Sunitinib Group Research Articles

EFFICACY OF NEOADJUVANT TARGETED THERAPY IN TREATMENT OF PATIENTS WITH LOCALISED CLEAR-CELL RENAL CELL CARCINOMA

Clear-cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, accounting for approximately 75-80% of all renal malignancies. Objectives: The main objective of the study is to find the efficacy of neoadjuvant targeted therapy in the treatment of patients with localised clear-cell renal cell carcinoma. Methods: This prospective study was conducted at Mardan Medical Complex from June 2023 to January 2024. Data were collected from 85 patients. Patients aged>18 years and have a histologically confirmed diagnosis of localized ccRCC were included in the study. Tumor size was required to be 4 cm or larger, but confined to the kidney, corresponding to Stage I to III disease. Results: Data were collected from 85 patients with an average baseline tumour size for the entire cohort was 7.5 cm, and after 12 weeks of treatment, tumours shrank to an average of 5.6 cm, resulting in a mean tumour reduction of 25%. In the sunitinib group, the tumour size decreased from 7.5 cm to 5.55 cm, reflecting a 26% reduction. Similarly, in the pazopanib group, the tumour size was reduced from 7.5 cm to 5.65 cm, with an average reduction of 24%. Conclusion: It is concluded that neoadjuvant targeted therapy, using agents such as sunitinib and pazopanib, effectively reduces tumour size and improves surgical outcomes in patients with localized clear-cell renal cell carcinoma.

Prognostic value of type of prior TKI in pretreated metastatic renal cell carcinoma patients receiving nivolumab.

Aim: To define the prognostic significance of first-line TKI in mRCC patients receiving nivolumab.Materials and methods: A total of 571mRCC patients who received ≥second line nivolumab were included in this subanalysis. The correlation between prior TKI (sunitinib vs. pazopanib) and overall response rate (ORR), disease control rate, progression-free survival and overall survival were investigated. Additionally, the impact of TKI choice according to the International Metastatic RCC Database Consortium prognostic score was examined.Results: There was no significant difference between sunitinib and pazopanib groups in terms of mPFS, mOS, overall response rate and disease control rate. Moreover, no difference between sunitinib and pazopanib was found according to the International Metastatic RCC Database Consortium prognostic score.Conclusion: There is no conclusive evidence favoring pazopanib or sunitinib treatment before initiating nivolumab therapy in metastatic renal cell carcinoma patients.

Comparison of the Efficacy and Safety of Nivolumab Plus Cabozantinib versus Sunitinib in the Treatment of Elderly Patients with Advanced Clear Cell Renal Cell Carcinoma.

Advanced clear cell renal cell carcinoma (ccRCC) seriously affects the life and health of patients, but effective treatment for this disease is still lacking in clinic. This study investigated the efficacy of nivolumab plus cabozantinib versus sunitinib in the treatment of elderly patients with advanced ccRCC. The clinical data of 216 elderly patients with advanced ccRCC in our hospital from January 2020 to January 2022 were retrospectively analysed. On the basis of different treatment regimens, patients were divided into the cabozantinib group (n = 111, receiving nivolumab and cabozantinib) and the sunitinib group (n = 105, receiving nivolumab and sunitinib). The overall survival time, disease control rates, health status, incidence of adverse events and identification of prognostic risk were compared between the two groups. The cabozantinib group had higher overall survival time, disease control rate and scores in the Functional Assessment of Cancer Therapy-Kidney Symptom Index and EuroQol-Five Dimensions-Three Levels Questionnaire than the sunitinib group. The incidence of adverse events in the cabozantinib group was lower than that in the sunitinib group (p < 0.001). However, no difference existed in the identification of prognostic risk between the two groups (p > 0.05). The effect of nivolumab plus cabozantinib on the treatment of elderly patients with advanced ccRCC is better than that of nivolumab plus sunitinib, with fewer adverse reactions and higher safety. However, the research results require further clinical studies to confirm and promote.

Sunitinib for metastatic progressive phaeochromocytomas and paragangliomas: results from FIRSTMAPPP, an academic, multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial

No randomised controlled trial has ever been done in patients with metastatic phaeochromocytomas and paragangliomas. Preclinical and first clinical evidence suggested beneficial effects of sunitinib. We aimed to evaluate the safety and efficacy of sunitinib in patients with metastatic phaeochromocytomas and paragangliomas. FIRSTMAPPP is a multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial done at 14 academic centres across four European countries. Eligible participants were adults (aged ≥18 years) with sporadic or inherited progressive metastatic phaeochromocytomas and paragangliomas. Patients were randomly assigned (1:1) to receive either oral sunitinib (37·5 mg per day) or placebo. Randomisation was stratified according to SDHB status (mutation present vs wild type) and number of previous systemic therapies (0 vs ≥1). Primary endpoint was the rate of progression-free survival at 12 months according to real-time central review (Response Evaluation Criteria in Solid Tumours version 1.1). On the basis of a two-step Simon model, we aimed for the accrual of 78 patients, assuming a 20% improvement of the 12-month progression-free survival rate from 20% to 40%, to conclude that sunitinib is effective. Crossover from the placebo group was allowed. This trial is registered with ClinicalTrials.gov, number NCT01371201, and is closed for enrolment. From Dec 1, 2011, to Jan 31, 2019, a total of 78 patients with progressive metastatic phaeochromocytomas and paragangliomas were enrolled (39 patients per group). 25 (32%) of 78 patients had germline SDHx variants and 54 (69%) had used previous therapies. The primary endpoint was met, with a 12-month progression-free survival in 14 of 39 patients (36% [90% CI 23-50]) in the sunitinib group. In the placebo group, the 12-month progression-free survival in seven of 39 patients was 19% (90% CI 11-31), validating the hypotheses of our study design. The most frequent grade 3 or 4 adverse events were asthenia (seven [18%] of 39 and one [3%] of 39), hypertension (five [13%] and four [10%]), and back or bone pain (one [3%] and three [8%]) in the sunitinib and placebo groups, respectively. Three deaths occurred in the sunitinib group: these deaths were due to respiratory insufficiency, amyotrophic lateral sclerosis, and rectal bleeding. Only the latter event was considered drug related. Two deaths occurred in the placebo group due to aspiration pneumonia and septic shock. This first randomised trial supports the use of sunitinib as the medical option with the highest level of evidence for anti-tumour efficacy in progressive metastatic phaeochromocytomas and paragangliomas. French Ministry of Health, through the National Institute for Cancer, German Ministry of Education and Research, and the German Research Foundation within the CRC/Transregio 205/2, EU Seventh Framework Programme, and a private donator grant.

FDA pooled analysis of overall survival according to depth of response as a continuous variable in frontline advanced immuno-oncology renal cell carcinoma trials.

418 Background: Retrospective analyses of individual studies of immune-oncology-containing combinations (IOC) for advanced renal cell carcinoma (aRCC) suggest that depth of response (DepOR; % reduction from baseline in sum of target lesion diameters) is associated with overall survival (OS). However, these analyses are limited by use of DepOR categories with a small number of patients and guarantee-time bias. We therefore sought to investigate the relationship of week 12 DepOR as a continuous variable with OS, hypothesizing not only complete but also deep partial responses might portend favorable longer-term survival. Methods: We pooled data from patients with treatment (tx)-naïve aRCC enrolled in randomized IO-based frontline aRCC trials submitted to FDA that included a Week 12 imaging assessment. We developed 36-month (mo) overall survival (OS) prediction models based on Week 12 DepOR per Independent Review Committee using Cox proportional hazards with natural spline in the IO-TKI combination (IOC) and sunitinib (SUN) groups. To avoid guarantee-time bias, OS was defined from date of an individual patient’s 12-week imaging, among the subset of patients who were alive and in follow-up at the Week 12 scan. Results: Four trials met inclusion criteria (KEYNOTE-426, JAVELIN Renal 100, CheckMate 9ER, CheckMate 214); in total there were 1364 patients in the IOC group and 1267 patients in the SUN group. Eligibility criteria, baseline patient characteristics, and endpoints were similar both between the trials and between tx groups. Deepest response occurred at median 31 weeks (interquartile range [IQR], 18-55) in the IOC group and 29 weeks (IQR range, 17-48) in the SUN group. At Week 12, 34.7% of patients had DepOR of at least 30%; median DepOR was 27.6% (interquartile range [IQR] 8.7 to 43.4%) in the IOC and 13.7% (IQR 2.5 to 26.3%) in the SUN group. DepOR and 36-month OS were correlated throughout the entire range of DepOR in both tx groups; at each DepOR, the IOC group had slightly higher 36-mo OS over SUN. We saw similar results modeling 24-month OS compared to 36-month OS. Conclusions: This pooled exploratory analysis suggests that deeper response is associated with better 36-month OS in patients treated with IOC or SUN and slightly higher probability of 36-month OS for any given DepOR for IOC vs. SUN. We saw no plateau in OS as DepOR approached complete response. However, caution should be used when interpreting DepOR at the tails due to sparse data. Further work characterizing the relationship between DepOR and OS at the trial level may advance understanding of the utility of DepOR as an early endpoint in signal-seeking trials and to facilitate efficient drug development. Additionally, identifying patients with favorable long-term prognosis based on DepOR provides hypotheses for new trial designs.

The Relationship Between Health-Related Quality of Life and Overall Survival in Patients With Advanced Renal Cell Carcinoma in CheckMate 214.

In CheckMate 214 (median follow-up, 25.2 months), nivolumab plus ipilimumab yielded greater overall survival (OS) benefit than sunitinib in patients with intermediate-/poor-risk advanced renal cell carcinoma (aRCC). Health-related quality of life (HRQoL) assessed by the Functional Assessment of Cancer Therapy-Kidney Symptom Index-19 (FKSI-19) was also more favorable for the nivolumab plus ipilimumab group than the sunitinib group. We investigated whether HRQoL scores can predict OS of patients with 5 years follow-up in CheckMate 214. CheckMate 214 was an open-label, phase III trial in previously untreated aRCC (N = 1096). Patients with intermediate-/poor-risk disease (International mRCC Database Consortium prognostic score ≥ 1; n = 847) were randomized to either nivolumab plus ipilimumab or sunitinib monotherapy. Pooled data for OS and FKSI-19 total and subscales (disease-related symptoms [DRS], DRS-physical [DRS-P], and function/well-being [FWB]) were analyzed. Relationships between HRQoL and OS were assessed using Cox proportional hazard models with baseline and longitudinal scores. Associations between HRQoL changes and OS were assessed by landmark analyses. Patients with higher FKSI-19 total and subscale scores at baseline had longer OS than patients with lower scores (HR ≤ 0.834; P < .0001). Longitudinal models indicated stronger associations between HRQoL and OS (HR ≤ 0.69; P < .001 for each). At 3 months after randomization, patients with stable/improved HRQoL versus baseline had longer median OS than patients with worsened/unobserved HRQoL versus baseline (55.9 and 26.0 months, respectively; HR = 0.56; 95% CI, 0.46-0.67; P < .0001). Results at 6-, 9-, and 12-month landmarks were consistent with these findings. In aRCC, patient-reported outcomes are important for HRQoL and prognostic evaluation. NCT02231749; https://clinicaltrials.gov/ct2/show/NCT02231749.

Toripalimab plus axitinib versus sunitinib as first-line treatment for advanced renal cell carcinoma: RENOTORCH, a randomized, open-label, phase III study

Immune checkpoint inhibitors in combination with tyrosine kinase inhibitors are standard treatments for advanced clear cell renal cell carcinoma (RCC). This phase III RENOTORCH study compared the efficacy and safety of toripalimab plus axitinib versus sunitinib for the first-line treatment of patients with intermediate-/poor-risk advanced RCC. Patients with intermediate-/poor-risk unresectable or metastatic RCC were randomized in a ratio of 1 : 1 to receive toripalimab (240 mg intravenously once every 3 weeks) plus axitinib (5 mg orally twice daily) or sunitinib [50 mg orally once daily for 4 weeks (6-week cycle) or 2 weeks (3-week cycle)]. The primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). The secondary endpoints were investigator-assessed PFS, overall response rate (ORR), overall survival (OS), and safety. A total of 421 patients were randomized to receive toripalimab plus axitinib (n= 210) or sunitinib (n= 211). With a median follow-up of 14.6 months, toripalimab plus axitinib significantly reduced the risk of disease progression or death by 35% compared with sunitinib as assessed by an IRC [hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.49-0.86; P= 0.0028]. The median PFS was 18.0 months in the toripalimab-axitinib group, whereas it was 9.8 months in the sunitinib group. The IRC-assessed ORR was significantly higher in the toripalimab-axitinib group compared with the sunitinib group (56.7% versus 30.8%; P < 0.0001). An OS trend favoring toripalimab plus axitinib was also observed (HR 0.61, 95% CI 0.40-0.92). Treatment-related grade ≥3 adverse events occurred in 61.5% of patients in the toripalimab-axitinib group and 58.6% of patients in the sunitinib group. In patients with previously untreated intermediate-/poor-risk advanced RCC, toripalimab plus axitinib provided significantly longer PFS and higher ORR than sunitinib and had a manageable safety profile TRIAL REGISTRATION: ClinicalTrials.gov NCT04394975.

Sorafenib exhibits lower toxicity and comparable efficacy to sunitinib as a first-line treatment for metastatic renal cell carcinoma: A systematic review and meta-analysis.

To assess the safety and efficacy of sorafenib and sunitinib as first-line treatments for metastatic renal cell carcinoma (mRCC), to provide evidence-based support for clinical decision-making regarding rational drug use. Until May 10, 2023, a comprehensive search was conducted across PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, China National Knowledge Infrastructure, and Wanfang databases to identify clinical studies comparing sorafenib with sunitinib as first-line treatment for mRCC. The literature was screened, data extracted, and quality evaluated independently by 2 researchers. Meta-analysis was conducted using Revman5.4 software. A total of 3741 patients were enrolled in 20 studies. The meta-analysis results indicated that there were no significant differences in the 2- and 5-year progression-free survival (PFS) and overall survival (OS) rates between the sorafenib and sunitinib groups (P > .05). The disease control rate (DCR) was comparable between the 2 groups (P > .05), while the objective response rate (ORR) was higher in the sunitinib group (P = .03). However, subgroup analysis revealed no significant differences in ORR, DCR, 2- and 5-year PFS, and OS rates between sorafenib and sunitinib among both Asian populations as well as European and American populations (P > .05). In terms of drug-related adverse events, the incidence of grade ≥ 3 hypertension, leukopenia, neutropenia, thrombocytopenia, anemia, nausea and vomiting were significantly lower in the sorafenib group compared to the sunitinib group (P < .05). In the first-line treatment of mRCC, sorafenib exhibits comparable efficacy to sunitinib but with lower toxicity.

Long-term liver and renal dysfunction in patients with metastatic renal cell carcinoma treated with TKI monotherapy: COMPARZ study post-hoc analysis.

e16536 Background: Tyrosine kinase inhibitors (TKI) are currently the recommended treatment option for advanced renal cell carcinoma (aRCC) patient. Previous studies have shown some hepatorenal toxicity of TKI regimens, but differences in toxicity and long-term toxicity of TKIs have rarely been reported. This study aims to compare short- and long-term hepatorenal toxicity differences between pazopanib and sunitinib, and to explore the factors predisposing to hepatorenal toxicity. Methods: COMPARZ study was a randomized phase III non-inferiority study comparing pazopanib and sunitinib in aRCC patients. Patients without liver metastasis and with available alanine transaminase (ALT), aspartate transaminase (AST), and total bilirubin results were enrolled to evaluate the effect of TKI on liver function. Patients with available serum creatinine (Cr), blood urea nitrogen (BUN), urine protein/creatinine ratio (UPC), and creatinine clearance (CrCl) were enrolled to evaluate factors associated with abnormal renal function. Lab indicators were compared between baseline and at months 12, 24, and 36 by paired t-test respectively. Linear mixed models were used to compare the difference in changes between treatment arms. Multivariate logistic regression was performed to examine the factors associated with recorded adverse events of hepatorenal toxicities. Results: Patients with abnormal liver function tests at baseline had higher elevated ALT, AST and total bilirubin levels at 12 months after TKIs treatment compared with patients who had normal baseline results. ALT levels were not significantly different between pazopanib arm and sunitinib arm at 12, 24 and 36 months. However, patients in the sunitinib arm had significantly higher AST levels than the pazopanib arm at 12 months (p = 0.049). There was no significant difference in total bilirubin level between pazopanib and sunitinib arm. Asian race and pazopanib were two factors that was significantly associated with increased risk of developing abnormal liver function. At 12 months, Cr levels were higher in the sunitinib arm compared with the pazopanib arm . BUN levels were lower in the pazopanib arm at 12 months but conversely was higher in the sunitinib arm at 24 months. UPC levels were significantly elevated in both treatment arms at 12 months (p &lt; 0.001) and 24 months (p = 0.008). CrCl levels decreased in both treatment arms, and was more obvious in the sunitinib group at 12 months and 24 months. Notably, male patients, Asian race, high BMI, and sunitinib were risk factors that were significantly associated with abnormal renal function. Conclusions: Compared with sunitinib, pazopanib was associated with a higher risk of hepatoxicity but lower risk of nephrotoxicity. Overall, Asian patients have a higher risk of developing abnormal liver and renal functions after TKI treatment.

FDA pooled analysis of overall survival according to depth of response as a continuous variable in frontline advanced immuno-oncology renal cell carcinoma trials.

e16532 Background: Retrospective analyses of individual studies of immune-oncology-containing combinations (IOC) for advanced renal cell carcinoma (aRCC) suggest that depth of response (DepOR; % reduction from baseline in sum of target lesion diameters) is associated with overall survival (OS). However, these analyses are limited by use of DepOR categories with a small number of patients and guarantee-time bias. We therefore sought to investigate the relationship of week 12 DepOR as a continuous variable with OS, hypothesizing not only complete but also deep partial responses might portend favorable longer-term survival. Methods: We pooled data from patients with treatment (tx)-naïve aRCC enrolled in randomized IO-based frontline aRCC trials submitted to FDA that included a Week 12 imaging assessment. We developed 36-month (mo) overall survival (OS) prediction models based on Week 12 DepOR per Independent Review Committee using Cox proportional hazards with natural spline in the IO-TKI combination (IOC) and sunitinib (SUN) groups. To avoid guarantee-time bias, OS was defined from date of an individual patient’s 12-week imaging, among the subset of patients who were alive and in follow-up at the Week 12 scan. Results: Four trials met inclusion criteria (KEYNOTE-426, JAVELIN Renal 100, CheckMate 9ER, CheckMate 214); in total, there were 1364 patients in the IOC group and 1267 patients in the SUN group. Eligibility criteria, baseline patient characteristics, and endpoints were similar both between the trials and between tx groups. Deepest response occurred at median 31 weeks (interquartile range [IQR], 18-55) in the IOC group and 29 weeks (IQR range, 17-48) in the SUN group. At Week 12, 34.7% of patients had DepOR of at least 30%; median DepOR was 27.6% (interquartile range [IQR] 8.7 to 43.4%) in the IOC and 13.7% (IQR 2.5 to 26.3%) in the SUN group. DepOR and 36-month OS were correlated throughout the entire range of DepOR in both tx groups; at each DepOR, the IOC group had slightly higher 36-mo OS over SUN. We saw similar results modeling 24-month OS compared to 36-month OS. Conclusions: This pooled exploratory analysis suggests that deeper response is associated with better 36-month OS in patients treated with IOC or SUN and slightly higher probability of 36-month OS for any given DepOR for IOC vs. SUN. We saw no plateau in OS as DepOR approached complete response. However, caution should be used when interpreting DepOR at the tails due to sparse data. Further work characterizing the relationship between DepOR and OS at the trial level may advance understanding of the utility of DepOR as an early endpoint in signal-seeking trials and to facilitate efficient drug development. Additionally, identifying patients with favorable long-term prognosis based on DepOR provides hypotheses for new trial designs.

Quality-of-life measurement in high-risk patients with uveal melanoma receiving adjuvant sunitinib or valproic acid.

e18692 Background: Despite the successful treatment of primary uveal melanoma (UM), metastasis occurs in up to half of the patients with UM. To delay metastasis for high-risk patients with UM, adjuvant therapy with sunitinib malate or valproic acid (VPA) is used. Therefore, assessing and addressing quality of life (QOL) during adjuvant therapy is essential to mitigate interferences that may prevent these patients from adherence to the therapy protocol and impair their well-being. The objective of this study is to analyze the QOL of these patients during adjuvant therapy with sunitinib or VPA, and to explore differences by the type of adjuvant therapy, age, sex, and the duration of adjuvant therapy. Methods: We analyzed longitudinal surveys of the FACT-G completed by high-risk patients with UM who participated in the randomized phase II clinical trial cohort 1 receiving 6 months of adjuvant sunitinib or VPA and Cohort 2 receiving 12 months of adjuvant sunitinib at a single center. Data were obtained before the initiation of adjuvant therapy and at 1, 3, and 6 months in cohort 1 and at 1, 3, 6, 9, and 12 months in cohort 2. We examined whether there were associations of QOL with the type of adjuvant therapy, age category, sex, and the time of adjuvant therapy using generalized estimating equations (GEE) modeling under the autoregressive working correlation structure (AR1) indexed within subjects by time. Results: There were 720 survey responses collected from 149 UM patients. In our sample, 70.4% (Cohort 1a, n = 45 and Cohort 2, n = 60) were treated with sunitinib and 29.5% (Cohort 1b, n = 44) with VPA. There was no significant difference in the QOL between the sunitinib group 1a and the VPA group 1b (p = 0.958). There was no significant difference in the overall QOL by age range (p = 0.093). However, participants aged 18 to 44 years had significantly lower emotional well-being mean scores (15.32, 95% Cl [13.53, 17.11]) compared to participants aged 65 years and above (19.06, 95% Cl [18.27, 19.86], p &lt; 0.001) but no significant difference with participants aged 45 to 64 years (18.35, 95% Cl [17.53, 19.16], p = 0.193). There was no significant difference in the QOL by sex (p = 0.863) or trend in overall QOL means scores over time as the estimated slope of 0.02 QOL units per month was not significant (95% CI [-0.35, 0.38], p = 0.94). Conclusions: In our high-risk patients with UM, the type of adjuvant therapy, age, sex, and time of adjuvant therapy were not significantly differentiating factors for the QOL scores. Participants aged 18 to 44 years had significantly lower emotional well-being scores. We did not find enough evidence to suggest that there was a change in QOL during adjuvant therapy with sunitinib or VPA.

Efficacy and Safety of First-Line Cytokines versus Sunitinib and Second-Line Axitinib for Patients with Metastatic Renal Cell Carcinoma (ESCAPE Study): A Phase III, Randomized, Sequential Open-Label Study.

The sequence of first-line cytokine and second-line molecular targeted therapies may be suitable for some patients with metastatic renal cell carcinoma (mRCC) because of the expectation of complete remission and durable response achieved with cytokine therapy. This was a phase III randomized controlled trial investigating the outcomes of low-dose interleukin-2 (IL-2) plus interferon alfa (IFNα) versus sunitinib as the first line and axitinib as the second line in patients with low- and intermediate-risk mRCC. Thirty-five patients were randomly assigned. The total progression-free survival (PFS) to the end of the second line was 29.0 months (95% CI, 11.7-46.3) in the IL-2 + IFNα group and 16.3 months (95% CI, 6.3-26.4) in the sunitinib group. The PFS hazard ratio for the IL-2 + IFNα group relative to the sunitinib group was 0.401 (95% CI, 0.121-1.328; p = 0.135). The hazard ratio for overall survival (OS) was 1.675 (95% CI, 0.418-6.705; p = 0.466), which was better in the sunitinib group than in the IL-2 + IFNα group but not statistically significant. The types of adverse events (AEs) differed significantly, although there was no significant difference in the incidence of AEs. There was a trend toward better total PFS for IL-2 + IFNα, but it was not significant. There was also no advantage of IL-2 + IFNα in terms of OS. The study was underpowered to draw any definitive conclusions. The results showed no clear advantage of IL-2 + IFNα over sunitinib in the first-line setting; however, it may be an option in some relatively low-risk mRCC cases due to the difference in the AE profile. This trial was registered with the University Hospital Medical Information Network (UMIN), center identifier UMIN 000012522.

Overall Survival and Updated Results for Sunitinib Compared With Interferon Alfa in Patients With Metastatic Renal Cell Carcinoma.

A randomized, phase III trial demonstrated superiority of sunitinib over interferon alfa (IFN-α) in progression-free survival (primary end point) as first-line treatment for metastatic renal cell carcinoma (RCC). Final survival analyses and updated results are reported. Seven hundred fifty treatment-naïve patients with metastatic clear cell RCC were randomly assigned to sunitinib 50 mg orally once daily on a 4 weeks on, 2 weeks off dosing schedule or to IFN-α 9 MU subcutaneously thrice weekly. Overall survival was compared by two-sided log-rank and Wilcoxon tests. Progression-free survival, response, and safety end points were assessed with updated follow-up. Median overall survival was greater in the sunitinib group than in the IFN-α group (26.4 v 21.8 months, respectively; hazard ratio [HR] = 0.821; 95% CI, 0.673 to 1.001; P = .051) per the primary analysis of unstratified log-rank test (P = .013 per unstratified Wilcoxon test). By stratified log-rank test, the HR was 0.818 (95% CI, 0.669 to 0.999; P = .049). Within the IFN-α group, 33% of patients received sunitinib, and 32% received other vascular endothelial growth factor-signaling inhibitors after discontinuation from the trial. Median progression-free survival was 11 months for sunitinib compared with 5 months for IFN-α (P < .001). Objective response rate was 47% for sunitinib compared with 12% for IFN-α (P < .001). The most commonly reported sunitinib-related grade 3 adverse events included hypertension (12%), fatigue (11%), diarrhea (9%), and hand-foot syndrome (9%). Sunitinib demonstrates longer overall survival compared with IFN-α plus improvement in response and progression-free survival in the first-line treatment of patients with metastatic RCC. The overall survival highlights an improved prognosis in patients with RCC in the era of targeted therapy.

Abstract 2003: Evaluation of liposome encapsulated sunitinib efficacy and immune modulation on renal cell carcinoma

Abstract Renal cell carcinoma (RCC) is one of the deadliest malignant tumors worldwide. The RCC’s standard treatments are including surgery, radiation, and chemotherapy. SUTENT® (sunitinib) was approved by US Food and Drug Administration (FDA) in 2016 to treat advanced RCC. According to the results from the clinical trial, sunitinib is associated with a higher objective response rate and survival rate than IFN-α, which indicates that it is an effective multiple tyrosine kinase inhibitor (TKi) against advanced RCC. Meanwhile, recent studies demonstrated sunitinib could cause tumor immune surveillance by upregulated autophagy to inhibit tumor PD-L1 expression. However, sunitinib targets not only tumor tissue but also multiple organs in the human body, which causes many serious side effects and even leads to death. In order to reduce the toxicity of sunitinib, our group design a novel nanocarrier by PEGylated liposome to encapsulate sunitinib (lipo-sunitinib). The PEGylated liposome could passively target tumor tissue by extravasation of nanoparticles through increased permeability of the tumor vasculature (enhanced permeability and retention, EPR effect). Moreover, the PEGylation on the liposome surface could prolong liposome half-life in the body through increased particle size. Through the EPR effect and PEGylation of lipo-sunitinib to target tumor cells precisely, we successfully increased RCC orthotopic tumor inhibition in mouse models compared with vehicle and sunitinib groups. Furthermore, the RCC tumor immunofluorescence staining revealed lipo-sunitinib had higher activated effector T cells (CD8+IL-2+IFN-γ+) and type 1 dendritic cells (CD11c+CD24+MHCII+) infiltration and lower vessel formation than sunitinib group. The flow cytometry also demonstrated that lipo-sunitinib had increased anti-tumor immune cells and inhibited immune suppressors in the systemic system. More importantly, lipo-sunitinib showed lower toxicity in mouse livers, hearts, and kidneys compared to the sunitinib group. Our results suggested lipo-sunitinib could inhibit tumor growth and prolong survival rate by modulating a positive anti-tumor microenvironment and anti-angiogenesis effects. In sum, with the polish of the delivery system, our novel nanodrug lipo-sunitinib could be a potential new treatment strategy for RCC patients. Citation Format: Po-Fu Yueh, Yuan Chang, Keng-Li Lan, Fei-Ting Hsu. Evaluation of liposome encapsulated sunitinib efficacy and immune modulation on renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2003.

Efficacy and safety analysis of TACE + sunitinib vs. sunitinib in the treatment of unresectable advanced renal cell carcinoma: a retrospective study

BackgroundSince renal cell carcinoma(RCC) is insensitive to conventional chemoradiotherapy, molecularly targeted drugs are commonly used treatments for unresectable advanced RCC. The aim of this study was to explore the efficacy and safety of TACE + sunitinib vs. sunitinib in the treatment of unresectable advanced RCC. MethodsThis study included 98 patients with unresectable advanced RCC who were treated in Union Hospital from January 2015 to December 2018, and they met the criteria. They were divided into two groups: TACE + Sunitinib group (N = 47) and Sunitinib group (N = 51). We conducted a retrospective study to analyze the efficacy and safety of the two groups of patients.Results(1)TACE + Sunitinib group: 4 patients (8.5%) achieved CR, 27 patients (57.5%) achieved PR, 9 patients (19.1%) achieved SD, and 7 patients (14.9%) achieved PD. Sunitinib group, 0 patients (0%) achieved CR, 20 patients (39.2%) achieved PR, 14 patients (27.5%) achieved SD, and 17 patients (33.3%) achieved PD. (P = 0.017) (2)ORR: TACE + sunitinib group, 66.0%; sunitinib group, 39.2%. (P = 0.009) (3)DCR: TACE + sunitinib group, 85.1%; sunitinib group, 66.7%. (P = 0.038) (4) In the TACE + sunitinib group, mPFS was 15.6 months, mOS was 35.0 months; in the sunitinib group, the mPFS was 10.9 months, mOS was 25.7 months. (P < 0.001) (5) The incidence of abdominal pain, fever, and vomiting was higher in the TACE + sunitinib group than in the sunitinib group (abdominal pain: 55.3% vs. 13.7%; fever: 61.7% vs. 7.8%; vomiting: 40.4% vs. 19.6%; P < 0.05). The technical success rate of TACE in TACE + Sunitinib group is 100%.ConclusionsThe TACE + sunitinib group had higher ORR and DCR, longer OS and PFS than the sunitinib alone group. TACE combined with sunitinib can play a complementary role and is a safe and effective treatment for advanced RCC.

Sunitinib versus imatinib dose escalation after failure of imatinib standard dose in patients with advanced Gastrointestinal stromal tumors – a real-world multi-center study

BackgroundWhether to escalate imatinib dosage or directly switch to sunitinib in gastrointestinal stromal tumors (GISTs) failing on standard dose 400 mg/d of imatinib is still controversial. MethodsWe evaluated progression-free survival (PFS), overall survival (OS), and time to sunitinib failure (TTSF) of patients selecting imatinib dose escalation or directly switching to sunitinib after the failure of imatinib 400 mg/d therapy from 3 tertery referring centers between January 2008 to December 2016. ResultsA total of 240 patients receiving sunitinib (37.5 mg continuous daily dose or 50 mg 4 weeks on with 2 weeks off) for at least 8 weeks were examined. After failure on imatinib 400 mg/d, 100 (49.3%) patients had dose escalation to 600 mg or 800 mg per day (IM group, imatinib group), and 103 (50.7%) directly switched to sunitinib (SU group, sunitinib group). The PFS in the SU and IM groups was 12 months and 5.0 months (P < 0.001), respectively. TTSF or OS in both groups was not statistically significantly different. ConclusionsAfter the progression of imatinib standard-dose treatment in recurrent/metastatic GISTs, the PFS of patients directly switching to sunitinib was significantly longer compared with the PFS of patients with imatinib dose escalation. However, when the patients continued with sunitinib therapy after the failure of IM dose escalation, TTSF and OS in the IM group were similar to those in the SU group. Further exploration of the characteristics of the population benefiting from imatinib dose escalation are warranted.

Cost-effectiveness analysis of anlotinib versus sunitinib as first-line treatment for metastatic renal cell carcinoma in China.

Sunitinib was approved several years ago as a first-line drug for treating metastatic renal cell carcinoma (mRCC); however, its high price and broad side effects when administered at the standard dose have limited its clinical use. A clinical trial (NCT02072031) confirmed that anlotinib could be used as the first-line treatment for mRCC. This study was conducted to evaluate the cost-effectiveness of anlotinib as a first-line treatment for mRCC compared to that of sunitinib in China. A Markov model was established to compare the cost-effectiveness of anlotinib with that of sunitinib. Clinical data were obtained from a multi-center phase II trial (clinical trial information: NCT02072031). Utility values were obtained from the literature. Total costs were calculated from a Chinese societal perspective. A sensitivity analysis was conducted to assess the model uncertainty. The life-year (LY), quality-adjusted life-year (QALY), and incremental cost-effectiveness ratio were calculated. The base-case analysis over a lifetime horizon of 10 years showed that the anlotinib group had 2.196 LYs and 1.487 QALYs at a total cost of $68,597.84. The sunitinib group had 2.194 LYs and 1.432 QALYs at a total cost of $88,060.02. This resulted in incremental cost-effectiveness ratios (ICER) of anlotinib versus sunitinib of $-9,210,858.93 per LYs and $-354,117.07 per QALYs, suggesting that anlotinib is a more effective and less costly strategy than sunitinib. Anlotinib may be a more cost-effective first-line treatment strategy for mRCC than sunitinib in China.

Secukinumab and Black Garlic Downregulate OPG/RANK/RANKL Axis and Devitalize Myocardial Interstitial Fibrosis Induced by Sunitinib in Experimental Rats.

Sunitinib has been associated with several cardiotoxic effects such as cardiac fibrosis. The present study was designed to explore the role of interleukin (IL)-17 in sunitinib-induced myocardial fibrosis (MF) in rats and whether its neutralization and/or administration of black garlic (BG), a form of fermented raw garlic (Allium sativum L.), could extenuate this adverse effect. Male Wistar albino rats received sunitinib (25 mg/kg three times a week, orally) and were co-treated with secukinumab (3 mg/kg, subcutaneously, three times total) and/or BG (300 mg/kg/day, orally) for four weeks. Administration of sunitinib induced significant increase in cardiac index, cardiac inflammatory markers, and cardiac dysfunction that were ameliorated by both secukinumab and BG, and to a preferable extent, with the combined treatment. Histological examination revealed disruption in the myocardial architecture and interstitial fibrosis in cardiac sections of the sunitinib group, which were reversed by both secukinumab and BG treatments. Both drugs and their co-administration restored normal cardiac functions, downregulated cardiac inflammatory cytokines, mainly IL-17 and NF-κB, along with increasing the MMP1/TIMP1 ratio. Additionally, they attenuated sunitinib-induced upregulation of the OPG/RANK/RANKL axis. These findings highlight another new mechanism through which sunitinib can induce interstitial MF. The current results propose that neutralizing IL-17 by secukinumab and/or supplementation with BG can be a promising therapeutic approach for ameliorating sunitinib-induced MF.

Proinflammatory activity of VEGF-targeted treatment through reversal of tumor endothelial cell anergy

PurposeOngoing angiogenesis renders the tumor endothelium unresponsive to inflammatory cytokines and interferes with adhesion of leukocytes, resulting in escape from immunity. This process is referred to as tumor endothelial cell anergy. We aimed to investigate whether anti-angiogenic agents can overcome endothelial cell anergy and provide pro-inflammatory conditions.Experimental designTissues of renal cell carcinoma (RCC) patients treated with VEGF pathway-targeted drugs and control tissues were subject to RNAseq and immunohistochemical profiling of the leukocyte infiltrate. Analysis of adhesion molecule regulation in cultured endothelial cells, in a preclinical model and in human tissues was performed and correlated to leukocyte infiltration.ResultsIt is shown that treatment of RCC patients with the drugs sunitinib or bevacizumab overcomes tumor endothelial cell anergy. This treatment resulted in an augmented inflammatory state of the tumor, characterized by enhanced infiltration of all major leukocyte subsets, including T cells, regulatory T cells, macrophages of both M1- and M2-like phenotypes and activated dendritic cells. In vitro, exposure of angiogenic endothelial cells to anti-angiogenic drugs normalized ICAM-1 expression. In addition, a panel of tyrosine kinase inhibitors was shown to increase transendothelial migration of both non-adherent and monocytic leukocytes. In primary tumors of RCC patients, ICAM-1 expression was found to be significantly increased in both the sunitinib and bevacizumab-treated groups. Genomic analysis confirmed the correlation between increased immune cell infiltration and ICAM-1 expression upon VEGF-targeted treatment.ConclusionThe results support the emerging concept that anti-angiogenic therapy can boost immunity and show how immunotherapy approaches can benefit from combination with anti-angiogenic compounds.

Dutch Gastrointestinal Stromal Tumor (GIST) Registry Data Comparing Sunitinib with Imatinib Dose Escalation in Second-Line Advanced Non-KIT Exon 9 Mutated GIST Patients.

The prognosis of patients with advanced gastrointestinal stromal tumor (GIST) has improved greatly after theintroduction of imatinib. However, primary or secondary resistance to imatinib occurs in the majority of patients. Sunitinib is the standard second line treatment in exon-9 mutated GIST. We compared the clinical outcomes of sunitinib with imatinib dose escalation in patients with progressive advanced non-KIT exon 9 mutated GIST after failure of first line imatinib. A retrospective study was performed, retrieving data from a real-life database (Dutch GIST Registry) including patients with GIST treated with sunitinib or imatinib dose escalation after failure on first line imatinib 400 mg daily. Primary outcome measures were progression free survival (PFS) and overall survival (OS). In total, 110 patients were included, 72 (65.5%) patients were treated with sunitinib (group A) and 38 (34.5%) received an imatinib dose escalation (group B). Important prognostic features at baseline, such as tumor size, stage at diagnosis, mitotic count and localization were equally distributed in both groups. No significant difference (p = 0.88) between median PFS in group A [8.7 months (95% CI 5.6-11.3)] and group B [5.6 months, (95% CI 2.6-8.7)] was observed. Moreover, the OS was similar between group A and group B; 63.2 months and 63.4 months, respectively. This study represents a proper sample size cohort containing detailed data on mutational status of patients with advanced GIST. We illustrated that imatinib dose escalation could serve as a good alternative for sunitinib as second-line treatment in patients with a non-KIT exon 9 mutation.