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Background Non-clear cell renal cell carcinoma (nccRCC) accounts for ≤20% of RCC cases. Lenvatinib (a multitargeted tyrosine kinase inhibitor) in combination with everolimus (an mTOR inhibitor) is approved for the treatment of advanced RCC after one prior antiangiogenic therapy. Objective To determine the safety and efficacy of lenvatinib plus everolimus as a first-line treatment for patients with advanced nccRCC. Design, setting, and participants This open-label, single-arm, multicenter, phase 2 study enrolled patients with unresectable advanced or metastatic nccRCC and no prior anticancer therapy for advanced disease. Intervention Lenvatinib (18 mg) plus everolimus (5 mg) orally once daily. Outcome measurements and statistical analysis The primary endpoint was the objective response rate (ORR) as assessed by investigators according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety assessments. The 95% confidence intervals (CIs) for ORRs were calculated using the two-sided Clopper-Pearson method. Median PFS and median OS were estimated using the Kaplan-Meier product-limit method and their 95% CIs were estimated via a generalized Brookmeyer and Crowley method. Results and limitations The study (start date: February 20, 2017) enrolled 31 patients with nccRCC (papillary, n = 20; chromophobe, n = 9; unclassified, n = 2). At the data cutoff date (July 17, 2019), the best overall response was a partial response (eight patients: papillary, n = 3; chromophobe, n = 4; unclassified, n = 1) for an overall ORR of 26% (95% CI 12–45). Median PFS was 9.2 mo (95% CI 5.5–not estimable), and median OS was 15.6 mo (95% CI 9.2–not estimable). The most common treatment-emergent adverse events were fatigue (71%), diarrhea (58%), decreased appetite (55%), nausea (55%), and vomiting (52%). Limitations include the small sample size and single-arm design. Conclusions Lenvatinib plus everolimus showed promising anticancer activity in patients with advanced nccRCC with an ORR of 26% and is worthy of further study. The safety profile was consistent with the established profile of the study-drug combination. Patient summary We examined the combination of lenvatinib plus everolimus as the first therapy for 31 patients who had advanced nccRCC. We found that this treatment seemed effective, because most patients had a decrease in tumor size and manageable treatment-related side effects. Clinical registration This trial is registered at ClinicalTrials.Gov as NCT02915783.

Hypoxia-inducible factor-2α (HIF-2α) is a transcription factor that frequently accumulates in clear cell renal cell carcinoma (ccRCC), resulting in constitutive activation of genes involved in carcinogenesis. Belzutifan (MK-6482, previously known as PT2977) is a potent, selective small molecule inhibitor of HIF-2α. Maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of belzutifan were evaluated in this first-in-human phase 1 study (NCT02974738). Patients had advanced solid tumors (dose-escalation cohort) or previously treated advanced ccRCC (dose-expansion cohort). Belzutifan was administered orally using a 3 + 3 dose-escalation design, followed by expansion at the recommended phase 2 dose (RP2D) in patients with ccRCC. In the dose-escalation cohort (n = 43), no dose-limiting toxicities occurred at doses up to 160 mg once daily, and the maximum tolerated dose was not reached; the RP2D was 120 mg once daily. Plasma erythropoietin reductions were observed at all doses; erythropoietin concentrations correlated with plasma concentrations of belzutifan. In patients with ccRCC who received 120 mg once daily (n = 55), the confirmed objective response rate was 25% (all partial responses), and the median progression-free survival was 14.5 months. The most common grade ≥3 adverse events were anemia (27%) and hypoxia (16%). Belzutifan was well tolerated and demonstrated preliminary anti-tumor activity in heavily pre-treated patients, suggesting that HIF-2α inhibition might offer an effective treatment for ccRCC. A first-in-human trial of hypoxia-inducible factor (HIF)-2α inhibitor belzutifan (MK-6482) has a favorable safety profile and shows promising clinical activity for the treatment of patients with renal cell carcinoma who have been heavily pre-treated.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to certain systemic therapy recommendations for patients with relapsed or stage IV RCC. They also discuss the addition of a new section to the guidelines that identifies and describes the most common hereditary RCC syndromes and provides recommendations for genetic testing, surveillance, and/or treatment options for patients who are suspected or confirmed to have one of these syndromes.

A number of therapeutic options are available for the treatment of advanced kidney cancer, including targeted therapy, immunotherapy, and nephrectomy. Choice of therapy for advanced kidney cancer is guided by risk stratification. Immunotherapy combinations are generally superior to vascular endothelial growth factor -based monotherapy, and overall survival rates continue to increase substantially. With new systemic therapy options, additional improvements have been noted in durable responses to treatment and in quality of life. Nephrectomy remains an important consideration in selected patients, particularly those with minimal burden of metastatic disease. Managing the adverse events of treatment of advanced kidney cancer requires close attention and multidisciplinary collaboration.

Aim: To assess the cost–effectiveness of treatment sequences for patients with intermediate- to poor-risk advanced renal cell carcinoma. Patients & methods: A discrete event simulation model was developed to estimate patients’ lifetime costs and survival. Efficacy inputs were derived from the CheckMate 214 and CheckMate 025 studies and network meta-analyses. Safety and cost data were obtained from the published literature. Results: The estimated average quality-adjusted life-years (QALYs) gained was the highest on nivolumab + ipilimumab-initiated sequences (3.6–5.3 QALYs) versus tyrosine kinase inhibitor (TKI)-initiated sequences (2.1–3.7 QALYs). Incremental cost per QALY gained for nivolumab + ipilimumab-initiated sequences was below the willingness-to-pay threshold of $150,000 versus other sequences. Conclusion: Immuno-oncology combination therapy followed by TKIs is cost-effective versus TKI sequences followed by immuno-oncology or sequencing TKIs.

Objective: Compare FDG-PET/CT, CT, and bone scan for detecting and monitoring bone metastases’ response in metastatic renal cell cancer (mRCC). Methods: Patients with mRCC prospectively underwent FDG-PET/CT, CT, and bone scans at baseline and after 8 weeks of therapy. Tumor visibility and metabolic activity were retrospectively recorded. Response was evaluated by PERCIST, RECIST, and MD Anderson bone criteria. Kaplan-Meier methodology estimated event-time distributions for PFS, OS, and time to symptomatic skeletal event (SSE). Log-rank test tested differences in event-time distributions between response at 8 weeks by response criteria. Results: Sixteen patients (n = 30; 53%) were evaluable. Baseline FDG-PET/CT detected more osseous metastases (n = 55) than CT (n = 45) or bone scan (n = 34). From baseline to 8 weeks, metabolic activity of lesions decreased >20%, while qualitative and quantitative CT and bone scan parameters were unchanged for most patients. Partial metabolic responders by PERCIST had longer PFS and OS (n = 5, 20+ months) versus those with stable (n = 9; PFS = 9.2 mos, OS = 8.7 mos) and progressive (n = 2; PFS = 5.4 mos, OS = 12.1 mos) metabolic disease, p = 0.09 and 0.42, respectively. By RECIST, longer PFS and OS was seen for stable (n = 12, PFS = 8.3 mos, OS = 17.7 mos) versus progressive (n = 4; PFS = 3.7 mos, OS = 7.5 mos) disease, p = 0.16, 0.02, respectively. OS was not reached, but estimated ≥20 mos, for 4 patients with RECIST SD and PERCIST PMR, compared to OS of 17.7 mos for other patients with RECIST SD. Conclusions: FDG-PET/CT identified more bone metastases and greater numbers of quantitative and qualitative treatment responses in mRCC compared to CT and bone scan. FDG-PET/CT also may identify a sub-group of patients with better outcomes than predicted by standard imaging modalities.

The phase II CABOSUN trial compared cabozantinib with sunitinib as initial treatment in patients with advanced renal cell carcinoma of intermediate or poor risk. This article presents subgroup analyses by baseline patient characteristics., Cabozantinib treatment prolonged progression‐free survival (PFS) and improved objective response rate (ORR) compared with sunitinib in patients with advanced renal cell carcinoma (RCC) of intermediate or poor risk by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria in the phase II CABOSUN trial (NCT01835158). In the trial, 157 patients were randomized 1:1 to receive cabozantinib or sunitinib, stratified by IMDC risk group and presence of bone metastases. Here, PFS and ORR, both determined by independent radiology committee (IRC), were analyzed by subgroups of baseline characteristics. Cabozantinib treatment was generally associated with improved PFS and ORR versus sunitinib across subgroups, including in groups defined by IMDC risk group, bone metastases, age, and tumor burden. Clinical trial identification number. NCT01835158.

Background TRC105 is an IgG1 endoglin monoclonal antibody that potentiates VEGF inhibitors in preclinical models. We assessed safety, pharmacokinetics, and antitumor activity of TRC105 in combination with axitinib in patients with metastatic renal cell carcinoma (mRCC). Subjects, Materials, and Methods Heavily pretreated mRCC patients were treated with TRC105 weekly (8 mg/kg and then 10 mg/kg) in combination with axitinib (initially at 5 mg b.i.d. and then escalated per patient tolerance to a maximum of 10 mg b.i.d.) until disease progression or unacceptable toxicity using a standard 3 + 3 phase I design. Results Eighteen patients (median number of prior therapies = 3) were treated. TRC105 dose escalation proceeded to 10 mg/kg weekly without dose-limiting toxicity. Adverse event characteristics of each drug were not increased in frequency or severity when the two drugs were administered concurrently. TRC105 and axitinib demonstrated preliminary evidence of activity, including partial responses (PR) by RECIST in 29% of patients, and median progression-free survival (11.3 months). None of the patients with PR had PR to prior first-line treatment. Lower baseline levels of osteopontin and higher baseline levels of TGF-β receptor 3 correlated with overall response rate. Conclusion TRC105 at 8 and 10 mg/kg weekly was well tolerated in combination with axitinib, with encouraging evidence of activity in patients with mRCC. A multicenter, randomized phase II trial of TRC105 and axitinib has recently completed enrollment (NCT01806064). Implications for Practice TRC105 is a monoclonal antibody to endoglin (CD105), a receptor densely expressed on proliferating endothelial cells and also on renal cancer stem cells that is implicated as a mediator of resistance to inhibitors of the VEGF pathway. In this Phase I trial, TRC105 combined safely with axitinib at the recommended single agent doses of each drug in patients with renal cell carcinoma. The combination demonstrated durable activity in a VEGF inhibitor-refractory population and modulated several angiogenic biomarkers. A randomized Phase II trial testing TRC105 in combination with axitinib in clear cell renal cell carcinoma has completed accrual.

Combination therapies involving antiangiogenic agents plus immune checkpoint inhibitors have recently demonstrated clinical efficacy in advanced renal cell carcinoma (RCC). This commentary summarizes the clinical advances and reviews the potential implications for RCC and other advanced solid tumors.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non-clear cell renal carcinoma. These guidelines are developed by a multidisciplinary panel of leading experts from NCCN Member Institutions consisting of medical oncologists, hematologists and hematologic oncologists, radiation oncologists, urologists, and pathologists. The NCCN Guidelines are in continuous evolution and are updated annually or sometimes more often, if new high-quality clinical data become available in the interim.

Purpose Bladder preservation therapy is an effective treatment for muscle-invasive urothelial carcinoma (UC). In this study we treated noncystectomy candidates with daily radiation and weekly paclitaxel for 7 weeks. Patients whose tumors showed her2/neu overexpression were additionally treated with weekly trastuzumab. Methods and Materials Sixty-eight evaluable patients were treated with radiation therapy and either paclitaxel + trastuzumab (group 1) or paclitaxel alone (group 2). Groups were assigned on the basis of her2/neu immunohistochemistry results. Patients received 1.8-Gy fractions to a total dose of 64.8 Gy. The primary endpoint of the study was treatment-related toxicity, and secondary endpoints included complete response (CR) rate, protocol completion rate, and survival. Results A total of 20 evaluable patients were treated in group 1 and 46 patients in group 2. Acute treatment-related adverse events (AEs) were observed in 7 of 20 patients in group 1 (35%) and 14 of 46 patients in group 2 (30.4%). Protocol therapy was completed by 60% (group 1) and 74% (group 2) of patients. Most incompletions were due to toxicity, and the majority of AEs were gastrointestinal, including 1 grade 5 AE (group 1). Two other deaths (both in group 2) were unrelated to protocol therapy. No unexpected cardiac, hematologic, or other toxicities were observed. The CR rate at 1 year was 72% for group 1 and 68% for group 2. Conclusions In patients with muscle-invasive UC who are not candidates for cystectomy, daily radiation combined with paclitaxel is an effective treatment strategy with a high completion rate and moderate toxicity. In patients with her2/neu-positive tumors, a group generally considered to have worse outcomes, the addition of trastuzumab appears to result in comparable efficacy and toxicity. Further biomarker-driven trials should be undertaken in advancing treatment of this challenging disease.

We conducted a retrospective analysis of two clinical trials in treatment-naïve patients (n = 402) with advanced renal cell carcinoma (RCC) treated with axitinib. Our objective was to compare duration of treatment (DT) and clinical outcome in patients who achieved DT18 months (longer DT) versus ≤18 months (shorter DT).DT, objective response rate (ORR), tumor shrinkage, and overall survival (OS) were summarized for patients with longer and shorter DT.Overall, 152 patients (37.8%) had longer DT and 250 (62.2%) had shorter DT (median, 34.7 vs. 6.5 months, respectively). ORR in all 402 patients with advanced RCC was 43.5%. ORR was 75% for longer DT versus 24.4% for shorter DT (p 0.0001). More patients with longer DT versus shorter DT had ≥10% tumor shrinkage at first scan (74.8% vs. 55.3%; p = 0.0001) and maximum on-study tumor shrinkage was greater in longer-DT versus shorter-DT group (-51.8% vs. -22.1%; p 0.0001). Median OS was 32.6 months in the overall population while in the patients with longer DT the median was not reached. Treatment-related adverse events (AEs) grade ≥3 were more frequent in longer-DT versus shorter-DT and included hypertension (25.7% vs. 18.8%), diarrhea (15.1% vs. 4.4%), and weight decrease (11.2% vs. 3.2%); however, these AEs decreased over time in both groups. Eastern Cooperative Oncology Group performance status 0, favorable hematology values, no bone or liver metastases, and baseline tumor burden below the overall median were associated with longer DT.Longer duration (18 months) of axitinib treatment was associated with increased frequency of early tumor shrinkage, greater magnitude of tumor shrinkage, and a favorable OS.

This book is the first and only study on implementing Universal Health Coverage in poor, rural and informal settings, with end-to-end guidance for rolling out a demand-driven and needs-based health insurance model. The chapters are comprehensive, covering topics such as data collection and analysis for contextual risk assessment, the design of suitable benefits packages, how to price microinsurance, insurance education for illiterate or innumerate populations, the setting up of governance bodies and training staff for key roles, and information management.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non–clear cell renal cell carcinoma, and are intended to assist with clinical decision-making. These NCCN Guidelines Insights summarize the NCCN Kidney Cancer Panel discussions for the 2020 update to the guidelines regarding initial management and first-line systemic therapy options for patients with advanced clear cell renal cell carcinoma.

Improving early cancer detection has the potential to substantially reduce cancer-related mortality. Cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) is a highly sensitive assay capable of detecting early-stage tumors. We report accurate classification of patients across all stages of renal cell carcinoma (RCC) in plasma (area under the receiver operating characteristic (AUROC) curve of 0.99) and demonstrate the validity of this assay to identify patients with RCC using urine cell-free DNA (cfDNA; AUROC of 0.86).

4507 Background: Cisplatin with gemcitabine (CG) remains the standard upfront chemotherapy regimen for metastatic urothelial cancer (mUC). Preclinical synergy was noted between cisplatin and berzosertib, a selective ATR inhibitor. The current study sought to determine if the combination of berzosertib and CG could improve clinical outcomes in mUC. Methods: An open-label, randomized study was conducted across 23 centers in the United States through the Experimental Therapeutics Clinical Trials Network of the National Cancer Institute. Key eligibility criteria included confirmed mUC, no prior cytotoxic therapy for metastatic disease, ≥ 12 months since perioperative therapy and eligibility for cisplatin based on standard criteria. Patients (pts) were randomized to receive either CG alone (control arm) or CG plus berzosertib (experimental arm). In the control arm, 70 mg/m2 of cisplatin was given on day 1 and gemcitabine at 1000 mg/m2 on days 1 and 8 of a 21-day cycle. In the experimental arm, 60 mg/m2 of cisplatin was given on day 1, gemcitabine at 875 mg/m2 on days 1 and 8 and berzosertib at 90 mg/m2 on days 2 and 9 of a 21-day cycle. The primary endpoint of the study was progression-free survival (PFS), with secondary endpoints including response rate (RR), overall survival (OS) and toxicity. Results: A total of 87 pts (median age 67; M:F 68:19) were randomized; 41 pts received CG alone while 46 received CG with berzosertib. Visceral metastases were present in 49% of pts and 52%, 45% and 3% of pts were Bajorin risk 0, 1 and 2, respectively. Median PFS was 8.0 months for both arms (Bajorin risk adjusted hazard ratio [HR] 1.22, 95% confidence interval [CI] 0.72-2.08). RR was 54%(4 CR, 21 PR) in the CG with berzosertib arm and 63% (4 CR, 22 PR) in CG alone arm (P = 0.66). Median OS was shorter with CG with berzosertib as compared to CG alone (14.4 versus 19.8 months; Bajorin risk adjusted HR 1.42, 95%CI 0.76-2.68). Notably higher rates of grade 3/4 thrombocytopenia (59% vs 39%) and neutropenia (37% vs 27%) were observed with CG plus berzosertib compared to CG alone. Higher rates of toxicity-related discontinuation were seen in the experimental arm (24% vs 15%), and the median cumulative cisplatin dose in the experimental arm was 250 mg/m2, as compared to 370 mg/m2 in the control arm (P < 0.001). Conclusions: No improvement in PFS was observed with the addition of berzosertib to CG, and a trend towards inferior survival was observed. These results suggest caution in reducing the starting dose of cytotoxic therapy to accommodate addition of a myelosuppressive agent, as in the experimental arm of this study. Clinical trial information: NCT02567409.

Purpose Cabozantinib is an oral potent inhibitor of vascular endothelial growth factor receptor 2, MET, and AXL and is a standard second-line therapy for metastatic renal cell carcinoma (mRCC). This randomized phase II multicenter trial evaluated cabozantinib compared with sunitinib as first-line therapy in patients with mRCC. Patients and Methods Eligible patients had untreated clear cell mRCC and Eastern Cooperative Oncology Group performance status of 0 to 2 and were intermediate or poor risk per International Metastatic Renal Cell Carcinoma Database Consortium criteria. Patients were randomly assigned at a one-to-one ratio to cabozantinib (60 mg once per day) or sunitinib (50 mg once per day; 4 weeks on, 2 weeks off). Progression-free survival (PFS) was the primary end point. Objective response rate (ORR), overall survival, and safety were secondary end points. Results From July 2013 to April 2015, 157 patients were randomly assigned (cabozantinib, n = 79; sunitinib, n = 78). Compared with sunitinib, cabozantinib treatment significantly increased median PFS (8.2 v 5.6 months) and was associated with a 34% reduction in rate of progression or death (adjusted hazard ratio, 0.66; 95% CI, 0.46 to 0.95; one-sided P = .012). ORR was 33% (95% CI, 23% to 44%) for cabozantinib versus 12% (95% CI, 5.4% to 21%) for sunitinib. All-causality grade 3 or 4 adverse events were 67% for cabozantinib and 68% for sunitinib and included diarrhea (cabozantinib, 10% v sunitinib, 11%), fatigue (6% v 15%), hypertension (28% v 22%), palmar-plantar erythrodysesthesia (8% v 4%), and hematologic adverse events (3% v 22%). Conclusion Cabozantinib demonstrated a significant clinical benefit in PFS and ORR over standard-of-care sunitinib as first-line therapy in patients with intermediate- or poor-risk mRCC.

We model the impact of agricultural droughts with a new multi-parameter index (using both climatic and non-climatic parameters) and propose a new risk transfer solution for crop insurance, called Climate Cost of Cultivation (CCC). We used 1979/80 to 2012/13 data relevant for wheat in Bihar, India to test the variation in the CCC values. The variance (risk to farmer) increased significantly in the second half of the period (two-tailed F-test, p=0.00045). We examine the efficiency of CCC by comparing it to typical index insurance (TII), and both indices to wheat yield data (2000/01 to 2012/13). The correlation of CCC index payouts with actual yield losses is improved by a factor of ~3.9 over TII results (76.0 per cent, compared with 19.6 per cent). The pure risk premium of the CCC index is lower by around 90 per cent than the premium of the TII. We also elaborate a method to quantify the premium’s climate change cost component.

42 Background: Patients with advanced genitourinary (GU) cancers are often hospitalized for complications of their cancer and symptom management. Yet, little is known about the symptom burden, functional status, and health care utilization of these patients. Methods: We prospectively enrolled patients with advanced cancer who experienced unplanned hospitalizations at an academic medical center. Upon admission, we asked patients to self-report their physical (Edmonton Symptom Assessment Scale-revised [ESAS-r]) and psychological (Patient Health Questionnaire-4 [PHQ-4]) symptoms. We also collected data from nursing assessments about impairments in activities of daily living (ADLs). We compared symptoms, functional impairment, readmissions, and overall survival (OS) between cancer types (dichotomizing GU cancers vs other cancer types) and within GU cancers (dichotomizing prostate cancer vs kidney/bladder/adrenal cancer) using univariate and multivariable regression analyses adjusted for age, sex, education, comorbidities, and time since advanced cancer diagnosis. Results: Among 971 patients enrolled, 106 (10.9%) had advanced GU cancers (39.6% prostate cancer, 32.1% kidney cancer, 25.5% bladder cancer, and 2.8% adrenal cancer). Compared to patients with other cancer types, patients with GU cancers were older (median: 69.0 vs 64.0 years, p < 0.001) and had more time since advanced cancer diagnosis (median: 14.0 vs 7.0 months, p < 0.001). In univariate analyses, a greater proportion of patients with GU cancers had an ADL impairment (57.5% vs 38.0%, p < 0.001) compared to other cancer types but the groups did not differ in their physical (Mean = 33.3 vs 32.6, p = 0.61) or depression (Mean = 4.1 vs 3.3, p = 0.05) symptoms. In multivariable models, patients with GU cancers had similar risk of readmission in 90 days (HR 1.31, p = 0.077), but worse survival (median OS: 102.0 days vs 133.5 days, p < 0.001; HR 1.27, p = 0.046). Within GU cancers, patients with kidney/bladder/adrenal cancer (vs. prostate cancer) were younger (median: 66.0 vs 74.0, p < 0.001) with less time since advanced cancer diagnosis (median: 9.0 vs 23.0 months, p = 0.012) but had no difference in symptoms or functional impairment. They were more likely to be admitted for symptom management (66% vs. 39% for prostate cancer, p = 0.026). Patients with kidney/bladder/adrenal cancer also had higher risk of readmission (HR 2.04, p = 0.043) but no difference in OS, compared to patients with prostate cancer. Conclusions: We found that hospitalized patients with advanced GU cancers had significantly greater functional impairment and worse survival compared to those with other cancer types, and those with kidney/bladder/adrenal cancer had significantly higher readmission risk compared to those with prostate cancer. These findings support the need to develop tailored supportive care for hospitalized patients with GU cancers.

273 Background: Clear cell RCC (ccRCC) accounts for ~70% of kidney cancer cases in the US. Several first-line therapies are approved for ccRCC, but few patients respond completely and most progress within 5-11 mo. A key oncogenic driver in RCC is the transcription factor hypoxia-inducible factor 2α (HIF-2α). MK-6482 is a small molecule HIF-2α inhibitor that blocks the heterodimerization of HIF-2α with HIF-1β, inducing tumor regression in mouse xenograft RCC models. Updated data presented here include additional follow-up from the expansion cohort of patients with ccRCC from the first-in-human phase 1/2 study of MK-6482 in advanced solid tumors (NCT02974738). Methods: Patients were aged ≥18 y with advanced ccRCC, received ≥1 prior therapy, and had RECIST v1.1 measurable disease, ECOG status 0 or 1, adequate organ function, and life expectancy ≥6 mo. They received 120 mg of MK-6482 orally once daily. Tumors were assessed at baseline, within 7 days before week 9, and then every 8 weeks; response was assessed using RECIST v1.1. The primary end point was safety. Secondary end points included ORR, duration of response (DOR), and PFS. Results: Fifty-five patients with ccRCC were treated with MK-6482 120 mg (52 in expansion and 3 in dose-escalation cohorts). The median number of prior therapies was 3 (range 1-9). Forty-two patients (81%) previously received PD-1/L1 inhibitors and 48 (92%) previously received VEGF inhibitors. Thirteen patients (24%) were classified as favorable risk and 42 (76%) as intermediate or poor risk per IMDC criteria. With a median follow-up of 28 mo, the most common all-grade, all-cause AEs >30% were anemia (76%), fatigue (71%), dyspnea (49%), nausea (36%), cough (31%), and hypoxia (31%). Anemia (27%) and hypoxia (16%) were the most common grade 3 AEs. Two patients (4%) experienced grade 4 AEs, and 4 patients (7%) experienced grade 5 AEs. No grade 4 or 5 AEs were related to treatment. ORR was 25%, with 14 confirmed PRs. Thirty patients (55%) had SD, with a disease control rate (CR+PR+SD) of 80%. Median DOR was not reached; 77% had a response ≥6 mo. By IMDC risk, 4 of 13 patients with favorable risk had PR (ORR = 31%) and 10 of 42 with intermediate or poor risk had PR (ORR = 24%); disease control rate was 92% and 76%, respectively. Median PFS for the total population was 14.5 mo; 51% had a PFS of 12 mo. As of June 1, 2020, 33 patients (60%) discontinued because of PD and 2 (4%) because of AEs; 11 patients (20%) had ongoing treatment. Conclusions: MK-6482 remained well tolerated with a favorable safety profile and promising single-agent activity in patients with ccRCC for all IMDC risk groups after further follow-up. A phase III trial in a similar population is underway. Clinical trial information: NCT02974738 .

306 Background: Approved rapalogs inhibit mTORC1 and have limited activity in mRCC, possibly due to compensatory feedback loops. Sapanisertib addresses the incomplete inhibition of the mTOR pathway through targeting of both mTORC1 and mTORC2 with antitumour activity demonstrated in patients with mRCC. In this multicenter, single arm phase II trial, we evaluated the efficacy of sapanisertib in patients with mRCC progressing on standard therapies (NCT03097328). Methods: Eligible mRCC patients had an ECOG performance status of 0-2 and had progressed on standard therapies. Prior therapy with rapalogs (everolimus, temsirolimus) and variant RCC histologies were permitted. Patients had a baseline biopsy and received treatment with sapanisertib 30 mg by mouth weekly until unacceptable toxicity or disease progression. The primary endpoint was overall response rate (ORR) by RECIST 1.1. Tissue biomarkers of mTOR pathway activation were explored. Results: We enrolled 38 mRCC patients (clear cell = 28; variant histology = 10) between August 2017 and November 2019. The majority had intermediate (76%) or poor risk (11%) by IMDC criteria. Twenty (53%) had received ≥ 3 lines of therapy; 13 (34%) patients received prior rapalogs. Median follow-up was 10.4 months (range 1-27.4) and median duration of therapy was 1.6 (range 0.3-13.8) months. ORR by central review was 2 of 38 (5.3% 90%CI: 1%-15.6%). 31.6% of all patients and 30.7% of those with prior rapalog exposure had some tumor shrinkage during course of treatment. Median progression free survival (PFS) was 2.5 months (95% CI 1.8,3.7). Twelve patients (32%) developed treatment-related grade 3 adverse events (AEs) with no grade 4 or 5 toxicity reported; 6 patients (16%) required dose reduction and 4 (11%) discontinued therapy for AEs. Oncopanel tumor sequencing identified alterations in the mTOR pathway in 6 of 29 patients ( MTOR n = 2, PTEN n = 3, TSC1 n = 1.) Reduced PTEN expression by immunohistochemistry was seen in 7 of 19 patients. There was no association between mTOR pathway mutations or PTEN loss and response to sapanisertib. Conclusions: In this study we demonstrate minimal activity of sapanisertib in patients with treatment refractory mRCC with no clear benefit among patients with mTOR/PTEN pathway alterations. Additional treatment strategies are needed for patients with refractory mRCC.

82 Background: Most men who die of prostate cancer are older than 70 years, and the impact of therapy in this population is poorly defined. The ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) randomized men of all ages with metastatic hormone-sensitive prostate cancer (mHSPC) to receive androgen deprivation therapy (ADT) with or without docetaxel. Methods: The results of CHAARTED showed an overall survival (OS) benefit for the addition of docetaxel to ADT in men with mHSPC. In a secondary analysis of this trial, we assessed patient characteristics and OS in patients ≥70 years (“older men”) versus

Objective In oncology, extrapolation of clinical outcomes beyond trial duration is traditionally achieved by parametric survival analysis using population-level outcomes. This approach may not fully capture the benefit/risk profile of immunotherapies due to their unique mechanisms of action. We evaluated an alternative approach—dynamic modeling—to predict outcomes in patients with advanced renal cell carcinoma. We compared standard parametric fitting and dynamic modeling for survival estimation of nivolumab and everolimus using data from the phase III CheckMate 025 study. Methods We developed two statistical approaches to predict longer-term outcomes (progression, treatment discontinuation, and survival) for nivolumab and everolimus, then compared these predictions against follow-up clinical trial data to assess their proximity to observed outcomes. For the parametric survival analyses, we selected a probability distribution based on its fit to observed population-level outcomes at 14-month minimum follow-up and used it to predict longer-term outcomes. For dynamic modeling, we used a multivariate Cox regression based on patient-level data, which included risk scores, and probability and duration of response as predictors of longer-term outcomes. Both sets of predictions were compared against trial data with 26- and 38-month minimum follow-up. Results Both statistical approaches led to comparable fits to observed trial data for median progression, discontinuation, and survival. However, beyond the trial duration, mean survival predictions differed substantially between methods for nivolumab (30.8 and 51.5 months), but not everolimus (27.2 and 29.8 months). Longer-term follow-up data from CheckMate 025 and phase I/II studies resembled dynamic model predictions for nivolumab. Conclusions Dynamic modeling can be a good alternative to parametric survival fitting for immunotherapies because it may help better capture the longer-term benefit/risk profile and support health-economic evaluations of immunotherapies.

Background & objectives: The evidence-base of the impact of community-based health insurance (CBHI) on access to healthcare and financial protection in India is weak. We investigated the impact of CBHI in rural Uttar Pradesh and Bihar s0 tates of India on insured households′ self-medication and financial position. Methods: Data originated from (i) household surveys, and (ii) the Management Information System of each CBHI. Study design was "staggered implementation" cluster randomized controlled trial with enrollment of one-third of the treatment group in each of the years 2011, 2012 and 2013. Around 40-50 per cent of the households that were offered to enroll joined. The benefits-packages covered outpatient care in all three locations and in-patient care in two locations. To overcome self-selection enrollment bias, we constructed comparable control and treatment groups using Kernel Propensity Score Matching (K-PSM). To quantify impact, both difference-in-difference (DiD), and conditional-DiD (combined K-PSM with DiD) were used to assess robustness of results. Results: Post-intervention (2013), self-medication was less practiced by insured HHs. Fewer insured households than uninsured households reported borrowing to finance care for non-hospitalization events. Being insured for two years also improved the HH′s location along the income distribution, namely insured HHs were more likely to experience income quintile-upgrade in one location, and less likely to experience a quintile-downgrade in two locations. Interpretation & conclusions: The realized benefits of insurance included better access to healthcare, reduced financial risks and improved economic mobility, suggesting that in our context health insurance creates welfare gains. These findings have implications for theoretical, ethical, policy and practice considerations.

Summary Background Currently, metastatic renal cell carcinoma is treated with sequential single agents targeting VEGF or mTOR. Here, we aimed to assess lenvatinib, everolimus, or their combination as second-line treatment in patients with metastatic renal cell carcinoma. Methods We did a randomised, phase 2, open-label, multicentre trial at 37 centres in five countries and enrolled patients with advanced or metastatic, clear-cell, renal cell carcinoma. We included patients who had received treatment with a VEGF-targeted therapy and progressed on or within 9 months of stopping that agent. Patients were randomised via an interactive voice response system in a 1:1:1 ratio to either lenvatinib (24 mg/day), everolimus (10 mg/day), or lenvatinib plus everolimus (18 mg/day and 5 mg/day, respectively) administered orally in continuous 28-day cycles until disease progression or unacceptable toxic effects. The randomisation procedure dynamically minimised imbalances between treatment groups for the stratification factors haemoglobin and corrected serum calcium. The primary objective was progression-free survival in the intention-to-treat population. This study is closed to enrolment but patients' treatment and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT01136733. Findings Between March 16, 2012, and June 19, 2013, 153 patients were randomly allocated to receive either the combination of lenvatinib plus everolimus (n=51), single-agent lenvatinib (n=52), or single-agent everolimus (n=50). Lenvatinib plus everolimus significantly prolonged progression-free survival compared with everolimus alone (median 14·6 months [95% CI 5·9–20·1] vs 5·5 months [3·5–7·1]; hazard ratio [HR] 0·40, 95% CI 0·24–0·68; p=0·0005), but not compared with lenvatinib alone (7·4 months [95% CI 5·6–10·2]; HR 0·66, 95% CI 0·30–1·10; p=0·12). Single-agent lenvatinib significantly prolonged progression-free survival compared with everolimus alone (HR 0·61, 95% CI 0·38–0·98; p=0·048). Grade 3 and 4 events occurred in fewer patients allocated single-agent everolimus (25 [50%]) compared with those assigned lenvatinib alone (41 [79%]) or lenvatinib plus everolimus (36 [71%]). The most common grade 3 or 4 treatment-emergent adverse event in patients allocated lenvatinib plus everolimus was diarrhoea (ten [20%]), in those assigned single-agent lenvatinib it was proteinuria (ten [19%]), and in those assigned single-agent everolimus it was anaemia (six [12%]). Two deaths were deemed related to study drug, one cerebral haemorrhage in the lenvatinib plus everolimus group and one myocardial infarction with single-agent lenvatinib. Interpretation Lenvatinib plus everolimus and lenvatinib alone resulted in a progression-free survival benefit for patients with metastatic renal cell carcinoma who have progressed after one previous VEGF-targeted therapy. Further study of lenvatinib is warranted in patients with metastatic renal cell carcinoma. Funding Eisai Inc.

BACKGROUND: Metastatic renal cell carcinoma (mRCC) prognostic models may be improved by incorporating treatment-induced toxicities. METHODS: In sunitinib-treated mRCC patients (N=770), baseline prognostic factors and treatment-induced toxicities (hypertension (systolic blood pressure ⩾140 mm Hg), neutropenia (grade ⩾2), thrombocytopenia (grade ⩾2), hand-foot syndrome (grade >0), and asthenia/fatigue (grade >0)) were analysed in multivariate analyses of progression-free survival (PFS) and overall survival (OS) end points. RESULTS: On-treatment neutropenia and hypertension were associated with longer PFS (P=0.0276 and P

BACKGROUND Sarcomatoid renal cell carcinoma (RCC) is associated with an aggressive biology and a poor prognosis. Poor-risk RCC is defined by clinical prognostic factors and demonstrates similarly aggressive behavior. No standard treatment exists for patients with sarcomatoid RCC, and treatment options for patients with poor-risk disease are of limited benefit. The objective of this study was to investigate the efficacy of antiangiogenic therapy in combination with cytotoxic chemotherapy in clinically aggressive RCC. METHODS This was a phase 2, single-arm trial of sunitinib and gemcitabine in patients with sarcomatoid or poor-risk RCC. The primary endpoint was the objective response rate (ORR). Secondary endpoints included the time to progression (TTP), overall survival (OS), safety, and biomarker correlatives. RESULTS Overall, 39 patients had sarcomatoid RCC, and 33 had poor-risk RCC. The ORR was 26% for patients with sarcomatoid RCC and 24% for patients with poor-risk RCC. The median TTP and OS for patients with sarcomatoid RCC were 5 and 10 months, respectively. For patients with poor-risk disease, the median TTP and OS were 5.5 and 15 months, respectively. Patients whose tumors had >10% sarcomatoid histology had a higher clinical benefit rate (ORR plus stable disease) than those with ≤10% sarcomatoid histology (P = .04). The most common grade 3 or higher treatment-related adverse events included neutropenia (n = 20), anemia (n = 10), and fatigue (n = 7). CONCLUSIONS These results suggest that antiangiogenic therapy and cytotoxic chemotherapy are an active and well-tolerated combination for patients with aggressive RCC. The combination may be more efficacious than either therapy alone and is currently under further investigation. Cancer 2015;121:3435–43. © 2015 American Cancer Society.

objective To evaluate an insurance awareness campaign carried out before the launch of three community-based health insurance (CBHI) schemes in rural India, answering the questions: Has the awareness campaign been successful in enhancing participants’ understanding of health insurance? What awareness tools were most useful from the participants’ point of view? Has enhanced awareness resulted in higher enrolment? methods Data for this analysis originates from a baseline survey (2010) and a follow-up survey (2011) of more than 800 households in the pre- and post-campaign periods. We used the differencein-differences method to evaluate the impact of awareness activities on insurance understanding. Assessment of usefulness of various tools was carried out based on respondents’ replies regarding the tool(s) they enjoyed and found most useful. An ordinary least square regression analysis was conducted to understand whether insurance knowledge and CBHI understanding are related with enrolment in CBHI. results The intervention cohort demonstrated substantially higher understanding of insurance concepts than the control group, and CBHI understanding was a positive determinant for enrolment. Respondents considered the ‘Treasure-Pot’ tool (an interactive game) as most useful in enhancing awareness to the effects of insurance. conclusions We conclude that awareness-raising is an important prerequisite for voluntary uptake of CBHI schemes and that interactive, contextualised awareness tools are useful in enhancing insurance understanding.

Objective The objective is to estimate the amount of money health microinsurance plans (a.k.a. Community-based health insurance - CBHI) require to launch, scale and reach sustainable operations in rural India. Methods We develop the methodology to calculate the capital required for a CBHI plan to reach sustainability. It includes algorithms to estimate operating costs, capital requirements, loan requirements, interest earned, loan repayment installments and scaling projections. We apply these methods to examine the sustainability of a prototype plan. We check the plausibility of assumptions posited for the model with data of 2 CBHI plans. Results A prototype CBHI plan, covering 40k persons requires US$ 62,477 to offset deficits in the initial years. Repayment of principal and interest requires 15 years. Plans could bear up to 14% p.a. Assuming 10.96% interest in local currency (INR) ≈ 5% in US$, the NPV is US$ 18,455 or 30% of the original investment. When expressed per person, this amount is US$1.56, and per policy-year (over 20 years) it is a mere US$0.10. Even the poorest populations can pay such overhead (while simultaneously paying the claims and operations costs). The per-capita operating costs drop as enrollment and renewal rates and average insured household size increase. Even with very low per capita annual premiums (US$ 3.51 to US$ 4.71), cumulative claims ratios stabilize around 70% (benchmark: 73% and 69%, in Bihar and Nepal, respectively). The CBHI plans can generate considerable additional resources as premiums for healthcare, estimated at US$52 (over 15 years) and US$85 (over 20 years) for every US$1 borrowed at inception. Conclusions The financial gains to investors flow from interest payments. Impact investors and CBHI plans have a margin to negotiate the interest rate from zero to 14 percent. The financial gains to the insured consist of the assets accumulated over and beyond payments of benefits. The amounts and the income smoothing effects are considerable. The social effects include extending health insurance to uninsured rural populations. The governance gains flow from large-scale standardization of rule-based participatory management of these mutual-aid plans. This investment opportunity is scalable from a small to substantial ticket size because the amount per CBHI plan is modest. The size of the investment determines the scale of populations covered. Governments and policymakers may contribute by creating a supportive regulatory environment. Governments could also consider collateral arrangements. Such investments cum supportive regulations may enable the development of a new market for reinsurance of outlier risks written by CBHI plans.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non-clear cell renal carcinoma. These NCCN Guidelines Insights highlight the recent updates/changes in these guidelines, and updates include axitinib as first-line treatment option for patients with clear cell renal carcinoma, new data to support pazopanib as subsequent therapy for patients with clear cell carcinoma after first-line treatment with another tyrosine kinase inhibitor, and guidelines for follow-up of patients with renal cell carcinoma.

Background & objectives: Despite remarkable progress in airborne, vector-borne and waterborne diseases in India, the morbidity associated with these diseases is still high. Many of these diseases are controllable through awareness and preventive practice. This study was an attempt to evaluate the effectiveness of a preventive care awareness campaign in enhancing knowledge related with airborne, vector-borne and waterborne diseases, carried out in 2011 in three rural communities in India (Pratapgarh and Kanpur-Dehat in Uttar Pradesh and Vaishali in Bihar). Methods: Data for this analysis were collected from two surveys, one done before the campaign and the other after it, each of 300 randomly selected households drawn from a larger sample of Self-Help Groups (SHGs) members invited to join community-based health insurance (CBHI) schemes. Results: The results showed a significant increase both in awareness (34%, p

Purpose: This study investigates the biologic activity of radium-223 with VEGF-targeted therapy in patients with advanced renal cell carcinoma (aRCC) and bone metastases. Patients and Methods: Fifteen treatment-naïve patients (n = 15) received pazopanib 800 mg orally once daily, and 15 previously treated patients received sorafenib 400 mg orally twice daily. Radium-223 55 kilobecquerel/kg was administered concurrently every 4 weeks for up to six infusions in both cohorts. The primary endpoint was decline in bone turnover markers (Procollagen I Intact N-Terminal, N-telopeptide, C-telopeptide, osteocalcin, and bone-specific alkaline phosphatase) compared with baseline. Secondary endpoints included safety, rate of symptomatic skeletal event (SSE) and time to first SSE, objective response rate, change in analgesic use, and quality of life. Exploratory analysis of tumor genomic alterations was performed. Results: Of the 30 patients enrolled, 83% had IMDC intermediate- or poor-risk disease, 33% had liver metastases, and 83% had a history of SSE prior to enrollment. No dose-limiting toxicity was observed. All bone turnover markers significantly declined from baseline at week 8 and 16. Forty percent of patients experienced treatment-related grade ≥3 adverse events. Response rates were 15% and 18% per RECIST v1.1 and bone response was 50% and 30% per MD Anderson criteria, in the pazopanib and sorafenib cohort, respectively. Median SSE-free interval was 5.8 months and not reached, respectively. Analgesic use remained stable over the study time. Conclusions: Radium-223 combined with VEGF-targeted therapy is biologically active and safe. Randomized-controlled trials are needed to define the role of radium-223 in aRCC with skeletal metastases. Clin Cancer Res; 24(17); 4081–8. ©2018 AACR.

Background The randomised phase 2 CABOSUN trial comparing cabozantinib with sunitinib as initial therapy for advanced renal cell carcinoma (RCC) of intermediate or poor risk met the primary end-point of improving progression-free survival (PFS) as assessed by investigator. We report PFS by independent radiology review committee (IRC) assessment, ORR per IRC and updated overall survival (OS). Patients and methods Previously untreated patients with advanced RCC of intermediate or poor risk by IMDC criteria were randomised 1:1 to cabozantinib 60 mg daily or sunitinib 50 mg daily (4 weeks on/2 weeks off). Stratification was by risk group and presence of bone metastases. Results A total of 157 patients were randomised 1:1 to cabozantinib (n = 79) or sunitinib (n = 78). Median PFS per IRC was 8.6 months (95% confidence interval [CI] 6.8–14.0) versus 5.3 months (95% CI 3.0–8.2) for cabozantinib versus sunitinib (hazard ratio [HR] 0.48 [95% CI 0.31–0.74]; two-sided p = 0.0008), and ORR per IRC was 20% (95% CI 12.0–30.8) versus 9% (95% CI 3.7–17.6), respectively. Subgroup analyses of PFS by stratification factors and MET tumour expression were consistent with results for the overall population. With a median follow-up of 34.5 months, median OS was 26.6 months (95% CI 14.6–not estimable) with cabozantinib and 21.2 months (95% CI 16.3–27.4) with sunitinib (HR 0.80 [95% CI 0.53–1.21]. The incidence of grade 3 or 4 adverse events was 68% for cabozantinib and 65% for sunitinib. Conclusions In this phase 2 trial, cabozantinib treatment significantly prolonged PFS per IRC compared with sunitinib as initial systemic therapy for advanced RCC of poor or intermediate risk. Trial Registration Number NCT01835158 .

We characterized clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib who were long-term responders (LTRs), defined as patients having progression-free survival (PFS)18 months.A retrospective analysis of data from 5714 patients with mRCC treated with sunitinib in 8 phase II/III clinical trials and the expanded access program. Duration on-study and objective response rate (ORR) were compared between LTRs and patients with PFS ≤ 18 months ("others"). PFS and overall survival (OS) were summarized using Kaplan-Meier methodology.Overall, 898 (15.7%) patients achieved a long-term response and 4816 (84.3%) patients did not achieve long-term response. The median (range) duration on-study was 28.6 (16.8-70.7) months in LTRs and 5.5 (0-68.8) months in others. ORR was 51% in LTRs versus 14% in others (P .0001). Median PFS in LTRs was 32.11 months and median OS was not reached. LTRs had higher percentage of early tumor shrinkage ≥ 10% at the first scan (67.1% vs. 51.2%; P = .0018) and greater median maximum on-study tumor shrinkage from baseline (-56.9 vs. -27.1; P .0001) versus others. White race, Eastern Cooperative Oncology Group performance status 0, time from diagnosis to treatment ≥ 1 year, clear cell histology, no liver metastasis, lactate dehydrogenase ≤ 1.5 upper limit of normal (ULN), corrected calcium ≤ 10 mg/dL, hemoglobin greater than the lower limit of normal, platelets less than or equal to ULN, body mass index ≥ 25 kg/mA subset of patients with mRCC treated with sunitinib achieved long-term response. LTRs had improved ORR, PFS, and OS.

611 Background: Hypoxia-inducible factor (HIF)-2α is a transcription factor that is a key oncogenic driver in RCC. MK-6482 is a first-in-class small molecule HIF-2α inhibitor that blocks the heterodimerization of HIF-2α with HIF-1β and induces regression in mouse xenograft RCC models. Methods: Pts with advanced ccRCC who had received at least 1 prior therapy were enrolled in an expansion cohort from the first-in-human phase 1/2 study of MK-6482 in advanced solid tumors (NCT02974738). Pts were administered 120 mg of MK-6482 orally once daily. Primary end point: safety. Key secondary end points: ORR, duration of response (DOR), and PFS. Results: Fifty-five pts were enrolled in the dose expansion cohort. Median (range) number of prior therapies was 3 (1-9); 67% received anti–PD-1 and anti-VEGF agents. Five pts (9%) were favorable risk, 40 (73%) were intermediate risk, and 10 (18%) were poor risk by IMDC criteria. With a median follow-up of 13 mo the most common all-grade, all-cause AEs > 30% were anemia (75%), fatigue (67%), dyspnea (47%), nausea (33%), and cough (31%). Anemia (26%) and hypoxia (15%) were the most common grade 3 AEs. No grade 4/5 drug-related AEs were observed. ORR was 24% with 13 confirmed PRs. Thirty-one pts (56%) had SD, with a disease control rate (CR+PR+SD) of 80%. Thirty-five of 52 (67%) pts with baseline and postbaseline assessments had tumor shrinkage. Median DOR was not reached; 81% of pts had response ≥6 mo per Kaplan-Meier estimate. Sixteen pts (29%) continued treatment beyond 12 mo. By IMDC risk, 2/5 pts with favorable risk had PR (ORR = 40%), 10/40 with intermediate risk had PR (ORR = 25%), and 1/10 with poor risk had PR (ORR = 10%); disease control rate was 100%, 80%, and 70%, respectively. Median PFS for the total population was 11.0 mo; the 12 mo PFS rate was 49%. Median PFS for favorable, intermediate, and poor IMDC risk was 16.5, 11.0, and 6.9 mo, respectively. As of May 15, 2019, 30 pts (55%) discontinued due to PD, 2 (4%) due to AEs. Sixteen pts (29%) had treatment ongoing. Conclusions: MK-6482 is well tolerated with a favorable safety profile and demonstrated promising single-agent activity in heavily pretreated pts with ccRCC across IMDC risk groups. A phase 3 trial in a similar population is planned. Clinical trial information: NCT02974738.

We retrospectively evaluated the prognostic impact of neutrophil-lymphocyte ratio (NLR) as a marker for inflammatory and immune state in men with progressive metastatic castration resistant prostate cancer (mCRPC) following docetaxel.The SUN-1120 phase III trial comparing prednisone combined with sunitinib (n = 584) or placebo (n = 289) for mCRPC following docetaxel-based chemotherapy was evaluated. The arms were combined for analysis, since no difference was observed in the primary endpoint of overall survival (OS). A logarithmic transformation was applied to non-normal factors. The Kaplan-Meier method was used for OS estimation. To identify an optimal prognostic model for survival, we used a Cox proportional hazards regression method with forward stepwise selection, stratifying for ECOG PS, progression type (prostate specific antigen [PSA] or radiographic) and treatment group. Patients were categorized into risk groups.Complete data was evaluable for 784 men. The factors used in the model that remained individually significant for OS in multivariable analysis were: log-lactate dehydrogenase level (LDH) level (HR 2.86 [95% CI = 2.29, 3.56], P.001), hemoglobin (0.80 [0.74, 0.85], P.001),1 organ involved by metastatic disease (1.49 [1.21, 1.84], P.001), log-alkaline phosphatase (1.13 [0.99, 1.28], P = .074), log-number of prior cycles of docetaxel (0.84 [0.71, 0.98], P = .031), progression on docetaxel (1.35 [1.00, 1.81], P = .049), log-PSA (1.06 [1.00, 1.12], P = .075) and log-NLR (1.55 [1.32, 1.83], P.001). NLR increased the c-statistic of the prognostic model from 0.703 to 0.715.High NLR may be associated with an independent poor prognostic impact in post-docetaxel patients with mCRPC. These data warrant external validation.

Purpose: Orteronel (TAK-700) is an investigational, nonsteroidal, oral, inhibitor of androgen synthesis with greater specificity for 17,20-lyase than for 17α-hydroxylase. We investigated orteronel without steroids in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC; M0). Experimental Design: Patients with nmCRPC and rising prostate-specific antigen (PSA) received orteronel 300 mg twice daily until PSA progression, metastases, or unacceptable toxicity. The primary endpoint was percentage of patients achieving PSA ≤0.2 ng/mL (undetectable levels) at 3 months. Secondary endpoints included safety, PSA response, time to metastases, and correlated endpoints. Results: Thirty-nine patients with a median baseline PSA doubling time of 2.4 months (range, 0.9–9.2) received a median of fourteen 28-day treatment cycles. PSA decreased >30% in 35 patients and 6 (16%) achieved PSA ≤ 0.2 ng/mL at 3 months. Median times to PSA progression and metastasis were 13.8 and 25.4 months, respectively. Kaplan–Meier estimates of freedom from PSA progression were 57% and 42% at 12 and 24 months, and of freedom from metastasis were 94% and 62% at 12 and 24 months, respectively. At 3 months, median testosterone declined by 89% from baseline. Adverse events led to therapy discontinuation in 12 patients and grade ≥3/4 adverse events occurred in 22 patients. Most frequent all-cause adverse events included fatigue (64%), hypertension (44%), diarrhea (38%), and nausea (33%), which were primarily grade 1/2. Conclusions: Single-agent orteronel produced marked and durable declines in PSA in patients with nmCRPC. Orteronel has moderate but manageable toxicities and its chronic administration without steroids appears feasible. Clin Cancer Res; 20(16); 4218–27. ©2014 AACR.

Objective To investigate the association of radiographic progression defined by Prostate Cancer Working Group (PCWG)-2 guidelines and overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC). Patients and Methods Two trials that used PCWG-2 guidelines to define progression were analysed: a randomized phase II trial (n = 221) comparing first-line docetaxel-prednisone plus AT-101 or placebo, and a phase III trial (n = 873) comparing prednisone plus sunitinib or placebo after docetaxel-based chemotherapy. Cox proportional hazards regression models were used to estimate the association of radiographic progression with OS. Landmark analyses compared progressing patients with those who had not progressed. Sub-analyses compared patients removed from trial for progression vs other reasons. Results An increased risk of death was seen for radiographic progression at landmark times from 6 to 12 months with docetaxel-based therapy (hazard ratio [HR] >1.7 at all time-points). An increased risk of death was also seen with post-docetaxel prednisone alone or with sunitinib for progression at landmark times from 2 to 8 months (HR >2.7 at all time-points). Kendall's τ was 0.50 (P < 0.001) in the setting of docetaxel-based therapy and 0.34 (P < 0.001) in the post-docetaxel setting for association between radiographic progression and death amongst patients with both events. Removal from study due to radiographic progression was associated with a significantly lower OS compared with removal for other reasons in both trials. Limitations of a retrospective analysis apply and there was no central radiology review. Conclusions Radiographic progression by PCWG-2 criteria was significantly associated with OS in patients with mCRPC receiving first-line docetaxel-based chemotherapy or post-docetaxel therapy. With external validation as a surrogate endpoint in trials showing survival benefits, the use of radiographic progression-free survival may expedite drug development in mCRPC, which has been hampered by the lack of intermediate endpoints.

Specialist bias, in which specialists recommend the therapy that they are capable of delivering, is thought to influence the treatment of patients with localized prostate cancer and to contribute to overtreatment of men with limited life expectancy. Consequently, rates of active surveillance, the preferred management modality per the National Comprehensive Cancer Network (NCCN) for patients with low- and very low-risk disease and a life expectancy of less than 10 and less than 20 years, respectively, are low. We sought to determine whether consultation with a medical oncologist is associated with increased rates of active surveillance in men with low-risk prostate cancer.We identified 188 patients with low-risk prostate cancer undergoing active surveillance at one of three referral centers in Boston, MA in 2009. Multivariable logistic regression was used to determine whether consultation with a medical oncologist was associated with selection of active surveillance. The data were reanalyzed for patients with low- and very low-risk disease and a life expectancy of less than 10 and less than 20 years, respectively.Consultation with a medical oncologist was associated with increased rates of active surveillance (37% v 21%, P = .01), an association that remained significant on multivariable logistic regression (odds ratio [OR] = 2.70; 95% CI, 1.27 to 5.75; P = .01). When applied to patients with limited life expectancy, this finding remained significant (OR = 4.74; 95% CI, 1.17 to 19.25; P = .03).Consultation with a medical oncologist is associated with increased rates of active surveillance, adherence to NCCN guidelines, and minimization of overtreatment in men with early prostate cancer and limited life expectancy.

ObjectiveAdvanced renal cell carcinoma (RCC) is commonly treated with vascular endothelial growth factor or mammalian target of rapamycin inhibitors. As new therapies emerge, interest grows in gaining a deeper understanding of treatment sequences. Recently, we developed a patient-level, discretely integrated condition event (DICE) simulation to estimate survival and lifetime costs for various cancer therapies, using a US payer perspective. Using this model, we explored the impact of treatments such as nivolumab and cabozantinib, and compared the clinical outcomes and cost consequences of commonly used treatment algorithms for patients with advanced RCC.MethodsIncluded treatment sequences were pazopanib or sunitinib as first-line treatment, followed by nivolumab, cabozantinib, axitinib, pazopanib or everolimus. Efficacy inputs were derived from the CheckMate 025 trial and a network meta-analysis based on available literature. Safety and cost data were obtained from publicly available sources or literature.ResultsBased on our analysis, the average cost per life-year (LY) was lowest for sequences including nivolumab (sunitinib → nivolumab, $75,268/LY; pazopanib → nivolumab, $84,459/LY) versus axitinib, pazopanib, everolimus and cabozantinib as second-line treatments. Incremental costs per LY gained were $49,592, $73,927 and $30,534 for nivolumab versus axitinib, pazopanib and everolimus-containing sequences, respectively. The model suggests that nivolumab offers marginally higher life expectancy at a lower cost versus cabozantinib-including sequences.ConclusionTreatment sequences using nivolumab in the second-line setting are less costly compared with sequential use of targeted agents. In addition to efficacy and safety data, cost considerations may be taken into account when considering treatment algorithms for patients with advanced RCC.

Lessons Learned The combination of axitinib and crizotinib has a manageable safety and tolerability profile, consistent with the profiles of the individual agents when administered as monotherapy. The antitumor activity reported here for the combination axitinib/crizotinib does not support further study of this combination treatment in metastatic renal cell carcinoma given the current treatment landscape. Background Vascular endothelial growth factor (VEGF) inhibitors have been successfully used to treat metastatic renal cell carcinoma (mRCC); however, resistance eventually develops in most cases. Tyrosine protein kinase Met (MET) expression increases following VEGF inhibition, and inhibition of both has shown additive effects in controlling tumor growth and metastasis. We therefore conducted a study of axitinib plus crizotinib in advanced solid tumors and mRCC. Methods This phase Ib study included a dose-escalation phase (starting doses: axitinib 3 mg plus crizotinib 200 mg) to estimate maximum tolerated dose (MTD) in patients with solid tumors and a dose-expansion phase to examine preliminary efficacy in treatment-naïve patients with mRCC. Safety, pharmacokinetics, and biomarkers were also assessed. Results No patients in the dose-escalation phase (n = 22) experienced dose-limiting toxicity; MTD was estimated to be axitinib 5 mg plus crizotinib 250 mg. The most common grade ≥3 adverse events were hypertension (18.2%) and fatigue (9.1%). In the dose-expansion phase, overall response rate was 30% (95% confidence interval [CI], 11.9–54.3), and progression-free survival was 5.6 months (95% CI, 3.5–not reached). Conclusion The combination of axitinib plus crizotinib, at estimated MTD, had a manageable safety profile and showed evidence of modest antitumor activity in mRCC.

TPS4597 Background: The anti-PD-1 antibody nivo improves overall survival (OS) in metastatic RCC and is well tolerated. There is no standard adjuvant (adjuv) systemic therapy that increases OS over surgery alone for non-metastatic RCC. Priming the immune system prior to surgery with anti-PD-1 has shown an OS benefit compared to a pure adjuv approach in mouse solid tumor models. Multiple ph 2 studies in bladder, lung and breast cancers have shown remarkable pathologic responses with neoadjuvant (neoadj) PD-1 blockade. Two ongoing ph 2 studies of perioperative nivo in M0 RCC patients are showing preliminary feasibility and safety with no surgical delays (NCT02575222; NCT02595918). PROSPER RCC (NCT03055013) aims to improve clinical outcomes by priming the immune system prior to nephrectomy with neoadj nivo and continued engagement with adjuv blockade in patients with high risk RCC compared to surgery alone. Methods: This global, unblinded, phase 3 National Clinical Trials Network study is currently accruing patients with clinical stage ≥T2 or TanyN+ RCC of any histology planned for nephrectomy. Oligometastases are permitted if can be rendered NED. We amended the study to enhance accrual and patient quality of life by changing nivo dosing to 480mg q4 wks and requiring baseline tumor biopsy only in the nivo arm. The investigational arm receives 1 dose of nivo prior to surgery followed by 9 adjuv doses. The control arm undergoes standard nephrectomy followed by observation. Randomized patients are stratified by clinical T stage, node positivity, and M stage. Accrual of 805 patients provides 84.2% power to detect a 14.4% absolute benefit in recurrence-free survival (RFS) at 5 years assuming the ASSURE historical control of ~56% to 70% (HR = 0.70). The study is powered to evaluate a significant increase in OS (HR 0.67). Critical perioperative therapy considerations such as safety, feasibility, and quality of life endpoints have been integrated. PROSPER RCC embeds a wealth of translational work aimed at investigating the impact of the baseline immune milieu, the changes induced by neoadjuvant anti-PD-1 priming, and how both may predict clinical outcomes. Clinical trial information: NCT03055013.

4566 Background: Immuno-oncology therapies (IOs) and tyrosine kinase inhibitors (TKIs) are recommended for the treatment of aRCC. As new drugs and combination regimens emerge, there is interest in gaining a deeper understanding of optimal treatment sequencing. We aimed to assess clinical and economic outcomes associated with treatment sequences for untreated aRCC patients with IMDC intermediate/poor risk. Methods: A discrete event simulation model was developed to estimate the total costs and survival (in life-years; LYs) over patients’ lifetimes when receiving sequential treatment with nivolumab + ipilimumab (N+I), sunitinib (SUN), pazopanib (PAZ), or cabozantinib (CAB) as first-line (1L) treatment, and nivolumab (NIVO), axitinib (AXI), PAZ, CAB, or lenvatinib + everolimus (LEN+EVE) as second line (2L). Efficacy inputs were derived from the CheckMate 214 trial and a network meta-analysis based on available literature. Safety and cost data were obtained from literature and publicly available sources. Results: N+I initiating sequences were estimated to provide longer survival in mean LYs and lower mean costs/LY versus sequences with 1L TKIs (table). The estimates of incremental cost-effectiveness ratio (ICER) for N+I initiating sequences with 2L TKI monotherapy were well below the willingness-to-pay threshold of $50,000. Using 2L LEN+EVE, compared with 2L monotherapies, provided an incremental survival gain but at costs/LY close to $100,000. Conclusions: Use of 1L N+I followed by TKI monotherapy is estimated to provide longer survival while being more cost-effective versus TKIs followed by IOs or sequences cycling TKIs, mainly driven by a longer time to 2L treatment and longer treatment-free survival with N+I. Clinical trials with head-to-head comparisons of treatment sequences would be necessary to validate the findings of the study. [Table: see text]

In the first published version of this article the abstract contained an error. The sentence ‘Probability of bankruptcy is fixed at 99.9%.’ was replaced with the sentence ‘Capital requirements drop significantly when confidence levels are lower than 99.9.’ The original article has been corrected.

These NCCN Guidelines Insights highlight treatment recommendations and updates specific to the management of patients with advanced non-clear cell carcinoma included in the 2014 version of the NCCN Clinical Practice Guidelines in Oncology for Kidney Cancer.

Background: Community-based health insurance (CBHI) schemes are increasingly implemented in low-income settings. These schemes limit the coverage they offer both by the types of care considered, and by applying thresholds and/or caps to costs reimbursed. The consequences of these thresholds and/or caps on insurance coverage have hitherto been usually ignored, for lack of data on the distributions of healthcare costs or understanding of their impact on effective coverage levels. This article describes a theoretical model to obtain the distributions even without data collection in the field, and demonstrates the quantitative impact of thresholds and/or caps on claim reimbursements. Methods: This model applies to applications on healthcare expenditures in low-income settings, following research methods examined in the Western world. We looked at hospitalizations and tests; we compared the simulated distributions to empirical data obtained through 11 household surveys conducted between 2008 and 2010 in rural locations (9 in India and 2 in Nepal). Results: We found that the shape of the distributions was very similar in all locations for both benefits, and could be represented by a model based on a lognormal distribution. The agreement between theoretical and empirical results was satisfactory (mostly within 10% difference). Conclusions: The model makes it possible to simulate the expected performance of the CBHI (represented by the percentage of costs or bills covered). The aim is to match costs with local levels of willingness-to-pay for health insurance. This model makes it possible to determine at the stage of package-design the optimal levels of thresholds and/or caps for each benefit-type included.