Circulating tumor cell (CTC) enumeration in patients (pts) with metastatic genitourinary (mGU) tumors treated in a phase I study of cabozantinib and nivolumab (CaboNivo) +/- ipilimumab (CaboNivoIpi).

4555 Background: CTCs may serve as biomarkers for clinical outcomes in GU tumor pts. We examined the association between baseline CTC enumeration, CTC heterogeneity, CTC morphologic subtypes, and progression-free-survival, overall survival and response to therapy with combination CaboNivo or CaboNivoIpi. Methods: 123 samples from 52 pts with mGU tumors treated with CaboNivo (38 pts) or CaboNivoIpi (14 pts) drawn at Baseline, Cycle (C) 2 Day (D) 1, and C3D1 were processed using the Epic Sciences platform. CTCs were defined as cytokeratin (CK)+, CD45-, distinct morphology, intact nucleus. PD-L1 expression was also assessed. Results: From 07/20/2016-09/01/2018, 52 pts [urothelial carcinoma (UC) N = 33; plasmacytoid N = 1; Clear cell renal cell carcinoma N = 4; bladder adenocarcinoma N = 8; bladder squamous cell carcinoma N = 2; bladder small cell N = 2; renal medullary N = 2] were treated. Median age was 61.5 years (range 20-82); 35 (67%) were male. N = 37 (71%) had visceral involvement, N = 15 (29%) with liver involvement, N = 11 (21%) with bone involvement. CTCs were found in the peripheral blood of 26/40 (65%) pts at baseline. 1/40 pts (bladder adenocarcinoma) had PDL1+ CTCs at Baseline. Median CTC/mL at Baseline, C2D1, C3D1, were not significantly different. CTC counts of > 2 and > 4 at C2D1 were potentially associated with shorter OS (p = 0.071 and p = 0.045 without adjustment for multiple cutoffs for evaluation). PFS results exhibited similar trends. Unsupervised clustering of CTC images identified 5 main CTC subtypes, of which the presence of one was significantly associated with shorter OS (p = 0.0014, not adjusted for multiple testing). Additionally, we observed a trend towards patients with higher CTC heterogeneity at C2D1 having longer OS, when adjusting for the risk associated with CTC enumeration (p = 0.084). Conclusions: CTC were detected in pts with mGU tumors treated with CaboNivo and CaboNivoIpi. CTC values were somewhat but not statistically lower in responders vs. non-responders. On treatment lower CTCs and the absence of aggressive CTC subtypes were associated with better clinical outcomes. Ongoing analyses include single cell genomics, and analysis of T-cell populations. Clinical trial information: NCT02496208.

Download Full-text

Circulating tumor cell (CTC) enumeration in patients (pts) with metastatic genitourinary (mGU) tumors treated in a phase I study of cabozantinib and nivolumab (CaboNivo) +/- ipilimumab (CaboNivoIpi).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.379 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 379-379

Author(s):

Zishuo Hu ◽

Amir Mortazavi ◽

Sumanta K. Pal ◽

Primo Lara ◽

Tina M. Mayer ◽

...

Keyword(s):

Cell Carcinoma ◽

Clinical Outcomes ◽

Progression Free Survival ◽

Medullary Carcinoma ◽

Circulating Tumor Cell ◽

Response To Therapy ◽

Cell Renal Cell Carcinoma ◽

Intact Nucleus ◽

Metastatic Urothelial Carcinoma ◽

Bladder Adenocarcinoma

379 Background: CTCs may serve as biomarkers for clinical outcomes in GU tumor pts. We examined the association between baseline CTC enumeration, change in CTC enumeration post treatment, progression-free-survival, overall survival and response to therapy with combination CaboNivo or CaboNivoIpi. Methods: 128 samples from 52 pts with mGU tumors treated with CaboNivo (38 pts) or CaboNivoIpi (14 pts) were drawn at baseline, cycle (C) 2 Day (D) 1, and C3D1 and processed with Epic Sciences platform. CTCs were defined as cytokeratin (CK)+, CD45-, distinct morphology, intact nucleus. PD-L1 expression was assessed. Results: From 07/20/2016-09/01/2018, 52 pts were treated for metastatic [urothelial carcinoma (UC) N = 33; UC plasmacytoid N = 1; clear cell renal cell carcinoma N = 4; bladder adenocarcinoma (BAC) N = 8; bladder squamous cell carcinoma N = 2; bladder small cell carcinoma N = 2; renal medullary carcinoma N = 2]. Median age was 61.5 years (range 20-82); 35 (67%) were male; N = 37(71%) had visceral involvement, N = 15(29%) had liver involvement, N = 11(21%) had bone involvement. CTCs were found in the peripheral blood of 39 (75%) pts, 1 pt (BAC) had PDL1+ CTCs at baseline. Median CTC/mL at C1D1, C2D1, C3D1, were 0.5 (0-357.1), 0.4 (0-71.8), and 0.75 (0-18), respectively. Median (lower and upper quartile) CTCs in pts with complete or partial responses (responders) vs stable or progressive disease (non-responders) were: 0.0 (0 to 5.40) vs 0.7 (0 to 2.5) at baseline; -0.35 (-3.65 to 0) vs 0 (-2 to 1.7) change from baseline to C2D1; and 0 (-5.4 to 0.5) vs 0 (-0.9 to 0.65) change from baseline to C3D1 (all p > 0.15). CTC counts of > 2 and > 4 at C2D1 were potentially associated with shorter OS (p = 0.071 and p = 0.045 without adjustment for multiple cutoffs for evaluation). PFS results exhibited similar trends. Conclusions: CTC were detected in pts with mGU tumors treated with CaboNivo and CaboNivoIpi. CTC values were lower in responders than in non-responders. On treatment lower CTCs were associated with better clinical outcomes. Ongoing analyses with the CTCs include cell morphology and heterogeneity, single cell genomics, and T-cell populations.

Download Full-text

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

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.641 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 641-641 ◽

Cited By ~ 1

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]

Download Full-text

Linking Gene Mutations to Clinical Outcomes and Response to Therapy in Clear-cell Renal Cell Carcinoma: Ready for Prime Time?

European Urology ◽

10.1016/j.eururo.2016.10.034 ◽

2017 ◽

Vol 71 (3) ◽

pp. 415-416 ◽

Cited By ~ 1

Author(s):

Pavlos Msaouel ◽

Gabriel G. Malouf ◽

Nizar M. Tannir

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Clinical Outcomes ◽

Renal Cell ◽

Clear Cell ◽

Gene Mutations ◽

Response To Therapy ◽

Prime Time ◽

Cell Renal Cell Carcinoma

Download Full-text

Cabozantinib for the Management of Metastatic Clear Cell Renal Cell Carcinoma

Journal of Kidney Cancer and VHL ◽

10.15586/jkcvhl.2018.109 ◽

2018 ◽

Vol 5 (4) ◽

pp. 1-5 ◽

Cited By ~ 9

Author(s):

Sharon Del Vecchio ◽

Robert J Ellis

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Kinase Inhibitor ◽

Progression Free Survival ◽

Current Treatment ◽

Phase Iii ◽

Solid Organ ◽

Cell Renal Cell Carcinoma ◽

Randomised Controlled

Cabozantinib is a multi-tyrosine kinase inhibitor used for the treatment of various solid-organ tumours. It was recently approved as a first- and second-line therapeutic for the management of advanced/metastatic renal cell carcinoma based on the results of two randomised controlled trials. The phase III METEOR trial compared cabozantinib against everolimus as a second- or greater line therapy and found benefits in progression-free and overall survival, and the phase II CABOSUN trial compared cabozantinib against sunitinib as a first-line therapeutic and found benefits in terms of progression-free survival. This review briefly summarises how cabozantinib fits into current treatment paradigms for the management of advanced renal cell carcinoma.

Download Full-text

NPM1 mutations define a specific subgroup of MDS and MDS/MPN patients with favorable outcomes with intensive chemotherapy

Blood Advances ◽

10.1182/bloodadvances.2018026989 ◽

2019 ◽

Vol 3 (6) ◽

pp. 922-933 ◽

Cited By ~ 17

Author(s):

Guillermo Montalban-Bravo ◽

Rashmi Kanagal-Shamanna ◽

Koji Sasaki ◽

Keyur Patel ◽

Irene Ganan-Gomez ◽

...

Keyword(s):

Clinical Outcomes ◽

Myeloproliferative Neoplasm ◽

Normal Karyotype ◽

Progression Free Survival ◽

Disease Status ◽

Response To Therapy ◽

Intensive Chemotherapy ◽

Clinicopathologic Characteristics ◽

Mutation Burden ◽

The Impact

Abstract Nucleophosmin (NPM1) mutations are common in acute myeloid leukemia and are associated with high remission rates and prolonged survival with intensive chemotherapy. NPM1 mutations are rare in myelodysplastic syndromes (MDS) or myelodysplastic/myeloproliferative neoplasm (MDS/MPN), and the clinical outcomes of these patients, when treated with intensive chemotherapy, are unknown. We retrospectively evaluated the clinicopathologic characteristics and the impact of therapy in 31 patients with MDS or MDS/MPN and NPM1 mutations. Next-generation sequencing was performed at diagnosis in 22 patients. Median age was 62 years (range, 19-86). Twenty-four patients (77%) had normal karyotype, and all had multilineage dysplasia. Most patients could be classified as MDS with excess blasts (19/31, 61%). NPM1 mutations were detected at a median allele frequency of 0.38 (range, 0.09-0.49). Mutation burden did not correlate with bone marrow blast frequency, and its clearance seemed to be associated with decreased morphologic dysplasia. Ten of the 31 patients (32%) received cytotoxic chemotherapy, 20 (65%) hypomethylating agents, and 1 (4%) lenalidomide. Sequential sequencing was available in 16 (52%) patients, and mutation burden correlated with disease status and response to therapy. Patients treated with chemotherapy had higher complete response rates (90% vs 28%, P = .004), longer median progression-free survival (not reached vs 7.5 months, P = .023), and overall survival (not reached vs 16 months, P = .047). Intensive chemotherapy and allogeneic stem cell transplantation (SCT) may be associated with improved clinical outcomes in patients with NPM1-mutated MDS or MDS/MPN who are candidates for this form of therapy.

Download Full-text

NOVEL PLASMA GLYCOPROTEIN BIOMARKERS PREDICT PROGRESSION-FREE SURVIVAL IN SURGICALLY RESECTED CLEAR CELL RENAL CELL CARCINOMA

10.1101/2022.01.11.21268517 ◽

2022 ◽

Author(s):

Daniel Serie ◽

Amanda A Myers ◽

Daniela A Haehn ◽

Alexander Parker ◽

Essa Bajalia ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Differential Expression ◽

Renal Cell ◽

Clear Cell ◽

Progression Free Survival ◽

P Value ◽

Cell Renal Cell Carcinoma ◽

Free Survival ◽

Kaplan Meier

Introduction: Limited data exists on utilization of protein post-translational modifications as biomarkers for clear cell renal cell carcinoma (ccRCC). We employed high-throughput glycoproteomics to evaluate differential expression of glycoprotein-isoforms as novel markers for ccRCC progression-free survival (PFS). Methods: Plasma samples were obtained from 77 patients treated surgically for ccRCC. Glycoproteomic analyses were carried out after liquid chromatography tandem mass spectrometry. Age-adjusted Cox proportional hazard models were constructed to evaluate PFS. Optimized Harrells c-index was employed to dichotomize the collective for the construction of Kaplan-Meier curves. Results: The average length of follow-up was 3.4 (range: 0.04-9.83) years. Glycoproteomic analysis identified 39 glycopeptides and 14 non-glycosylated peptides that showed statistically significant (false discovery rate p ≤0.05) differential expression associated with PFS. Five of the glycosylated peptides conferred continuous hazard ratio of > 6 (range 6.3-11.6). These included prothrombin A2G2S glycan motif (HR=6.47, P=9.53E-05), immunoglobulin J chain FA2G2S2 motif (HR=10.69, P=0.001), clusterin A2G2 motif (HR=7.38, P=0.002), complement component C8A A2G2S2 motif (HR=11.59, P=0.002), and apolipoprotein M glycopeptide with non-fucosylated and non-sialylated hybrid-type glycan (HR=6.30, P=0.003). Kaplan-Meier curves based on dichotomous expression of these five glycopeptides resulted in hazard ratios of 3.9-10.7, all with p-value < 0.03. Kaplan-Meyer plot using the multivariable model comprising 3 of the markers yielded HR of 11.96 (p <0.0001). Conclusion: Differential glyco-isoform abundance of plasma proteins may be a useful source of biomarkers for the clinical course and prognosis of ccRCC.

Download Full-text

Real-world clinical outcomes with first-line avelumab in locally advanced/metastatic Merkel cell carcinoma in the USA: SPEAR-Merkel

Future Oncology ◽

10.2217/fon-2020-1250 ◽

2021 ◽

Author(s):

Charles Lance Cowey ◽

Frank X Liu ◽

Ruth Kim ◽

Marley Boyd ◽

Nicole Fulcher ◽

...

Keyword(s):

Cell Carcinoma ◽

Clinical Outcomes ◽

Merkel Cell Carcinoma ◽

Real World ◽

Locally Advanced ◽

Progression Free Survival ◽

Response Rates ◽

Merkel Cell ◽

First Line ◽

The Usa

Aim: To assess clinical outcomes in patients with locally advanced (la) or metastatic (m) Merkel cell carcinoma (MCC) initiating first-line (1L) avelumab in a USA community oncology setting. Materials & methods: Adults with laMCC or mMCC initiating 1L avelumab were identified from The US Oncology Network electronic health record database and chart review. Results: Median overall survival and progression-free survival were not reached in laMCC (n = 9) vs 20.2 and 10.0 months in mMCC (n = 19); response rates were similar (66.7% vs 63.2%). Conclusion: This is the first study to show clinical benefit in patients with laMCC receiving 1L avelumab in a US real-world setting. Response rates in patients with mMCC were consistent with pivotal trials.

Download Full-text

Association of the neutrophil to eosinophil ratio with response to immunotherapy-based combinations in metastatic renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.341 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 341-341

Author(s):

Matthew D Tucker ◽

Katy Beckermann ◽

Kristin Kathleen Ancell ◽

Kerry Schaffer ◽

Renee McAlister ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Clinical Outcomes ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Objective Response ◽

Progression Free Survival ◽

Rank Test ◽

Cancer Center ◽

Exact Test

341 Background: Neutrophilia is known to be associated with worse prognosis in metastatic renal cell carcinoma (mRCC); however, less is known about the role of eosinophils in the response to immunotherapy (IO). We investigated the association of the baseline neutrophil to eosinophil ratio (NER) with outcomes to IO-based combination treatment in mRCC. Methods: Patients with mRCC treated with ipilimumab plus nivolumab, pembrolizumab plus axitinib, or avelumab plus axitinib at the Vanderbilt-Ingram Cancer Center were retrospectively identified. Patients on >10mg prednisone and patients with prior IO were excluded. Baseline NER (at time of first IO) and association with progression free survival (PFS), overall survival (OS), and objective response rate (ORR) were investigated. Data cutoff was 9/1/2020. Analysis for PFS and OS was performed using the log-rank test and Mantel-Haenszel method, and analysis of the odds ratio for ORR was performed using Fischer’s exact test. Results: Sixty-one patients were identified: 89% clear cell histology, 74% prior nephrectomy, 69% IMDC intermediate risk, and 72% treatment-naïve. Patients with baseline NER < median (N=31) had improved clinical outcomes compared to patients with baseline NER > median (N=30) (Table). Improvement in PFS by NER was maintained when stratified by anti-PD-1/CTLA-4 and anti-PD(L)-1/VEGF (p= 0.0062 and p= 0.049); however, differences in OS and ORR were no longer significant. The median baseline NER among patients with partial response (PR) was significantly lower at 22.7 (95% CI 18.9-31.1) vs. 51.6 (95% CI 39.5-93.1) among those with progressive disease (PD) (p= 0.0054). For comparison, the median neutrophil to lymphocyte ratio was not significantly different between PR (2.60) and PD (3.84, p= 0.056). Conclusions: Patients with a low baseline NER treated with IO-based combinations had improved clinical outcomes compared to patients with a high baseline NER. Additional investigation of this parameter in larger cohorts is warranted. [Table: see text]

Download Full-text