Activity of Tivozanib in Non-clear Cell Renal Cell Carcinoma: Subgroup Analysis From a Phase II Randomized Discontinuation Trial.

BACKGROUND: Non-clear cell renal cell carcinoma (nccRCC) is a blanket term for a collection of heterogeneous and biologically diverse RCC histologies, including but not limited to papillary, chromophobe, and unclassified subtypes. Tivozanib is a selective vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) that demonstrated activity in RCC with clear cell component. The objective of this analysis was to determine the efficacy of tivozanib in histologically unclassified/mixed RCC. METHODS: We identified patients with nccRCC enrolled in Study 201 (NCT00502307) between October 2007 and July 2008. This was a phase II randomized discontinuation trial of tivozanib in patients with RCC who had no prior VEGFR-targeted treatment. Clinical outcomes including investigator-assessed objective response rate (ORR), disease control rate (DCR, defined by complete response + partial response + stable disease), and progression-free survival (PFS) were examined. RESULTS: Of the 272 patients enrolled, 46 (16.9%) patients had nccRCC: 11 (4%) papillary, 2 (0.7%) chromophobe, 2 (0.7%) collecting duct, and 31 (11.4%) mixed/unclassified. Of the 46 patients with nccRCC, 38 were continuously treated with tivozanib and the best ORR was 21.1% (confirmed) and 31.6% (confirmed and unconfirmed). The DCR was 73.7% and median PFS was 6.7 months (95% confidence interval, 125-366 days). There were no new safety signals compared to the ITT population. Limitations include the small number of individual nccRCC subtypes and the randomized discontinuation design. CONCLUSION: Tivozanib demonstrated activity and a favorable safety profile in patients with nccRCC. These data add to the body of evidence supporting the use of VEGFR-TKI in advanced nccRCC.

Clinical Activity of Ipilimumab Plus Nivolumab in Patients With Metastatic Non-Clear Cell Renal Cell Carcinoma.

INTRODUCTION: Ipilimumab plus nivolumab has been approved for intermediate- and poor-risk metastatic renal cell carcinoma (RCC). However, the activity in non-clear cell RCC (nccRCC) is unknown. PATIENTS AND METHODS: Patients from Cleveland Clinic and the University of Texas Southwestern who had received ipilimumab plus nivolumab for metastatic nccRCC from October 2017 to May 2019 were retrospectively identified. Ipilimumab plus nivolumab was administered in accordance with the CHECKMATE 214 trial. Imaging was obtained at baseline and every 12 weeks. The baseline patient characteristics, objective response per Response Evaluation Criteria in Solid Tumors, version 1.1, and treatment-related adverse events (TRAEs) per Common Terminology Criteria for Adverse Events, version 5.0, were analyzed. RESULTS: Eighteen patients were identified. The median age was 59 years (range, 32-81 years), 77.8% were men, and the Eastern Cooperative Oncology Group performance status was 0 (38%) or 1 (50%). The median treatment duration was 2.4 months (range, 0.7-12.3 months). The non-clear cell histologic types included 6 papillary, 5 chromophobe, 3 unclassified, 2 adenocarcinoma of renal origin, 1 translocation, and 1 medullary. Most had an intermediate (66%) or poor (22%) International Metastatic Database Consortium risk. The best objective response included 6 partial responses (PRs; 33.3%) and 3 with stable disease (16.7%). Of the patients with a PR, the median time to the best response was 3.0 months, and median duration of the PR was 4.3 months. The median progression-free survival was 7.1 months. All-grade TRAEs were noted in 11 patients (61.1%) and included colitis (22%), hepatotoxicity (16%), rash (11%), and fatigue (11%). Eleven patients (61%) had TRAEs requiring high-dose glucocorticoids (> 40 mg of prednisone equivalent daily). CONCLUSIONS: Ipilimumab plus nivolumab demonstrated objective responses and notable toxicity in patients with nccRCC.

Identifying Prostate Surface Antigen Patterns of Change in Patients with Metastatic Hormone Sensitive Prostate Cancer Treated with Abiraterone and Prednisone.

BACKGROUND: Despite treatment with abiraterone acetate and prednisone (AA/P), most patients with metastatic hormone sensitive prostate cancer (mHSPC) will develop castration-resistant disease (metastatic castration-resistant prostate cancer [mCRPC]). The early identification of who will progress on AA/P is limited. OBJECTIVE: This study investigates the role of prostate surface antigen (PSA) kinetics as a predictor of progression in mHSPC patients treated with AA/P. PATIENTS AND METHODS: All patients with mHSPC who initiated androgen deprivation therapy (ADT) and AA/P from June 2017 to February 2019 at the Cleveland Clinic were eligible. PSA-mCRPC was defined as a PSA rise at two consecutive time points. Patients were followed until first mCRPC or last contact after AA/P. Patterns of PSA change were evaluated using a longitudinal mixed model at time 0, 3, 6, 9, and 12 months from AA/P initiation. The association between PSA profile at 3 months and PSA-mCRPC was examined using survival analysis. Radiographic progression (Rad-mCRPC) was also analyzed. RESULTS: A total of 130 men with follow-up were included. The median (interquartile range [IQR]) follow-up time was 15.3 (10.5, 22.5) months. Eighty-two percent were Caucasian (median age 68.5 years); participants had a median (IQR) PSA of 16.8 (5.3, 48.0) ng/mL. Half of the patients had de novo disease, and 46.2% had high-risk disease (61% had a Gleason score ≥ 8, 16% had visceral disease, and 54% had three or more bony lesions). The greatest PSA percentage reduction from baseline after AA/P initiation occurred at the first 3 months (median 98.3%). The reduction at 6-12 months from baseline was small (99.7-100%). Patients without PSA-mCRPC had a significantly greater 3-month reduction of PSA values compared to patients who developed PSA-mCRPC (p interaction = 0.0002). 50.8% of patients were able to achieve a non-detectable PSA (median 13.1 months). PSA-mCRPC (n = 20) was observed from 4 to 24 months after AA/P, with the majority of events occurring within the first 12 months. Patients with PSA < 0.3 ng/mL (12-month PSA-mCRPC-free 94.5% vs. 69.4%, p = 0.0004) or a ≥ 98% reduction (94.9% vs. 68.0%, p = 0.0002) at 3 months had better PSA-mCRPC-free survival compared to their counterparts. Absolute reduction at 3 months was not associated with PSA-mCRPC. Similar PSA patterns were seen in those who had Rad-mCRPC compared to no Rad-mCRPC (p interaction < 0.05). CONCLUSION: The degree of PSA decline at 3 months predicted serologic progression to mCRPC. Those who developed castration-resistant disease had higher PSA and a lower percentage reduction by 3 months. Tracking early PSA pattern changes may alert clinicians to poor treatment effect and potential progression; they should consider frequent PSA measurement and imaging, as well as the initiation of sequential therapy.

Salvage Ipilimumab and Nivolumab in Patients With Metastatic Renal Cell Carcinoma After Prior Immune Checkpoint Inhibitors.

PURPOSE: Immune checkpoint inhibitors (ICIs) are standard therapy in metastatic renal cell carcinoma (RCC). The safety and activity of the combination of ipilimumab and nivolumab in patients who have received prior ICI targeting the programmed death 1 (PD-1) pathway remains unknown. We evaluated ipilimumab and nivolumab in patients with metastatic RCC after prior treatment with anti-PD-1 pathway-targeted therapy. PATIENTS AND METHODS: Patients with metastatic RCC who received prior anti-PD-1 pathway-targeted therapy and subsequently received ipilimumab and nivolumab were reviewed. Objective response rate and progression-free survival per investigator assessment were recorded. Toxicity of ipilimumab and nivolumab was also assessed. RESULTS: Forty-five patients with metastatic RCC were included. All patients (100%) received prior ICIs targeting the PD-1 pathway. The median age was 62 years (range, 21-82 years). At a median follow-up of 12 months, the objective response rate to ipilimumab and nivolumab was 20%. The median progression-free survival while on ipilimumab and nivolumab was 4 months (range, 0.8-19 months). Immune-related adverse events (irAEs) of any grade with ipilimumab and nivolumab were recorded in 29 (64%) of the 45 patients; grade 3 irAEs were recorded in 6 (13%) of the 45 patients. CONCLUSION: Ipilimumab and nivolumab demonstrated antitumor activity with acceptable toxicity in patients with metastatic RCC who had prior treatment with checkpoint inhibition.

Individualised axitinib regimen for patients with metastatic renal cell carcinoma after treatment with checkpoint inhibitors: a multicentre, single-arm, phase 2 study.

BACKGROUND: Checkpoint inhibitor therapy is a standard of care for patients with metastatic renal cell carcinoma. Treatment options after checkpoint inhibitor therapy include vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitors, although no prospective data regarding their use in this setting exist. Axitinib is a VEGF-R inhibitor with clinical data supporting increased activity with dose titration. We aimed to investigate the activity of dose titrated axitinib in patients with metastatic renal cell carcinoma who were previously treated with checkpoint inhibitor. METHODS: We did a multicentre, phase 2 trial of axitinib given on an individualised dosing algorithm. Patients at least 18 years of age with histologically or cytologically confirmed locally recurrent or metastatic renal cell carcinoma with clear cell histology, a Karnofsky Performance Status of 70% or more, and measurable disease who received checkpoint inhibitor therapy as the most recent treatment were eligible. There was no limit on number of previous therapies received. Patients received oral axitinib at a starting dose of 5 mg twice daily with dose titration every 14 days in 1 mg increments (ie, 5 mg twice daily to 6 mg twice daily, up to 10 mg twice daily maximum dose) if there was no axitinib-related grade 2 or higher mucositis, diarrhoea, hand-foot syndrome, or fatigue. If one or more of these grade 2 adverse events occurred, axitinib was withheld for 3 days before the same dose was resumed. Dose reductions were made if recurrent grade 2 adverse events despite treatment breaks or grade 3-4 adverse events occurred. The primary outcome was progression-free survival. Analyses were done per protocol in all patients who received at least one dose of axitinib. Recruitment has been completed and the trial is ongoing. This trial is registered with ClincalTrials.gov, number NCT02579811. FINDINGS: Between Jan 5, 2016 and Feb 21, 2018, 40 patients were enrolled and received at least one dose of study treatment. With a median follow-up of 8·7 months (IQR 3·7-14·2), the median progression-free survival was 8·8 months (95% CI 5·7-16·6). Fatigue (83%) and hypertension (75%) were the most common all-grade adverse events. The most common grade 3 adverse event was hypertension (24 patients [60%]). There was one (3%) grade 4 adverse event (elevated lipase) and no treatment-related deaths occurred. Serious adverse events that were likely related to therapy occurred in eight (20%) patients; the most common were dehydration (n=4) and diarrhoea (n=2). INTERPRETATION: Individualised axitinib dosing in patients with metastatic renal cell inoma previously treated with checkpoint inhibitors did not meet the prespecified threshold for progression free survival, but these data show that this individualised titration scheme is feasible and has robust clinical activity. These prospective results warrant consideration of axitinib in this setting. FUNDING: Pfizer.

A phase II trial of intermittent nivolumab in patients with metastatic renal cell carcinoma (mRCC) who have received prior anti-angiogenic therapy.

BACKGROUND: Nivolumab is approved for mRCC patients who have received prior anti-angiogenic therapy but the duration of therapy required for sustained clinical benefit is unknown. A phase II clinical trial to investigate the feasibility of intermittent nivolumab dosing was conducted. METHODS: Patients ≥18 years of age with mRCC who were previously treated with at least one antiangiogenic therapy were eligible. Patients were treated with nivolumab for twelve weeks. Patients who had RECIST PD were removed from the trial. Patients who did not initially achieve ≥10% reduction in tumor burden (TB) continued nivolumab per standard of care. Patients with ≥10% TB reduction entered a treatment-free observation phase with re-imaging every 12 weeks. Nivolumab was restarted in patients with a ≥ 10% TB increase and again held with TB reduction ≥10%. This intermittent nivolumab dosing continued until RECIST PD while on nivolumab. The primary objective was feasibility of intermittent nivolumab, defined as the proportion of patients eligible for intermittent therapy who elect to receive intermittent nivolumab. Intermittent nivolumab would be considered "feasible" if the acceptance rate was ≥80%. Forty patients provides > 95% power with 0.05 type I error, assuming a null acceptance rate of 50%. With the approval of the combination of ipilimumab/nivolumab (April 2018) in front-line mRCC, this cohort was closed prior to completed pre-planned approval. RESULTS: Of the 14 patients enrolled, 13 (93%) were male with a median age 65. All had a prior nephrectomy and 12 (86%) were intermediate-risk by IMDC criteria. Five patients (36%) met the criteria for the intermittent phase of the trial (median TB decrease 46%) and all agreed to intermittent therapy. With a median follow-up of 48 weeks, only one patient restarted therapy. The four remaining patients have a sustained response for a median of 34 weeks (range, 16-53) off therapy. No patients developed RECIST PD while off therapy. CONCLUSIONS: This prospective experience of intermittent nivolumab dosing in mRCC supports further investigation of intermittent immunotherapy dosing strategies in RCC. TRIAL REGISTRATION: NCT03126331 (Intermittent Nivolumab in Metastatic Renal Cell Carcinoma Patients; Date of registration 4/27/2017; https://clinicaltrials.gov/ct2/show/NCT03126331 ).

Myalgia and Arthralgia Immune-related Adverse Events (irAEs) in Patients With Genitourinary Malignancies Treated With Immune Checkpoint Inhibitors.

BACKGROUND: Myalgia and arthralgia immune-related adverse events (irAEs) in patients treated with checkpoint inhibitors (CPIs) present a clinical challenge. We describe the clinical characteristics and treatment of myalgia and arthralgia irAEs in CPI-treated patients with genitourinary (GU) malignancies. PATIENTS AND METHODS: Patients with GU malignancies who were treated with CPIs and developed myalgia and arthralgia irAEs that resulted in interruption or discontinuation of CPI therapy were reviewed. Patient-, disease-, and irAE-related data were collected and analyzed. RESULTS: Twenty-one patients were identified. Eighteen (86%) had renal cell carcinoma; 3 (14%) had urothelial carcinoma. The majority (71%) were male; the median age at diagnosis was 56 years (range, 36-78 years). CPI therapy included anti-programmed death-ligand 1 (29%), anti-programmed cell death protein 1 (48%), and combined programmed cell death protein 1/cytotoxic T-lymphocyte-associated protein 4 antibodies (24%). The median time from CPI initiation to myalgia and arthralgia irAE was 5.1 months (range, 0.23-50.5 months). All patients were treated with prednisone with a median initial dose of 40 mg/d (range, 10-90 mg/d) for a median duration of 64 weeks (range, 3-242 weeks). Treatment with methotrexate (14%), infliximab (14%), tocilizumab (10%), gabapentin (10%), and etanercept (5%) was also required in some patients. Six (29%) patients restarted CPI therapy following symptom improvement, 3 (15%) switched to a subsequent therapy, and 12 (55%) patients had an ongoing sustained response to therapy (median, 14.5 months; range, 3-55 months) despite no subsequent anti-cancer therapy. CONCLUSION: Myalgia and arthralgia irAEs in CPI-treated patients with GU malignancies vary in timing of presentation, severity, and treatment. Multidisciplinary teams that include a rheumatologist are critical for optimal management. Durable response to CPIs can be maintained even after therapy discontinuation.

Therapy Management Using Modified 2-Weeks-On/1-Week-Off Dosing Schedule in Patients With Metastatic Renal Cell Carcinoma Receiving Sunitinib: A Hypothetical, Illustrative Case Scenario.

This patient case is fictional and does not represent events or a response from an actual patient. The authors developed this fictional case for educational purposes only. Brady, a 54-year-old white male, was diagnosed with metastatic renal cell carcinoma (mRCC). Two and a half years prior, he had undergone a complete left nephrectomy for clear-cell RCC, with clean margins and negative lymph nodes. Post nephrectomy, he was routinely surveyed (every 3-6 months) by radiologic imaging. After 15 months of monitoring, a CT scan revealed small nodules in the left lung. Repeated scans were ordered to be taken in 6 weeks to assess growth kinetics, wherein an increase in the size of a number of nodules was detected. Of particular concern was the location of one of the larger nodules very close to a bronchus. Consequently, a needle biopsy was performed, which recovered malignant cells consistent with mRCC. It was then decided to begin systemic treatment for mRCC. Prior to starting treatment, Brady's Eastern Cooperative Oncology Group performance status (ECOG PS) was 0, and he had a Karnofsky score of 90, as he had only slightly diminished stamina that was considered disease related. Accordingly, he was classified as favorable risk by both Memorial Sloan Kettering Cancer Center and International Metastatic Renal Cell Carcinoma Database Consortium criteria (Table 1). Brady is married and lives with his wife. He drinks alcohol occasionally but does not have a history of smoking. For the past 22 years, he has been employed full time as a factory assembly line worker, performing skilled, light assembly. In this capacity, Brady works with his hands and must remain on his feet approximately 30% of the working day. As Brady is eligible for early retirement in 11 months, he intends to continue working full time during treatment, if possible. Brady's medical history includes nonvalvular atrial fibrillation, which is treated with apixaban; hypertension that is adequately controlled (blood pressure 137/79 mm Hg) with lisinopril at 20 mg/day; coronary artery disease; and hyperlipidemia that is treated with atorvastatin at 20 mg/day. He is also taking daily low-dose aspirin (81 mg).

Patterns, predictors and subsequent outcomes of disease progression in metastatic renal cell carcinoma patients treated with nivolumab.

BACKGROUND: Nivolumab is approved for the treatment of refractory metastatic renal cell carcinoma. Patterns and predictors of progressive disease (PD) on nivolumab, and outcomes in such patients are lacking. METHODS: A retrospective analysis of patients (pts) with metastatic clear cell renal cell carcinoma (ccRCC) who received nivolumab at Cleveland Clinic (2015-2017) was performed. PD was defined per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or clinical progression as per treating physician. Univariate analyses (UVA) and multivariate analyses (MVA) were used to identify clinical and laboratory markers as potential predictors of progression-free survival (PFS). RESULTS: Ninety patients with mean age of 65, 74% men, and 83% good or intermediate International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group were included. Median number of prior systemic treatments was 2 (range, 1-6). Median overall survival (OS) and PFS were 15.8 and 4.4 months, respectively. Fifty-seven patients (63%) had PD and 44% of patients with radiographic PD had new organ sites of metastases with brain (8/23, 35%) being the most common. Twelve patients received treatment beyond progression (TBP), and among 6 patients with available data, 3 (50%) had any tumor shrinkage (2 pts. with 17% shrinkage, one pt. with 29% shrinkage). Of 57 patients with PD, 28 patients (49%) were able to initiate subsequent treatment, mainly with axitinib and cabozantinib, while 40% of patients were transitioned to hospice after PD. In MVA, a higher baseline Neutrophil-to-Lymphocyte ratio (NLR) (HR, 1.86; 95% CI, 1.05-3.29; p = 0.033) was associated with an increased risk of progression, whereas higher (> 0.1 k/uL) baseline eosinophil count was associated with a lower risk of progression (HR, 0.54; 95% CI, 0.30-0.98; p = 0.042). CONCLUSION: Brain was the most common site of PD in patients treated with nivolumab, and only half of patients progressing on nivolumab were able to initiate subsequent treatment. The risk of PD increased with a higher baseline NLR and reduced with a higher baseline eosinophil count.

The association between facility case volume and overall survival in patients with metastatic renal cell carcinoma in the targeted therapy era.

BACKGROUND: Improved overall survival of cancer patients treated by high-volume providers has been reported in surgical oncology and radiation oncology literature. Whether this volume-outcome association exists in medical oncology-managed metastatic solid tumors is uncertain. This study aimed to investigate the effect of facility case volume (FCV) on overall survival in patients with metastatic renal cell carcinoma (mRCC) diagnosed in the targeted therapy era. MATERIALS AND METHODS: Adult patients diagnosed with mRCC between 2006 and 2015 were identified in the National Cancer Database. The primary exposure was FCV, which was defined by mRCC case volume of each treating facility. The association between FCV and all-cause mortality in mRCC was investigated in multivariable Cox regression model and validated with inverse propensity-score weighting method. Logistic regression was used to identify independent predictors for treatment at high-volume facilities. Covariates adjusted for were sociodemographics, tumor characteristics and treatment modalities. RESULTS: There were 31,329 mRCC patients identified. The mean follow-up time was 14.3 months. When FCV was coded as a continuous variable, each increment of 10 mRCC cases/y was associated with reduced all-cause mortality after baseline covariates adjustment [adjusted hazard ratio: 0.93, 95% confidence interval: 0.90-0.96, P value:<0.0001]. In dichotomized models, improved all-cause mortality was observed at cutoffs of 85th (4.3 cases/y), 90th (5.4 cases/y) and 95th (7.4 cases/y) but not at 50th (2.2 cases/y) and 75th (3.4 cases/y) percentiles. For illustrative purpose, 95th percentile was chosen and inverse propensity-score weighting-adjusted Kaplan-Meier curve demonstrated improved overall survival for mRCC patients treated at high-volume facilities (adjusted hazard ratio: 0.90, 95% confidence interval: 0.88-0.94, P value <0.0001; the 1-, 2-, 3-year survival rates were 41%, 26%, and 19% vs. 36%, 22%, and 16% for patients treated at high and low-volume facilities, respectively). Patients without insurance or with Medicaid status, with shorter travel distance, living in nonmetropolitan area or in area with lower averaged education level were less likely to be treated at high-volume facilities. CONCLUSIONS: Patients diagnosed with mRCC in the targeted therapy era have improved overall survival when treated at high mRCC-volume facilities, suggesting a volume-outcome association in medical oncology-managed metastatic solid tumors.

The efficacy of VEGFR TKI therapy after progression on immune combination therapy in metastatic renal cell carcinoma.

BACKGROUND: The outcome of patients who progress on front-line immune-based combination regimens (IC) including immune checkpoint inhibitors (CPI) and receive subsequent systemic therapy is unknown. METHODS: Retrospective analysis of consecutive patients with clear-cell mRCC who progressed on one of seven clinical trials investigating an IC and received ≥1 line of subsequent VEGFR TKI therapy. RESULTS: Thirty-three patients [median age 57 (37-77), 85% male, 73% ECOG 0] were included. For evaluable patients (N = 28), the best response to first subsequent therapy was 29% partial response, 54% stable disease, and 18% progressive disease. The median PFS (mPFS) for first subsequent therapy was 6.4 months (95% CI, 4.4-8.4); no difference in mPFS by prior type of IC (VEGFR TKI-CPI vs. CPI-CPI) was noted (p = 0.310). Significant AEs were observed in 30% of patients, more frequently transaminitis (9%). CONCLUSIONS: VEGFR TKIs have clinical activity in mRCC refractory to IC therapy, possibly impacted by the mechanism of prior combination therapy.

Atezolizumab in Metastatic Urothelial Carcinoma Outside Clinical Trials: Focus on Efficacy, Safety, and Response to Subsequent Therapies.

BACKGROUND: Little is known about the outcomes, safety, and response to subsequent therapies of patients with metastatic urothelial carcinoma (mUC) treated with atezolizumab outside clinical trials. OBJECTIVES: The objectives of the study include to report the clinical efficacy and safety of atezolizumab, and the response to future therapies in clinical practice outside clinical trials. PATIENT AND METHODS: This is a retrospective, single-center study including consecutive patients with confirmed mUC who received at least one dose of atezolizumab 1200 mg every 3 weeks between May 2016 and April 2017. RESULTS: Seventy-nine patients, median age 72 years (range 29-93), 71% men and 76% ECOG PS 0-1, were identified. Most patients (79%) had primary cancer in the bladder, 62% had prior surgery, and 75% received at least one prior line of treatment (34 patients had prior cisplatin-based chemotherapy). Best response included 18% partial response, 29% stable disease, and 53% progressive disease. Patients were on atezolizumab for a median of 2.7 months (95%CI, 1.8-3.6) and median PFS was 3.2 months (95%CI, 1.6-4.8). A total of 33 (42%) patients had significant (any cause) AEs, including grade 4 hyperbilirubinemia in two patients; no toxic deaths were reported. At time of data analysis, only 18% of patients received at least one subsequent line of treatment for a median of 1.8 months (95%CI, 0.0-5.0) while 42% were referred to palliative care/hospice or died. CONCLUSIONS: Patients with mUC who progressed on atezolizumab were unlikely to receive subsequent systemic treatments and the benefit of those treatments appeared limited in our cohort. The findings may impact timing and designs of clinical trials in mUC.

A Phase II Study of Intermittent Sunitinib in Previously Untreated Patients With Metastatic Renal Cell Carcinoma.

Purpose Sunitinib is a standard initial therapy in metastatic renal cell carcinoma (mRCC), but chronic dosing requires balancing toxicity with clinical benefit. The feasibility and clinical outcome with intermittent sunitinib dosing in patients with mRCC was explored. Patients and Methods Patients with treatment-naïve, clear cell mRCC were treated with four cycles of sunitinib (50 mg once per day, 4 weeks of receiving treatment followed by 2 weeks of no treatment). Patients with a ≥ 10% reduction in tumor burden (TB) after four cycles had sunitinib held, with restaging scans performed every two cycles. Sunitinib was reinitiated for two cycles in those patients with an increase in TB by ≥ 10%, and again held with ≥ 10% TB reduction. This intermittent sunitinib dosing continued until Response Evaluation Criteria in Solid Tumors-defined disease progression while receiving sunitinib, or unacceptable toxicity occurred. The primary objective was feasibility, defined as the proportion of eligible patients who underwent intermittent therapy. Results Of 37 patients enrolled, 20 were eligible for intermittent therapy and all patients (100%) entered the intermittent phase. Patients were not eligible for intermittent sunitinib because of progressive disease (n = 13), toxicity (n = 1), or consent withdrawal (n = 3) before the end of cycle 4. The objective response rate was 46% after the first four cycles of therapy. The median increase in TB during the periods off sunitinib was 1.6 cm (range, -2.9 to 3.4 cm) compared with the TB immediately before stopping sunitinib. Most patients exhibited a stable sawtooth pattern of TB reduction while receiving sunitinib and TB increase while not receiving sunitinib. Median progression-free survival to date is 22.4 months (95% CI, 5.4 to 37.6 months) and median overall survival is 34.8 months (95% CI, 14.8 months to not applicable). Conclusion Periodic extended sunitinib treatment breaks are feasible and clinical efficacy does not seem to be compromised.

Clinical Effect of Dose Escalation After Disease Progression in Patients With Metastatic Renal Cell Carcinoma.

BACKGROUND: Given the variability in drug levels with tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma (mRCC), dose escalation at the occurrence of progressive disease (PD) might have antitumor effects. PATIENTS AND METHODS: The data from patients with mRCC who were treated at the Cleveland Clinic with TKIs and received a dose escalation after PD in accordance with Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1, were retrospectively reviewed. Patient- and disease-related data were collected and summarized as frequency counts and percentages or medians and ranges. The Kaplan-Meier method was used to summarize the treatment duration for the escalated doses. RESULTS: Twenty-two patients were identified. Most patients (82%) were men; the median age at diagnosis was 58 years (range, 40-71 years). The most common histologic type was clear cell (73%). Axitinib was the most frequently escalated agent after PD (17 patients), followed by sunitinib (3 patients), and pazopanib (2 patients). Before PD, the median treatment duration was 6.8 months (range, 1.6-50.6 months). Of the 18 patients with evaluable tumor measurements after dose escalation, 14 (78%) had a decrease in tumor burden. The median decrease in tumor burden after dose escalation was 14% (range, 2%-58%); 4 patients (22%) had decreases ≥10%, 2 (11%) ≥20%, and 4 (22%) >30% (RECIST partial response). At the last follow-up examination, 5 patients (23%) continued to be treated at escalated doses. The median duration of escalated therapy was estimated at 10.1 months (range, 0.6 to 37.9 months). CONCLUSION: Dose escalation of TKIs after PD for select patients with mRCC can lead to a reduction in tumor burden and extend the duration of therapy.