Search

BACKGROUND: The historical standard of care for locally advanced renal cell carcinoma (RCC) is nephrectomy + active surveillance. Despite a high recurrence rate ( 40% ), adjuvant therapy was previously not included in the standard of care. This review of adjuvant pharmacotherapy reflects conflicting results from multiple trials. OBJECTIVE: The objective of this review is to summarize the efficacy of therapy vs surveillance in resected early-stage intermediate to high-risk renal cell carcinoma. METHODS: We performed a systematic literature search using PubMed, EMBASE, and SCOPUS. Keywords such as “renal cell carcinoma”, “adjuvant therapy” and “nephrectomy” were used. In the literature search, 2,711 studies were identified and screened. RESULTS: We included a total of 21 publications. The most common histology seen in trials was clear cell carcinoma. A variety of interventions were reviewed including immunotherapy, medroxyprogesterone acetate, interferon alfa, and tyrosine kinase inhibitors. Most trials did not demonstrate a benefit in relapse-free survival (RPS) or overall survival (OS). Pembrolizumab demonstrated a significant difference in disease recurrence in the KEYNOTE-564 trial although median data was not reached. Blinded independent reviewers identified a benefit in disease-free survival (DFS) with Sunitinib in the S-TRAC trial. CONCLUSION: There was not a clear benefit in using adjuvant therapy broadly for resected locoregional RCC; however, further investigation should be done in the highest-risk group to elucidate potential benefit.

PURPOSE To determine the value of tumor cell programmed death-ligand 1 (PD-L1) expression as a predictive biomarker of nivolumab monotherapy efficacy in treatment-naive patients with clear cell renal cell carcinoma (ccRCC) and the efficacy of salvage nivolumab/ipilimumab in patients with tumors unresponsive to nivolumab monotherapy. METHODS Eligible patients with treatment-naive ccRCC received nivolumab until progressive disease (PD), toxicity, or completing 96 treatment weeks (part A). Patients with PD before or stable disease at 48 weeks could receive salvage nivolumab/ipilimumab (part B). The primary end point was improvement in 1-year progression-free survival in patients with tumor PD-L1 expression > 20% versus 0%. RESULTS One hundred twenty-three patients were enrolled. The objective response rate (ORR) was 34.1% (95% CI, 25.8 to 43.2). ORR by International Metastatic RCC Database Consortium category was favorable-risk 57.1%, intermediate-risk/poor-risk 25.0%, and by sarcomatoid features 36.4%. The ORR was 26.9%, 50.0%, and 75.0% for patients with the tumor PD-L1 expression of 0, 1-20, or > 20%, respectively (trend test P value = .002). The median duration of response was 27.6 (19.3 to not reached) months, with 26 of 42 responders including 17 of 20 with favorable-risk disease remaining progression-free. The 1-year progression-free survival was 34.6% and 75.0% in the PD-L1 = 0% and > 20% categories, respectively ( P = .050). Ninety-seven patients with PD or prolonged stable disease were potentially eligible for part B, and 35 were enrolled. The ORR for part B was 11.4%. Grade ≥ 3 treatment-related adverse events occurred in 35% of patients on nivolumab and 43% of those on salvage nivolumab/ipilimumab. CONCLUSION Nivolumab monotherapy is active in treatment-naive ccRCC. Although efficacy appears to be less than that of nivolumab/ipilimumab in patients with intermediate-risk/poor-risk disease, favorable-risk patients had notable benefit. Efficacy correlated with tumor PD-L1 status. Salvage nivolumab/ipilimumab was frequently not feasible and of limited benefit.

Background ADXS31-142 is an attenuated Listeria monocytogenes-based immunotherapy targeting prostate-specific antigen (PSA), being evaluated as monotherapy and combined with pembrolizumab for metastatic castration-resistant prostate cancer (mCRPC). Patients and Methods The 2-part phase I/II KEYNOTE-046 study enrolled men with mCRPC who have progressed after 2 or fewer prior systemic treatment regimens in the metastatic setting. In Part A, intravenous ADXS31-142 monotherapy was given every 3 weeks (q3w) to 3 dose-escalation cohorts. In Part B, ADXS31-142 (1 × 109 colony-forming units) plus pembrolizumab (200 mg) was administered intravenously q3w for 3 doses with a fourth pembrolizumab dose 3 weeks later (12-week cycles) for up to 24 months or until progression/toxicity. Endpoints included safety, overall response rate, progression-free survival (PFS), overall survival (OS), and immunogenicity. Results Fifty patients received ADXS31-142 alone (n = 13) or with pembrolizumab (n = 37). Among the 37 RECIST-evaluable patients (n = 8 Part A; n = 29 Part B), there were no objective responses. Median PFS was 2.2 months (95% CI: 0.8-7.4) with monotherapy and 5.4 months (95% CI: 2.3-7.9) with the combination; median OS was 7.8 months (95% CI: 4.4-18.5) and 33.7 months (95% CI: 15.4–not evaluable), respectively. Promising OS benefit was observed in combination-treated patients who had received prior docetaxel (16.0 months, 95% CI: 6.4-34.6; n = 20) and those with visceral metastasis (16.4 months, 95% CI 4.0-not evaluable; n = 11). All patients had ≥1 treatment-related adverse event, mostly grade 1/2 manageable events. No additive toxicity was observed with combination treatment. Conclusions Combining ADXS31-142 with pembrolizumab was safe and well tolerated. The observed OS in mCRPC warrants further testing of this combination. Clinical Trial registration NCT02325557.

Significant strides have been made in the frontline treatment of patients with advanced clear cell renal cell carcinoma (ccRCC). There are multiple standard-of-care doublet regimens consisting of either the combined dual immune checkpoint inhibitors, ipilimumab and nivolumab, or combinations of a vascular endothelial growth factor receptor tyrosine kinase inhibitor and an immune checkpoint inhibitor. Currently, there is an emergence of clinical trials examining triplet combinations. In COSMIC-313, a randomized phase III trial for patients with untreated advanced ccRCC, the triplet combination of ipilimumab, nivolumab, and cabozantinib was compared with a contemporary control arm of ipilimumab and nivolumab. While patients receiving the triplet regimen demonstrated improved progression-free survival, these patients also experienced greater toxicity and the overall survival data are still maturing. In this article, we discuss the role of doublet therapy as standard of care, the current data available for the promise of triplet therapy, the rationale to continue pursuing trials with triplet combinations, and factors for clinicians and patients to consider when choosing among frontline treatments. We present ongoing trials with an adaptive design that may serve as alternative methods for escalating from doublet to triplet regimens in the frontline setting and explore clinical factors and emerging predictive biomarkers (both baseline and dynamic) that may guide future trial design and frontline treatment for patients with advanced ccRCC.

Legends for Supplementary Tables S1-S6

Quartiles for pazopanib steady-state early and late Ctrough

Supplementary Data from Telaglenastat Plus Cabozantinib or Everolimus for Advanced or Metastatic Renal Cell Carcinoma: An Open-Label Phase I Trial

Supplementary Data from Effect of Granulocyte/Macrophage Colony-Stimulating Factor on Circulating CD8+ and CD4+ T-Cell Responses to a Multipeptide Melanoma Vaccine: Outcome of a Multicenter Randomized Trial

Supplementary Table S1. List of antibodies used in reverse phase protein array (RPPA). A table summarizing the antibodies used for RPPA in this study.

Supplemental Figures 1 and 2 (S1. Measurement of autophagic vesicles in PBMC and S2 Massively parallel sequencing and outcome.

Purpose:Dual inhibition of glucose and glutamine metabolism results in synergistic anticancer effects in solid tumor models. Telaglenastat, an investigational, small-molecule, glutaminase inhibitor, exhibits modest single-agent activity in renal cell carcinoma (RCC) patients. This phase Ib trial evaluated telaglenastat plus cabozantinib or everolimus, agents known to impair glucose metabolism in patients with metastatic RCC (mRCC).Patients and Methods:mRCC patients received escalating doses of telaglenastat [400–800 mg per os (p.o.) twice daily] in a 3 + 3 design, plus either everolimus (10 mg daily p.o.; TelaE) or cabozantinib (60 mg daily p.o.; TelaC). Tumor response (RECISTv1.1) was assessed every 8 weeks. Endpoints included safety (primary) and antitumor activity.Results:Twenty-seven patients received TelaE, 13 received TelaC, with median 2 and 3 prior therapies, respectively. Treatment-related adverse events were mostly grades 1 to 2, most common including decreased appetite, anemia, elevated transaminases, and diarrhea with TelaE, and diarrhea, decreased appetite, elevated transaminases, and fatigue with TelaC. One dose-limiting toxicity occurred per cohort: grade 3 pruritic rash with TelaE and thrombocytopenia with TelaC. No maximum tolerated dose (MTD) was reached for either combination, leading to a recommended phase II dose of 800-mg telaglenastat twice daily with standard doses of E or C. TelaE disease control rate (DCR; response rate + stable disease) was 95.2% [20/21, including 1 partial response (PR)] among 21 patients with clear cell histology and 66.7% (2/3) for papillary. TelaC DCR was 100% (12/12) for both histologies [5/10 PRs as best response (3 confirmed) in clear cell].Conclusions:TelaE and TelaC showed encouraging clinical activity and tolerability in heavily pretreated mRCC patients.

Purpose: Sunitinib and sorafenib are used widely in the treatment of renal cell carcinoma (RCC). These agents are associated with a significant incidence of cardiovascular (CV) dysfunction and left ventricular ejection fraction (LVEF) declines, observed largely in the metastatic setting. However, in the adjuvant population, the CV effects of these agents remain unknown. We prospectively defined the incidence of cardiotoxicity among resected, high-risk RCC patients treated with these agents.Experimental Design: Sunitinib, sorafenib, or placebo was administered for up to 12 months in patients with high-risk, resected RCC. LVEF was measured by multigated acquisition (MUGA) scans at standard intervals. Additional CV adverse events were reported according to NCI Common Terminology Criteria for Adverse Events (CTCAE).Results: Among 1,943 patients randomized, 1,599 had at least 1 post-baseline MUGA. Within 6 months, 21 patients (1.3%) experienced a cardiac event, defined as an LVEF decline from baseline that was >15% and below the institutional lower limit of normal. Nine of 513 patients (1.8%) were on sunitinib, 7 of 508 (1.4%) on sorafenib, and 5 of 578 (0.9%) on placebo (P = 0.28 and 0.56 comparing sunitinib and sorafenib to placebo, respectively). With dose interruption or adjustment, 16 of the 21 recovered their LVEF to >50%. The incidence of symptomatic heart failure, arrhythmia, or myocardial ischemia did not differ among groups.Conclusions: In the adjuvant setting, we prospectively define low incidence of cardiotoxicity with sunitinib and sorafenib. These findings may be related to close CV monitoring, or potentially to fewer CV comorbidities in our nonmetastatic population. Clin Cancer Res; 21(18); 4048–54. ©2015 AACR.

Purpose: Granulocyte/macrophage colony-stimulating factor (GM-CSF) administered locally together with vaccines can augment T-cell responses in animal models. Human experience has been limited to small and uncontrolled trials. Thus, a multicenter randomized phase II trial was done to determine whether local administration of GM-CSF augments immunogenicity of a multipeptide vaccine. It also assessed immunogenicity of administration in one versus two vaccine sites.Experimental Design: One hundred twenty-one eligible patients with resected stage IIB to IV melanoma were vaccinated with 12 MHC class Irestricted melanoma peptides to stimulate CD8+ T cells plus a HLA-DRrestricted tetanus helper peptide to stimulate CD4+ T cells, emulsified in incomplete Freund's adjuvant, with or without 110 g GM-CSF. Among 119 evaluable patients, T-cell responses were assessed by IFN- ELIspot assay and tetramer analysis. Clinical outcomes were recorded.Results: CD8+ T-cell response rates to the 12 MHC class Irestricted melanoma peptides (by day 50) with or without GM-CSF were 34 and 73, respectively (P < 0.001), by direct ELIspot assay. Tetramer analyses corroborated the functional data. CD4+ T-cell responses to tetanus helper peptide were higher without GM-CSF (95 versus 77; P = 0.005). There was no significant difference by number of vaccine sites. Three-year overall and disease-free survival estimates (95 confidence interval) were 76 (67-83) and 52 (43-61), respectively, with too few events to assess differences by study group.Conclusions: High immune response rates for this multipeptide vaccine were achieved, but CD8+ and CD4+ T-cell responses were lower when administered with GM-CSF. These data challenge the value of local GM-CSF as a vaccine adjuvant in humans. (Clin Cancer Res 2009;15(22):703644)

Purpose:The use of VEGFR TKIs for the adjuvant treatment of renal cell carcinoma (RCC) remains controversial. We investigated the effects of adjuvant VEGFR TKIs on circulating cytokines in the ECOG-ACRIN 2805 (ASSURE) trial.Experimental Design:Patients with resected high-risk RCC were randomized to sunitinib, sorafenib, or placebo. Plasma from 413 patients was analyzed from post-nephrectomy baseline, 4 weeks, and 6 weeks after treatment initiation. Mixed effects and Cox proportional hazards models were used to test for changes in circulating cytokines and associations between disease-free survival (DFS) and cytokine levels.Results:VEGF and PlGF increased after 4 weeks on sunitinib or sorafenib (P < 0.0001 for both) and returned to baseline at 6 weeks on sunitinib (corresponding to the break in the sunitinib schedule) but not sorafenib (which was administered continuously). sFLT-1 decreased after 4 weeks on sunitinib and 6 weeks on sorafenib (P < 0.0001). sVEGFR-2 decreased after both 4 and 6 weeks of treatment on sunitinib or sorafenib (P < 0.0001). Patients receiving placebo had no significant changes in cytokine levels. CXCL10 was elevated at 4 and 6 weeks on sunitinib and sorafenib but not on placebo. Higher baseline CXCL10 was associated with worse DFS (HR 1.41 per log increase in CXCL10, Bonferroni-adjusted P = 0.003). This remained significant after adjustment for T-stage, Fuhrman grade, and ECOG performance status.Conclusions:Among patients treated with adjuvant VEGFR TKIs for RCC, drug–host interactions mediate changes in circulating cytokines. Elevated baseline CXCL10 was associated with worse DFS. Studies to understand functional consequences of these changes are under way.

Supplementary Figure: Consort diagram of patients participating in cardiac sub study

CCR Translation for the Article from Effect of Granulocyte/Macrophage Colony-Stimulating Factor on Circulating CD8+ and CD4+ T-Cell Responses to a Multipeptide Melanoma Vaccine: Outcome of a Multicenter Randomized Trial

Distribution of baseline KIM-1 values

Purpose:No circulating biomarkers are currently available to identify patients at highest risk of recurrence after nephrectomy for renal cell carcinoma (RCC). Kidney injury molecule-1 (KIM-1) is overexpressed in RCC and its ectodomain circulates in plasma. We investigated whether plasma KIM-1 is a prognostic biomarker in patients with localized RCC after nephrectomy.Experimental Design:The ECOG-ACRIN E2805 (ASSURE) trial evaluated adjuvant sunitinib, sorafenib, or placebo in resected high-risk RCC. KIM-1 levels were measured from banked plasma at trial enrollment 4–12 weeks after nephrectomy. Lognormal accelerated failure time models were used to test for association between KIM-1 and disease-free survival (DFS) as well as overall survival (OS).Results:Plasma from 418 patients was analyzed. Higher post-nephrectomy KIM-1 was associated with worse DFS across all study arms after adjustment for Fuhrman grade, T stage, N stage, and tumor histology [survival time ratio 0.56 for 75th vs. 25th percentile of KIM-1; 95% confidence interval (CI), 0.42–0.73; P < 0.001]. The association between KIM-1 and DFS was stronger among patients with pathologic nodal involvement (Pinteraction = 0.0086). The addition of post-nephrectomy KIM-1 improved the concordance of clinical prognostic models [Stage, Size, Grade, and Necrosis (SSIGN) concordance 0.57 vs. 0.43, P = 0.05; UCLA International Staging System (UISS) concordance 0.60 vs. 0.40, P = 0.0005]. Higher post-nephrectomy KIM-1 was also associated with worse OS after multivariable adjustment (survival time ratio 0.71 for 75th vs. 25th percentile of KIM-1; 95% CI, 0.56–0.91; P < 0.001).Conclusions:Post-nephrectomy plasma KIM-1 is associated with DFS and OS in RCC, and may be a biomarker for microscopic residual disease.

Multivariable analysis of clinical and pathologic variables and their association with overall survival in RCC

Prediction-corrected visual predictive checks of early (A) and late (B) Ctrough in study PROTECT

Supplemental Table 1: Catalog numbers for MSD assays Supplemental Figure 1: Hazard ratio for CXCL10 and DFS by treatment arm Supplemental Figure 2: Assessment of log-linearity for relationship between IP-10 and recurrence risk Supplemental Table 2: Median changes in cytokines at weeks 4 and 6 Supplemental Table 3: Relationship between on-treatment cytokine levels and DFS Supplemental Table 4: Subset analysis for cytokine changes among patients who did not recur Supplemental Table 5: Evaluation for interaction effects between treatment arm and the association between baseline CXCL10 and DFS

Purpose: PROTECT, a phase III, randomized, placebo-controlled study, evaluated pazopanib efficacy and safety in the adjuvant renal cell carcinoma setting. The relationship between pazopanib exposure (Ctrough) and efficacy and safety was evaluated.Patients and Methods: Evaluable steady-state blood trough concentrations were collected from 311 patients at week 3 or 5 (early Ctrough) and 250 patients at week 16 or 20 (late Ctrough). Pazopanib pharmacokinetic (PK) data were analyzed via a population model approach. Relationship between Ctrough or dose intensity and disease-free survival (DFS) was explored via Kaplan–Meier and multivariate analysis. Adverse events (AE) and AE-related treatment discontinuation proportions were summarized by Ctrough quartiles.Results: Most (>90%) patients with early or late Ctrough data started on 600 mg. Mean early and late Ctrough overlapped across dose levels. Patients with higher early Ctrough quartiles achieved longer DFS (adjusted HR, 0.58; 95% confidence interval, 0.42–0.82; P = 0.002). Patients achieving early or late Ctrough >20.5 μg/mL had significantly longer DFS: not estimable (NE) versus 29.5 months, P = 0.006, and NE versus 29.9 months, P = 0.008, respectively. Dose intensity up to week 8 did not correlate with DFS, consistent with population PK model–based simulations showing overlapping pazopanib exposure with 600 and 800 mg doses. The proportion of AE-related treatment discontinuation and grade 3/4 AEs, with the exception of hypertension, was not correlated to Ctrough.Conclusions: In the adjuvant setting, higher pazopanib Ctrough was associated with improved DFS and did not increase treatment discontinuations or grade 3/4 AEs, with the exception of hypertension. Clin Cancer Res; 24(13); 3005–13. ©2018 AACR.See related commentary by Rini, p. 2979

Purpose:Everolimus inhibits the mTOR, activating cytoprotective autophagy. Hydroxychloroquine inhibits autophagy. On the basis of preclinical data demonstrating synergistic cytotoxicity when mTOR inhibitors are combined with an autophagy inhibitor, we launched a clinical trial of combined everolimus and hydroxychloroquine, to determine its safety and activity in patients with clear-cell renal cell carcinoma (ccRCC).Patients and Methods:Three centers conducted a phase I/II trial of everolimus 10 mg daily and hydroxychloroquine in patients with advanced ccRCC. The objectives were to determine the MTD of hydroxychloroquine with daily everolimus, and to estimate the rate of 6-month progression-free survival (PFS) in patients with ccRCC receiving everolimus/hydroxychloroquine after 1–3 prior treatment regimens. Correlative studies to identify patient subpopulations that achieved the most benefit included population pharmacokinetics, measurement of autophagosomes by electron microscopy, and next-generation tumor sequencing.Results:No dose-limiting toxicity was observed in the phase I trial. The recommended phase II dose of hydroxychloroquine 600 mg twice daily with everolimus was identified. Disease control [stable disease + partial response (PR)] occurred in 22 of 33 (67%) evaluable patients. PR was observed in 2 of 33 patients (6%). PFS ≥ 6 months was achieved in 15 of 33 (45%) of patients who achieved disease control.Conclusions:Combined hydroxychloroquine 600 mg twice daily with 10 mg daily everolimus was tolerable. The primary endpoint of >40% 6-month PFS rate was met. Hydroxychloroquine is a tolerable autophagy inhibitor in future RCC or other trials.

Supplementary Tables 1-5, Figures 1-3. Supplemental Table 1: Events per person-year of follow-up Supplemental Table 2: Event rates among patients randomized to sorafenib or sunitinib who started at reduced vs. full dose Supplemental Table 3a. Event rates among patients who did or did not discontinue treatment due to adverse events, and among patients with ECOG PS 0 vs. 1 Supplemental Table 3b: Baseline LVEF and change in LVEF among patients who did or did not discontinue treatment due to adverse events Supplemental Table 4: Relationship among treatment duration, baseline LVEF by MUGA, and probability of an event by any definition Supplemental Table 5: Relationship among treatment duration, baseline LVEF by MUGA, and probability of an event by the definition "Per Protocol Including Other" Supplemental Figure 1: Relationship among baseline LVEF by MUGA, treatment duration, and event status, where event is defined by any of the criteria Supplemental Figure 2: Relationship among baseline LVEF by MUGA, treatment duration, and event status, where event is defined as a decline in LVEF of 16% or more to below the lower limit of normal, or a grade 3 or higher cardiac adverse event Supplemental Figure 3: Algorithm for management of study drug-induced hypertension

List of PROTECT Study investigators

Sensitivity analysis AFT model for DFS with imputation of KIM-1 levels below lower limit of detection (9.1 pg/mL)

Supplementary Figure from Telaglenastat Plus Cabozantinib or Everolimus for Advanced or Metastatic Renal Cell Carcinoma: An Open-Label Phase I Trial

Purpose: The objectives of the study were to evaluate the safety of daily oral PX-866 in combination with twice daily vemurafenib and to identify potential predictive biomarkers for this novel combination.Experimental Design: We conducted a phase I, open-label, dose-escalation study in patients with advanced BRAF V600–mutant solid tumors. PX-866 was administered on a continuous schedule in combination with vemurafenib. Patients underwent a baseline and on-treatment biopsy after 1-week of PX-866 monotherapy for biomarker assessment.Results: Twenty-four patients were enrolled. The most common treatment-related adverse events were gastrointestinal side effects. One dose-limiting toxicity (DLT) of grade 3 rash and one DLT of grade 3 pancreatitis were observed in cohort 2 (PX-866 6 mg daily; vemurafenib 960 mg twice daily) and cohort 3 (PX-866 8 mg daily; vemurafenib 960 mg twice daily), respectively. Of 23 response-evaluable patients, seven had confirmed partial responses (PR), 10 had stable disease, and six had disease progression. Decreases in intratumoral pAKT expression were observed following treatment with PX-866. Patients who achieved PRs had higher rates of PTEN loss by IHC (80% vs. 58%) and pathogenic PTEN mutations and/or deletions (57% vs. 25%). Two patients with durable PRs had an increase in intratumoral CD8+ T-cell infiltration following treatment with PX-866.Conclusions: PX-866 was well tolerated at its maximum tolerated single-agent dose when given in combination with a modified dose of vemurafenib (720 mg twice daily). Response to treatment appeared to be associated with PTEN loss and treatment with PX-866 seemed to increase CD8+ T-cell infiltration in some patients. Clin Cancer Res; 24(1); 22–32. ©2017 AACR.

Purpose: Increased vascularity is a hallmark of renal cell carcinoma (RCC). Microvessel density (MVD) is one measurement of tumor angiogenesis; however, its utility as a biomarker of outcome is unknown. ECOG-ACRIN 2805 (E2805) enrolled 1,943 resected high-risk RCC patients randomized to adjuvant sunitinib, sorafenib, or placebo. We aimed to determine the prognostic and predictive role of MVD in RCC.Experimental Design: We obtained pretreatment primary RCC nephrectomy tissues from 822 patients on E2805 and constructed tissue microarrays. Using quantitative immunofluorescence, we measured tumor MVD as the area of CD34-expressing cells. We determined the association with disease-free survival (DFS), overall survival (OS), treatment arm, and clinicopathologic variables.Results: High MVD (above the median) was associated with prolonged OS for the entire cohort (P = 0.021) and for patients treated with placebo (P = 0.028). The association between high MVD and OS was weaker in patients treated with sunitinib or sorafenib (P = 0.060). MVD was not associated with DFS (P = 1.00). On multivariable analysis, MVD remained independently associated with improved OS (P = 0.013). High MVD correlated with Fuhrman grade 1–2 (P < 0.001), clear cell histology (P < 0.001), and absence of necrosis (P < 0.001) but not with gender, age, sarcomatoid features, lymphovascular invasion, or tumor size.Conclusions: High MVD in resected high-risk RCC patients is an independent prognostic, rather than predictive, biomarker of improved OS. Further studies should assess whether incorporating MVD into clinical models will enhance our ability to predict outcome and if low MVD can be used for selection of high-risk patients for adjuvant therapy trials. Clin Cancer Res; 24(1); 217–23. ©2017 AACR.

Background: The first interim analysis of the KEYNOTE-564 study showed improved disease-free survival with adjuvant pembrolizumab compared with placebo after surgery in patients with clear cell renal cell carcinoma at an increased risk of recurrence. The analysis reported here, with an additional 6 months of follow-up, was designed to assess longer-term efficacy and safety of pembrolizumab versus placebo, as well as additional secondary and exploratory endpoints. Methods: In the multicentre, randomised, double-blind, placebo-controlled, phase 3 KEYNOTE-564 trial, adults aged 18 years or older with clear cell renal cell carcinoma with an increased risk of recurrence were enrolled at 213 hospitals and cancer centres in North America, South America, Europe, Asia, and Australia. Eligible participants had an Eastern Cooperative Oncology Group performance status of 0 or 1, had undergone nephrectomy 12 weeks or less before randomisation, and had not received previous systemic therapy for advanced renal cell carcinoma. Participants were randomly assigned (1:1) via central permuted block randomisation (block size of four) to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for up to 17 cycles. Randomisation was stratified by metastatic disease status (M0 vs M1), and the M0 group was further stratified by ECOG performance status and geographical region. All participants and investigators involved in study treatment administration were masked to the treatment group assignment. The primary endpoint was disease-free survival by investigator assessment in the intention-to-treat population (all participants randomly assigned to a treatment). Safety was assessed in the safety population, comprising all participants who received at least one dose of pembrolizumab or placebo. As the primary endpoint was met at the first interim analysis, updated data are reported without p values. This study is ongoing, but no longer recruiting, and is registered with ClinicalTrials.gov, NCT03142334. Findings: Between June 30, 2017, and Sept 20, 2019, 994 participants were assigned to receive pembrolizumab (n=496) or placebo (n=498). Median follow-up, defined as the time from randomisation to data cutoff (June 14, 2021), was 30·1 months (IQR 25·7–36·7). Disease-free survival was better with pembrolizumab compared with placebo (HR 0·63 [95% CI 0·50–0·80]). Median disease-free survival was not reached in either group. The most common all-cause grade 3–4 adverse events were hypertension (in 14 [3%] of 496 participants) and increased alanine aminotransferase (in 11 [2%]) in the pembrolizumab group, and hypertension (in 13 [3%] of 498 participants) in the placebo group. Serious adverse events attributed to study treatment occurred in 59 (12%) participants in the pembrolizumab group and one (

OBJECTIVES To study the effects of adjuvant therapy in patients with sarcomatoid renal cell carcinoma (sRCC) enrolled in the randomised phase III clinical trial E2805. PATIENTS AND METHODS The original trial (E2805) was a randomised, double-blinded phase III clinical trial comparing outcomes in 1943 patients with RCC accrued between 2006 and 2010 and treated with up to 1 year of adjuvant placebo, sunitinib, or sorafenib. The present study analyses the cohort of patients with sRCC that participated in E2805. RESULTS A total of 171 patients (8.8%) had sarcomatoid features. Of these, 52 patients received sunitinib, 58 received sorafenib, and 61 received placebo. Most patients were pT3-4 (71.1%, 63.7%, and 70.5%, respectively); 17.3%, 19.0%, and 27.9% had pathologically positive lymph nodes; and 59.6%, 62.1%, and 62.3% of the patients were University of California Los Angeles (UCLA) Integrated Staging System (UISS) very-high risk. In 49% of patients with subsequent development of metastatic disease, recurrence occurred in the lung, followed by 30% in the lymph nodes, and 13% in the liver. There was a high local recurrence rate in the renal bed (16%, 29%, and 18%, respectively). The 5-year disease-free survival (DFS) rates were 33.6%, 36.0%, and 27.8%, for sunitinib, sorafenib and placebo, respectively (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.45-1.20 for sunitinib vs placebo, and HR 0.82, 95% CI 0.53-1.28 for sorafenib vs placebo). CONCLUSIONS Adjuvant therapy with sunitinib or sorafenib did not show an improvement in DFS or OS in patients with sRCC.

Chimeric antigen receptor (CAR) T cells have not induced meaningful clinical responses in solid tumors. Loss of T cell stemness, poor expansion capacity, and exhaustion during prolonged tumor antigen exposure are major causes of CAR T cell therapeutic resistance. Single-cell RNA-sequencing analysis of CAR T cells from a first-in-human trial in metastatic prostate cancer identified two independently validated cell states associated with antitumor potency or lack of efficacy. Low expression of PRDM1 , encoding the BLIMP1 transcription factor, defined highly potent TCF7 [encoding T cell factor 1 (TCF1)]–expressing CD8 + CAR T cells, whereas enrichment of HAVCR2 [encoding T cell immunoglobulin and mucin-domain containing-3 (TIM-3)]–expressing CD8 + T cells with elevated PRDM1 was associated with poor outcomes. PRDM1 knockout promoted TCF7 -dependent CAR T cell stemness and proliferation, resulting in marginally enhanced leukemia control in mice. However, in the setting of PRDM1 deficiency, a negative epigenetic feedback program of nuclear factor of activated T cells (NFAT)–driven T cell dysfunction was identified. This program was characterized by compensatory up-regulation of NR4A3 and other genes encoding exhaustion-related transcription factors that hampered T cell effector function in solid tumors. Dual knockout of PRDM1 and NR4A3 skewed CAR T cell phenotypes away from TIM-3 + CD8 + and toward TCF1 + CD8 + to counter exhaustion of tumor-infiltrating CAR T cells and improve antitumor responses, effects that were not achieved with PRDM1 and NR4A3 single knockout alone. These data underscore dual targeting of PRDM1 and NR4A3 as a promising approach to advance adoptive cell immuno-oncotherapy.

Background As use of oral cancer therapies increases, patient adherence has become critical when evaluating the effectiveness of therapy. In a phase III trial for renal cell carcinoma, we: (a) characterized adherence to sorafenib, sunitinib, and/or placebo and (b) identified factors associated with non‐adherence. Methods ECOG‐ACRIN E2805 was a double‐blind, placebo‐controlled, randomized trial comparing adjuvant sorafenib or sunitinib in patients with resected primary renal cell carcinoma at high risk for recurrence. We used patient‐completed pill diaries to measure adherence as the number of pills taken divided by the number of pills prescribed. Log‐binomial regression was used to identify correlates of non‐adherence (, In a randomized clinical trial for renal cell carcinoma, adherence to oral therapy was lower (85%) than adherence to placebo (95%). Adherence was also worse among racial/ethnic minorities, patients experiencing certain toxicities, and high volume enrolling sites, highlighting several challenges to address in clinical practice as oral therapies become increasingly common.

Cancer immunotherapy tools include antibodies, vaccines, cytokines, oncolytic viruses, bispecific molecules, and cellular therapies. This review will focus on adoptive cellular therapy, which involves the isolation of a patient’s own immune cells followed by their ex vivo expansion and reinfusion. The majority of adoptive cellular therapy strategies utilize T cells isolated from tumor or peripheral blood, but may utilize other immune cell subsets. T-cell therapies in the form of tumor-infiltrating lymphocytes, T-cell receptor T cells, and CAR T cells may act as “living drugs” as these infused cells expand, engraft, and persist in vivo, allowing adaptability over time and enabling durable remissions in subsets of patients. Adoptive cellular therapy has been less successful in the management of solid tumors because of poor homing, proliferation, and survival of transferred cells. Strategies are discussed, including expression of transgenes to address these hurdles. Additionally, advances in gene editing using CRISPR/Cas9 and similar technologies are described, which allow for clinically translatable gene-editing strategies to enhance the antitumor activity and to surmount the hostilities advanced by the host and the tumor. Finally, the common toxicities and approaches to mitigate these are reviewed.

Precision medicine approaches for managing patients with metastatic castrate-resistant prostate cancer (mCRPC) are lacking. Non-invasive approaches for molecular monitoring of disease are urgently needed, especially for patients suffering from bone metastases for whom tissue biopsy is challenging. Here we utilized baseline blood samples to identify mCRPC patients most likely to benefit from abiraterone plus prednisone (AAP) or enzalutamide. Baseline blood samples were collected for circulating tumor cell (CTC) enumeration and qPCR-based gene expression analysis from 51 men with mCRPC beginning treatment with abiraterone or enzalutamide. Of 51 patients (median age 68 years [51–82]), 22 received AAP (abiraterone 1000 mg/day plus prednisone 10 mg/day) and 29 received enzalutamide (160 mg/day). The cohort was randomly divided into training (n = 37) and test (n = 14) sets. Baseline clinical variables (Gleason score, PSA, testosterone, and hemoglobin), CTC count, and qPCR-based gene expression data for 141 genes/isoforms in CTC-enriched blood were analyzed with respect to overall survival (OS). Genes with expression most associated with OS included MSLN, ARG2, FGF8, KLK3, ESRP2, NPR3, CCND1, and WNT5A. Using a Cox-elastic net model for our test set, the 8-gene expression signature had a c-index of 0.87 (95% CI [0.80, 0.94]) and was more strongly associated with OS than clinical variables or CTC count alone, or a combination of the three variables. For patients with a low-risk vs. high-risk gene expression signature, median OS was not reached vs. 18 months, respectively (HR 5.32 [1.91–14.80], p = 0.001). For the subset of 41 patients for whom progression-free survival (PFS) data was available, the median PFS for patients with a low-risk vs high-risk gene expression signature was 20 vs. 5 months, respectively (HR 2.95 [1.46–5.98], p = 0.003). If validated in a larger prospective study, this test may predict patients most likely to benefit from second-generation antiandrogen therapy.

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.

Oncogenic drivers in solid tumors include aberrant activation of mesenchymal epithelial transition factor (MET) and AXL.This study investigated the safety and antitumor activity of glesatinib, a multitargeted receptor tyrosine kinase inhibitor that inhibits MET and AXL at clinically relevant doses, in combination with erlotinib or docetaxel.The phase I portion of this open-label, multicenter study included two parallel arms in which ascending doses of oral glesatinib (starting dose 96 mg/mTen dose levels of glesatinib across three glycolate formulations (unmicronized, micronized, or micronized version 2 [V2] tablets) available during the course of the study were investigated in 14 dose-escalation cohorts (n = 126). MTDs of unmicronized glesatinib plus erlotinib or docetaxel, and micronized glesatinib plus erlotinib were not reached. Micronized glesatinib 96 mg/mThe safety profile of glesatinib plus erlotinib or docetaxel was acceptable and there were no PK interactions. MADs of glesatinib 700 mg twice daily (micronized V2) with erlotinib 150 mg once daily or docetaxel 75 mg/mClinicalTrials.gov NCT00975767; 11 September 2009.

Immunotherapy has failed to achieve durable remissions in advanced prostate cancer patients. More potent T-cell–redirecting strategies may be needed to overcome the immunologically exclusive and suppressive tumor microenvironment. Clinical trials are underway, seeking to define the optimal target for T-cell redirection, such as PSMA, PSCA, or STEAP-1, as well as the optimal strategy, with CAR or bispecific antibodies. As results continue to emerge from these trials, understanding differential toxicity and efficacy of these therapies based on their targets and functional modifications will be key to advancing these promising therapies toward clinical practice. This review provides a unique depth and breadth of perspective regarding the diverse immunotherapy strategies currently under clinical investigation for men with advanced prostate cancer.

698 Background: Nivolumab (nivo) monotherapy demonstrated anti-tumor activity in treatment-naïve renal cell carcinoma (RCC) in Part A of HCRN GU16-260 across all IMDC groups and in multiple histologies. Patient tumor samples were collected to characterize the tumor-immune microenvironmental (TME) determinants of effective anti-tumor immunity with nivo. Methods: Eligible patients (with clear cell or non-clear cell histology) underwent tumor biopsy prior to and/or at resistance to nivo monotherapy. Fresh tissue fragments were cryopreserved locally and centrally processed to extract viable single-cells from the RCC TME. Single-cell RNA-sequencing (scRNA-seq) and T cell receptor (TCR)-sequencing (scTCR-seq) was performed on all tumor samples. Gene expression signatures discovered through scRNA-seq were used to interrogate previously published bulk transcriptomic data from the CheckMate-009/010/025 trials of nivo in the treatment-refractory setting. Results: In total, 72,730 viable single-cells (56,900 immune and 15,830 tumor or stromal cells) were sequenced from 17 patients (8 with baseline only, 7 with progression only, and 2 with paired baseline and progression samples) across 7 trial sites. Trajectory inference analysis of tumor-infiltrating T cells revealed a bifurcating trajectory, starting with naïve T cells and ending either in PMCH+ terminally exhausted CD8+ T cells or SLAMF7+ CD8+ T cells. Notably, the SLAMF7+ T cell population expressed high levels of cytotoxic genes (including GZMA, GZMB, GNLY) and markers of tissue residency ( ZNF683/HOBIT and ITGAE/CD103), and had a restricted TCR diversity (normalized Shannon index = 0.57). Among patients with at least 100 sequenced T cells (n = 14), a higher percentage of SLAMF7+ CD8+ T cells (relative to total T cells) was associated with primary resistance (progressive disease [PD] as best response) to nivo (mean percentage in PD [n = 4] patients 32.7%; stable disease [n = 4] patients, 9.1%; complete or partial response [CR/PR; n = 6] patients, 2.2%; p = 0.019 for CR/PR vs PD). A signature derived using genes expressed in the T cell trajectory branch containing the SLAMF7+ CD8+ T cell population was used to interrogate bulk RNA-seq data from 172 pre-treatment tumors from the nivo arms of the CheckMate-009/010/025 trials. The signature score was enriched in patients with PD compared to CR/PR as best response (p = 0.032). Analysis of bulk whole exome sequencing and RNA-seq from patients enrolled in the HCRN GU16-260 is pending. Conclusions: Single-cell transcriptomic analysis uncovered a SLAMF7+ CD8 + T cell population with markers of cytotoxicity and tissue residency that was associated with resistance to nivo monotherapy in RCC. Further, the study highlights that scRNA-seq is a viable scientific strategy for deep correlative analysis in multicenter clinical trials.

42 Background: 18F-DCFPyL imaging was recently approved for initial staging in patients (pts) with prostate cancer and suspected metastasis and for those with biochemical recurrence (BCR). 18F-DCFPyL recently became available at our NCI-Designated Comprehensive Cancer Center comprising 6 teaching hospitals and 2 outpatient facilities. As real-world data on 18F-DCFPyL usage in the US are lacking, our objective was to describe prescription patterns and utilization for 18F-DCFPyL. Methods: We identified 18F-DCFPyL scans performed at our center from 1/1/2022-5/10/2022 and abstracted corresponding clinical data through electronic medical record (EMR) review. Demographic, laboratory, pathological and clinical data and provider-level usage were characterized by review of the EMR and, if necessary and feasible, provider interview. Results: There were 164 18F-DCFPyL scans performed across the study period for 164 unique pts (median age 70 years, 73.8% White, 20.1% Black). Ordering providers belonged to Medical Oncology (54.3%), Radiation Oncology (42.7%), Urology (2.4%), and Nuclear Medicine (1%). The majority of scans were ordered for isolated PSA rise (n=93, 56.7%) and initial staging (n=26, 15.9%), in concordance with FDA-approved indications. Nevertheless, many scans were ordered for alternate indications. Restaging of pts with known refractory or metastatic disease (11.0%), PSA persistence after definitive therapy (8.5%), and PSA rises below the threshold of BCR (4.9%) were common alternate rationales for imaging. A minority of scans had a secondary indication such as RT field planning, distinguishing between two primary cancers, PSA persistence in high-risk disease, possible radioisotope therapy, and, most frequently, clarification of lesions seen on conventional imaging (n = 7). 22 pts were on androgen-deprivation (ADT, n=17) or anti-androgens (AR, n=11) when receiving PSMA imaging, with 5 pts on both; the median testosterone at time of imaging was 18F-DCFPyL has been prescribed in various clinical settings outside of FDA approvals. Around 1/8 were performed with pts on ADT/AR, with testosterone at castrate levels. Findings of uncertain malignant etiology included solitary (7%) and multifocal (2%) rib lesions. These data reveal substantial variability in usage and areas of uncertainty in the interpretation of 18F-DCFPyL imaging in real-world clinical settings, underlining the need for further studies on its potential usefulness in expanded indications.

666 Background: Activation of the GAS6/AXL pathway promotes tumor cell proliferation; high levels of GAS6 and AXL have been associated with drug resistance and decreased survival. Batiraxcept is an ultra-high affinity decoy protein that captures GAS6, preventing it from activating AXL signaling. Serum soluble AXL (sAXL)/GAS6 ratio correlates with response to batiraxcept in advanced ovarian cancer. Batiraxcept in combination with cabozantinib is being evaluated in patients (pts) with metastatic clear cell renal cell carcinoma (ccRCC) in this study. Prior studies of cabozantinib in similar pt populations have shown an overall response rate (ORR) ranging from 15 – 32.5% and progression-free survival (PFS) from 3.7-7.2 months (mo). Methods: Key eligibility criteria include previously treated ccRCC pts, excluding prior cabozantinib. Objectives were to determine the safety of batiraxcept plus cabozantinib 60 mg, the recommended phase 2 dose (RP2D), ORR, PFS, duration of response. Correlative endpoints included assessment of baseline serum sAXL/GAS6 with ORR and PFS. Results: In Phase 1b (P1b), 26 pts received at least one dose of batiraxcept with cabozantinib (16 pts - 15 mg/kg; 10 pts - 20 mg/kg). Median age was 60 (range 40-81), male 85% (n=22), IMDC intermediate/poor risk 77% (n=20). All pts received prior immuno-oncology (IO) therapy, 54% (n=14) also received VEGF-TKI; 85% (n=22) received 1 to 2 prior lines of therapy (range 1-6). Median follow-up time was 11.6 mo (range 3.7-18). The RP2D is 15 mg/kg. Related adverse events (AE) any grade and grade ≥ 3 were 100% and 39% (n=10), respectively. Cabozantinib dose reductions occurred in 54% (n=14). AEs of special interest were grade 1 or 2 infusion related reactions, 27% (n=7). Batiraxcept was discontinued due to disease progression 62% (n=16) or toxicity 12% (n=3). The table shows P1b efficacy, ORR of 42%, median PFS of 9.3 mo, and DCR of 84%. Twenty (77%) pts had high baseline sAXL/GAS6 levels; ORR was 55% (11/20) with mPFS of 9.3 mo, compared to 0% ORR and mPFS 6.4 mo in the low sAXL/GAS6 pts. Conclusions: Batiraxcept was well tolerated when combined with cabozantinib. No new safety signals were noted. Efficacy for the combination is encouraging compared to historical cabozantinib monotherapy data. Higher GAS6 levels were predictive for treatment response. The P2 accrual is complete and efficacy data are maturing. A P3 trial plans to evaluate the efficacy in ccRCC patients who have progressed on IO-based and VEGF-TKI therapies. Clinical trial information: NCT04300140 . [Table: see text]

58 Background: 18F-DCFPyL recently gained FDA approval for the staging of biochemically recurrent prostate cancer (PCa). After 18F-DCFPyL became available at our NCI-Designated Comprehensive Cancer Center, 164 PCa pts underwent imaging by 5/2022. Given its novelty, the clinical utility of 18F-DCFPyL versus conventional imaging (CI) is not well-defined. We evaluated the concordance and treatment impact of 18F-DCFPyL compared to CI in suspected first biochemical recurrence (BCR) and upstaging rates of 18F-DCFPyL in initial staging. Methods: The electronic medical record was queried to identify 18F-DCFPyL scans performed at our center. We selected patients (pts) with PSA recurrence after definitive frontline therapy or those undergoing initial staging. CI was within 3 months of 18F-DCFPyL. Concordance between CI and 18F-DCFPyL was assessed, with probable disease defined through assessments by the radiologist and treating oncologist and the clinical setting. Provider notes were used to capture anticipated treatment plans before and after 18F-DCFPyL. Results: For suspected BCR 30 pts had CI and 6 had two types of CI. The majority (n = 20) were MRIs of the prostate/pelvis. The remainder were nuclear bone scans (n = 4), body CTs (n = 4), 18F-fluciclovine scans (n = 3), FDG-PET (n = 1), and spinal imaging (n = 3). Discordant findings were present for 12/30 patients in shared imaging fields, of which 7 had likely disease captured solely on 18F-DCFPyL, 1 instance of disease missed on 18F-DCFPyL, and 4 instances where findings of uncertain malignant potential on CI were not tracer-avid on 18F-DCFPyL. The missed disease on 18F-DCFPyL was a PIRADS 4 prostate lesion captured on MRI. In this group, 4 cases of pelvic nodal lesions were identified on 18F-DCFPyL and not MRI. 18F-DCFPyL influenced treatment plans in 4/30 cases. Therapy was selected as follows: local salvage radiation (RT) was chosen after rule-out of systemic disease, RT was restricted to the prostate bed after a culprit lesion was found, and observation was chosen (n = 2) after disease was ruled out on PSMA-PET. For initial staging, 15 pts were thought to have prostate-only disease. On 18F-DCFPyL, 3/15 were upstaged to distant metastatic disease and 2/15 were upstaged to pelvic nodal disease. Three pts were thought to have extra-prostatic pelvic disease, of which 1/3 were upstaged to distant metastatic disease on 18F-DCFPyL. Conclusions: In the BCR setting, in which disease is often low volume, 18F-DCFPyL frequently adds valuable guidance. In our cohort 18F-DCFPyL captured additional pelvic nodal disease and helped clarify equivocal imaging, limiting unnecessary treatment. For initial staging, the 33% of pts upstaged is substantial, and further data will show whether subsequent changes in management affect outcomes. Limitations include inability to verify disease histologically and to forecast treatment decisions if PSMA-PET were not available.

604 Background: Treatment with immunotherapy can be associated with prolonged disease control after discontinuation without the need for further anticancer therapy. Toxicity from therapy can also persist after cessation. TFS with and without toxicity can characterize survival time. Significant TFS was reported for CheckMate 067 trial in pts with metastatic melanoma (Regan et al JITC 2021) and CheckMate 214 trial for pts with aRCC (Regan et al CCR 2021), but treatment was often halted for toxicity rather than a pre-defined treatment endpoint. We therefore sought to assess TFS in the HCRN GU16 260 trial, which was designed to reduce toxicity and to cap immunotherapy duration (Atkins et al JCO 2022). Methods: Data were analyzed from 128 patients (pts) with clear-cell aRCC treated with first-line nivolumab (NIVO) monotherapy for up to 2 years. As part of the protocol, salvage nivolumab/ipilimumab (NIVO/IPI) for up to 1 year was provided to eligible patients with disease progression at any point or stable disease at 48 weeks (28% of pts). TFS was defined as the area between Kaplan-Meier curves for time from registration to protocol therapy cessation and for time from registration to subsequent therapy initiation or death, estimated from 36-month (mo) mean times. The time on treatment or off treatment with grade 3+ treatment-related adverse events (TRAEs) was also captured. Results: At 36 mos from enrollment, 68.3% of pts were alive: 96.8% of IMDC favorable-risk (FAV) pts and 56.6% of those with intermediate/poor-risk (I/P), respectively. The 36-mo mean time on protocol therapy was 11.5 mos (16.0 mos for FAV pts and 9.6 mos for I/P pts). The 36-mo mean TFS for the whole population was 9.4 mos. For FAV pts the mean TFS was 12.9 mos, of which TFS with grade 3+ TRAEs was 1.5 mos. For I/P pts, the mean TFS was 8.0 mos, of which TFS with grade 3+ TRAEs was 1.0 mos. At 36 mos, 65.6% of FAV pts and 27.1% of I/P pts were alive and second-line treatment-free. Conclusions: NIVO monotherapy with salvage NIVO/IPI in non-responders is an active treatment approach in treatment-naïve pts with aRCC and results in substantial TFS and toxicity-free TFS. TFS was particularly noted in pts with FAV disease, further supporting the use of an immunotherapy-only regimen in this population. Clinical trial information: NCT03117309 . [Table: see text]