Trials In Renal Cell Carcinoma Research Articles

Abstract NG13: Metabolomic adaptations and correlates of survival to immune checkpoint blockade

Abstract NG13: Metabolomic adaptations and correlates of survival to immune checkpoint blockade

FDA pooled analysis of time to treatment discontinuation (TTD) in frontline advanced renal cell carcinoma trials.

5081 Background: Time to treatment discontinuation (TTD) has been proposed as a potential pragmatic real-world data (RWD) endpoint, and was closely correlated with progression-free survival (PFS) in pooled analyses of non-small cell lung cancer (NSCLC) and breast cancer trials across therapeutic classes (Blumenthal, Ann Onc 2019; Gao, SABCS Abstract P5-14-02). Methods: We analyzed data from all randomized patients (pts) in the phase 3 trials submitted to FDA 2016-18 evaluating a combination therapy (Rx) of an immuno-oncology agent and another systemic Rx (IO-X) versus sunitinib (SUN) for treatment-naïve advanced renal cell carcinoma (RCC). Protocols specified treatment until progression, but treatment beyond progression was allowed. TTD was defined as the time from the start of Rx to time of treatment discontinuation of both drugs in combination Rx or SUN. We measured TTD in treatment-defined subgroups (IO-X and SUN) and across all pts, and pt-level correlation (Pearson’s r) between TTD and PFS and between TTD and overall survival (OS). We also determined rates of disparity between TTD and PFS greater than 3 months. Results: Of 3758 pts (IO-X, n=1878; SUN, n=1880), 3190 pts (85%) had a TTD event, and 1899 pts (51%) had a PFS event. Median TTD was longer among pts receiving IO-X than SUN (12.3 versus 8.0 months). Regardless of drug class, more pts had early (TTD shorter than PFS by ≥ 3 months) TTD events than late TTD (13.4% versus 6.4%, overall). We found higher correlation between TTD and PFS in pts receiving SUN ( r = 0.89) than pts receiving IO-X ( r = 0.72). Overall, TTD was more closely associated with PFS ( r = 0.80) than with OS (0.61). Conclusions: Observed correlations of TTD to PFS were stronger compared to the correlation of TTD to OS. This may be expected because OS is farther removed in time from TTD than is PFS. In contrast to TTD in NSCLC, more than twice as many pts in RCC trials had early TTD than late TTD, regardless of Rx group, which may indicate earlier discontinuation with combination Rx due to additive toxicity. Limitations include the censoring of PFS and OS and the post-hoc nature of this analysis. [Table: see text]

PROSPER: Phase III randomized study comparing perioperative nivolumab versus observation in patients with renal cell carcinoma (RCC) undergoing nephrectomy (ECOG-ACRIN EA8143).

TPS5101 Background: There is no standard adjuvant systemic therapy that increases overall survival (OS) over surgery alone for non-metastatic RCC. Anti-PD-1 nivolumab (nivo) improves OS in metastatic RCC and is well tolerated. In mouse models, priming the immune system prior to surgery with anti-PD-1 results in superior OS compared to adjuvant dosing. Remarkable pathologic responses have been seen with neoadjuvant PD-1 in multiple ph 2 studies in bladder, lung and breast cancers. Phase 2 neoadjuvant RCC trials of nivo show preliminary feasibility and safety with no surgical delays. PROSPER RCC seeks to improve clinical outcomes by priming the immune system with neoadjuvant nivo prior to nephrectomy followed by continued immune system engagement with adjuvant blockade in patients (pts) with high risk RCC compared to standard of care surgery alone. Methods: This global, unblinded, phase 3 National Clinical Trials Network study is accruing pts with clinical stage ≥T2 or TanyN+ RCC of any histology planned for radical or partial nephrectomy. Select oligometastatic disease is permitted if the pt can be rendered ‘no evidence of disease’ within 12 weeks of nephrectomy (≤3 metastases; no brain, bone or liver). In the investigational arm, nivo is administered 480mg IV q4 weeks with 1 dose prior to surgery followed by 9 adjuvant doses. The control arm is nephrectomy followed by standard of care surveillance. There is no placebo. Baseline tumor biopsy is required only in the nivo arm but encouraged in both. Randomized pts are stratified by clinical T stage, node positivity, and M stage. 805 pts provide 84.2% power to detect a 14.4% absolute benefit in recurrence-free survival at 5 years assuming the ASSURE historical control of ~56% to 70% (HR = 0.70). The study is powered to evaluate a significant increase in OS (HR 0.67). Critical perioperative therapy considerations such as safety, feasibility, and quality of life metrics are integrated. PROSPER RCC embeds a wealth of translational studies to examine the contribution of the baseline immune milieu and neoadjuvant priming with anti-PD-1 on clinical outcomes. As of February 2020, 396 patients have been enrolled. Clinical trial information: NCT03055013 .

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

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]

PROSPER: Phase III randomized study comparing perioperative nivolumab versus observation in patients with renal cell carcinoma (RCC) undergoing nephrectomy (ECOG-ACRIN EA8143).

TPS765 Background: There is no standard adjuvant systemic therapy that increases overall survival (OS) over surgery alone for non-metastatic RCC. Anti-PD-1 nivolumab (nivo) improves OS in metastatic RCC and is well tolerated. In mouse models, priming the immune system prior to surgery with anti-PD-1 results in superior OS compared to adjuvant dosing. Remarkable pathologic responses have been seen with neoadjuvant PD-1 in multiple ph 2 studies in bladder, lung and breast cancers. Phase 2 neoadjuvant RCC trials of nivo show preliminary feasibility and safety with no surgical delays. PROSPER RCC seeks to improve clinical outcomes by priming the immune system with neoadjuvant nivo prior to nephrectomy followed by continued immune system engagement with adjuvant blockade in patients (pts) with high risk RCC compared to standard of care surgery alone. Methods: This global, unblinded, phase 3 National Clinical Trials Network study is accruing pts with clinical stage ≥T2 or TanyN+ RCC of any histology planned for radical or partial nephrectomy. Select oligometastatic disease is permitted if the pt can be rendered ‘no evidence of disease’ within 12 weeks of nephrectomy (≤3 metastases; no brain, bone or liver). In the investigational arm, nivo is administered 480mg IV q4 weeks with 1 dose prior to surgery followed by 9 adjuvant doses. The control arm is nephrectomy followed by standard of care surveillance. There is no placebo. Baseline tumor biopsy is required only in the nivo arm but encouraged in both. Randomized pts are stratified by clinical T stage, node positivity, and M stage. 805 pts provide 84.2% power to detect a 14.4% absolute benefit in recurrence-free survival at 5 years assuming the ASSURE historical control of ~56% to 70% (HR = 0.70). The study is powered to evaluate a significant increase in OS (HR 0.67). Critical perioperative therapy considerations such as safety, feasibility, and quality of life metrics are integrated. PROSPER RCC embeds a wealth of translational studies to examine the contribution of the baseline immune milieu and neoadjuvant priming with anti-PD-1 on clinical outcomes. As of October 18, 2019, 317 patients have been enrolled. Clinical trial information: NCT03055013.

Factors associated with clinical trial participation for patients with renal cell carcinoma.

670 Background: Clinical trials are critical for the development of new treatment paradigms for renal cell carcinoma (RCC). The primary objective of this study was to characterize the factors associated with clinical trial participation for patients with RCC. The secondary objective was to examine survival outcomes in the clinical trial and control cohorts. Methods: The National Cancer Database (NCDB) was queried for patients with RCC who were coded as having enrolled in a clinical trial. Trial patients were matched in a 1:5 ratio to controls from the same institution based on clinical stage. Sociodemographic variables were compared between the two groups and univariate and multivariate logistic regression models evaluated factors associated with clinical trial participation. Kaplan-Meier product limit estimate was used to compare overall survival (OS) between the groups. Results: From 2004-2015, 681 patients enrolled in clinical trials were included for analysis. The mean age of trial patients was 56.4 compared to 62 in the matched cohort (p<0.0001). More patients in the trial group had a Charlson-Deyo comorbidity score of 0 (81.6% vs. 73.9%, p<0.0001). On multivariate analysis, male patients (OR 1.27; 95%CI 1.06-1.54, p=0.012) and white patients (OR 1.88, 95%CI 1.23-2.87; p=0.003) were more likely to participate in a trial. Having Medicaid (OR 0.42; 95%CI 0.27-0.64; p<0.0001) or Medicare (OR 0.6; 95%CI 0.46-0.77; p<0.0001) was negatively associated with clinical trial participation. Median OS was greater among clinical trial participants than that the control cohort (106.61 vs 87.62 months, p<0.0001). Conclusions: In this contemporary analysis of RCC patients from a national hospital registry database, we found that patient sociodemographic factors remain associated with clinical trial participation and that clinical trial participants experienced superior OS. Further work, both qualitative and quantitative, is necessary to identify clinical and non-clinical barriers to research participation in order to improve the validity of RCC trials.

Tivozanib in renal cell carcinoma: a new approach to previously treated disease.

Targeted therapies have been a mainstay of the renal cell carcinoma (RCC) treatment paradigm for the better part of two decades. Multikinase inhibitors of the vascular endothelial growth factor receptor tyrosine kinases (VEGF-TKIs) comprise nearly all targeted therapies in RCC, having been prospectively tested through large, multi-institutional phase III trials. Tivozanib is a VEGF-TKI with high selectivity for VEGF receptors 1–3. Tivozanib has been under investigation for nearly 15 years, with a robust portfolio of preclinical and clinical data. This review seeks to characterize tivozanib within the context of RCC by highlighting preclinical and early clinical trials alongside the phase III trials in RCC, TIVO-1, and TIVO-3. We also aim to explore further trials of tivozanib, whether in combination with other agents and/or in differing disease settings, while providing insight into the utility of tivozanib as a clinical tool for the management of RCC.

A Plea for Optimizing Selection in Current Adjuvant Immunotherapy Trials for High-risk Nonmetastatic Renal Cell Carcinoma According to Expected Cancer-specific Mortality.

Tyrosine kinase inhibitor-based adjuvant therapy showed no survival benefits for patients with high-risk nonmetastatic renal cell carcinoma (nmRCC). Five randomized immune-oncology checkpoint inhibitor trials are ongoing. We assessed the effect of stage, grade, and histologic type on cancer-specific mortality (CSM) in candidates for 1 of the 4 North American ongoing immune-oncology checkpoint inhibitor trials of high-risk nmRCC. From the Surveillance, Epidemiology, and End Results database (2001-2015), we identified patients who had undergone surgery for nmRCC and had met the inclusion criteria for the PROSPER RCC (nivolumab in treating patients with localized kidney cancer undergoing nephrectomy), CheckMate 914 (a study comparing the combination of nivolumab and ipilimumab versus placebo in participants with localized renal cell carcinoma), KEYNOTE-564 [safety and efficacy study of pembrolizumab (MK-3475) as monotherapy in the adjuvant treatment of renal cell carcinoma post nephrectomy], or IMmotion010 [a study of atezolizumab as adjuvant therapy in participants with renal cell carcinoma (RCC) at high risk of developing metastasis following nephrectomy] trials. Kaplan-Meier and multivariable Cox regression models were used to assess the 10-year CSM rates in the overall cohort according to stage, grade, and histologic characteristics, and in 4 generated random samples according to the eligible patients for each of the 4 trials. Of 116,750 patients who had undergone surgery for nmRCC, 18,559 (15.9%) had fulfilled the inclusion criteria for 1 of the 4 trials. The greatest proportion of higher stage and grade combinations and sarcomatoid histologic features would have qualified for IMmotion010, followed by KEYNOTE-564, CheckMate 914, and PROSPER RCC. Multivariable Cox regression models demonstrated the most unfavorable prognosis for stage N1 grade 3/4 (hazard ratio [HR], 11.5; P< .001), stage T4N0 grade 3/4 (HR, 9.8; P< .001), and sarcomatoid histologic features (HR, 5.5; P<.001). Among the 4 random samples, the difference in the qualifying criteria resulted in the greatest versus progressively lower CSM rates in the IMmotion010, KEYNOTE-564, CheckMate 914, and PROSPER RCC trials, respectively (P< .001). Our findings indicate that participation in adjuvant immunotherapy trials should be predominantly encouraged for patients with high-grade stage T3, T4, and N1 and patients with any stage with sarcomatoid pathologic features.

LBA56 - Primary efficacy analysis results from the SORCE trial (RE05): Adjuvant sorafenib for renal cell carcinoma at intermediate or high risk of relapse: An international, randomised double-blind phase III trial led by the MRC CTU at UCL

LBA56 - Primary efficacy analysis results from the SORCE trial (RE05): Adjuvant sorafenib for renal cell carcinoma at intermediate or high risk of relapse: An international, randomised double-blind phase III trial led by the MRC CTU at UCL

Novel Therapeutic Approaches and Targets Currently Under Evaluation for Renal Cell Carcinoma: Waiting for the Revolution.

Management of metastatic renal cell carcinoma has drastically changed in the last few years, witnessing the advent of more and more target therapies and, recently, of immune-checkpoint inhibitors. On the other hand, the adjuvant setting still lacks a clear beneficial treatment. Medical treatment still remains a compelling challenge. A large number of clinical trials is ongoing with the aim to identify new therapeutic approaches to expand the options in our repertoire. Several strategies are under investigation in renal cell carcinoma (RCC). These include new targeted agents and combinations of target therapy and immunotherapy. Programmed death receptor-1 (PD-1), programmed death receptor ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA4) are just part of the intricate network that regulates our immune response to cancer cells. Co-stimulators, such as glucocorticoid-induced TNFR-related protein (GITR) and tumor necrosis factor receptor superfamily, member 4 (OX40), and co-repressors, example.g. T cell immunoglobulin and mucin domain 3 (TIM-3) and lymphocyte-activation gene 3 (LAG-3), also take part. As knowledge of the functioning of the immune system grows, so do these pathways to target with new drugs. This review is an overview of the current state of the clinical research, providing a report of ongoing Phase I, II and III clinical trials for localized and metastatic RCC, including novel target therapies, novel immunotherapy agents and new combinations strategies.

Rates of occult brain metastases in patients (pts) with advanced renal cell carcinoma (RCC): A cohort study from patients treated across 22 clinical trials.

673 Background: National guidelines for RCC management only recommend brain imaging ‘if clinically indicated’; the rate of occult brain metastases is not defined. Early detection of CNS disease has major implications as it typically triggers early intervention with the aim to limit morbidity, including major complications of local progression. In an effort to define the utility of brain screening, we investigated the rate of occult brain metastasis in a large cohort of metastatic RCC pts. Methods: We performed a retrospective review of completed and actively accruing metastatic RCC clinical trials conducted at Memorial Sloan Kettering Cancer Center. Individual charts of pts screening for those studies with mandatory brain imaging at baseline were reviewed to identify subjects harboring occult brain metastases. We collected patient demographics, International Metastatic Database Consortium (IMDC) risk status, sites of metastatic disease, and tumor histology. Patients with neurologic symptoms were excluded. Descriptive statistics were applied to analyze findings across the cohort. Results: A total of 22 clinical trials for metastatic RCC conducted from 2004-2017 required brain imaging at baseline, and a total of 535 pts were screened in this context. A total of 25/535 pts were found to have occult brain metastasis (4.67%), which was multi-focal in 10/25 (40%) and sub-cm in 15/25 (60%). For these 25 pts, the mean age at diagnosis was 56 years (38-77), and IMDC risk score at enrollment was: 1/24 favorable (4%), 21/24 intermediate (88%), and 2/24 poor-risk (8%) patients. 18/25 patients presented with de novo metastatic disease; 13/25 had received prior therapies; and 24/25 patients (96%) had &gt; 2 additional non-CNS sites of metastatic disease at time of screening. 21/23 pts and 2/23 pts were then treated with radiation and surgical resection, respectively. Conclusions: This retrospective cohort study shows a 5% rate of occult CNS disease in asymptomatic patients with advanced RCC. These findings can inform current screening guidelines for full disease assessment in metastatic RCC patients.

PROSPER: A phase III randomized study comparing perioperative nivolumab (nivo) versus observation in patients with localized renal cell carcinoma (RCC) undergoing nephrectomy (ECOG-ACRIN 8143).

TPS684 Background: The anti-PD-1 antibody nivo improves overall survival in metastatic RCC and is well tolerated. There is no standard adjuvant systemic therapy that increases overall survival (OS) over surgery alone for non-metastatic RCC. Priming the immune system prior to surgery with anti-PD-1 has shown an OS benefit compared to a pure adjuvant approach in mouse solid tumor models. The PROSPER RCC trial aims to improve clinical outcomes by priming the immune system prior to nephrectomy with neoadjuvant nivo and continued engagement with adjuvant blockade in patients with high risk M0 RCC compared to surgery alone. Methods: This global, unblinded, phase 3 National Clinical Trials Network study is currently accruing patients with clinical stage ≥T2 or node positive M0 RCC of any histology. Tumor biopsy prior to randomization is mandatory to ensure RCC and permits in depth correlative science. The investigational arm will receive two doses of nivo 240mg prior to surgery followed by adjuvant nivo for 9 months (q2 wks x 3 mo followed by 480mg q4 wks x 6 mo). The control arm will undergo standard nephrectomy followed by observation. Randomized patients are stratified by clinical T stage, node positivity, and histology. To enhance accrual and patient quality of life, key upcoming amendments are being instituted. These include biopsy only in the nivo arm, allowance of oligometastatic disease and bilateral renal masses that can be fully resected/ablated, and change of nivo dosing to q4 wks (1 neoadj; 9 adj). With accrual of 766 patients, there is 84.2% power to detect a 14.4% absolute benefit in recurrence-free survival (RFS) at 5 years assuming the ASSURE historical control of ~56% to 70% (HR = 0.70). The study is also powered to evaluate a significant increase in overall survival (HR 0.67). Safety, feasibility, and quality of life endpoints critical to adjuvant therapy considerations are incorporated. PROSPER RCC embeds a wealth of translational work aimed at investigating the impact of the baseline immune milieu, the changes induced by neoadjuvant anti-PD-1 priming, and how both correlate with clinical outcomes. Clinical trial information: NCT03055013.

Hypoxia-inducible factor 2α: a novel target in gliomas.

Hypoxia is an important contributor to aggressive behavior and resistance mechanisms in glioblastoma. Upregulation of hypoxia inducible transcription factors (HIFs) is the primary adaptive cellular response to a hypoxic environment. While HIF1α has been widely studied in cancer, HIF2α offers a potentially more specific and appealing target in glioblastoma given expression in glioma stem cells and not normal neural progenitors, activation in states of chronic hypoxia and expression that correlates with glioma patient survival. A first-in-class HIF2α inhibitor, PT2385, is in clinical trials for renal cell carcinoma, and provides the first opportunity to therapeutically target this important pathway in glioma biology.

Comparative analysis for renal stereotactic body radiotherapy using Cyberknife, VMAT and proton therapy based treatment planning.

PurposeWe conducted this dosimetric analysis to evaluate the feasibility of a multi‐center stereotactic body radiation therapy (SBRT) trial for renal cell carcinoma (RCC) using different SBRT platforms.Materials/methodsThe computed tomography (CT) simulation images of 10 patients with unilateral RCC previously treated on a Phase 1 trial at Institution 1 were anonymized and shared with Institution 2 after IRB approval. Treatment planning was generated through five different platforms aiming a total dose of 48 Gy in three fractions. These platforms included: Cyberknife and volumetric modulated arc therapy (VMAT) at institution 1, and Cyberknife, VMAT, and pencil beam scanning (PBS) Proton Therapy at institution 2. Dose constraints were based on the Phase 1 approved trial.ResultsCompared to Cyberknife, VMAT and PBS plans provided overall an equivalent or superior coverage to the target volume, while limiting dose to the remaining kidney, contralateral kidney, liver, spinal cord, and bowel.ConclusionThis dosimetric study supports the feasibility of a multi‐center trial for renal SBRT using PBS, VMAT and Cyberknife.

Simultaneous monitoring of pazopanib and its metabolites by UPLC–MS/MS

Pazopanib is a multi-targeted tyrosine kinase inhibitor (TKI) approved as first-line treatment for patients with advanced renal cell carcinoma (RCC) and as second-line treatment for patients with advanced soft tissue sarcoma (STS) previously treated with chemotherapy. The most common adverse events, observed during the RCC and STS trials, were gastrointestinal disorders, hypertension, fatigue, elevated ALAT and ASAT, but the molecular mechanisms explaining pazopanib toxicity remain unclear. Therapeutic activity is considered to be mainly dependent on pazopanib exposure as the primary metabolites are inactive or display low plasma concentrations, but metabolites may be involved in toxicity as relationships between metabolite profiles and toxicity have not been evaluated.We report here, for the first time, the validation of a method for the simultaneous quantification of pazopanib and semi-quantification of its metabolites (relative determination). As there are no standards available, pazopanib metabolites were generated with human liver microsomes (HLM) to provide controls in the development of an UPLC–MS/MS method for monitoring both pazopanib and metabolites. The optimised method was validated for specificity, linearity, sensitivity, precision, accuracy, matrix effect and stability. The coefficient of variation (CV%) for intra-day and inter-day precision varied from 2.1% to 7.9% and 5.6% to 13.1% respectively. The biases varied from −12% to 2.3% (intra-day) and 3.8% to 13.1% (inter-day) for accuracy evaluation. Intra-day and inter-day precision CV were respectively 20.1% and 19.6% and accuracy biases were between 20.7% (intra-day) and 3.8% (inter-day) at the limit of quantification. The recoveries from matrix samples spiked with pazopanib were respectively 102.6 ± 12.9% and 102.5 ± 1.2% at low and high levels of calibration range. No matrix effect was evidenced as demonstrated by the normalised matrix factor values: 1.3 ± 0.1 and 1.2 ± 0.2 respectively measured at low and high part of calibration range. A good stability of pazopanib was observed during short term, long term and in process storage conditions and after three freeze/thaw cycles.The method was applied to clinical samples from three patients treated with pazopanib to establish the metabolite profiles (semi-quantitative data) during treatment. The assessment of metabolite profiles could be useful to improve our understanding of the occurrence of adverse events and to improve pazopanib pharmacokinetic-pharmacodynamic relationships.

Surrogate end points for overall survival in trials of PD-(L)1 inhibitors for urinary cancers: a systematic review.

Numerous trials for PD-(L)1 inhibitors in the management of advanced urinary cancers (urothelial carcinoma and renal cell carcinoma) were published recently. It is not known exactly what should be the optimal surrogate end point for overall survival (OS) in this context. PubMed database and ASCO meeting library were searched till August 2017. Eligible studies included prospective clinical studies evaluating PD-(L)1 inhibitors for the management of advanced urothelial carcinoma or renal cell carcinoma. The review author extracted relevant data on the characteristics of participants and the outcomes of the different studies. In order to conduct a proper correlation analysis, normality testing using Shapiro-Wilk test was first used. Based on the result of the normality testing, either Pearson's product-moment correlation or Spearman's rank correlation was used. Thirteen trials (nine urothelial carcinoma and four renal cell carcinoma trials) with 2792 participants were included. The correlation of overall response rate with median OS was very weak to weak (for urothelial carcinoma: r= -0.120, n=9, p=0.758; for renal cell carcinoma: r= -0.397, n=6, p=0.436). Likewise, the correlation of progression-free survival with median OS was very weak to weak (for urothelial carcinoma: r= -0.024, n=8, p=0.955; for renal cell carcinoma: r=0.394, n=6, p=0.440). On the other hand, 1-year survival rate may be a better surrogate end point for median OS (for urothelial carcinoma: r=0.806, n=8, p=0.016; for renal cell carcinoma: r=0.941, n=6, p=0.005). RECIST-defined overall response rate and progression-free survival are not reliable surrogate end points for median OS in trials of PD-(L)1 inhibitor therapy for urinary cancers. The use of other surrogate end points (e.g., 1-year survival) in early phase studies may be considered.

The Evolution of Clinical Trials in Renal Cell Carcinoma: A Status Report for 2013-2016 from the ClinicalTrials.gov Website.

Background:We previously published an analysis of clinical trials in renal cell carcinoma (RCC) using the publicly available ClinicalTrials.gov registry. Here we present a 3-year update to understand clinical research current trends in RCC compared to 2013.Methods:The Website’s advanced search function was used to search for RCC trials. The characteristics of the trial were extracted, summarized and compared to 2013 data using Fisher’s exact tests.Results:We locked our search on May 26, 2016 with 165 trials eligible, compared with 169 trials on Sep 25, 2013. There were more phase I and I/II trials in 2016 compared to 2013 (40.8% vs 24.9%, p = 0.05). More clinical trials in 2016 compared to 2013 used immunotherapy (IT) alone or in combination with other drugs (24.2% vs 10.7%, p = 0.001), and the use of targeted therapy alone (TT) declined (32.9% vs 47.9%, p = 0.005). TT+IT combination trials more than doubled (6.7% vs 2.3%, p = 0.07). The number of trials with treatment in (neo)adjuvant settings in 2016 and 2013 were similar (9.7% vs 10.6%, p = 0.77), respectively. Compared to 2013, the number of trials with non-clear cell histology remained low (n = 10). Many more trials were sponsored by the pharmaceutical industry in 2016 vs 2013 (41.5% vs 16.0%, p = <0.001).Conclusion:IT-based and industry sponsored clinical trials significantly increased from 2013 to 2016 with a concomitant drop in TT only trials. The increase in industry-sponsored studies may reflect the rapid uptake of expensive IT drugs. There continues to be a paucity of (neo)adjuvant studies and for non-clear cell histologies.

Transforming the Perioperative Treatment Paradigm in Non-Metastatic RCC-A Possible Path Forward.

In 2017, there is no adjuvant systemic therapy proven to increase overall survival in non-metastatic renal cell carcinoma (RCC). The anti-PD-1 antibody nivolumab improves overall survival in metastatic treatment refractory RCC and is generally tolerable. Mouse solid tumor models have revealed a benefit with a short course of neoadjuvant PD-1 blockade compared to adjuvant therapy. Two ongoing phase 2 studies of perioperative nivolumab in RCC patients have shown preliminary feasibility and safety with no surgical delays or complications. The recently opened PROSPER RCC trial (A Phase 3 RandOmized Study Comparing PERioperative Nivolumab vs. Observation in Patients with Localized Renal Cell Carcinoma Undergoing Nephrectomy; EA8143) will examine if the addition of perioperative nivolumab to radical or partial nephrectomy can improve clinical outcomes in patients with high risk localized and locally advanced RCC. With the goal of increasing cure and recurrence-free survival (RFS) rates in non-metastatic RCC, we are executing a three-pronged, multidisciplinary approach of presurgical priming with nivolumab followed by resection and adjuvant PD-1 blockade. We plan to enroll 766 patients with clinical stage ≥T2 or node positive M0 RCC of any histology in this global, randomized, unblinded, phase 3 National Clinical Trials Network study. The investigational arm will receive two doses of nivolumab 240 mg IV prior to surgery followed by adjuvant nivolumab for 9 months. The control arm will undergo the current standard of care: surgical resection followed by observation. Patients are stratified by clinical T stage, node positivity, and histology. The trial is powered to detect a 14.4% absolute benefit in the primary endpoint of RFS from the ASSURE historical control of 55.8% to 70.2% at 5 years (HR = 0.70). The study is also powered to detect a significant overall survival benefit (HR 0.67). Key safety, feasibility, and quality of life endpoints are incorporated. PROSPER RCC exemplifies team science with a host of planned correlative work to investigate the impact of the baseline immune milieu and changes after neoadjuvant priming on clinical outcomes.

Abstract 4589: Preclinical investigation of SGN-CD70A antibody-drug conjugate in T cell lymphomas

Abstract CD70 is a member of the tumor necrosis factor (TNF) superfamily and aberrantly expressed in several solid tumors and a variety of hematologic malignancies. The CD70 protein is expressed on highly activated lymphocytes (like in T and B cell lymphomas). Since normal lymphocytes do not express much CD70, it is suggested that anti-CD70 antibodies could be a potential treatment for CD70 positive lymphomas. SGN-CD70A is a novel antibody-drug conjugate that combines an anti-CD70 monoclonal antibody with a synthetic DNA cross-linking molecule, pyrrolobenzodiazepine (PBD) dimer. It is currently under phase I clinical trials for renal cell carcinoma, mantle-cell, diffuse large B-cell, and follicular lymphoma. The aim of this study is to investigate the anti-tumor activity of SGN-CD70A in T cell lymphomas. We first examined CD70 expression in 36 cases of mature T or NK cell lymphomas using immunohistochemical (IHC) staining of patient biopsy specimens. The IHC results were reviewed and scored by 2 independent pathologists. We further investigated CD70 expression in Sezary syndrome (SS), mycosis fungoides (MF), and T cell acute lymphoblastic leukemia (T-ALL) cell lines, along with patient-derived T cell lymphoma primary cells and healthy donors’ peripheral blood mononuclear cells (PBMC) by flow cytometry. We next evaluated the anti-tumor activity of SGN-CD70A in cutaneous T cell lymphoma (CTCL) cell lines and patient-derived T cell lymphoma primary cells. Cell lines or primary cells were treated with SGN-CD70A at various concentrations, after which growth inhibition and apoptosis were assessed by CellTiter-Glo Assay, flow cytometry or Caspase-Glo 3/7 Assay, respectively. CD70 negative T-ALL cell lines were treated in parallel as negative controls for CD70 positive CTCL cell lines. Additionally, h00d-1910, an isotype control of the anti-CD70 antibody conjugated to PBD, was used as the negative control for SGN-CD70A. CD70 expression was observed across all subtypes of T cell lymphomas and all CTCL cell lines. In contrast, CD70 is not expressed in PBMC from healthy subjects. We demonstrated that SGN-CD70A potently inhibited cell growth in CD70-positive CTCL lines, but had no significant activity in CD70-negative T-ALL lines. In addition, SGN-CD70A induced more apoptosis and cell death in CTCL cell lines compared with media and h00d-1910 treated controls. Furthermore, we showed that SGN-CD70A inhibited cell proliferation and induced higher caspase 3/7 activity in CD70-expressing patient-derived T cell lymphoma primary cells in a dose-dependent manner, while h00d-1910 treated in parallel had no significant effects. In summary, CD70 is expressed in both nodal and cutaneous T cell lymphomas but not in healthy donors. SGN-CD70A not only shows anti-tumor activity in CTCL cell lines expressing CD70, but also inhibits proliferation and induces apoptosis in patient-derived T cell lymphoma primary cells, indicating it is a promising treatment for T cell lymphomas. Citation Format: Chen-Yen Yang, Linlin Wang, Laura Pincus, Frank McCormick, Ryan Gill, Wei Ai. Preclinical investigation of SGN-CD70A antibody-drug conjugate in T cell lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4589. doi:10.1158/1538-7445.AM2017-4589

Abstract CT143: Pooled analysis of PD-L1 expression across 6 tumor types in the nivolumab clinical program

Abstract Introduction: Programmed death ligand 1 (PD-L1) is a key biomarker for PD-1 checkpoint inhibitors; PD-L1 evaluation is incorporated across the nivolumab clinical trial program. Understanding relative expression of PD-L1 for a specific tumor type is important in evaluating its predictive and prognostic value. In this analysis, we present prevalence data from 13 050 patients across 6 tumor types from 23 nivolumab clinical trials. Methods: PD-L1 expression on tumor cells was evaluated with the Dako PD-L1 IHC 28-8 pharmDx assay in select clinical studies: melanoma (MEL), non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), small-cell lung cancer (SCLC), urothelial cancer (UC), and squamous cell carcinoma of the head and neck (SCCHN). All tumor types included previously treated patients; MEL, NSCLC, and RCC trials also included treatment-naive. PD-L1 IHC staining and interpretation was conducted by reference laboratories. Interpretation was based on a scoring guideline developed for each tumor type, consistent with Dako development standards. Cut-off for data collection was November 23, 2016. Results: Across all tumor types, 93% of samples were evaluable for PD-L1 (Table). PD-L1 expression was evaluated in individual tumor types; proportion of samples with PD-L1 expression ≥1% varied by type (9.0% [SCLC] to 62.8% [MEL]). Proportion of samples at other expression levels also varied, with the highest proportion of ≥50% PD-L1 expression in NSCLC (28.4%). Evaluating the 3 largest nivolumab programs (MEL, NSCLC, and RCC), the profile of PD-L1 expression was significantly different between tumor types (P&amp;lt;0.0001). Conclusion: Prevalence of PD-L1 expression ≥1% and expression levels for screened patients vary significantly by tumor type with minor differences between treatment-naive and overall population. PD-L1 prevalence in nivolumab NSCLC trials is consistent with previously published results, including those with other PD-L1 assays (Aggarwal et al, Ann Oncol 2016;27[s6]). Table 1.PD-L1 expression by tumor type in 23 nivolumab clinical trials evaluated for PD-L1 expressionTumor typeMELNSCLCSCCHNUCRCCSCLCTotal, nNumber of trials, n67133323Patients with PD-L1 tests, n40525241309685204571813 050Treatment-naive3424372600109808248Previously treated62815153096859477184802Total in all trials, %Evaluable PD-L1 tests, % (n)96.6 (3915)91.1 (4777)88.7 (273)92.3 (632)96.0 (1964)79.0 (568)93.0Quantifiable PD-L1 in total population analyzed, %Mean, %≥1% expression62.861.956.942.724.49.043.0&amp;lt;1% expression37.238.143.157.375.691.057.1Total in all trials, %Non-evaluable PD-L1 tests, % (n)3.4 (137)8.9 (464)11.3 (35)7.7 (53)4.0 (81)20.9 (150)7.0Indeterminate PD-L1 tests, % (n)6.3 (247)0.1 (6)0000.4 (2)2.1 Citation Format: Gabriel Krigsfeld, James Novotny, Emin Oroudjev, Josette Carnahan, Songlan Zuo, Steven D. Averbuch, Virginia Burns. Pooled analysis of PD-L1 expression across 6 tumor types in the nivolumab clinical program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT143. doi:10.1158/1538-7445.AM2017-CT143