Phase II Study of Carfilzomib in Patients With Refractory Renal Cell Carcinoma

BackgroundA von Hippel Lindau (VHL) mutation or functional inactivation occurs in the a large proportion of patients with clear-cell renal cell carcinoma (ccRCC), which results in the dysregulation of a number of key cellular functions. A high throughput screen and candidate compound assessment revealed that agents with proteasome inhibition properties were able to stabilize point-mutated VHL and restore some of its functions.Patients and MethodsNine patients with histologically confirmed metastatic ccRCC with disease progression during at least 1 previous systemic therapy were treated with carfilzomib at a dose of 20 mg/m² over 30 minutes via intravenous (I.V.) infusion on days 1 and 2 and a dose of 56 mg/m² over 30 minutes via I.V. infusion on days 8, 9, 15, and 16 of each 4-week cycle.ResultsThe study was stopped after 9 patients were enrolled because of futility. Of the 9 patients treated in the study, all patients had disease progression within 4 months, with a median time of 1.8 months (95% confidence interval, 0.8-3.6 months). No patient showed a response according to Response Evaluation Criteria In Solid Tumors. Three patients showed a best response of stable disease. The most common side effects were musculoskeletal pain, elevated creatinine level, anemia, hyperkalemia, leukopenia, lymphopenia, and fatigue.ConclusionAlthough the negative safety and efficacy results of this study do not favor the use of carfilzomib for the treatment of ccRCC, previous studies have shown selected patients achieved partial or complete response to this class of agent. Further preclinical investigations to evaluate the molecular characteristics of the patients who respond to proteasome inhibitors will better characterize the underlying mechanism of response, and might allow for the selection of an appropriate patient population in future studies.     

Yttrium-90 (Y-90) Resin Microsphere Therapy for Patients with Unresectable Hepatocellular Carcinoma: a Single-Center Experience

Background/Aim

Selective intraarterial radionuclide therapy (SIRT) with yttrium-90 (Y-90) resin microspheres presently has successful results in primary or metastatic inoperable liver tumors. This procedure, which is also known as radioembolisation, delivers high doses of radiation selectively to hepatic tumors while minimum healthy liver exposure. The aim of this study was to present our clinical experience of radiomicrosphere therapy for the treatment of patients with unresectable hepatocellular carcinoma (HCC).

Methods

We performed 40 Y-90 microsphere therapies in 28 patients (5 females, 23 males; mean age ± SD 48 ± 8) with HCC during the period from April 2008 through December 2016. Pretreatment Tc-99m microaggregated albumin (MAA) scintigraphy was performed to all patients in order to detect eligibility for SIRT. All patients had pre- and post-biochemical tests (hemogram and serologic tests) and imaging methods (CT or MRI or PET/CT) at regular intervals to detect any possible complication and determine response rates.

Results

The mean shunting to the lungs on MAA scan was 6.5% and the mean ± SD administered dose of Y-90 was 1.55 ± 0.32 GBq in all patients. The estimated doses to the target tumors, normal liver parenchyma and lungs were 105.7 ± 55.3, 25.5 ± 8.2 and 5.8 ± 1.7 Gy, respectively. No significant complication was observed during or early after (first week) the treatment procedure and it was well tolerated by all the patients. Only one patient developed a treatment-related gastroduodenal ulcer 3 weeks after the treatment. In control imaging tests (MRI or FDG PET/CT) performed 2.5 months after the treatment, we observed complete response in 2 (7%) patients, partial response in 10 (36%) patients, stable disease in 5 (18%) patients and progressive disease in 11 (39%) patients.

Conclusion

According to our clinical experience, we can conclude that Y-90 microsphere therapy is a safe and effective treatment option for the patients with unresectable HCC without any serious side effects.

     

Selective Internal Radiation Therapy with Yttrium-90 for Intrahepatic Cholangiocarcinoma: A Systematic Review on Post-Treatment Dosimetry and Concomitant Chemotherapy

Selective internal radiation therapy (SIRT) with yttrium-90 (⁹⁰Y)-loaded microspheres is increasingly used for the treatment of Intrahepatic Cholangiocarcinoma (ICC). Dosimetry verifications post-treatment are required for a valid assessment of any dose-response relationship. We performed a systematic review of the literature to determine how often clinics conducted post-treatment dosimetry verification to measure the actual radiation doses delivered to the tumor and to the normal liver in patients who underwent SIRT for ICC, and also to explore the corresponding dose-response relationship. We also investigated other factors that potentially affect treatment outcomes, including the type of microspheres used and concomitant chemotherapy. Out of the final 47 studies that entered our study, only four papers included post-treatment dosimetry studies after SIRT to quantitatively assess the radiation doses delivered. No study showed that one microsphere type provided a benefit over another, one study demonstrated better imaging-based response rates associated with the use of glass-based TheraSpheres, and two studies found similar toxicity profiles for different types of microspheres. Gemcitabine and cisplatin were the most common chemotherapeutic drugs for concomitant administration with SIRT. Future studies of SIRT for ICC should include dosimetry to optimize treatment planning and post-treatment radiation dosage measurements in order to reliably predict patient responses and liver toxicity.     

Phase I Study of Dalteparin in Combination With Sunitinib in Patients With Metastatic Clear Cell Renal Carcinoma

Background

Based on the tumor-driven concomitant activation of angiogenesis and coagulation we conducted a phase I combination study of sunitinib with the low molecular weight heparin dalteparin in patients with metastatic clear cell renal cell carcinoma (ccRCC).

Systemic Therapy in Patients With Metastatic Xp11.2 Translocation Renal Cell Carcinoma

BackgroundXp11.2 translocation renal cell carcinoma (Xp11.2 tRCC) is a unique subtype with poor prognosis, its response to systemic therapy is not fully understood, we evaluated the benefit of systemic therapy in these patients.Patients and MethodsBetween May 2006 and December 2019, patients diagnosed with Xp11.2 tRCC from Peking university cancer hospital were collected. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) distributions.ResultsMetastatic Xp11.2 tRCC was found in 45 patients. The median PFS and median OS was 7.4 months (4.5-8.8) and 17.9 months (12.4-24.4), respectively. First-line treatment mainly included sunitinib (n = 14), sorafenib (n = 15), axitinib (n = 6), and pazopanib (n = 5), and the median PFS of these regimens were 7.4 months, 5.4 months, 9.4 months, 8.9 months, respectively. Two patients who received Vascular endothelial growth factor receptor - tyrosine kinase inhibitor (VEGFR-TKI) plus immune checkpoint inhibitor (ICI) as first line therapy had a PFS of more than 16.6 months and more than 25.6 months, respectively. Twenty-four patients received subsequent therapies, which included VEGFR-TKI/ICI, VEGFR-TKI and mTOR inhibitor. The ORR and median PFS was 33% and 7.1 months, 7.7% and 4.3 months, 0% and 2.1 months for these treatments, respectively. The estimated median OS was 17.3 months (95% CI, 11.2 to not reached) in patients with TKI/ICI treatment and 11.0 months (95% CI, 6.1 to not reached) without TKI/ICI treatment in subsequent therapies (P = .04). Patients with serous cavity effusion or IMDC poor risk groups had significantly shorter median PFS and median OS.ConclusionMetastatic Xp11.2 tRCC is an aggressive disease. VEGFR-TKI agents appeared to demonstrate some efficacy, VEGFR-TKI /ICI combination might be a useful tool for the treatment of metastatic Xp11.2 tRCC.     

A Phase II Trial of Intrapatient Dose-Escalated Sorafenib in Patients With Metastatic Renal Cell Carcinoma

PurposeSorafenib has been demonstrated as second-line therapy, with limited significant adverse events at a dose of 400 mg twice a day (b.i.d.) in patients with metastatic renal cell carcinoma. This study evaluated the ability of patients to dose-escalate, response rate, progression-free survival (PFS), and overall survival.MethodsThe initial dose of sorafenib was 400 mg b.i.d.. Dose escalation of sorafenib to 600 mg b.i.d. occurred from days 29-56 and increased to 800 mg b.i.d. on day 57 and beyond as tolerated. Dose modifications were performed for toxicity per the National Cancer Institute Common Toxicity Criteria version 3.0. The patients were evaluated every 2 cycles (8 weeks) by using Response Evaluation Criteria in Solid Tumors version 1.0.ResultsForty-four patients were evaluable for response. Median age was 62.5 years, 39 patients had a Karnofsky Perfomance Status of 100%. Twenty-two patients received no prior therapy. Of the evaluable patients, 42 were dose escalated to 600 mg b.i.d., and 74% (31) of these were further dose escalated to 800 mg b.i.d.. Eight patients had a complete response (CR), 13 patients demonstrated a partial response (PR), and 21 patients had stable disease. Common treatment-related adverse events included hypertension, hand-foot syndrome, skin rash, diarrhea, dry skin, alopecia, and facial redness.DiscussionThe majority of patients were escalated to 600 mg b.i.d. or 800 mg b.i.d.. Intrapatient dose-escalated sorafenib has promising antitumor activity as demonstrated by a 48% CR-PR rate (21 patients). Antitumor activity is further suggested by a prolonged PFS ≥6 months in 64% (28) of patients. Significant antitumor activity and reversible adverse events has been demonstrated in escalated doses of sorafenib.     

A Phase I,Open-Label Study of Trebananib Combined With Sorafenib or Sunitinib in Patients With Advanced Renal Cell Carcinoma

BackgroundTrebananib, an investigational peptibody, binds to angiopoietin 1 and 2, thereby blocking their interaction with Tie2.Patients and MethodsThis open-label phase I study examined trebananib 3 mg/kg or 10 mg/kg intravenous (I.V.) once weekly plus sorafenib 400 mg twice per day or sunitinib 50 mg once per day in advanced RCC. Primary end points were adverse event incidence and pharmacokinetics.ResultsThirty-seven patients were enrolled. During trebananib plus sorafenib administration (n = 17), the most common treatment-related adverse events (TRAEs) included rash (n = 12; 71%), diarrhea (n = 12; 71%), hypertension (n = 11; 65%), and fatigue (n = 11; 65%); grade ≥ 3 TRAEs (n = 7; 41%); and 2 patients (12%) had peripheral edema. During trebananib plus sunitinib administration (n = 19), the most common TRAEs included diarrhea (n = 14; 74%), fatigue (n = 13; 68%), hypertension (n = 11; 58%), and decreased appetite (n = 11; 58%); grade ≥ 3 TRAEs (n = 13; 68%); and 8 (42%) patients had peripheral edema. Trebananib did not appear to alter the pharmacokinetics of sorafenib or sunitinib. No patient developed anti-trebananib antibodies. Objective response rates were 29% (trebananib plus sorafenib) and 53% (trebananib plus sunitinib).ConclusionThe toxicities of trebananib 3 mg/kg or 10 mg/kg I.V. plus sorafenib or sunitinib in RCC were similar to those of sorafenib or sunitinib monotherapy, with peripheral edema being likely specific to the combinations. Antitumor activity was observed.     

Nivolumab VERSUS Cabozantinib as Second-Line Therapy in Patients With Advanced Renal Cell Carcinoma: A Real-World Comparison

BackgroundTyrosine-kinase inhibitors (TKIs) still represent a first-line option for selected patients with metastatic Renal Cell Carcinoma (mRCC). We aimed to compare the real-world efficacy of nivolumab or cabozantinib as second-line therapy in specific mRCC subpopulations.Patients and MethodsWe retrospectively collected data from 11 centers from Italy, Spain and US. Overall Survival (OS) and Progression-Free Survival (PFS) were analyzed using Kaplan-Meier curves. Cox proportional models were used at univariate and multivariate analyses.ResultsWe collected data from 343 patients with mRCC, 123 (36%) treated with cabozantinib and 220 (64%) with nivolumab. The median OS resulted longer, but not statistically significant, with nivolumab in patients aged >70 years (21.4 vs. 15.4 months, P = .746), treated with first-line pazopanib (26.8 vs. 11.6 months, P = .450), or with good (47.0 vs. 15.5 months, P = .285) or intermediate-risk criteria (14.4 vs. 11.0 months, P = .357), while it was longer, but even not statistically significant, for cabozantinib in patients who received previous sunitinib (25.7 vs. 21.7 months, P = .638) or with bone metastases (28.4 vs. 24.4 months, P = .871). The median PFS was significantly longer with cabozantinib in patients with clear cell histology (7.8 vs. 5.4 months, P = .026) and in patients with good risk features (12.3 vs. 5.7 months, P = .022).ConclusionsNivolumab and cabozantinib resulted active in mRCC patients, showing distinct results when stratified into clinico-pathological features.     

Predictive Factors for Late Recurrence in Patients With Stage T1 Clear Cell Renal Cell Carcinoma: A Multiinstitutional Study

BackgroundThe purpose of this study was to identify predictive factors for late recurrence in Korean patients with stage T1 clear cell renal cell carcinoma (RCC) more than 5 years after treatment with radical nephrectomy (RN) or partial nephrectomy (PN).Patients and MethodsBetween 1999 and 2011, 3567 patients with RCC underwent RN or PN at 5 institutions in Korea. Of these, 423 patients with pathologically confirmed stage T1 clear cell RCC remained free of disease for at least 5 years. To determine the pathologic and clinical factors that influenced late recurrence, univariate and multivariate analyses using the Cox proportional hazards model were performed. Recurrence-free survival curves were estimated by using the Kaplan-Meier method.ResultsDuring a median follow-up period of 83.9 months (range 60.0-156.4 months), late recurrence was observed in 14 of the 423 (3.3%) patients. Univariate and multivariate analyses revealed that symptoms at diagnosis and pathologic T stage were independent predictive factors for late recurrence. Patients with symptoms at diagnosis or stage T1b disease had a significantly shorter time to late recurrence than did those who were asymptomatic or had stage T1a disease (log-rank test P = .027 and P = .034, respectively).ConclusionsLate recurrence in stage T1 clear cell RCC is a relatively rare event. Predictive factors for late recurrence were identified in the present study. Careful long-term follow-up is necessary, especially in patients who have symptoms at diagnosis or stage T1b tumors, even if they have been free of disease for more than 5 years.     

A Phase Ib Study of Combined VEGFR and mTOR Inhibition With Vatalanib and Everolimus in Patients With Advanced Renal Cell Carcinoma

BackgroundVatalanib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), whereas everolimus inhibits mammalian target of rapamycin (mTOR). Combination therapy with VEGFR and mTOR inhibitors has not been well tolerated to date but may have efficacy in renal cell carcinoma (RCC).Patients and MethodsA phase Ib study of vatalanib and everolimus was performed in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), safety, and tolerability of the combination. A dose-expansion cohort of 20 patients with metastatic RCC was studied to further define toxicity and preliminary efficacy in patients with RCC.ResultsWe evaluated 32 patients over 3 dose levels and a dose-expansion cohort. The most common toxicities of any grade were proteinuria, fatigue, hypertriglyceridemia, nausea, and vomiting. Dose-limiting toxicities (DLTs) included severe hypertension, diarrhea, neutropenia, mucositis, and fatigue. The MTD for the combination was vatalanib 1000 mg daily and everolimus 5 mg daily. In all patients, median overall survival (OS) was 16.3 months. In patients with RCC, median progression-free survival (PFS) was 5.8 months, and OS was 16.5 months. OS was significantly better in treatment-naive patients (25.1 months) compared with patients who had received previous vascular endothelial growth factor (VEGF)-targeted therapy (6.3 months). Seven of 24 (29.2%) evaluable patients demonstrated a partial response, and an additional 15 patients exhibited stable disease. Long-term tolerability (> 1 year) was demonstrated in 19% of patients.ConclusionRelevant doses of vatalanib and everolimus were achieved in combination, with expected toxicities. A substantial number of patients with RCC achieved an objective response in the treatment-naive setting, with prolonged tolerability and survival. Further comparative phase II/III studies of specifically targeted VEGF and mTOR inhibitor combinations may be warranted in patients with RCC.     

索坦治疗14例晚期肾透明细胞癌的疗效和安全性临床观察

目的观察苹果酸舒尼替尼胶囊(索坦)对晚期肾透明细胞癌患者常用化疗剂量的疗效和安全性。方法设置2个剂量观察组:4/2方案组按50 mg·d^(-1),用4周歇2周,6周为1周期;持3方案组按37.5mg·d^(-1),持续治疗直至疾病进展;出现不良事件后,4/2方案可调整为2/1方案(按25 mg·d^(-1),用2周停1周,3周为1周期)。每组7例,若每组≥2例出现剂量限制性毒性(DLT),将停止继续用药。结果 14例可评价疗效患者中3例PR,8例SD,3例PD。4/2方案组7例患者中,出现2例严重不良事件和2例次DLT,而持3方案组7例患者未出现DLT。结论索坦具有显著抗肿瘤活性,DLT是手足皮肤毒性和血小板减少。持3方案患者耐受性较好。对中国人而言,4/2方案出现不良事件后调整为2/1方案较为安全,而对于年轻和体质好的患者优先采用4/2方案。     

A Phase I Study of Temsirolimus and Bryostatin‐1 in Patients With Metastatic Renal Cell Carcinoma and Soft Tissue Sarcoma

Background.

Temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR) complex 1, is approved for the treatment of metastatic renal cell carcinoma (RCC). Bryostatin-1 inhibits protein kinase C, a downstream effector of mTOR complex 2. We observed antitumor effects with the combination of temsirolimus and bryostatin-1 in RCC cell lines.

Methods.

Four cohorts of patients received weekly bryostatin-1 (20 μg/m²) with temsirolimus (10, 15, 25, or 37.5 mg) in 28-day cycles.

Results.

Thirty patients received a total of 138 cycles across four dose levels. Twenty-five patients had RCC (17 clear cell, 7 papillary, and 1 unclassified). Two sarcoma patients with prior cytotoxic therapy experienced dose-limiting toxicity at 15 mg of temsirolimus (grade 3 neutropenia and grade 3 hypophosphatemia). Subsequently, patients with prior cytotoxic therapy were excluded. Two additional dose-limiting toxicities were noted with 37.5 mg of temsirolimus (grade 3 neutropenia and grade 3 creatinine elevation). Consequently, the maximum tolerated dose was defined as temsirolimus at 25 mg and bryostatin-1 at 20 μg/m² every 28 days. Of the 25 RCC patients, 3 patients had partial responses that lasted for 14 months, 28 months, and ≥80 months, respectively. Partial responses were seen in both clear cell and papillary histology.

Conclusion.

This combination of 37.5 mg of temsirolimus with 20 μg/m² of bryostatin-1 was reasonably safe and well tolerated. Durable responses were observed in 3 of 25 patients with RCC.     

Prognostic Significance of Pancreatic Metastases in Patients With Advanced Renal Cell Carcinoma Treated With Systemic Therapy

BackgroundPancreatic metastases (PM) are rare in renal cell carcinoma. It has been suggested that patients with metastases to the pancreas have a more favorable prognosis, but little is known about the long-term outcomes with systemic therapy. We sought to understand the outcomes of patients with metastatic renal cell carcinoma with PM treated with systemic therapy.Patients and MethodsWe conducted a pooled analysis of 4736 patients with metastatic renal cell carcinoma treated on phase II/III clinical trials. Systemic therapies included anti-vascular endothelial growth factor targeted therapy, mammalian target of rapamycin-targeted therapy, and cytokine therapy.ResultsThe primary end point was overall survival (OS) in patients with versus without PM. Statistical analyses were performed using Kaplan-Meier analysis and Cox regression. Among 4736 patients, 235 (5.0%) were identified to have baseline PM at therapy initiation. The median OS in patients with PM was significantly prolonged with OS of 41.7 months versus 19.0 months (adjusted hazard ratio, 0.52; P < .0001). Similarly, progression-free survival was significantly prolonged in patients with PM (10.9 vs. 6.9 months; adjusted hazard ratio, 0.72; P = .004). The effect of PM on OS and progression-free survival was independent of other sites of metastasis or International mRCC Database Consortium risk group.ConclusionThe presence of PM in RCC is an independent positive predictor for survival and improved response to systemic therapy. These findings suggest RCC with PM is associated with favorable outcomes and further work to understand the underlying disease biology of these patients is warranted.