Costello, Brian A.

AbstractBackgroundThe VESPER trial demonstrated improved progression‐free (PFS) and (preliminarily) overall survival (OS) with six cycles of neoadjuvant dose‐dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVACx6) versus four cycles of gemcitabine and cisplatin (GCx4) before radical cystectomy (RC) for muscle‐invasive bladder cancer (MIBC), but with increased toxicity. This study compares the cost‐effectiveness of these regimens.MethodsA cost‐effectiveness analysis of neoadjuvant ddMVACx6 and GCx4 was performed using a decision‐analytic Markov model with 5‐year, 10‐year, and lifetime horizons. Probabilities were derived from reported VESPER data. Utility values were obtained from the literature. Primary outcomes were effectiveness measured in quality‐adjusted life years (QALY) and incremental cost‐effectiveness ratio (ICER) with a willingness to pay threshold of $100,000 per QALY. One‐way and probabilistic sensitivity analyses were performed to evaluate the robustness of the model.ResultsAt 5 years, ddMVACx6 improved QALYs by 0.30 at an additional cost of $16,100, rendering it cost‐effective relative to GCx4 (ICER: $53,284/QALY). Additionally, probabilistic sensitivity analysis found ddMVACx6 to be cost‐effective in 79% and 81% of microsimulations at10‐year and lifetime horizons, respectively. One‐way sensitivity analysis demonstrated a minimum difference in 5‐year progression of 0.9% and progression mortality of 0.7% between ddMVACx6 and GCx4 was necessary for ddMVACx6 to remain cost‐effective.ConclusionsNeoadjuvant ddMVACx6 was more cost‐effective than GCx4 for MIBC. These data, together with the improved PFS and (albeit preliminary) OS noted in VESPER, support use of this regimen in appropriate candidates for neoadjuvant chemotherapy before RC.Lay summary We performed a benefit‐to‐cost analysis using evidence from a randomized controlled trial that compared two different chemotherapy treatments before bladder removal for bladder cancer that had invaded into the bladder muscle. Despite being more expensive and having a greater likelihood of toxicity, six cycles of dose‐dense methotrexate, vinblastine, doxorubicin, and cisplatin was more cost‐effective (or had higher value) than four cycles of gemcitabine and cisplatin.

Abstract NRG-1 signals through epidermal growth factor receptor (EGFR) family members. Despite promising preclinical data, HER2 blockade in prostate cancer has failed to improve outcomes in clinical trials.1-4 We have discovered a novel complex systemic role of NRG-1 that drives sensitivity and resistance to androgen deprivation therapy (ADT) in castration-sensitive (CSPC) and castration resistant prostate cancer (CRPC), respectively. Significantly, sensitivity to ADT can be restored in CRPC by manipulating NRG-1 signaling. Our data posit NRG-1 as a systemic “switch” in prostate cancer. Plasma NRG-1 is elevated in our cohort of patients with metastatic CRPC (mean 4.9ng/ml) versus healthy controls (mean 3.2ng/ml, p<0.0001) or metastatic CSPC (mean 3.4ng/ml, p<0.0001). Paradoxically, high systemic NRG-1 predicted superior OS and PFS in CSPC but inferior clinical outcomes in CRPC. Consistently, opposite cell survival between LNCaP (CSPC) vs Du145 & PC3 (CRPC) was observed with recombinant human NRG-1 and enzalutamide (ENZ). ENZ combined with increasing NRG-1 concentration induced LNCaP cell death in an additive manner, but NRG-1 rescued Du145 & PC3 from ENZ-induced death in a dose-dependent manner. We next hypothesized that differential NRG-1 downstream signaling is mediated by engagement with distinct EGFR receptor dimers. While HER2 expression is similar, LNCaP express higher HER3 than Du145 & PC3. High ratio of HER2 to HER3 in Du145 & PC3 mirrors clinical reports of HER2 upregulation in CRPC5,6 and also predicts patient survival in the Stand Up to Cancer cohort.7 Significantly, we recapitulated the CRPC phenotype in LNCaP by inducing HER2 overexpression, HER3 suppression, and chemically-mediated HER2/HER3 dimerization. Conversely, HER2 knockdown sensitized Du145 cells to ENZ. Next, we queried composite single-cell whole human8 and CRPC9 transcriptomes for NRG-1 expression and discovered that the source of NRG-1 is the patients’ own mesenchymal stem cells (MSCs). Bone-derived MSC outgrowth cells produced copious NRG-1, which was increased substantially by coincubation with prostate cancer cell supernatants. Importantly, we were able to manipulate MSCs to reduce their NRG-1 production as a possible clinical translation. Similarly, patients treated with these compounds showed significant reduction in plasma NRG-1 levels after treatment. Additional clinical studies are pending. Together, our observations confirm that NRG-1 has differential signaling: HER3 homodimerization leads to prostate cancer cell death, whereas heterodimerization of HER3 with HER2 leads to prostate cancer cell survival via ADT resistance in a plasma NRG-1 dependent manner. Consequently, HER2 and HER3 receptor availability determine the molecular switch of NRG-1 in prostate cancer. Therefore, NRG-1 can be both a prognostic marker and therapeutic target in CRPC, and multiple clinical trials are pending. Citation Format: Jacob Orme, Roman Thaler, Dejie Wang, Siven Chinniah, Jacob Hirdler, Fernando Quevedo, Lance Pagliaro, Kwon Eugene, Alan Bryce, Brian Costello, Haojie Huang, Sean Park. Mesenchymal stem cell-derived systemic NRG-1 mediates a targetable molecular switch in metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 397.

Abstract Background: NL-201 is a selective and long-acting computationally designed alpha-independent agonist of the IL-2 and IL-15 receptors, which share beta and gamma signaling subunits. NL-201 is being developed as a potent activator of CD8+ T cells and NK cells for cancer immunotherapy. Binding to the beta and gamma subunits stimulates dose-dependent expansion and tumor infiltration of cytotoxic CD8+ T cells and NK cells, thereby enhancing the immune response in the tumor. The absence of binding to the IL-2 alpha subunit reduces the undesirable effects of traditional IL-2 therapies, such as vascular leak syndrome and expansion of immunosuppressive regulatory T cells. As such, NL-201 is designed to promote the desired immunomodulatory anti-tumor effects of IL-2 with an improved safety profile. Methods: NL201-101 is a Phase 1 first-in-human, open-label, dose-escalation and cohort expansion study consisting of two parts. Part 1 is a monotherapy dose-escalation study in up to 60 adult patients with advanced and/or refractory solid tumors to define the safety profile and the recommended Phase 2 dose (RP2D) and schedule of NL-201. During dose escalation, two different schedules will be evaluated: dosing every 21 days (Schedule A), or on days 1 and 8 of each 21-day cycle (Schedule B). Tumor response will be assessed by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 and/or RECIST for use in cancer immunotherapy trials (iRECIST). In Part 2, patients with pathologically proven diagnosis of melanoma and renal cell carcinoma (up to N=30/cohort), who have advanced and/or refractory measurable disease and have failed at least one line of treatment, which may include checkpoint inhibitors, will be enrolled. Key exclusion criteria include history of brain cancer or active brain metastases, carcinomatous meningitis, neurologic autoimmune disease; patients previously receiving CAR-T or IL-2-based therapies are not eligible. Recruitment of Part 1 began in April 2021, and the trial is actively enrolling. Clinicaltrials.gov identifier: NCT04659629. Citation Format: Aung Naing, Margaret Callahan, Brian A. Costello, Brendan Curti, Evan Hall, Aaron Hansen, Georgina V. Long, Anthony M. Joshua, Cynthia Wetmore, Andrew Weickhardt. A first-in-human phase 1 study of NL-201 in patients with relapsed or refractory cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT250.

e17036 Background: Elevated serum CGA is associated with an intrinsic or treatment-related neuroendocrine differentiation in men with mCRPC. We previously demonstrated that elevated serum CGA was negatively associated with OS in men with mCRPC. Fluctuations in serum CGA during mCRPC therapy is not well known. We analyzed the impact of (i) rising serum CGA and (ii) baseline CGA/PSA ratio during treatment to identify associations with AA therapy. Methods: Between June 2013 and August 2015, 92 men with mCRPC were enrolled in a prospective trial (“PROMOTE”; NCT#01953640) with uniform serum processing performed prior to initiating abiraterone acetate/prednisone (AA/P) and serially after 12 weeks of AA/P treatments. Serum CGA was measured using a homogenous automated immunofluorescent assay. Patients (pts) receiving proton pump inhibitors or with abnormal renal function were excluded due to possible false elevations of serum CGA (n = 21 excluded). All patients underwent a composite response assessment at 12-weeks with imaging/PSA/QOL questionnaires. Kaplan Meier estimates, and Cox Regression models were used to calculate association with time-to-treatment failure (TTF) analyses, defined as time from treatment initiation to AA/P discontinuation based on disease progression (BlueSky Statistics, Chicago, IL, USA). Results: Of the 71 eligible pts, 67/71 had paired baseline and 12-week CGA and 70/71 pts had a baseline and a 12-week PSA available. The median baseline CGA was 83.0ng/ml (range: 53.0 - 127.0 ng/ml), median baseline PSA was 14.4 ng/ml (range: 6.4-40.2 ng/ml), and the median TTF was 10 months (range: 6-25 months). The median CGA after 12 weeks of AA/P was 98.0 ng/ml (58.0 -148.0 ng/ml) and we observed a CGA rise in 41/67 (61.2%) pts. An increase in chromogranin was associated with a lower risk of treatment failure (HR: 0.52, p = 0.0181). The median CGA/PSA ratio was 7.8 (2.6 -16.0). An elevated pretreatment CGA/PSA ratio above the median was associated with a lower risk of treatment failure (HR: 0.54 p value = 0.0185). Conclusions: We show that an increasing chromogranin on AA/P and an elevated baseline CGA/PSA in pts with mCRPC were associated with a favorable response to AA/P. Further studies are needed to assess if rising CGA during therapy reflects neuroendocrine differentiation and may indicate a sign of treatment effect targeting the androgen susceptible cells. Clinical trial information: NCT#01953640.

AbstractPurposeRural populations are disproportionately affected by the COVID‐19 pandemic. We characterized urban‐rural disparities in patient portal messaging utilization for COVID‐19, and, of those who used the portal during its early stage in the Midwest.MethodsWe collected over 1 million portal messages generated by midwestern Mayo Clinic patients from February to August 2020. We analyzed patient‐generated messages (PGMs) on COVID‐19 by urban‐rural locality and incorporated patients’ sociodemographic factors into the analysis.FindingsThe urban‐rural ratio of portal users, message senders, and COVID‐19 message senders was 1.18, 1.31, and 1.79, indicating greater use among urban patients. The urban‐rural ratio (1.69) of PGMs on COVID‐19 was higher than that (1.43) of general PGMs. The urban‐rural ratios of messaging were 1.72‐1.85 for COVID‐19‐related care and 1.43‐1.66 for other health care issues on COVID‐19. Compared with urban patients, rural patients sent fewer messages for COVID‐19 diagnosis and treatment but more messages for other reasons related to COVID‐19‐related health care (eg, isolation and anxiety). The frequent senders of COVID‐19‐related messages among rural patients were 40+ years old, women, married, and White.ConclusionsIn this Midwest health system, rural patients were less likely to use patient online services during a pandemic and their reasons for its use differ from urban patients. Results suggest opportunities for increasing equity in rural patient engagement in patient portals (in particular, minority populations) for COVID‐19. Public health intervention strategies could target reasons why rural patients might seek health care in a pandemic, such as social isolation and anxiety.

321 Background: KEYNOTE-564 demonstrated that adjuvant pembrolizumab after nephrectomy for high-risk clear cell renal cell carcinoma (RCC) decreased the risk of disease progression and – albeit with immature follow-up (2 years) – found a signal of improved overall survival as well. Herein, we used extrapolations from a Markov-model, accounting for the costs and toxicities of pembrolizumab relative to its efficacy, to investigate its utility at a population level. Methods: A decision-analytic Markov Model was used to conduct a cost-utility analysis of adjuvant pembrolizumab versus placebo after nephrectomy for high risk RCC, using data from KEYNOTE-564 to inform model probabilities. Transition probabilities not found in KEYNOTE-564, in addition to utility values, were extracted from the literature. Base case analyses were conducted with 5-year and 15-year time horizons (using extrapolations from 2-year outcomes), and 3-week time cycles. Primary outcomes were Quality-adjusted life years (QALYs), 2021 US Medicare costs, and Incremental cost-effectiveness ratios (ICERs). The willingness-to-pay threshold was set at $100,000/QALY. One-way sensitivity analyses were used to identify cost-effectiveness thresholds of individual parameters while probabilistic sensitivity analyses with 100,000 Monte-Carlo simulations were used to simultaneously vary all model inputs. Results: Pembrolizumab was associated with higher QALYs and costs relative to placebo (Table). Pembrolizumab was not cost-effective at a 5-year time horizon but was cost-effective at 15 years and beyond. One-way sensitivity analysis noted that pembrolizumab became cost-effective at 5-years if: 1) its administration cost was less than $5,064 (base = $10,278) or 2) if the 5-year risk of progression was 18.8% higher in placebo vs pembrolizumab (base = 9%). Using pembrolizumab’s reported hazard ratio of 0.68 for progression from KEYNOTE-564, we estimated that pembrolizumab would be cost-effective at 5-years for all patients with a Mayo Progression Free Survival Score of 10 or higher. Probabilistic sensitivity analysis found that pembrolizumab was cost-effective for 29% and 58% of microsimulations at 5 and 15 years, respectively. Conclusions: At current prices, adjuvant pembrolizumab was not cost-effective for all trial patients at a population level at 5-years after treatment but may be cost-effective for time horizons over 15 years. Instead, adjuvant pembrolizumab was found to be cost-effective only for the highest risk subsets of RCC at 5-years. Longer term trial data of progression-free survival and overall survival are necessary to confirm these extrapolations.[Table: see text]

The NCCN Guidelines for Kidney Cancer focus on the screening, diagnosis, staging, treatment, and management of renal cell carcinoma (RCC). Patients with relapsed or stage IV RCC typically undergo surgery and/or receive systemic therapy. Tumor histology and risk stratification of patients is important in therapy selection. The NCCN Guidelines for Kidney Cancer stratify treatment recommendations by histology; recommendations for first-line treatment of ccRCC are also stratified by risk group. To further guide management of advanced RCC, the NCCN Kidney Cancer Panel has categorized all systemic kidney cancer therapy regimens as “Preferred,” “Other Recommended Regimens,” or “Useful in Certain Circumstances.” This categorization provides guidance on treatment selection by considering the efficacy, safety, evidence, and other factors that play a role in treatment selection. These factors include pre-existing comorbidities, nature of the disease, and in some cases consideration of access to agents. This article summarizes surgical and systemic therapy recommendations for patients with relapsed or stage IV RCC.

Abstract The second-generation antiandrogens have achieved an ever-growing list of approvals and indications in subsets of prostate cancer. Here, we provide an overview of second-generation antiandrogen trials and FDA approvals and outline a rational sequencing approach for the use of these agents as they relate to chemotherapy and other available treatment modalities in advanced prostate cancer. All published phase II-III randomized controlled trials reporting outcomes with the use of second-generation antiandrogens in prostate cancer are included as well as all published trials and retrospective studies of second-generation antiandrogen sequencing and/or combinations. Complete tabular and graphical representation of all available evidence is provided regarding the use and sequencing of second-generation antiandrogens in prostate cancer. In metastatic castration-resistant prostate cancer, evidence suggests prioritization of abiraterone before chemotherapy, chemotherapy after second-generation antiandrogen failure, and postchemotherapy enzalutamide in select patients to maximize agent efficacy and tolerability. We conclude that a rational, optimized sequencing of second-generation antiandrogens with other treatment options is feasible with present data.