A Review of Selected Presentations From the Sixteenth International Kidney Cancer Symposium • November 3-4, 2017 • Miami, Florida
VEGF Tyrosine Kinase Inhibitors/Immunotherapy Combinations Will Become the Standard of Care Soon
Dr Tian Zhang presented an overview of treatment with immunotherapy in combination with inhibitors of the vascular endothelial growth factor (VEGF) among patients with renal cell carcinoma (RCC).1 In tumors of the kidney, the presence of tumor-infiltrating lymphocytes that express programmed death 1 (PD-1) protein is associated with a worse prognosis.2 Unsupervised gene expression clus-tering of localized clear cell RCC tumors recently revealed an immune-regulated cluster that was associated with aggressive histologic features and a high risk of disease progression after nephrectomy.3 These tumors harbored tumor-infil-trating lymphocytes that expressed CD8, PD-1, Tim-3, and Lag-3, as well as CD4-positive and ICOS-positive cells that have a T-regulatory phenotype (such as CD25+CD127–Foxp3+/Helios+GITR+). The VEGF inhibitors have been associated with immunomodulatory effects. Treatment with cabozantinib, a tyrosine kinase inhibitor (TKI) that is directed against the VEGF receptor 2, AXL, and MET, has decreased T-regulatory cells in patients with urothelial cancer (P=.015), through a mechanism involving inhibition of Foxp3 (Figure 1).4 In a retrospective analysis of patients in the phase 3 S-TRAC trial (A Clinical Trial Comparing Efficacy and Safety of Sunitinib Versus Placebo for the Treatment of Patients at High Risk of Recurrent Renal Cell Cancer), outcomes in patients with high-risk RCC were assessed according to results from immunohistochemical staining of PD-L1, CD4, CD8, and CD68 in nephrectomy specimens.5 Patients with a CD8-positive T-cell density above the median had a longer disease-free survival than patients with a density below the median (not reached vs 3.47 years; hazard ratio [HR], 0.40; 95% CI, 0.20-0.81; P=.009). In contrast, no difference was observed with placebo treatment based on CD8-positive T-cell density (HR, 0.80; 95% CI, 0.42-1.50; P=.484).
Recent clinical trials have evaluated TKIs in renal cell carcinoma, leading to new management options. In late December 2017, the US Food and Drug Administration (FDA) expanded the approval of cabozantinib to include first-line treatment of patients with advanced renal cell carcinoma. Approval was based on results from the CABOSUN study (Cabo-zantinib-S-Malate or Sunitinib Malate in Treating Patients With Previously Untreated Locally Advanced or Metastatic Kidney Cancer). This study randomly assigned patients with untreated metastatic RCC to receive cabozantinib or sunitinib.6 Progression-free survival (PFS) was 8.6 months with cabozantinib vs 5.3 months with sunitinib (HR, 0.48; 95% CI, 0.31-0.74; P=.0008; Table 1). The objective response rate (ORR) was 20% with cabozantinib vs 9% with sunitinib. In the phase 3 CheckMate 214 trial (Nivolumab Combined With Ipilimumab Versus Sunitinib in Previously Untreated Advanced or Metastatic Renal Cell Carcinoma), patients with metastatic RCC were randomly assigned to receive nivolumab plus ipilimumab or sunitinib monotherapy.7 Median PFS was approximately 12 months for both arms (HR, 0.98; 99.1% CI, 0.79-1.23; P=.8498), with confirmed ORRs of 39% (95% CI, 35%-43%) among patients treated with nivolumab plus ipilimumab and 32% (95% CI, 28%-36%) among those treated with sunitinib.
Results from early-phase clinical trials investigating the combination of VEGF TKIs plus PD-1 or PD ligand 1 (L1) checkpoint inhibitors in patients with metastatic RCC are now available. Disease control rates ranged from 78% to 100%. 8-13 Most of the reported ORRs ranged from 58% to 83%. Exceptions included the regimen of bevacizumab plus atezolizumab, which yielded an ORR of 32%, and the combination of cabozantinib, ipilimumab, and nivolumab, which had an ORR of 33% (this trial enrolled patients with any metastatic genitourinary malignancy).12,13 Durable responses were also observed in many of the patients.9,11 The common toxicities were those most often associated with VEGF TKIs, and included diarrhea, hypertension, fatigue, and hand-foot syndrome. Most grade 3/4 adverse events (AEs) were observed in fewer than 10% of patients, with the exceptions of hypertension, neutropenia, and increased lipase levels.
The combination of a VEGF TKI plus immunotherapy enables the targeting of multiple drivers of tumorigenesis and disease progression, and early-stage trials suggest that response rates are higher than those observed in trials of VEGF TKI monotherapy. Responses with combination treatment may also be more durable. However, combination therapy may have some disadvantages. Treatment has not been defined for patients who developed progressive disease during treatment with a VEGF TKI plus immunotherapy. It will be necessary to investigate optimal sequencing of different VEGF TKIs and checkpoint inhibitors. It is not known whether the high response rates observed in early-phase clinical trials will yield higher rates of PFS and overall survival (OS). Questions that must be resolved include how to measure outcomes against older controls and how to determine when to stop treatment of patients with a complete response (CR). Other issues include management of toxicities and identification of biomarkers for improved patient selection.
1. Zhang T. VEGF TKI/immunotherapy combinations will become the standard of care soon. Presented at: the Sixteenth International Kidney Cancer Symposium; November 3-4, 2017; Miami, Florida.
2. Thompson RH, Dong H, Lohse CM, et al. PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma. Clin Cancer Res. 2007;13(6):1757-1761.
3. Giraldo NA, Becht E, Vano Y, et al. Tumor-infiltrating and peripheral blood T-cell immunophenotypes predict early relapse in localized clear cell renal cell carcinoma. Clin Cancer Res. 2017;23(15):4416-4428.
4. Apolo AB, Tomita Y, Lee MJ, et al. Effect of cabozantinib on immunosuppressive subsets in metastatic urothelial carcinoma [ASCO abstract 4501]. J Clin Oncol. 2014;32(5 suppl).
5. George J, Martini JF, Chang YH, et al. Phase 3 trial of adjuvant sunitinib in patients with high-risk renal cell carcinoma: exploratory molecular analysis of tumor biomarkers. Presented at: the Annual Meeting of the American Association for Cancer Research; April 1-6, 2017; Washington, DC. Abstract 1771.
6. Choueiri TK, Hessel C, Halabi S, et al. Progression-free survival (PFS) by independent review and updated overall survival (OS) results from Alliance A031203 trial (CABOSUN): cabozantinib versus sunitinib as initial targeted therapy for patients (pts) with metastatic renal cell carcinoma (mRCC) [ESMO abstract LBA38]. Ann Oncol. 2017;28(suppl 5).
7. Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: efficacy and safety of nivolumab + ipilimumab (N+I) v sunitinib (S) for treatment-naïve advanced or metastatic renal cell carcinoma (mRCC), including IMDC risk and PD-L1 expression subgroups [ESMO abstract LBA5]. Ann Oncol. 2017;28(suppl 5).
8. Atkins M, Plimack E, Puzanov I, et al. Axitinib in combination with pembrolizumab in patients (pts) with advanced renal cell carcinoma (aRCC): preliminary safety and efficacy results [ESMO abstract 773PD]. Ann Oncol. 2016;27(suppl 9).
9. Choueiri TK, Larkin JMG, Oya M, et al. First-line avelumab + axitinib therapy in patients (pts) with advanced renal cell carcinoma (aRCC): results from a phase Ib trial [ASCO abstract 4504]. J Clin Oncol. 2017;35(15 suppl).
10. Chowdhury S, McDermott DF, Voss MH, et al. A phase I/II study to assess the safety and efficacy of pazopanib (PAZ) and pembrolizumab (PEM) in patients (pts) with advanced renal cell carcinoma (aRCC) [ASCO abstract 4506]. J Clin Oncol. 2017;35(15 suppl).
11. Lee C, Makker V, Rasco D, et al. A phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with renal cell carcinoma [ESMO abstract 8470]. Ann Oncol. 2017;28(suppl 5).
12. McDermott DF, Atkins MB, Motzer RJ, et al. A phase II study of atezolizumab with or without bevacizumab versus sunitinib in untreated metastatic renal cell carcinoma patients [ASCO GU abstract 431]. J Clin Oncol. 2017;35(suppl 6S).
13. Nadal R, Mortazavi A, Stein M, et al. Final results of a phase I study of cabozantinib (cabo) plus nivolumab (nivo) and cabonivo plus ipilimumab (Ipi) in patients (pts) with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignancies [ESMO abstract 8460]. Ann Oncol. 2017;28(suppl 5).
Non–Clear Cell Renal Cell Carcinoma
Variants of RCC differ in terms of clinical behavior, prognosis, and response to systemic therapy.1 Dr Pavlos Msaouel presented an overview of renal medullary carcinoma, one of the most aggressive RCC subtypes.2 Renal medullary carcinoma occurs most commonly in patients with sickle cell hemoglobinopathies. Most patients present with metastatic disease, and two-thirds are male.1 Guidelines for the diagnosis and treatment of renal medullary carcinoma have been proposed.3 Treatment with anti-VEGF TKIs has not been successful in these patients. Cytotoxic chemotherapy has an ORR of approximately 29%, but responses are typically brief, and few patients survive past 2 years. Radical nephrectomy should be considered in patients with good performance status and low metastatic burden, and in those who respond to systemic therapy. SMARCB1 is a tumor suppressor gene that has been implicated in the development of renal medullary carcinoma. SMARCB1 was inactivated in all 5 specimens in a series of renal medullary carcinoma tumors.4 Four of the cases had developed in patients with sickle cell disease, and in these patients, interchromosomal balanced translocations accounted for SMARCB1 gene inactivation. Sickle cell disease is associated with reduced interstitial osmolality in the inner medulla, which may contribute to an environment that favors SMARCB1 deletion and/or translocation.
Dr Gabriel Malouf presented an update on collecting duct carcinoma, another rare and aggressive type of RCC.5 In a study of 20 archival cases of collecting duct RCC, the complete loss of SMARCB1/INI1 expression was observed in 15% of cases.6 A recent analysis from the National Cancer Database showed that 71% of patients with collecting duct RCC presented with metastatic disease, and the median survival was 13 months after diagnosis.7 Among 184 patients with metastatic collecting duct RCC, improved outcomes were observed in those who underwent both cytoreductive nephrectomy and chemoradiation compared with cytoreductive nephrectomy alone (HR, 0.51; 95% CI, 0.32-0.79). In an unpublished study of 29 patients with collecting duct RCC, a worse outcome was seen in those with metastatic disease and those older than 40 years. Genomic studies suggest an overlap between collecting duct RCC, unclassified RCC, renal medullary carcinoma, and papillary type II RCC. Transcriptome sequencing revealed a unique signature characterized by immunogenic and metabolic aberrations for collecting duct RCC compared with other RCC subtypes.8 Collecting duct RCC tumors are infiltrated with high levels of CD8-positive lymphocytes; therefore, targeting immunological checkpoints may be an option in this setting. In a recent study, loss of CDKN2A expression was observed in 62.5% of patients with collecting duct RCC, providing a potential pathway for the development of targeted therapies.9
Dr James Hsieh discussed unclassified RCC, which represents approximately 5% of RCC cases.10 Treatments for metastatic clear cell RCC have advanced markedly in the last decade, particularly with the recent approval of cabozantinib, lenvatinib, and nivolumab.11 However, no standard therapy exists for treatment of unclassified RCC. The development of new treatments has been limited by a lack of knowledge regarding the molecular features of unclassified RCC. To address this limitation, a study was conducted to identify molecular characteristics of unclassified RCC tumors.12 Targeted next-generation sequencing of 230 oncogenes, tumor suppressor genes, and components of pathways considered candidates for targeted therapy was used to evaluate 62 high-grade primary unclassified RCC tumors. The study identified recurrent somatic mutations in 29 genes, including NF2 (18%), BAP1 (13%), KMT2C (10%), and MTOR (8%). Integrated analysis revealed distinct molecular attributes that char-acterized 76% of the unclassified RCC tumors, including distinct profiles for subsets of patients with a better or worse clinical outcome. NF2 is a key mediator of cell-cell contact inhibition and growth factor signaling, and it is involved in the Hippo developmental pathways. Among the 62 tumors, 11 harbored NF2 mutations, suggesting that the loss of NF2 expression could characterize an important subset of unclassified RCC tumors. Several lines of evidence showed NF2 loss in 26% of unclassified RCC cases, along with dysregulated Hippo signaling and YAP activation. NF2 may act as an early driver of tumorigenesis. Other aberrations identified in the unclassified RCC tumors included mTORC1 hyperactivity, fumarate hydratase deficiency, and defective chromatin modulation. In a study by Casuscelli and colleagues, high-risk features included TP53 and PTEN mutations, as well as imbalanced chromosome dup-lication (Figure 2).13
Dr Laurence Albiges discussed papillary RCC, the most common non–clear cell subtype of RCC.14 The classification includes indolent tumors with multifocal presentation and solitary tumors that are highly aggressive. A retrospective analysis of RCC patients in the International Metastatic Renal Cell Carcinoma Database Consortium identified 5474 patients with metastatic RCC, of whom 5008 (91%) had clear cell RCC and 466 (8.5%) had papillary RCC.15 In patients with clear cell RCC, OS was 8 months longer, and the HR for death was 0.71. To identify potential molecular targets, 98 frozen papillary RCC samples were assessed using human whole-genome arrays.16 MET gene expression was high across all samples. MET gene amplification was observed in 81% of type I papillary RCC and 46% of type II papillary RCC tumors, suggesting that MET inhibition may be a potential approach for treating papillary RCC. Eleven mutations (including 4 new ones) in exons 16 to 19 of the MET gene were observed in 21.5% of samples. The findings support earlier studies showing strong expression of MET in most papillary RCC tumors.17 A comprehensive molecular characterization of 161 primary papillary RCC tumors by The Cancer Genome Atlas Research Network showed that type I and type II papillary tumors had different molecular alterations.18 Type I tumors were characterized by MET alterations, whereas type 2 tumors were characterized by CDKN2A silencing, activation of the NRF2-ARE pathway, and other aberrations.
A retrospective analysis evaluated the efficacy of cabozantinib in patients with non–clear cell RCC who were treated in a phase 3 study.19 Among 30 patients with metastatic non–clear cell RCC, 17 patients (57%) had papillary RCC. The median age was 58 years (range, 25-81 years), and 87% of patients were male. Prior treatment with a VEGF TKI was reported in 87% of patients. Median PFS among the 30 patients was 8.6 months (95% CI, 6.1-14.7 months; Figure 3). The results suggest that cabozantinib may produce a clinically meaningful benefit in patients with non–clear cell RCC.
1. Shuch B, Amin A, Armstrong AJ, et al. Understanding pathologic variants of renal cell carcinoma: distilling therapeutic opportunities from biologic complexity. Eur Urol. 2015;67(1):85-97.
2. Msaouel P. Renal medullary carcinoma. Presented at: the Sixteenth International Kidney Cancer Symposium; November 3-4, 2017; Miami, Florida.
3. Beckermann KE, Sharma D, Chaturvedi S, et al. Renal medullary carcinoma: establishing standards in practice. J Oncol Pract. 2017;13(7):414-421.
4. Calderaro J, Masliah-Planchon J, Richer W, et al. Balanced translocations disrupting SMARCB1 are hallmark recurrent genetic alterations in renal medullary carcinomas. Eur Urol. 2016;69(6):1055-1061.
5. Malouf GG. Collecting duct carcinomas. Presented at: the Sixteenth International Kidney Cancer Symposium; November 3-4, 2017; Miami, Florida.
6. Elwood H, Chaux A, Schultz L, et al. Imm-unohistochemical analysis of SMARCB1/INI-1 expres-sion in collecting duct carcinoma. Urology. 2011;78(2):474.e1-474.e5.
7. Sui W, Matulay JT, Robins DJ, et al. Collecting duct carcinoma of the kidney: disease characteristics and treatment outcomes from the National Cancer Database. Urol Oncol. 2017;35(9):540.e13-540.e18.
8. Malouf GG, Comperét E, Yao H, et al. Unique transcriptomic profile of collecting duct carcinomas relative to upper tract urothelial carcinomas and other kidney carcinomas. Sci Rep. 2016;6:30988.
9. Wang J, Papanicolau-Sengos A, Chintala S, et al. Collecting duct carcinoma of the kidney is associated with CDKN2A deletion and SLC family gene up-regulation. Oncotarget. 2016;7(21):29901-29915.
10. Hsieh J. Unclassified RCC (uRCC). Presented at: the Sixteenth International Kidney Cancer Symposium; November 3-4, 2017; Miami, Florida.
11. Hsieh JJ, Purdue MP, Signoretti S, et al. Renal cell carcinoma. Nat Rev Dis Primers. 2017;3:17009.
12. Chen YB, Xu J, Skanderup AJ, et al. Molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets. Nat Commun. 2016;7:13131.
13. Casuscelli J, Weinhold N, Gundem G, et al. Gen-omic landscape and evolution of metastatic chro-mophobe renal cell carcinoma. JCI Insight. 2017;
14. Albiges L. Papillary RCC. Presented at: the Sixteenth International Kidney Cancer Symposium; November 3-4, 2017; Miami, Florida.
15. Connor Wells J, Donskov F, Fraccon AP, et al. Characterizing the outcomes of metastatic papillary renal cell carcinoma. Cancer Med. 2017;6(5):902-909.
16. Albiges L, Guegan J, Le Formal A, et al. MET is a potential target across all papillary renal cell carcinomas: result from a large molecular study of pRCC with CGH array and matching gene expression array. Clin Cancer Res. 2014;20(13):3411-3421.
17. Choi JS, Kim MK, Seo JW, et al. MET expression in sporadic renal cell carcinomas. J Korean Med Sci. 2006;21(4):672-677.
18. Linehan WM, Spellman PT, Ricketts CJ, et al; Cancer Genome Atlas Research Network. Comprehensive molecular characterization of papillary renal-cell carcinoma. N Engl J Med. 2016;374(2):135-145.
19. Campbell MT, Bilen MA, Duran C, et al. Cabozantinib for the treatment of patients with metastatic variant histology renal cell carcinoma (vhRCC): a retrospective study [ESMO abstract 912P]. Ann Oncol. 2017;28(suppl 5).
Ipilimumab/Nivolumab Is the New Standard of Care in Metastatic Renal Cell Carcinoma
Dr Brian Rini presented results from the open-label, randomized phase 3 CheckMate 214 trial, which evaluated the combination of ipilimumab plus nivolumab vs sunitinib monotherapy in patients with treatment-naive, advanced or metastatic, clear cell RCC.1 Results were also presented at the 2017 European Society for Medical Oncology meeting.2 Patients in the combination arm received nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks for 4 doses followed by nivolumab (3 mg/kg)
every 2 weeks. Patients in the sun-itinib arm received sunitinib (50 mg) once daily for 4 weeks in 6-week cycles. Patients were treated until disease progression or unacceptable toxicity. The primary endpoints of the trial were OS, ORR, and PFS among patients at intermediate to poor risk, who constituted approximately 75% of the entire intent-to-treat population.
Patients had a median age of 61 years, and approximately 73% were male. In the intent-to-treat population, patients were randomly assigned to receive nivolumab plus ipilimumab (n=550) or sunitinib (n=546). Prognostic scores, as assessed by criteria from the International Metastatic Renal Cell Carcinoma Database Consortium, were favorable in 21%, intermediate in 61%, and poor in 18% of patients. Intermediate-risk or poor-risk disease was reported in 425 patients in the combination arm and 422 in the sunitinib monotherapy arm. Among these patients, the confirmed ORR was 42% (95% CI, 37%-47%) in the combination treatment arm and 27% (95% CI, 22%-31%) in the sunitinib arm (P<.0001). The CR rate was 9% in the combination arm vs 1% in the comparator arm, and the partial response (PR) rate was 32% vs 25%. The median duration of response was not reached (95% CI, 21.8 months to not estimable [NE]) in the combination arm vs 18.2 months (95% CI, 14.8 months to NE) in the comparator arm. An ongoing response was reported in 72% in the combination arm vs 63% in the sunitinib arm. Median PFS was 11.6 months (95% CI, 8.7-15.5 months) in patients treated with nivolumab plus ipilimumab vs 8.4 months (95% CI, 7.0-10.8 months) in patients treated with sunitinib (HR, 0.82; 99.1% CI, 0.64-1.05; P=.0331; Figure 4). Median OS was not reached (95% CI, 28.2 months to NE) in the combination treatment arm vs 26.0 months (95% CI, 22.1 months to NE) in the sunitinib arm (HR, 0.63; 99.8% CI, 0.44-0.89; P=.00003).
In the entire study population of 1096 patients, the confirmed ORR was 39% (95% CI, 35%-43%) in the nivolumab plus ipilimumab arm vs 32% (95% CI, 28%-36%) in the sunitinib monotherapy arm (P=.0191). Median PFS was 12.4 months (95% CI, 9.9-16.5 months) in the combination arm vs 12.3 months (95% CI, 9.8-15.2 months) in the comparator arm (HR, 0.98; 99.1% CI, 0.79-1.23; P=.8498). Median OS was not reached (95% CI, NE to NE) in the combination arm vs 32.9 months (95% CI, NE to NE) in the sunitinib arm (HR, 0.68; 99.8% CI, 0.49-0.95; P=.00028). In the subset of 249 patients with favorable-risk disease, the confirmed ORR was 29% (95% CI, 21%-38%) for combination treatment vs 52% (95% CI, 43%-61%) for sunitinib monotherapy (P=.0002). Median PFS was 15.3 months (95% CI, 9.7-20.3 months) for combination treatment vs 25.1 months (95% CI, 20.9 months to NE) for sunitinib (HR, 2.18; 99.1% CI, 1.29-3.68; P<.0001). (ORR and PFS were assessed by Response Evaluation Criteria In Solid Tumors [RECIST] criteria rather than immune-related RECIST criteria.)
Antitumor activity was assessed according to levels of PD-L1. In patients with a PD-L1 expression of less than 1% who were at intermediate to poor risk, ORR was 37% (95% CI, 32%-43%) with nivolumab plus ipilimumab vs 28% (95% CI, 23%-34%; P=.0252) with sunitinib. In patients with a PD-L1 expression of at least 1% who were at intermediate to poor risk, ORR was 58% with combination treatment vs 22% with sunitinib (95% CI, 15%-31%; P<.0001). In the intent-to-treat patients with low PD-L1 expression, ORR was 36% (95% CI, 31%-41%) with nivolumab plus ipilimumab vs 35% (95% CI, 31%-40%) with sunitinib monotherapy (P=.8799). In the intent-to-treat patients with PD-L1 expression of at least 1%, the ORR was 53% (95% CI, 44%-63%) with combination therapy vs 22% (95% CI, 15%-30%) with sunitinib monotherapy (P<.0001). For all of these patient cohorts, combination treatment yielded a superior CR rate. In patients at intermediate to poor risk, median PFS was similar for both treatments in those with PD-L1 expression of less than 1% (11.0 months vs 10.4 months; P=.9670). However, median PFS was significantly better with combination treatment in patients with higher PD-L1 expression (22.8 months vs 5.9 months; P=.0003).
At the 2017 meeting of the Society for Immunotherapy of Cancer, data were presented for OS.3 Nivolumab plus ipilimumab was superior to sunitinib, regardless of the patient’s PD-L1 expression (<1%: HR, 0.73; 95% CI, 0.56-0.96 and ≥1%: HR, 0.45; 95% CI, 0.29-0.71). OS was not reached for nivolumab plus ipilimumab or sunitinib for patients with PD-L1 levels of less than 1%. For patients with PD-L1 levels of 1% or higher, the median OS was not reached for the combination vs 19.6 months for sunitinib.
As Dr Rini reported, grade 3/4 AEs were observed in 46% of patients in the combination treatment arm vs 63% of patients in the sunitinib monotherapy arm. The most common grade 3/4 AEs in the combination arm were fatigue (4%), diarrhea (4%), and nausea (2%) in the combination arm and hypertension (16%), fatigue (9%), and palmar-plantar erythrodysesthesia syndrome (9%) in the sunitinib arm. AEs leading to discontinuation occurred in 22% of patients in the combination arm vs 12% in the sunitinib arm.
1. Rini BI. Ipi/nivo is the new standard of care in mRCC. Presented at: the Sixteenth International Kidney Cancer Symposium; November 3-4, 2017; Miami, Florida.
2. Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: efficacy and safety of nivolumab + ipilimumab (N+I) v sunitinib (S) for treatment-naïve advanced or metastatic renal cell carcinoma (mRCC), including IMDC risk and PD-L1 expression subgroups [ESMO abstract LBA5]. Ann Oncol. 2017;28(suppl 5).
3. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab + ipilimumab (N+I) vs sunitinib (S) for treatment-naïve advanced or metastatic renal cell carcinoma (aRCC): results from CheckMate 214, including overall survival by subgroups [SITC abstract O38]. J Immunother Cancer. 2017;5(suppl 3).
How Should We Treat Brain Metastases From Renal Cell Carcinoma?
Dr Bernard Escudier discussed treatment of brain metastases in patients with RCC.1 Brain metastases develop in approximately 8% of RCC patients and are associated with a negative prognosis.2-5 Local therapy is recommended when pos-sible. Single metastases are more likely to be controlled than multiple metastases, and the risk of recurrence rises with increasing numbers of met-astases, worsening symptoms, and larger size.6 Stereotactic radiotherapy is effective, and tumor control can be achieved with a single dose of 24 Gy.7 Although survival decreases with increasing numbers of brain lesions (Figure 5), as many as 10 brain metastases can be treated with stereotactic radiotherapy.8 Local control becomes more chall-enging with increasing lesion size. Owing to increasing risk of relapse and radionecrosis, 3 cm is considered the largest size appropriate for treatment with stereotactic radiotherapy.9-12
Brain metastases are highly heterogeneous across tumor types. In patients with non–small cell lung cancer, PD-L1 expression levels are higher in brain metastases compared with the paired primary tumor.13 The presence of a dense infiltration of effector cells is associated with an improved prognosis. However, in a study of brain metastases in patients with various primary tumor types, PD-L1 expression did not correlate with the density of tumor-infiltrating lymphocytes.14 The density of tumor-infiltrating lymphocytes varied among primary tumor types, with the highest density observed in the brain metastases of patients with primary melanoma, followed by RCC and lung cancer. A high density of infiltration was most common in tumor-infiltrating lymphocytes that were CD3+ (82%) and least common in those that were PD1+ (15.5%; P<.001). The density of certain tumor-infiltrating lymphocytes positively correlated with improved median OS. The expression of PD-L1 and MET was further investigated in a large study of patients with metastatic RCC.15 The study evaluated specimens from 42 primary tumors and 138 metastases, including 87 brain and 51 pancreatic metastases. The study found lower expression of PD-L1 and MET in the primary RCC tumor vs brain or pancreatic metastases, and expression of MET was significantly higher in brain metastases compared with pancreatic metastases.
Treatment with nivolumab mon-otherapy was evaluated in a prospective phase 2 study that included 55 patients with metastatic RCC and brain metastases.16 The proportion of patients with 1, 2, or more than 2 brain metastases was 67%, 12%, and 21%, respectively. Two-thirds of patients had not received prior treatment for their brain metastases. Patients were treated with nivolumab (3 mg/kg) every 2 weeks. Objective responses were observed in 23% of patients, all of whom had received prior treatment for their brain metastases (consisting of either surgery or radiotherapy). Local tumor progression was reported in 48% of patients, and 32% experienced neurological deterioration requiring treatment with corticosteroids. There-fore, local therapy is rec-om-mended before initiation of therapy directed toward PD1/PD-L1.
The use of cabozantinib to treat brain metastases in patients with primary RCC is supported by the strong MET expression seen in these metastases, even if there is little or no expression in the primary tumor. Through the Italian expanded access program, 91 patients with metastatic RCC received treatment with cabozantinib.17 Five of these patients had brain metastases. Cabozantinib
(60 mg) was administered daily in 28-day cycles. Early data from these 5 patients suggested that cabozantinib treatment is feasible in this setting. In addition, isolated case studies suggest that cabozantinib may be active in reducing brain metastases in patients with RCC.
1. Escudier BJ. How should we treat brain metastases from RCC? Presented at: the Sixteenth International Kidney Cancer Symposium; November 3-4, 2017; Miami, Florida.
2. Bianchi M, Sun M, Jeldres C, et al. Distribution of metastatic sites in renal cell carcinoma: a population-based analysis. Ann Oncol. 2012;23(4):973-980.
3. Grassi P, Verzoni E, Porcu L, et al. Targeted therapies in advanced renal cell carcinoma: the role of metastatic sites as a prognostic factor. Future Oncol. 2014;10(8):1361-1372.
4. Shuto T, Matsunaga S, Suenaga J, Inomori S, Fujino H. Treatment strategy for metastatic brain tumors from renal cell carcinoma: selection of gamma knife surgery or craniotomy for control of growth and peritumoral edema. J Neurooncol. 2010;98(2):169-175.
5. Culine S, Bekradda M, Kramar A, Rey A, Escudier B, Droz JP. Prognostic factors for survival in patients with brain metastases from renal cell carcinoma. Cancer. 1998;83(12):2548-2553.
6. Shuch B, La Rochelle JC, Klatte T, et al. Brain metastasis from renal cell carcinoma: presentation, recurrence, and survival. Cancer. 2008;113(7):1641-1648.
7. Zelefsky MJ, Greco C, Motzer R, et al. Tumor control outcomes after hypofractionated and single-dose stereotactic image-guided intensity-modulated radiotherapy for extracranial metastases from renal
cell carcinoma. Int J Radiat Oncol Biol Phys. 2012;82(5):1744-1748.
8. Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): multi-institutional prospective observational study. Lancet Oncol. 2014;15(4):387-395.
9. Hasegawa T, Kondziolka D, Flickinger JC, Lunsford LD. Stereotactic radiosurgery for brain metastases from gastrointestinal tract cancer. Surg Neurol. 2003;60(6):506-514.
10. Shiau CY, Sneed PK, Shu HK, et al. Radiosurgery for brain metastases: relationship of dose and pattern of enhancement to local control. Int J Radiat Oncol Biol Phys. 1997;37(2):375-383.
11. Molenaar R, Wiggenraad R, Verbeek-de Kanter A, Walchenbach R, Vecht C. Relationship between volume, dose and local control in stereotactic radiosurgery of brain metastasis. Br J Neurosurg. 2009;23(2):170-178.
12. Vogelbaum MA, Angelov L, Lee SY, Li L, Barnett GH, Suh JH. Local control of brain metastases by stereotactic radiosurgery in relation to dose to the tumor margin. J Neurosurg. 2006;104(6):907-912.
13. Berghoff AS, Venur VA, Preusser M, Ahluwalia MS. Immune checkpoint inhibitors in brain metastases: from biology to treatment. Am Soc Clin Oncol Educ Book. 2016;35:e116-e122.
14. Berghoff AS, Fuchs E, Ricken G, et al. Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases. Oncoimmunology. 2015;5(1):e1057388.
15. Derosa L, Le Teuff G, Khordahi M, et al. Inter and intra-tumor heterogeneity of PD-L1 and MET expression in metastatic renal cell carcinoma (mRCC) [ASCO abstract 4569]. J Clin Oncol. 2017;35(15 suppl).
16. Escudier BJ, Chabaud S, Borchiellini D, et al. Efficacy and safety of nivolumab in patients with metastatic renal cell carcinoma (mRCC) and brain metastases: preliminary results from the GETUG-AFU 26 (Nivoren) study [ASCO abstract 4563]. J Clin Oncol. 2017;35(15 suppl).
17. Procopio G, Prisciandaro M, Iacovelli R, et al. Safety and efficacy of cabozantinib for metastatic renal cell carcinoma (mRCC): real world data from an Italian Expanded Access Program (EAP) [ESMO abstract 901P]. Ann Oncol. 2017;28(suppl 5).
Guidelines on Managing Small Renal Masses: Compare and Contrast
Dr Houston Thompson com-pared guidelines for the management of small renal masses.1-5 For these tumors, the Canadian Urological Association recommends partial nephrectomy by open surgery or laparoscopy, or with robotic assistance.2 Laparoscopic radical nephrectomy is reserved for tumors that are not suitable for partial nephrectomy. The Canadian guidelines state that open partial nephrectomy is preferred to laparoscopic radical nephrectomy. Ablation is also an option, although it is less successful in patients with endophytic central tumors. A biopsy should be obtained at the time of ablation. A laparoscopic approach is unnecessary. Active surveillance is a primary consideration for the elderly and infirm.
The European Association of Urology (EAU) guidelines also rec-ommend partial nephrectomy and state that surgery is the only curative treatment supported by high-quality evidence.3 Laparoscopic radical neph-rectomy is recommended for renal masses that are not eligible for treatment with partial nephrectomy. Owing to a lack of high-quality studies, the EAU guidelines provide no recommendations on ablation. How-ever, the guidelines state that ablation can be offered to patients with comorbidities, RCC syn-dromes, bilateral tumors, or sol-itary kidney tumors. Ablation is not recommended for larger tumors or those near the hilum or ureter. Similarly to the Canadian guidelines, the EAU guidelines state that active surveillance is an option for elderly patients and those with comorbidities.
Guidelines from the Ameri-can Society of Clinical Oncology (ASCO), published in early 2017, state that active surveillance should be the initial approach in patients with a life expectancy of less than 5 years, or patients with a renal mass of less than 1 cm and a life expectancy of less than 10 years.4 Active treatment should be considered if the mass grows more than 5 mm annually or if it exceeds 4 cm. Partial nephrectomy is standard for patients who need treatment. Ablation is an option when complete removal of the mass is possible, and a biopsy should be performed before or during the procedure. The guidelines contradict the historical notion that ablation is limited to patients who are infirm or who have comorbidities. Even at centers with expertise, radical nephrectomy should be reserved for cases in which partial nephrectomy is not an option and the tumor shows significant complexity.
Guidelines from the Australian Urology Asso-ciation state that partial nephrectomy should be prioritized when intervention is indicated, and that most cT1b/T2 tumors are eligible for this procedure.5 Radical nephrectomy is preferred if all of the following conditions are met: high tumor complexity, no chronic kidney disease or proteinuria, a normal contralateral kidney, and, after treatment, anticipation of a normal glomerular filtration rate exceeding 45 mL/min. Radical nephrectomy should be avoided for cT1a renal masses. Ablation is an option for tumors of less than 3 cm. A percutaneous technique is preferred, and the physician should counsel the patient on the increased risk of local recurrence. Active surveillance is an acceptable option, especially if the tumor is less than 2 cm. Intervention may be considered if there is more than 5 mm of growth annually (which is in agreement with the ASCO guidelines), or if the tumor is greater than 3 cm (vs >4 cm in the ASCO guidelines). Rates of local recurrence were evaluated for partial nephrectomy and percutaneous ablation for the treatment of cT1 renal masses.6 The authors searched the prospectively maintained Mayo Clinic Renal Tumor Registry and identified 1803 patients with cT1N0M0 renal masses treated between 2000 and 2011. Rates of recurrence-free survival were similar among patients who underwent partial nephrectomy or percutaneous ablation. Among patients with a cT1a renal mass, metastases-free survival was superior with partial nephrectomy and cryoablation when compared with radiofrequency ablation (Figure 6).
1. Thompson RH. Guidelines on managing SRMs: compare and contrast. Presented at: the Sixteenth International Kidney Cancer Symposium; November 3-4, 2017; Miami, Florida.
2. Jewett MA, Rendon R, Lacombe L, et al. Canadian guidelines for the management of small renal masses (SRM). Can Urol Assoc J. 2015;9(5-6):160-163.
3. Ljungberg B, Bensalah K, Canfield S, et al. EAU guidelines on renal cell carcinoma: 2014 update. Eur Urol. 2015;67(5):913-924.
4. Finelli A, Ismaila N, Bro B, et al. Management of small renal masses: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2017;35(6):668-680.
5. Campbell S, Uzzo RG, Allaf ME, et al. Renal mass and localized renal cancer: AUA Guideline. J Urol. 2017;198(3):520-529.
6. Thompson RH, Atwell T, Schmit G, et al. Comparison of partial nephrectomy and percutaneous ablation for cT1 renal masses. Eur Urol. 2015;67(2):252-259.
Imaging in Renal Cell Carcinoma: Novel Methods and Approaches
Dr Mark Ball presented insights on novel imaging methods in RCC.1 RCC tumors have been shown to exhibit grade heterogen-eity, with most small renal masses and high-grade tumors exhibiting nuclear-grade heterogeneity (Figure 7).2 Imaging mod-alities, including computed tomography (CT), magnetic resonance imaging (MRI), and nuclear medicine may provide more detailed tumor information for use in classification and risk stratification.
Diffusion-weighted MRI has been evaluated for its ability to further characterize focal renal lesions.3 The method provides contrast within tiss-ues and is sensitive to cell density, membrane integrity, and tissue microstructure.4 A retrospective study evaluated the apparent diffusion coefficient in the solid portions of RCC specimens, as well as in cystic or hemorrhagic areas, and in normal parenchyma in specimens from 33 patients with 36 RCC tumors.3 Histologic subtype, nuclear grade, and cell count were also determined for each lesion. A decrease in the apparent diffusion coefficient was observed with increasing tumor grade, and the mean apparent diffusion coefficient of high-grade RCC tumors was significantly lower than in high-grade tumors (P=.005). Moreover, the mean apparent diffusion coefficient for clear cell RCC tumors was significantly higher than for non–clear cell tumors (P=.005).
This approach was further investigated in a study examining 152 lesions consisting of the following types: 97 clear cell RCCs, 29 papillary RCCs, and 26 oncocytomas.5 Apparent diffusion coefficient maps were segmented for volumetric and pixel-based histogram analysis. The histopathology of surgical specimens was used as a reference standard for the diagnosis of various RCC subtypes. The apparent diffusion coefficient ranged from 258 mm2/sec to 3407 mm2/sec for papillary RCC tumors and from 246 mm2/sec to 3686 mm2/sec for clear cell RCC tumors. The best percentile showed 96% sensitivity and 84% specificity, reflecting the highest sensitivity and specificity among all of the features (with an area under the curve of 95.2).
Nuclear imaging is also being explored as a noninvasive method to characterize localized RCC tumors. An open-label, multicenter study evaluated positron emission tomography (PET)/CT with iodine-124 conjugated to girentuximab in patients with clear cell RCC masses that were scheduled for resection.6 Girentuximab is a chimeric monoclonal antibody that binds to carbonic anhydrase, which is overexpressed in more than 90% of clear cell RCC tumors. Iodine I-124 girentuximab was administered intra-venously 2 to 6 days before imaging. Imaging was performed by PET/CT and contrast-enhanced CT. The average sensitivity was 86.2% for PET/CT and 75.5% for contrast-enhanced CT (P=.023). The average specificity was 85.9% for PET/CT and 46.8% for contrast-enhanced CT (P=.005). The negative predictive value was 94.4%, the positive predictive value was 69.4%, and the accuracy was 86.2%. The study validated iodine I-124 girentuximab as a molecular imaging biomarker for the detection of clear cell RCC.
Benign oncocytoma and RCC can be differentiated through imaging with technetium-99m-methoxyisobutylisonitrile (99mTc-MIBI) single-photon emission CT (SPECT).7 Three patients with oncocytoma and 3 with RCC underwent imaging with 99mTc-MIBI SPECT/CT. The 3 oncocytomas showed radiotracer uptake at levels near or exceeding that of the normal renal parenchyma, with ratios ranging from 0.85 to 1.78. In contrast, uptake levels for the 3 RCC tumors ranged from 0.21 to 0.31. In a separate study, 99mTc-sestamibi combined with SPECT/CT correctly identified 5 of 6 oncocytomas and 2 of 2 hybrid oncocytic/chromophobe tumors.8 The overall sensitivity was 87.5% (95% CI, 47.4%-99.7%), and specificity was 95.2% (95% CI, 83.8%-99.4%).
1. Ball M. Imaging in RCC: novel methods and approaches. Presented at: the Sixteenth International Kidney Cancer Symposium; November 3-4, 2017; Miami, Florida.
2. Ball MW, Bezerra SM, Gorin MA, et al. Grade heterogeneity n small renal masses: potential implications for renal mass biopsy. J Urol. 2015;193(1):36-40.
3. Goyal A, Sharma R, Bhalla AS, et al. Diffusion-weighted MRI in renal cell carcinoma: a surrogate marker for predicting nuclear grade and histological subtype. Acta Radiol. 2012;53(3):349-358.
4. O’Flynn EA, DeSouza NM. Functional magnetic resonance: biomarkers of response in breast cancer. Breast Cancer Res. 2011;13(1):204.
5. Mirmomen SM, Nikpanah M, Gautam R, et al. Diffusion weighted imaging: differentiation of clear cell from papillary renal cell carcinoma [AUA abstract MP18-12]. J Urol. 2017;197(4s).
6. Divgi CR, Uzzo RG, Gatsonis C, et al. Positron emission omography/computed tomography identification of clear cell renal cell carcinoma: results from the REDECT trial. J Clin Oncol. 2013;31(2):187-194.
7. Rowe SP, Gorin MA, Gordetsky J, et al. Initial experience using 99mTc-MIBI SPECT/CT for the differentiation of oncocytoma from renal cell carcinoma. Clin Nucl Med. 2015;40(4):309-313.
8. Gorin MA, Rowe SP, Baras AS, et al. Prospective evaluation of (99m)Tc-sestamibi SPECT/CT for the diagnosis of renal oncocytomas and hybrid oncocytic/chromophobe tumors. Eur Urol. 2016;69(3):413-416.
A Perspective on Adjuvant Renal Cell Carcinoma Trials
Dr Tim Eisen discussed recent trials in RCC, with a focus on patient eligibility, endpoints, controversies across similar trials, and how to ensure that academic studies have regulatory impact in the context of adjuvant trials.1 The currently available risk-scoring systems must be updated as new biomarkers and methods are developed. The SSIGN score (Stage, Size, Grade, and Necrosis) can be used to stratify patients based on the risk of metastasis-free survival.2 Factors such as tumor stage, regional lymph node status, tumor size, nuclear grade, and histologic tumor necrosis were significantly associated with pro-gression to metastasis in patients with clear cell RCC. Circulating tumor DNA (ctDNA) may provide a useful additional characteristic to moni-tor.3-6 The half-life of ctDNA is very short; therefore, if complete resection of the tumor has been achieved, the ctDNA level should drop to 0 ng/mL soon after resection. ctDNA is most often monitored in patients with advanced disease who are receiving treatment. However, ctDNA could also find use in early diagnosis and screening. A study in stage II colorectal cancer demonstrated that ctDNA can be used to provide direct evidence of residual disease. Assays that incorporated massively parallel sequencing to detect ctDNA were used to investigate the ability to identify patients with minimal residual disease.7 The study evaluated 1046 plasma samples from a prospective cohort of 230 patients with resected stage II colon cancer.7 Among patients who did not receive adjuvant chemotherapy, ctDNA was detected postoperatively in 7.9%, and recurrence was observed in only 9.8% of patients with negative ctDNA (HR, 18; 95% CI, 7.9-40; P<.001). The presence of ctDNA in patients after completion of chemotherapy was also associated with an inferior recurrence-free survival (HR, 11; 95% CI, 1.8-68; P=.001). Other methods that should be considered for updating risk stratification include genetic signatures and imaging analyses.
Study endpoints are imperfect ways of measuring outcomes. OS is the gold standard in any study of adjuvant therapy. However, use of OS as a study endpoint can lead to trials of excessive duration, and it can limit the number of questions that can be addressed. Disease-free survival and metastasis-free survival are acceptable endpoints in other settings, but there are doubts regarding their value as surrogate endpoints for survival. Quality-of-life and safety endpoints are important for assessing risk vs benefit, but the instruments available to measure them are not very accurate. These endpoints are unlikely to lead to new drug approvals.
Study data can be interpreted in different ways, leading to controversies. This situation is reflected in recent adjuvant trials in RCC, some of which are considered negative and others positive.8 Similar questions are often asked across several different trials, and it might be more effective to design trials that are complementary instead of directly competing. In addition, enabling meta-analyses and incorporating patient-level data could prove fruitful. It is important for academic studies to have regulatory impact, but academic groups face major challenges in attracting industry support. It is expensive and difficult to prepare the regulatory quality data package. To increase the odds of successful regulatory review, data must be prepared in a format that suits submission requirements. Studies must be designed with central review of radiology, blinded evaluation by statisticians, on-site monitoring, peri-odic quality assessment, and use of electronic case report forms.
1. Eisen T. Perspective(s) on adjuvant trials. Presented at: the Sixteenth International Kidney Cancer Symposium; November 3-4, 2017; Miami, Florida.
2. Leibovich BC, Blute ML, Cheville JC, et al. Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. Cancer. 2003;97(7):1663-1671.
3. Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6(224):224ra24.
4. Dawson SJ, Rosenfeld N, Caldas C. Circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013;369(1):93-94.
5. Diehl F, Schmidt K, Choti MA, et al. Circulating mutant DNA to assess tumor dynamics. Nat Med. 2008;14(9):985-990.
6. Forshew T, Murtaza M, Parkinson C, et al. Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci Transl Med. 2012;4(136):136ra68.
7. Tie J, Wang Y, Tomasetti C, et al. Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer. Sci Transl Med. 2016;8(346):346ra92.
8. Porta C, Chiellino S. ASSURE vs. S-TRAC: conflicting results of adjuvant treatments for kidney cancer in the era of targeted agents and genomics. Ann Transl Med. 2016;4(suppl 1).
Axitinib and Cabozantinib in the Treatment of Sunitinib-Refractory Patients With Metastatic Renal Cell Carcinoma: Results of Matching Adjusted Indirect Treatment Comparison Analysis of the AXIS and METEOR Trials
Dr Irina Proskorovsky pre-sented results of matching-adjusted indirect treatment of comparison (MAIC) analysis of 2 trials that evaluated axitinib or cabozantinib in patients with metastatic RCC.1 The phase 3 AXIS trial (Axitinib [AG 013736] As Second Line Therapy For Metastatic Renal Cell Cancer) evaluated axitinib vs sorafenib as second-line treatment in patients with metastatic RCC.2 The open-label, phase 3 METEOR trial (A Phase 3, Randomized, Controlled Study of Cabozantinib [XL184] vs Everolimus in Subjects With Metastatic Renal Cell Carcinoma That Has Progressed After Prior VEGFR Tyrosine Kinase Inhibitor Therapy) compared cabo-zantinib vs everolimus in patients with metastatic RCC who developed progressive disease after treatment with a VEGF TKI.3 Imbalances between studies preclude direct comparison of outcomes. MAIC analysis is a method for comparing results in similar trials by adjusting for imbalances in baseline patient characteristics.4 MAIC analysis was performed to compare PFS and OS with axitinib vs cabozantinib in sunitinib-refractory patients enrolled in the AXIS and METEOR trials. The analysis was based on patient-level data from AXIS and published summary data from METEOR.
The comparison included 3 key steps. Baseline characteristics were mathematically adjusted so that the aggregate characteristics of the axitinib subgroup in AXIS matched those of the cabozantinib subgroup in METEOR. The adjustment factors derived in step 1 were then applied to generate the adjusted PFS and OS outcomes using a weighted Kaplan-Meier approach. Estimates of the comparative effect were quantified as an HR with a 95% CI. All available patient characteristics in both trials were used for adjustment, including risk classification based on criteria from the Memorial Sloan Kettering Cancer Center (MSKCC).5 MSKCC risk was calculated differently in the 2 trials. The Karnofsky performance score (PS) was collected in METEOR, but not AXIS. The AXIS trial used criteria from the Eastern Cooperative Oncology Group (ECOG) to assess performance. The respective PS values in each trial were used to calculate the MSKCC risk classification. To evaluate the sensitivity of the results to the MSKCC definition in AXIS, 2 sets of MAIC analyses were performed. ECOG PS 1 was considered a risk factor in the base case analysis, but not in the sensitivity analysis.
Before the MAIC adjustment, a higher proportion of patients in the AXIS subgroup had bone or lung metastasis compared with the METEOR subgroup. The proportion of patients with ECOG PS 1 and the distribution of MSKCC PS scores were also imbalanced in the initial study populations. Other characteristics that were matched for the MAIC comparison included the geographic location, prior nephrectomy, and prior radiotherapy. After these characteristics were matched, the patient characteristics were balanced between the sunitinib-refractory populations in both studies.
PFS and OS were analyzed by MAIC analysis. Base case analysis of PFS showed no significant differences between the sunitinib-refractory patients from AXIS vs METEOR (HR, 1.152; 95% CI, 0.815-1.626; P=.423). Sensitivity analysis was consistent with a marginally superior PFS for cabozantinib (HR, 1.387; 95% CI, 0.999-1.924; P=.0504; Figure 8). Base case analysis of OS also showed similar outcomes for axitinib vs cabozantinib (HR, 1.004; 95% CI, 0.689-1.463; P=.9830), as did sensitivity analysis (HR, 1.347; 95% CI, 0.948-1.925; P=.0963).
There were several limitations to the analysis, including the earlier timing of the PFS assessments in the AXIS trial, the inability to fully adjust for differences in the definitions of the MSKCC score between the 2 trials, and the availability of only a subset of patient characteristics for the sunitinib-refractory population in the METEOR trial.
1. Proskorovsky I, Benedict A, Negrier S, et al. Axitinib and cabozantinib in the treatment of sunitinib-refractory patients with metastatic renal cell carcinoma (mRCC): results of matching adjusted indirect treatment comparison (MAIC) analysis of AXIS and METEOR trials. Presented at: the Sixteenth International Kidney Cancer Symposium; November 3-4, 2017; Miami, Florida.
2. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931-1939.
3. Choueiri TK, Escudier B, Powles T, et al ; METEOR investigators. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17(7):917-927.
4. Signorovitch JE, Sikirica V, Erder MH, et al. Matching-adjusted indirect comparisons: a new tool for timely comparative effectiveness research. Value Health. 2012;15(6):940-947.
5. Motzer RJ, Bacik J, Mazumdar M. Prognostic factors for survival of patients with stage IV renal cell carcinoma: Memorial Sloan-Kettering Cancer Center experience. Clin Cancer Res. 2004;10(18 pt 2):6302s-6303s.
Nivolumab in the CheckMate 374, CheckMate 016, and CheckMate 025 Trials
Several posters presented find-ings from studies that eval-uated nivolumab in various settings. The open-label, phase 3b/4 CheckMate 374 study evaluated nivo-lumab in 3 cohorts of patients with advanced or metastatic RCC: those with clear cell RCC, those with non–clear cell RCC, and those with brain metastases.1 Treatment consisted of intravenous nivolumab (240 mg) every 2 weeks. The study included 98 patients with clear cell RCC, 43 patients with non–clear cell RCC, and 1 patient with brain metastases. Nearly all of the patients (99%) with clear cell RCC had received at least 1 prior systemic therapy for their advanced disease, whereas the majority of non–clear cell RCC patients (65%) were treatment-naive. After a median follow-up of 8.0 months, the primary reason for treatment discontinuation was disease progression. Discontinuations owing to nivolumab toxicity occurred in 9 patients (9%) with clear cell RCC and 2 patients (5%) with non–clear cell RCC. The median duration of exposure was 5.1 months for patients with clear cell RCC and 3.3 months for patients with non–clear cell RCC. Grade 3/4 immune-related AEs reported in the clear cell RCC cohort included hepatitis (3.1%), increased levels of alanine transaminase and aspartate transaminase (both 1.0%), increased blood bilirubin (1.0%), and hyperbilirubinemia (1.0%). No grade 3/4 immune-related AEs were reported in the non–clear cell patient cohort, and no grade 5 immune-related AEs occurred across the 3 cohorts.
CheckMate 016 is a multicenter, open-label, parallel-cohort, dose‑escalation phase 1 study of nivo-lumab in combination with ipilimumab, sunitinib, or pazopanib in patients with advanced or metastatic RCC.2 The study assigned 33 patients to nivolumab (2 mg/kg every 3 weeks) plus sunitinib (50 mg daily) and 20 to nivolumab (2 mg/kg every 3 weeks) plus pazopanib (800 mg daily). The proportion of patients who had received prior systemic therapy was 42.4% in the nivolumab plus sunitinib arm and 100% in the nivolumab plus pazopanib arm. In the nivolumab plus sunitinib arm, the median duration of therapy was 45.1 weeks for nivolumab and 28.0 weeks for sunitinib. In the nivolumab plus pazopanib arm, the median duration of treatment was 15.1 weeks for nivolumab and 13.9 weeks for pazopanib. Grade 3/4 treatment-related AEs were observed in 82% of patients in the nivolumab plus sunitinib arm and in 70% of patients treated with nivolumab plus pazopanib. The most common treatment-related AEs in both arms were fatigue, diarrhea, and hypertension. Immune-modulating medication was used by 55% to 60% of patients in both arms. Serious treatment-related AEs of any grade were reported in 42% of patients in the nivolumab/sunitinib arm and in 10% of patients in the nivolumab/pazopanib arm. For the sunitinib combination, the confirmed ORR was 54.5% (95% CI, 36.4%-71.9%), and the median PFS was 12.7 months. For the pazopanib combination, the confirmed ORR was 45.0% (95% CI, 23.1%-68.5%), and the median PFS was 7.2 months.
The combination of nivolumab plus ipilimumab at different doses was evaluated in the CheckMate 016 trial.3 Patients with advanced or metastatic RCC received 4 cycles of treatment every 3 weeks consisting of intravenous nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg (arm N3I1), nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg (arm N1I3), or nivolumab at 3 mg/kg plus ipilimumab at 3 mg/kg (arm N3I3). Thereafter, patients received nivolumab (3 mg/kg) every 2 weeks until disease progression or unacceptable toxicity. Forty-seven patients were enrolled in each arm.
The high-dosage arm (nivolumab at 3 mg/kg plus ipilimumab at 3 mg/kg) was stopped early owing to dose-limiting toxicity.4 Median follow-up was approximately 3 years in the other arms. Among patients treated with nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg (N3I1), 72.3% discontinued owing to disease progression and 12.8% discontinued owing to toxicity. Among patients who received nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg (N1I3), 46.8% discontinued owing to disease progression and 29.8% owing to toxicity.
In the N3I1 arm, grade 3/4 treatment-related AEs occurred in 42.6% of patients, grade 3/4 treatment-related AEs leading to discontinuation were reported in 6.4% of patients, serious grade 3/4 treatment-related AEs occurred in 19.1% of patients, and AEs requiring immune-modulating medication occurred in 31.9% of patients. In the N1I3 arm, these rates were 63.8%, 19.1%, 34.0%, and 48.9%, respectively. The confirmed ORR was 36.2% in the N3I1 arm (including CRs in 10.6%), and 40.4% in the N1I3 arm (including CRs in 2.1%). Median PFS was 7.0 months in the N3I1 arm and 9.4 months in the N1I3 arm (Figure 9). Median OS was not reached in either arm. The results supported further investigation of the N3I1 combination in the phase 3 CheckMate 214 study.5
The phase 3 CheckMate 025 study demonstrated superior OS and a higher ORR for nivolumab compared with everolimus after at least 14 months of follow-up.6 After a minimum follow-up of approximately 38 months, results from CheckMate 025 continued to demonstrate a survival benefit over everolimus in previously treated patients with advanced or metastatic RCC.7 The study assigned 406 patients to nivolumab (3 mg/kg every 2 weeks) and 397 to everolimus (10 mg daily). The median duration of treatment was 5.5 months (range, 5.1-6.9 months) with nivolumab and 3.7 months (range, 3.3-4.1 months) with everolimus. In both arms, the primary reason for discontinuation was disease progression (77% in the nivolumab arm and 74% in the everolimus arm). The median OS was 25.8 months with nivolumab vs 19.7 months with everolimus (HR, 0.74; P=.0005). Median PFS was 4.2 months with nivolumab vs 4.5 months with everolimus (HR, 0.85; P=.0371; Figure 10). The ORR was 26% with nivolumab vs 5% with everolimus.
Grade 3/4 treatment-related AEs occurred in 21% of patients treated with nivolumab and 37% of those treated with everolimus. Treatment-related AEs leading to discontinuation occurred in 5% vs 7%. The safety profile was consistent with the primary analysis, and the majority of AEs resolved.
1. McFarlane J, Olsen M, Molina A, et al. Safety of nivolumab in patients with clear cell or non–clear cell renal cell carcinoma: results from the phase IIIb/IV CheckMate 374 study. Presented at: the Sixteenth International Kidney Cancer Symposium; November 3-4, 2017; Miami, Florida.
2. Amin A, Plimack ER, Lewis LD, et al. Updated results from a phase I study of nivolumab in combination with sunitinib or pazopanib in metastatic renal cell carcinoma: the CheckMate 016 study. Presented at: the Sixteenth International Kidney Cancer Symposium; November 3-4, 2017; Miami, Florida.
3. Plimack ER, Bauer TM, Pal S, et al. Updated results from a phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate 016 study. Presented at: the Sixteenth International Kidney Cancer Symposium; November 3-4, 2017; Miami, Florida.
4. Hammers HJ, Plimack ER, Infante JR, et al. Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate 016 study. J Clin Oncol. 2017;35(34):3851-3858.
5. Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: efficacy and safety of nivolumab + ipilimumab (N+I) v sunitinib (S) for treatment-naïve advanced or metastatic renal cell carcinoma (mRCC), including IMDC risk and PD-L1 expression subgroups [ESMO abstract LBA5]. Ann Oncol. 2017;28(suppl 5).
6. Motzer RJ, Escudier B, McDermott DF, et al; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-1813.
7. Sharma P, Tykodi SS, Escudier B, et al. Three-year efficacy and safety update from the phase III CheckMate 025 study of nivolumab versus everolimus in patients with advanced renal cell carcinoma. Presented at: the Sixteenth International Kidney Cancer Symposium; November 3-4, 2017; Miami, Florida.
Highlights in Renal Cell Carcinoma From the Sixteenth International Kidney Cancer Symposium: Commentary
Robert A. Figlin, MD, FACP
Presentations at the Sixteenth International Kidney Cancer Symposium provided important insights into the evolving management of patients with renal cell carcinoma. Data were presented from new studies, subanalyses of pivotal trials, and retrospective analyses. Several of the abstracts were particularly noteworthy for the practicing clinician. The following discussion represents a perspective on the importance of these trial results as applied to the management of patients with renal cell carcinoma.
The CheckMate Trials
Dr Elizabeth Plimack presented an updated analysis from the phase 1 CheckMate 016 trial (Checkpoint Pathway and Nivolumab Clinical Trial Evaluation 016).1 CheckMate 016 evaluated nivolumab in combination with ipilimumab, sunitinib, or pazopanib in previously treated or treatment-naive patients with advanced or metastatic renal cell carcinoma.2 The analysis by Dr Plimack focused on the cohort of patients treated with nivolumab plus ipilimumab, at 3 different dose levels. The results are potentially practice-changing, and they will likely be part of the submission package to the US Food and Drug Administration (FDA) for approval of combined immunooncology therapies in kidney cancer. Among the remarkable aspects of the study results is the tolerability of nivolumab plus ipilimumab. In addition, for the first time, a treatment has led to complete responses in addition to an overall response. With the regimen of nivolumab administered at 3 mg/kg plus ipilimumab at 1 mg/kg, the complete response rate exceeded 10%. (Complete responses are often associated with a significant improvement for patients with cancer.) The overall response rate was more than 35%, and the 12-month progression-free survival rate was 36%, which is impressive, especially in patients with refractory disease. Some of these responses were not only complete, but also durable. Treatment improved survival.
The phase 3 CheckMate 025 study compared nivolumab vs everolimus in patients with advanced kidney cancer.3 Dr Padmanee Sharma presented an analysis of 3-year efficacy and safety.4 Nivolumab is currently a standard-of-care treatment supported by level 1 evidence in patients with renal cell carcinoma previously treated with tyrosine kinase inhibitors (TKIs). This 3-year efficacy analysis aimed to determine whether responses to immuno-oncology agents are durable. The responses seen with nivolumab were remarkably durable, with a median overall survival of just under 26 months. On the Kaplan-Meier graph, there appears to be the potential for a tail to the curve at the 20% to 30% range, suggesting that these treatments may be associated with durable remissions that can be maintained. The optimal duration of nivolumab treatment is not known. The safety profile was favorable and consistent with the previously published primary data.3 This analysis of the 3-year overall survival, efficacy, and safety further supports the use of immuno-oncology drugs, such as nivolumab, in the post-TKI population.
Not all combinations of immuno-oncology therapies are well-tolerated, as shown in an analysis of the phase 1 CheckMate 016 study presented by Dr Asim Amin.5 This analysis focused on nivolumab in combination with either sunitinib or pazopanib. Targeted agents, such as the TKIs sunitinib or pazopanib, may prove to be less optimal for use in combination with immuno-oncology therapies. CheckMate 016 showed encouraging anti-tumor activity with an immuno-oncology therapy plus sunitinib or pazopanib, but these agents significantly increased the incidence of high-grade adverse events and dose-limiting toxicities. These combinations will not be evaluated further in the clinic or in pivotal phase 3 trials.
Ongoing phase 3 trials are combining targeted therapies with bevacizumab, cabozantinib, lenvatinib, and axitinib.6-9 It is important to remember that not all combinations of immuno-oncology agents and targeted therapies are safe, and it will be necessary to wait for results from pivotal phase 3 trials to discern their importance and any potential differences among them.
Dr Bernard Escudier presented a summary of the use of sunitinib, including safety and therapy management, among patients with resected high-risk localized renal cell carcinoma enrolled in the S-TRAC trial (A Clinical Trial Comparing Efficacy and Safety of Sunitinib Versus Placebo for the Treatment of Patients at High Risk of Recurrent Renal Cell Cancer).10 In November 2017, the FDA approved sunitinib for the treatment of patients with high-risk resected renal cell carcinoma based on results from the S-TRAC trial.11 This updated analysis demonstrated no new safety signals, and adverse events were similar to those previously reported with sunitinib in patients with advanced disease. The adverse events were predictable, manageable, and reversible. With effective therapy management, one could hope to achieve the prolonged disease-free survival benefit that has been seen in this population of patients treated with sunitinib. In fact, 71% of the patients were able to remain on treatment with sunitinib for at least 8 months, reaching cycle 6, and 56% of patients completed the entire year of treatment. This analysis further demonstrates that sunitinib is an option for the adjuvant treatment of kidney cancer in selected high-risk patients, as it is FDA-approved and associated with manageable, predictable side effects. Most patients can tolerate long-term treatment. A balanced discussion with patients in this subgroup is warranted.
Deferred Systemic Therapy for Metastatic Renal Cell Carcinoma
Dr Michael Harrison provided a preliminary prospective analysis evaluating deferred systemic therapy for metastatic renal cell carcinoma.12 This issue is becoming increasingly important. The study by Dr Harrison builds on observations made in retrospective analyses by Dr Brian Rini and others suggesting that in some patients with kidney cancer, systemic therapy for advanced disease can be withheld until there is evidence of disease progression.13,14 This strategy is known as active surveillance. The study by Dr Harrison prospectively enrolled more than 500 patients with asymptomatic metastatic disease at 46 US sites, in both community and academic centers. At study entry, patients could be observed and followed without active therapy. Importantly, the results, although still preliminary, suggested that approximately one quarter of patients with advanced metastatic disease can be followed for up to nearly a year before they require systemic therapy. What does that mean for patients? For some asymptomatic patients with primarily lymph node– or lung-predominant disease who have previously undergone a nephrectomy, active surveillance is a reasonable alternative to treatment. These patients should undergo repeated computed tomography scans, and systemic therapy should be initiated when there is evidence of clinical progression. This prospective evaluation further demonstrates that an active surveillance approach may be appropriate for some patients.
Emerging Management Strategies
The year 2018 promises to be another important one in the evolution of kidney cancer care. On December 19, 2017, the FDA approved the use of cabozantinib in previously untreated metastatic patients. The approval was based on results from the CABOSUN study (Cabozantinib-S-Malate or Sunitinib Malate in Treating Patients With Previously Untreated Locally Advanced or Metastatic Kidney Cancer), which demonstrated superiority with cabozantinib compared with sunitinib.15 We anxiously await the FDA’s decision regarding the combination of ipilimumab/nivolumab in a similar population. After more than a decade
of using TKIs within the initial treatment paradigm for advanced disease, we may be entering the era of upfront immuno-oncology approaches, based on the improvements seen in many endpoints, including survival. We also await the results of studies evaluating the combinations of checkpoint inhibitors combined with targeted agents, and the possibility that the ADAPT trial (Phase 3 Trial of Autologous Dendritic Cell Immunotherapy Plus Standard Treatment of Advanced Renal Cell Carcinoma) may provide information about the evolving role of vaccine therapy in this disease.16
Dr Figlin receives research funding from BMS, Peloton, Argos, Exelixis, and Merck. He serves as a consultant for Johnson & Johnson, CB Therapeutics, and Pfizer.
1. Plimack ER, Bauer TM, Pal S, et al. Updated results from a phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate 016 study. Presented at: the Sixteenth International Kidney Cancer Symposium; November 3-4, 2017; Miami, Florida.
2. Hammers HJ, Plimack ER, Infante JR, et al. Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate 016 study. J Clin Oncol. 2017;35(34):3851-3858.
3. Motzer RJ, Escudier B, McDermott DF, et al; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-1813.
4. Sharma P, Tykodi SS, Escudier B, et al. Three-year efficacy and safety update from the phase III CheckMate 025 study of nivolumab versus everolimus in patients with advanced renal cell carcinoma. Presented at: the Sixteenth International Kidney Cancer Symposium; November 3-4, 2017; Miami, Florida.
5. Amin A, Plimack ER, Lewis LD, et al. Updated results from a phase I study of nivolumab in combination with sunitinib or pazopanib in metastatic renal cell carcinoma: the CheckMate 016 study. Presented at: the Sixteenth International Kidney Cancer Symposium; November 3-4, 2017; Miami, Florida.
6. ClinicalTrials.gov. Everolimus and bevacizumab in advanced non-clear cell renal cell carcinoma (RCC). https://clinicaltrials.gov/ct2/show/NCT01399918. Identifier: NCT01399918. Accessed December 18, 2017.
7. ClinicalTrials.gov. Study of pembrolizumab and cabozantinib in patients with metastatic renal cell carcinoma. ttps://clinicaltrials.gov/ct2/show/NCT03149822. Identifier: NCT03149822. Accessed December 14, 2017.
8. ClinicalTrials.gov. Trial to assess safety and efficacy of lenvatinib in combination with everolimus in participants with renal cell carcinoma. https://clinicaltrials.gov/ct2/show/NCT03173560. Identifier: NCT03173560. Accessed December 14, 2017.
9. ClinicalTrials.gov. A randomized phase 2 trial of axitinib and TRC105 versus axitinib alone in patients with advanced or metastatic renal cell carcinoma. https://clinicaltrials.gov/ct2/show/NCT01806064. Identifier: NCT01806064. Accessed December 14, 2017.
10. Escudier B, George DJ, Motzer RJ, et al. Sunitinib in patients with high-risk renal cell carcinoma: safety and therapy management in S-TRAC trial. Presented at: the Sixteenth International Kidney Cancer Symposium; November 3-4, 2017; Miami, Florida.
11. Ravaud A, Motzer RJ, Pandha HS, et al; S-TRAC Investigators. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. 2016;375(23):2246-2254.
12. Harrison MR, Costello BA, Bhavsar NA, et al. Deferred systemic therapy for metastatic renal cell carcinoma: preliminary prospective experience. Presented at: the Sixteenth International Kidney Cancer Symposium; November 3-4, 2017; Miami, Florida.
13. Rini BI, Dorff TB, Elson P, et al. Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial. Lancet Oncol. 2016;17(9):1317-1324.
14. Mitchell AP, Hirsch BR, Harrison MR, Abernethy AP, George DJ. Deferred systemic therapy in patients with metastatic renal cell carcinoma. Clin Genitourin Cancer. 2015;13(3):e159-e166.
15. Choueiri TK, Hessel C, Halabi S, et al. Progression-free survival (PFS) by independent review and updated overall survival (OS) results from Alliance A031203 trial (CABOSUN): cabozantinib versus sunitinib as initial targeted therapy for patients (pts) with metastatic renal cell carcinoma (mRCC) [ESMO abstract LBA38]. Ann Oncol. 2017;28(suppl 5).
16. Figlin R, Nicolette C, Tannir N, et al. Interim analysis of the phase 3 ADAPT trial evaluating rocapuldencel-T (AGS-003), an individualized immunotherapy for the treatment of newly-diagnosed patients with metastatic renal cell carcinoma (mRCC) [ESMO abstract 1137O]. Ann Oncol. 2017;28