Metastatic Renal Cell Cancer Patients Research Articles

Optimal timing of delayed cytoreductive nephrectomy in metastatic renal cell carcinoma during the immunotherapy era.

403 Background: The CARMENA study found no survival benefit from cytoreductive nephrectomy (CN) in poor-risk metastatic renal cell cancer (mRCC) patients treated with first line Sunitinib. Although retrospective studies have reported survival benefits with CN following immunotherapy (IO)-based therapy, the timing remains unclear. We aimed to investigate the ideal timing of CN following IO using the National Cancer Database. Methods: 783 patients with de novo mRCC were diagnosed between 2016 and 2020 who received upfront systemic therapy and underwent CN, 343 patients met our criteria. Patients were categorized into four groups based on the timing of nephrectomy: CN ≤3 months (Group A), 4 to 6 months (Group B), 7 to 9 months (Group C) and ≥ 10 months (Group D) following the initiation of IO-based therapy. Descriptive analysis was performed to examine the demographic and clinical characteristics. Follow up time was measured from the date of surgery to reduce bias. Kaplan-Meier plots were used to analyze survival curves, and a multivariable cox regression analysis was performed to explore associations between timing and survival. Results: 343 patients who received upfront IO -based therapy were divided into four groups: 104 (30%) in A, 114 (33%) in B, 74 (22%) in C and 51 (15%) in D. 71%were male, white (90%), age 40 – 64 (62%), comorbidity index 0 (70%), clear cell histology (69%), sarcomatoid (14%). 54% were treated in academia, 57% had bone metastasis, 50% had lung, 11% had liver, and 7% had brain metastases. 66% received only IO, and 34% received IO + TKI. No significant association between CN timing and survival observed in multivariate cox regression model. (HR 0.87, 95% CI: 0.5- 1.7, p = 0.84). Compared to group A, the HR were 0.96 (95% CI, 0.73 to 1.27; p=0.78), 0.77 (95% CI, 0.53 to 1.13; p=0.19), and 0.66 (95% CI, 0.37 to 1.20; p=0.17) respectively for groups B, C and D. Conclusions: Our study did not find significant survival improvement with an optimal timing of CN following IO-based therapy, while HRs were reduced after 6 months of delay, though insignificant. This could be due to the small sample size or other confounders.

Outcomes of Targeted Therapy Plus Immunotherapy and High-Dose Stereotactic Ablative Body Radiotherapy (SABR) for Metastatic Renal Cell Cancer Patients.

Stereotactic ablative body radiotherapy (SABR) is one of the treatment options for metastatic renal cell carcinoma (mRCC) but is limited by a lack of data to evaluate targeted therapy plus immunotherapy concurrently with high-dose SABR to multiple sites. We evaluated the safety and disease control for mRCC patients who concurrently received the above tri-modality treatment. Patients were treated with SABR (40-70 Gy/5-10 fractions) for small lesions or partial-SABR (tumor center boosted with 6-8 Gy/3-5 fractions with 50-60 Gy/20-25 fractions to the whole tumor volume) for bulky tumors or tumors adjacent to critical organs. When SABR/partial-SABR was not feasible, a moderate fractionated radiotherapy plan, usually 60Gy/20 fractions were applied. of Targeted therapy plus immunotherapy (PD-1 inhibitor) was not interrupted during or after radiotherapy (RT). Adverse events (AEs) were evaluated. Disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were calculated. The PFS1 was defined as the first progression since the start of RT. The PFS2 was defined as the second progression after the second RT course, if new metastases occurred after first RT were all re-irradiated, and the systemic therapy was not changed. The Kaplan-Meier method was used for time-to-event endpoints. A total of 51 patients, with a median age of 57 yr, were enrolled. The median follow-up was 12 months. There were 75% of patients with intermediate-risk and 18% with favorable-risk disease. 61% of the patients were oligometastatic. 71% had clear cell renal cancer. There were 241 metastases while 161 (67%) were irradiated. 80% of the lesions received SABRP/partial SABR. 1 patient with 14 lesions irradiated received proton therapy. All the surviving patients are continuing using targeted therapy while 81% patients complete at least 1-year PD-1 therapy. 10 patients (20%) had grade 3 drug-related AEs: pneumonitis (n = 2), elevated alanine transaminase (n = 4), myositis (n = 1), hand-foot syndrome myositis (n = 1), enteritis (n = 1), fatigue (n = 1). There were 1 grade 4 AEs of upper gastrointestinal bleeding. No grade 3-5 RT-related AEs was found. ORR and DCR for irradiated lesion were 51% and 98%. Median OS and PFS2 was not reached. Median PFS1 was 14(6-22) months. Estimated 1- and 2-yr OS, PFS1 and PFS2 were 90% and 90%, 56% and 38%, 74% and 51% respectively. Univariate analysis showed that an PFS1 benefit was found in patients who received radiation before systemic therapy failure (p = 0.038). We investigated the high-dose RT in combination of concurrent targeted and immunotherapy in patients with metastatic RCC. We found that this treatment regimen was well tolerated, with good cancer control. Early use of high-dose RT to multi-lesions may improve PFS. Partial-SABR for bulky lesions close to critical organs could be safely and effectively applied under certain circumstances. These encouraging findings warrant further investigation.

Inflammatory Prognostic Index in Metastatic Renal Carcinoma Treated with Nivolumab.

To evaluate the utility of inflammatory prognostic index (IPI), albumin, c-reactive protein (CRP), and lactate dehydrogenase (LDH) as predictive biomarkers of oncologic outcome in metastatic renal cell cancer (mRCC) patients treated with nivolumab. Descriptive study. Manisa Celal Bayar University, Aydın Adnan Menderes University, Bitlis Tatvan State Hospital and Private Hatay Defne Hospital Medical Oncology Clinics, Turkey, from January 2017 to June 2020. Seventy-five mRCC patients treated with nivolumab between January 2017 and June 2020 were enrolled. Several factors were retrospectively investigated, including IPI, CRP, LDH, and albumin level, for their association with progression-free survival (PFS) and overall survival (OS). The IPI was calculated as CRP × NLR/albumin. Univariate and multivariate analyses were performed to assess the prognostic value of relevant factors. When analysed according to the calculated IPI score, it is seen that the group with <2.153 has an OS duration of 96.3 months, while the group with ≥2.153 has a shorter time of 42.9 months (p=0.02). In the analysis performed according to albumin level, it was reported that those with low levels (22.8 months) had worse median OS than those with high levels (92.8 months) (p=0.004). According to the cox regression analysis results, it was determined that those with a high IPI score significantly increased the risk of death compared to those with a low score (HR:2.4, p=0.023). However, this significance could not be confirmed in the multivariate analysis. It was analysed that those with low albumin levels significantly increased the risk of death compared to both univariate analysis (HR:3.3, p=0.007) and multivariate analysis (HR:4.4, p=0.003). Those with high IPI scores and low albumin levels were associated with worse median OS. However, only the multivariate analysis analysed albumin level as an independent prognostic variable. Prospective and more extensive research is needed to consolidate the potential prognostic power of these markers. Albumin, Immune checkpoint inhibitor, IPI score, Metastatic renal cell carcinoma, Nivolumab, overall survival, Progression-free survival.

Perirenal Fat Thickness Significantly Associated with Prognosis of Metastatic Renal Cell Cancer Patients Receiving Anti-VEGF Therapy.

Although high body mass index (BMI) was reported to associate with a better prognosis for metastatic renal cell cancer (mRCC) patients receiving anti-vascular endothelial growth factor (anti-VEGF) therapy, it is an imperfect proxy for the body composition, especially in Asian patients with a lower BMI. The role of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and perirenal fat thickness (PRFT) in mRCC patients was still unknown. Therefore, a multicenter retrospective study of 358 Chinese mRCC patients receiving anti-VEGF therapy was conducted and their body composition was measured via computed tomography. We parameterized VAT, SAT and PRFT according to their median value and BMI according to Chinese criteria (overweight: BMI ≥ 24). We found VAT, SAT, and PRFT (all p < 0.05) but not BMI, significantly associated with overall survival (OS) and progression-free survival (PFS). Multivariate Cox analysis identified PRFT was the independent predictor of OS and PFS, and IMDC expanded with PRFT showed the highest C-index in predicting OS (OS:0.71) compared with VAT, SAT, and BMI. PRFT could increase the area under the curve of the traditional International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model in OS (70.54% increase to 74.71%) and PFS (72.22% increase to 75.03%). PRFT was introduced to improve the IMDC model and PRFT-modified IMDC demonstrated higher AIC in predicting OS and PFS compared with the traditional IMDC model. Gene sequencing analysis (n = 6) revealed that patients with high PRFT had increased angiogenesis gene signatures (NES = 1.46, p = 0.04) which might explain why better drug response to anti-VEGF therapy in mRCC patients with high PRFT. The main limitation is retrospective design. This study suggests body composition, especially PRFT, is significantly associated with prognosis in Chinese mRCC patients receiving anti-VEGF therapy. PRFT-modified IMDC model proposed in this study has better clinical predictive value.

Dynamic contrast-enhanced CT-derived blood flow measurements enable early prediction of long term outcome in metastatic renal cell cancer patients on antiangiogenic treatment.

To evaluate the role of dynamic contrast-enhanced CT (DCE-CT) as an independent non-invasive biomarker in predicting long term outcome in patients with metastatic renal cell carcinoma (mRCC) on antiangiogenic treatment. Eighty two mRCC patients were prospectively enrolled from 09/2011 to 04/2015, out of which 71 were included in the final data analysis; the population was observed until 12/2020 to obtain complete overall survival data. DCE-CT imaging was performed at baseline and 10 to 12 weeks after start of treatment with targeted therapy. DCE-CT included a dynamic acquisition after injection of 50 ml of nonionic contrast agent at 6 ml/s using a 4D spiral mode (10 cm z-axis coverage, acquisition time 43 sec, 100 kVp (abdomen), 80 kVp (chest), 80-100 mAs) on a dual source scanner (Definition FLASH, Siemens). Blood flow (BF) was calculated for target tumor volumes using a deconvolution model. Progression free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier statistics (SPSS version 24). Patients were treated with either sunitinib, pazopanib, sorafenib, tivozanib, axitinib, or cabozantinib. A cut-off value of 50% blood flow reduction at follow-up allowed for identification of patients with favorable long-term outcome: Median OS in n = 42 patients with an average blood flow reduction of >50% (mean, 79%) was 34 (range, 14-54) months, while n = 21 patients with an average reduction of less than 50% (mean, 28%) showed a median OS of 12 (range, 6-18) months, and n = 8 patients with an increase in blood flow survived for a median of 7 (range, 3-11) months. Blood flow in metastases measured with DCE-CT at first follow-up is a strong predictor of overall survival in mRCC patients on antiangiogenic treatment.

PD40-12 DEFINING THE IMPACT OF PERIOPERATIVE MORBIDITY FROM CYTOREDUCTIVE NEPHRECTOMY ON THE TIMING OF SYSTEMIC THERAPY: A CONTEMPORARY SERIES FROM FIVE CENTERS

INTRODUCTION AND OBJECTIVE:For metastatic renal cell cancer (mRCC) patients considering cytoreductive nephrectomy (CN), perioperative morbidity may delay or preclude post-operative systemic therapy...

537P-SC Exposure-response analysis of cabozantinib in patients with metastatic renal cell cancer treated in routine care

In the registration trial, cabozantinib (cabo) exposure ≥750 μg/L correlated to improved tumor size reduction, response rate and progression-free survival (PFS) in metastatic renal cell cancer (mRCC) patients (pts). Because pts in routine care differ from pts in clinical trials, we explored the cabo exposure-response (E-R) relationship in mRCC pts treated in routine care.

Nephrectomy improves the survival of metastatic renal cell cancer patients with moderate to good performance status\u2014results from a Finnish nation-wide population-based study from 2005 to 2010

BackgroundThe purpose of this study was to evaluate the effects of cytoreductive nephrectomy (CN) and metastasectomies on the survival of patients with synchronous metastatic renal cell cancer (mRCC) using real-life, population-based national dataset.MethodsNationwide data, including all cases of synchronous mRCC in Finland diagnosed on a 6-year timeframe, based on the Finnish Cancer Registry and complemented with patient records from the treating hospitals, were analyzed. Patients with Eastern Cooperative Oncology Group (ECOG) performance status 3–4 were excluded. Univariate and adjusted multivariable survival analysis were performed, including subgroup analysis for patients with different medical therapies. Nephrectomy complications were also analyzed.ResultsA total of 732 patients were included in the analysis. CN was performed for 389 (53.1%) patients, whereas 68 (9.3%) patients underwent nephrectomy and metastasectomies of all lesions (surgery with curative intent). Median overall survival (OS) for patients who did not undergo nephrectomy was 5.9 (95% confidence interval [CI] = 4.6–7.2) months. Patients who had a CN had a median OS of 16.6 (95% CI = 14.2–19.1, p < 0.001) months, whereas patients who had surgery with curative intent had a median OS of 51.3 (95% CI = 36.0–66.6, p < 0.001) months. The survival benefit of CN and metastasectomies remained significant in all medical therapy subgroups and in both of the applied multivariable statistical models.ConclusionsSurgical treatment of metastatic renal cell cancer is associated with a significant survival benefit in patients with good and moderate performance status, regardless of the chosen medical therapy.

Peri-operative morbidity and mortality in a modern series of patients treated with cytoreductive nephrectomy (CN) at five centers.

268 Background: For metastatic renal cell cancer (mRCC) patients considering cytoreductive nephrectomy (CN), perioperative morbidity is important to discuss but few contemporary multi-institutional data are available. The objective of this study is to describe factors associated with perioperative outcomes in a modern multi-institutional cohort of patients treated with cytoreductive nephrectomy. Methods: Data for perioperative complications was recorded for patients treated with CN at 5 centers from 2005-2019. Postoperative complications within 90 days were categorized using Clavien- Dindo system. Univariate and multivariable analysis was used to evaluate for associations with complications and 90-day mortality. Factors evaluated included receipt of pre-surgical systemic therapy, ECOG performance status (PS), Charlson comorbidity index (CCI), concurrent IVC thrombectomy, age, and surgical approach (open vs. laparoscopic/robotic). Results: Perioperative outcomes were evaluated in 937 consecutive patients treated with CN at 5 institutions from 2005-2019. Median age at surgery was 61 years (IQR 53-68) and median tumor diameter was 9.8cm (IQR 7-12).Venous thrombus was present in 406/937 (43.3%) patients overall including 65/406 (16%) patients for whom IVC thrombus extended above the hepatic veins. Open and laparoscopic/robotic approach was used in 715 (76.3%) and 290 (23.4%) patients. The median ECOG PS was 1 (IQR 0-1) and median CCI was 1 (IQR 0-2). Pre-surgical systemic therapy was given to 243 (25.9%) patients prior to CN. The median length of hospital stay was 5 days (IQR 4-7) and 429 (34.6%) received blood transfusion. Median length of stay was 3.0 (IQR 2-4) for laparoscopic/robotic approach and 6 days (IQR 4-8) for patients with IVC thrombectomy. Hospital readmission within 30 days was identified in 112 (9.0%) patients. A total of 93/937 (9.9%) patients had major (≥Clavien 3) complications identified within 90 days postoperatively. On multivariable analysis, IVC thrombectomy was associated with higher risk of major complications OR 1.95 (95% CI 1.2-3.1), p = 0.006. Pre-surgical systemic therapy, ECOG PS, CCI, age and surgical approach were not associated with major complications (p = 0.09-0.85). Perioperative mortality was 12/937 (1.3%) at 30 days and 51/937 (6.7%) at 90 days. After multivariable analysis, pre-surgical systemic therapy, ECOG PS, CCI, age, and IVC thrombectomy were not associated with perioperative mortality (p = 0.1-0.85). Conclusions: Cytoreductive nephrectomy is associated with major complications for 10% of patients and 1% mortality at 30 days. Pre-surgical systemic therapy was not associated with increased risk of complications or mortality.

Association between Immune Related Adverse Events and Outcome in Patients with Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors.

Simple SummaryPatients treated with immune-checkpoint inhibitors often experience a wide range of peculiar adverse events, called immune-related adverse events (irAEs). Lately, it has been described that the presence of irAEs may be associated with better clinical response to immunotherapy. The aim of our retrospective study was to observe the onset of the most common side effects and to evaluate their potential prognostic impact in a cohort of metastatic renal cell cancer patients treated with immunotherapy. We confirmed a correlation between irAEs and progression free survival in patients with cutaneous and thyroid adverse reactions as well as in patients that experienced two or more irAEs. Thus, the development of irAEs could act as a clinical marker of efficacy in metastatic renal cell patients treated with immunotherapy.Background: It has been reported that the occurrence of immune-related adverse events (irAEs) in oncological patients treated with immune-checkpoint inhibitors (ICIs) may be associated with favorable clinical outcome. We reported the clinical correlation between irAEs and the efficacy of ICIs in a real-world cohort of metastatic renal cell cancer (mRCC) patients. Methods: We retrospectively evaluated 43 patients with mRCC who were treated with nivolumab or with nivolumab plus ipilimumab. We considered seven specific classes of irAEs including pulmonary, hepatic, gastrointestinal, cutaneous, endocrine, rheumatological, and renal manifestations. We assessed progression-free survival (PFS) of specific irAEs classes compared to the no-irAEs group. Results: Twenty-nine out of 43 patients (67.4%) experienced a total of 49 irAEs registered. The most frequent irAE was thyroid dysfunction (n = 14). The median PFS after the beginning of therapy was significantly longer in patients with thyroid dysfunction and cutaneous reactions. In multivariate analysis, thyroid dysfunction was an independent factor for favorable outcome [HR: 0.29 (95% CI 0.11–0.77) p = 0.013]. Moreover, experiencing ≥2 irAEs in the same patient correlated in multivariate analysis with better outcome compared with none/one irAE [HR: 0.33 (95% CI 0.13–0.84) p = 0.020]. Conclusions: This retrospective study suggests an association between specific irAES (thyroid dysfunction and skin reaction) and efficacy of ICIs in metastatic RCC. Notably, multiple irAEs in a single patient were associated with better tumor response.

Toxicities of axitinib, sunitinib and temsirolimus: implications for progression-free and overall survival in metastatic renal cell cancer.

The aim of this study was to evaluate the association between axitinib, sunitinib and temsirolimus toxicities and patient survival in metastatic renal cell cancer patients. Overall survival (OS) and progression-free survival (PFS) of metastatic renal cell cancer patients from the prospective multicenter STAR-TOR study were assessed using multivariable Cox models. A total of 1195 patients were included (n=149 axitinib; n=546 sunitinib; n=500 temsirolimus). The following toxicities significantly predicted outcomes: hand-foot skin reaction (hazard ratio [HR] =0.29) for PFS with axitinib; stomatitis (HR=0.62) and pneumonitis (HR=0.23) for PFS with temsirolimus; stomatitis (HR=0.52) and thrombocytopenia (HR=0.6) for OS with temsirolimus; fatigue (HR=0.71) for PFS with sunitinib; hand-foot skin reaction (HR=0.56) and fatigue (HR=0.58) for OS with sunitinib. In conclusion, in metastatic renal cell cancer, axitinib, sunitinib and temsirolimus demonstrate specific toxicities that are protective OS/PFS predictors.

An Italian, multicenter, real-world, retrospective study of first-line pazopanib in unselected metastatic renal-cell carcinoma patients: the 'Pamerit' study.

Despite the current immunotherapy era, VEGFR inhibitors maintain effectiveness in metastatic renal cell cancer. Real-world data concerning pazopanib are limited. The aim of this study is to add information about efficacy and safety of pazopanib as first-line treatment in metastatic renal cell cancer patients not enrolled into clinical trials. Retrospective analysis (the PAMERIT study) of first-line pazopanib in real-world metastatic renal cell cancer patients among 39 Centers in Italy. Outcomes were progression-free survival, overall survival, objective response rate and treatment-related adverse events. Kaplan-Meier curves, log-rank test and multivariable Cox's models were used and adjusted for age, histology, previous renal surgery, International Metastatic RCC Database Consortium score and pazopanib initial dose. Among 474 patients, 87.3% had clear cell metastatic renal cell cancer histology. Most of them (84.6%) had upfront renal surgery. Median progression-free survival and overall survival were 15.8 and 34.4months, respectively, significantly correlating with International Metastatic RCC Database Consortium's good prognosis (P<0.001), ECOG PS 0 (P<0.001), age (<75years, P=0.005), surgery (P<0.001) and response to pazopanib (P<0.001). After 3months of pazopanib, overall disease control rate have been observed in 76.6% patients. Among International Metastatic RCC Database Consortium's favorable group patients, 57/121 (47%) showed complete/partial response. No unexpected AEs emerged. In this real-world study, metastatic renal cell cancer patients treated with first-line pazopanib reached greater progression-free survival and overall survival than in pivotal studies and had high response rates when belonging to International Metastatic RCC Database Consortium's favorable group, without new toxicities. Pazopanib has been confirmed a valid first-line option for International Metastatic RCC Database Consortium's good prognosis metastatic renal cell cancer patients who cannot be submitted to immunotherapy.

Tyrosine kinase inhibitors in the treatment of metastatic renal cell cancer patients with early cytokine intolerance: TURCOS, a Turkish national, prospective observational study

Cytokines have been the mainstay of treatment in metastatic renal cell cancer (mRCC) for decades before the introduction of tyrosine kinase inhibitors (TKIs), which dramatically changed the therapeutic landscape in these patients. This observational study was designed to evaluate use of TKIs in the treatment of cytokine-intolerant mRCC patients. A total of 151 cytokine-intolerant mRCC patients who were treated with TKIs (sunitinib, pazopanib and sorafenib) were enrolled in this prospective, non-interventional, multi-center observational study at 16 oncology centers across Turkey. Mean (SD) age was 61.3 (11.1) years and 74.8% were males. Data on duration of TKI treatment was the primary outcome measure. Additionally, overall response rate (ORR), progression free survival (PFS), overall survival (OS) and safety data were recorded. Median duration of treatment was 8.2 months at a median follow up of 17.9 months. ORR and disease control rate were 12.5% and 70.8%, respectively. Median PFS and OS were 7.5 months (95%CI: 6.4-10.4) and 27.3 months (95%CI: 17.6-27.3) with no significant difference among three TKI agents in terms of treatment duration, ORR, PFS and OS. The most common adverse events excluding progression-which was the protocol requirement were diarrhea (13.6%), asthenia (13.6%) and hand-foot syndrome (12.6%). Dose modifications were required in 30.5% of the patients and 15% discontinued TKIs because of toxicity. Our findings confirm the efficacy and safety profile of TKIs in the first-line treatment of mRCC patients intolerant to cytokine treatment. There was no significant difference among three TKI agents in terms of treatment duration, ORR, PFS and OS.Trial registration: TURCOS ClinicalTrials.gov Identifier: NCT01585974. Registered April 25, 2012.

Genetic Alterations in Renal Cancers: Identification of The Mechanisms Underlying Cancer Initiation and Progression and of Therapeutic Targets.

Renal cell cancer (RCC) involves three most recurrent sporadic types: clear-cell RCC (70–75%, CCRCC), papillary RCCC (10–15%, PRCC), and chromophobe RCC (5%, CHRCC). Hereditary cases account for about 5% of all cases of RCC and are caused by germline pathogenic variants. Herein, we review how a better understanding of the molecular biology of RCCs has driven the inception of new diagnostic and therapeutic approaches. Genomic research has identified relevant genetic alterations associated with each RCC subtype. Molecular studies have clearly shown that CCRCC is universally initiated by Von Hippel Lindau (VHL) gene dysregulation, followed by different types of additional genetic events involving epigenetic regulatory genes, dictating disease progression, aggressiveness, and differential response to treatments. The understanding of the molecular mechanisms that underlie the development and progression of RCC has considerably expanded treatment options; genomic data might guide treatment options by enabling patients to be matched with therapeutics that specifically target the genetic alterations present in their tumors. These new targeted treatments have led to a moderate improvement of the survival of metastatic RCC patients. Ongoing studies based on the combination of immunotherapeutic agents (immune check inhibitors) with VEGF inhibitors are expected to further improve the survival of these patients.

Prognostic Importance of Metastatic Site in Intermediate-risk Group Metastatic Renal Cell Cancer Treated with Tyrosine Kinase Inhibitors.

To determine the prognostic importance of the metastatic site in metastatic renal cell cancer (mRCC) patients in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate-risk. Observational study. Department of Medical Oncology, Dr Abdurrahman Yurtaslan Oncology Training and Research Hospital, Ankara, Turkey, from January 2010 to November 2018. Records of 113 mRCC patients, determined to be in the intermediate-risk group according to IMDC criteria, were reviewed retrospectively. All patients used a tyrosine kinase inhibitor - sunitinib or pazopanib - for metastatic disease. Patients' records included age, gender, metastatic site, number of metastases and treatment regimen. The Kaplan-Meier method was used for survival analysis, and a Cox regression model was formed. The median age of the patients was 58 years (Q1 - Q3: 44 - 66 years) and 87.6% of the patients had ≥2 metastatic sites. The most common metastatic sites were the lung (51.3%), lymph nodes (26.5%), bone (26.5%) and brain (17.7%). Median overall survival (OS) was shorter in the patients with bone and brain metastasis than in those without (15.0 months vs. 21.0 months, p = .026 and 14.0 months vs. 21.0 months, p = .009, respectively). Multivariate analysis showed that brain and bone metastasis were independent prognostic risk factors (HR: 2.43, p = .017 and HR: 2.10, p = .042, respectively). Bone and brain metastasis had a negative effect on OS in IMDC intermediate-risk group mRCC patients. Key Words: Metastatic site, Brain metastasis, Bone metastasis, Renal cell carcinoma, Prognosis.

A phase II multicenter study of stereotactic radiotherapy (SRT) for oligoprogression in metastatic renal cell cancer (mRCC) patients receiving tyrosine kinase inhibitor (TKI) therapy.

5065 Background: SRT is increasingly considered to delay the need to change systemic therapy in metastatic cancer patients who develop oligoprogression. This prospective phase II study evaluated the use of SRT in the setting of mRCC patients who developed oligoprogression while on 1st or 2nd line TKI therapy. Methods: IMDC favourable or intermediate risk mRCC patients (pts) who had previous stability or response on ≥ 3 months of TKI therapy were eligible if they developed radiographic progression of ≤ 5 metastases. The oligoprogressive tumours were treated with SRT while other metastases which were stable or responding to TKI therapy were left alone. TKI therapy was temporarily stopped during SRT, and the same TKI drug then resumed. Endpoints included local control of the irradiated lesions, progression free survival (PFS), overall survival (OS), and cumulative incidence of changing systemic therapy after study entry. Results: 37 pts (median age 63, IMDC favourable 12, intermediate 25) with 57 oligoprogressive tumours were enrolled. 35 pts were on sunitinib and 2 on pazopanib. Median duration of TKI therapy prior to study entry was 18.6 months. 4 pts had IL-2 therapy prior to a 2nd line TKI. 21 pts had a solitary oligoprogressive tumour, while 17 pts had 2-3 oligoprogressive tumours treated with SRT. Median biological effective dose (BED10) was 72 Gy, corresponding to an SRT dose of 40 Gy in 5 fractions. Irradiated tumour sites were the following: 21 lung/pleural, 15 bone, 7 lymph node, 4 adrenal, 4 liver, 3 brain, 2 spleen, and 1 pancreas. At a median followup of 11.6 (1.8-53.5) months the median PFS from study entry was 9.6 months (95%CI 7.4-20.5) with the vast majority of progression occurring outside of the irradiated areas. The 2-year local control of the irradiated tumours was 96%. The 2-year OS from study entry was 77%. The cumulative incidence of changing systemic therapy was 47% at 1 year and 75% at 2 years, with a median time to a change in systemic therapy of 12.6 months. There were no grade 3-5 SRT related toxicities. Conclusions: To our knowledge, this is the first prospective evaluation of the use of SRT for oligoprogressive metastatic cancer. Local control of irradiated oligoprogressive mRCC tumours was high. After delivering SRT, mRCC patients did not need a change in their systemic therapy for a median of 1 year, effectively increasing the PFS of their TKI therapy. This novel approach should be studied in patients with oligoprogression on immunotherapy. Clinical trial information: NCT02019576 .

A systematic review: Role of systemic therapy on treatment and prevention of brain metastasis in renal cell carcinoma.

To define the inclusion/exclusion status of patients with brain metastasis in phase-III clinical trials and the effect of systemic therapies in metastatic renal cell cancer patients with brain metastasis. "kidney neoplasms"[MeSH Terms] OR ("kidney"[All Fields] AND "neoplasms"[All Fields]) OR "kidney neoplasms"[All Fields] OR ("kidney"[All Fields] AND "cancer"[All Fields]) OR "kidney cancer"[All Fields] AND "brain metastasis" were used for searching "PubMed" electronic database and "clinicaltrials.gov" website. Five of 19 landmark phase-III clinical trials included patients with stable or asymptomatic brain metastasis and there was no data about outcomes of brain metastasis. The effect of systemic therapy on prevention of brain metastasis in renal cell cancer was evaluated in four studies. Two studies showed that the incidence of brain metastasis decreased, while the other two studies showed no effect of antiangiogenic agents on the prevention of brain metastasis in patients with renal cell cancer. There were 10 trials regarding systemic therapy of renal cell cancer brain metastasis. The overall response rate improved through a combination of targeted therapies and local treatment. The results of the trials studying the effect of tyrosine kinase inhibitors without local treatment were controversial. None of the ongoing clinical trials included patients with active brain metastasis. In metastatic renal cell cancer patients with brain metastasis, the overall response rate improved with the combination of targeted agents and local treatment. Further trials are needed to evaluate the effect of systemic treatment on the prevention or treatment of brain metastasis in patients with renal cell cancer.

Cytoreductive nephrectomy: does CARMENA (Cancer du Rein Metastatique Nephrectomie et Antiangiogéniques) change everything?

Over the past few years the treatment options for renal cell cancer (RCC) have rapidly evolved. Even in the setting of metastatic disease, a consistent component of treatment in RCC patients has been cytoreductive nephrectomy based on the results of research carried out over a decade ago. Despite huge shifts in systemic treatment modalities, cytoreductive nephrectomy continued to be recommended despite a lack of evidence for its use in metastatic RCC in those patients receiving state-of-the-art therapies. To address the lack of evidence, two recent trials [Cancer du Rein Metastatique Nephrectomie et Antiangioge[Combining Acute Accent]niques (CARMENA) and SURTIME] sought to assess the role and sequence of cytoreductive nephrectomy in metastatic RCC patients receiving vascular endothelial growth factor-targeted tyrosine kinase inhibitor treatment. The results of one of these trials, namely CARMENA, demonstrated no benefit of cytoreductive nephrectomy when used in combination with the vascular endothelial growth factor-targeted tyrosine kinase inhibitor Sunitinib. However, with further developments in medical treatment and questions regarding the specific methods of the trial - do these results change everything for the role of cytoreductive nephrectomy? While the results from CARMENA and SURTIME are not conclusive, they suggest that those patients with advanced disease requiring systemic therapy should indeed receive this first prior to any cytoreductive nephrectomy.

212P - Immunotherapy with nivolumab in metastatic renal cell carcinoma patients in India: Bringing a change in clinical practice

BackgroundThe standard practice for management of metastatic renal cell cancer (mRCC) patients in India has been sunitinib or pazopanib in the first line setting, and everolimus at progression. Nivolumab in the second line setting, showed a median overall survival (OS) of 26 months, 2year OS rate of 52% and objective response rate(ORR) of 26%; which was better than everolimus in the Checkmate 025 study. There is sparse data about nivolumab in Indian RCC patients. MethodsThis is a single centre, retrospective analysis, which included mRCC patients who received nivolumab between April 2016 to April 2019. The endpoints were ORR, OS and adverse events (AEs). Results31 patients of mRCC received nivolumab at 3 mg/kg or flat dose of 240mg. Median age was 60 years (22-82 years). There were 27 males and 4 females. 4 patients received first line nivolumab, and 27 patients as second line. 16 patients had earlier received sunitinib, 10 pazopanib, and 1 sorafinib. 3 patients (9.7%) achieved complete response(CR), 8(25.8%) achieved partial response, 8(25.8%)had stable disease and 12(38.7%)had progressive disease. The 3 patients with CR, received 18 doses, after which their treatment was stopped; and they continue to be in CR at followup of 36, 32 and 26 months respectively. 10 patients have completed more than 12 cycles. OS at 1 year is 60% and median OS has not been reached. The common AEs were fatigue in 8(25.8%), hypothyroidism in 6(19.3%), skin rash in 4(12.9%) and pneumonitis in 3(9.7%) patients. Colitis, arthritis, immune retinopathy, and myocarditis was each seen in 1 patient. Treatment was discontinued in 3 patients who developed grade 3 AEs. ConclusionsWith an ORR of 35.5%, nivolumab has replaced everolimus, and has become our standard second line regimen in mRCC. Achieving an OS at 1 year of 60% is the best we have seen in the second line setting. The most exciting impact has been the durable long lasting response seen (duration ranging 2-3 years) even after discontinuing treatment, in our 3 CR patients. This has prompted us to make 1 year of treatment as a standard duration of nivolumab for responding patients at our center; enabling us to reduce cost of treatment. It is very well tolerated; but a careful watch should be kept for immune related AEs. Legal entity responsible for the studyAmit Rauthan. FundingHas not received any funding. DisclosureA. Rauthan: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: Pfizer. All other authors have declared no conflicts of interest.

1274P - A prospective cohort study on the pharmacokinetics of nivolumab in metastatic non-small cell lung cancer, melanoma, and renal cell cancer patients

BackgroundNivolumab is currently administered in a weight-based or fixed-flat dosing regimen. Approved fixed-flat dosing regimens have been solely based on simulations from dose-finding clinical trials. For patients with non-small cell lung cancer (NSCLC), a potential exposure-response relationship has recently been reported, suggesting that nivolumab dosing needs further optimization. In this study, we determined nivolumab pharmacokinetics (PK) and assessed the relationship between nivolumab clearance (CL) and tumor response in patients with NSCLC, melanoma, and renal cell cancer (RCC). MethodsIn this prospective observational cohort study (MULTOMAB trial; Dutch Trial Registry NL6828), individual estimates of nivolumab CL and the impact of baseline covariates were determined using population-PK (PPK) modeling. The study was approved by the independent ethics committee (MEC 16-011). All patients provided written informed consent. Stratified by tumor type, CL was related to best overall response (RECIST v1.1) using ANOVA and post-hoc samples t-test. ResultsIn total 1,715 nivolumab serum concentrations were analyzed from 221 patients who were treated with monotherapy nivolumab (NSCLC n=158; melanoma n=48; RCC n=14; mesothelioma n=1). The baseline parameters gender, body surface area (BSA), and serum albumin had a significant effect on nivolumab CL and were internally validated in the PPK model. Women had 22% lower CL than men, Patients with BSA > 2.2 m2 or with baseline albumin <37.5g/L had >20% higher CL than the population mean. For NSCLC, CL was 42% higher in patients with progressive disease (mean: 0.24; 95%CI: 0.22-0.27L/day) compared to patients with partial/complete response (0.17; 0.15-0.19). Although a similar trend was observed in RCC, no CL-response relationship was observed in melanoma patients. ConclusionsWe generated the first real-world PPK model of nivolumab, in which covariate analysis revealed a significant effect of gender, BSA, and albumin on nivolumab CL. A significant CL-response relationship was observed in patients with NSCLC, but not in patients with melanoma. Individualized dosing regimens might therefore increase nivolumab efficacy in patients with NSCLC. Clinical trial identificationMULTOMAB trial; Dutch Trial Registry NL6828. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureA.A.M. Van der Veldt: Advisory / Consultancy: BMS. J.G. Aerts: Advisory / Consultancy: BMS. All other authors have declared no conflicts of interest.