Trends of First-Line Targeted Therapy in Korean Patients With Metastatic Clear Cell Renal Cell Carcinoma: Sunitinib Versus Pazopanib, a Multicenter Study

PurposeSunitinib and pazopanib are multitargeted tyrosine kinase inhibitors (TKIs) that act against vascular endothelial growth factor receptors and are standard first-line treatment options for metastatic clear cell renal cell carcinoma (ccRCC). The Brazilian public health system diverges from the randomized clinical trials in the availability of first and subsequent lines of treatment and in clinical and demographic characteristics of patients. Therefore, it is essential to describe the history of advanced ccRCC during and after TKI treatment in this population.MethodsWe performed a retrospective analysis of patients with advanced ccRCC treated with a first-line TKI (either sunitinib or pazopanib) between February 2009 and March 2017 in a single academic Brazilian cancer center (Instituto do Câncer do Estado de São Paulo).ResultsOf the 222 patients, 109 were treated with sunitinib and 113 with pazopanib. The median duration of treatment and overall survival (OS) were 6.4 and 15.2 months for sunitinib and 6.7 and 14.2 months for pazopanib, respectively. Discontinuation of treatment occurred secondarily to progressive disease or death in 64.2% of patients using sunitinib and in 54.8% of patients using pazopanib. Adverse events were responsible for discontinuation of treatment in 28.4% of patients in the sunitinib group and in 22.1% in the pazopanib group. According to Memorial Sloan-Kettering Cancer Center risk categories, the OS was 32.9 months, 15.9 months, and 8.1 months for low risk, intermediate risk, and poor risk, respectively (hazard ratio, 1.72; 95% CI, 1.13 to 2.26; P < .001).ConclusionThe use of TKI inhibitors as first-line treatment of metastatic RCC is effective and feasible in the Brazilian public health. However, the median OS of our population is considerably lower compared with the prospective trials that evaluated the same drugs.

Objective: To investigate the efficacy and drug related adverse reactions of sorafenib and sunitinib as first-line tyrosine-kinase inhibitors (TKIs) for patients with metastatic renal cell carcinoma (mRCC) and analyze the clinical prognostic factor for survival. Methods: The data of 271 patients with metastatic renal cell carcinoma who had complete clinicopathological data were retrospectively analyzed, including 174 cases in sorafenib group and 97 cases in sunitinib group, to access patients' overall survival (OS) and progression-free survival (PFS). Prognostic values of all characteristics were determined by using univariate and multivariate Cox regression models. Results: The objective response rates (ORR) of the sorafenib and sunitinib groups were 14.9% and 19.6%, respectively, and the disease control rates (DCR) were 85.1% and 88.6%, respectively. No significant difference was found between the sorafenib and sunitinib group in ORR (P=0.325) or DCR (P=0.408). The most common grade 3 to 4 adverse events in the sorafenib group were hand-foot syndrome (6.7%), diarrhea (2.3%), and rash (2.3%). The most common grade 3 to 4 adverse events in the sunitinib group were neutropenia (6.2%), hand-foot syndrome (6.2%), and thrombocytopenia (4.6%). During the follow-up, 97 cases death occurred and 81 cases disease progression occurred in sorafenib group. The median PFS was 12 months (95% CI: 9-15 months), and the median OS was 25 months (95% CI: 21-29 months) in sorafenib group. While 74 cases death occurred and 40 cases disease progression occurred in sunitinib group, the median PFS was 12 months (95% CI: 10-12 months) and the median OS was 23 months (95% CI: 20-32 months) in sunitinib group. No significant difference was found between the sorafenib and the sunitinib group in PFS (P=0.771) or OS (P=0.548). Multivariate analysis showed Fuhrman grades (HR=1.358, 95%CI: 1.004-1.835), number of metastatic sites (HR=1.550, 95%CI: 1.143-2.101) and MSKCC risk grade (Intermediate risk group: HR=1.621, 95%CI: 1.117-2.232; Poor risk group: HR=2.890, 95%CI: 1.942-4.298) were independent prognostic factors for PFS. Fuhrman grades (HR=2.135, 95%CI: 1.533-2.974), number of metastatic sites (HR=1.774, 95%CI: 1.279-2.461) and MSKCC risk grade (Intermediate risk group: HR=1.415, 95%CI: 1.002-1.998; Poor risk group: HR=3.161, 95%CI: 2.065-4.838) were independent prognostic factors for OS. Conclusions: The results of this study indicate that sorafenib and sunitinib are both effective as the first-line TKIs for mRCC patients and sorafenib has comparable efficacy to sunitinib. But they have differences in the incidence of adverse effects. Fuhrman grades, number of metastatic sites and MSKCC risk grade are independent prognostic factors for mRCC patients.

Objective To evaluate the efficacy and safety of sunitinib in the individualized treatment of metastatic clear cell and papillary renal cell carcinoma.Methods The data of 44 patients (33 cases of metastatic renal clear cell carcinoma (mRCC) and 11 cases of metastatic papillary renal cell carcinoma) were analyzed retrospectively in West China Hospital from Apr.2008 to Sept.2012.Progression free survival (PFS),overall survival (OS) and adverse events were compared,and SPSS17.0 software was used to evaluate the effect,adverse events and the risk factors.Results The median sunitinib therapeutic cycle was 19.1 and the median follow-up time was 30 months.Among the 44 patients,18 patients were treated with standard therapeutic schedule,while 26 patients were treated with adjusted alternative schedule.The median PFS,OS,tumor objective response rate and disease control rate for the entire cohort were 14 months,37 months,34％ (15/44) and 71％ (31/44),respectively.Survival analysis demonstrated that neither histological types nor individual therapeutic regimen was associated with efficacy of sunitinib.Multivariate analysis demonstrated that solitary lung or lymph node metastasis was the only independent factor predicting the effectiveness of sunitinib in the treatment of mRCC.Although incidence of hypertension,hand-foot syndrome and oral mucositis was relatively high,all adverse events were tolerable and reversible.Compared to patients with standard schedule,the proptrtion of dose reduction or interruption was much lower in patients with alternative schedule (35％ vs.67％,P=0.034).Conclusion Sunitinib may have similar effect on metastatic renal clear cell carcinoma and papillary renal cell carcinoma,and the individualized therapeutic schedules of sunitinib maximize the efficacy and safety of sunitinib. Key words: Sunitinib; Metastatic renal cell carcinoma; Individualized treatment; Efficacy

Background: While doublet therapies provide important first-line treatment options in metastatic renal cell carcinoma (mRCC), novel and mechanistically distinct agents are needed for pts who are not cured by/intolerant of such therapies. Due to the high incidence (~80%) of CD70 antigen expression in primary and mRCC, yet limited expression in normal tissue, ccRCC is an attractive proof-of-concept tumor for CD70 directed allogeneic CAR T. TRAVERSE (NCT04696731), a first-in-human trial, seeks to identify a maximum tolerated dose (MTD) of ALLO-316 after conditioning with fludarabine/cyclophosphamide with/without ALLO-647 in pts with advanced or metastatic ccRCC. ALLO-316 is an anti-CD70 allogeneic CAR T cell product that utilizes TALEN® gene editing to knock out TCRα constant gene to reduce the risk of graft-versus-host disease (GvHD) and knock out CD52 gene to permit use of ALLO-647 (a humanized anti-CD52 mAb) to selectively deplete host T cells without affecting allogeneic CAR T cells. Methods: This multicenter, single-arm, open-label, 3+3 dose-escalation trial enrolls adults with advanced or metastatic ccRCC and ≥1 measurable lesion and ECOG Performance Status 0 or 1. Prior treatment with an immune checkpoint inhibitor and a vascular endothelial growth-factor targeted therapy was required, with evidence of progression on/after treatment or discontinuation due to toxicity. ALLO-316 is administered at escalating doses (40 - 240 × 106 allogeneic CAR+ cells IV) on Day 0 after conditioning. The primary endpoint is a target incidence rate for dose-limiting toxicities (DLTs) &amp;lt;33% in the first 28 days after infusion of ALLO-316. Results: By 12/3/2022, 18 pts with ccRCC (median age: 63 yrs; 82% male) were enrolled; all (100%) 17 pts who received ALLO-316, had metastatic disease with 3 lines (median) of prior therapy. Eleven (65%) of these pts experienced CRS, all low Gr except one (6%) Gr 3. No ICANS or GVHD was observed. One (6%) DLT (elevated LFT) was observed and required dose expansion. MTD has not yet been reached. Three pts achieved best overall response of PR at all time points with two PRs confirmed at subsequent visits; ORR = 12% and disease control rate (DCR) = 71%. In pts with confirmed CD70+ tumors (n=9), confirmed ORR = 22% (unconfirmed ORR = 33%) and DCR = 100%. High CAR T cell expansion was observed in peripheral blood (median Cmax &amp;gt; 35,000 copies/μg) and high VCN in available tumor aspirates (n=3). Conclusions: ALLO-316, an allogeneic CAR T cell product targeting CD70 in advanced mRCC, is demonstrating encouraging antitumor activity and a manageable safety profile. A single administration of ALLO-316 could be an effective treatment for pts with CD70+ solid tumors, including RCC, and hematologic malignancies. The MTD for ALLO-316 in TRAVERSE will support Phase 2 trial design. Enrollment of pts with CD70+ tumors is ongoing. Citation Format: Samer Srour, Ritesh Kotecha, Brendan Curti, Jad Chahoud, Alexandra Drakaki, Lily Tang, Lovely Goyal, Sacha Prashad, Victoria Szenes, Kevin Norwood, Sumanta Pal. A phase 1 multicenter study (TRAVERSE) evaluating the safety and efficacy of ALLO-316 following conditioning regimen in pts with advanced or metastatic clear cell renal cell carcinoma (ccRCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT011.

Background: Metastatic clear-cell renal cell carcinoma (RCC) is largely incurable, and its treatment remains challenging. Sunitinib, a tyrosine kinase inhibitor, is one of the current standard-of-care options for treatment-naïve patients with metastatic RCC. Despite the proven efficacy of sunitinib, prolonged treatment with some tyrosine kinase inhibitors (TKIs) has been associated with significant adverse events (AEs). Therefore, we aimed to calculate the exact prevalence of all sunitinib-related AEs in a pooled analysis from all available randomized controlled trials (RCTs). Methods: A comprehensive electronic database search was conducted for all RCTs comparing the clinical outcomes and adverse events of sunitinib versus all other available treatments for treatment-naïve advanced/metastatic clear-cell renal cell carcinoma. We then calculated the pooled prevalence of the most common reported side effects of sunitinib. All statistical analyses were performed using R Statistical Software v3.4.0 (R Foundation, Vienna, Austria). Results: We included 8 RCTs, with a total of 4,106 patients. The mean age was 62, with 66.44% males. Any grade AEs were reported in 72% of patients with the following frequencies: fatigue, 44%; diarrhea, 38%; nausea, 31%; hand-foot syndrome, 30%; hypertension, 27%; dysgeusia, 25%; hypothyroidism, 25%; cconstipation, 20%; stomatitis, 20%; inflammation of the mucosa, 18%; dyspepsia, 16%; vomiting, 14%; rash, 12%; asthenia, 11%; and epistaxis, 10%. Grade 3 (severe) AEs were reported in 52% of patients with the following frequencies: hypertension, 9%; fatigue, 8%; hand-foot syndrome, 5%; asthenia, 5%; diarrhea, 4%; and inflammation of the mucosa, 2%. Laboratory abnormalities were also reported as follows: increased AST, 7%; increased lipase, 6%; neutropenia, 6%; thrombocytopenia, 6%; hypophosphatemia, 5%; lymphocytopenia, 5%; anemia, 4%; and leukopenia, 3%. Conclusion: Despite sunitinib being one of the current standard treatments for patients with metastatic/advanced clear-cell RCC, its safety profile is concerning, with a high prevalence of reported dangerous side effects. These findings underscore the importance of the emergence of newer drugs and treatment plans for patients with metastatic RCC, not only to achieve similar or better clinical outcomes but also to decrease the burden of adverse events.

Renal Cell Carcinoma: Diagnosis Based on Metastatic Manifestations

Comparison of Cabozantinib and Axitinib as Second-line Therapy After Nivolumab Plus Ipilimumab in Patients With Metastatic Clear Cell Renal Cell Carcinoma: A Comparative Analysis of Retrospective Real-world Data

Objective To summarize the safety and efficacy of Sunitinib in the treatment of metastatic renal clear cell carcinoma. Methods Fifteen patients with clear cell metastatic RCC were treated with Sunitinib,with 11 males and 4 females,aged from 26 to 74 years with median age of 55 years.Thirteen cases of 15 were T3 to T4 stage,and 8 cases underwent radical nephrectomy,while 5 other cases underwent renal biopsy with the pathological diagnosis of renal cancer.The other two cases (one man and one woman)with the solitary kidney renal cell carcinoma ( stage T1a) and renal insufficiency,were diagnosed as metastatic renal cell carcinoma by biopsy.Sunitinib monotherapy was administered by the regimen of 6 weeks per cycle with daily oral Sunitinib 4 weeks,followed by 2 weeks off ( from 1 - 10 cycles).Response was evaluated by RECIST.Renal tumor was 9.52 ± 3.3 cm in diameter at baseline,and the assessment of metastases included retroperitoneal lymph nodes (6 cases),mediastinal lymph nodes (3 cases),brain (2 cases),lung (6 cases),bone (2 cases) and liver (2 cases).Karnofsky score,tumor changes,adverse events and the survival of each patient was assessed and recorded. Results The follow-up duration was from 1.5 - 15months,with median follow-up of 6 months,and tumor response was evaluated by RECIST.Seven of 15 patients (46.7％) treated with Sunitinib achieved partial responses (PR),7 patients (46.7％) demonstrated stable disease (SD),and 1 patient (6.7％) developed progressive disease (PD) during the follow-up.Objective Response Rate (ORR) was 46.7％,PR + SD was 93.3％,6 months PFS was 93.3％,and median PFS was 12 months,respectively.Renal tumor was 8.7 ± 4.0 cm in diameter after therapy.Two PR patients with the obvious effectiveness had experienced progressed hypertension,and one cases with hypertension that could be controlled below 140/90 mm Hg ( 1 mm Hg =0.133 kPa) by a single drug before treatment,showed increased blood pressure ( ＞ 160/105 mm Hg) following the second cycles treatment,who were administered increased dosage and combination therapy.The other case without history of hypertension,showed high blood pressure ( ＞ 150/100 mm Hg) in the third cycle,and could be controlled well by antihypertensive drugs.Fortunately,the tumor of these two cases reduced obviously by more than 50％. 1/2 adverse reactions of 12 cases:yellowing of the skin and yellow sweat ( 12 cases,80％ ),fatigue ( 12 cases,80％ ),4 cases of hypothyroidism (26.7％),bilirubin and triglyceride levels elevated in 7case (46.7％); Four cases showed 3/4 degree adverse events with the emergence of gastrointestinal bleeding in one case secondary to platelets reduction (6.7％).Three cases (20％) showed serious fatigue,nausea,vomiting and severe hand-foot skin reaction. Conclusions Sunitinib is recommended for the treatment of metastatic renal clear cell carcinoma with good efficacy and safety. Key words: Carcinoma, renal cell; Sunitinib; Hypertension

IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): a multicentre, open-label, randomised, controlled, phase 3 trial

Comparison of Outcomes Between African American and European American Patients With Metastatic Clear Cell Renal Cell Carcinoma Receiving Immune Checkpoint Inhibitors.

Metastatic renal cell carcinoma in the gallbladder is extremely rare, with reported frequencies of less than 0.6% in large autopsy reviews. Only 40 cases were reported in the literature. We report a first case of gallbladder polypoid tumor revealing metastatic clear cell renal cell carcinoma, which demonstrates the importance of radiological tests, histology and immunohistochemistry when making a definitive diagnosis. These examinations also allow differentiating metastatic clear cell renal cell carcinoma from other polypoid lesions in the gallbladder with clear cell morphology. Cholecystectomy should be performed to obtain a definitive diagnosis and to improve survival in case of solitary metastatic renal cell carcinoma.Virtual slidesThe virtual slides’ for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8956897238238989

Introduction: Sunitinib and pazopanib are both standard first-line therapies for clear-cell metastatic renal-cell carcinoma (mRCC). Everolimus is a well-established second-line treatment. Objective: To estimate the efficacy and safety of second-line everolimus following pazopanib or sunitinib. Methods: SUNPAZ was an open-label, phase 4 clinical trial of everolimus in patients with clear-cell mRCC progressing after first-line sunitinib or pazopanib. The primary end point was the number of patients without progression 6 months after starting everolimus. Secondary end points included progression-free survival (PFS), overall survival (OS), and overall response rate. Enrollment was terminated early due to slow recruitment; all analyses are descriptive. Results: Patients who received prior sunitinib (n = 16) or pazopanib (n = 13) were enrolled. One of 12 patients in the sunitinib group and 6/13 patients in the pazopanib group were progression-free by month 6 in the full analysis set. Median PFS in the sunitinib and pazopanib groups was 2.8 and 8.0 months, and median OS was 14.8 months and 20.4 months, respectively. Fifteen patients in the sunitinib group and 13 in the pazopanib group experienced adverse events. Conclusions: Safety and efficacy results confirm the second-line everolimus profile. However, baseline differences in patient populations should be taken into consideration.

473 Background: The VEGFR-TKIs Sunitinib and Pazopanib are the currently recommended 1st line agents for the treatment of renal cell carcinoma (RCC). Everolimus is a well-established treatment option after failure of a prior VEGFR-TKI. However, few prospective clinical data exist on the efficacy and safety of Everolimus after failure of a single line of VEGFR-TKI therapy and no clinical data exists on the efficacy and safety of Everolimus following Pazopanib treatment. Methods: This phase IV clinical trial investigated Everolimus 10 mg daily in patients who have progressed on or after 1st line treatment with Sunitinib or Pazopanib. Adult patients with advanced clear cell RCC and an ECOG 0-1 were included. The primary endpoint was the rate of patients progression-free after 6 months of treatment. Results: 16 and 13 patients who received prior Sunitinib and Pazopanib, respectively, have been enrolled at 13 German sites. The median age was 65 years in the Sunitinib (SUN) group and 74 years in the Pazopanib (PAZ) group. After 6 months of Everolimus treatment, 11/12 (92%) patients in the SUN group showed disease progression, whereas 6/13 (46%) patients in the PAZ group remained progression-free (FAS population). The median OS was 14.8 months in the SUN group (95% CI 9.4 – not reached (NR)) and 20.4 months in the PAZ group (95% CI 11.7 – NR). The most common adverse events (AE) regardless of any relation to study drug included anemia (31.1% (SUN group) vs. 53.8% (PAZ group)), nausea (25.0 vs. 46.2%), stomatitis (12.5 vs. 61.5%), peripheral edema (12.5 vs. 53.8%), and dyspnea (12.5 vs. 46.2%). Conclusions: Patients in the PAZ group showed a lower rate of tumor progression within 6 months and a longer PFS as compared to the SUN group. The results confirm Everolimus as an effective 2nd line treatment option with a favorable safety profile, especially following Pazopanib, and the sequence Pazopanib - Everolimus as effective treatment option for mRCC patients. However, due to the small number of patients enrolled in the study, results have to be interpreted with caution. The types of observed AE are consistent with the well-known toxicity profile of Everolimus. Clinical trial information: NCT01514448.

Characterization of Patients With Metastatic Renal Cell Carcinoma Experiencing Complete Response to First-line Therapies: Results From the International Metastatic Renal Cell Carcinoma Database Consortium.

BackgroundDespite advancements in managing metastatic clear cell renal carcinoma (mccRCC) through antiangiogenic tyrosine kinase inhibitors and immunotherapy, there remains a demand for novel treatments for patients experiencing progression despite the use of these medications. There is currently no established standard treatment for patients receiving third therapy line. Prostate Specific Membrane Antigen (PSMA) whose high expression has been demonstrated in metastatic aggressive prostate adenocarcinoma is also highly expressed in neovessels of various solid tumors including renal cell carcinoma (RCC): 86% of clear cell RCC, 61% of chromophobe RCC, and 28% of papillary RCC. Therefore, PSMA may be a target expressed in metastatic ccRCC for radionuclide therapy using PSMA ligands radiolabeled with Lutetium-177 (PRLT). 177Lu-PSMA delivers ß-particle radiation to PSMA-expressing cells and the surrounding microenvironment with demonstrated efficacy in metastatic prostate cancer.MethodsThis is a multicenter phase I/II study designed to assess the tolerability and effectiveness of 177Lu-PSMA-1 in individuals with PSMA-positive metastatic clear cell renal cell carcinoma (ccRCC), identified through 68Ga-PSMA PET, conducted in France (PRadR). 48 patients will be treated with 4 cycles of 7.4 GBq of 177Lu-PSMA-1 every 6 weeks. The primary objective is to evaluate the safety of 177Lu-PSMA-1 (phase I) and the efficacy of 177Lu-PSMA-1 in mccRCC patients (phase II). Primary endpoints are incidence of Severe Toxicities (ST) occurring during the first cycle (i.e. 6 first weeks) and disease Control Rate after 24 weeks of treatment (DCR24w) as per RECIST V1.1. Secondary objective is to further document the clinical activity of 177Lu-PSMA-1 in mccRCC patients (duration of response (DoR), best overall response rate (BORR), progression fee survival (PFS) and overall survival (OS).DiscussionOur prospective study may lead to new potential indications for the use of 177Lu-PSMA-1 in mccRCC patients and should confirm the efficacy and safety of this radionuclide therapy with limited adverse events. The use of 177Lu-PSMA-1may lead to increase disease control, objective response rate and the quality of life in mccRCC patients.Trial registrationClinicalTrials.gov: NCT06059014.