Phase 2 trial of a DNA vaccine (pTVG-HP) and nivolumab in patients with castration-sensitive non-metastatic (M0) prostate cancer.

PURPOSE: We have previously reported that a plasmid DNA vaccine encoding prostatic acid phosphatase (pTVG-HP) had greater clinical activity when given in combination with pembrolizumab to patients with metastatic, castration-resistant prostate cancer. The current trial was conducted to evaluate vaccination with PD-1 blockade, using nivolumab, in patients with early, recurrent (M0) prostate cancer. METHODS: Patients with M0 prostate cancer were treated with pTVG-HP (100 µg administered intradermally) and nivolumab (240 mg intravenous infusion) every 2 weeks for 3 months, and then every 4 weeks for 1 year of total treatment. Patients were then followed for an additional year off treatment. The primary objectives were safety and complete prostate-specific antigen (PSA) response (PSA<0.2 ng/mL). RESULTS: 19 patients were enrolled. No patients met the primary endpoint of complete PSA response; however, 4/19 (21%) patients had a PSA decline >50%. Median PSA doubling times were 5.9 months pretreatment, 25.6 months on-treatment (p=0.001), and 9.0 months in the subsequent year off-treatment. The overall median radiographic progression-free survival was not reached. Grade 3 or 4 events included adrenal insufficiency, fatigue, lymphopenia, and increased amylase/lipase. 9/19 (47%) patients developed immune-related adverse effects (irAE). The development of irAE and increased CXCL9 were associated with increased PSA doubling time. Quantitative NaF PET/CT imaging showed the resolution of subclinical lesions along with the development of new lesions at each time point. CONCLUSIONS: In this population, combining nivolumab with pTVG-HP vaccination was safe, and immunologically active, prolonged the time to disease progression, but did not eradicate disease. Quantitative imaging suggested that additional treatments targeting mechanisms of resistance may be required to eliminate tumors. TRIAL REGISTRATION NUMBER: NCT03600350.

Neutrophil-to-eosinophil ratio as a biomarker for clinical outcomes in advanced stage melanoma patients treated with anti-PD-1 therapy.

Neutrophil-to-lymphocyte ratios (NLR) and eosinophil counts are associated with improved survival in melanoma patients treated with immune checkpoint inhibitors, but no study has investigated neutrophil-to-eosinophil ratios (NER) as a predictive indicator in this population. In this retrospective study evaluating anti-PD-1 treated patients with advanced melanoma, progression-free survival (PFS), overall survival (OS), objective response rates (ORR), and risk of high-grade (grade ≥3) immune-related adverse events (irAEs) were compared between groups defined by median pretreatment NLR and NER as well as median NLR and NER at 1-month post-treatment. Lower baseline NLR and NER were associated with improved OS [HR: 0.504, 95% CI: 0.328-0.773, p = .002 and HR: 0.442, 95% CI: 0.288-0.681, p < .001, respectively] on univariate testing. After accounting for multiple covariates, our multivariate analysis found that lower pretreatment NER was associated with better ORR (by irRECIST) (OR: 2.199, 95% CI: 1.071-4.582, p = .033) and improved OS (HR: 0.480, 95% CI: 0.296-0.777, p = .003). Baseline NLR, 1-month NLR, and 1-month NER were not associated with ORR, PFS, or OS outcomes; but 1-month NER correlated with lower risk of grade ≥3 irAEs (OR: 0.392, 95% CI: 0.165-0.895, p = .029). Our findings suggest baseline NER merits additional investigation as a novel prognostic marker for advanced melanoma patients receiving anti-PD-1-based regimens.

Outcomes of Consolidative Nephrectomy following Primary Immunotherapy in Advanced Renal Cell Carcinoma: A Multicenter Analysis.

BACKGROUND: To evaluate effect and outcomes of combination primary immunotherapy (IO) and nephrectomy for advanced renal cell carcinoma (RCC). METHODS: We conducted a multicenter, retrospective analysis of patients with advanced/metastatic RCC who received IO followed by nephrectomy. Primary outcome was Bifecta (negative surgical margins and no 30-day surgical complications). Secondary outcomes included progression-free survival (PFS) following surgery, reduction in tumor/thrombus size, RENAL score, and clinical/pathologic downstaging. Cox regression multivariable analysis was conducted for predictors of Bifecta and PFS. Kaplan-Meier analysis assessed PFS, comparing Bifecta and non-Bifecta groups. RESULTS: A total of 56 patients were analyzed (median age 63 years; median follow-up 22.5 months). A total of 40 (71.4%) patients were intermediate IMDC risk. Patients were treated with immunotherapy for median duration of 8.1 months. Immunotherapy resulted in reductions in tumor size (P < .001), thrombus size (P = .02), and RENAL score (P < .001); 38 (67.9%) patients were clinically downstaged on imaging (P < .001) and 25 (44.6%) patients were pathologically downstaged following surgery (P < .001). Bifecta was achieved in 38 (67.9%) patients. Predictors for bifecta achievement included decreasing tumor size (HR 1.08, P = .043) and pathological downstaging (HR 2.13, P = .047). Bifecta (HR 5.65, P = .009), pathologic downstaging (HR 5.15, P = .02), and increasing reduction in tumor size (HR 1.2, P = .007) were associated with improved PFS. Bifecta patients demonstrated improved 2-year PFS (84% vs. 71%, P = .019). CONCLUSIONS: Primary immunotherapy reduced tumor/thrombus size and complexity. Pathologically downstaged patients were more likely to achieve bifecta, and these patients displayed improved 2-year PFS. Our study supports further inquiry in the use of CRN following primary immunotherapy for advanced renal cancer.

Pathological Outcomes of Patients With Advanced Renal Cell Carcinoma Who Receive Nephrectomy Following Immunotherapy.

BACKGROUND: Even though cytoreductive nephrectomy (CN) was once the standard of care for patients with advanced renal cell carcinoma (RCC), its role in treatment has not been well analyzed or defined in the era of immunotherapy (IO). MATERIALS AND METHODS: This study analyzed pathological outcomes in patients with advanced or metastatic RCC who received IO prior to CN. This was a multi-institutional, retrospective study of patients with advanced or metastatic RCC. Patients were required to receive IO monotherapy or combination therapy prior to radical or partial CN. The primary endpoint assessed surgical pathologic outcomes, including American Joint Committee on Cancer (AJCC) staging and frequency of downstaging, at the time of surgery. Pathologic outcomes were correlated to clinical variables using a Wald-chi squared test from Cox regression in a multi-variable analysis. Secondary outcomes included objective response rate (ORR) defined by response evaluation criteria in solid tumors (RECIST) version 1.1 and progression-free survival (PFS), which were estimated using the Kaplan-Meier method with reported 95% CIs. RESULTS: Fifty-two patients from 9 sites were included. Most patients were male (65%), 81% had clear cell histology, 11% had sarcomatoid differentiation. Overall, 44% of patients experienced pathologic downstaging, and 13% had a complete pathologic response. The ORR immediately prior to nephrectomy was stable disease in 29% of patients, partial response in 63%, progressive disease in 4%, and 4% unknown. Median follow-up for the entire cohort was 25.3 months and median PFS was 3.5 years (95% CI, 2.1-4.9). CONCLUSIONS: IO-based interventions prior to CN in patients with advanced or metastatic RCC demonstrates efficacy, with a small fraction of patients showing a complete response. Additional prospective studies are warranted to investigate the role of CN in the modern IO-era.

Understanding the Tumor Immune Microenvironment in Renal Cell Carcinoma.

Scientific understanding of how the immune microenvironment interacts with renal cell carcinoma (RCC) has substantially increased over the last decade as a result of research investigations and applying immunotherapies, which modulate how the immune system targets and eliminates RCC tumor cells. Clinically, immune checkpoint inhibitor therapy (ICI) has revolutionized the treatment of advanced clear cell RCC because of improved outcomes compared to targeted molecular therapies. From an immunologic perspective, RCC is particularly interesting because tumors are known to be highly inflamed, but the mechanisms underlying the inflammation of the tumor immune microenvironment are atypical and not well described. While technological advances in gene sequencing and cellular imaging have enabled precise characterization of RCC immune cell phenotypes, multiple theories have been suggested regarding the functional significance of immune infiltration in RCC progression. The purpose of this review is to describe the general concepts of the anti-tumor immune response and to provide a detailed summary of the current understanding of the immune response to RCC tumor development and progression. This article describes immune cell phenotypes that have been reported in the RCC microenvironment and discusses the application of RCC immunophenotyping to predict response to ICI therapy and patient survival.

PARP inhibitors in metastatic prostate cancer.

Poly-ADP ribose polymerase inhibitors (PARPi) are an emerging therapeutic option for the treatment of prostate cancer. Their primary mechanism of action is via induction of synthetic lethality in cells with underlying deficiencies in homologous recombination repair (HRR). In men with metastatic castrate-resistant prostate cancer (mCRPC) and select HRR pathway alterations, PARPi treatment has been shown to induce objective tumor responses as well as improve progression free and overall survival. Presently, there are two PARPi, olaparib and rucaparib, that are FDA approved in the treatment of mCRPC. Ongoing research is focused on identifying which HRR alterations are best suited to predict response to PARPi so that these therapies can be most effectively utilized in the clinic. While resistance to PARPi remains a concern, combination therapies may represent a mechanism to overcome or delay resistance.

Concurrent durvalumab and radiation therapy (DUART) followed by adjuvant durvalumab in patients with localized urothelial cancer of bladder: results from phase II study, BTCRC-GU15-023.

BACKGROUND: Patients with bladder cancer (BC) who are cisplatin ineligible or have unresectable disease have limited treatment options. Previously, we showed targeting programmed death-ligand 1 (PD-L1) with durvalumab (durva) and radiation therapy (RT) combination was safe in BC. We now report results from a phase II study evaluating the toxicity and efficacy of durva and RT in localized BC. METHODS: This is a single-arm, multi-institutional phase II study; N=26. Enrolled patients had pure or mixed urothelial BC (T2-4 N0-2 M0) with unresectable tumors and were unfit for surgery or cisplatin ineligible. Patients received durva concurrently with RT ×7 weeks, followed by adjuvant durva × 1 year. PRIMARY ENDPOINTS: (A) progression-free survival (PFS) at 1 year and (B) disease control rate (DCR) post adjuvant durva. Key secondary endpoints: (A) complete response (CR) post durvaRT (8 weeks), (B) overall survival (OS), (C) PFS and (D) toxicity. Correlative studies included evaluation of baseline tumor and blood (baseline, post durvaRT) for biomarkers. RESULTS: Median follow-up was 27 months. Evaluable patients: 24/26 post durvaRT, 22/26 for DCR post adjuvant durva, all patients for PFS and OS. Post adjuvant durva, DCR was seen in 72.7%, CR of 54.5%. 1-year PFS was 71.5%, median PFS was 21.8 months. 1-year OS was 83.8%, median OS was 30.8 months. CR at 8 weeks post durvaRT was 62.5%. Node positive (N+) patients had similar median PFS and OS. DurvaRT was well tolerated. Grade ≥3 treatment-related adverse events: anemia, high lipase/amylase, immune-nephritis, transaminitis, dyspnea (grade 4-COPD/immune), fatigue, rash, diarrhea and scleritis. No difference in outcome was observed with PD-L1 status of baseline tumor. Patients with CR/PR or SD had an increase in naïve CD4 T cells, a decrease in PD-1+CD4 T cells at baseline and an increase in cytokine-producing CD8 T cells, including interferon gamma (IFNγ) producing cells, in the peripheral blood. CONCLUSION: Durva with RT followed by adjuvant durva was safe with promising efficacy in localized BC patients with comorbidities, including N+ patients. Larger randomized studies, like S1806 and EA8185, are needed to evaluate the efficacy of combining immunotherapy and RT in BC. TRIAL REGISTRATION NUMBER: NCT02891161.

Patterns of Health Portal Use by Regular Portal Users Among Patients With Cancer: Results From the UWCCC Survivorship Program.

PURPOSE: We sought to evaluate the patterns of portal usage among patients with cancer who regularly log in to the portal. These data will inform approaches to facilitate portal use among patients with cancer. PATIENTS AND METHODS: We conducted a retrospective analysis of patient portal usage by patients with cancer at the University of Wisconsin Carbone Cancer Center. Our analysis focuses on patterns of portal use by regular users (≥ 2 portal logins/year, > 3 months) receiving ongoing oncology care between January 1, 2017, and December 31, 2019. Demographics, cancer characteristics, number of oncology visits per month, and portal usage data were extracted. Regular portal users were grouped and compared on the basis of their frequency of use. A linear mixed-effects model was used to determine if the frequency of oncology visits influenced the number of logins. RESULTS: We identified 2076 regular portal users. The median number of portal logins/year was 72 for the entire cohort. Age and race were associated with frequency of portal logins. There was no difference in frequency of portal login on the basis of cancer type or stage. Each additional oncology office visit in a month increased the frequency of portal logins by 3.05 ± 0.11 (SE) within the same month. Messages and test result functionalities were used by 98.7% and 98.9% of the regular users, respectively. Regular users who logged in to portal more frequently used all five studied portal functionalities. CONCLUSION: Patients with cancer who use portals regularly use it more in proximity to an oncology office visit and use multiple available portal functionalities. These findings can direct strategic planning to facilitate portal utilization among those not engaged with this tool.

A clinical-grade liquid biomarker detects neuroendocrine differentiation in prostate cancer.

BackgroundNeuroendocrine prostate cancer (NEPC) is an aggressive subtype, the presence of which changes the prognosis and management of metastatic prostate cancer.MethodsWe performed analytical validation of a Circulating Tumor Cell (CTC) multiplex RNA qPCR assay to identify the limit of quantification (LOQ) in cell lines, synthetic cDNA, and patient samples. We next profiled 116 longitudinal samples from a prospectively collected institutional cohort of 17 patients with metastatic prostate cancer (7 NEPC, 10 adenocarcinoma) as well as 265 samples from 139 patients enrolled in 3 adenocarcinoma phase II trials of androgen receptor signaling inhibitors (ARSIs). We assessed a NEPC liquid biomarker via the presence of neuroendocrine markers and the absence of androgen receptor (AR) target genes.ResultsUsing the analytical validation LOQ, liquid biomarker NEPC detection in the longitudinal cohort had a per-sample sensitivity of 51.35% and a specificity of 91.14%. However, when we incorporated the serial information from multiple liquid biopsies per patient, a unique aspect of this study, the per-patient predictions were 100% accurate, with a receiver-operating-curve (ROC) AUC of 1. In the adenocarcinoma ARSI trials, the presence of neuroendocrine markers, even while AR target gene expression was retained, was a strong negative prognostic factor.ConclusionOur analytically validated CTC biomarker can detect NEPC with high diagnostic accuracy when leveraging serial samples that are only feasible using liquid biopsies. Patients with expression of NE genes while retaining AR-target gene expression may indicate the transition to neuroendocrine differentiation, with clinical characteristics consistent with this phenotype.FundingNIH (DP2 OD030734, 1UH2CA260389, R01CA247479, and P30 CA014520), Department of Defense (PC190039 and PC200334), and Prostate Cancer Foundation (Movember Foundation - PCF Challenge Award).

Supporting Structured Data Capture for Patients With Cancer: An Initiative of the University of Wisconsin Carbone Cancer Center Survivorship Program to Improve Capture of Malignant Diagnosis and Cancer Staging Data.

PURPOSE: Structured data elements within electronic health records are health-related information that can be entered, stored, and extracted in an organized manner at later time points. Tracking outcomes for cancer survivors is also enabled by structured data. We sought to increase structured data capture within oncology practices at multiple sites sharing the same electronic health records. METHODS: Applying engineering approaches and the Plan-Do-Study-Act cycle, we launched dual quality improvement initiatives to ensure that a malignant diagnosis and stage were captured as structured data. Intervention: Close Visit Validation (CVV) requires providers to satisfy certain criteria before closing ambulatory encounters. CVV may be used to track open clinical encounters and chart delinquencies to encourage optimal clinical workflows. We added two cancer-specific required criteria at the time of closing encounters in oncology clinics: (1) the presence of at least one malignant diagnosis on the Problem List and (2) staging all the malignant diagnoses on the Problem List when appropriate. RESULTS: Six months before the CVV implementation, the percentage of encounters with a malignant diagnosis on the Problem List at the time of the encounter was 65%, whereas the percentage of encounters with a staged diagnosis was 32%. Three months after cancer-specific CVV implementation, the percentages were 85% and 75%, respectively. Rates had increased to 90% and 88% more than 2 years after implementation. CONCLUSION: Oncologist performance improved after the implementation of cancer-specific CVV criteria, with persistently high percentages of relevant malignant diagnoses and cancer stage structured data capture 2 years after the intervention.

Management of Metastatic Clear Cell Renal Cell Carcinoma: ASCO Guideline.

PURPOSE: To provide recommendations for the management of patients with metastatic clear cell renal cell carcinoma (ccRCC). METHODS: An Expert Panel conducted a systematic literature review to obtain evidence to guide treatment recommendations. RESULTS: The panel considered peer-reviewed reports published in English. RECOMMENDATIONS: The diagnosis of metastatic ccRCC should be made using tissue biopsy of the primary tumor or a metastatic site with the inclusion of markers and/or stains to support the diagnosis. The International Metastatic RCC Database Consortium risk criteria should be used to inform treatment. Cytoreductive nephrectomy may be offered to select patients with kidney-in-place and favorable- or intermediate-risk disease. For those who have already had a nephrectomy, an initial period of active surveillance may be offered if they are asymptomatic with a low burden of disease. Patients with favorable-risk disease who need systemic therapy may be offered an immune checkpoint inhibitor (ICI) in combination with a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI); patients with intermediate or poor risk should be offered a doublet regimen (no recommendation was provided between ICIs or an ICI in combination with a VEGFR TKI). For select patients, monotherapy with either an ICI or a VEGFR TKI may be offered on the basis of comorbidities. Interleukin-2 remains an option, although selection criteria could not be identified. Recommendations are also provided for second- and subsequent-line therapy as well as the treatment of bone metastases, brain metastases, or the presence of sarcomatoid features. Participation in clinical trials is highly encouraged for patients with metastatic ccRCC.Additional information is available at www.asco.org/genitourinary-cancer-guidelines.

Longitudinal Molecular Profiling of Circulating Tumor Cells in Metastatic Renal Cell Carcinoma.

PURPOSE: Liquid biopsies in metastatic renal cell carcinoma (mRCC) provide a unique approach to understand the molecular basis of treatment response and resistance. This is particularly important in the context of immunotherapies, which target key immune-tumor interactions. Unlike metastatic tissue biopsies, serial real-time profiling of mRCC is feasible with our noninvasive circulating tumor cell (CTC) approach. METHODS: We collected 457 longitudinal liquid biopsies from 104 patients with mRCC enrolled in one of two studies, either a prospective cohort or a phase II multicenter adaptive immunotherapy trial. Using a novel CTC capture and automated microscopy platform, we profiled CTC enumeration and expression of HLA I and programmed cell death-ligand 1 (PD-L1). Given their diametric immunological roles, we focused on the HLA I to PD-L1 ratio (HP ratio). RESULTS: Patients with radiographic responses showed significantly lower CTC abundances throughout treatment. Furthermore, patients whose CTC enumeration trajectory was in the highest quartile (> 0.12 CTCs/mL annually) had shorter overall survival (median 17.0 months v 21.1 months, P < .001). Throughout treatment, the HP ratio decreased in patients receiving immunotherapy but not in patients receiving tyrosine kinase inhibitors. Patients with an HP ratio trajectory in the highest quartile (≥ 0.0012 annually) displayed significantly shorter overall survival (median 18.4 months v 21.2 months, P = .003). CONCLUSION: In the first large longitudinal CTC study in mRCC to date to our knowledge, we identified the prognostic importance of CTC enumeration and the change over time of both CTC enumeration and the HP ratio. These insights into changes in both tumor burden and the molecular profile of tumor cells in response to different treatments provide potential biomarkers to predict and monitor response to immunotherapy in mRCC.

Telaglenastat plus Everolimus in Advanced Renal Cell Carcinoma: A Randomized, Double-Blinded, Placebo-Controlled, Phase II ENTRATA Trial.

PURPOSE: Glutaminase is a key enzyme, which supports elevated dependency of tumors on glutamine-dependent biosynthesis of metabolic intermediates. Dual targeting of glucose and glutamine metabolism by the mTOR inhibitor everolimus plus the oral glutaminase inhibitor telaglenastat showed preclinical synergistic anticancer effects, which translated to encouraging safety and efficacy findings in a phase I trial of 2L+ renal cell carcinoma (RCC). This study evaluated telaglenastat plus everolimus (TelaE) versus placebo plus everolimus (PboE) in patients with advanced/metastatic RCC (mRCC) in the 3L+ setting (NCT03163667). PATIENTS AND METHODS: Eligible patients with mRCC, previously treated with at least two prior lines of therapy [including ≥1 VEGFR-targeted tyrosine kinase inhibitor (TKI)] were randomized 2:1 to receive E, plus Tela or Pbo, until disease progression or unacceptable toxicity. Primary endpoint was investigator-assessed progression-free survival (PFS; one-sided α <0.2). RESULTS: Sixty-nine patients were randomized (46 TelaE, 23 PboE). Patients had a median three prior lines of therapy, including TKIs (100%) and checkpoint inhibitors (88%). At median follow-up of 7.5 months, median PFS was 3.8 months for TelaE versus 1.9 months for PboE [HR, 0.64; 95% confidence interval (CI), 0.34-1.20; one-sided P = 0.079]. One TelaE patient had a partial response and 26 had stable disease (SD). Eleven patients on PboE had SD. Treatment-emergent adverse events included fatigue, anemia, cough, dyspnea, elevated serum creatinine, and diarrhea; grade 3 to 4 events occurred in 74% TelaE patients versus 61% PboE. CONCLUSIONS: TelaE was well tolerated and improved PFS versus PboE in patients with mRCC previously treated with TKIs and checkpoint inhibitors.

Phase 2 trial of T-cell activation using MVI-816 and pembrolizumab in patients with metastatic, castration-resistant prostate cancer (mCRPC).

BACKGROUND: We previously reported a trial using a DNA vaccine encoding prostatic acid phosphatase (MVI-816, pTVG-HP), given over 12 weeks concurrently or sequentially with pembrolizumab, in patients with mCRPC. We report the final analysis of this trial following two additional treatment arms in which patients with mCRPC continued concurrent treatment until progression. MATERIALS AND METHODS: Patients with mCRPC were treated with MVI-816 and pembrolizumab every 3 weeks (arm 3, n=20) or MVI-816 every 2 weeks and pembrolizumab every 4 weeks (arm 4, n=20). The primary objectives were safety, 6-month progression-free survival (PFS), median time to radiographic progression, and objective response rates. Secondary objectives included immunological evaluations. RESULTS: In 25 patients with measurable disease, there were no complete response and one confirmed partial response in a patient who subsequently found to have an MSIhi tumor. 4/40 patients (10%) had a prostate-specific antigen decline >50%. The estimated overall radiographic PFS rate at 6 months was 47.2% (44.4% arm 3, 61.5% arm 4). Accounting for all off-study events, overall median time on treatment was 5.6 months (95% CI: 5.4 to 10.8 months), 5.6 months for arm 3 and 8.1 months for arm 4 (p=0.64). Thirty-two per cent of patients remained on trial beyond 6 months without progression. Median overall survival was 22.9 (95% CI: 16.2 to 25.6) months. One grade 4 event (hyperglycemia) was observed. Immune-related adverse events (irAEs) >grade 1 were observed in 42% of patients overall. Interferon-γ and/or granzyme B immune response to prostatic acid phosphatase was detected in 2/20 patients in arm 3 and 6/20 patients in arm 4. Plasma cytokines associated with immune activation and CD8+ T-cell recruitment were augmented at weeks 6 and 12. The development of irAE was significantly associated with a prolonged time on treatment (HR=0.42, p=0.003). Baseline DNA homologous recombination repair mutations were not associated with longer time to progression. CONCLUSIONS: Findings here demonstrate that combining programmed cell death 1 blockade with MVI-816 is safe, can augment tumor-specific T cells, and can result in a favorable 6-month disease control rate. Correlative studies suggest T-cell activation by vaccination is critical to the mechanism of action of this combination. Future randomized clinical trials are needed to validate these findings. TRIAL REGISTRATION NUMBER: NCT02499835.

Safety and efficacy of nivolumab plus ipilimumab in patients with advanced renal cell carcinoma with brain metastases: CheckMate 920.

BACKGROUND: Nivolumab plus ipilimumab (NIVO + IPI) has demonstrated long-term efficacy and safety in patients with previously untreated, advanced renal cell carcinoma (aRCC). Although most phase 3 clinical trials exclude patients with brain metastases, the ongoing, multicohort phase 3b/4 CheckMate 920 trial (ClincalTrials.gov identifier NCT02982954) evaluated the safety and efficacy of NIVO + IPI in a cohort that included patients with aRCC and brain metastases, as reported here. METHODS: Patients with previously untreated aRCC and asymptomatic brain metastases received NIVO 3 mg/kg plus IPI 1 mg/kg every 3 weeks × 4 followed by NIVO 480 mg every 4 weeks. The primary end point was the incidence of grade ≥3 immune-mediated adverse events (imAEs) within 100 days of the last dose of study drug. Key secondary end points were progression-free survival and the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1 (both determined by the investigator). Exploratory end points included overall survival, among others. RESULTS: After a minimum follow-up of 24.5 months (N = 28), no grade 5 imAEs occurred. The most common grade 3 and 4 imAEs were diarrhea/colitis (n = 2; 7%) and hypophysitis, rash, hepatitis, and diabetes mellitus (n = 1 each; 4%). The objective response rate was 32% (95% CI, 14.9%-53.5%) with a median duration of response of 24.0 months; 4 of 8 responders remained without reported progression. Seven patients (25%) had intracranial progression. The median progression-free survival was 9.0 months (95% CI, 2.9-12.0 months), and the median overall survival was not reached (95% CI, 14.1 months to not estimable). CONCLUSIONS: In patients who had previously untreated aRCC and brain metastases-a population with a high unmet medical need that often is underrepresented in clinical trials-the approved regimen of NIVO + IPI followed by NIVO showed encouraging antitumor activity and no new safety signals.

Quantitative imaging biomarkers of immune-related adverse events in immune-checkpoint blockade-treated metastatic melanoma patients: a pilot study.

PURPOSE: To develop quantitative molecular imaging biomarkers of immune-related adverse event (irAE) development in malignant melanoma (MM) patients receiving immune-checkpoint inhibitors (ICI) imaged with 18F-FDG PET/CT. METHODS: 18F-FDG PET/CT images of 58 MM patients treated with anti-PD-1 or anti-CTLA-4 ICI were retrospectively analyzed for indication of irAE. Three target organs, most commonly affected by irAE, were considered: bowel, lung, and thyroid. Patient charts were reviewed to identify which patients experienced irAE, irAE grade, and time to irAE diagnosis. Target organs were segmented using a convolutional neural network (CNN), and novel quantitative imaging biomarkers - SUV percentiles (SUVX%) of 18F-FDG uptake within the target organs - were correlated with the clinical irAE status. Area under the receiver-operating characteristic curve (AUROC) was used to quantify irAE detection performance. Patients who did not experience irAE were used to establish normal ranges for target organ 18F-FDG uptake. RESULTS: A total of 31% (18/58) patients experienced irAE in the three target organs: bowel (n=6), lung (n=5), and thyroid (n=9). Optimal percentiles for identifying irAE were bowel (SUV95%, AUROC=0.79), lung (SUV95%, AUROC=0.98), and thyroid (SUV75%, AUROC=0.88). Optimal cut-offs for irAE detection were bowel (SUV95%>2.7 g/mL), lung (SUV95%>1.7 g/mL), and thyroid (SUV75%>2.1 g/mL). Normal ranges (95% confidence interval) for the SUV percentiles in patients without irAE were bowel [1.74, 2.86 g/mL], lung [0.73, 1.46 g/mL], and thyroid [0.86, 1.99 g/mL]. CONCLUSIONS: Increased 18F-FDG uptake within irAE-affected organs provides predictive information about the development of irAE in MM patients receiving ICI and represents a potential quantitative imaging biomarker for irAE. Some irAE can be detected on 18F-FDG PET/CT well before clinical symptoms appear.

Efficacy of enfortumab vedotin in advanced urothelial cancer: Analysis from the Urothelial Cancer Network to Investigate Therapeutic Experiences (UNITE) study.

BACKGROUND: Enfortumab vedotin (EV) is a novel antibody-drug conjugate approved for advanced urothelial cancer (aUC) refractory to prior therapy. In the Urothelial Cancer Network to Investigate Therapeutic Experiences (UNITE) study, the authors looked at the experience with EV in patient subsets of interest for which activity had not been well defined in clinical trials. METHODS: UNITE was a retrospective study of patients with aUC treated with recently approved agents. This initial analysis focused on patients treated with EV. Patient data were abstracted from chart reviews by investigators at each site. The observed response rate (ORR) was investigator-assessed for patients with at least 1 post-baseline scan or clear evidence of clinical progression. ORRs were compared across subsets of interest for patients treated with EV monotherapy. RESULTS: The initial UNITE analysis included 304 patients from 16 institutions; 260 of these patients were treated with EV monotherapy and included in the analyses. In the monotherapy cohort, the ORR was 52%, and it was >40% in all reported subsets of interest, including patients with comorbidities previously excluded from clinical trials (baseline renal impairment, diabetes, and neuropathy) and patients with fibroblast growth factor receptor 3 (FGFR3) alterations. Progression-free survival and overall survival were 6.8 and 14.4 months, respectively. Patients with a pure urothelial histology had a higher ORR than patients with a variant histology component (58% vs 42%; P = .06). CONCLUSIONS: In a large retrospective cohort, responses to EV monotherapy were consistent with data previously reported in clinical trials and were also observed in various patient subsets, including patients with variant histology, patients with FGFR3 alterations, and patients previously excluded from clinical trials with an estimated glomerular filtration rate < 30 mL/min and significant comorbidities. LAY SUMMARY: Enfortumab vedotin, approved by the Food and Drug Administration in 2019, is an important new drug for the treatment of patients with advanced bladder cancer. This study looks at the effectiveness of enfortumab vedotin as it has been used at multiple centers since approval, and focuses on important patient populations previously excluded from clinical trials. These populations include patients with decreased kidney function, diabetes, and important mutations. Enfortumab vedotin is effective for treating these patients. Previously reported clinical trial data have been replicated in this real-world setting, and support the use of this drug in broader patient populations.

Image intensity histograms as imaging biomarkers: application to immune-related colitis.

Purpose.To investigate image intensity histograms as a potential source of useful imaging biomarkers in both a clinical example of detecting immune-related colitis (irColitis) in18F-FDG PET/CT images of immunotherapy patients and an idealized case of classifying digital reference objects (DRO).Methods.Retrospective analysis of bowel18F-FDG uptake in N = 40 patients receiving immune checkpoint inhibitors was conducted. A CNN trained to segment the bowel was used to generate the histogram of bowel18F-FDG uptake, and percentiles of the histogram were considered as potential metrics for detecting inflammation associated with irColitis. A model of the colon was also considered using cylindrical DRO. Classification of DRO with different intensity distributions was undertaken under varying geometry and noise settings.Results.The most predictive biomarker of irColitis was the 95th percentile of the bowel SUV histogram (SUV95%). Patients later diagnosed with irColitis had a significantly higher increase in SUV95%from baseline to first on-treatment PET than patients who did not experience irColitis (p = 0.02). An increase in SUV95%> + 40% separated pre-irColitis change from normal variability with a sensitivity of 75% and specificity of 88%. Furthermore, histogram percentiles were ideal metrics for classifying 'hot center' and 'cold center' DRO, and were robust to varying DRO geometry and noise, and to the presence of spoiler volumes unrelated to the detection task.Conclusions.The 95th percentile of the bowel SUV histogram was the optimal metric for detecting irColitis on18F-FDG PET/CT. Image intensity histograms are a promising source of imaging biomarkers for clinical tasks.