Poor-risk mRCC Research Articles

Ipilimumab plus nivolumab (Ipi/Nivo) as salvage therapy in patients with immunotherapy (IO)-refractory metastatic renal cell carcinoma (mRCC).

669 Background: Ipi/Nivo is now FDA approved for the first line treatment of patients (pts) with intermediate and poor risk mRCC but activity in IO refractory mRCC patients is still not well reported. Here we seek to report activity of Ipi/Nivo in IO refractory mRCC pts. Methods: In this retrospective review, we identified a total of 30 pts with mRCC from 4 academic medical centers across the USA who received salvage Ipi/Nivo after disease progression on IO therapy. Pts with only predominant clear cell histology were captured. Ipi/Nivo was administered as per CHECKMATE 214. Investigator-assessed response rate were noted. Immune related adverse events (irAE) were captured in accordance with CTCAE v5.0. Results: The baseline demographics included median age of 60 years (21-82), ECOG PS 0-2, and 73% (22) male and 27% (8) female. IMDC risk categories at the time of salvage Ipi/Nivo initiation were 23% (7), 60% (18) and 3% (1) with favorable, intermediate and poor risk, respectively. The median number of prior systemic therapies was 3 (1-6). Prior IO therapies included nivolumab monotherapy (14), avelumab plus axitinib (3), high dose interleukin-2 (3), pembrolizumab monotherapy (2) and Ipi/Nivo, nivolumab plus hypoxia inducible factor (HIF) inhibitor, atezolizumab plus interferon, atezolizumab monotherapy, pembrolizumab plus bevacizumab, pembrolizumab plus axitinib, varlilumab plus atezolizumab and an oral adenosine inhibitor (1 each). The median time on prior IO therapy was 7 months (1-50), best response was 3% (1) CR, 40% (12) PR, 23% (7) SD and 33% (10) PD. 73% (22) had restaging scans to assess response to ipi/nivo of which 17% (5), 3% (3) and 47% (14) showed PR, SD and, PD respectively. 37% (11) developed any grade irAEs and 6% (2) had grade ≥3 irAE including one patient with splenic rupture and one with rash and pneumonitis. Conclusions: Ipi/Nivo is feasible and safe in IO-refractory mRCC population with preliminary evidence of anti-tumor activity. Updated response data will be presented.

Overview of current and future systemic therapy for metastatic renal cell carcinoma.

Since the 2000s, there have been dramatic advances in the treatment of metastatic renal cell carcinoma (mRCC), including drugs targeting vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways. The first VEGF inhibitors approved for mRCC were sorafenib and sunitinib. Subsequently, two mTOR inhibitors (everolimus and temsirolimus) and other VEGF inhibitors (pazopanib and axitinib) were approved. Overall survival (OS) of mRCC patients has significantly increased during this period. Two novel VEGF inhibitors have recently been approved overseas, including cabozantinib and lenvatinib. Additionally, the recent advent of immunotherapy with checkpoint inhibitors has led to significant changes in the treatment of mRCC. The PD-1 inhibitor nivolumab improved the OS rate of patients with mRCC following VEGF inhibitors. Moreover, the CheckMate 214 trial demonstrated the benefit of nivolumab plus ipilimumab combination therapy in OS and objective response rate in treatment-naive intermediate- and poor-risk mRCC. In this review, current evidence related to the clinical use of targeted therapies and checkpoint inhibitors for the treatment of patients with mRCC is discussed. In addition, we review ongoing trials investigating combinations of checkpoint inhibitors with targeted agents and the identification of biomarkers to guide patient selection and enable individualization of therapy.

Immunotherapy Is Changing First-Line Treatment of Metastatic Renal-Cell Carcinoma.

The incidence of renal-cell carcinoma has been increasing each year, with nearly one third of new cases diagnosed at advanced or metastatic stage. The advent of targeted therapies for metastatic renal-cell carcinoma (mRCC) has underscored the need to subtype tumors according to tumor-immune expression profiles that may more reliably predict treatment outcomes. Over the past 2 decades, several vascular endothelial growth factor (VEGF) and tyrosine kinase inhibitors have been the mainstay for first- and second-line treatment of mRCC. Very recently, immunotherapy checkpoint inhibitors have significantly changed the treatment landscape for patients with mRCC, particularly for first-line treatment of intermediate to poor risk mRCC patients. Now, combination immunotherapy as well as combinations of immunotherapy with targeted agents can significantly alter disease outcomes. The field of immuno-oncology for mRCC has unveiled a deeper understanding of the immunoreactivity inherent to these tumors, and as a result combination therapy is evolving as a first-line modality. This review provides a timeline of advances and controversies in first-line treatment of mRCC, describes recent advances in understanding the immunoreactivity of these tumors, and addresses the future of combination anti-VEGF and immunotherapeutic platforms.

Ipilimumab in combination with nivolumab for the treatment of renal cell carcinoma

ABSTRACTIntroduction: Renal cell carcinoma (RCC) is a highly immunogenic neoplasm, and cytokine-based immunotherapies have been used for decades with limited success. In recent years, antibody-based immunotherapies targeting immune checkpoint receptors PD-1 and CTLA-4 have demonstrated clinical efficacy in metastatic RCC (mRCC) patients, leading to FDA approval of the combination of nivolumab and ipilimumab in treatment-naïve patients with intermediate- or poor-risk disease in April 2018.Areas covered: The pharmacodynamics and pharmacokinetics of nivolumab and ipilimumab are reviewed. Clinical safety and efficacy results from pivotal phase I and III trials of the combination of nivolumab plus ipilimumab in mRCC are summarized, and the combination is reviewed in the context of other available systemic therapies for RCC. Ongoing clinical studies involving the combination of nivolumab plus ipilimumab in RCC are discussed.Expert opinion: The combination of nivolumab and ipilimumab has demonstrated superior efficacy for treatment-naïve patients with intermediate- and poor-risk mRCC with clear cell histology and is likely to replace anti-angiogenic therapies as the treatment-of-choice in this patient population in the United States. Development of additional combination strategies, novel trial designs, and predictive biomarkers of response will be important to further optimize therapeutic selection and clinical outcomes.

The Rapidly Evolving Landscape of Immunotherapy in RCC

The Rapidly Evolving Landscape of Immunotherapy in RCC

Targeting bacteroides in the stool microbiome and response to treatment (Rx) with first-line VEGFTKI in metastatic renal cell carcinoma (mRCC).

584 Background: Diarrhea occurs in ~50% patients with mRCC receiving VEGFTKIs, and is a common cause of VEGFTKI Rx dose reductions/delays/interruptions. Stool bacteroides level directly correlates with diarrhea in these patients on Rx with VEGFTKI (Pal SK, Clinical Cancer Research 2015, PMID:26152743). Hypothesis was that mRCC patients on incidental antibiotics (ABX) which also target stool bacteroides will have less diarrhea, leading to improved Rx compliance, and improved outcomes on VEGFTKI. Methods: A retrospective study of mRCC patients with MSKCC intermediate or poor risk mRCC on 1st line VEGFRTKIs between 2005-2017. ABX usage was categorized by ABX bacteroides sensitivity at anytime during Rx with 1st line VEGFTKI along with the total number of days on ABX. 1st line VEGFRTKI progression free survival (PFS) was assessed by Kaplan-Meier and Cox proportional hazard models. Results: 145 patients with intermediate (n = 123, 85%) or poor risk (n = 22, 15%) mRCC on a VEGFTKI were identified. ABX were prescribed incidentally in 50 (34%) patients. 18 patients were prescribed ABX with bacteroides coverage of which 13 had ABX with high sensitivity for bacteroides. The median number of days supplied of all ABX was 7 (IQR 1-15 days). The median number of days supplied of ABX with bacteroides coverage was 6 (IQR 1.5-15.5 days). The median PFS in those prescribed ABX with bacteroides sensitivity was 18 months versus 8 months in those prescribed no ABX (p = 0.067), and 9 months in those prescribed ABX without bacteroides sensitivity. Duration of bacteroides ABX coverage resulted in a hazard ratio of 0.92 (95% CI 0.83-0.99, p = 0.043) for each additional day an ABX with bacteroides coverage was prescribed compared to those with no ABX. Conclusions: In these hypothesis generating data, incidental targeting of stool bacteroides with ABX correlated with improved PFS in mRCC patients on 1st line VEGFTKIs. Data need validation. Equal contribution: SAV, CDF, AWH

Improved survival rates in kidney cancer patients with brain metastases treated with modern multidisciplinary approaches.

601 Background: Brain metastases (BM) in RCC have been associated with poor overall survival. Systemic targeted and immunotherapy and the increasing use of stereotactic radiosurgery (SRS) is likely to improve outcomes. Methods: A retrospective database of mRCC patients treated at our institution between 2006 and 2015 was compiled and patients with BM identified. Overall survival (OS) was analyzed by the Kaplan-Meier method. BM patients were compared to non-BM patients after adjusting for the timing of BM diagnosis, either prior to or during 1st line systemic therapy (ST). Results: 56 of 248 mRCC patients (22.6%) were diagnosed with BM, 35 (62.5%) prior to and 21 (37.5%) during 1st line ST. 43/56 (77%) received definitive local therapy for BM (surgery 10, SRS 26, or both 7). 9 received WBRT only and 4 had no CNS-directed therapy. All patients received ST. The median OS for ST-naïve BM patients compared with non-BM patients was 19.5 vs. 28.7 months (p = 0.012). Survival for patients developing BM on 1st-line therapy was not significantly different from patients without BM progressing on 1st line ST (11.8 vs. 17.8 months, p = 0.66). BM patients with poor risk mRCC by IMDC criteria did worse than those without BM regardless of line of therapy. Conclusions: Survival for patients with BM and favorable or intermediate risk mRCC is significantly better than historical reports and similar to non-BM patients in our population which was heavily treated with both systemic and local therapies. Patients with BM and poor risk RCC had significantly worse survival, suggesting that risk group should be considered when counseling on prognosis and selecting treatment. [Table: see text]

Characterization of patients (pts) with poor risk metastatic renal cell carcinoma (mRCC): Results from a pooled clinical trials database.

515 Background: Survival outcomes are heterogeneous across different subsets of mRCC pts. Poor risk pts have grim outcomes and are less likely to be enrolled in clinical trials, hence the lack of prospective data characterizing this pt population. We provide a comprehensive analysis of poor risk pts, as defined by three widely used prognostic models, in the era of targeted therapy. Methods: We conducted a pooled retrospective analysis of 4,736 mRCC pts treated on phase II and III clinical trials. Pts were defined as poor risk according to the Memorial Sloan Kettering Cancer Center (MSKCC), International Metastatic Database Consortium (IMDC), and Hudes prognostic risk models. We evaluated overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) in poor risk pts in each of the risk models in the total cohort and in a subset of pts who remained on treatment for >12 months (mos). The models’ concordance (c-) index was used to assess their prognostic performance. Results: We identified 1145 (24.2%), 904 (19.1%), and 1901 (40.1%) poor risk pts by IMDC, MSKCC, and Hudes models, respectively. The majority were <65 years of age (70-73%) with clear-cell histology (85-88%), prior nephrectomy (62-66%), and no prior systemic therapy (80-86%). The efficacy and toxicity outcomes as well as the c-indexes for each of the models are reported in the table below. Additionally, 9-14% of poor risk pts remained on therapy for >12 mos and had higher OS (29.8-35.2 mos) and ORR (42-53%). Conclusions: In this large database of poor risk mRCC pts, we highlight that the models have similar predictive accuracy in the targeted therapy era. We also demonstrate that poor risk pts continue to have dismal outcomes and should be considered for trials of novel agents and combinations. A subset of these pts appears to derive prolonged clinical benefit and should be further explored.[Table: see text]

Tumor Mutational Load and Immune Parameters across Metastatic Renal Cell Carcinoma Risk Groups.

Patients with metastatic renal cell carcinoma (mRCC) have better overall survival when treated with nivolumab, a cancer immunotherapy that targets the immune checkpoint inhibitor programmed cell death 1 (PD-1), rather than everolimus (a chemical inhibitor of mTOR and immunosuppressant). Poor-risk mRCC patients treated with nivolumab seemed to experience the greatest overall survival benefit, compared with patients with favorable or intermediate risk, in an analysis of the CheckMate-025 trial subgroup of the Memorial Sloan Kettering Cancer Center (MSKCC) prognostic risk groups. Here, we explore whether tumor mutational load and RNA expression of specific immune parameters could be segregated by prognostic MSKCC risk strata and explain the survival seen in the poor-risk group. We queried whole-exome transcriptome data in renal cell carcinoma patients (n = 54) included in The Cancer Genome Atlas who ultimately developed metastatic disease or were diagnosed with metastatic disease at presentation and did not receive immune checkpoint inhibitors. Nonsynonymous mutational load did not differ significantly by the MSKCC risk group, nor was the expression of cytolytic genes-granzyme A and perforin-or selected immune checkpoint molecules different across MSKCC risk groups. In conclusion, this analysis revealed that mutational load and expression of markers of an active tumor microenvironment did not correlate with MSKCC risk prognostic classification in mRCC. Cancer Immunol Res; 4(10); 820-2. ©2016 AACR.

Management of poor-risk metastatic renal cell carcinoma: current approaches, the role of temsirolimus and future directions.

Targeted therapies have substantially improved outcomes in metastatic renal cell carcinoma (mRCC). As expected, poor-risk patients have the worst outcomes. Temsirolimus is currently the only agent licensed for treatment of poor-risk mRCC patients. It is associated with meaningful improvements in survival and quality of life, highlighting the importance of correctly stratifying risk in mRCC patients so they receive optimal treatment. Currently, data for other targeted therapies in poor-risk patients are relatively sparse. Optimizing outcomes in these patients is the subject of ongoing research, including studies of biomarkers and studies to elucidate the role of nephrectomy and neoadjuvant targeted therapy in poor-risk mRCC patients. The impacts of novel combinations including temsirolimus have also been explored to further improve outcomes.

Survival with AGS-003, an autologous dendritic cell-based immunotherapy, in combination with sunitinib in unfavorable risk patients with advanced renal cell carcinoma (RCC): Phase 2 study results.

BackgroundAGS-003 is an autologous immunotherapy prepared from fully matured and optimized monocyte-derived dendritic cells, which are co-electroporated with amplified tumor RNA plus synthetic CD40L RNA. AGS-003 was evaluated in combination with sunitinib in an open label phase 2 study in intermediate and poor risk, treatment naïve patients with metastatic clear cell renal cell carcinoma (mRCC).MethodsTwenty-one intermediate and poor risk patients were treated continuously with sunitinib (4 weeks on, 2 weeks off per 6 week cycle). After completion of the first cycle of sunitinib, patients were treated with AGS-003 every 3 weeks for 5 doses, then every 12 weeks until progression or end of study. The primary endpoint was to determine the complete response rate. Secondary endpoints included clinical benefit, safety, progression free survival (PFS) and overall survival (OS). Immunologic response was also monitored.ResultsThirteen patients (62%) experienced clinical benefit (9 partial responses, 4 with stable disease); however there were no complete responses in this group of intermediate and poor risk mRCC patients and enrollment was terminated early. Median PFS from registration was 11.2 months (95% CI 6.0, 19.4) and the median OS from registration was 30.2 months (95% CI 9.4, 57.1) for all patients. Seven (33%) patients survived for at least 4.5 years, while five (24%) survived for more than 5 years, including 2 patients who remain progression-free with durable responses for more than 5 years at the time of this report. AGS-003 was well tolerated with only mild injection-site reactions. The most common adverse events were related to expected toxicity from sunitinib therapy. In patients who had sequential samples available for immune monitoring, the magnitude of the increase in the absolute number of CD8+ CD28+ CD45RA− effector/memory T cells (CTLs) after 5 doses of AGS-003 relative to baseline, correlated with overall survival.ConclusionsAGS-003 in combination with sunitinib was well tolerated and yielded supportive immunologic responses coupled with extension of median and long-term survival in an unselected, intermediate and poor risk prognosis mRCC population.Clinical Trial Registry#NCT00678119

837P - Poor Risk Metastatic Renal Cell Carcinoma (Mrcc) Patients are not a Homogeneous Group: a New Stratificating Model in the Era of Targeted Therapy

ABSTRACT Aim: The prognostic stratification of poor risk mRCC patients in the era of targeted therapy represents an unmet medical need. We analyzed, individually, each prognostic factor included in modified Memorial Sloan-Kettering Cancer Center (MSKCC) and Heng criteria to investigate their prognostic relevance in poor risk mRCC patients and proposed a model to stratify poor risk patients into 3 separate subgroups. Methods: Data were collected from 20 Italian and 2 Spanish centers. Overall survival (OS) was estimated using Kaplan-Meier method. Hemoglobin, Performance Status, Thrombocytosis, Neutrophilia, Number of metastatic sites, Time from diagnosis to treatment, LDH and Hypercalcemia, according to modified MSKCC and Heng criteria, were included in the Cox analysis. Results: 239 (151 males; 205 clear cell) poor risk mRCC pts were enrolled according to, at least, three of MSKCC, or modified MSKCC or Heng criteria. 233 pts were treated with a first line therapy (56 pts with temsirolimus, 163 pts with tyrosine kinase inhibitors (TKI), 14 pts with other agents); 101 pts with a second line (50 everolimus, 49 TKI, 2 other agents) and 31 pts with a third line ( 4 everolimus; 20 TKI, 7 other agents). Only Hemoglobin (13 vs 8 months; p = 0.005), Performance Status (14 vs 7 months; p = 0.002), and Time from diagnosis to treatment (22 vs. 8 months; p Conclusions: This is the first study that identifies three different prognostic subgroups among poor risk RCC patients. Kaplan Meier survival curves of each subgroup will be presented during the meeting. Disclosure: All authors have declared no conflicts of interest.

A proposed new model for prognostic stratification of poor-risk patients with metastatic renal cell carcinoma (mRCC) in the era of targeted therapy.

e15588 Background: The stratification of poor risk mRCC patients in the era of targeted therapy represents an unmet medical need. We analyzed, individually, each prognostic factor included in modif...

Experience with sunitinib in the treatment of metastatic renal cell carcinoma

Following approval of the oral, multitargeted tyrosine kinase inhibitor sunitinib malate for the treatment of patients with metastatic renal cell carcinoma (mRCC) in Europe and the USA in 2006, the agent has had a substantial impact on the treatment landscape in this setting. Sunitinib is now recommended in international treatment guidelines for the first-line treatment of favourable- or intermediate-risk mRCC and as an alternative option in poor-risk mRCC. In the 6 years since the approval of sunitinib, the range of agents available for the treatment of mRCC has expanded substantially, and this, together with a number of additional therapies in late-stage development, has increased the treatment options available to patients. Results from a phase III trial and a global expanded access study have provided robust data to support the efficacy of sunitinib in mRCC, including in real-world populations. Data also suggest a significant quality of life benefit with sunitinib, with superior patient-reported outcomes observed with this agent compared with interferon-α therapy. Both clinical and real-world study data also support the safety profile of sunitinib; most treatment-associated adverse events are mild to moderate in severity and can be managed effectively with close monitoring and proactive management. Clinical experience with sunitinib has demonstrated that therapy management, involving optimal dosing, maximum treatment duration and prompt and effective adverse event management, supports optimal patient outcomes with sunitinib. In this review we discuss clinical experience with sunitinib in mRCC, with an emphasis on real-world data, and utilize clinical case studies to examine the successful implementation of therapy management strategies for optimal patient outcomes. An increasing body of evidence suggests that side effects associated with sunitinib therapy, including hypertension, hand-foot syndrome and hypothyroidism, may represent effective markers of treatment response, and these will also be discussed.

Another Step Toward the Cure of Metastatic Renal Cell Carcinoma?

Another Step Toward the Cure of Metastatic Renal Cell Carcinoma?

Phase II trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma.

e15076 Background: Sunitinib is a standard front-line treatment for metastatic renal cell carcinoma (mRCC) patients (pts), but is not proven to be beneficial in pts with poor-risk clinical features or sarcomatoid histology. These two populations of mRCC pts typically have short median survival. We are conducting a phase 2 study of combination treatment with sunitinib and gemcitabine in clinical or pathologic poor-risk mRCC. Methods: Eligible pts with mRCC have either elements of sarcomatoid histology or poor-risk disease by modified clinical criteria (3 or more of the following: ECOG PS > 1, time from diagnosis to treatment < 12 months, anemia, hypercalcemia, LDH ≥ 1.5 normal, or ≥ 2 sites of disease). Treatment consists of 21-day cycles of sunitinib 37.5 mg daily (2 weeks on, 1 week off), and gemcitabine 1000 mg/m2 on days 1 and 8. Pts may have received no more than one prior therapy for mRCC. A total of 36 pts will be enrolled, and the primary endpoint is radiographic response rate by RECIST. Secondary endpoints include progression free survival (PFS), safety and tolerability, and overall survival. Results: Twenty five pts have been treated to date. Of these, 13 were eligible due to sarcomatoid histology, and the remaining pts were eligible based on clinical poor-risk criteria. Among 20 patients evaluable for response, 5 had confirmed partial response (25%), including 3 with sarcomatoid histology, and an additional 10/20 exhibited stable disease for ≥ 12 weeks (50%). None of 5 pts with underlying papillary or chromophobe RCC histology has responded. Median PFS is 4.6 months among the patients with sarcomatoid RCC (range 2-12 months), 5.9 months among clinical poor- risk pts (range: 1-8 months), and 4.8 months overall. Five pts have been removed from study due to adverse events, including fatigue, hemolytic anemia, renal dysfunction, and cumulative grade 2 toxicities. Median overall survival has not been reached. Conclusions: Treatment of mRCC pts with sarcomatoid histology or clinical poor-risk features using a combination regimen of sunitinib and gemcitabine results in a clinical benefit rate of 75% and PFS of 4.8 months. Further prospective study of this regimen is warranted in these subpopulations of mRCC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories, Aggenix, Antigenics, AVEO, Bayer, Genentech, GlaxoSmithKline, Novartis, Onyx, Pfizer, Roche, Wyeth Pfizer, Wyeth Amgen, Bayer, Genentech, Novartis, Pfizer

Treatment Options in Metastatic Renal Cell Carcinoma: Focus on mTOR Inhibitors.

THE AGENTS CURRENTLY APPROVED FOR USE IN METASTATIC RENAL CELL CARCINOMA (MRCC) CAN BE DIVIDED BROADLY INTO TWO CATEGORIES: (1) vascular endothelial growth factor receptor (VEGFR)-directed therapies or (2) inhibitors of the mammalian target of rapamycin (mTOR). The latter category includes everolimus and temsirolimus, both approved for distinct indications in mRCC. Everolimus gained its approval on the basis of phase III data showing a benefit in progression-free survival relative to placebo in patients previously treated with sunitinib and/or sorafenib. In contrast, temsirolimus was approved on the basis of a phase III trial in treatment-naïve patients with poor-risk mRCC, demonstrating an improvement in overall survival relative to interferon-alfa. While these pivotal trials have created unique positions for everolimus and temsirolimus in current clinical algorithms, the role of mTOR inhibitors in mRCC is being steadily revised and expanded through ongoing trials testing novel sequences and combinations. The clinical development of mTOR inhibitors is outlined herein.

Temsirolimus (TEM) in metastatic renal cell carcinoma (mRCC): Safety and efficacy in patients (pts) previously treated with VEGF-targeted therapy

16067 Background: TEM is a selective inhibitor of mTOR, a regulator of cell proliferation, growth and survival, approved for advanced RCC based on a phase III trial in untreated poor-risk mRCC. TEM...