Genomic biomarkers of response to lenvatinib/pembrolizumab (Len/Pembro) in patients with advanced renal cell carcinoma.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 733-733 ◽  
Author(s):  
Chung-Han Lee ◽  
Renzo G. DiNatale ◽  
Diego Chowell ◽  
Chriag Krishna ◽  
Vladimir Makarov ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Renal Cell Carcinoma ◽  
Antigen Presentation ◽  
Cell Carcinoma ◽  
Tumor Antigen ◽  
Renal Cell ◽  
Objective Response ◽  
Evolutionary Divergence ◽  
Loss Of Function ◽  
Genomic Biomarkers

733 Background: A phase 1b/2 clinical trial indicated that len/pembro shows promise in the treatment of renal cell carcinoma (RCC) in both PD-1/PD-L1 immune checkpoint blockade (ICB)-naïve and pretreated patients (NCT02501096). The combination is being further investigated in a phase 3 clinical trial in RCC (NCT02811861). Tumor antigen presentation depends on multiple factors, including HLA diversity, which can be measured by HLA evolutionary divergence (HED). HED quantitates the capacity of a patient’s HLA genotype to present different peptide antigens. This study is investigating the genomic components of tumor antigen presentation in ICB-naïve patients who have RCC and are treated with len/pembro. Methods: Whole exome sequencing (WES) was performed on pretreatment tumor-derived DNA. Somatic mutations, tumor mutation burden (TMB), neoantigen (NA) load, germline HLA zygosity and somatic loss of heterozygosity (LOH), and HED were correlated with objective response rate (ORR) and progression-free survival (PFS). An updated clinical cutoff was March 29, 2019. Results: Twenty four (80%) of 30 ICB-naïve patients underwent WES. A top-quartile cutoff was used. Increased mean HED was associated with improved PFS, while HLA homozygosity or LOH trended toward worse PFS. Loss-of-function mutations in PBRM1 (PBRM1 LOF) trended toward improved PFS. However, TMB and NA load were not correlated to PFS. No genomic biomarkers were correlated to ORR. Conclusions: Increased HLA diversity was associated with improved PFS, while decreased HLA diversity may be associated with worse PFS. PBRM1 mutation may be associated with improved PFS; however, TMB and NA load were not correlated to outcomes. These findings warrant further examination in larger datasets to rule out possible artifacts from multiple testing in a small cohort. Clinical trial information: NCT02811861. [Table: see text]

Genomic biomarkers of response to nivolumab/ipilimumab (nivo/ipi) and nivolumab (nivo) monotherapy in 108 patients with advanced renal cell carcinoma.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 641-641 ◽  
Author(s):  
Chung-Han Lee ◽  
Renzo G Di Natale ◽  
Diego Chowell ◽  
Vladimir Makarov ◽  
Almedina Redzematovic ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Multiple Testing ◽  
Objective Response ◽  
Progression Free Survival ◽  
Cell Renal Cell Carcinoma ◽  
Genomic Biomarkers ◽  
Predictors Of Response ◽  
Mutation Burden

641 Background: Both the combination of nivo/ipi and nivo monotherapy have shown efficacy across multiple malignancies including clear cell Renal Cell Carcinoma (ccRCC). Biomarkers such as tumor mutation burden (TMB) are prognostic in other malignancies, however, remain unvalidated in ccRCC. This study investigates genomic biomarkers associated with nivo/ipi and nivo clinical response. Methods: Whole exome sequencing (WES) was performed on pretreatment tumor derived DNA from nivo/ipi and nivo treated patients from MSKCC and publicly available WES datasets (Miao D, Science, 2018, 359: 6377). Somatic mutations, TMB, neoantigen load (NA), and HLA zyogosity were correlated to objective response rate (ORR), progression free survival (PFS), and Overall Survival (OS). Alterations occurring in < 10% of the cohort were considered non-evaluable (NE). Results: 108 patients had tumors studied; 32 patients with nivo/ipi and 76 patients with nivo therapy. No individual factors showed significant correlations to ORR or both PFS and OS. In the combined cohort, homozygosity at HLA-C was associated with shorter OS (HR=2.55 95% CI 1.17-5.57; P=0.02). In the nivo/ipi cohort, TMB (HR=0.36 95% CI 0.16-0.84; P=0.02) and NA (HR=0.43 95% CI 0.19-0.98; P=0.04) were associated with longer PFS. Conclusions: Increased TMB and NA load may predict for improved outcomes, and homozygosity at HLA loci may predict for worse outcomes. The predictors of response to nivo may not be generalizable to nivo/ipi. To rule out artifacts of multiple testing in a small cohort, validation in a larger dataset is necessary. [Table: see text]

Sunitinib versus sorafenib as first-line therapy for patients with metastatic renal cell carcinoma with favorable or intermediate MSKCC risk factors: A multicenter randomized trial, CROSS-J-RCC.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 502-502 ◽  
Author(s):  
Yoshihiko Tomita ◽  
Sei Naito ◽  
Naoto Sassa ◽  
Atsushi Takahashi ◽  
Tsunenori Kondo ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Renal Cell Carcinoma ◽  
Brain Metastasis ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Objective Response ◽  
Phase Iii ◽  
First Line ◽  
Primary Tumors

502 Background: Sorafenib (SO), an earlier introduced kinase inhibitor, and sunitinib (SU), a standard first-line treatment drug for metastatic renal cell carcinoma (mRCC), were associated with progression-free survival (PFS) of 5.7 and 11 months (M) in independent clinical trials, respectively. We compared PFS of first-line SU and SO in a multicenter, randomized, open-label, phase III trial. Methods: Patients with untreated, measurable (by RECIST v1.1) clear-cell mRCC stratified according to MSKCC risk criteria, nephrectomy, and institution were randomized in 1:1 to receive SU (50 mg qd 4 wks on-2 wks off) or SO (400 mg bid). The calculated sample size was 59/group for α = 0.05, β = 0.10, and a censoring rate of 15%. Results: Of 124 enrolled patients, from Feb. 2010 to Jul. 2012, from 39 institutions, 120 were evaluable (SU, 57 and SO, 63). Patient baseline characteristics in the SU vs SO groups were as follows: favorable risk, 21% vs 22%; presence of stable brain metastasis, 8.8% vs 1.6% and with nephrectomy, 88% vs 89%. Median PFS (mPFS) was 8.7 and 7.0 M in the SU and SO groups, respectively (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.42–1.08; p= 0.095). mPFS was 31.2 and 6.2 M (HR 0.27, 95%CI 0.08–0.90; p = 0.023) in the favorable risk group, 11.9 and 6.5 M (HR 0.31, 95%CI 0.14–0.69; p = 0.035) in patients with T1 or T2 primary tumors, and 11.6 and 7.0 M (HR 0.41, 95%CI 0.36–0.98; p = 0.038) in those without brain metastasis, in the SU and SO groups, respectively. Objective response rates for SU group was 35.3%; SO was 27.8% (p = 0.407). Overall survival was not reached. The most common adverse events (all grade, all cause) were hand-foot syndrome (SU vs SO, 71% vs 86%), hypothyroidism (70% vs 33%), fatigue (57% vs 40%), hypertension (55% vs 44%) and diarrhea (23% vs 38%). Conclusions: The primary endpoint was not achieved, but SU tended to be associated with longer mPFS in all cases. In patients with favorable risk, T1 or T2 primary tumors or in those without brain metastasis, significantly longer mPFS were noticed. Brain metastasis was associated with poorer prognosis even if it was stable at baseline. Clinical trial number: NCT01481870. Clinical trial information: 01481870.

Progression-free survival as a clinical trial endpoint in advanced renal cell carcinoma

2011 ◽  
Vol 18 (0) ◽  
Author(s):  
Sebastien J. Hotte ◽  
G.A. Bjarnason ◽  
D.Y.C. Heng ◽  
M.A.S. Jewett ◽  
A. Kapoor ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Progression Free Survival ◽  
Advanced Renal Cell Carcinoma ◽  
Free Survival ◽  
Clinical Trial Endpoint ◽  
Trial Endpoint

scholarly journals Positive feedback regulation of lncRNA PVT1 and HIF2α contributes to clear cell renal cell carcinoma tumorigenesis and metastasis

Oncogene ◽  
2021 ◽  
Author(s):  
Ming-xiao Zhang ◽  
Li-zhen Zhang ◽  
Liang-min Fu ◽  
Hao-hua Yao ◽  
Lei Tan ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Positive Feedback ◽  
Renal Cell ◽  
Clear Cell ◽  
Biological Significance ◽  
Specific Inhibitor ◽  
Migration And Invasion ◽  
Loss Of Function ◽  
Cell Renal Cell Carcinoma

AbstractLong noncoding RNAs (lncRNAs) have been reported to exert important roles in tumors, including clear cell renal cell carcinoma (ccRCC). PVT1 is an important oncogenic lncRNA which has critical effects on onset and development of various cancers, however, the underlying mechanism of PVT1 functioning in ccRCC remains largely unknown. VHL deficiency-induced HIF2α accumulation is one of the major factors for ccRCC. Here, we identified the potential molecular mechanism of PVT1 in promoting ccRCC development by stabilizing HIF2α. PVT1 was significantly upregulated in ccRCC tissues and high PVT1 expression was associated with poor prognosis of ccRCC patients. Both gain-of-function and loss-of function experiments revealed that PVT1 enhanced ccRCC cells proliferation, migration, and invasion and induced tumor angiogenesis in vitro and in vivo. Mechanistically, PVT1 interacted with HIF2α protein and enhanced its stability by protecting it from ubiquitination-dependent degradation, thereby exerting its biological significance. Meanwhile, HIF2α bound to the enhancer of PVT1 to transactivate its expression. Furthermore, HIF2α specific inhibitor could repress PVT1 expression and its oncogenic functions. Therefore, our study demonstrates that the PVT1/ HIF2α positive feedback loop involves in tumorigenesis and progression of ccRCC, which may be exploited for anticancer therapy.

scholarly journals Low intratumor heterogeneity correlates with increased response to PD-1 blockade in renal cell carcinoma

2020 ◽  
Vol 12 ◽  
pp. 175883592097711
Author(s):  
Xia Ran ◽  
Jinyuan Xiao ◽  
Yi Zhang ◽  
Huajing Teng ◽  
Fang Cheng ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Checkpoint Inhibitors ◽  
Simulated Data ◽  
The Cancer Genome Atlas ◽  
Intratumor Heterogeneity ◽  
Cell Renal Cell Carcinoma ◽  
Immune Activity

Background: Intratumor heterogeneity (ITH) has been shown to be inversely associated with immune infiltration in several cancers including clear cell renal cell carcinoma (ccRCC), but it remains unclear whether ITH is associated with response to immunotherapy (e.g. PD-1 blockade) in ccRCC. Methods: We quantified ITH using mutant-allele tumor heterogeneity, investigated the association of ITH with immune parameters in patients with ccRCC ( n = 336) as well as those with papillary RCC (pRCC, n = 280) from The Cancer Genome Atlas, and validations were conducted in patients with ccRCC from an independent cohort ( n = 152). The relationship between ITH and response to anti-PD-1 immunotherapy was explored in patients with metastatic ccRCC from a clinical trial of anti-PD-1 therapy ( n = 35), and validated in three equal-size simulated data sets ( n = 60) generated by random sampling with replacement based on this clinical trial cohort. Results: In ccRCC, low ITH was associated with better survival, more reductions in tumor burden, and clinical benefit of anti-PD-1 immunotherapy through modulating immune activity involving more neoantigens, elevated expression of HLA class I genes, and higher abundance of dendritic cells. Furthermore, we found that the association between the level of ITH and response to PD-1 blockade was independent of the mutation status of PBRM1 and that integrating both factors performed better than the individual predictors in predicting the benefit of anti-PD-1 immunotherapy in ccRCC patients. In pRCC, increased immune activity was also observed in low- versus high-ITH tumors, including higher neoantigen counts, increased abundance of monocytes, and decreased expression of PD-L1 and PD-L2. Conclusions: ITH may be helpful in the identification of patients who could benefit from PD-1 blockade in ccRCC, and even in pRCC where no genomic metrics has been found to correlate with response to immune checkpoint inhibitors.

scholarly journals Efficacy and Safety of Nivolumab and Ipilimumab for Advanced or Metastatic Renal Cell Carcinoma: A Multicenter Retrospective Cohort Study

2021 ◽  
Vol 28 (2) ◽  
pp. 1402-1411
Author(s):  
Koji Iinuma ◽  
Koji Kameyama ◽  
Kei Kawada ◽  
Shota Fujimoto ◽  
Kimiaki Takagi ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Objective Response ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Predictive Marker ◽  
Efficacy And Safety ◽  
Lymphocyte Ratio

We conducted a multicenter, retrospective study to evaluate the efficacy and safety of combination nivolumab plus ipilimumab (NIVO+IPI) in 35 patients with advanced or metastatic renal cell carcinoma (mRCC). In this study, we focused on patients who received NIVO+IPI and were stratified into intermediate- or poor-risk disease according to the International Metastatic Renal Cell Carcinoma Database Consortium model at five institutions in Japan. The primary endpoint was overall survival (OS). Secondary endpoints were disease control rate (DCR), best overall response (BOR), objective response rate (ORR), and progression-free survival (PFS). In addition, we evaluated the role of inflammatory cell ratios, namely neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), as predictive biomarkers in patients with mRCC. The median follow-up period was 1 year, and the 1-year OS rate was 95.8%. The ORR and DCR were 34.3% and 80.0%, respectively. According to BOR, four patients (11.4%) achieved complete response. According to NLR stratification, the 1-year PFS rates were 82.6% and 23.7% when the NLR was ≤4.6 and >4.6, respectively (p = 0.04). Based on PLR stratification, the 1-year PFS rates were 81.7% and 34.3% when the PLR was ≤188.1 and >188.1, respectively (p = 0.033). Although 71.4% of the patients experienced treatment-related adverse events (TRAEs) with NIVO+IPI, only four patients discontinued NIVO+IPI due to grade 3/4 TRAEs. Patients treated with NIVO+IPI as a first-line therapy for advanced or mRCC achieved relatively better oncological outcomes. Therefore, NIVO+IPI may have potential advantages and may lead to a treatment effect compared to those receiving targeted therapies. In addition, PLR >188.1 may be a useful predictive marker for mRCC patients who received NIVO+IPI.

Objective response and time to progression on sequential treatment with sunitinib and sorafenib in metastatic renal cell carcinoma

2012 ◽  
Vol 29 (5) ◽  
pp. 3321-3324 ◽  
Author(s):  
Tomas Buchler ◽  
Tomas Pavlik ◽  
Zbynek Bortlicek ◽  
Alexandr Poprach ◽  
Rostislav Vyzula ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Objective Response ◽  
Sequential Treatment ◽  
Time To Progression

scholarly journals Association of baseline neutrophil-to-eosinophil ratio with response to nivolumab plus ipilimumab in patients with metastatic renal cell carcinoma

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Matthew D. Tucker ◽  
Landon C. Brown ◽  
Yu-Wei Chen ◽  
Chester Kao ◽  
Nathan Hirshman ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Complete Blood Count ◽  
Objective Response ◽  
Progression Free Survival ◽  
Cancer Center ◽  
Median Baseline ◽  
Treatment Naïve

Abstract Background The identification of biomarkers to select patients with metastatic renal cell carcinoma (mRCC) most likely to respond to combination immunotherapy (IO) is needed. We sought to investigate an association of the baseline neutrophil-to-eosinophil ratio (NER) with outcomes to nivolumab plus ipilimumab for patients with mRCC. Methods We performed a retrospective review of patients with clear cell mRCC treated with nivolumab plus ipilimumab from Vanderbilt-Ingram Cancer Center and Duke Cancer Institute. Patients with prior receipt of immunotherapy and those without available baseline complete blood count with differential were excluded. Patients were divided into groups by the median baseline NER and analyzed for overall survival (OS), progression free survival (PFS), and objective response rate (ORR). Patients were also divided by median baseline neutrophil-to-lymphocyte ratio (NLR) and analyzed for clinical outcome. Further analyses of patients above/below the median NER and NLR were performed in subgroups of IMDC intermediate/poor risk, IMDC favorable risk, and treatment naïve patients. Results A total of 110 patients were included: median age was 61 years and 75% were treatment naïve. The median NER (mNER) at baseline was 26.4. The ORR was 40% for patients with <mNER compared to 21.8% among patients with >mNER (OR 2.39, p = 0.04). The median PFS for patients with <mNER was significantly longer at 8.6 months (mo) compared to 3.2 mo for patients with >mNER (HR 0.50, p < 0.01). Median OS was not reached (NR) for patients with <mNER compared with 27.3 mo for patients with >mNER (HR 0.31, p < 0.01). The median NLR (mNLR) was 3.42. While patients with <mNLR showed improvement in OS (HR 0.42, p = 0.02), PFS and ORR did not differ compared with patients in the >mNLR group. Conclusions A lower baseline NER was associated with improved clinical outcomes (PFS, OS, and ORR) in patients with mRCC treated with nivolumab plus ipilimumab, and prospective validation of the baseline NER as a predictive biomarker for response to immunotherapy-based combinations in mRCC is warranted.

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