bluuebunny/crossref_metadata_2025 huggingface dataset:
Nivolumab + cabozantinib (NIVO+CABO) versus sunitinib (SUN) for advanced renal cell carcinoma (aRCC): Outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate 9ER.
Authors: Motzer Robert J. , Choueiri Toni K. , Powles Thomas , Burotto Mauricio , Bourlon Maria Teresa , Hsieh James J , Maruzzo Marco , Shah Amishi Yogesh , Suarez Cristina , Barrios Carlos H. , Richardet Martin Eduardo , Porta Camillo , Goh Jeffrey C. , Tomita Yoshihiko , Bedke Jens , Zhang Joshua , Simsek Burcin , Scheffold Christian , Gupta Saurabh , Apolo Andrea B.
Published: March 2021

308

Background: First-line NIVO+CABO met primary and secondary efficacy endpoints by improving progression-free survival (PFS; HR 0.51, P < 0.0001), overall survival (OS; HR 0.60, P = 0.0010), and objective response rate (ORR; 55.7% vs 27.1%; P < 0.0001) vs SUN in patients (pts) with aRCC in CheckMate 9ER (Choueiri et al. ESMO 2020). Efficacy benefits with NIVO+CABO vs SUN were consistent across prespecified subgroups including by IMDC risk group, and regardless of tumor PD-L1 expression (database lock for primary analysis, March 30, 2020). Updated analyses are needed to establish durability of benefit with first-line NIVO+CABO and assess outcomes in aRCC pts with sarcomatoid features (sRCC)—an aggressive histologic subtype associated with poor prognoses. Methods: In this phase III open-label trial, adults with confirmed aRCC (with a clear cell component including those with sRCC) were randomized 1:1 (stratified by IMDC risk score, tumor PD-L1 expression, geographic region) to NIVO 240 mg IV Q2W + CABO 40 mg PO QD vs SUN 50 mg PO (4 weeks of 6-week cycles). The primary endpoint was RECIST v1.1-defined PFS by blinded independent central review (BICR) in all randomized (intent-to-treat [ITT]) pts; secondary endpoints included OS, ORR by BICR, and safety. Pts with and without sRCC were identified by local pathology report, and outcomes in these pts were evaluated via prespecified supportive subset analyses. Results: The presence of sRCC was assessed in ITT pts (N = 651) at enrollment. Overall, 75 (11.5%) pts had sRCC and 557 (85.6%) did not; sRCC status was not reported in 19 pts (2.9%). Overall, 34 vs 41 pts with sRCC were randomized to NIVO+CABO vs SUN, respectively. At a median follow-up of 18.1 months, NIVO+CABO improved PFS, OS, and ORR in sRCC pts vs SUN (Table). Notable PFS, OS, and ORR benefits were observed with NIVO+CABO vs SUN in the subgroup of pts without sRCC. Median PFS was doubled, the risk of death was lower, and ORR was consistently higher with NIVO+CABO vs SUN regardless of sarcomatoid status. Key updated PFS, OS, response, and safety outcomes in the ITT population and in pts with and without sRCC will be reported with additional follow-up based on a September 10, 2020 database lock. Conclusions: NIVO+CABO demonstrated improved efficacy and prolonged survival vs SUN in previously untreated aRCC pts regardless of sarcomatoid status. Updated results with extended follow-up will assess the durability of outcomes in this trial. Clinical trial information: NCT03141177 . [Table: see text]
Patterns of progression in patients treated with nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) for first-line treatment of advanced renal cell carcinoma (aRCC) in CheckMate 214.
Authors: Tannir Nizar M. , Motzer Robert J. , Albiges Laurence , Plimack Elizabeth R. , George Saby , Powles Thomas , Donskov Frede , Rini Brian I. , Grünwald Viktor , Hammers Hans J. , Choueiri Toni K. , Gurney Howard , Tykodi Scott S. , Porta Camillo , Burotto Mauricio , Tomita Yoshihiko , Lee Chung-Wei , Tang Chad , McDermott David F. , McKay Rana R.
Published: March 2021

313

Background: First-line NIVO+IPI demonstrates superior survival and response benefits in intent-to-treat (ITT) patients (pts) with aRCC after long-term follow-up in the phase 3 CheckMate 214 trial. Data are scarce on tumor relapse and patterns of disease progression with immuno-oncology agents in this setting. This exploratory analysis of CheckMate 214 characterizes patterns of progression with NIVO+IPI vs SUN with 4 years minimum follow-up. Methods: Pts with clear cell aRCC were randomized to NIVO+IPI Q3W×4 followed by NIVO monotherapy Q2W, or SUN QD×4 weeks (6-week cycle). Patterns of progression were characterized in ITT pts and analyzed post hoc using descriptive statistics. Progression patterns were defined by ≥ 20% target lesion growth (T), unequivocal progression of nontarget lesions (NT), and new lesion(s) (NL). Response and progression were assessed per independent radiology review committee via RECIST v1.1. Results: Radiographic progression (RP) was documented in 299/550 (54.4%) ITT pts with NIVO+IPI vs 289/546 (52.9%) with SUN. Among ITT pts with a confirmed response (objective response = 215/550 [39.1%, NIVO+IPI] vs 177/546 [32.4%, SUN]), 71/215 (33.0%) vs 84/177 (47.5%) pts experienced post-response RP with NIVO+IPI vs SUN; 8/59 (13.6%) vs 3/14 (21.4%) progressed after complete response, and 63/156 (40.4%) vs 81/163 (49.7%) progressed after partial response, respectively. The pattern of RP differed between arms (Table). With NIVO+IPI, 106/299 (35.5%) RPs resulted from NL only vs 74/289 (25.6%) with SUN, and this differential was more pronounced in pts with an initial confirmed response (36/71 [50.7%] vs 23/84 [27.4%]). Most NL-only RPs in initial responders occurred in a single organ (34/36 [94.4%] for NIVO+IPI; 20/23 [87.0%] for SUN) with the most common being lymph nodes (11/34 [32.4%]), brain (8/34 [23.5%]), and lung (5/34 [14.7%]) with NIVO+IPI, and lymph nodes (7/20 [35.0%]), brain (4/20 [20.0%]) and adrenal gland (3/20 [15.0%]) with SUN. Additional progression details, baseline characteristics, and key efficacy outcomes in progressors will be reported. Conclusions: Differential patterns of tumor relapse and disease progression were observed after long-term follow up of patients treated with NIVO+IPI vs SUN in CheckMate 214. NL-only progression occurred more often with NIVO+IPI vs SUN, in particular in the subset of pts who progressed post-response. These patterns may have therapeutic implications. Clinical trial information: NCT02231749 . [Table: see text]
Nivolumab as second-line treatment and beyond for metastatic renal cell carcinoma: A real-life experience from Turkish Oncology Group Kidney Cancer Consortium (TKCC) Database.
Authors: Yekeduz Emre , Erturk Ismail , Tural Deniz , Karadurmus Nuri , Karakaya Serdar , Hizal Mutlu , Arslan Çağatay , Taban Hakan , Küçükarda Ahmet , Şentürk Öztaş Nihan , Sever Ozlem Nuray , Uçar Gokhan , Sendur Mehmet Ali Nahit , Demirci Umut , Kilickap Saadettin , Cicin Irfan , Oksuzoglu Berna , Ozguroglu Mustafa , Urun Yuksel ,   Turkish Oncology Group Kidney Cancer Consortium (TKCC)
Published: March 2021

321

Background: Immune checkpoint inhibitors (ICIs) started a new era in the treatment of metastatic renal cell carcinoma (mRCC). CheckMate-025 and CheckMate-214 trials established the effect of ICIs in the second-line and upfront therapy of mRCC, respectively. This study aimed to share a real-life experience regarding nivolumab in the second-line treatment and beyond in mRCC Methods: We retrospectively searched the Turkish Oncology Group Kidney Cancer Consortium (TKCC) database, which is the multicenter registry system, and extracted patients treated with nivolumab in the second line and beyond. The patients treated with nivolumab plus targeted therapy or ipilimumab were excluded. The primary endpoint was overall survival (OS). The secondary endpoints were response rates and safety. Results: A total of 134 patients were included in this study. The median age at the starting of nivolumab treatment was 61 years (Inter Quartile Range (IQR):55-67). Three out of four patients were male. One hundred four patients (78%) had previous nephrectomy. The majority of patients had clear-cell pathology (83%). Thirteen patients (10%) had sarcomatoid features. According to International Metastatic RCC Database Consortium (IMDC) risk score, seventy patients (52%) were in the intermediate and poor prognostic group. The previous drugs administered in each line before nivolumab are shown in the table below. The number of patients treated with nivolumab was 63(47%), 45(33%), 17(13%), and 9(7%) in the second-, third-, fourth-, and fifth-line setting, respectively. The median OS was 34 months (95% Confidence Interval (CI): 24.1-43.8)) with the 15 months (IQR:5-26) median follow-up. Objective response rate (ORR) and disease control rate (DCR) was 33% and 57%, respectively. The most common grade 3 or higher AEs leading to treatment discontinuation were pneumonitis (%1.4) and colitis (<%1). Conclusions: In compliance with the CheckMate-025 trial results, nivolumab improved OS for mRCC patients treated in the second line and beyond. The median OS was slightly higher in our study than the CheckMate-025 (34 months versus 25.8 months). It may be associated with the patient population in our study. Patients up to the fifth-line setting of mRCC treatment were included in this study. Of note, there was no additional safety concern for nivolumab. [Table: see text]
UNISON - nivolumab then ipilimumab + nivolumab in advanced non-clear cell renal cell carcinoma (ANZUP 1602): Part 1—Nivolumab monotherapy.
Authors: Gedye Craig , Pook David William , Krieger Laurence Eliot Miles , Harris Carole A. , Goh Jeffrey C. , Kichenadasse Ganessan , Gurney Howard , Underhill Craig , Parnis Francis , Joshua Anthony M. , Ferguson Tom , Roncolato Felicia , Harrison Michelle L. , Begbie Stephen , Morris Michelle Frances , Hovey Elizabeth J. , George Mathew , Prithviraj Prashanth , Liow Elizabeth Chien Hern , Davis Ian D. ,   ANZUP Cancer Trials Group
Published: March 2021

325

Background: Immune checkpoint inhibitors (ICI) are active in many cancers, but people with rare variant, non clear-cell renal cell carcinoma (nccRCC) have been excluded from most clinical trials in RCC. UNISON (NCT03177239) aimed to test 2 hypotheses; the activity of nivolumab in nccRCC (Part 1), and the benefit of adding ipilimumab to nivolumab, in people whose cancers progress on nivolumab (Part 2). Methods: 83 participants (pts) with advanced nccRCC with good (ECOG0/1) performance status, were enrolled including papillary type 1 (17%), papillary type 2 (28%), chromophobe (18%), Xp11 translocation (6%), hereditary leiomyomatosis renal cell carcinoma syndrome-associated renal cell carcinoma (6%), RCC unclassified (10%) and other (15%) histological subtypes. Participants took nivolumab (N) 240mg every two weeks in Part 1 in total. If they experienced progression and remained eligible they could take N (3mg/kg) plus ipilimumab (I; 1mg/kg) every 3 weeks for up to 4 doses (Part 2). Pts with disease control after N or N + I could continue N for up to 1 year. UNISON was powered to distinguish a clinically-relevant improvement in objective tumor response rate (OTRR) from 15% to 30% in people taking N+I in Part 2 in pts whose cancers were refractory to single-agent first-line N. Here we report results of Part 1. Results: Pts experience of N appeared similar to previous reports, with most experiencing mild adverse events. 12 treatment related SAE occurred in 11 patients (13%). 14 pts (17%) experienced treatment delays, or permanent treatment discontinuation (10%). The median time on treatment was 5.1 months. The OTRR was 17% with 3 complete responses and 11 partial responses. The median duration of response was 21 months. Stable disease occurred in 49% of pts and disease progression in 34%. The disease control rate at 6 months was 45% (95% CI: 34%, 56%). The median PFS was 4.0 months (95% CI: 3.6, 7.4). The 6 month progression-free survival (PFS) was 45% (95% CI: 34-55) and the 12 months PFS was 30% (95% CI: 21%, 40%). Conclusions: Pts with nccRCC treated with N experience similar adverse events compared to pts with other cancers. A substantial minority of people with nccRCC derive benefit, but many pts have cancers refractory to anti-PD1, similar to other reports. The activity of I and N in this PD1-refractory population is of considerable interest and will be reported at a later date. Clinical trial information: NCT03177239 .
Change in neutrophil to lymphocyte ratio (NLR) as a predictor of treatment failure in renal cell carcinoma patients: Analysis of the IROC (Investigating RCC Outcomes) cohort.
Authors: Basu Arnab , Phone Audrey , Bice Tristan , Sweeney Patrick , Acharya Luna , Suri Yash , Chan Abigail Sy , Nandagopal Lakshminarayanan , Garje Rohan , Zakharia Yousef , Kilari Deepak , Koshkin Vadim S , De Shazo Mollie R. , Barata Pedro C. , Desai Arpita
Published: March 2021

344

Background: IROC is an expanding multi-institution collaborative database which includes socioeconomic, genomic, pathologic, clinical and laboratory data in metastatic RCC patients (pts), primarily in the modern setting. Elevated baseline NLR is now an established poor prognostic factor in renal cell carcinoma (RCC) but currently has limited practical use. We hypothesized that an increase in NLR of 3 or more (NLR Failure) at 2 months on therapy could be a predictor of eventual treatment failure and shorter overall survival and thus augment the utility of this marker. Methods: Patients with complete data on NLR at time = 0 and +2 months of therapy were analyzed. Information on comorbidities, previous therapy, demographics were collected for adjusted analysis. NLR failure was defined as an increase of 3 or more compared to baseline NLR. Cox proportional hazard models were used to analyze the risk of progression and death with NLR failure at 2 months (+/- 2 weeks). Kaplan Meier graphs were constructed to trace survival functions for PFS and OS by NLR. Results: Among 165 pts; 121 were eligible (Table). NLR failure at 2 months was associated with a highly statistically significant increase in the risk of death in < 1 year (HR 6.82, 95% CI [3.16-14.70], p<0.001). In a model adjusted for NLR change, the value of baseline NLR to predict OS <1 year was non-significant (HR 1.02, p = 0.65). Similarly, NLR failure increased the risk of treatment failure in less than 6 months (HR 4.83 95% CI [ 2.29-10 .19], p<0.001), while baseline NLR did not predict it (HR 1.03, p = 0.34). These findings were unaffected by immunotherapy vs TKI therapy. NLR failure at 2 months had a 78% (11/14) positive predictive value for survival <1 year and 86% (12/14) [p=.0001] for treatment failure in 6 months. Conclusions: In this multi-institutional cohort of RCC pts; an increase in NLR of 3 or more at 2 months following therapy start predicts for an increasing risk of death and impending treatment failure with a high PPV. The prognostic value of baseline NLR is non-significant when adjusting for NLR change. NLR failure should be validated in prospective studies and could have clinical utility in management of RCC pts. [Table: see text]
Prediction model for brain metastasis (BM) in patients with metastatic germ-cell tumors (mGCT) accounting for size of pulmonary metastases.
Authors: Ashkar Ryan , Althouse Sandra K. , Cary Clint , Masterson Timothy A. , Foster Richard , Hanna Nasser H. , Einhorn Lawrence H. , Adra Nabil
Published: March 2021

378

Background: BM is an independent adverse prognostic factor that can lead to treatment complications and failure in pts with mGCT. We aimed to establish an effective and practical BM prediction model accounting for size of pulmonary metastases. Methods: 2,291 consecutive pts with mGCT treated at Indiana University between January 1990 and September 2017 were identified. Pts were divided into 2 categories: BM present (N=154) and BM absent (N=2137). Kaplan-Meier methods were used to analyze progression free survival (PFS) and overall survival (OS). Logistic regression was used to determine a predictive model for whether BM was present. The data was separated 50/50 into training and validation datasets with equal numbers of events in each. Size of pulmonary metastases were calculated based on the sum of long axis diameter of pulmonary metastases for each patient and were divided into <3cm vs. ≥3cm. Results: Baseline characteristics for 2 groups are listed in the table below. 2-yr PFS and OS for pts with vs without BM: 17% vs 65% (p<0.001) and 62% vs 91% (p<0.001) respectively. Among the 154 pts with BM, 64 (42%) had radiation only (whole-brain radiotherapy or gamma knife), 22 (14%) had BM-surgery only, 14 (9%) had both radiation and BM-surgery. 54 pts (35%) did not receive local therapy for BM. A stepwise selection was used to determine the best model with p<0.15 as the entry and staying criteria. The model with the largest ROC AUC was used moving forward. The model was tested in the validation dataset. A model was generated including age at diagnosis≥40 (1 point), pre-chemotherapy hCG≥5000 (1 point), presence of bone metastases (1 point), choriocarcinoma predominant histology (2 points), and presence of pulmonary metastases size <3 cm (2 points) or ≥3 cm (3 points). Patients with 0 points had a 0.6% probability of having BM, 1 point → 1.4%, 2 points → 3.5%, 3 points → 8.2%, 4 points → 18.3%, 5 points → 36%, 6 points → 58%, 7 points → 78%, and 8 points → 90%. Conclusions: The prediction model developed in this study demonstrated discrimination capability of predicting BM occurrence in mGCT and can be used by clinicians to identify high-risk pts. [Table: see text]
Management of fibroblast growth factor receptor inhibitor (FGFRi) treatment-emergent adverse events (TEAEs) of interest in patients (Pts) with locally advanced or metastatic urothelial carcinoma (mUC).
Authors: Siefker-Radtke Arlene O. , Necchi Andrea , Park Se Hoon , García-Donas Jesús , Huddart Robert A , Burgess Earle F , Fleming Mark T. , Rezazadeh Arash , Mellado Begona , Varlamov Sergei , Joshi Monika , Duran Ignacio , Tagawa Scott T. , Zakharia Yousef , Qi Keqin , Monga Manish , Sondhi Manu , OHagan Anne , Loriot Yohann
Published: March 2021

426

Background: Erdafitinib (ERDA), a pan-FGFR kinase inhibitor, was US FDA approved for adults with mUC with susceptible FGFR3/2 alterations ( FGFRa) who progressed on ≥ 1 line of prior platinum-based chemotherapy based on primary results of the BLC2001 trial (NCT02365597). At final analysis (median 2-y follow-up), ERDA showed median OS of 11.3 mo and a manageable safety profile. Some FGFRi toxicities are distinct from those of other small-molecule TKIs. Proactive AE management can avoid treatment discontinuation, ensuring maximum benefit. We report the frequency and management of TEAEs of interest (central serous retinopathy [CSR], hyperphosphatemia [“on-target” FGFRi class effect], stomatitis, and skin and nail toxicities) for the optimal schedule of ERDA from the final analysis of BLC2001. Methods: The open-label, phase II BLC2001 study enrolled pts with measurable mUC, prespecified FGFRa, and progression during/after ≥ 1 line of prior chemotherapy or ≤ 12 mos of (neo)adjuvant chemotherapy or who were cisplatin ineligible, chemo naive. Optimal dose schedule in the study was 8 mg/d continuous ERDA in 28-d cycles with uptitration to 9 mg/d (ERDA 8 mg/d UpT) if prespecified serum phosphate level was not reached and no significant TEAEs occurred. ERDA 8 mg/d UpT safety results as of Aug 9, 2019 (final analysis) are summarized here. AEs were graded using NCI CTCAE v4.0. Results: Median follow-up for 101 pts treated with ERDA 8 mg/d UpT was 24.0 mos; median treatment duration was 5.4 mos. All pts had ≥ 1 TEAE. Hyperphosphatemia, stomatitis, nail disorders, skin disorders, and CSR TEAEs occurred in 78%, 59%, 59%, 55%, and 27% of pts, respectively (few were grade [gr] 3; none were gr ≥ 4; Table). TEAEs were mostly managed with concomitant treatment and dose modifications. As of data cutoff, hyperphosphatemia had resolved in 74/79 (94%) pts; stomatitis in 44/60 (73%); nail and skin TEAEs in 26/60 (43%) and 25/55 (45%), respectively; and CSR in 17/27 (63%). Most unresolved TEAEs were gr 1–2. No treatment-related deaths occurred. Conclusions: ERDA had measurable benefit in pts with advanced UC with FGFRa. As with other targeted therapies, exposure to ERDA is associated with a pattern of AEs. The most common and FGFRi class effect TEAEs were generally reversible and managed by supportive care and dose modification. Clinical trial information: NCT02365597 . Research Sponsor: Janssen Research & Development, LLC[Table: see text]
Preliminary analysis of a phase II, multicenter, randomized, active-control study to evaluate the efficacy and safety of eganelisib (IPI 549) in combination with nivolumab compared to nivolumab monotherapy in patients with advanced urothelial carcinoma.
Authors: Tomczak Piotr , Popovic Lazar , Barthelemy Philippe , Janicic Aleksander , Sevillano Fernandez Elena , Borchiellini Delphine , Aglietta Massimo , Maroto José , Carnot Aurelien , O'Connell Brenda , ZIZLSPERGER NORA , Zhang Halle Huihong , Valderrama Begoña P.
Published: March 2021

436

Background: Inhibition of the PD-1 pathway has demonstrated clinical benefit in metastatic urothelial carcinoma (mUC); however, response rates of 15% to 29% highlight the need for more effective therapies, especially for PD-L1- patients. Eganelisib is a first-in-class, novel, oral agent which selectively inhibits PI3K-γ, with the goal of improving the immune response to checkpoint inhibitors (CPI). Methods: Eligible patients (pts) with mUC who progressed on > 1 platinum-based chemotherapy regimen and were CPI naïve were enrolled. Pts were randomized 2:1 to receive eganelisib in combination with nivolumab (EN) or placebo with nivolumab (PN). Pts were stratified by baseline circulating monocytic myeloid derived suppressor cells (mMDSC) level. The primary endpoint was objective response rate (ORR) per RECIST v1.1 in pts with high baseline mMDSC levels. Other endpoints included ORR, progression free survival (PFS) and overall survival (OS) in all pts and PD-L1 +/- pts. Results: We report preliminary data (as of 9/1/2020) for the first 49 pts with 33 randomized to receive EN and 16 PN. Preliminary ORR/PFS is presented in the table below. Except for the mMDSC high subgroup, ORR and PFS were improved in the EN arm compared to the PN arm. The duration of exposure was a median of 15 weeks for EN and 11 for PN. Most common all-Gr AEs (EN vs PN %) were pyrexia (33 vs 0), decreased appetite (30 vs 19), pruritis (24 vs 6), rash (24 vs 6), asthenia (21 vs 31), and transaminase elevation (21 vs 6). Most common Gr≥3 AEs (EN vs PN %) include hepatotoxicity (15 vs 0), transaminase elevation (12 vs 6), and rash (9 vs 0). Following an early safety review, eganelisib dose was reduced from 40 to 30 mg, resulting in a reduction of hepatic AEs. Conclusions: Preliminary data demonstrates that the combination of eganelisib, once reduced to 30 mg, and nivolumab was well tolerated with hepatic and skin-related toxicities more common in the EN arm. When compared to PN, the combination demonstrated an improved ORR and PFS, especially in the PD-L1- subset. Updated efficacy, including PFS and OS, safety and translational data will be presented. Clinical trial information: NCT03980041 . [Table: see text]
177Lu-PSMA-617 (LuPSMA) versus cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel: Updated results including progression-free survival (PFS) and patient-reported outcomes (PROs) (TheraP ANZUP 1603).
Authors: Hofman Michael S , Emmett Louise , Sandhu Shahneen Kaur , Iravani Amir , Joshua Anthony M. , Goh Jeffrey C. , Pattison David A. , Tan Thean Hsiang , Kirkwood Ian D. , Ng Siobhan , Francis Roslyn J. , Gedye Craig , Rutherford Natalie K. , Zhang Alison Yan , McJannett Margaret Mary , Stockler Martin R. , Violet John A. , Williams Scott , Martin Andrew James , Davis Ian D. ,   ANZUP Cancer Trials Group
Published: March 2021

6

Background: TheraP is a randomized phase 2 trial that showed LuPSMA significantly improved the primary endpoint of PSA≥50% reduction (66% vs. 37%) compared to cabazitaxel in men with docetaxel-treated mCRPC. We now report results on other clinical endpoints and PROs reached the pre-specified target of 170 PFS events. Methods: 200 men with mCRPC (median age 72 y, prior enza/abi 91%) and high PSMA-expression by 68Ga-PSMA-11 and no sites of FDG-positive/PSMA-negative disease, were randomly assigned (1:1) to LuPSMA (6-8.5GBq q6wk up to 6 cycles; N = 99) or cabazitaxel (20mg/m2 q3wk up to 10 cycles; N = 101). Secondary endpoints include PSA/radiologic PFS (PCWG3), pain response (≥2 point reduction on McGill-Melzack Present Pain Intensity scale, objective response rate (ORR) (RECIST 1.1), adverse events (CTCAE), PROs (EORTC QLQ-C30) and overall survival (OS). Cut-off date for analysis of 20JUL20. Results: At a median follow-up of 18.4 months, PFS was significantly longer in those assigned Lu-PSMA rather than cabazitaxel (rates at 1y 19% [95%CI 12-27%] vs 3% [1-9%], hazard ratio (HR) 0.63, 95%CI 0.46-0.86; p = 0.003; 173 events). Similar benefit was seen for rPFS (HR 0.64, 95%CI 0.46-0.88; p = 0.007; 160 events) and PSA-PFS (HR 0.60 95%CI 0.44-0.83; p = 0.002; 172 events). ORR in 78 men with measurable disease was significantly greater in the LuPSMA arm (49% vs 24%, RR 2.1, 95%CI 1.1-4.1; p = 0.019). In 90 men with pain at baseline, pain responses occurred in 60% in the Lu-PSMA arm vs 43% for cabazitaxel (RR 1.42, 95%CI 0.84-4.48; p = 0.10). Patient-reported global health status was similar (LuPSMA 64 [95%CI 61-67] vs cabazitaxel 60 [57-64]) with significantly better outcomes reported for fatigue (34 [95%CI 31-37] vs 40 [36-43]), social functioning (79 [76-82] vs 73 [69-77]), insomnia (24 [20-27] vs 29 [25-33]) and diarrhoea (8.3 [5.6-11.0] vs 15.6 [12.6-18.6]) domains. No PRO domains were superior for cabazitaxel. G3-4 AEs were similar to previously reported (33% vs 53%). OS data remains immature (90 deaths). Conclusions: In men with docetaxel-treated mCRPC, LuPSMA is a promising alternative to cabazitaxel with significantly higher activity (PSA≥50%, PFS, ORR), fewer G3-4 AEs, similar effects on global health status, and improvements in some PRO domains. Clinical trial information: NCT03392428.
Biomarker analysis from a randomized phase II study of olaparib with or without cediranib in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: McKay Rana R. , Radke Marc R , Shyr Yu , Zhao Shilin , Taplin Mary-Ellen , Davis Nancy B. , Monk Paul , Appleman Leonard Joseph , Lara Primo "Lucky" N. , Vaishampayan Ulka N. , Zhang Jingsong , Paul Asit K. , Bubley Glenn , Huang Ying , Shapiro Geoffrey , LoRusso Patricia , Ivy S. Percy , Petrylak Daniel Peter , Swisher Elizabeth M. , Kim Joseph W.
Published: March 2021

7

Background: We previously reported that cediranib, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, combined with olaparib, a poly (ADP-ribose) polymerase inhibitor, prolonged radiographic progression-free survival (rPFS) compared with olaparib alone in patients with mCRPC. Herein, we present updated clinical data in the overall population and in subgroups by homologous recombination (HR) gene status. Methods: Men with a minimum of one prior line of systemic therapy for mCRPC were randomized 1:1 to receive olaparib 200 mg by mouth twice daily with cediranib 30 mg by mouth daily (C+O) or olaparib 300 mg by mouth twice daily (O). Patients were required to undergo a baseline metastasis biopsy. Next generation sequencing of HR genes was performed on available samples using BROCA-HR assay. HR deficiency (HRD) was defined by presence of homozygous deletions or deleterious mutations in HR genes including BRCA1, BRCA2, ATM, and others. The primary endpoint was rPFS and secondary endpoint was overall survival (OS). Results: Eighty-four patients were included in the analysis of whom 26 patients (31.0%) had HRD mCRPC. The most common HR gene alterations included BRCA2 (n=17, 20%), CDK12 (n=9, 11%), and ATM (n=7, 8%). Consistent with our prior report, in the overall cohort, C+O compared to O resulted in a significant improvement in rPFS (Table). The benefit in rPFS was most pronounced in patients with HRD mCRPC; however, there was no difference between arms in HR proficient (HRP) cancers. Independent of arm allocation, rPFS and OS were numerically longer in patients with HRD mCRPC compared to HRP mCRPC (rPFS: 8.8 versus 4.3 months, p=0.14; OS: 18.6 vs. 12.3 months, p=0.24). Conclusions: C+O improved rPFS in patients with mCPRC compared with O alone. The biomarker analyses revealed that the rPFS benefit of C+O over O is likely driven by patients with HRD mCRPC. Our data warrant validation and support further investigation of the combination of C+O in patients with HRD mCRPC. Clinical trial information: NCT02893917. [Table: see text]
Abiraterone decanoate (AD): Potent and long-acting activity of a novel intramuscular (IM) abiraterone prodrug depot in a castrate monkey model.
Authors: Moore William R. , Sharp Matthew , Bell Caroline , Freeman Stuart , Parr Alan , Eisner Joel Robert , Schotzinger Robert
Published: March 2021

78

Background: Oral abiraterone acetate (AA) is a standard of care for castration-resistant (CRPC) and castration-sensitive prostate cancer (CSPC). Due to poor oral bioavailability, the recommended AA dose is 1,000 mg (4 x 250mg) once-daily on an empty stomach. The daily oral regimen produces high peak plasma concentrations that may be associated with safety issues (e.g., hepatotoxicity) and low trough concentrations that may be associated with inadequate CYP17 inhibition. AD is one of a series of novel abiraterone prodrugs that were designed to provide a controlled release of abiraterone and long-acting CYP17 inhibition with IM delivery. Following successful preclinical pilot studies, AD was further developed into a clinically acceptable formulation (PRL-02) and its PK/PD characteristics were evaluated and compared to oral AA in a castrate monkey pharmacology model in support of future clinical development. Methods: Sexually mature male cynomolgus monkeys underwent chemical castration using Lupron depot. Plasma samples were analyzed for prodrug, abiraterone and steroid concentrations following a single oral AA dose (5, 15 or 45 mg/kg) and a single IM AD injection (10, 30 or 100 mg/kg) (n=3/dose group). The combined activity of IM AD plus glucocorticoid replacement (single 0.5 mg/kg IM dexamethasone (DEX) dose or weekly doses of 1.29 mg/kg IM methylprednisolone acetate (MPA)) was also evaluated. AD, abiraterone and adrenal steroid levels were evaluated by LC-MS/MS. Results: Chemical castration resulted in a plasma testosterone (T) decrease of 72% from intact. T was further reduced to sub-castrate levels by both AA and AD (98.6% and 99.7% maximum decrease from castrate baseline, respectively). All dose levels of AD were highly effective in reducing plasma T yet led to abiraterone plasma concentrations (Cmax, AUC, Cmin) that were much less than those associated with steady-state clinical levels from oral AA. Sustained T suppression was observed following all single AD IM doses for 14 weeks, the last timepoint tested.The addition of a glucocorticoid replacement (DEX or MPA) starting at week 9 further reduced T in all AD groups. Conclusions: Single-dose IM AD suppressed T to the same or greater extent than single-dose oral AA in castrate monkeys, while providing much lower abiraterone exposures than the oral acetate prodrug. As such, IM AD may offer an improved risk-benefit profile due to the consistently lower abiraterone levels. The durable, profound T reductions provided by all AD doses are consistent with a 3-month clinical regimen that can be given in conjunction with Lupron. IM AD may thus offer patients with CSPC and CRPC a more convenient, safe and effective alternative than daily oral AA.
ICEPAC: A phase II multicenter study of avelumab combined with stereotactic ablative body radiotherapy (SABR) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Azad Arun , Spain Lavinia Anne , Anton Angelyn , Gan Chun Loo , Garrett Linda , Chang Deborah , Bennett Caitlin , Kothari Gargi , Shaw Mark , Parente Phillip , Pezaro Carmel Jo , Tran Ben , Siva Shankar , Kwan Edmond Michael
Published: March 2021

86

Background: Studies investigating immune checkpoint inhibitors (ICI) in mCRPC have produced modest results. Radiation therapy may be synergistic with ICIs. We hypothesised that SABR would enhance anti-tumour activity of PD-L1 inhibitor avelumab in patients (pts) with progressive mCRPC. Methods: This phase II, single arm, multicentre study enrolled mCRPC pts following progression on ≥1 novel androgen receptor-directed therapy. Up to two lines of prior taxane chemotherapy were permitted. Pts received avelumab 10mg/kg IV q2weeks for a total of 24 weeks (12 cycles). A single fraction of 20Gy SABR was administered to 1-2 disease sites within five days prior to first and second doses of avelumab. Primary endpoint was disease control rate (DCR); secondary endpoints were PSA response (PSA50), overall response rate (ORR), radiographic progression-free survival (rPFS), overall survival (OS) and safety. Radiographic disease assessment (CT and bone scintigraphy) was performed after cycles 6 and 12 of avelumab treatment. Following enrolment of 14 pts, a protocol amendment allowed avelumab beyond 12 cycles in pts with disease control at 24 weeks. Results: Thirty-one pts were enrolled, with 30 evaluable for the primary endpoint. Median follow-up was 18 months (mo). Pt characteristics: median age 71 years (IQR 64-75), bone-only disease 42%, visceral disease 16%, prior taxane chemotherapy 84%, treatment with both abiraterone and enzalutamide 13%. Seventy metastatic sites received SABR, most frequently to bone (90%) and soft tissue (29%) disease. Avelumab was given as second-line, third-line and fourth- or greater line systemic therapy in 29%, 42% and 29% of pts, respectively. Median cycles of avelumab administered was 9 (IQR 5-13). DCR (95% CI) was 50% (31-69) and 60% (32-84) in all-comers and soft tissue disease subgroup, respectively. Following protocol amendment, 7/17 pts (41%) received avelumab beyond 12 cycles. Incidence of grade 3-4 treatment-related AEs was 16% (no grade 5 events), with three pts requiring oral/IV corticosteroid therapy. Conclusions: Avelumab with SABR demonstrated durable disease control in treatment-refractory mCRPC with an acceptable toxicity profile. This combination warrants further investigation. Clinical trial information: ACTRN12618000954224. [Table: see text]
DASL-HiCaP: Darolutamide augments standard therapy for localized very high-risk cancer of the prostate (ANZUP1801)—A randomized phase III double-blind, placebo-controlled trial of adding darolutamide to androgen deprivation therapy and definitive or salvage radiation.
Authors: Niazi Tamim , Williams Scott , Davis Ian D. , Stockler Martin R. , Martin Andrew James , Bracken Karen , Roncolato Felicia , Horvath Lisa , Martin Jarad , Lim Tee Sin , Hughes Simon , McDermott Raymond S. , Catto James WF , Kelly Paul J. , McBride Sean Matthew , Parulekar Wendy R. , Morgan Scott Carlyle , Rendon Ricardo A. , Sweeney Christopher ,   Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: March 2021

TPS266

Background: Radiation therapy (RT), plus androgen deprivation therapy (ADT) with a luteinizing hormone releasing hormone analogue (LHRHA), is standard of care for men with very high-risk localized prostate cancer (PC), or with very high- risk features and persistent PSA after radical prostatectomy (RP). Despite this, incurable distant metastases develop within 5 years in 15% of men with very high-risk features. Darolutamide is a structurally distinct oral androgen receptor antagonist with low blood-brain-barrier penetration, a demonstrated favorable safety profile and low potential for drug-drug interactions. Our aim is to determine the efficacy of adding darolutamide to ADT and RT in the setting of either primary definitive therapy, or adjuvant therapy for very high-risk PC. Methods: This study is a randomized (1:1) phase III placebo-controlled, double-blind trial for men planned for RT who have very high-risk localized PC; or very high-risk features with PSA persistence or rise within one year following RP. The trial will be stratified by: RP; use of adjuvant docetaxel; pelvic nodal involvement. 1100 participants will be randomized to darolutamide 600 mg or placebo twice daily for 96 weeks. Participants will receive LHRHA for 96 weeks, plus RT starting week 8-24 from randomisation. Participants are allowed nonsteroidal antiandrogen (up to 90 days) in addition to LHRHA up until randomisation. Early treatment with up to 6 cycles of docetaxel completed at least 4 weeks prior to RT is permitted. The primary endpoint is metastasis-free survival (ICECaP-validated), with secondary endpoints overall survival, PC-specific survival, PSA-progression free survival, time to subsequent hormonal therapy, time to castration-resistance, frequency and severity of adverse events, health related quality of life, fear of recurrence. Tertiary endpoints include incremental cost-effectiveness, and identification of prognostic and/or predictive biomarkers of treatment response, safety and resistance to study treatment. Clinical trial information: NCT04136353.
Phase III study evaluating efficacy and safety of MK-6482 + lenvatinib versus cabozantinib for second- or third-line therapy in patients with advanced renal cell carcinoma (RCC) who progressed after prior anti-PD-1/L1 therapy.
Authors: Motzer Robert J. , Liu Yanfang , Perini Rodolfo F. , Zhang Yayan , Heng Daniel Yick Chin
Published: March 2021

TPS372

Background: There is an unmet need for treatment options in the second-line or later setting following anti–PD-1/L1 or VEGF tyrosine kinase inhibitor (TKI) therapy in patients with advanced RCC. Hypoxia-inducible factor (HIF)-2α is a transcription factor that has been established as an oncogenic driver in clear cell RCC (ccRCC). Promising antitumor activity has been reported for the first-in-class small molecular HIF-2α inhibitor, MK-6482, in heavily pretreated patients with ccRCC and patients with VHL disease–associated RCC. HIF-2α also regulates VEGF gene expression and plays a role in resistance to anti-VEGF therapy. Therefore, combining MK-6842 with a VEGF receptor TKI, such as lenvatinib, is an attractive treatment option in the advanced RCC setting. Methods: This is a randomized, open-label, active-controlled, multicenter phase III trial evaluating the efficacy and safety of MK-6482 + lenvatinib compared with cabozantinib in patients with advanced ccRCC who have progressed on prior anti–PD-1/L1 therapy (NCT04586231). Eligibility criteria include age ≥18 years; histologically confirmed, unresectable, locally advanced or metastatic ccRCC; disease progression on or after first- or second-line systemic treatment with an anti–PD-1/L1 therapy (monotherapy or in combination with other agent[s]) for locally advanced or metastatic disease, the immediately preceding line of treatment must be an anti–PD-1/L1 therapy; no more than 2 prior systemic regimens, with only 1 prior anti–PD-1/L1 therapy; measurable disease per RECIST v1.1; and Karnofsky performance status ≥70%. Patients must provide tissue for biomarker analysis. Approximately 708 patients will be randomly assigned in a 1:1 ratio to receive MK-6482 120 mg orally once daily (QD) + lenvatinib 20 mg orally QD or cabozantinib 60 mg orally QD. Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent. The stratification factors are International mRCC Database Consortium prognostic scores (0, 1-2, or 3-6), number of prior lines of therapy (1 or 2), and geographic region (North America, Western Europe, or rest of the world). Imaging will be assessed by CT or MRI every 8 weeks through week 80, then every 12 weeks thereafter. The dual primary end points are progression-free survival per RECIST v1.1 as assessed by blinded independent central review (BICR) and overall survival. Secondary end points are objective response rate and duration of response per RECIST v1.1 as assessed by BICR, and safety. Safety and tolerability will be evaluated using a tiered approach. Clinical trial information: NCT04586231 .
A shortcut tour of quantum control methods for modern quantum technologies
Authors: Stefanatos D. , Paspalakis E.
Published: March 2021

Quantum control methods, like rapid adiabatic passage, stimulated Raman adiabatic passage, shortcuts to adiabaticity and optimal control, have become an integral part of modern quantum technologies, for example quantum computation and sensing, where they are exploited in order to find the optimal pulse sequences which drive quantum systems to the desired target state in minimum time or with maximum fidelity, overcoming decoherence and dissipation. In this perspective, we use the basic example of adiabatic population inversion in a two-level system in order to present these methods and review the latest developments in the field, while we touch upon the emerging method of reinforcement learning.
The Conditional Effects of Health on Voter Turnout
Authors: Lyon Gregory
Published: March 2021

Context: Voting is the central instrument of democracy, yet there are a number of impediments that affect citizens' ability to turn out to vote. Health is one such impediment.

Methods: This study draws on 2012 and 2016 election data from the Cooperative Congressional Election Study and the American National Election Studies and uses objective validated measures of voter turnout as well as postelection data on respondents' reasons for nonvoting to examine the relationship between self-reported health and voter turnout.

Findings: The results indicate poor health depresses turnout among low-income voters but not high-income voters. A low-income citizen in poor health is 7 points less likely to turn out to vote than a low-income citizen in excellent health is. In contrast, a high-income citizen in poor health is just as likely to vote as a high-income citizen in excellent health is. Moreover, low-income citizens in poor health are 10 points more likely to cite sickness as an impediment to voting than are otherwise similar high-income citizens who are also in poor health.

Conclusions: The findings have implications for health policy and unequal electoral engagement and suggest that health may narrow the scope of US democracy as poor health pushes low-income citizens out of the electoral sphere while high-income citizens continue to turn out to vote regardless of their underlying health conditions.
Sales Revenue As a Key Audit Issue in Russia
Authors: Sotnikova Lyudmila
Published: March 2021

Organizations whose securities are traded with the organizers of trading in the securities market, which include public joint stock companies, are subject to mandatory audit. Th e auditor’s reports, in accordance with the requirements of International Standard on Auditing 701, issued to such organizations, must disclose key audit matters. Very oft en, auditors opt for such a key issue as “revenue recognition”. Th e article discusses situations when the choice of the topic of the key question on revenue seems insuffi ciently justifi ed, and the wording of the key questions is as identical as if their text was standardized, while the adoption of standard 701 had the opposite goal — information transparency, specifi city and reflection of the characteristics of the activities of each audited entity.
The Influence of Corporate Income Taxes on Investment Location: Evidence from Corporate Headquarters Relocations
Authors: Chow Travis , Huang Sterling , Klassen Kenneth J. , Ng Jeffrey
Published: March 2021

This study examines the effects of jurisdictions’ corporate taxes and other policies on firms’ headquarters (HQ) location decisions. Using changes in state corporate income tax rates across time and states as the setting, we find that a one-percentage-point increase in the HQ state corporate income tax rate increases the likelihood of firms relocating their HQ out of the state by 16.8%, and an equivalent decrease in the HQ state rate decreases the likelihood of HQ relocations by 9.1%. Exploiting the unique tax policy features within the state apportionment system lends strong support to the interpretation that taxation drives this effect. Our analyses also demonstrate that state income tax features affect the destination of the HQ move. We contribute to the literature on corporate decision making by showing how state income taxation affects a real corporate decision that has significant economic consequences for the company and the state.

This paper was accepted by Brian Bushee, accounting.
More firms and organisations can use the Financial Ombudsman Service to get redress against financial product providers
Authors: Bernstein Adam
Published: March 2021

Adam Bernstein explains the purpose of the Financial Ombudsman Service and provides some background information to assist in gaining a further understanding of the service
The nursing management required to provide effective end-of-life care in a care home setting: a case study
Authors: Hickey Simona , Williams Mary
Published: March 2021

Background:

This case study is a practical experience example from a nursing home setting. It will describe how a holistic approach to care, provided to a resident living with dementia at end of life, ensured a peaceful death.

Aims:

The importance of advance care planning and effective pain and symptom management in end-of-life care will be explored. The psychosocial issues experienced by the resident and their family and any ethical issues associated with the delivery of care will be addressed. The factors and challenges that need to be overcome in order to ensure effective pain and symptom management for the dying patient, particularly in a nursing home setting, are discussed. Finally, this article will make recommendations for future practice.

Methods:

This is a case study based on an author's experience while working in a nursing home setting.

Findings:

Challenges associated with end-of-life care have been identified and recommendations have been made.
Why chronic obstructive pulmonary disease care needs a breath of fresh air
Authors: Greener Mark
Published: March 2021

About one million people in the UK have diagnosed chronic obstructive pulmonary disease and live with persistent, unpleasant and often debilitating symptoms. The condition is common among nursing home residents, yet is often poorly recognised by the general public and even by some health professionals. Recent research highlights why nursing and residential care staff should remain vigilant for this common respiratory condition.
The shocking revelations of the Care Quality Commission's report on DNACPR decisions
Authors: Halliwell Amanda
Published: March 2021

During the COVID-19 pandemic, after concerns were raised, the Care Quality Commission was commissioned by the Department of Health and Social care to review DNACPR decision-making. Amanda Halliwell reviews their interim report.
Impact of Biochar on Growth, Physiology and Antioxidant Activity of Common Bean Subjected to Salinity Stress
Authors: Kul Raziye , Ekinci Melek , Turan Metin , Yildirim Ertan
Published: March 2021

A pot study was carried out to evaluate the impacts of biochar applications on the growth, physiological properties, and antioxidant enzyme activity of common beans under salinity stress. The experiment was conducted in a completely randomized design with two salinity levels of NaCl [S0 (control, 0 mM NaCl) and S1 (100 mM NaCl)] and three biochar levels [BC-0 (control, non-biochar), BC-1 (2.5%) and BC-2 (5 %)]. Results of the study revealed that plant growth, relative leaf water content (LRWC), and chlorophyll reading value (CRV) of common bean decreased significantly, while malondialdehyde (MDA), hydrogen peroxide (H2O2), proline, and sucrose content increased significantly with salinity stress. Biochar applications mitigated the negative impact of salinity stress on plant growth and physiological characteristics of common beans. The salinity tolerance due to biochar applications could be associated with a significant reduction of antioxidant activity, MDA and H2O2, and an increase of LRWC and chlorophyll content. Therefore, it can be concluded that biochar could be used to reduce the negative impacts of salinity stress in common bean.