Craig Norton

Third-line Targeted Therapy in Metastatic Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium

BACKGROUND The use of third-line targeted therapy (TTT) in metastatic renal cell carcinoma (mRCC) is not well characterized and varies due to the lack of robust data to guide treatment decisions. This study examined the use of third-line therapy in a large international population. OBJECTIVE To evaluate the use and efficacy of targeted therapy in a third-line setting. DESIGN, SETTING, AND PARTICIPANTS Twenty-five international cancer centers provided consecutive data on 4824 mRCC patients who were treated with an approved targeted therapy. One thousand and twelve patients (21%) received TTT and were included in the analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Patients were analyzed for overall survival (OS) and progression-free survival using Kaplan-Meier curves, and were evaluated for overall response. Cox regression analyses were used to determine the statistical association between OS and the six factors included in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model. Subgroup analysis was performed on patients stratified by their IMDC prognostic risk status. RESULTS AND LIMITATIONS Everolimus was the most prevalent third-line therapy (27.5%), but sunitinib, sorafenib, pazopanib, temsirolimus, and axitinib were all utilized in over ≥9% of patients. Patients receiving any TTT had an OS of 12.4 mo, a progression-free survival of 3.9 mo, and 61.1% of patients experienced an overall response of stable disease or better. Patients not receiving TTT had an OS of 2.1 mo. Patients with favorable- (7.2%) or intermediate-risk (65.3%) disease had the highest OS with TTT, 29.9 mo and 15.5 mo, respectively, while poor-risk (27.5%) patients survived 5.5 mo. Results are limited by the retrospective nature of the study. CONCLUSIONS TTT remains highly heterogeneous. The IMDC prognostic criteria can be used to stratify third-line patients. TTT use in favorable- and intermediate-risk patients was associated with the greatest OS. PATIENT SUMMARY Patients with favorable- and intermediate-prognostic criteria disease treated with third-line targeted therapy have an associated longer overall survival compared with those with poor risk disease.

Durable clinical benefit in metastatic renal cell carcinoma patients who discontinue PD-1/PD-L1 therapy for immune-related adverse events (irAEs)

mRCC patients who had a clinical response to PD-1/PD-L1 blockade and discontinued treatment due to irAE continued to derive prolonged clinical benefit after treatment was stopped. Current clinical trials are exploring customized approaches to application of PD-1/PD-L1 blockade. The current standard of care for treatment of metastatic renal cell carcinoma (mRCC) patients is PD-1/PD-L1 inhibitors until progression or toxicity. Here, we characterize the clinical outcomes for 19 mRCC patients who experienced an initial clinical response (any degree of tumor shrinkage), but after immune-related adverse events (irAE) discontinued all systemic therapy. Clinical baseline characteristics, outcomes, and survival data were collected. The primary endpoint was time to progression from the date of treatment cessation (TTP). Most patients had clear cell histology and received anti–PD–1/PD-L1 therapy as second-line or later treatment. Median time on PD-1/PD-L1 therapy was 5.5 months (range, 0.7–46.5) and median TTP was 18.4 months (95% CI, 4.7–54.3) per Kaplan–Meier estimation. The irAEs included arthropathies, ophthalmopathies, myositis, pneumonitis, and diarrhea. We demonstrate that 68.4% of patients (n = 13) experienced durable clinical benefit off treatment (TTP of at least 6 months), with 36% (n = 7) of patients remaining off subsequent treatment for over a year after their last dose of anti–PD-1/PD-L1. Three patients with tumor growth found in a follow-up visit, underwent subsequent surgical intervention, and remain off systemic treatment. Nine patients (47.4%) have ongoing irAEs. Our results show that patients who benefitted clinically from anti–PD-1/PD-L1 therapy can experience sustained beneficial responses, not needing further therapies after the initial discontinuation of treatment due to irAEs. Investigation of biomarkers indicating sustained benefit to checkpoint blockers are needed. Cancer Immunol Res; 6(4); 402–8. ©2018 AACR.

Targeted genomic landscape of metastases compared to primary tumours in clear cell metastatic renal cell carcinoma

BackgroundThe genomic landscape of primary clear cell renal cell carcinoma (ccRCC) has been well described. However, little is known about cohort genomic alterations (GA) landscape in ccRCC metastases, or how it compares to primary tumours in aggregate. The genomic landscape of metastases may have biological, clinical, and therapeutic implications.MethodsWe collected targeted next-generation sequencing mutation calls from two independent cohorts and described the metastases GA landscape and descriptively compared it to the GA landscape in primary tumours.ResultsThe cohort 1 (n = 578) consisted of 349 primary tumours and 229 metastases. Overall, the most common mutations in the metastases were VHL (66.8%), PBRM1 (41.87%), and SETD2 (24.7%). TP53 was more frequently mutated in metastases compared to primary tumours (14.85% versus 8.9%; p = 0.031). No other gene had significant difference in the cohort frequency of mutations between the metastases and primary tumours. Mutation burden was not significantly different between the metastases and primary tumours or between metastatic sites. The second cohort (n = 257) consisted of 177 primary tumours and 80 metastases. No differences in frequency of mutations or mutational burden were observed between primaries and metastases.ConclusionsThese data support the theory that ccRCC primary tumours and metastases encompass a uniform distribution of common genomic alterations tested by next-generation sequencing targeted panels. This study does not address variability between matched primary tumours and metastases or the change in genomic alterations over time and after sequential systemic therapies.

Abstract A18: Genomic and neoantigen evolution and resistance to immune checkpoint blockade in metastatic renal cell carcinoma

Blockade of the PD1/PD-L1 T cell immune checkpoint yields responses and survival benefits exceeding mTOR blockade alone in metastatic renal cell carcinoma (mRCC). However, predictors of response to anti-PD1/PD-L1 therapy are mostly unknown, and pathways of acquired resistance to immune checkpoint therapy are poorly understood. In this study, we undertook whole exome sequencing and neoantigen analysis of matched “trios” (primary tumor resection, immune-checkpoint-refractory metastasis, and germline tissue) from 3 patients treated with anti-PD1 or anti-PD-L1 therapy for mRCC. Patients RCC-001 and RC-002 received anti-PD1 therapy after VEGF-targeted therapy and patient RCC-003 received anti-PD-L1 first-line for mRCC. All 3 patients experienced tumor regression on immune checkpoint therapy, with treatment durations of 10 months, 2 years, and 3 months, respectively. Progressive disease samples were sequenced for analysis of genomic mechanisms of treatment resistance. Whole transcriptome sequencing was obtained on primary and metastatic tumors from RCC-003. Nonsynonymous mutation load was moderate in all samples (range: 33-46 primary, 36-67 resistant). Alterations in VHL were seen in RCC-001 and RCC-002 before and after treatment. RCC-003 had a frameshift deletion in the tumor suppressor NF2 and a nonsense mutation in the MHCI antigen-processing protein TAP1 in both primary and refractory tumors. Resistance-associated mutations in RCC-002 included a frameshift deletion in MR1, involved in MHC I antigen presentation, and missense mutations in TJP1, implicated in JAK/STAT signaling, and PIAS2, implicated in STAT2 and PTEN regulation. JAK2 amplifications have been found to upregulate PD-L1 expression (Green et al. 2010, Blood), and PTEN loss mediates resistance to T cell-mediated immmunotherapy in vitro (Peng et al. 2016, Cancer Discovery). None of the primary tumors harbored alterations in microsatellite-instability-associated genes, and loss of β2 microglobulin was not observed in any sample. Despite moderate mutational loads, each sample harbored a sizeable number of neoantigens (range: 24-76 primary, 50-104 resistant). Across the 6 samples, 28 to 69% of nonsynonymous mutations were predicted to yield at least one neoantigen, with one alteration yielding a maximum of 12 unique neoantigens. Up to 60% of neoantigens observed in the primary tumor were not seen in the resistant setting (range: 20.8-59.2%). Whole transcriptome sequencing in RCC-003 showed 18/24 predicted neoantigens were expressed in the primary tumor and 24/50 in the refractory sample. 13 neoantigens were shared between the two samples, while 5 were unique to the pre-treatment tumor. Integrated whole exome and whole transcriptome sequencing with matched germline profiling identified 5 neoantigens in RCC-003 that were found exclusively in the primary tumor (lost in the treatment-resistant tumor). This could represent immune evasion via deletion of immunogenic mutations, cytotoxic killing of immunogenic tumor clones, or intrinsic resistance to immune checkpoint therapy in heterogenous tumors. Ongoing in vitro analysis of reactivity of predicted neoantigens from all 3 samples with patient-derived T cells will further clarify the biological significance these putative tumor antigens. Citation Format: Diana Miao, Guillermo De Velasco, Dennis Adeegbe, Craig Norton, Dylan Martini, Stephanie Mullane, Raphael Moreira, Sabina Signoretti, Kwok-Kin Wong, Toni Choueiri, Eliezer Van Allen. Genomic and neoantigen evolution and resistance to immune checkpoint blockade in metastatic renal cell carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A18.

The clinical presentation, survival outcomes and management of patients with renal cell carcinoma and cardiac metastasis without inferior vena cava involvement: Results from a pooled clinical trial database and systematic review of reported cases

Background Cardiac metastases from renal cell carcinoma (RCC) are uncommon and there are limited data regarding the presentation and outcomes of this population. The objective of this study was to evaluate the characteristics and outcomes of patients with RCC with cardiac metastasis without inferior vena cava (IVC) involvement. Materials and Methods We conducted a pooled retrospective analysis of metastatic RCC patients treated in 4 clinical trials. Additionally, we conducted a systematic review of cases reported in the literature from 1973 to 2015. Patients with cardiac metastases from RCC without IVC involvement were included. Patient and disease characteristics were described. Additionally, treatments, response to therapy, and survival outcomes were summarized. Results Of 1765 metastatic RCC patients in the clinical trials database, 10 had cardiac metastases without IVC involvement. All patients received treatment with targeted therapy. There was 1 observed partial response (10%) and 6 patients showed stable disease (60%). The median progression‐free survival was 6.9 months. The systematic review of reported clinical cases included 39 patients. In these patients, the most common cardiac site of involvement was the right ventricle (51%; n = 20). Patients were treated with medical (28%; n = 11) and/or surgical treatment (49%; n = 19) depending on whether disease was isolated (n = 13) or multifocal (n = 26). Conclusion To our knowledge, this is the first series to report on the presentation and outcomes of patients with cardiac metastasis without IVC involvement in RCC. We highlight that although the frequency of patients with cardiac metastases without IVC involvement is low, these patients have a unique clinical presentation and warrant special multidisciplinary management. Micro‐Abstract Cardiac metastases from renal cell carcinoma (RCC) are uncommon. We conducted a pooled analysis investigating the outcomes of RCC patients with cardiac metastases without inferior vena cava involvement and also a systemic review of reported cases. Our data highlight that these patients have a unique clinical presentation with poor outcomes.

Abstract 3159: Identification of circulating tumor cells from renal cell carcinoma patients by a multi-parameter flow cytometry assay

BACKGROUND: Renal cell carcinoma (RCC) is one of the top ten causes of cancer death in the United States. The last ten years have shown a dramatic increase in the number of available treatment options, however metastatic RCC remains largely incurable. The classes of drugs that have been developed can be divided into agents that target the Vascular Endothelial Growth Factor (VEGF) pathway (Sunitinib, Sorafenib, Pazopanib, Axitinib, Bevacizumab), those that target the mammalian Target of Rapamycin (mTOR) pathway (Everolimus, Temsirolimus) and immune based therapies (IL-2 and PD-1 inhibition). There are currently limited biomarkers to guide clinical decisions, mainly due to the lack of tumor cells for longitudinal molecular analysis. Circulating tumor cells (CTCs) are potential a source of tumor cells that can be identified from a blood draw for serial analysis. CTCs have not been reliably detected in RCC due to the significant heterogeneity and high rate of false positive events in this disease when EpCAM has been used. We sought to identify RCC CTCs with alternative markers, such as carbonic anhydrase IX (CAIX) which is found in greater than 90% of clear cell RCC tumors. METHODS AND RESULTS: To evaluate for the presence and subtypes of CTCs from patients with RCC, we utilized a multi-parametric flow cytometry assay. We evaluated heterogeneity across subpopulations of putative CTCs with Epithelial Cell Adhesion Molecule (EpCAM), Carbonic Anhydrase IX (CAIX), Carbonic Anhydrase XII (CAXII), PAX8, and Cytokeratin (CK). Negative controls for immune and endothelial events were performed with markers for CD45, CD14, CD34, CD11b and CD61. We tested twenty blood samples from patients with RCC at the Dana Farber Cancer Institute and University of Wisconsin Carbone Cancer Center. CTC frequency in RCC ranges from 0-5410 CAIX+/CK+ events with a median of 24.5 putative CTCs/7.5mL of blood. A subset of patients with radiographic progression had a higher number of CTCs with a median of 295.2 CTCs/7.5 mL. A range of 1-231 EpCAM+/CK+ events were identified with a median of 5.5 CTCs/7.5mL. There was low frequency of events being CAIX+/EpCAM+/CK+, with a median of 1 CTC/7.5mL of blood. Assay specificity was dramatically improved through the combination of multiple positive markers with stains for immune and endothelial cells given frequent non-specific staining for cytokeratin in RCC blood samples. CONCLUSIONS: CTCs can be identified in patients with RCC using non-traditional markers. CAIX is a more sensitive marker than EpCAM to identify putative CTCs from patients with RCC. Specificity in the assay is critical given the high frequency of false positive events identified if only CD45 is used as a marker for immune cells. Our investigation is ongoing for further molecular characterization of orthogonal endpoints in identified CTCs. Future directions include longitudinal monitoring of CTCs during treatment with VEGF inhibitors. Citation Format: Joshua A. Desotelle, Chorom Pak, Erika Heninger, Jennifer L. Schehr, Rana R. McKay, Benjamin K. Gibbs, Craig Norton, Toni K. Choueiri, Joshua M. Lang. Identification of circulating tumor cells from renal cell carcinoma patients by a multi-parameter flow cytometry assay. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3159.