ABSTRACT
Brain metastases are a challenging manifestation of renal cell carcinoma. We have a limited understanding of brain metastasis tumor and immune biology, drivers of resistance to systemic treatment, and their overall poor prognosis. Current data support a multimodal treatment strategy with radiation treatment and/or surgery. Nonetheless, the optimal approach for the management of brain metastases from renal cell carcinoma remains unclear. To improve patient care, the authors sought to standardize practical management strategies. They performed an unstructured literature review and elaborated on the current management strategies through an international group of experts from different disciplines assembled via the network of the International Kidney Cancer Coalition. Experts from different disciplines were administered a survey to answer questions related to current challenges and unmet patient needs. On the basis of the integrated approach of literature review and survey study results, the authors built algorithms for the management of single and multiple brain metastases in patients with renal cell carcinoma. The literature review, consensus statements, and algorithms presented in this report can serve as a framework guiding treatment decisions for patients. CA Cancer J Clin. 2022;72:454-489.
Subject(s)
Brain Neoplasms , Carcinoma, Renal Cell , Kidney Neoplasms , Brain Neoplasms/therapy , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/therapy , Combined Modality Therapy , Humans , Kidney Neoplasms/pathology , Kidney Neoplasms/therapyABSTRACT
Renal medullary carcinoma (RMC) is an aggressive kidney cancer that almost exclusively develops in individuals with sickle cell trait (SCT) and is always characterized by loss of the tumor suppressor SMARCB1. Because renal ischemia induced by red blood cell sickling exacerbates chronic renal medullary hypoxia in vivo, we investigated whether the loss of SMARCB1 confers a survival advantage under the setting of SCT. Hypoxic stress, which naturally occurs within the renal medulla, is elevated under the setting of SCT. Our findings showed that hypoxia-induced SMARCB1 degradation protected renal cells from hypoxic stress. SMARCB1 wild-type renal tumors exhibited lower levels of SMARCB1 and more aggressive growth in mice harboring the SCT mutation in human hemoglobin A (HbA) than in control mice harboring wild-type human HbA. Consistent with established clinical observations, SMARCB1-null renal tumors were refractory to hypoxia-inducing therapeutic inhibition of angiogenesis. Further, reconstitution of SMARCB1 restored renal tumor sensitivity to hypoxic stress in vitro and in vivo. Together, our results demonstrate a physiological role for SMARCB1 degradation in response to hypoxic stress, connect the renal medullary hypoxia induced by SCT with an increased risk of SMARCB1-negative RMC, and shed light into the mechanisms mediating the resistance of SMARCB1-null renal tumors against angiogenesis inhibition therapies.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Sickle Cell Trait , Animals , Humans , Mice , Carcinoma, Renal Cell/pathology , Hypoxia/genetics , Hypoxia/metabolism , Kidney/metabolism , Kidney Neoplasms/pathology , Sickle Cell Trait/genetics , Sickle Cell Trait/metabolism , SMARCB1 Protein/genetics , SMARCB1 Protein/metabolismABSTRACT
BACKGROUND: Tivozanib has been approved as a third-line or later therapy for advanced renal cell carcinoma based on the TIVO-3 trial, which was conducted before immune checkpoint therapies (ICT), cabozantinib, and lenvatinib/everolimus became incorporated in the current sequential treatment paradigm for advanced clear cell RCC (ccRCC). METHODS: We performed a retrospective study of patients with advanced ccRCC treated with tivozanib at MD Anderson Cancer Center during 6/2021-7/2023. A blinded radiologist assessed tumor response by RECIST v1.1. We assessed overall response rate (ORR), clinical benefit rate (CBR) [percentage of all treated patients who achieved radiologic response or stable disease (SD) forâ ≥â 6 months], progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Of 30 analyzed patients, 23% had performance statusâ ≥â 2; 47% had International Metastatic RCC Database Consortium (IMDC) poor-risk disease. Median number of prior therapies was 4 (range 1-8). All patients received prior ICT, 87% cabozantinib and 60% lenvatinib ± everolimus. Of 26 evaluable patients, 2 patients had confirmed partial response (ORR 7.7%); 5 patients had SD forâ ≥â 6 months (CBR 23.3%). Median PFS was 3.8 months (range 0.7-13.9); median OS was 14.1 months (range 0.3-28.5). Fifteen patients (50%) hadâ ≥â 1 treatment-related adverse event (TRAE). There were 6 gradeâ ≥â 3 TRAEs [hypertension, congestive heart failure (3), mucositis, and GI perforation (grade 5)]. CONCLUSIONS: In this cohort of heavily pretreated patients with advanced ccRCC, tivozanib yielded a modest clinical benefit in a minority of patients who received prior ICT, cabozantinib, and lenvatinib ± everolimus. TRAEs were consistent with previously published reports.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Phenylurea Compounds , Quinolines , Humans , Carcinoma, Renal Cell/drug therapy , Female , Male , Aged , Kidney Neoplasms/drug therapy , Kidney Neoplasms/pathology , Quinolines/therapeutic use , Quinolines/adverse effects , Middle Aged , Retrospective Studies , Phenylurea Compounds/therapeutic use , Phenylurea Compounds/adverse effects , Adult , Aged, 80 and overABSTRACT
Racial disparities have been documented in the biology and outcome of certain renal cell carcinomas (RCCs) among Black patients. However, little is known about racial differences in MiT family translocation RCC (TRCC). To investigate this issue, we performed a case-control study using data from The Cancer Genome Atlas (TCGA) and the Chinese OrigiMed2020 cohort. A total of 676 patients with RCC (14 Asian, 113 Black, and 525 White) were identified in TCGA, and TRCC was defined as RCC with TFE3/TFEB translocation or TFEB amplification, leading to 21 patients with TRCC (2 Asian, 8 Black, 10 White, and 1 unknown). Asian (2 of 14 [14.3%] vs 10 of 525 [1.9%]; P = .036) and Black (8 of 113 [7.1%] vs 1.9%; P = .007) patients with RCC showed significantly higher prevalence of TRCC compared with White patients with RCC. The overall mortality rate of TRCC was slightly higher in Asian and Black patients compared with White patients (HR: 6.05, P = .069). OrigiMed2020 Chinese patients with RCC had a significantly higher proportion of TRCC with TFE3 fusions than TCGA White patients with RCC (13 of 250 [5.2%] vs 7 of 525 [1.3%]; P = .003). Black patients with TRCC were more likely to exhibit the proliferative subtype than White patients (6 of 8 [75%] vs 2 of 9 [22.2%]; P = .057) for those who had RNA-seq profiles. We present evidence of higher prevalence of TRCC in Asian and Black patients with RCC compared with White patients and show that these tumors in Asian and Black patients have distinct transcriptional signatures and are associated with poor outcomes.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Carcinoma, Renal Cell/pathology , Kidney Neoplasms/pathology , Case-Control Studies , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics , Translocation, GeneticABSTRACT
BACKGROUND: Despite the clinical benefit of immune checkpoint inhibitors (ICIs), patients with a viral hepatitis have been excluded from clinical trials because of safety concerns. The purpose of this study was to determine the incidence rate of adverse events (AEs) in patients with viral hepatitis who received ICIs for cancer treatment. MATERIALS AND METHODS: We conducted a retrospective study in patients with cancer and concurrent hepatitis B or C, who had undergone treatment with ICI at MD Anderson Cancer Center from January 1, 2010 to December 31, 2019. RESULTS: Of the 1076 patients screened, we identified 33 with concurrent hepatitis. All 10 patients with HBV underwent concomitant antiviral therapy during ICI treatment. Sixteen of the 23 patients with HCV received it before the initiation of ICI. The median follow-up time was 33 months (95% CI, 23-45) and the median duration of ICI therapy was 3 months (IQR, 1.9-6.6). Of the 33 patients, 12 (39%) experienced irAEs (immune-related adverse events) of any grade, with 2 (6%) having grade 3 or higher. None of the patients developed hepatitis toxicities. CONCLUSION: ICIs may be a therapeutic option with an acceptable safety profile in patients with cancer and advanced liver disease.
Subject(s)
Hepatitis, Viral, Human , Neoplasms , Humans , Immune Checkpoint Inhibitors/adverse effects , Retrospective Studies , Neoplasms/drug therapy , Antiviral AgentsABSTRACT
BACKGROUND: There remains a paucity of data regarding the efficacy of immune checkpoint therapy (ICT) combinations ± vascular endothelial growth factor (VEGF) targeted therapy (TT) in translocation renal cell carcinoma (tRCC). METHODS: This is a retrospective study of patients with advanced tRCC treated with ICT combinations at 11 centers in the US, France, and Belgium. Only cases with confirmed fluorescence in situ hybridization (FISH) were included. Objective response rates (ORR) and progression-free survival (PFS) were assessed by RECIST, and overall survival (OS) was estimated by Kaplan-Meier methods. RESULTS: There were 29 patients identified with median age of 38 (21-70) years, and F:M ratio 0.9:1. FISH revealed TFE3 and TFEB translocations in 22 and 7 patients, respectively. Dual ICT and ICT + VEGF TT were used in 18 and 11 patients, respectively. Seventeen (59%) patients received ICT combinations as first-line therapy. ORR was 1/18 (5.5%) for dual ICT and 4/11 (36%) for ICT + VEGF TT. At a median follow-up of 12.9 months, median PFS was 2.8 and 5.4 months in the dual ICT and ICT + VEGF TT groups, respectively. Median OS from metastatic disease was 17.8 and 30.7 months in the dual ICT and ICT + VEGF TT groups, respectively. CONCLUSION: In this retrospective study of advanced tRCC, limited response and survival were seen after frontline dual ICT combination therapy, while ICT + VEGF TT therapy offered some efficacy. Due to the heterogeneity of tRCC, insights into the biological underpinnings are necessary to develop more effective therapies.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/genetics , Kidney Neoplasms/drug therapy , Kidney Neoplasms/genetics , Vascular Endothelial Growth Factor A/genetics , Retrospective Studies , In Situ Hybridization, FluorescenceABSTRACT
BACKGROUND: Metastatic RCC with sarcomatoid and/or rhabdoid (S/R) dedifferentiation is an aggressive disease associated with improved response to immune checkpoint therapy (ICT). The outcomes of patients treated with VEGFR-targeted therapies (TT) following ICT progression have not been investigated. PATIENTS AND METHODS: Retrospective review of 57 patients with sarcomatoid (S), rhabdoid (R), or sarcomatoid plus rhabdoid (Sâ +â R) dedifferentiation who received any TT after progression on ICT at an academic cancer center. Clinical endpoints of interest included time on TT, overall survival (OS) from initiation of TT, and objective response rate (ORR) by RECIST version 1.1. Multivariable models adjusted for epithelial histology, IMDC risk, prior VEGFR TT, and inclusion of cabozantinib in the post-ICT TT regimen. RESULTS: 29/57 patients had S dedifferentiation and 19 had R dedifferentiation. The most frequently used TT was cabozantinib (43.9%) followed by selective VEGFR TT (22.8%). The median time on TT was 6.4 months for all, 6.1 months for those with S dedifferentiation, 15.6 months for R dedifferentiation, and 6.1 months for Sâ +â R dedifferentiation. Median OS from initiation of TT was 24.9 months for the entire cohort, and the ORR was 20.0%. Patients with R dedifferentiation had significantly longer time on TT than those with S dedifferentiation (HR 0.44, 95% CI, 0.21-0.94). IMDC risk was associated with OS. CONCLUSIONS: A subset of patients with S/R dedifferentiation derive clinical benefit from TT after they have progressive disease on ICT. Patients with R dedifferentiation appeared to derive more benefit from TT than those with S dedifferentiation.
ABSTRACT
BACKGROUND: Conditional survival estimates provide critical prognostic information for patients with advanced renal cell carcinoma (aRCC). Efficacy, safety, and conditional survival outcomes were assessed in CheckMate 214 (ClinicalTrials.gov identifier NCT02231749) with a minimum follow-up of 5 years. METHODS: Patients with untreated aRCC were randomized to receive nivolumab (NIVO) (3 mg/kg) plus ipilimumab (IPI) (1 mg/kg) every 3 weeks for 4 cycles, then either NIVO monotherapy or sunitinib (SUN) (50 mg) daily (four 6-week cycles). Efficacy was assessed in intent-to-treat, International Metastatic Renal Cell Carcinoma Database Consortium intermediate-risk/poor-risk, and favorable-risk populations. Conditional survival outcomes (the probability of remaining alive, progression free, or in response 2 years beyond a specified landmark) were analyzed. RESULTS: The median follow-up was 67.7 months; overall survival (median, 55.7 vs 38.4 months; hazard ratio, 0.72), progression-free survival (median, 12.3 vs 12.3 months; hazard ratio, 0.86), and objective response (39.3% vs 32.4%) benefits were maintained with NIVO+IPI versus SUN, respectively, in intent-to-treat patients (N = 550 vs 546). Point estimates for 2-year conditional overall survival beyond the 3-year landmark were higher with NIVO+IPI versus SUN (intent-to-treat patients, 81% vs 72%; intermediate-risk/poor-risk patients, 79% vs 72%; favorable-risk patients, 85% vs 72%). Conditional progression-free survival and response point estimates were also higher beyond 3 years with NIVO+IPI. Point estimates for conditional overall survival were higher or remained steady at each subsequent year of survival with NIVO+IPI in patients stratified by tumor programmed death ligand 1 expression, grade ≥3 immune-mediated adverse event experience, body mass index, and age. CONCLUSIONS: Durable clinical benefits were observed with NIVO+IPI versus SUN at 5 years, the longest phase 3 follow-up for a first-line checkpoint inhibitor-based combination in patients with aRCC. Conditional estimates indicate that most patients who remained alive or in response with NIVO+IPI at 3 years remained so at 5 years.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/pathology , Female , Humans , Ipilimumab , Kidney Neoplasms/drug therapy , Kidney Neoplasms/pathology , Male , Nivolumab/therapeutic use , SunitinibABSTRACT
BACKGROUND: MiT family translocation renal cell carcinoma (TRCC) is a rare and aggressive subgroup of renal cell carcinoma harboring high expression of c-MET. While TRCC response rates to VEGF receptor tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors are limited, efficacy of cabozantinib (a VEGFR, MET, and AXL inhibitor) in this subgroup is unclear. METHODS: We performed a multicenter, retrospective, international cohort study of patients with TRCC treated with cabozantinib. The main objectives were to estimate response rate according to RECIST 1.1 and to analyze progression-free survival (PFS) and overall survival (OS). RESULTS: Fifty-two patients with metastatic TRCC treated in the participating centers and evaluable for response were included. Median age at metastatic diagnosis was 40 years (IQR 28.5-53). Patients' IMDC risk groups at diagnosis were favorable (9/52), intermediate (35/52), and poor (8/52). Eleven (21.2%) patients received cabozantinib as frontline therapy, 15 (28.8%) at second line, and 26 (50%) at third line and beyond. The proportion of patients who achieved an objective response was 17.3%, including 2 complete responses and 7 partial responses. For 26 (50%) patients, stable disease was the best response. With a median follow-up of 25.1 months (IQR 12.6-39), median PFS was 6.8 months (95%CI 4.6-16.3) and median OS was 18.3 months (95%CI 17.0-30.6). No difference of response was identified according to fusion transcript features. CONCLUSION: This real-world study provides evidence of the activity of cabozantinib in TRCC, with more durable responses than those observed historically with other VEGFR-TKIs or ICIs.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Adult , Humans , Middle Aged , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/genetics , Cohort Studies , Kidney Neoplasms/drug therapy , Kidney Neoplasms/genetics , Retrospective StudiesABSTRACT
OBJECTIVE: To study whether delivering definitive radiotherapy (RT) to sites of oligoprogression in metastatic renal cell carcinoma (mRCC) enabled deferral of systemic therapy (ST) changes without compromising disease control or survival. PATIENTS AND METHODS: We identified patients with mRCC who received RT to three or fewer sites of extracranial progressive disease between 2014 and 2019 at a large tertiary cancer centre. Inclusion criteria were: (1) controlled disease for ≥3 months before oligoprogression, (2) all oligoprogression sites treated with a biologically effective dose of ≥100 Gy, and (3) availability of follow-up imaging. Time-to-event end-points were calculated from the start of RT. RESULTS: A total of 72 patients were identified (median follow-up 22 months, 95% confidence interval [CI] 19-32 months), with oligoprogressive lesions in lung/mediastinum (n = 35), spine (n = 30), and non-spine bone (n = 5). The most common systemic therapies before oligoprogression were none (n = 33), tyrosine kinase inhibitor (n = 23), and immunotherapy (n = 13). At 1 year, the local control rate was 96% (95% CI 87-99%); progression-free survival (PFS), 52% (95% CI 40-63%); and overall survival, 91% (95% CI 82-96%). At oligoprogression, ST was escalated (n = 16), maintained (n = 49), or discontinued (n = 7), with corresponding median (95% CI) PFS intervals of 19.7 (8.2-27.2) months, 10.1 (6.9-13.2) months, and 9.8 (2.4-28.9) months, respectively. Of the 49 patients maintained on the same ST at oligoprogression, 21 did not subsequently have ST escalation. CONCLUSION: Patients with oligoprogressive mRCC treated with RT had comparable PFS regardless of ST strategy, suggesting that RT may be a viable approach for delaying ST escalation. Randomised controlled trials comparing treatment of oligoprogression with RT vs ST alone are needed.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Radiosurgery , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/radiotherapy , Female , Humans , Kidney Neoplasms/drug therapy , Kidney Neoplasms/radiotherapy , Male , Progression-Free Survival , Protein Kinase Inhibitors , Radiosurgery/methods , Retrospective StudiesABSTRACT
INTRODUCTION: METEOR was a phase 3 trial (NCT01865747) of cabozantinib versus everolimus in adults with advanced or metastatic clear cell RCC previously treated with VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs). This post hoc analysis of METEOR compared outcomes for patients recruited from European and non-European countries. MATERIAL AND METHODS: Adults with advanced/metastatic clear cell RCC who had received ≥ 1 prior VEGFR-TKI treatment were randomized 1:1 to receive cabozantinib or everolimus. Patients were categorized by recruitment region: Europe or outside of Europe (rest of world [RoW]). Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and adverse events (AEs) were compared between regional subgroups. RESULTS: In total, there were 320 eligible patients from Europe (cabozantinib, 167; everolimus, 153) and 338 from RoW (North America, 240 patients; Asia-Pacific, 86; Latin America, 12; randomized as cabozantinib, 163; everolimus, 175). PFS and OS were longer with cabozantinib than with everolimus and similar for the Europe and RoW subgroups. For PFS, the hazard ratio (HR) for cabozantinib versus everolimus was 0.54 for the Europe subgroup (p < .001) and 0.50 for the RoW subgroup (p < .001). For OS, the HR was 0.75 for the Europe subgroup (p = .034) and 0.69 for the RoW subgroup (p = .006). ORR in the Europe subgroup was 15% for cabozantinib and 3.9% for everolimus (p < .001). For the RoW subgroup, ORR was 20% for cabozantinib and 2.9% for everolimus (p < .001). Incidence of grade 3/4 AEs were similar for the Europe (cabozantinib, 74%; everolimus, 58%) and RoW subgroups (cabozantinib, 69%; everolimus, 64%). CONCLUSION: In the METEOR trial, efficacy outcomes for patients recruited from European and non-European countries favored cabozantinib over everolimus. The efficacy and safety results for the regional subgroups were consistent with those of the overall METEOR population.
Subject(s)
Antineoplastic Agents , Carcinoma, Renal Cell , Kidney Neoplasms , Anilides/adverse effects , Antineoplastic Agents/adverse effects , Carcinoma, Renal Cell/drug therapy , Everolimus/adverse effects , Humans , Kidney Neoplasms/drug therapy , Protein Kinase Inhibitors/adverse effects , PyridinesABSTRACT
BACKGROUND: The role of radiotherapy in metastatic renal cell carcinoma is controversial. We prospectively tested the feasibility and efficacy of radiotherapy to defer systemic therapy for patients with oligometastatic renal cell carcinoma. METHODS: This single-arm, phase 2, feasibility trial was done at one centre in the USA (The MD Anderson Cancer Center, Houston, TX, USA). Patients (aged ≥18 years) with five or fewer metastatic lesions, an Eastern Cooperative Oncology Group status of 0-2, and no more than one previous systemic therapy (if this therapy was stopped at least 1 month before enrolment) without limitations on renal cell carcinoma histology were eligible for inclusion. Patients were treated with stereotactic body radiotherapy (defined as ≤5 fractions with ≥7 Gy per fraction) to all lesions and maintained off systemic therapy. When lesion location precluded safe stereotactic body radiotherapy, patients were treated with hypofractionated intensity-modulated radiotherapy regimes consisting of 60-70 Gy in ten fractions or 52·5-67·5 Gy in 15 fractions. Additional rounds of radiotherapy were allowed to treat subsequent sites of progression. Co-primary endpoints were feasibility (defined as all planned radiotherapy completed with <7 days unplanned breaks) and progression-free survival. All efficacy analyses were intention-to-treat. Safety was analysed in the as-treated population. A second cohort, with the aim of assessing the feasibility of sequential stereotactic body radiotherapy alone in patients with low-volume metastatic disease, was initiated and will be reported separately. This study is registered with ClinicalTrials.gov, NCT03575611. FINDINGS: 30 patients (six [20%] women) were enrolled from July 13, 2018, to Sept 18, 2020. All patients had clear cell histology and had a nephrectomy before enrolment. All patients completed at least one round of radiotherapy with less than 7 days of unplanned breaks. At a median follow-up of 17·5 months (IQR 13·2-24·6), median progression-free survival was 22·7 months (95% CI 10·4-not reached; 1-year progression-free survival 64% [95% CI 48-85]). Three (10%) patients had severe adverse events: two grade 3 (back pain and muscle weakness) and one grade 4 (hyperglycaemia) adverse events were observed. There were no treatment-related deaths. INTERPRETATION: Sequential radiotherapy might facilitate deferral of systemic therapy initiation and could allow sustained systemic therapy breaks for select patients with oligometastatic renal cell carcinoma. FUNDING: Anna Fuller Foundation, the Cancer Prevention and Research Institute of Texas (CPRIT), and the National Cancer Institute.
Subject(s)
Carcinoma, Renal Cell/radiotherapy , Kidney Neoplasms/radiotherapy , Radiotherapy, Intensity-Modulated/mortality , Aged , Carcinoma, Renal Cell/epidemiology , Carcinoma, Renal Cell/pathology , Feasibility Studies , Female , Follow-Up Studies , Humans , Kidney Neoplasms/epidemiology , Kidney Neoplasms/pathology , Male , Middle Aged , Prognosis , Survival Rate , Texas/epidemiologyABSTRACT
Nivolumab plus ipilimumab (nivo/ipi) is an approved therapy for patients with intermediate-risk or poor-risk metastatic renal cell carcinoma (mRCC). Clinical factors that guide the selection of this regimen for patients with mRCC are urgently needed. We retrospectively analyzed medical records of patients with mRCC who were hospitalized at MD Anderson Cancer Center because of cancer-related symptoms and received their first cycle of nivo/ipi in the inpatient setting. Clinical parameters, including demographics, histology, clinical history, response, and survival, were collected. The 4-month survival probability, progression-free survival (PFS), and overall survival (OS) were calculated using Kaplan-Meier methods. Between November 2017 and 21 June 2020 patients were identified that fit the search: 19 patients (91%) had poor-risk disease based on the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score; 17 patients (81%) had ≥4 risk factors; and 9 patients (43%) had sarcomatoid features on histology. Shortness of breath (28%) and abdominal pain (19%) were the two most common reasons for hospitalization. Partial response was achieved in 14% (3/21) of patients. Median PFS for all patients was 1.7 months (95% CI 0-3.9); median OS for all patients was 1.7 months (95% CI 0-4.2); and the 4-month survival probability was 36% (95% CI 25%-47%). In this retrospective study, patients with intermediate-risk or poor-risk mRCC who are hospitalized at a large tertiary referral center for cancer-related symptoms derive limited clinical benefit from nivo/ipi when started in the inpatient setting. Alternative, more effective systemic therapies should be considered for these patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Renal Cell/drug therapy , Ipilimumab/administration & dosage , Kidney Neoplasms/drug therapy , Nivolumab/administration & dosage , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Endpoint Determination , Female , Hospitalization , Humans , Ipilimumab/adverse effects , Male , Middle Aged , Neoplasm Metastasis , Nivolumab/adverse effects , Retrospective Studies , Survival Analysis , Tertiary Care Centers , Treatment OutcomeABSTRACT
Interleukin (IL)-10 has anti-inflammatory and CD8+ T-cell-stimulating properties. Pegilodecakin (pegylated recombinant human IL-10) induces intratumoral antigen-specific CD8 + T-cells and upregulates IFNγ and major histocompatibility complexes (MHC) I and II. Pegilodecakin has single-agent activity with manageable toxicity in advanced renal cell carcinama (aRCC) (data cutoff 24 March 2016). Pegilodecakin with pembrolizumab or nivolumab revealed clinical activity in aRCC (data cutoff 1 July 2018). Here, we report for the first time the results of pegilodecakin+ pazopanib, and final results for monotherapy and long-term follow-up with pegilodecakin + anti-programmed cell death 1 (anti-PD-1) inhibitors (data cutoff 19 February 2019). Phase 1/1b multi-cohort dose escalation IVY study enrolled 353 patients. Sixty-six patients with aRCC were treated with pegilodecakin alone or with pazopanib or anti-PD-1 inhibitor in cohorts A, G, H and I (data cutoff 19 February 2019). Primary endpoints included safety and tolerability. Secondary endpoint was tumor response by immune-related response criteria (irRC). Pegilodecakin plus nivolumab or pembrolizumab yielded median progression-free survival (mPFS) of 13.9 months and 6-month PFS probability of 60%, 76% 1-year overall survival (OS) probability and 61% 2-year OS probability. Pegilodecakin monotherapy produced mPFS of 1.8 months, 6-month PFS probability 25%, 1-year OS 50%, and 2-year OS 17%. Median OS was not reached in both combinations. Objective response rates (ORRs) were 33% with pazopanib and 43% with anti-PD-1. Most common Grade 3/4 treatment-related adverse events included anemia, thrombocytopenia and hypertriglyceridemia. In these heavily pretreated renal cell carcinama cohorts of IVY, pegilodecakin+anti-PD-1 inhibitor showed promising clinical activity. Safety profile of pegilodecakin alone and with anti-PD-1 inhibitors was consistent as previously reported.
Subject(s)
Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Renal Cell/drug therapy , Indazoles/administration & dosage , Interleukin-10/administration & dosage , Kidney Neoplasms/drug therapy , Polyethylene Glycols/administration & dosage , Pyrimidines/administration & dosage , Sulfonamides/administration & dosage , Adult , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Drug Administration Schedule , Female , Humans , Indazoles/therapeutic use , Interleukin-10/therapeutic use , Male , Middle Aged , Nivolumab/administration & dosage , Nivolumab/therapeutic use , Polyethylene Glycols/therapeutic use , Pyrimidines/therapeutic use , Sulfonamides/therapeutic use , Survival Analysis , Treatment Outcome , Young AdultABSTRACT
INTRODUCTION: Lenvatinib (Len) plus everolimus (Eve) is an approved therapy for metastatic renal cell carcinoma (mRCC) after first-line vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs), but limited data exist on the efficacy of Len ± Eve after progression on immune checkpoint inhibitors (ICIs) and VEGFR-TKIs. METHODS: We retrospectively reviewed the records of patients with mRCC at our institution who were treated with Len ± Eve after ICI and VEGFR-TKI. A blinded radiologist assessed objective response as defined by RECIST version 1.1. Descriptive statistics and the Kaplan-Meier method were used. RESULTS: Fifty-five patients were included in the analysis. Of these patients, 81.8% had clear-cell histology (ccRCC), and 76.4% had International Metastatic RCC Database Consortium intermediate-risk disease. Median number of prior therapies was four (range, 2-10); all patients had prior ICIs and VEGFR-TKIs, and 80% were previously treated with ICI and at least two VEGFR-TKIs, including cabozantinib. One patient (1.8%) achieved a complete response, and 11 patients (20.0%) achieved a partial response, for an overall response rate (ORR) of 21.8%; 35 patients (63.6%) achieved stable disease. In all patients, median progression-free survival (PFS) was 6.2 months (95% confidence interval [CI], 4.8-9.4) and median overall survival (OS) was 12.1 months (95% CI, 8.8-16.0). In patients with ccRCC, ORR was 24.4%, PFS was 7.1 months (95% CI, 5.0-10.5), and OS was 11.7 months (95% CI, 7.9-16.1). 50.9% of patients required dose reductions and 7.3% discontinued treatment because of toxicity. CONCLUSION: Len ± Eve demonstrated meaningful clinical activity and tolerability in heavily pretreated patients with mRCC after disease progression with prior ICIs and VEGFR-TKIs. IMPLICATIONS FOR PRACTICE: As the therapeutic landscape for patients with metastatic renal cell carcinoma continues to evolve, this single-center, retrospective review highlights the real-world efficacy of lenvatinib with or without everolimus in heavily pretreated patients. This article supports the use of lenvatinib with or without everolimus as a viable salvage strategy for patients whose disease progresses after treatment with immune checkpoint inhibitors and vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies, including cabozantinib.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Carcinoma, Renal Cell/drug therapy , Everolimus/therapeutic use , Humans , Immune Checkpoint Inhibitors , Kidney Neoplasms/drug therapy , Phenylurea Compounds , Protein Kinase Inhibitors/therapeutic use , Quinolines , Receptors, Vascular Endothelial Growth Factor/therapeutic use , Retrospective Studies , Vascular Endothelial Growth Factor AABSTRACT
BACKGROUND: Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma. METHODS: We randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level, 0.04), objective response rate (alpha level, 0.001), and progression-free survival (alpha level, 0.009) among patients with intermediate or poor prognostic risk. RESULTS: A total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follow-up of 25.2 months in intermediate- and poor-risk patients, the 18-month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P<0.001). The objective response rate was 42% versus 27% (P<0.001), and the complete response rate was 9% versus 1%. The median progression-free survival was 11.6 months and 8.4 months, respectively (hazard ratio for disease progression or death, 0.82; P=0.03, not significant per the prespecified 0.009 threshold). Treatment-related adverse events occurred in 509 of 547 patients (93%) in the nivolumab-plus-ipilimumab group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events occurred in 250 patients (46%) and 335 patients (63%), respectively. Treatment-related adverse events leading to discontinuation occurred in 22% and 12% of the patients in the respective groups. CONCLUSIONS: Overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 214 ClinicalTrials.gov number, NCT02231749 .).
Subject(s)
Antibodies, Monoclonal/administration & dosage , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Renal Cell/drug therapy , Indoles/administration & dosage , Ipilimumab/administration & dosage , Kidney Neoplasms/drug therapy , Pyrroles/administration & dosage , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/adverse effects , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Renal Cell/mortality , Disease-Free Survival , Humans , Indoles/adverse effects , Ipilimumab/adverse effects , Male , Middle Aged , Nivolumab , Pyrroles/adverse effects , Quality of Life , Risk , Sunitinib , Survival Analysis , Survival RateABSTRACT
BACKGROUND: In the phase 3 METEOR trial, cabozantinib improved progression-free survival (PFS) and overall survival (OS) versus everolimus in patients with advanced RCC after prior antiangiogenic therapy. METHODS: In this exploratory analysis, plasma biomarkers from baseline and week 4 from 621 of 658 randomized patients were analyzed for CA9, HGF, MET, GAS6, AXL, VEGF, VEGFR2, and IL-8. PFS and OS were analyzed by baseline biomarker levels as both dichotomized and continuous variables using univariate and multivariable methods. For on-treatment changes, PFS and OS were analyzed using fold change in biomarker levels at week 4. Biomarkers were considered prognostic if p < 0.05 and predictive if pinteraction < 0.05 for the interaction between treatment and biomarker. RESULTS: Hazard ratios for PFS and OS favored cabozantinib versus everolimus for both low and high baseline levels of all biomarkers (hazard ratios ≤0.78). In univariate analyses, low baseline HGF, AXL, and VEGF were prognostic for improvements in both PFS and OS with cabozantinib, and low HGF was prognostic for improvements in both PFS and OS with everolimus. Low AXL was predictive of relative improvement in PFS for cabozantinib versus everolimus. Results were generally consistent when baseline biomarkers were expressed as continuous variables, although none were predictive of benefit with treatment. In multivariable analysis, low baseline HGF was independently prognostic for improved PFS for both cabozantinib and everolimus; low HGF, GAS6, and VEGF were independently prognostic for improved OS with cabozantinib. No biomarkers were independently prognostic for OS with everolimus. On-treatment increases in some biomarkers appeared prognostic for PFS or OS with cabozantinib in univariate analyses; however, none were independently prognostic in multivariable analysis. CONCLUSIONS: PFS and OS were improved with cabozantinib versus everolimus at high and low baseline levels of all biomarkers. Low baseline HGF was consistently identified as a prognostic biomarker for improved PFS or OS with cabozantinib or everolimus, supporting further prospective evaluation of the prognostic significance of HGF in advanced RCC. TRIAL REGISTRATION: ClinicalTrials.gov NCT01865747 (registered on 05/31/2013).
Subject(s)
Anilides/therapeutic use , Biomarkers, Tumor/blood , Carcinoma, Renal Cell/blood , Carcinoma, Renal Cell/drug therapy , Everolimus/therapeutic use , Kidney Neoplasms/blood , Kidney Neoplasms/drug therapy , Pyridines/therapeutic use , Anilides/administration & dosage , Anilides/adverse effects , Carcinoma, Renal Cell/diagnosis , Carcinoma, Renal Cell/mortality , Everolimus/administration & dosage , Everolimus/adverse effects , Humans , Kaplan-Meier Estimate , Kidney Neoplasms/diagnosis , Kidney Neoplasms/mortality , Prognosis , Pyridines/administration & dosage , Pyridines/adverse effects , Retreatment , Treatment OutcomeABSTRACT
BACKGROUND: The management of metastatic renal cell carcinoma (mRCC) has evolved rapidly, and results from the Cancer du Rein Metastatique Nephrectomie et Antiangiogéniques (CARMENA) trial bring into question the utility of cytoreductive nephrectomy (CN). The objective of this study was to examine overall survival (OS) and identify risk factors associated with patients less likely to benefit from CN in the targeted therapy era. METHODS: Patients with mRCC undergoing CN from 2005 to 2017 were identified. Kaplan-Meier methods and Cox proportional hazards regression analyses were used to assess OS and risk-stratify patients, respectively, on the basis of preoperative clinical and laboratory data. RESULTS: Six hundred eight patients were eligible with a median follow-up of 29.4 months. Ninety-five percent of the patients had an Eastern Cooperative Oncology Group performance status less than or equal to 1, and 70% had a single site of metastatic disease. In a multivariable analysis, risk factors significantly associated with decreased OS included systemic symptoms at diagnosis, retroperitoneal and supradiaphragmatic lymphadenopathy, bone metastasis, clinical T4 disease, a hemoglobin level less than the lower limit of normal (LLN), a serum albumin level less than the LLN, a serum lactate dehydrogenase level greater than the upper limit of normal, and a neutrophil/lymphocyte ratio greater than or equal to 4. Patients were stratified into 3 risk groups: low (fewer than 2 risk factors), intermediate (2-3 risk factors), and high (more than 3 risk factors). These groups had median OS of 58.9 months (95% confidence interval [CI], 44.3-66.6 months), 30.6 months (95% CI, 27.0-35.0 months), and 19.2 months (95% CI, 13.9-22.6 months), respectively (P < .0001). The median time to postoperative systemic therapy was 45 days (interquartile range, 30-90 days). CONCLUSIONS: Patients with more than 3 risk factors did not seem to benefit from CN. Importantly, OS in this group was equivalent to, if not higher than, OS for patients in the CN plus sunitinib arm of CARMENA, and this raises the possibility that a well-selected population might benefit from CN.
Subject(s)
Bone Neoplasms/drug therapy , Bone Neoplasms/surgery , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/surgery , Patient Selection , Aged , Bone Neoplasms/pathology , Bone Neoplasms/secondary , Carcinoma, Renal Cell/epidemiology , Carcinoma, Renal Cell/pathology , Cytoreduction Surgical Procedures/adverse effects , Disease-Free Survival , Female , Hemoglobins/metabolism , Humans , Kaplan-Meier Estimate , Lymphocytes/pathology , Male , Middle Aged , Neoplasm Metastasis , Nephrectomy/adverse effects , Neutrophils/pathology , Proportional Hazards Models , Risk Factors , Sunitinib/administration & dosage , Sunitinib/adverse effects , Treatment OutcomeABSTRACT
BACKGROUND: CheckMate 025 has shown superior efficacy for nivolumab over everolimus in patients with advanced renal cell carcinoma (aRCC) along with improved safety and tolerability. This analysis assesses the long-term clinical benefits of nivolumab versus everolimus. METHODS: The randomized, open-label, phase 3 CheckMate 025 trial (NCT01668784) included patients with clear cell aRCC previously treated with 1 or 2 antiangiogenic regimens. Patients were randomized to nivolumab (3 mg/kg every 2 weeks) or everolimus (10 mg once a day) until progression or unacceptable toxicity. The primary endpoint was overall survival (OS). The secondary endpoints were the confirmed objective response rate (ORR), progression-free survival (PFS), safety, and health-related quality of life (HRQOL). RESULTS: Eight hundred twenty-one patients were randomized to nivolumab (n = 410) or everolimus (n = 411); 803 patients were treated (406 with nivolumab and 397 with everolimus). With a minimum follow-up of 64 months (median, 72 months), nivolumab maintained an OS benefit in comparison with everolimus (median, 25.8 months [95% CI, 22.2-29.8 months] vs 19.7 months [95% CI, 17.6-22.1 months]; hazard ratio [HR], 0.73; 95% CI, 0.62-0.85) with 5-year OS probabilities of 26% and 18%, respectively. ORR was higher with nivolumab (94 of 410 [23%] vs 17 of 411 [4%]; P < .001). PFS also favored nivolumab (HR, 0.84; 95% CI, 0.72-0.99; P = .0331). The most common treatment-related adverse events of any grade were fatigue (34.7%) and pruritus (15.5%) with nivolumab and fatigue (34.5%) and stomatitis (29.5%) with everolimus. HRQOL improved from baseline with nivolumab but remained the same or deteriorated with everolimus. CONCLUSIONS: The superior efficacy of nivolumab over everolimus is maintained after extended follow-up with no new safety signals, and this supports the long-term benefits of nivolumab monotherapy in patients with previously treated aRCC. LAY SUMMARY: CheckMate 025 compared the effects of nivolumab (a novel immunotherapy) with those of everolimus (an older standard-of-care therapy) for the treatment of advanced kidney cancer in patients who had progressed on antiangiogenic therapy. After 5 years of study, nivolumab continues to be better than everolimus in extending the lives of patients, providing a long-lasting response to treatment, and improving quality of life with a manageable safety profile. The results demonstrate that the clinical benefits of nivolumab versus everolimus in previously treated patients with advanced kidney cancer continue in the long term.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Renal Cell/drug therapy , Everolimus/therapeutic use , Kidney Neoplasms/drug therapy , Nivolumab/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carcinoma, Renal Cell/pathology , Everolimus/pharmacology , Female , Follow-Up Studies , Humans , Kidney Neoplasms/pathology , Male , Nivolumab/pharmacology , Treatment OutcomeABSTRACT
INTRODUCTION: Nivolumab alone and in combination with ipilimumab is approved for the treatment of patients with metastatic renal cell carcinoma (RCC) who received prior vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI) and those who are treatment naive, respectively. However, the clinical activity of nivolumab in non-clear cell RCC (nccRCC) is unknown, as these patients were excluded from the trials. MATERIALS AND METHODS: We reviewed the records of patients who received nivolumab for nccRCC and ccRCC with >20% rhabdoid with the primary endpoint to assess the objective response rate (ORR). We assessed radiographic response using RECIST, v1.1. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). We also reviewed the literature to identify studies reporting on the clinical activity of immune checkpoint inhibitors in nccRCC, and performed a meta-analysis of proportions for ORR and disease control rate (DCR). RESULTS: Twelve patients (30%) had papillary histology, 11 (27.5%) had unclassified, 8 (20%) had ccRCC with rhabdoid component, 5 (12.5%) had chromophobe, 3 (7.5%) had translocation, and 1 (2.5%) had mucinous tubular and spindle cell carcinoma. Overall, seven patients (21.6%, 95% confidence interval [CI], 8.7%-37.9%) had an objective response, including three patients (8.8%, 95% confidence interval [CI], 1.9%-23.7%) who achieved a complete remission. At a median follow-up of 24.5 monoths (95% CI, 17.7-32.6), median PFS was 4.9 monoths (95% CI, 3.53-10.27) and median OS was 21.7 monoths (95% CI, 7.83 mo to not reached). There were no treatment-related deaths. We also identified two retrospective studies reporting best ORR in patients with nccRCC receiving PD-1/PD-L1 checkpoint blockade. The ORR and DCR for the total cohort were, respectively, 18.6% (95% CI, 11.9%-26.4%) and 53.4% (95% CI, 44.2%-62.5%). CONCLUSION: Nivolumab demonstrated activity in unclassified nccRCC and ccRCC with >20% rhabdoid; further randomized clinical trials are warranted. IMPLICATIONS FOR PRACTICE: This article reports on the clinical activity and safety of immune checkpoint inhibitors in non-clear cell kidney cancer. The retrospective data with the meta-analysis provides a summary that will help guide the treatment of this rare and heterogeneous group of kidney cancers.