mg/kg and 1.8 mg/kg had disease control after 37 weeks (37.5 – 141 weeks).
Conclusion: AGS-16C3F was tolerated and had durable antitumor activity at 1.8 mg/kg every 3 weeks.
Radium-223 dichloride in combination with vascular endothelial growth factor-targeting therapy in advanced renal cell carcinoma with bone metastases. McKay RR, Bossé D, Gray KP, et al. Clin Cancer Res. 2018 May 30; pii: clincanres.3577.2017. doi: 10.1158/1078-0432.CCR-17-3577.
Summary: This study investigated the biologic activity of radium-223 with vascular endothelial growth factor (VEGF)-targeted therapy in patients with advanced RCC and bone metastases. Fifteen treatment-naïve patients (n=15) received pazopanib 800 mg orally once-daily and 15 previously-treated patients received sorafenib 400 mg orally twice-daily. Radium-223 55 kilobecquerel/kg was administered concurrently every four weeks for up to 6 infusions in both cohorts. The primary endpoint was decline in bone turnover markers (Procollagen I Intact N-Terminal, N-telopeptide, C-telopeptide, osteocalcin and bone-specific alkaline phosphatase) compared to baseline. Secondary endpoints included safety, rate of symptomatic-skeletal event (SSE) and time to first SSE, objective response rate, change in analgesic use and quality of life. Exploratory analysis of tumor genomic alterations was performed. Of the 30 patients enrolled, 83% had IMDC intermediate- or poor-risk disease, 33% had liver metastases and 83% had a history of SSE prior to enrolment.
No dose-limiting toxicity was observed. All bone turnover markers significantly declined from baseline at week 8 and 16. Forty percent of patients experienced treatment-related grade ≥3 adverse events. Response rates were 15% and 18% per RECIST v1.1 and bone response was 50% and 30% per MD Anderson criteria, in the pazopanib and sorafenib cohort, respectively. Median SSE-free interval was 5.8 months and not reached, respectively. Analgesic use remained stable over the study time.
Conclusion: Radium-223 combined with VEGF-targeted therapy is biologically active and safe. Randomized-controlled trials are needed to define the role of radium-223 in advanced RCC with skeletal metastases. KCJ