Publications by authors named "Robert J Motzer"

349 Publications

Germline Variants Identified in Patients with Early-onset Renal Cell Carcinoma Referred for Germline Genetic Testing.

Eur Urol Oncol 2021 Oct 12. Epub 2021 Oct 12.

Department of Medicine, Clinical Genetics Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Background: Despite guidelines recommending genetic counseling for patients with early-onset renal cell carcinoma (RCC), studies interrogating the spectrum of germline mutations and clinical associations in patients with early-onset RCC are lacking.

Objective: To define the germline genetic spectrum and clinical associations for patients with early-onset RCC diagnosed at age ≤46 yr who underwent genetic testing.

Design, Setting, And Participants: We retrospectively identified patients with early-onset RCC who underwent germline testing at our institution from February 2003 to June 2020.

Outcome Measurement And Statistical Analysis: The frequency and spectrum of pathogenic/likely pathogenic (P/LP) variants were determined. Clinical characteristics associated with mutation status were analyzed using two-sample comparison (Fisher's exact or χ test).

Results And Limitations: Of 232 patients with early-onset RCC, 50% had non-clear-cell histology, including unclassified RCC (12.1%), chromophobe RCC (9.7%), FH-deficient RCC (7.0%), papillary RCC (6.6%), and translocation-associated RCC (4.3%). Overall, 43.5% had metastatic disease. Germline P/LP variants were identified in 41 patients (17.7%), of which 21 (9.1%) were in an RCC-associated gene and 20 (8.6%) in a non-RCC-associated gene, including 17 (7.3%) in DNA damage repair genes such as BRCA1/2, ATM, and CHEK2. Factors associated with RCC P/LP variants include bilateral/multifocal renal tumors, non-clear-cell histology, and additional extrarenal primary malignancies. In patients with only a solitary clear-cell RCC, the prevalence of P/LP variants in RCC-associated and non-RCC-associated genes was 0% and 9.9%, respectively.

Conclusions: Patients with early-onset RCC had high frequencies of germline P/LP variants in genes associated with both hereditary RCC and other cancer predispositions. Germline RCC panel testing has the highest yield when patients have clinical phenotypes suggestive of underlying RCC gene mutations. Patients with early-onset RCC should undergo comprehensive assessment of personal and family history to guide appropriate genetic testing.

Patient Summary: In this study of 232 patients with early-onset kidney cancer who underwent genetic testing, we found a high prevalence of mutations in genes that increase the risk of cancer in both kidneys and other organs for patients and their at-risk family members. Our study suggests that patients with early-onset kidney cancer should undergo comprehensive genetic risk assessment.
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http://dx.doi.org/10.1016/j.euo.2021.09.005DOI Listing
October 2021

Quality-adjusted Time Without Symptoms or Toxicity (Q-TWiST) for Lenvatinib plus Everolimus Versus Everolimus Monotherapy in Patients with Advanced Renal Cell Carcinoma.

Eur Urol Open Sci 2021 Sep 15;31:1-9. Epub 2021 Jul 15.

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: The lenvatinib (LEN) plus everolimus (EVE) combination demonstrated improved progression-free survival over everolimus alone in a phase 2 trial (Study-205).

Objective: To compare quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST) between LEN + EVE and EVE alone among patients with advanced renal cell carcinoma (RCC) following one prior antiangiogenic therapy.

Design Setting And Participants: This was a post hoc analysis of Study-205.

Outcome Measurements And Statistical Analysis: Survival time was partitioned into three mutually exclusive health states: time with grade 3/4 toxicity (TOX); time before disease progression and without grade 3/4 toxicity (TWiST); and time after disease progression (REL). The mean time in each state was weighted by utility measures and summed to calculate Q-TWiST. Nonparametric bootstrapping generated 95% confidence intervals (CIs). In the base case, utility for TWiST, TOX, and REL was assigned as 1.0, 0.5, and 0.5, respectively. Sensitivity analyses applied alternative utility values for REL, TOX, and TWiST. A relative gain in Q-TWiST of ≥10% and ≥15% has been established as clinically important and clearly clinically important, respectively.

Results And Limitations: Patients receiving LEN + EVE ( = 51) had a significant mean Q-TWiST gain of 3.7 mo (14.7 vs 11.0 mo; 95% CI for difference 1.3-6.3), with a relative gain of 24% compared to EVE alone. In a sensitivity analysis using alternative utility values for TWiST (varied from 0.55 to 0.9) with utility set to 0.5 for both TOX and REL, the relative Q-TWiST gain was maintained (ranging from 11.0% to 21.2%; all significant) across varying utility values. Limitations include the sample size, the absence of utility estimates, and the length of adverse events from the trial.

Conclusions: LEN + EVE showed a significant and clearly clinically important improvement in quality-adjusted survival time versus EVE alone.

Patient Summary: Patients with advanced kidney cancer who had received other previous treatments experienced a clearly clinically important improvement in quality survival time when treated with lenvatinib plus everolimus compared to everolimus alone.
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http://dx.doi.org/10.1016/j.euros.2021.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385286PMC
September 2021

Outcomes based on plasma biomarkers in METEOR, a randomized phase 3 trial of cabozantinib vs everolimus in advanced renal cell carcinoma.

BMC Cancer 2021 Aug 7;21(1):904. Epub 2021 Aug 7.

Duke Cancer Institute, Durham, NC, USA.

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 p < 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).
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http://dx.doi.org/10.1186/s12885-021-08630-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349489PMC
August 2021

Evolving biological associations of upfront cytoreductive nephrectomy in metastatic renal cell carcinoma.

Cancer 2021 Nov 19;127(21):3946-3956. Epub 2021 Jul 19.

Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: Systemic responses to cytoreductive nephrectomy (CN) in the management of metastatic renal cell carcinoma (mRCC) are variable and difficult to anticipate. The authors aimed to determine the association of CN with modifiable International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factors and oncological outcomes.

Methods: Consecutive patients with mRCC referred for potential CN (2009-2019) were reviewed. The primary outcome was overall survival (OS); variables of interest included undergoing CN and the baseline number of modifiable IMDC risk factors (anemia, hypercalcemia, neutrophilia, thrombocytosis, and reduced performance status). For operative cases, the authors evaluated the effects of IMDC risk factor dynamics, measured 6 weeks and 6 months after CN, on OS and postoperative treatment disposition.

Results: Of 245 treatment-naive patients with mRCC referred for CN, 177 (72%) proceeded to surgery. The CN cases had fewer modifiable IMDC risk factors (P = .003), including none in 71 of 177 patients (40.1%); fewer metastases (P = .011); and higher proportions of clear cell histology (P = .012). In a multivariable analysis, surgical selection, number of IMDC risk factors, metastatic focality, and histology were associated with OS. Total risk factors changed for 53.8% and 57.2% of the patients from the preoperative period to 6 weeks and 6 months after CN, respectively. Adjusted for preoperative IMDC risk scores, an increase in IMDC risk factors at 6 weeks and 6 months was associated with adverse OS (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.13-2.19; P = .007; HR, 2.52; 95% CI, 1.74-3.65; P < .001).

Conclusions: IMDC risk factors are dynamic clinical variables that can improve after upfront CN in select patients, and this suggests a systemic benefit of cytoreduction, which may confer clinically meaningful prognostic implications.
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http://dx.doi.org/10.1002/cncr.33790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8516697PMC
November 2021

Prevalence and Landscape of Actionable Genomic Alterations in Renal Cell Carcinoma.

Clin Cancer Res 2021 Oct 14;27(20):5595-5606. Epub 2021 Jul 14.

Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: We report our experience with next-generation sequencing to characterize the landscape of actionable genomic alterations in renal cell carcinoma (RCC).

Experimental Design: A query of our institutional clinical sequencing database (MSK-IMPACT) was performed that included tumor samples from 38,468 individuals across all cancer types. Somatic variations were annotated using a precision knowledge database (OncoKB) and the available clinical data stratified by level of evidence. Alterations associated with response to immune-checkpoint blockade (ICB) were analyzed separately; these included DNA mismatch repair (MMR) gene alterations, tumor mutational burden (TMB), and microsatellite instability (MSI). Data from The Cancer Genome Atlas (TCGA) consortium as well as public data from several clinical trials in metastatic RCC were used for validation purposes. Multiregional sequencing data from the TRAcking Cancer Evolution through Therapy (TRACERx) RENAL cohort were used to assess the clonality of somatic mutations.

Results: Of the 753 individuals with RCC identified in the MSK-IMPACT cohort, 115 showed evidence of targetable alterations, which represented a prevalence of 15.3% [95% confidence interval (CI), 12.7%-17.8%). When stratified by levels of evidence, the alterations identified corresponded to levels 2 (11.3%), 3A (5.2%), and 3B (83.5%). A low prevalence was recapitulated in the TCGA cohort at 9.1% (95% CI, 6.9%-11.2%). Copy-number variations predominated in papillary RCC tumors, largely due to amplifications in the gene. Notably, higher rates of actionability were found in individuals with metastatic disease (stage IV) compared with those with localized disease (OR, 2.50; 95% CI, 1.16-6.16; Fisher's = 0.01). On the other hand, the prevalence of alterations associated with response to ICB therapy was found to be approximately 5% in both the MSK-IMPACT and TCGA cohorts and no associations with disease stage were identified (OR, 1.35; 95% CI, 0.46-5.40; = 0.8). Finally, multiregional sequencing revealed that the vast majority of actionable mutations occurred later during tumor evolution and were only present subclonally in RCC tumors.

Conclusions: RCC harbors a low prevalence of clinically actionable alterations compared with other tumors and the evidence supporting their clinical use is limited. These aberrations were found to be more common in advanced disease and seem to occur later during tumor evolution. Our study provides new insights on the role of targeted therapies for RCC and highlights the need for additional research to improve treatment selection using genomic profiling.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4058DOI Listing
October 2021

Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study.

Lancet Oncol 2021 07 15;22(7):946-958. Epub 2021 Jun 15.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Despite advances in the first-line treatment of metastatic renal cell carcinoma (RCC), there is an unmet need for options to address disease progression during or after treatment with immune checkpoint inhibitors (ICIs). Pembrolizumab and lenvatinib are active as monotherapies in RCC; thus, we aimed to evaluate the combination of lenvatinib plus pembrolizumab in these patients.

Methods: We report results of the metastatic RCC cohort from an open-label phase 1b/2 study of lenvatinib plus pembrolizumab in patients aged at least 18 years with selected solid tumours and an Eastern Cooperative Oncology Group performance status of 0-1. Oral lenvatinib at 20 mg was given once daily along with intravenous pembrolizumab at 200 mg once every 3 weeks. Patients remained on study drug treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent. Efficacy was analysed in patients with clear cell metastatic RCC receiving study drug by previous therapy grouping: treatment naive, previously treated ICI naive (previously treated with at least one line of therapy but not with an anti-PD-1 or anti-PD-L1 ICI), and ICI pretreated (ie, anti-PD-1 or anti-PD-L1) patients. Safety was analysed in all enrolled and treated patients. The primary endpoint was the objective response rate at week 24 per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) by investigator assessment. This trial is registered with ClinicalTrials.gov (NCT02501096) and with the EU Clinical Trials Register (EudraCT2017-000300-26), and is closed to new participants.

Findings: Between July 21, 2015, and Oct 16, 2019, 145 patients were enrolled in the study. Two patients had non-clear cell RCC and were excluded from the efficacy analysis (one in the treatment-naive group and one in the ICI-pretreated group); thus, the population evaluated for efficacy comprised 143 patients (n=22 in the treatment-naive group, n=17 in the previously treated ICI-naive group, and n=104 in the ICI-pretreated group). All 145 enrolled patients were included in the safety analysis. The median follow-up was 19·8 months (IQR 14·3-28·4). The number of patients with an objective response at week 24 by irRECIST was 16 (72·7%, 95% CI 49·8-89·3) of 22 treatment-naive patients, seven (41·2%, 18·4-67·1) of 17 previously treated ICI-naive patients, and 58 (55·8%, 45·7-65·5) of 104 ICI-pretreated patients. Of 145 patients, 82 (57%) had grade 3 treatment-related adverse events and ten (7%) had grade 4 treatment-related adverse events. The most common grade 3 treatment-related adverse event was hypertension (30 [21%] of 145 patients). Treatment-related serious adverse events occurred in 36 (25%) patients, and there were three treatment-related deaths (upper gastrointestinal haemorrhage, sudden death, and pneumonia).

Interpretation: Lenvatinib plus pembrolizumab showed encouraging antitumour activity and a manageable safety profile and might be an option for post-ICI treatment of metastatic RCC.

Funding: Eisai and Merck Sharp & Dohme.
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http://dx.doi.org/10.1016/S1470-2045(21)00241-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316679PMC
July 2021

High Response Rate and Durability Driven by HLA Genetic Diversity in Patients with Kidney Cancer Treated with Lenvatinib and Pembrolizumab.

Mol Cancer Res 2021 Sep 26;19(9):1510-1521. Epub 2021 May 26.

Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, New York.

Immune checkpoint blockade (ICB) therapy has substantially improved the outcomes of patients with many types of cancers, including renal cell carcinoma (RCC). Initially studied as monotherapy, immunotherapy-based combination regimens have improved the clinical benefit achieved by ICB monotherapy and have revolutionized RCC treatment. While biomarkers like PD-L1 and tumor mutational burden (TMB) are FDA approved as biomarkers for ICB monotherapy, there are no known biomarkers for combination immunotherapies. Here, we describe the clinical outcomes and genomic determinants of response from a phase Ib/II clinical trial on patients with advanced RCC evaluating the efficacy of lenvatinib, a multi-kinase inhibitor mainly targeting VEGFR and FGFR plus pembrolizumab, an anti-PD1 immunotherapy. Concurrent treatment with lenvatinib and pembrolizumab resulted in an objective response rate of 79% (19/24) and tumor shrinkage in 96% (23/24) of patients. While tumor mutational burden (TMB) did not predict for clinical benefit, germline HLA-I diversity strongly impacted treatment efficacy. Specifically, HLA-I evolutionary divergence (HED), which measures the breadth of a patient's immunopeptidome, was associated with both improved clinical benefit and durability of response. Our results identify lenvatinib plus pembrolizumab as a highly active treatment strategy in RCC and reveal HLA-I diversity as a critical determinant of efficacy for this combination. HED also predicted better survival in a separate cohort of patients with RCC following therapy with anti-PD-1-based combination therapy. IMPLICATIONS: These findings have substantial implications for RCC therapy and for understanding immunogenetic mechanisms of efficacy and warrants further investigation.
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http://dx.doi.org/10.1158/1541-7786.MCR-21-0053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419018PMC
September 2021

Single-cell sequencing links multiregional immune landscapes and tissue-resident T cells in ccRCC to tumor topology and therapy efficacy.

Cancer Cell 2021 May 15;39(5):662-677.e6. Epub 2021 Apr 15.

Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Clear cell renal cell carcinomas (ccRCCs) are highly immune infiltrated, but the effect of immune heterogeneity on clinical outcome in ccRCC has not been fully characterized. Here we perform paired single-cell RNA (scRNA) and T cell receptor (TCR) sequencing of 167,283 cells from multiple tumor regions, lymph node, normal kidney, and peripheral blood of two immune checkpoint blockade (ICB)-naïve and four ICB-treated patients to map the ccRCC immune landscape. We detect extensive heterogeneity within and between patients, with enrichment of CD8A tissue-resident T cells in a patient responsive to ICB and tumor-associated macrophages (TAMs) in a resistant patient. A TCR trajectory framework suggests distinct T cell differentiation pathways between patients responding and resistant to ICB. Finally, scRNA-derived signatures of tissue-resident T cells and TAMs are associated with response to ICB and targeted therapies across multiple independent cohorts. Our study establishes a multimodal interrogation of the cellular programs underlying therapeutic efficacy in ccRCC.
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http://dx.doi.org/10.1016/j.ccell.2021.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268947PMC
May 2021

A qualitative framework of non-selection factors for cytoreductive nephrectomy.

World J Urol 2021 Sep 29;39(9):3359-3365. Epub 2021 Mar 29.

Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, USA.

Purpose: Cytoreductive nephrectomy (CN) benefits a subset of patients with metastatic renal cell carcinoma (mRCC), however proper patient selection remains complex and controversial. We aim to characterize urologists' reasons for not undertaking a CN at a quaternary cancer center.

Methods: Consecutive patients with mRCC referred to MSKCC urologists for consideration of CN between 2009 and 2019 were included. Baseline clinicopathologic characteristics were used to compare patients selected or rejected for CN. The reasons cited for not operating and the alternative management strategies recommended were extrapolated. Using an iterative thematic analysis, a framework of reasons for rejecting CN was designed. Kaplan-Meier estimates tested for associations between the reasons for not undertaking a CN and overall survival (OS).

Results: Of 297 patients with biopsy-proven mRCC, 217 (73%) underwent CN and 80 (27%) did not. Median follow-up of patients alive at data cut-off was 27.3 months. Non-operative patients were older (p = 0.014), had more sites of metastases (p = 0.008), harbored non-clear cell histology (p = 0.014) and reduced performance status (p < 0.001). The framework comprised seven distinct themes for recommending non-operative management: two patient-fitness considerations and five oncological considerations. These considerations were associated with OS; four of the oncological factors conferred a median OS of less than 12 months (p < 0.001).

Conclusion: We developed a framework of criteria by which patients were deemed unsuitable candidates for CN. These new insights provide a novel perspective on surgical selection, could potentially be applicable to other malignancies and possibly have prognostic implications.
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http://dx.doi.org/10.1007/s00345-021-03650-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478968PMC
September 2021

Efficacy and Safety of Atezolizumab Plus Bevacizumab Following Disease Progression on Atezolizumab or Sunitinib Monotherapy in Patients with Metastatic Renal Cell Carcinoma in IMmotion150: A Randomized Phase 2 Clinical Trial.

Eur Urol 2021 05 5;79(5):665-673. Epub 2021 Mar 5.

Beth Israel Deaconess Medical Center, Boston, MA, USA.

Background: The use of immune checkpoint inhibitors combined with vascular endothelial growth factor (VEGF)-targeted therapy as second-line treatment for metastatic clear cell renal cancer (mRCC) has not been evaluated prospectively.

Objective: To evaluate the efficacy and safety of atezolizumab + bevacizumab following disease progression on atezolizumab or sunitinib monotherapy in patients with mRCC.

Design, Setting, And Participants: IMmotion150 was a multicenter, randomized, open-label, phase 2 study of patients with untreated mRCC. Patients randomized to the atezolizumab or sunitinib arm who had investigator-assessed progression as per RECIST 1.1 could be treated with second-line atezolizumab + bevacizumab.

Intervention: Patients received atezolizumab 1200 mg intravenously (IV) plus bevacizumab 15 mg/kg IV every 3 wk following disease progression on either atezolizumab or sunitinib monotherapy.

Outcome Measurements And Statistical Analysis: The secondary endpoints analyzed during the second-line part of IMmotion150 included objective response rate (ORR), progression-free survival (PFS), and safety. PFS was examined using Kaplan-Meier methods.

Results And Limitations: Fifty-nine patients in the atezolizumab arm and 78 in the sunitinib arm were eligible, and 103 initiated second-line atezolizumab + bevacizumab (atezolizumab arm, n = 44; sunitinib arm, n = 59). ORR (95% confidence interval [CI]) was 27% (19-37%). The median PFS (95% CI) from the start of second line was 8.7 (5.6-13.7) mo. The median event follow-up duration was 19.4 (12.9-21.9) mo among the 25 patients without a PFS event. Eighty-six (83%) patients had treatment-related adverse events; 31 of 103 (30%) had grade 3/4 events. Limitations were the small sample size and selection for progressors.

Conclusions: The atezolizumab + bevacizumab combination had activity and was tolerable in patients with progression on atezolizumab or sunitinib. Further studies are needed to investigate sequencing strategies in mRCC.

Patient Summary: Patients with advanced kidney cancer whose disease had worsened during treatment with atezolizumab or sunitinib began second-line treatment with atezolizumab + bevacizumab. Tumors shrank in more than one-quarter of patients treated with this combination, and side effects were manageable.
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http://dx.doi.org/10.1016/j.eururo.2021.01.003DOI Listing
May 2021

Comprehensive Molecular Characterization and Response to Therapy in Fumarate Hydratase-Deficient Renal Cell Carcinoma.

Clin Cancer Res 2021 May 3;27(10):2910-2919. Epub 2021 Mar 3.

Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare, aggressive form of RCC associated with hereditary leiomyomatosis and RCC syndrome. Evidence for systemic therapy efficacy is lacking.

Experimental Design: We studied clinical and genomic characteristics of FH-RCC, including response [objective response rate (ORR)] to systemic therapies and next-generation sequencing (NGS). Patients with metastatic FH-RCC, defined by presence of pathogenic germline or somatic mutation plus IHC evidence of FH loss, were included.

Results: A total of 28 of 32 included patients (median age 46; range, 20-74; M:F, 20:12) underwent germline testing; 23 (82%) harbored a pathogenic germline variant. Five (16%) were negative for germline mutations; all had biallelic somatic loss. Somatic NGS (31/32 patients) revealed co-occurring mutation most frequently ( = 5). Compared with clear-cell RCC, FH-RCC had a lower mutation count (median 2 vs. 4; < 0.001) but higher fraction of genome altered (18.7% vs. 10.3%; = 0.001). A total of 26 patients were evaluable for response to systemic therapy: mTOR/VEGF combination ( = 18, ORR 44%), VEGF monotherapy ( = 15, ORR 20%), checkpoint inhibitor therapy ( = 8, ORR 0%), and mTOR monotherapy ( = 4, ORR 0%). No complete responses were seen. Median overall and progression-free survival were 21.9 months [95% confidence interval (CI): 14.3-33.8] and 8.7 months (95% CI: 4.8-12.3), respectively.

Conclusions: Although most FH-RCC tumors are due to germline alterations, a significant portion result from biallelic somatic loss. Both somatic and germline FH-RCC have similar molecular characteristics, with NF2 mutations, low tumor mutational burden, and high fraction of genome altered. Although immunotherapy alone produced no objective responses, combination mTOR/VEGF therapy showed encouraging results.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127353PMC
May 2021

Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma.

N Engl J Med 2021 03;384(9):829-841

From the Department of Medical Oncology, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston (T.K.C.); the Department of Genitourinary Oncology, Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free National Health Service Trust, London (T.P.); the Bradford Hill Clinical Research Center, Santiago, Chile (M.B.); the Department of Medical Oncology, Gustave Roussy, Villejuif, France (B.E.); the Department of Hemato-Oncology, Urologic Oncology Clinic, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City (M.T.B.), the Department of Medical Oncology, Centro Universitario contra el Cáncer, Hospital Universitario "Dr. José Eleuterio González," Universidad Autónoma de Nuevo León, Nuevo León (V.M.O.J.), and the Department of Medical Oncology, Hospital H+ Querétaro, Querétaro (J.P.F.) - all in Mexico; the Department of Outpatient Chemotherapy, Professor Franciszek Lukaszczyk Oncology Center, Bydgoszcz (B.Z.), and the Department of Clinical Oncology and Hematology, Regional Specialist Hospital, Biała Podlaska (J. Żołnierek) - both in Poland; the Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis (J.J.H.); Oncology Unit 1, Department of Oncology, Istituto Oncologico Veneto IRCCS, Padua (U.B.), the Department of Medical Oncology, Ospedale San Donato, Istituto Toscano i, Arezzo (A.H.), the Department of Internal Medicine, University of Pavia, Pavia (C.P.), and the University of Bari "A. Moro," Bari (C.P.) - all in Italy; the Department of Genitourinary Medical Oncology, M.D. Anderson Cancer Center, Houston (A.Y.S.); the Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona (C.S.); the Department of Medical Oncology, Royal Brisbane and Women's Hospital, Herston, QLD (J.C.G.), and Cabrini Monash University Department of Medical Oncology, Cabrini Health, Malvern, VIC (D.P.) - both in Australia; the Oncology Research Center, Hospital São Lucas, Porto Alegre, Brazil (C.B.); Fundacion Richardet Longo, Instituto Oncologico de Cordoba, Cordoba (M.R.), and Instituto Multidisciplinario de Oncología, Clínica Viedma, Viedma (R.K.) - both in Argentina; the Division of Medical Oncology, Department of Internal Medicine, University of Colorado School of Medicine, Aurora (E.R.K.); the Departments of Urology and Molecular Oncology, Niigata University Graduate School of Medical and Dental Sciences, Niigata (Y.T.), and the Department of Urology, Keio University School of Medicine, Tokyo (R.M.) - both in Japan; the Department of Urology, Eberhard Karls University Tübingen, Tübingen, Germany (J.B.); the Departments of Clinical Research (J. Zhang.), Clinical Oncology (M.A.M.), Biostatistics (B.S.), and Health Economics and Outcomes Research (F.E.), Bristol Myers Squibb, Princeton, NJ; the Department of Clinical Oncology, Exelixis, Alameda, CA (G.M.S.); the Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (A.B.A.); and the Department of Medicine, Memorial Sloan Kettering Cancer Center, New York (R.J.M.).

Background: The efficacy and safety of nivolumab plus cabozantinib as compared with those of sunitinib in the treatment of previously untreated advanced renal-cell carcinoma are not known.

Methods: In this phase 3, randomized, open-label trial, we randomly assigned adults with previously untreated clear-cell, advanced renal-cell carcinoma to receive either nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg once daily) or sunitinib (50 mg once daily for 4 weeks of each 6-week cycle). The primary end point was progression-free survival, as determined by blinded independent central review. Secondary end points included overall survival, objective response as determined by independent review, and safety. Health-related quality of life was an exploratory end point.

Results: Overall, 651 patients were assigned to receive nivolumab plus cabozantinib (323 patients) or sunitinib (328 patients). At a median follow-up of 18.1 months for overall survival, the median progression-free survival was 16.6 months (95% confidence interval [CI], 12.5 to 24.9) with nivolumab plus cabozantinib and 8.3 months (95% CI, 7.0 to 9.7) with sunitinib (hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.64; P<0.001). The probability of overall survival at 12 months was 85.7% (95% CI, 81.3 to 89.1) with nivolumab plus cabozantinib and 75.6% (95% CI, 70.5 to 80.0) with sunitinib (hazard ratio for death, 0.60; 98.89% CI, 0.40 to 0.89; P = 0.001). An objective response occurred in 55.7% of the patients receiving nivolumab plus cabozantinib and in 27.1% of those receiving sunitinib (P<0.001). Efficacy benefits with nivolumab plus cabozantinib were consistent across subgroups. Adverse events of any cause of grade 3 or higher occurred in 75.3% of the 320 patients receiving nivolumab plus cabozantinib and in 70.6% of the 320 patients receiving sunitinib. Overall, 19.7% of the patients in the combination group discontinued at least one of the trial drugs owing to adverse events, and 5.6% discontinued both. Patients reported better health-related quality of life with nivolumab plus cabozantinib than with sunitinib.

Conclusions: Nivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free survival, overall survival, and likelihood of response in patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol Myers Squibb and others; CheckMate 9ER ClinicalTrials.gov number, NCT03141177.).
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http://dx.doi.org/10.1056/NEJMoa2026982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436591PMC
March 2021

Four Cycles of Etoposide plus Cisplatin for Patients with Good-Risk Advanced Germ Cell Tumors.

Oncologist 2021 06 12;26(6):483-491. Epub 2021 Mar 12.

Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York, USA.

Background: The National Comprehensive Cancer Network recommends either three cycles of bleomycin, etoposide, and cisplatin or four cycles of etoposide and cisplatin (EPx4) as initial chemotherapy for the treatment of good-risk germ cell tumors (GCTs). To assess the response, toxicity, and survival outcomes of EPx4, we analyzed our experience.

Material And Methods: Response and survival outcomes, selected toxicities, and adherence to chemotherapy dose and schedule were assessed in patients with good-risk GCT who received EPx4 at Memorial Sloan Kettering Cancer Center between 1982 and 2016. The results were compared with our past results and published data.

Results: Between 1982 and 2016, 944 patients with GCT were treated with EPx4, 289 who were previously reported plus 655 treated between January 2000 and August 2016. A favorable response was achieved in 928 of 944 patients (98.3%). Five-year progression-free, disease-specific, and overall survival rates were 93.9%, 98.6%, and 97.9%, respectively. Median follow-up was 7.3 years (range, 2.8 months to 35.5 years). Viable, nonteratomatous malignant GCT was present in 3.5% of 432 postchemotherapy retroperitoneal lymph node dissection specimens from patients with nonseminomatous GCT. Febrile neutropenia and thromboembolic events occurred in 16.0% and 8.9%, respectively, with one treatment-related death. In the more recent 655-patient cohort, full-dose EPx4 was administered to 631 (96.3%), with deviations from planned treatment driven mainly by vascular (n = 13), hematologic (n = 11), renal (n = 7), or infectious (n = 5) events.

Conclusion: EPx4 is highly effective and well tolerated in patients with good-risk GCTs and remains a standard of care.

Implications For Practice: Four cycles of etoposide and cisplatin (EPx4) is a standard-of-care regimen for all patients with good-risk germ cell tumors with a favorable response rate and disease-specific survival of 98%. Full-dose administration of etoposide and cisplatin and complete resection of residual disease lead to optimal outcomes. EPx4 should be the recommended regimen in active smokers, patients with reduced or borderline kidney function, and patients aged 50 years or older, which are patient groups at increased risk for bleomycin pulmonary toxicity. Because of a risk of acquired severe pulmonary illness, EPx4 may also be favored for patients who vape or use e-cigarettes and during ongoing transmission of severe acute respiratory syndrome coronavirus 2.
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http://dx.doi.org/10.1002/onco.13719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176973PMC
June 2021

Genitourinary Medical Oncology Expert Opinion Survey Regarding Treatment Management in the COVID-19 Pandemic.

Clin Genitourin Cancer 2021 06 7;19(3):e178-e183. Epub 2021 Jan 7.

Division of Solid Tumor Oncology, Department of Medicine, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY; Weill Cornell Medical College, Cornell University, New York, NY. Electronic address:

Background: The worldwide Coronavirus disease 2019 (COVID-19) public health pandemic has restructured clinical care of patients with cancer throughout the world. The specific changes in the management of genitourinary (GU) cancers in different cancer centers owing to COVID-19 are not known, and some clinical scenarios remain controversial. We conducted an opinion survey to determine what changes in cancer treatment strategies are occurring owing to the COVID-19 pandemic.

Materials And Methods: A 20-item online survey was sent on May 25, 2020 to 170 expert GU medical oncologists from Europe and North America. The survey solicited responses to changes in GU cancer management in the setting of the COVID-19 pandemic. Data was collected and managed via a secure REDCap Database.

Results: Surveys were completed by 78 (45.8%) of 170 GU oncologists between May 25, 2020 and June 25, 2020. Clinical practice changes owing to COVID-19 in at least one scenario were reported by 79.1% of responders, most pronounced in prostate cancer (71.8%) and least pronounced in urothelial cancer (23%). Preferences for change in management varied by country, with 78% (37/47) of United States oncologists indicating a change in their practice, 57% (4/7) of Canadian oncologists, and 79% (19/24) of European oncologists.

Conclusions: This study suggests international practice changes are occurring in GU cancer care during the COVID-19 pandemic. The variability in practice changes between countries may reflect differences in COVID-19 case load during the time point of data collection. These results, based on expert opinion during this rapidly changing crisis, may inform the oncologic community regarding the effects of COVID-19 on GU cancer care.
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http://dx.doi.org/10.1016/j.clgc.2020.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787909PMC
June 2021

Prognosis of Incidental Brain Metastases in Patients With Advanced Renal Cell Carcinoma.

J Natl Compr Canc Netw 2021 04 12;19(4):432-438. Epub 2021 Feb 12.

1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: Metastatic renal cell carcinoma (mRCC) management guidelines recommend brain imaging if clinically indicated and the rate of occult central nervous system (CNS) metastasis is not well-defined. Early detection could have major therapeutic implications, because timely interventions may limit morbidity and mortality.

Patients And Methods: A retrospective review was performed to characterize patients with mRCC incidentally diagnosed with asymptomatic brain metastases during screening for clinical trial participation at Gustave Roussy and Memorial Sloan Kettering Cancer Center. Descriptive statistics and time-to-event methods were used to evaluate the cohort.

Results: Across 68 clinical trials conducted between 2001 and 2019 with a median 14.1-month follow-up, 72 of 1,689 patients (4.3%) with mRCC harbored occult brain metastases. The International Metastatic RCC Database Consortium (IMDC) risk status was favorable (26%), intermediate (61%), and poor (13%), and 86% of patients had ≥2 extracranial sites of disease, including lung metastases in 92% of patients. CNS involvement was multifocal in 38.5% of patients, and the largest brain metastasis was >1 cm in diameter in 40% of the cohort. Localized brain-directed therapy was pursued in 93% of patients, predominantly radiotherapy. Median overall survival was 10.3 months (range, 7.0-17.9 months), and the 1-year overall survival probability was 48% (95% CI, 37%-62%). IMDC risk and number or size of lesions did not correlate with survival (log-rank, P=.3, P=.25, and P=.067, respectively).

Conclusions: This large multi-institutional mRCC cohort study identified occult brain metastasis in a notable proportion of patients (4.3%) and highlights that the risk of asymptomatic CNS involvement extends to those with favorable risk features per IMDC risk assessment. These data provide rationale for brain screening in patients with advanced RCC.
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http://dx.doi.org/10.6004/jnccn.2020.7634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407454PMC
April 2021

Adjuvant Pazopanib Versus Placebo After Nephrectomy in Patients With Localized or Locally Advanced Renal Cell Carcinoma: Final Overall Survival Analysis of the Phase 3 PROTECT Trial.

Eur Urol 2021 03 15;79(3):334-338. Epub 2021 Jan 15.

Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA.

Most studies indicate no benefit of adjuvant therapy with VEGFR tyrosine kinase inhibitors in advanced renal cell carcinoma (RCC). PROTECT (NCT01235962) was a randomized, double-blind, placebo-controlled phase 3 study to evaluate adjuvant pazopanib in patients with locally advanced RCC at high risk of relapse after nephrectomy (pazopanib, n = 769; placebo, n = 769). The results of the primary analysis showed no difference in disease-free survival between pazopanib 600 mg and placebo. Here we report the final overall survival (OS) analysis (median follow-up: pazopanib, 76 mo, interquartile range [IQR] 66-84; placebo, 77 mo, IQR 69-85). There was no significant difference in OS between the pazopanib and placebo arms (hazard ratio 1.0, 95% confidence interval 0.80-1.26; nominal p > 0.9). OS was worse for patients with T4 disease compared to those with less advanced disease and was better for patients with body mass index (BMI) ≥30 kg/m compared to those with lower BMI. OS was significantly better for patients who remained diseasefree at 2 yr after treatment compared with those who relapsed within 2 yr. These findings are consistent with the primary outcomes from PROTECT, indicating that adjuvant pazopanib does not confer a benefit in terms of OS for patients following resection of locally advanced RCC. PATIENT SUMMARY: In the randomized, double-blind, placebo-controlled phase 3 PROTECT study, overall survival was similar for patients with locally advanced renal cell carcinoma (RCC) at high risk of relapse after nephrectomy who received adjuvant therapy with pazopanib or placebo. Pazopanib is not recommended as adjuvant therapy following resection of locally advanced RCC. This trial is registered at Clinicaltrials.gov as NCT01235962.
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http://dx.doi.org/10.1016/j.eururo.2020.12.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407394PMC
March 2021

Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial.

ESMO Open 2020 11;5(6):e001079

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Purpose: To report updated analyses of the phase III CheckMate 214 trial with extended minimum follow-up assessing long-term outcomes with first-line nivolumab plus ipilimumab (NIVO+IPI) versus (vs) sunitinib (SUN) in patients with advanced renal cell carcinoma (aRCC).

Methods: Patients with aRCC with a clear cell component were stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk and randomised to NIVO (3 mg/kg) plus IPI (1 mg/kg) every three weeks ×4 doses, followed by NIVO (3 mg/kg) every two weeks; or SUN (50 mg) once per day ×4 weeks (6-week cycle). Efficacy endpoints included overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) per independent radiology review committee in patients with intermediate/poor-risk disease (I/P; primary), intent-to-treat patients (ITT; secondary) and in patients with favourable-risk disease (FAV; exploratory).

Results: Overall, 1096 patients were randomised (ITT: NIVO+IPI, n=550, SUN, n=546; I/P: NIVO+IPI, n=425, SUN, n=422; FAV: NIVO+IPI, n=125, SUN, n=124). After 4 years minimum follow-up, OS (HR; 95% CI) remained superior with NIVO+IPI vs SUN in ITT (0.69; 0.59 to 0.81) and I/P patients (0.65; 0.54 to 0.78). Four-year PFS probabilities were 31.0% vs 17.3% (ITT) and 32.7% vs 12.3% (I/P), with NIVO+IPI vs SUN. ORR remained higher with NIVO+IPI vs SUN in ITT (39.1% vs 32.4%) and I/P (41.9% vs 26.8%) patients. In FAV patients, the HRs (95% CI) for OS and PFS were 0.93 (0.62 to 1.40) and 1.84 (1.29 to 2.62); ORR was lower with NIVO+IPI vs SUN. However, more patients in all risk groups achieved complete responses with NIVO+IPI: ITT (10.7% vs 2.6%), I/P (10.4% vs 1.4%) and FAV (12.0% vs 6.5%). Probability (95% CI) of response ≥4 years was higher with NIVO+IPI vs SUN (ITT, 59% (0.51 to 0.66) vs 30% (0.21 to 0.39); I/P, 59% (0.50 to 0.67) vs 24% (0.14 to 0.36); and FAV, 60% (0.41 to 0.75) vs 38% (0.22 to 0.54)) regardless of risk category. Safety remained favourable with NIVO+IPI vs SUN.

Conclusion: After long-term follow-up, NIVO+IPI continues to demonstrate durable efficacy benefits vs SUN, with manageable safety.

Trial Registration Details: ClinicalTrials.gov identifier: NCT02231749.
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http://dx.doi.org/10.1136/esmoopen-2020-001079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703447PMC
November 2020

Expression of T-Cell Exhaustion Molecules and Human Endogenous Retroviruses as Predictive Biomarkers for Response to Nivolumab in Metastatic Clear Cell Renal Cell Carcinoma.

Clin Cancer Res 2021 03 20;27(5):1371-1380. Epub 2020 Nov 20.

Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.

Purpose: We sought to validate levels of CD8 tumor-infiltrating cells (TIC) expressing PD-1 but not TIM-3 and LAG-3 (IF biomarker; Pignon and colleagues, 2019) and to investigate human endogenous retroviruses (hERV) as predictors of response to anti-PD-1 in a randomized trial of nivolumab (nivo) versus everolimus (evero) in patients with metastatic clear cell renal cell carcinoma (mccRCC; CheckMate-025).

Experimental Design: Tumor tissues (nivo: = 116, evero: = 107) were analyzed by multiparametric immunofluorescence (IF) and qRT-PCR. Genomic/transcriptomic analyses were performed in a subset of samples. Clinical endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and durable response rate (DRR, defined as complete response or partial response with a PFS ≥ 12 months).

Results: In the nivo (but not evero) arm, patients with high-IF biomarker density (24/116, 20.7%) had higher ORR (45.8% vs. 19.6%, = 0.01) and DRR (33.3% vs. 14.1%, = 0.03) and longer median PFS (9.6 vs. 3.7 months, = 0.03) than patients with low-IF biomarker. By RNA sequencing, several inflammatory pathways ( < 0.1) and immune-related gene signature scores ( < 0.05) were enriched in the high-IF biomarker group. When combined with the IF biomarker, tumor cell (TC) PD-L1 expression (≥1%) further separated clinical outcomes in the nivo arm. expression was associated with increased DRR and longer PFS in nivo-treated patients.

Conclusions: High levels of CD8 TIC expressing PD-1 but not TIM-3 and LAG-3 and expression predicted response to nivo (but not to evero) in patients with mccRCC. Combination of the IF biomarker with TC PD-L1 improved its predictive value, confirming our previous findings.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443005PMC
March 2021

Molecular Subsets in Renal Cancer Determine Outcome to Checkpoint and Angiogenesis Blockade.

Cancer Cell 2020 12 5;38(6):803-817.e4. Epub 2020 Nov 5.

Vanderbilt University Medical Center, Nashville, TN, USA.

Integrated multi-omics evaluation of 823 tumors from advanced renal cell carcinoma (RCC) patients identifies molecular subsets associated with differential clinical outcomes to angiogenesis blockade alone or with a checkpoint inhibitor. Unsupervised transcriptomic analysis reveals seven molecular subsets with distinct angiogenesis, immune, cell-cycle, metabolism, and stromal programs. While sunitinib and atezolizumab + bevacizumab are effective in subsets with high angiogenesis, atezolizumab + bevacizumab improves clinical benefit in tumors with high T-effector and/or cell-cycle transcription. Somatic mutations in PBRM1 and KDM5C associate with high angiogenesis and AMPK/fatty acid oxidation gene expression, while CDKN2A/B and TP53 alterations associate with increased cell-cycle and anabolic metabolism. Sarcomatoid tumors exhibit lower prevalence of PBRM1 mutations and angiogenesis markers, frequent CDKN2A/B alterations, and increased PD-L1 expression. These findings can be applied to molecularly stratify patients, explain improved outcomes of sarcomatoid tumors to checkpoint blockade versus antiangiogenics alone, and develop personalized therapies in RCC and other indications.
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http://dx.doi.org/10.1016/j.ccell.2020.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436590PMC
December 2020

Estimand framework: Are we asking the right questions? A case study in the solid tumor setting.

Pharm Stat 2021 03 5;20(2):324-334. Epub 2020 Nov 5.

Duke Cancer Center, Durham, North Carolina, USA.

The estimand framework requires a precise definition of the clinical question of interest (the estimand) as different ways of accounting for "intercurrent" events post randomization may result in different scientific questions. The initiation of subsequent therapy is common in oncology clinical trials and is considered an intercurrent event if the start of such therapy occurs prior to a recurrence or progression event. Three possible ways to account for this intercurrent event in the analysis are to censor at initiation, consider recurrence or progression events (including death) that occur before and after the initiation of subsequent therapy, or consider the start of subsequent therapy as an event in and of itself. The new estimand framework clarifies that these analyses address different questions ("does the drug delay recurrence if no patient had received subsequent therapy?" vs "does the drug delay recurrence with or without subsequent therapy?" vs "does the drug delay recurrence or start of subsequent therapy?"). The framework facilitates discussions during clinical trial planning and design to ensure alignment between the key question of interest, the analysis, and interpretation. This article is a result of a cross-industry collaboration to connect the International Council for Harmonisation E9 addendum concepts to applications. Data from previously reported randomized phase 3 studies in the renal cell carcinoma setting are used to consider common intercurrent events in solid tumor studies, and to illustrate different scientific questions and the consequences of the estimand choice for study design, data collection, analysis, and interpretation.
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http://dx.doi.org/10.1002/pst.2079DOI Listing
March 2021

Sarcomatoid renal cell carcinoma: biology, natural history and management.

Nat Rev Urol 2020 Dec 13;17(12):659-678. Epub 2020 Oct 13.

Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Sarcomatoid dedifferentiation is an uncommon feature that can occur in most histological subtypes of renal cell carcinomas (RCCs) and carries a decidedly poor prognosis. Historically, conventional treatments for sarcomatoid RCCs (sRCCs) have shown little efficacy, and median survival is commonly 6-13 months. Despite being first described in 1968, the mechanisms driving sarcomatoid dedifferentiation remain poorly understood, and information and treatment options available to physicians and patients are limited. When diagnosed at an early stage, surgical intervention remains the treatment of choice. However, preoperative identification through routine imaging or biopsy is unreliable and most patients present with advanced disease and systemic symptoms. For these patients, the role of cytoreductive nephrectomy is disputed. The expansion of immunotherapies approved for RCCs has generated a search for biomarkers that might be indicative of treatment response in sRCCs, although a proven effective systemic agent remains elusive. PDL1 expression is increased in sarcomatoid dedifferentiated renal tumours, which suggests that patients with sRCCs could benefit from PD1 and/or PDL1 immune checkpoint blockade therapy. Treatment outcomes for sarcomatoid tumours have remained relatively consistent compared with other RCCs, but further investigation of the tumour-immune cell microenvironment might yield insights into further therapeutic possibilities.
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http://dx.doi.org/10.1038/s41585-020-00382-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551522PMC
December 2020

Exploratory analysis of the platelet-to-lymphocyte ratio prognostic value in the adjuvant renal cell cancer setting.

Future Oncol 2021 Feb 8;17(4):403-409. Epub 2020 Oct 8.

Duke Cancer Institute, Durham, NC 27710, USA.

To examine the prognostic value of the platelet-to-lymphocyte ratio (PLR) in the adjuvant renal cell carcinoma setting. Patients received adjuvant sunitinib (50 mg/day; 4 weeks on/2 weeks off) or placebo. The primary end point was disease-free survival (DFS). In 609 patients, DFS was similar for baseline PLR <140 versus ≥140 overall (median: 6.4 vs 5.9 years; hazard ratio: 0.9; 95% CI: 0.7-1.2). A ≥25% decrease in PLR at week 4 overall was associated with longer DFS versus no change (hazard ratio: 0.8; 95% CI: 0.6-1.0). Baseline PLR was not prognostic for DFS with adjuvant sunitinib treatment in patients with renal cell carcinoma. Clinical Trials Registration: NCT00375674 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2020-0652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488532PMC
February 2021

Correlative serum biomarker analyses in the phase 2 trial of lenvatinib-plus-everolimus in patients with metastatic renal cell carcinoma.

Br J Cancer 2021 01 7;124(1):237-246. Epub 2020 Oct 7.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: No biomarkers have been established to predict treatment efficacy in renal cell carcinoma (RCC). In an exploratory retrospective analysis of a Phase 2 study, we constructed composite biomarker scores (CBSs) to predict progression-free survival (PFS) and overall survival (OS) in patients with metastatic RCC randomised to receive lenvatinib-plus-everolimus.

Methods: Of 40 biomarkers tested, the 5 most strongly associated with PFS (HGF, MIG, IL-18BP, IL-18, ANG-2) or OS (TIMP-1, M-CSF, IL-18BP, ANG-2, VEGF) were used to make a 5-factor PFS-CBS or OS-CBS, respectively. A 2-factor CBS was generated with biomarkers common to PFS-CBS and OS-CBS. Patients were divided into groups accordingly (5-factor-CBS high: 3-5, CBS-low: 0-2; 2-factor-CBS high: 1-2, CBS-low: 0).

Results: PFS/OS with lenvatinib-plus-everolimus were significantly longer in the 5-factor CBS-high group versus the CBS-low group (P = 0.0022/P < 0.0001, respectively). In the CBS-high group, PFS/OS were significantly longer with lenvatinib-plus-everolimus versus everolimus (P < 0.001/P = 0.0079, respectively); PFS was also significantly longer with lenvatinib-plus-everolimus versus lenvatinib (P = 0.0046). The 5-factor-CBS had a predictive role in PFS and OS after multivariate analysis. Similar trends were observed with the 2-factor-CBS for PFS (i.e., lenvatinib-plus-everolimus versus everolimus).

Conclusions: The 5-factor CBS may identify patients with metastatic RCC who would benefit from lenvatinib-plus-everolimus versus everolimus; additional validation is required.

Clinical Trial Registration: The clinical trial registration number is NCT01136733.
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http://dx.doi.org/10.1038/s41416-020-01092-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782770PMC
January 2021

Everolimus plus bevacizumab is an effective first-line treatment for patients with advanced papillary variant renal cell carcinoma: Final results from a phase II trial.

Cancer 2020 12 25;126(24):5247-5255. Epub 2020 Sep 25.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: We previously reported on a phase 2 study of everolimus plus bevacizumab across various nonclear cell renal cell carcinoma (nccRCC) histologies and observed encouraging activity among patients with papillary RCC (pRCC) and unclassified RCC (uRCC) with a major papillary component. We subsequently expanded the study to enroll additional patients with pRCC variants.

Methods: Everolimus plus bevacizumab was administered at standard doses until disease progression or intolerance to therapy. The primary endpoint was the 6-month progression-free survival (PFS) rate; secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Correlative analyses included next-generation sequencing (NGS) from tumor and germline across >341 genes of interest.

Results: In addition to 19 patients with pRCC variants in the original cohort, 20 patients with similar features were enrolled on the expansion cohort (uRCC with papillary features [n = 24], pRCC [n = 14], and translocation-associated RCC with papillary features [n = 1]). Among 37 evaluable patients, the 6-month PFS rate was 78%, the median PFS was 13.7 months (95% CI, 10.8-16.4 months), and the ORR was 35%. With a median follow-up of 17.6 months, the median OS was 33.9 months (95% CI, 23.3-71.9). Tolerance was consistent with prior reports for everolimus plus bevacizumab. NGS results (n = 33) identified responses in patients with a wide spectrum of genomic alterations, including ARID1A, FH, and MET mutations.

Conclusion: The expansion cohort results confirm robust activity of everolimus plus bevacizumab in metastatic pRCC variants, supporting this regimen as a standard option for this patient population.
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http://dx.doi.org/10.1002/cncr.33148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366407PMC
December 2020

Avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma: biomarker analysis of the phase 3 JAVELIN Renal 101 trial.

Nat Med 2020 11 7;26(11):1733-1741. Epub 2020 Sep 7.

Department of Medical Oncology, The Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA, USA.

We report on molecular analyses of baseline tumor samples from the phase 3 JAVELIN Renal 101 trial (n = 886; NCT02684006 ), which demonstrated significantly prolonged progression-free survival (PFS) with first-line avelumab + axitinib versus sunitinib in advanced renal cell carcinoma (aRCC). We found that neither expression of the commonly assessed biomarker programmed cell death ligand 1 (PD-L1) nor tumor mutational burden differentiated PFS in either study arm. Similarly, the presence of FcɣR single nucleotide polymorphisms was unimpactful. We identified important biological features associated with differential PFS between the treatment arms, including new immunomodulatory and angiogenesis gene expression signatures (GESs), previously undescribed mutational profiles and their corresponding GESs, and several HLA types. These findings provide insight into the determinants of response to combined PD-1/PD-L1 and angiogenic pathway inhibition and may aid in the development of strategies for improved patient care in aRCC.
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http://dx.doi.org/10.1038/s41591-020-1044-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493486PMC
November 2020

NCCN Guidelines Insights: Kidney Cancer, Version 1.2021.

J Natl Compr Canc Netw 2020 09;18(9):1160-1170

UCLA Jonsson Comprehensive Cancer Center.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to certain systemic therapy recommendations for patients with relapsed or stage IV RCC. They also discuss the addition of a new section to the guidelines that identifies and describes the most common hereditary RCC syndromes and provides recommendations for genetic testing, surveillance, and/or treatment options for patients who are suspected or confirmed to have one of these syndromes.
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http://dx.doi.org/10.6004/jnccn.2020.0043DOI Listing
September 2020

Efficacy and Safety of Nivolumab Plus Ipilimumab versus Sunitinib in First-line Treatment of Patients with Advanced Sarcomatoid Renal Cell Carcinoma.

Clin Cancer Res 2021 01 1;27(1):78-86. Epub 2020 Sep 1.

Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.

Purpose: Patients with advanced renal cell carcinoma with sarcomatoid features (sRCC) have poor prognoses and suboptimal outcomes with targeted therapy. This analysis of the phase III CheckMate 214 trial analyzed the efficacy of nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib in patients with sRCC.

Patients And Methods: Patients with sRCC were identified via independent central pathology review of archival tumor tissue or histologic classification per local pathology report. Patients were randomized 1:1 to receive nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks (four doses) then nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg orally every day (4 weeks; 6-week cycles). Outcomes in patients with sRCC were not prespecified. Endpoints in patients with sRCC and International Metastatic Renal Cell Carcinoma Database Consortium intermediate/poor-risk disease included overall survival (OS), progression-free survival (PFS) per independent radiology review, and objective response rate (ORR) per RECIST v1.1. Safety outcomes used descriptive statistics.

Results: Of 1,096 randomized patients in CheckMate 214, 139 patients with sRCC and intermediate/poor-risk disease and six with favorable-risk disease were identified. With 42 months' minimum follow-up in patients with sRCC and intermediate/poor-risk disease, median OS [95% confidence interval (CI)] favored NIVO+IPI [not reached (NR) (25.2-not estimable [NE]); = 74] versus sunitinib [14.2 months (9.3-22.9); = 65; HR, 0.45 (95% CI, 0.3-0.7; = 0.0004)]; PFS benefits with NIVO+IPI were similarly observed [median 26.5 vs. 5.1 months; HR, 0.54 (95% CI, 0.33-0.86; = 0.0093)]. Confirmed ORR was 60.8% with NIVO+IPI versus 23.1% with sunitinib, with complete response rates of 18.9% versus 3.1%, respectively. No new safety signals emerged.

Conclusions: NIVO+IPI showed unprecedented long-term survival, response, and complete response benefits versus sunitinib in previously untreated patients with sRCC and intermediate/poor-risk disease, supporting the use of first-line NIVO+IPI for this population..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2063DOI Listing
January 2021

A pan-cancer analysis of PBAF complex mutations and their association with immunotherapy response.

Nat Commun 2020 08 20;11(1):4168. Epub 2020 Aug 20.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

There is conflicting data regarding the role of PBAF complex mutations and response to immune checkpoint blockade (ICB) therapy in clear cell renal cell carcinoma (ccRCC) and other solid tumors. We assess the prevalence of PBAF complex mutations from two large cohorts including the pan-cancer TCGA project (n = 10,359) and the MSK-IMPACT pan-cancer immunotherapy cohort (n = 3700). Across both cohorts, PBAF complex mutations, predominantly PBRM1 mutations, are most common in ccRCC. In multivariate models of ccRCC patients treated with ICB (n = 189), loss-of-function (LOF) mutations in PBRM1 are not associated with overall survival (OS) (HR = 1.24, p = 0.47) or time to treatment failure (HR = 0.85, p = 0.44). In a series of 11 solid tumors (n = 2936), LOF mutations are not associated with improved OS in a stratified multivariate model (HR = 0.9, p = 0.7). In a current series of solid tumors treated with ICB, we are unable to demonstrate favorable response to ICB in patients with PBAF complex mutations.
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http://dx.doi.org/10.1038/s41467-020-17965-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441387PMC
August 2020

Nivolumab versus everolimus in patients with advanced renal cell carcinoma: Updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial.

Cancer 2020 09 16;126(18):4156-4167. Epub 2020 Jul 16.

Department of Clinical Trials, Bristol Myers Squibb, Princeton, New Jersey.

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.
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http://dx.doi.org/10.1002/cncr.33033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415096PMC
September 2020
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