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1.
Clin Genitourin Cancer ; : 102177, 2024 Jul 23.
Article in English | MEDLINE | ID: mdl-39218752

ABSTRACT

In this study we evaluated outcomes of patients with metastatic renal cell carcinoma who received immunotherapy before surgery. We found that receiving immunotherapy combinations before surgery can offer patients benefits in reducing tumor size and improving disease control. BACKGROUND: Immunotherapy (IO) has improved outcomes for patients with metastatic renal cell carcinoma (mRCC). However, the timing of surgical intervention for cytoreductive nephrectomy (CN) is still controversial for this group of patients. PATIENTS AND METHODS: We identified patients with mRCC receiving IO-based therapies and undergoing CN. Patients were divided into 2 cohorts: those who underwent upfront CN and those who underwent deferred CN. Pathologic and radiographic features along with clinical outcomes were systematically collected. Comparisons were performed using Chi-square test, paired t-Test or Mann-Whitney-U test. Progression Free survival (PFS) and Overall Survival (OS) were estimated using the Kaplan-Meier method. RESULTS: Fifty-one patients with mRCC were included, with a median follow-up of 21 months. 38 (74.5%) patients received IO-based therapies prior to CN, while 13 (25.5%) patients underwent up-front CN. IO-based therapies reduced median tumor size from pretreatment 10 cm to 8.6 cm post-treatment when given prior to CN. IO-TKI had a trend toward higher tumor shrinkage (-2.3 vs -1.2 cm). Pathologic T downstaging occurred in 42% (n=16) of patients, 11% (n=4) of whom had pT0 disease. Thrombus downstaging occurred in 13% (n=6) of patients, all with either partial response (PR) or complete response (CR) in metastases. PFS (HR=0.7, 95% CI 0.29-1.98, p=0.58) and OS (HR 0.4, 95% CI 0.13-1.57, p=0.21) were not statistically significant between 2 cohorts. CONCLUSIONS: IO-based therapies, particularly IO-TKIs, resulted in pathologic necrosis and reductions in tumor size prior to deferred CN. PFS and OS were similar for patients who received either upfront IO-based therapy or after CN.

2.
J Clin Invest ; 134(14)2024 May 30.
Article in English | MEDLINE | ID: mdl-39007269

ABSTRACT

BACKGROUNDMetastases are the hallmark of lethal cancer, though underlying mechanisms that drive metastatic spread to specific organs remain poorly understood. Renal cell carcinoma (RCC) is known to have distinct sites of metastases, with lung, bone, liver, and lymph nodes being more common than brain, gastrointestinal tract, and endocrine glands. Previous studies have shown varying clinical behavior and prognosis associated with the site of metastatic spread; however, little is known about the molecular underpinnings that contribute to the differential outcomes observed by the site of metastasis.METHODSWe analyzed primary renal tumors and tumors derived from metastatic sites to comprehensively characterize genomic and transcriptomic features of tumor cells as well as to evaluate the tumor microenvironment at both sites.RESULTSWe included a total of 657 tumor samples (340 from the primary site [kidney] and 317 from various sites of metastasis). We show distinct genomic alterations, transcriptomic signatures, and immune and stromal tumor microenvironments across metastatic sites in a large cohort of patients with RCC.CONCLUSIONWe demonstrate significant heterogeneity among primary tumors and metastatic sites and elucidate the complex interplay between tumor cells and the extrinsic tumor microenvironment that is vital for developing effective anticancer therapies.


Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Tumor Microenvironment , Humans , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Tumor Microenvironment/genetics , Female , Male , Neoplasm Metastasis , Transcriptome , Middle Aged , Gene Expression Regulation, Neoplastic , Aged
3.
J Immunother Cancer ; 12(7)2024 Jul 25.
Article in English | MEDLINE | ID: mdl-39060019

ABSTRACT

BACKGROUND: Immunotherapy can be associated with prolonged disease control even after cessation of treatment without the need for further cancer-directed therapy. Treatment-related adverse events (TRAEs) can also persist after discontinuation of therapy. Treatment-free survival (TFS) with and without toxicity as a component of a partitioned survival model can characterize patient survival time, which is not captured by standard outcome measures. METHODS: Data from 1096 patients with advanced renal cell carcinoma treated with first-line nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) in the CheckMate 214 trial were analyzed. TFS was defined as the area between two Kaplan-Meier curves for time from randomization to protocol therapy discontinuation and time from randomization to subsequent systemic therapy initiation or death, estimated as the difference in 60-month restricted mean times with confidence intervals (CIs) obtained using bootstrap sampling. Time on protocol therapy and TFS were further characterized as time with and without grade 2+ and 3+TRAEs. Survival functions were estimated in subgroups including International Metastatic Renal Cell Carcinoma Database Consortium risk groups using the Kaplan-Meier method. RESULTS: At 5 years from randomization, 48% of patients treated with NIVO+IPI and 37% of patients treated with SUN were alive. In the intent-to-treat population, 18% of the NIVO+IPI-treated and 5% of SUN-treated patients are surviving treatment-free. For favorable-risk patients, the 60-month mean TFS was 14.4 months for NIVO+IPI versus 5.5 months for SUN (difference 8.9 months (95% CI 4.9 to 12.8)). TFS for NIVO+IPI versus SUN with grade 2+TRAEs was 5.0 and 2.1 months, respectively, and with grade 3+TRAEs was 1.2 and 0.3 months, respectively. For intermediate/poor-risk patients, the 60-month mean TFS was 10.1 months for NIVO+IPI versus 4.1 months for SUN (difference 6.1 months (95% CI 4.2 to 7.9)). TFS for NIVO+IPI versus SUN with grade 2+TRAEs was 4.0 versus 2.0 months, respectively, and 0.6 versus 0.3 months with grade 3+TRAEs. CONCLUSIONS: Although overall survival was similar, favorable-risk patients treated with NIVO+IPI spent more time surviving treatment-free with and without toxicity versus SUN after 60 months of follow-up. Intermediate/poor-risk patients treated with NIVO+IPI had longer survival and longer TFS without toxicity versus SUN. TRIAL REGISTRATION NUMBER: NCT02231749.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Carcinoma, Renal Cell , Ipilimumab , Kidney Neoplasms , Nivolumab , Sunitinib , Humans , Ipilimumab/therapeutic use , Ipilimumab/administration & dosage , Ipilimumab/pharmacology , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/pathology , Sunitinib/therapeutic use , Sunitinib/administration & dosage , Sunitinib/pharmacology , Nivolumab/therapeutic use , Nivolumab/administration & dosage , Nivolumab/pharmacology , Kidney Neoplasms/drug therapy , Kidney Neoplasms/pathology , Kidney Neoplasms/mortality , Male , Female , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Middle Aged , Aged , Survival Analysis , Adult
4.
Front Immunol ; 15: 1351739, 2024.
Article in English | MEDLINE | ID: mdl-38690281

ABSTRACT

Background: A useful clinical biomarker requires not only association but also a consistent temporal relationship. For instance, chemotherapy-induced neutropenia and epidermal growth-factor inhibitor-related acneiform rash both occur within weeks of treatment initiation, thereby providing information prior to efficacy assessment. Although immune checkpoint inhibitor (ICI)-associated immune-related adverse events (irAE) have been associated with therapeutic benefit, irAE may have delayed and highly variable onset. To determine whether ICI efficacy and irAE could serve as clinically useful biomarkers for predicting each other, we determined the temporal relationship between initial efficacy assessment and irAE onset in a diverse population treated with ICI. Methods: Using two-sided Fisher exact and Cochran-Armitage tests, we determined the relative timing of initial efficacy assessment and irAE occurrence in a cohort of 155 ICI-treated patients (median age 68 years, 40% women). Results: Initial efficacy assessment was performed a median of 50 days [interquartile range (IQR) 39-59 days] after ICI initiation; median time to any irAE was 77 days (IQR 28-145 days) after ICI initiation. Median time to first irAE was 42 days (IQR 20-88 days). Overall, 58% of any irAE and 47% of first irAE occurred after initial efficacy assessment. For clinically significant (grade ≥2) irAE, 60% of any and 53% of first occurred after initial efficacy assessment. The likelihood of any future irAE did not differ according to response (45% for complete or partial response vs. 47% for other cases; P=1). In landmark analyses controlling for clinical and toxicity follow-up, patients demonstrating greater tumor shrinkage at initial efficacy assessment were more likely to develop future grade ≥2 (P=0.05) and multi-organ (P=0.02) irAE. Conclusions: In contrast to that seen with chemotherapy and molecularly targeted therapies, the temporal relationship between ICI efficacy and toxicity is complex and bidirectional. In practice, neither parameter can be routinely relied on as a clinical biomarker to predict the other.


Subject(s)
Biomarkers , Immune Checkpoint Inhibitors , Neoplasms , Humans , Female , Male , Aged , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Inhibitors/therapeutic use , Middle Aged , Neoplasms/drug therapy , Neoplasms/immunology , Neoplasms/therapy , Immunotherapy/adverse effects , Immunotherapy/methods , Treatment Outcome , Time Factors
5.
J Clin Invest ; 134(11)2024 Apr 23.
Article in English | MEDLINE | ID: mdl-38652565

ABSTRACT

Molecular profiling of clear cell renal cell carcinoma (ccRCC) tumors of patients in a clinical trial has identified distinct transcriptomic signatures with predictive value, yet data in non-clear cell variants (nccRCC) are lacking. We examined the transcriptional profiles of RCC tumors representing key molecular pathways, from a multi-institutional, real-world patient cohort, including ccRCC and centrally reviewed nccRCC samples. ccRCC had increased angiogenesis signature scores compared with the heterogeneous group of nccRCC tumors, while cell cycle, fatty acid oxidation/AMPK signaling, and fatty acid synthesis/pentose phosphate signature scores were increased in one or more nccRCC subtypes. Among both ccRCC and nccRCC tumors, T effector scores statistically correlated with increased immune cell infiltration and were more commonly associated with immunotherapy-related markers (PD-L1+/TMBhi/MSIhi). In conclusion, this study provides evidence of differential gene transcriptional profiles among ccRCC versus nccRCC tumors, providing insights for optimizing personalized and histology-specific therapeutic strategies for patients with advanced RCC.


Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Transcriptome , Humans , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/metabolism , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Kidney Neoplasms/metabolism , Female , Male , Gene Expression Regulation, Neoplastic , Middle Aged , Aged , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Gene Expression Profiling
6.
N Engl J Med ; 390(15): 1359-1371, 2024 Apr 18.
Article in English | MEDLINE | ID: mdl-38631003

ABSTRACT

BACKGROUND: Adjuvant pembrolizumab therapy after surgery for renal-cell carcinoma was approved on the basis of a significant improvement in disease-free survival in the KEYNOTE-564 trial. Whether the results regarding overall survival from the third prespecified interim analysis of the trial would also favor pembrolizumab was uncertain. METHODS: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 1:1 ratio) participants with clear-cell renal-cell carcinoma who had an increased risk of recurrence after surgery to receive pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks for up to 17 cycles (approximately 1 year) or until recurrence, the occurrence of unacceptable toxic effects, or withdrawal of consent. A significant improvement in disease-free survival according to investigator assessment (the primary end point) was shown previously. Overall survival was the key secondary end point. Safety was a secondary end point. RESULTS: A total of 496 participants were assigned to receive pembrolizumab and 498 to receive placebo. As of September 15, 2023, the median follow-up was 57.2 months. The disease-free survival benefit was consistent with that in previous analyses (hazard ratio for recurrence or death, 0.72; 95% confidence interval [CI], 0.59 to 0.87). A significant improvement in overall survival was observed with pembrolizumab as compared with placebo (hazard ratio for death, 0.62; 95% CI, 0.44 to 0.87; P = 0.005). The estimated overall survival at 48 months was 91.2% in the pembrolizumab group, as compared with 86.0% in the placebo group; the benefit was consistent across key subgroups. Pembrolizumab was associated with a higher incidence of serious adverse events of any cause (20.7%, vs. 11.5% with placebo) and of grade 3 or 4 adverse events related to pembrolizumab or placebo (18.6% vs. 1.2%). No deaths were attributed to pembrolizumab therapy. CONCLUSIONS: Adjuvant pembrolizumab was associated with a significant and clinically meaningful improvement in overall survival, as compared with placebo, among participants with clear-cell renal-cell carcinoma at increased risk for recurrence after surgery. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.).


Subject(s)
Antineoplastic Agents, Immunological , Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Adjuvants, Immunologic/administration & dosage , Adjuvants, Immunologic/adverse effects , Adjuvants, Immunologic/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/surgery , Double-Blind Method , Kidney Neoplasms/drug therapy , Kidney Neoplasms/mortality , Kidney Neoplasms/surgery , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Agents, Immunological/therapeutic use , Disease-Free Survival , Combined Modality Therapy , Survival Analysis
7.
Eur J Cancer ; 204: 114048, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38653033

ABSTRACT

BACKGROUND: The Lung Immune Prognostic Index (LIPI) is associated with immune checkpoint inhibitors (ICI) outcomes across different solid tumors, particularly in non-small cell lung cancer. Data regarding the prognostic and/or predictive role of LIPI in metastatic renal cell carcinoma (mRCC) are still scarce. The aim of this study was to evaluate whether LIPI could be predictive of survival in mRCC patients. METHODS: We used patient level data from three different prospective studies (NIVOREN trial: nivolumab; TORAVA trial: VEGF/VEGFR-targeted therapy (TT); CheckMate 214: nivolumab-ipilimumab vs sunitinib). LIPI was calculated based on a derived neutrophils/(leukocyte-neutrophil) ratio > 3 and lactate-dehydrogenase >upper limit of normal, classifying patients into three groups (LIPI good, 0 factors;LIPI intermediate (int), 1 factor;LIPI poor, 2 factors) and/or into two groups (LIPI good, 0 factors;LIPI int/poor, 1-2 factors) according to trial sample size. Primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS). RESULTS: In the Nivolumab dataset (n = 619), LIPI was significantly associated with OS (LIPI-good 30.1 vs 13.8 months in the LIPI int/poor; HR= 0.47) and PFS (HR=0.74). In the VEGF/VEGFR-TT dataset (n = 159), only a correlation with PFS was observed. In the CheckMate214 dataset (n = 1084), LIPI was significantly associated with OS (nivolumab-ipilimumab OS LIPI good vs int/poor: HR=0.55, p < 0.0001; sunitinib: OS LIPI good vs int/poor: 0.38, p < 0.0001) in both treatment groups in univariate and multivariate analysis. CONCLUSIONS: Pretreatment-LIPI correlated with worse survival outcomes in mRCC treated with either ICI or antiangiogenic therapy, confirming LIPI's prognostic role in mRCC irrespective of systemic treatment used.


Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Lung Neoplasms , Humans , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/secondary , Kidney Neoplasms/drug therapy , Kidney Neoplasms/pathology , Kidney Neoplasms/immunology , Kidney Neoplasms/mortality , Male , Female , Middle Aged , Aged , Prognosis , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lung Neoplasms/mortality , Lung Neoplasms/immunology , Prospective Studies , Biomarkers, Tumor/analysis , Sunitinib/therapeutic use , Immune Checkpoint Inhibitors/therapeutic use , Nivolumab/therapeutic use , Progression-Free Survival , Adult
8.
J Immunother Cancer ; 12(4)2024 Apr 11.
Article in English | MEDLINE | ID: mdl-38604810

ABSTRACT

BACKGROUND: As part of a partitioned survival analysis, treatment-free survival (TFS) can characterize the overall survival time patients spend between the cessation of immunotherapy and the start of subsequent therapy; both with and without toxicity. Significant TFS was reported for the nivolumab/ipilimumab arms of the CheckMate 067 and 214 trials for patients with advanced melanoma or renal cell carcinoma (aRCC), respectively, where immunotherapy was often halted for toxicity rather than a predefined treatment endpoint. We therefore sought to assess TFS in the HCRN GU16-260 trial, which was designed to reduce toxicity and cap immunotherapy duration. METHODS: Data were analyzed from 128 patients with clear-cell aRCC treated with first-line nivolumab monotherapy for up to 2 years. Salvage nivolumab/ipilimumab for up to 1 year was provided to eligible patients with disease progression at any point or stable disease at 48 weeks (29% of patients). TFS was defined as the area between Kaplan-Meier curves for a time from registration to protocol therapy cessation and for a time from registration to subsequent systemic therapy initiation or death, estimated from 36-month mean times. The time on or off protocol treatment with grade 3+treatment-related adverse events (TRAEs) was also captured. RESULTS: At 36 months from enrollment, 68.3% of patients were alive: 96.8% of International Metastatic RCC Database Consortium (IMDC) favorable-risk patients and 56.6% of those with intermediate/poor-risk, respectively. The 36-month mean time on protocol therapy was 11.5 months including 0.6 months with grade 3+TRAEs (16.0 months for favorable-risk patients and 9.6 months for intermediated/poor-risk patients). The 36-month mean TFS for the whole population was 9.4 months (12.9 months including 1.5 months with grade 3+TRAEs for favorable-risk and 8.0 months including 1.0 months with grade 3+TRAEs for intermediate/poor-risk). At 36 months, 65.6% of favorable-risk patients and 27.1% of intermediate/poor-risk patients were alive and subsequent systemic treatment-free. CONCLUSIONS: Nivolumab monotherapy with salvage nivolumab/ipilimumab in non-responders is an active treatment approach in treatment-naïve patients with aRCC and, similar to nivolumab/ipilimumab in CheckMate 214, results in substantial TFS and toxicity-free TFS. TFS was greatest in patients with favorable-risk disease, supporting the use of an immunotherapy-only regimen in this population.


Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Melanoma , Humans , Carcinoma, Renal Cell/drug therapy , Nivolumab/pharmacology , Nivolumab/therapeutic use , Ipilimumab/adverse effects , Kidney Neoplasms/drug therapy , Kidney Neoplasms/pathology
9.
Sci Rep ; 14(1): 1458, 2024 01 17.
Article in English | MEDLINE | ID: mdl-38228729

ABSTRACT

Novel perioperative strategies are needed to reduce recurrence rates in patients undergoing nephrectomy for high-risk, non-metastatic clear cell renal cell carcinoma (ccRCC). We conducted a prospective, phase I trial of neoadjuvant nivolumab prior to nephrectomy in 15 evaluable patients with non-metastatic ccRCC. We leveraged tissue from that cohort to elucidate the effects of PD-1 inhibition on immune cell populations in ccRCC and correlate the evolving immune milieu with anti-PD-1 response. We found that nivolumab durably induces a pro-inflammatory state within the primary tumor, and baseline immune infiltration within the primary tumor correlates with nivolumab responsiveness. Nivolumab increases CTLA-4 expression in the primary tumor, and subsequent nephrectomy increases circulating concentrations of sPD-L1, sPD-L3 (sB7-H3), and s4-1BB. These findings form the basis to consider neoadjuvant immune checkpoint inhibition (ICI) for high-risk ccRCC while the tumor remains in situ and provide the rationale for perioperative strategies of novel ICI combinations.


Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Nivolumab/pharmacology , Carcinoma, Renal Cell/drug therapy , Neoadjuvant Therapy , Prospective Studies
10.
Oncologist ; 29(2): 91-98, 2024 Feb 02.
Article in English | MEDLINE | ID: mdl-38048064

ABSTRACT

The 5th Kidney Cancer Research Summit was a hybrid event hosted in Boston, MA in July 2023. As in previous editions, the conference attracted a wide representation of global thought leaders in kidney cancer spanning all stages of clinical and laboratory research. Sessions covered tumor metabolism, novel immune pathways, advances in clinical trials and immunotherapy, and progress toward biomarkers. The abstract presentations were published as a supplement in The Oncologist (https://academic.oup.com/oncolo/issue/28/Supplement_1). Aiming to be more concise than comprehensive, this commentary summarizes the most important emerging areas of kidney cancer research discussed and debated among the stakeholders at the conference, with relevant updates that have occurred since.


Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Carcinoma, Renal Cell/therapy , Kidney Neoplasms/therapy , Biomarkers , Research , Boston
11.
J Immunother Cancer ; 11(3)2023 03.
Article in English | MEDLINE | ID: mdl-36948504

ABSTRACT

BACKGROUND: To determine the efficacy and toxicity of nivolumab monotherapy in treatment-naïve patients with non-clear cell renal cell carcinoma (nccRCC) and the efficacy of nivolumab/ipilimumab salvage therapy in patients with tumors unresponsive to initial nivolumab monotherapy. METHODS: Eligible patients with treatment-naïve nccRCC received nivolumab until progressive disease (PD), toxicity, or completion of 96 weeks of treatment (Part A). Patients with PD prior to, or stable disease (SD) at 48 weeks (prolonged SD) were potentially eligible to receive salvage nivolumab/ipilimumab (Part B). Patients were required to submit tissue from a metastatic lesion obtained within 12 months prior to study entry and prior to Part B for correlative studies. RESULTS: 35 patients with nccRCC were enrolled: 19 (54%) had papillary, 6 (17%) had chromophobe and 10 (29%) had unclassified histology. At median follow-up of 22.9 months, RECIST-defined objective response rate (ORR) was 5 of 35 (14.3% 95% CI 4.8% to 30.3%) (complete response (CR) 2 (5.7%) and partial response (PR) 3 (8.6%)). ORR by histology was: papillary-1/19 (5%); chromophobe-1/6 (17%); and unclassified-3/10 (30%). Nine patients (26%) had tumors with sarcomatoid features with 3 (33%) (2 unclassified and 1 papillary) responding. ORR was 0/18, 3/11 (27%) and 2/6 (33%) for patients with tumor progammed death ligand 1 (PD-L1) expression of <5%, ≥5% or not measured, respectively. Median progression-free survival was 4.0 (2.7-4.3) months. Two of five responders have progressed. Thirty-two patients had PD or prolonged SD and therefore, were potentially eligible for salvage nivolumab/ipilimumab (Part B), but 15 patients did not enroll due to grade 2-3 toxicity (6) on nivolumab, symptomatic disease progression (5), or other reasons including no biopsy tissue (4). In the 17 Part B patients, there was one PR (6%) (unclassified/non-sarcomatoid). Grade >3 treatment-related adverse events were seen in 7/35 (20%) on nivolumab and 7/17 (41%) on salvage nivolumab/ipilimumab with one patient experiencing sudden death. CONCLUSIONS: Nivolumab monotherapy has limited activity in treatment-naïve nccRCC with most responses (4 of 5) seen in patients with sarcomatoid and/or unclassified tumors. Toxicity is consistent with prior nivolumab studies. Salvage treatment with nivolumab/ipilimumab was provided in half of these patients with minimal activity. TRIAL REGISTRATION NUMBER: NCT03117309.


Subject(s)
Carcinoma, Renal Cell , Sarcoma , Soft Tissue Neoplasms , Humans , Nivolumab/pharmacology , Nivolumab/therapeutic use , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/pathology , Ipilimumab/adverse effects , Salvage Therapy
12.
JAMA Oncol ; 9(1): 102-111, 2023 01 01.
Article in English | MEDLINE | ID: mdl-36480191

ABSTRACT

Importance: Increased survival with immune checkpoint inhibitors has been reported for patients with obesity vs a normal body mass index (BMI). However, the association of obesity with the safety of immune checkpoint inhibitors warrants study. Objective: To investigate associations between BMI and immune-related adverse events (irAEs) among patients with advanced cancers treated with nivolumab monotherapy and nivolumab plus ipilimumab combination therapy. Design, Setting, and Participants: This study was a retrospective pooled analysis of 3772 patients from 14 multicenter CheckMate clinical trials across 8 tumor types. Patients with advanced cancers received nivolumab, 3 mg/kg (n = 2746); nivolumab, 3 mg/kg, plus ipilimumab, 1 mg/kg (n = 713); or nivolumab, 1 mg/kg, plus ipilimumab, 3 mg/kg (n = 313). Baseline BMI was categorized as normal weight or underweight (<25), overweight (25 to <30), or obese (≥30) according to World Health Organization criteria. The studies began patient enrollment between February 9, 2012, and May 21, 2015, and patients were followed up to database lock on May 1, 2019. Data analysis was conducted from May 1 to September 1, 2019. Interventions: Nivolumab, 3 mg/kg; nivolumab, 3 mg/kg, plus ipilimumab, 1 mg/kg; and nivolumab, 1 mg/kg, plus ipilimumab, 3 mg/kg. Main Outcomes and Measures: Odds ratios (ORs) and 95% CIs for incidence of any-grade and grade 3 or 4 irAEs were calculated for patients with obesity vs normal weight or underweight BMI in the overall cohort and in subgroups based on patient and tumor characteristics. Analyses for nivolumab plus ipilimumab cohorts were exploratory. Results: A total of 3772 patients were included, 2600 were male (69%), and median age was 61 years (range, 18-90 years). For patients receiving monotherapy with nivolumab, 3 mg/kg (n = 2746), the incidence of any-grade irAEs was higher in patients with obesity (n = 543) vs those with normal weight or underweight BMI (n = 1266; OR, 1.71; 95% CI, 1.38-2.11). Incidence of grade 3 or 4 irAEs did not differ between patients with obesity and those with normal weight or underweight BMI (OR, 1.21; 95% CI, 0.92-1.61). Risk of any-grade and grade 3 or 4 irAEs appeared consistent with that in the overall population across all subgroups evaluated except for a higher likelihood of grade 3 or 4 irAEs among female patients with obesity vs normal weight or underweight BMI (OR, 1.73; 95% CI, 1.07-2.79). For patients receiving nivolumab plus ipilimumab, the incidence of irAEs appeared consistent across BMI categories. Conclusions and Relevance: Obesity appeared to be associated with an increased incidence of any-grade irAEs among patients treated with nivolumab monotherapy and with grade 3 or 4 irAEs among female patients only. These findings may inform the monitoring of patients at high risk of developing irAEs.


Subject(s)
Neoplasms , Nivolumab , Humans , Male , Female , Middle Aged , Nivolumab/adverse effects , Ipilimumab/therapeutic use , Body Mass Index , Retrospective Studies , Immune Checkpoint Inhibitors/therapeutic use , Thinness/chemically induced , Thinness/drug therapy , Neoplasms/etiology , Obesity/chemically induced , Obesity/epidemiology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use
13.
Cancers (Basel) ; 14(17)2022 Aug 30.
Article in English | MEDLINE | ID: mdl-36077745

ABSTRACT

The vascular disrupting activity of a promising tubulin-binding agent (OXi6196) was demonstrated in mice in MDA-MB-231 human breast tumor xenografts growing orthotopically in mammary fat pad and syngeneic RENCA kidney tumors growing orthotopically in the kidney. To enhance water solubility, OXi6196, was derivatized as its corresponding phosphate prodrug salt OXi6197, facilitating effective delivery. OXi6197 is stable in water, but rapidly releases OXi6196 in the presence of alkaline phosphatase. At low nanomolar concentrations OXi6196 caused G2/M cell cycle arrest and apoptosis in MDA-MB-231 breast cancer cells and monolayers of rapidly growing HUVECs underwent concentration-dependent changes in their morphology. Loss of the microtubule structure and increased bundling of filamentous actin into stress fibers followed by cell collapse, rounding and blebbing was observed. OXi6196 (100 nM) disrupted capillary-like endothelial networks pre-established with HUVECs on Matrigel®. When prodrug OXi6197 was administered to mice bearing orthotopic MDA-MB-231-luc tumors, dynamic bioluminescence imaging (BLI) revealed dose-dependent vascular shutdown with >80% signal loss within 2 h at doses ≥30 mg/kg and >90% shutdown after 6 h for doses ≥35 mg/kg, which remained depressed by at least 70% after 24 h. Twice weekly treatment with prodrug OXi6197 (20 mg/kg) caused a significant tumor growth delay, but no overall survival benefit. Similar efficacy was observed for the first time in orthotopic RENCA-luc tumors, which showed massive hemorrhage and necrosis after 24 h. Twice weekly dosing with prodrug OXi6197 (35 mg/kg) caused tumor growth delay in most orthotopic RENCA tumors. Immunohistochemistry revealed extensive necrosis, though with surviving peripheral tissues. These results demonstrate effective vascular disruption at doses comparable to the most effective vascular-disrupting agents (VDAs) suggesting opportunities for further development.

14.
Eur Urol Oncol ; 5(6): 695-703, 2022 12.
Article in English | MEDLINE | ID: mdl-35985982

ABSTRACT

BACKGROUND: Evidence-based guidelines for the management of systemic therapy-naïve oligometastatic renal cell carcinoma (RCC) are lacking. OBJECTIVE: To evaluate the potential of stereotactic ablative radiotherapy (SAbR) to provide longitudinal disease control while preserving quality of life (QOL) in patients with systemic therapy-naïve oligometastatic RCC. DESIGN, SETTING, AND PARTICIPANTS: RCC patients with three or fewer extracranial metastases were eligible. SAbR was administered longitudinally to all upfront and, as applicable, subsequent metastases. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: This prospective phase II single-arm trial was powered to achieve a primary objective of freedom from systemic therapy for >1 yr in >60% of patients (using the Clopper and Pearson methodology). Secondary endpoints included progression-free survival (PFS), defined as the time from first SAbR to progression not amenable to SAbR (local failure at SAbR-treated sites, new metastases not amenable to SAbR, more than three new metastases, or brain metastases); patient-reported QOL metrics; local control (LC) rates; toxicity; cancer-specific survival (CSS); and overall survival (OS). RESULTS AND LIMITATIONS: Twenty-three patients received SAbR to 33 initial and 57 total sites. The median follow-up was 21.7 mo (interquartile range 16.3-30.3). Exceeding the prespecified 60% benchmark, freedom from systemic therapy at 1 yr was 91.3% (95% confidence interval [CI]: 69.5, 97.8). One-year PFS was 82.6% (95% CI: 60.1, 93.1). QOL was largely unaffected. LC was 100%. There were no grade 3/4 toxicities, but there was one death due to immune-related colitis 3 mo after SAbR while on subsequent checkpoint inhibitor therapy, where a SAbR contribution could not be excluded. One-year OS was 95.7% (95% CI: 72.9, 99.4); one-year CSS was 100%. CONCLUSIONS: SAbR for oligometastatic RCC was associated with meaningful longitudinal disease control while preserving QOL. These data support further evaluation of SAbR for systemic therapy-naïve oligometastatic RCC. PATIENT SUMMARY: Sequential stereotactic radiation therapy can safely and effectively control metastatic kidney cancer with limited spread for over a year without compromising patients' quality of life.


Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Radiosurgery , Humans , Radiosurgery/methods , Quality of Life , Prospective Studies , Kidney Neoplasms/pathology
15.
Int J Mol Sci ; 23(13)2022 Jun 28.
Article in English | MEDLINE | ID: mdl-35806163

ABSTRACT

We previously reported the design and synthesis of a small-molecule drug conjugate (SMDC) platform that demonstrated several advantages over antibody-drug conjugates (ADCs) in terms of in vivo pharmacokinetics, solid tumor penetration, definitive chemical structure, and adaptability for modular synthesis. Constructed on a tri-modal SMDC platform derived from 1,3,5-triazine (TZ) that consists of a targeting moiety (Lys-Urea-Glu) for prostate-specific membrane antigen (PSMA), here we report a novel class of chemically identical theranostic small-molecule prodrug conjugates (T-SMPDCs), [18/19F]F-TZ(PSMA)-LEGU-TLR7, for PSMA-targeted delivery and controlled release of toll-like receptor 7 (TLR7) agonists to elicit de novo immune response for cancer immunotherapy. In vitro competitive binding assay of [19F]F-TZ(PSMA)-LEGU-TLR7 showed that the chemical modification of Lys-Urea-Glu did not compromise its binding affinity to PSMA. Receptor-mediated cell internalization upon the PSMA binding of [18F]F-TZ(PSMA)-LEGU-TLR7 showed a time-dependent increase, indicative of targeted intracellular delivery of the theranostic prodrug conjugate. The designed controlled release of gardiquimod, a TLR7 agonist, was realized by a legumain cleavable linker. We further performed an in vivo PET/CT imaging study that showed significantly higher uptake of [18F]F-TZ(PSMA)-LEGU-TLR7 in PSMA+ PC3-PIP tumors (1.9 ± 0.4% ID/g) than in PSMA- PC3-Flu tumors (0.8 ± 0.3% ID/g) at 1 h post-injection. In addition, the conjugate showed a one-compartment kinetic profile and in vivo stability. Taken together, our proof-of-concept biological evaluation demonstrated the potential of our T-SMPDCs for cancer immunomodulatory therapies.


Subject(s)
Prodrugs , Prostatic Neoplasms , Antigens, Surface/metabolism , Cell Line, Tumor , Delayed-Action Preparations , Glutamate Carboxypeptidase II/metabolism , Humans , Male , Positron Emission Tomography Computed Tomography/methods , Precision Medicine , Prodrugs/pharmacology , Prostatic Neoplasms/metabolism , Toll-Like Receptor 7 , Urea
16.
Cancer ; 128(11): 2085-2097, 2022 06 01.
Article in English | MEDLINE | ID: mdl-35383908

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 , Sunitinib
17.
J Clin Oncol ; 40(25): 2913-2923, 2022 09 01.
Article in English | MEDLINE | ID: mdl-35442713

ABSTRACT

PURPOSE: To determine the value of tumor cell programmed death-ligand 1 (PD-L1) expression as a predictive biomarker of nivolumab monotherapy efficacy in treatment-naive patients with clear cell renal cell carcinoma (ccRCC) and the efficacy of salvage nivolumab/ipilimumab in patients with tumors unresponsive to nivolumab monotherapy. METHODS: Eligible patients with treatment-naive ccRCC received nivolumab until progressive disease (PD), toxicity, or completing 96 treatment weeks (part A). Patients with PD before or stable disease at 48 weeks could receive salvage nivolumab/ipilimumab (part B). The primary end point was improvement in 1-year progression-free survival in patients with tumor PD-L1 expression > 20% versus 0%. RESULTS: One hundred twenty-three patients were enrolled. The objective response rate (ORR) was 34.1% (95% CI, 25.8 to 43.2). ORR by International Metastatic RCC Database Consortium category was favorable-risk 57.1%, intermediate-risk/poor-risk 25.0%, and by sarcomatoid features 36.4%. The ORR was 26.9%, 50.0%, and 75.0% for patients with the tumor PD-L1 expression of 0, 1-20, or > 20%, respectively (trend test P value = .002). The median duration of response was 27.6 (19.3 to not reached) months, with 26 of 42 responders including 17 of 20 with favorable-risk disease remaining progression-free. The 1-year progression-free survival was 34.6% and 75.0% in the PD-L1 = 0% and > 20% categories, respectively (P = .050). Ninety-seven patients with PD or prolonged stable disease were potentially eligible for part B, and 35 were enrolled. The ORR for part B was 11.4%. Grade ≥ 3 treatment-related adverse events occurred in 35% of patients on nivolumab and 43% of those on salvage nivolumab/ipilimumab. CONCLUSION: Nivolumab monotherapy is active in treatment-naive ccRCC. Although efficacy appears to be less than that of nivolumab/ipilimumab in patients with intermediate-risk/poor-risk disease, favorable-risk patients had notable benefit. Efficacy correlated with tumor PD-L1 status. Salvage nivolumab/ipilimumab was frequently not feasible and of limited benefit.


Subject(s)
Carcinoma, Renal Cell , Nivolumab , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , B7-H1 Antigen/metabolism , Carcinoma, Renal Cell/drug therapy , Humans , Ipilimumab , Nivolumab/adverse effects
18.
Clin Genitourin Cancer ; 20(3): 260-269, 2022 06.
Article in English | MEDLINE | ID: mdl-35277350

ABSTRACT

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have become a standard of care in metastatic renal cell carcinoma (mRCC) but are associated with immune-related adverse events (irAEs) including colitis. Growing evidence suggests proton pump inhibitors (PPIs) increase the risk of inflammatory bowel disease (IBD). Given the pathophysiological overlap between IBD and ICI colitis, we sought to evaluate the relationship between PPI use and ICI colitis in mRCC patients. PATIENTS AND METHODS: We performed a retrospective study of adult patients who received ICI therapy for mRCC between 2015 and 2018 at University of Texas Southwestern Medical Center affiliated hospitals. Clinical characteristics, oncological outcomes, ICI colitis details, and PPI use details were collected by manual chart review. The diagnosis of ICI colitis was made via biopsy when available, or by clinical criteria (symptoms and response to immunosuppressive therapy) when biopsy specimens were unavailable or inconclusive. Univariable and multivariable logistic regression analyses were conducted to assess the potential contribution of PPIs to ICI colitis. RESULTS: A total of 176 patients received ICI therapy for mRCC, of which 16 (9.1%) were diagnosed with ICI colitis. Patients with ICI colitis presented with elevated stool lactoferritin and calprotectin and a wide range of endoscopic and histologic findings. There were no significant differences between patients with and without ICI colitis in age, gender, medical comorbidities, RCC history, and overall survival. However, exposure to ipilimumab and PPI use were more frequently observed in patients with ICI colitis than those without. In univariable and multivariable logistic regression analyses, exposure to ipilimumab and chronic use of PPIs > 8 weeks were significantly associated with ICI colitis. CONCLUSION: In addition to ipilimumab use, chronic use of PPIs may be associated with ICI colitis in patients with mRCC.


Subject(s)
Carcinoma, Renal Cell , Colitis , Inflammatory Bowel Diseases , Kidney Neoplasms , Adult , Carcinoma, Renal Cell/drug therapy , Colitis/chemically induced , Colitis/drug therapy , Humans , Immune Checkpoint Inhibitors/adverse effects , Inflammatory Bowel Diseases/drug therapy , Ipilimumab/therapeutic use , Kidney Neoplasms/drug therapy , Proton Pump Inhibitors/adverse effects , Retrospective Studies
19.
Eur Urol Oncol ; 5(2): 216-224, 2022 04.
Article in English | MEDLINE | ID: mdl-34986993

ABSTRACT

BACKGROUND: Patients with metastatic renal cell carcinoma (mRCC) treated with systemic therapy sometimes progress at limited sites.The best treatment approach for patients with oligoprogression remains unclear. OBJECTIVE: To determine the ability of stereotactic ablative radiation (SAbR) to extend ongoing systemic therapy in mRCC patients with oligoprogression. DESIGN, SETTING, AND PARTICIPANTS: A single-arm phase II clinical trial was conducted at a university medical center and county hospital, including 20 patients with mRCC on first- to fourth-line systemic therapy with three or fewer sites of progression (including new sites) involving ≤30% of all sites. INTERVENTION: SAbR to oligoprogressing metastases at outset and longitudinally, while radiated sites remain controlled and overall disease oligoprogressive. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary objective was to extend ongoing systemic therapy by >6 mo in >40% of patients. Secondary endpoints included overall survival, toxicity, and patient-reported quality of life. RESULTS AND LIMITATIONS: Twenty patients were enrolled. Upfront and sequential SAbR was administered to a total of 37 sites. The local control rate was 100%. At a median follow-up of 10.4 mo (interquartile range: 5.8-16.4), SAbR extended the duration of the ongoing systemic therapy by >6 mo in 14 patients (70%, 95% confidence interval [CI]: 49.9-90.1). The median time from SAbR to the onset of new systemic therapy or death was 11.1 mo (95% CI: 4.5-19.3). The median duration of SAbR-aided systemic therapy was 24.4 mo (95% CI: 15.3-42.2). Median overall survival was not reached. One patient developed grade 3 gastrointestinal toxicity possibly related to treatment. There was no significant decline in quality of life. Limitations include nonrandomized design and a small patient cohort. CONCLUSIONS: SAbR extended the duration of the ongoing systemic therapy for patients with oligoprogressive mRCC without undermining quality of life. These data support the evaluation of SAbR for oligoprogressive mRCC in a prospective randomized clinical trial. PATIENT SUMMARY: Patients with metastatic kidney cancer on systemic therapy but progressing at limited sites may benefit from focused radiation to progressive sites. Focused radiation was safe and effective, and extended the duration of the ongoing systemic therapy.


Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Radiosurgery , Carcinoma, Renal Cell/radiotherapy , Carcinoma, Renal Cell/surgery , Female , Humans , Kidney Neoplasms/radiotherapy , Male , Prospective Studies , Quality of Life , Radiosurgery/methods
20.
Clin Genitourin Cancer ; 20(1): 1-10, 2022 02.
Article in English | MEDLINE | ID: mdl-34364796

ABSTRACT

INTRODUCTION: The Metastatic Renal Cell Carcinoma (MaRCC) Registry provides prospective data on real-world treatment patterns and outcomes in patients with metastatic renal cell carcinoma (mRCC). METHODS AND MATERIALS: Patients with mRCC and no prior systemic therapy were enrolled at academic and community sites. End of study data collection was in March 2019. Outcomes included overall survival (OS). A survey of treating physicians assessed reasons for treatment initiations and discontinuations. RESULTS: Overall, 376 patients with mRCC initiated first-line therapy; 171 (45.5%) received pazopanib, 75 (19.9%) sunitinib, and 74 (19.7%) participated in a clinical trial. Median (95% confidence interval) OS was longest in the clinical trial group (50.3 [35.8-not reached] months) versus pazopanib (39.0 [29.7-50.9] months) and sunitinib 26.2 [19.9-61.5] months). Non-clear cell RCC (21.5% of patients) was associated with worse median OS than clear cell RCC (18.0 vs. 47.3 months). Differences in baseline characteristics, treatment starting dose, and relative dose exposure among treatment groups suggest selection bias. Survey results revealed a de-emphasis on quality of life, toxicity, and patient preference compared with efficacy in treatment selection. CONCLUSION: The MaRCC Registry gives insights into real-world first-line treatment selection, outcomes, and physician rationale regarding initial treatment selection prior to the immunotherapy era. Differences in outcomes between clinical trial and off-study patients reflect the difficulty in translating trial results to real-world patients, and emphasize the need to broaden clinical trial eligibility. Physician emphasis on efficacy over quality of life and toxicity suggests more data and education are needed regarding these endpoints.


Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Carcinoma, Renal Cell/pathology , Female , Humans , Immunotherapy , Indazoles/therapeutic use , Kidney Neoplasms/drug therapy , Male , Prospective Studies , Quality of Life , Registries , Retrospective Studies , Sunitinib/therapeutic use , Treatment Outcome
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