bluuebunny/crossref_metadata_2025 huggingface dataset:
Green analytical chemistry-based spectrophotometric techniques for ternary component analysis of pain relievers
Authors: Arunagiri Thirumalai , Ganesan Alagammai , Ravi Kumaran Vamsi , Masilamani Bharathraj , Kannaiah Kanaka Parvathi , Narayanasamy Damodharan
Published: June 2024

Background

The management of pain presents a significant challenge in healthcare, particularly in cases where conventional therapies prove inadequate. In response to this need, this study aims to devise two innovative UV spectrophotometric techniques rooted in the principles of green analytical chemistry for the analysis of Aceclofenac (ACE), Paracetamol (PAR), and Tramadol (TRM) in both bulk and tablet forms.

Results

Utilizing advanced mathematical methodologies such as the double divisor ratio spectra method and area under the curve, the concentrations of these drugs were accurately determined. Validation of the developed methods adhered to the guidelines outlined by the International Council for Harmonisation in the Q2 (R1), revealing linear calibration curves for ACE (8–12 µg/mL), PAR (22.75–35.75 µg/mL), and TRM (2.62–4.12 µg/mL). Furthermore, statistical analyses employing Student’s t test and F test were conducted to ensure the robustness of the proposed method. The evaluation of environmental impact through green metric tools confirmed the eco-friendliness of the proposed methodologies.

Conclusion

The assessment performed utilizing green metric tools has substantiated the environmental sustainability of the proposed approach. Thus, this methodology offers accurate and reliable outcomes for the determination of three drugs, as indicated by the complete overlap observed in the zero-order spectra.
[68Ga]Ga-ABY-025 PET in HER2-positive breast cancer: Benefits and pitfalls in staging of axillary disease.
Authors: Alhuseinalkhudhur Ali , Lindman Henrik , Liss Per , Frejd Fredrik Y. , Feldwisch Joachim , Brun Nikolai C. , Lubberink Mark , Velikyan Irina , Sörensen Jens
Published: June 2024

1035

Background: [68Ga]Ga-ABY-025 PET showed promising results in quantifying human epidermal growth factor receptor Type 2 (HER2) expression in breast cancer patients [1]. In this study we extend the findings from [68Ga]Ga-ABY-025 PET with data from both treatment-naïve patients and previously treated patients with recurrences, mimicking the clinical situation other sites might encounter when HER2-targeting imaging is made more widely available. The focus of this additional data analysis is on staging, potential pitfalls and changes in uptake patterns associated with previous treatments. Methods: [68Ga]Ga-ABY-025 PET and [18F]-FDG PET images from 50 women with biopsy confirmed HER2 positive breast cancer were examined. Each patient underwent both scans within 1 week. A follow-up [18F]-FDG PET was performed after 2 courses of HER2-targeted treatment to assess metabolic response. Results: Twelve out of 50 patients showed heterogeneous [68Ga]Ga-ABY-025 uptake. Three out of these 12 patients presented with a wider local spread that was only detectable using [68Ga]Ga-ABY-025 PET as distinct uptake in lymph nodes of 2-5 mm size. Based on the additional information from [68Ga]Ga-ABY-025 PET, restaging was evaluated in two of the three cases, both of which had lobular carcinoma, and resulted in modifications in treatment plans. Two patients who received COVID-19 vaccine closely before undergoing PET scans showed high uptake on [18F]-FDG PET in lymph nodes ipsilateral to the vaccine injection site, but not on [68Ga]Ga-ABY-025 PET. Additionally, the physiological [68Ga]Ga-ABY-025 uptake in thyroid gland and axillary sweat glands was inversely correlated with the number of previous treatments and was significantly more pronounced in treatment-naïve patients. Conclusions: [68Ga]Ga-ABY-025 PET provided additional information that, in conjunction with [18F]-FDG PET findings, might help in accurate staging, particularly in cases with very small lymph node metastases. It also helped reduce false positive results as [68Ga]Ga-ABY-025 uptake was so far not seen in any benign inflammatory lesions. Physiological uptake can be seen in thyroid and apocrine glandular tissues but gradually disappear with subsequent HER2-targeted therapies. 1,Alhuseinalkhudhur, A. et al. J Nucl Med, 2023 64(9): p. 1364-1370. Clinical trial information: NCT03655353 .
Effects of immune-enhancing nutrition on radical cystectomy outcomes: Primary results from the randomized phase III double-blind clinical trial (S1600).
Authors: Hamilton-Reeves Jill , Unger Joseph M. , Holzbeierlein Jeffrey , Lew Danika , Mark James Ryan , Daneshmand Siamak , Kukreja Janet Baack , Lee Eugene K. , Tabayoyong William , Hershman Dawn L. , Fisch Michael Jordan , Henry Norah Lynn
Published: June 2024

4501

Background: SWOG S1600 was a randomized, double-blind, phase III trial comparing the impact of consuming Specialized IMmunonutrition (SIM) to oral nutritional support (ONS) on postoperative complications following radical cystectomy (RC). SIM is fortified with nutrients: L-arginine; omega-3 fatty acids; and dietary nucleotides. Methods: Patients with bladder carcinoma planning to undergo RC were enrolled and randomized 1:1 to SIM vs. ONS. The primary endpoint was any (≥Grade I) postoperative complication assessed by the Clavien-Dindo (CD) scale at Day 30 after RC. Multivariable logistic regression was used, adjusted for the stratification factors: diversion type (neobladder vs. ileal conduit), prior neoadjuvant chemotherapy (any vs. none), and baseline nutrition status (well-nourished vs. moderate malnutrition). Additional outcomes included 90-day complications and high-grade (CD ≥Grade III) complications. Two-year progression-free survival (PFS) and overall survival (OS) were assessed; differences by arm were reported using Log-rank test statistics. Protocol-specified intention-to-treat (ITT) analyses based on all randomized patients and 1-sided alpha=.05 tests were performed. Results: Among N=203 enrolled patients (99 on SIM, 104 on ONS), median age was 68.8 years, 20% were female and 5% were Black. Five patients did not meet eligibility criteria (1 on SIM, 4 on ONS) but were included under the ITT design. Seventeen patients withdrew consent prior to their Day 30 assessment, and 8 patients were not assessed; thus, n=178 (90 on SIM, 88 on ONS) were evaluable at Day 30. The proportion of patients experiencing CD Grade ≥1 complications was 62.2% for SIM and 58.0% for ONS; in multivariable regression, there was no difference in Grade ≥1 complications by arm (OR=1.18, 95% CI, 0.64-2.18, 1-sided p=.71). There were no differences by arm in high-grade complications at Day 30, in any or high-grade complications at Day 90 or overall. To date, among all 203 patients, 17 on SIM and 26 on ONS have progressed or died, with 2-year PFS estimates of 77.2% and 68.3%, respectively (1-sided p=.16). Nine patients on SIM and 17 on ONS have died, with 2-year OS estimates of 87.4% and 78.2%, respectively (1-sided p=.07). Conclusions: There was no difference in any grade CD complications by type of nutritional supplement for patients with bladder cancer undergoing RC. Fewer patients on the SIM arm have progressed or died, although differences were not statistically significant; follow-up for survival will continue through 3-years after enrollment. Future work to understand the interaction of diet on cancers sensitive to immune modulation is needed. Clinical trial information: NCT03757949 .
Characterization of complete responders to nivolumab + gemcitabine-cisplatin vs gemcitabine-cisplatin alone and patients with lymph node–only metastatic urothelial carcinoma from the CheckMate 901 trial.
Authors: Galsky Matt D. , Sonpavde Guru P. , Powles Thomas , Claps Melanie , Burotto Mauricio , Schenker Michael , Sade Juan Pablo , Bamias Aristotelis , Beuzeboc Philippe , Bedke Jens , Oldenburg Jan , Ürün Yüksel , Ye Ding-Wei , Valderrama Begoña Pérez , Tomita Yoshihiko , Filian Jeiry , Wang Lily , Purcea Daniela , Van Der Heijden Michiel Simon
Published: June 2024

4509

Background: In the CheckMate 901 trial, combination nivolumab (NIVO) + gemcitabine-cisplatin (GC) demonstrated significant improvements in overall survival (OS) and progression-free survival (PFS) with compelling objective response rates (ORR; 57.6% with NIVO+GC vs 43.1% with GC alone) and deep, durable complete responses (CR; 21.7% with NIVO+GC vs 11.8% with GC alone) in patients (pts) with previously untreated unresectable or metastatic urothelial carcinoma (mUC). Lymph node (LN)-only metastatic disease is a favorable prognostic factor in pts with mUC and a subset of pts achieve durable disease-free, treatment-free survival with GC +/- surgical consolidation. We conducted a post hoc analysis to characterize the subset of pts with CR, with further analysis of pts with LN-only mUC. Methods: In the global, open-label, randomized, phase 3 CheckMate 901 (NCT03036098) trial, cisplatin-eligible pts received NIVO 360 mg + GC every 3 wk for ≤6 cycles followed by NIVO 480 mg every 4 wk until disease progression/unacceptable toxicity or up to a maximum of 2 yrs, or GC every 3 wk for ≤6 cycles. Primary endpoints were OS and PFS by blinded independent central review (BICR). ORR per BICR and safety were exploratory endpoints. These post hoc analyses evaluated treatment outcomes in complete responders and in pts with LN-only disease. Results: Of the 608 pts randomized, 102 (16.8%) achieved a CR. Baseline disease characteristics of these pts are shown in the Table. As pts with LN-only mUC were enriched in the CR group, additional analysis of this subgroup was performed. Of all randomized pts, 54 treated with NIVO+GC and 56 treated with GC had LN-only mUC. In these pts, the ORR and CR rate was 81.5% (95% CI 68.6-90.7) and 63.0% versus 64.3% (50.4-76.6%) and 33.9% for NIVO+GC and GC, respectively. Median OS (95% CI) in LN-only pts was 46.3 (24.0-NE) mos with NIVO+GC vs 24.9 (21.4-29.9) with GC (HR, 0.58, 95% CI 0.34-1.00), and median PFS (95% CI) was 30.5 (9.6-NE) mos with NIVO+GC vs 8.8 (7.5-10.9) mos with GC (HR 0.38, 95% CI 0.22-0.66). Conclusions: NIVO+GC generated deep responses in CheckMate 901 with a fixed duration of chemotherapy and up to 2 years NIVO. Exploratory characterization of pts with CR identified a group of pts enriched with LN-only disease.In pts with LN-only mUC, NIVO+GC induced durable disease control and clinically meaningful improvements in OS and PFS vs GC alone. These results provide additional support for NIVO plus cisplatin-based chemo as a first-line treatment option for pts with mUC. Clinical trial information: NCT03036098 . [Table: see text]
A multicenter phase II study of modified FOLFIRINOX for first-line treatment for advanced urachal cancer (ULTMA; KCSG GU20-03).
Authors: Lee Jae-Lyun , Park Inkeun , Yoon Shinkyo , Shin Sang Joon , Shin Seong-Hoon , Park Kwonoh , Kim Jung Hoon , Lee Hyo Jin
Published: June 2024

4510

Background: Systemic therapy is used for advanced urachal cancer that is not amenable to surgery. However, due to the low incidence of this disease, prospective clinical trials have not been conducted and there is no established standard of care. 5-FU, oxaliplatin, and irinotecan have synergistic mechanisms of action, do not overlap in major side effects, and all have the potential to be effective in urachal cancer. The ongoing ULTIMA trial (NCT04611724) is evaluating the efficacy and safety of modified FOLFIRINOX in patients with advanced urachal cancer. Methods: Patients with recurrent or metastatic urachal cancer with measurable lesions received modified FOLFIRINOX (Oxaliplatin 85 mg/m2 over 2 hours, Irinotecan 150 mg/m2 over 1.5 hours, Leucovorin 400 mg/m2 over 2 hours and 5-FU 2400 mg/m2 over 46 hours) with prophylactic pegteograstim 6 mg SC on day 3 Q2W till 12 cycles (or until progression or unacceptable toxicities). Response evaluation was done every 6 weeks. The primary endpoint is an ORR. The secondary objectives include PFS, OS and incidence of febrile neutropenia. Simon’s minimax two-stage design was employed to test null hypothesis P0=17% and P1=36%, with alpha of 5% and beta of 20%. The primary endpoint was met at the first stage and we decided to report the results. Results: From April 2021 to November 2023, 21 patients with advanced urachal cancer were enrolled in 5 cancer centers. A median age was 50 (28-68) and 15 were male. Lung was the most frequent site of metastasis (47.6%) followed by lymph node (38.1%) and peritoneal seeding (33.3%). As of December 2023, 18 patients discontinued treatment. A total of 235 cycles were administered with a median of 12 (6-12) cycles per patient. Two patients achieved CR and 11 patients PR with an ORR of 61.9%; the study met the primary endpoint in the first stage. With a median FU duration of 15.2 months, the median PFS was 9.3 months (95% CI, 6.6~12.0) and estimated median OS was 26.4 months (95% CI, 14.7-38.1). The treatment was tolerable and have no unexpected adverse events. Grade 3 adverse events included neutropenia (4.8%), anemia (9.5%), thrombocytopenia (4.8%) and diarrhea (4.8%). There were neither febrile neutropenia nor grade 4 adverse events. Conclusions: The first prospective ULTIMA study showed encouraging ORR and PFS in patients with advanced urachal cancer. The regimen is well tolerated without febrile neutropenia with prophylactic pegteograstim. Further analysis of efficacy will be presented. Clinical trial information: NCT04611724 .
A phase 1 study of JNJ-69086420 (JNJ-6420), an actinium-225 (225Ac) -labeled antibody targeting human kallikrein 2 (hK2), for metastatic castration-resistant prostate cancer (mCRPC).
Authors: Morris Michael J. , Wong Jeffrey Y.C. , Nordquist Luke , Szmulewitz Russell Zelig , Agarwal Neeraj , Attiyeh Edward F. , Max Steven I , Divgi Chaitanya R. , Patricia Daniel , Cao Yu , Li Xiang , Yu Alex , Urtishak Karen , Lauring Josh David , Sartor Oliver
Published: June 2024

5010

Background: hK2 (encoded by the KLK2gene) is a novel target expressed on the cell surface of prostate cancer cells with restricted expression elsewhere. JNJ-6420 is a first-in-class anti-hK2 antibody–based targeted radiotherapy delivering 225Ac, a high-energy short-range alpha-particle emitter, to prostate cancer cells. Here we report the first-in-human study evaluating JNJ-6420 in heavily pretreated biomarker-unselected participants (pts) with mCRPC who received ≥1 prior androgen receptor pathway inhibitor. Methods: Intravenous JNJ-6420 was escalated from 50 μCi to 400 μCi every 8-12 weeks in the outpatient setting with no residential radioprotective restrictions. Prior radioisotopic therapy was an exclusion criterion. Primary objectives were safety and defining a recommended phase 2 dose (RP2D). Secondary objectives included preliminary assessment of clinical activity. Results: As of January 5, 2024, 67 pts received ≥1 JNJ-6420 dose. Exposure and clinical activity for the 57 pts in the ≥150 μCi JNJ-6420 cohorts are summarized (see Table); 35/57 (61.4%) experienced grade ≥3 TEAEs, and 21 (36.8%) had a serious TEAE. TEAEs of note included thrombocytopenia (63.2%) and interstitial lung disease (ILD, 9%). All instances of ILD occurred at cumulative doses ≥500 μCi and prior to implementation of pulmonary function surveillance. Grade ≥3 TEAEs (≥10%) included anemia (26.3%), thrombocytopenia (17.5%), lymphopenia (10.5%), and leukopenia (10.5%). 9/57 (15.8%) pts discontinued treatment due to TRAEs; 4 TRAEs resulted in death. At doses ≥150 μCi, the PSA50 rate was 45.6%. To date, across all dose cohorts, 31 pts (46%) remained on treatment for ≥24 weeks. Prolonged clinical, biochemical, and radiographic responses were noted in pts receiving doses of 150 μCi and higher. Durable responses included pts on treatment for 112 weeks (96 weeks since last dose), 88 weeks (13 weeks since last dose), and 46 weeks (after a single dose). Conclusions: In this first-in-human study, key TEAEs of JNJ-6420 were thrombocytopenia and ILD, both associated with repeated dosing. At ≥150 μCi, 1-2 doses of JNJ-6420 elicited profound and durable biochemical and radiographic responses. Evaluation of the RP2D is ongoing. These data highlight hK2 as a novel target for targeted alpha-particle therapy. Clinical trial information: NCT04644770 . [Table: see text]
Oncogenic alteration rates, race, and prostate cancer specific mortality in Veterans with metastatic prostate cancer undergoing somatic tumor next generation sequencing.
Authors: Valle Luca Faustino , Li Jiannong , Desai Heena , Hausler Ryan , Haroldsen Candace , Kelley Michael J. , Rebbeck Timothy , Rose Brent S. , Rettig Matthew , Nickols Nicholas George , Garraway Isla , Yamoah Kosj , Maxwell Kara Noelle
Published: June 2024

5017

Background: National guidelines recommend next generation sequencing (NGS) of tumors from patients diagnosed with metastatic prostate cancer (PCa) to identify potential actionable alterations. We sought to determine associations between alteration frequencies of PCa-related genes and pathways, self-identified race, and PCa specific mortality (PCSM) in Veterans. Methods: This comprehensive retrospective cohort study evaluated the association of somatic alterations with race in Veterans with metastatic PCa who obtained NGS through the Veterans Affairs National Precision Oncology Program. NGS data was linked to clinicopathologic and social determinants of health (SDOH) data elements. Multivariate logistic regression permitted associations between race and genomic alteration frequencies, adjusted for specimen tested and clinical and SDOH co-variates. Cox proportional hazards models permitted associations of race, alteration frequencies, and PCSM, stratified by genomic alteration frequencies and adjusting for race, clinicopathologic features, and SDOH. Results: 5015 Veterans with metastatic PCa and self-identified race/ethnicity as non-Hispanic Black (NHB, n=1784) and non-Hispanic White (NHW, n= 3231) were included. NGS was conducted on primary tumors (n= 2359), metastases (n = 1011), and cfDNA (n = 1644). NHB Veterans were younger, had higher PSA at PCa diagnoses, were less likely to report Agent Orange exposure, and resided in more deprived neighborhoods. Upon adjusting for tissue sequenced and clinicopathologic variables, NHB race/ethnicity was significantly associated with a higher rate of genomic alterations in immunotherapy targets, SPOP and BRAF(p<0.05 for all) .Furthermore , NHB race/ethnicity was significantly associated with lower rates of genomic alterations in the AKT/PI3K pathway, AR axis ,and tumor suppressor genes including TP53and PTEN(p<0.05 for all). While alterations in TP53 (HR 1.5 [1.1-2.0], p=0.007), and tumor suppressor pathways (HR 1.3 [1.0-1.8], p=0.04) conferred a significantly higher risk of PCSM in all men on adjusted analysis, race was not independently associated with PCSM. Conclusions: In this diverse cohort of Veterans undergoing NGS for metastatic PCa in the equal access VA healthcare system, we observed significant differences in alteration rates of several oncogenic genes/pathways by race. While alterations in tumor suppressor genes were significantly associated with PCSM, race was not. Thus, there remains a critical need for integrating personalized approaches to patient selection for metastatic PCa treatments in order to improve disease-specific outcomes across diverse populations.
Prognostic implications of PSA levels at 7 months in metastatic hormone-sensitive prostate cancer treated with enzalutamide: Landmark analysis of ENZAMET (ANZUP 1304).
Authors: Mc Laughlin Ronan Andrew , Thomas Hayley , Davis Ian D. , Zielinski Robert Richard , Thomson Alastair , Tan Thean Hsiang , Sandhu Shahneen , Reaume M. Neil , Pook David William , Parnis Francis , North Scott A. , Marx Gavin M. , McCaffrey John , McDermott Raymond S. , Horvath Lisa , Frydenberg Mark , Chowdhury Simon , Chi Kim N. , Stockler Martin R. , Sweeney Christopher ,   Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: June 2024

5079

Background: ENZAMET (NCT02446405) showed that enzalutamide added to testosterone suppression (TS) with or without docetaxel improves overall survival (OS) compared with TS plus standard non-steroidal anti-androgen (NSAA) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We assessed PSA levels in ENZAMET participants at 7 months after randomization to determine correlations with OS. In CHAARTED, participants with mHSPC high volume disease (HV), 20% achieved PSA ≤ 0.2 with ADT (androgen deprivation therapy) alone versus 44% with low volume disease (LV) and for HV with ADT + Docetaxel, 36% achieved PSA ≤ 0.2 vs 64% with LV. Methods: Participants were included if they were followed for at least 7 months after randomization, and had availability of PSA and outcome data. Landmark analysis at 7 months used prognostic classifiers as previously identified in SWOG 9346 and CHAARTED of PSA ≤ 0.2 and > 0.2 at 7 months after initiation of therapy. Results: The total number of ENZAMET participants (pts) with PSA at 7 months of ≤0.2ng/mL was 646 of 1125 (57%): 271/562 (48%) in the NSAA arm versus 375/563 (67%) in the ENZA arm. Five-year OS for TS + NSAA (±Doc) arm PSA ≤ 0.2 = 71% vs PSA > 0.2 = 36% and for TS + ENZA (±Doc) arm PSA ≤ 0.2 = 74% vs PSA > 0.2 = 43%. The % of pts with PSA levels at 7 months ≤0.2ng/mL and corresponding 5-year OS outcomes by key prognostic groups (HV vs LV) ± docetaxel is shown (Table). In comparison with CHAARTED in those with HV, 37% achieved PSA ≤ 0.2 with ADT alone versus 61% with LV which increased to 55% for HV and 79% for LV respectively with addition of enzalutamide. In those with HV treated with ADT + D 39% achieved PSA ≤ 0.2 vs 58% with LV increasing to 60% for HV and 74% for LV respectively with addition of enzalutamide. Conclusions: A PSA nadir of ≤0.2 at 7 months is associated with a longer OS regardless of treatment and prognostic group (HV vs LV). Enzalutamide increased the rate of achievement of PSA <0.2 for all groups. Clinical trial information: NCT02446405 . [Table: see text]
Correlation of body mass index (BMI) with survival outcomes in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC): Analysis of patient (pt)-level data from SWOG 1216 study.
Authors: Swami Umang , Jo Yeonjung , Narang Arshit , Plets Melissa , Hage Chehade Chadi , Gebrael Georges , Gupta Shilpa , Myint Zin , Tangen Catherine , Lara Primo N , Thompson Ian M. , Hussain Maha H. A. , Dorff Tanya B. , Lerner Seth P. , Agarwal Neeraj
Published: June 2024

5081

Background: Obesity has been associated with improved survival outcomes in metastatic castration-resistant prostate cancer (PMID: 34226662). However, association of obesity with survival has not been reported in mHSPC setting. Herein we report the correlation of BMI with survival outcomes from patient level data from phase III study, SWOG 1216 which randomized pts with mHSPC in 1:1 to ADT + bicalutamide or ADT + orteronel. Methods: Inclusion: all pts treated on SWOG 1216 study with available BMI. Overall survival (OS) was summarized by median survival and its 95% confidence interval (CI). Multivariate analysis for OS was conducted using Cox proportional hazard model with categorized BMI as a continuous variable, and adjusted for treatment arm, disease burden, Gleason score, log 2 PSA, age and Zubrod performance status. All analysis was conducted using R v4.2.1. Results: Of 1279 pts, 12 were underweight, 252 had normal BMI, 958 were overweight and 57 were obese. Median age was 67.8 (IQR: 61.9, 73.9) years, no visceral metastases (88%) and baseline log2 median PSA of 4.89 (IQR: 3.27, 6.76). All four BMI cohorts had similar age, Gleason score, extensive disease burden, liver metastases and treatment allocation (p>0.05). Differences in baseline PSA and Zubrod performance status were observed between BMI cohorts (p<0.05). The OS (in years) in underweight, normal, overweight and obese cohorts was 1.8, 4.4, 6.5 and 4.8 for bicalutamide arm and 2.8, 5.7, not reached (NR) and NR for orteronel arm, respectively. After adjusting for prognostic variables, multivariate analysis confirmed that high BMI is associated with better OS (HR=0.82, 95% CI: 0.68-0.98; p=0.029) (Table). Conclusions: Our results show that as categorized BMI increased, the risk of death decreased in pts with mHSPC. These data warrant external validation in other randomized phase III studies and can help counseling and prognostication of patients with mHSPC in the clinic. Funding: NIH/NCI grants CA180888, CA180819, and in part by Millennium Pharmaceuticals (Takeda Oncology Company). Clinical trial information: NCT01809691 . [Table: see text]
Impact of alterations in tumor suppressor genes (TSG-alt) on survival outcomes in patients (pts) with de novo metastatic castration-sensitive prostate cancer (dn-mCSPC) receiving androgen deprivation therapy (ADT) with androgen receptor pathway inhibition (ARPI) or docetaxel.
Authors: Narang Arshit , Graf Ryon P , Gebrael Georges , Hage Chehade Chadi , Li Gerald , Ozay Zeynep Irem , Mazumder Archisman , Mathew Thomas Vinay , Maughan Benjamin L. , McKay Rana R. , Antonarakis Emmanuel S. , Swami Umang , Agarwal Neeraj
Published: June 2024

5091

Background: TSG-alt have been associated with poor survival in the mCRPC setting (PMID: 31061129) and in the mCSPC setting from small single institution cohorts (PMID: 34294873). However, large studies evaluating their impact on survival outcomes with ADT intensification in mCSPC setting are lacking. Herein, we evaluate the impact of TSG-alt on outcomes in a large real-world patient population with dn-mCSPC receiving ADT treatment (Rx) with ARPI or docetaxel. Methods: This study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine Prostate Cancer clinical-genomic database (FH-FMI CGDB), with de-identified data originating from approximately 800 US cancer clinics. Inclusion criteria: dn-mCSPC, tissue biopsy within 90 days of diagnosis, and initiation of ARPI or docetaxel + ADT within 120 days of diagnosis. Time to castration-resistance (TTCR) and overall survival (OS), indexed from metastatic diagnosis, were evaluated with Cox proportional hazards models adjusted for baseline prognostic factors (PSA, Gleason score, age, ECOG, hemoglobin, alkaline phosphatase, and albumin). OS risk intervals were left truncated to date of comprehensive genomic profiling report to adjust for immortal time bias. Results: Of 5356 pts in FH-FMI CGDB, 571 met inclusion criteria. Of these, 321 received ADT + ARPI and 250 ADT + docetaxel. Pts with pathogenic TSG alt were: 214 TP53 (37%), 154 PTEN (27%), and 37 RB1 (6%). Results are summarized in Table. Conclusions: In this real-world analysis, alt RB1 and alt TP53 had worse OS than their respective wild-type (wt) counterparts with both ARPI and docetaxel whereas alt PTEN had similar OS with ARPI and Docetaxel in dn-mCSPC pts. Based on these results, RB1 and TP53 may represent prognostic biomarkers guiding treatment selection and clinical trial enrollment in dn-mCSPC and may assist with counseling and prognostication. [Table: see text]
A phase 1/2 study of the TORC1/2 inhibitor onatasertib combined with toripalimab in patients with advanced solid tumors: Cervical cancer cohort.
Authors: Yuan Li , Shu Pei , Li Xiaoyu , Li Guiling , Zhang Keqiang , Lai Lin , Hong Jinsheng , Huang Chu-Ying , Wang Yongsheng , Xie Hui , Zheng Li , Zhou Qi
Published: June 2024

5509

Background: Preliminary clinical data of oral TORC1/2 inhibitor, onatasertib (ATG-008), demonstrated anti-tumor activity and acceptable tolerability when combined with toripalimab (tori), an anti-PD-1 monoclonal antibody in solid tumors, especially in cervical cancer (CC). Here, we present results from the anti-PD1 naïve CC cohort of the TORCH-2 study who had at least prior 1 line of chemotherapy with the combination of onatasertib and tori. Methods: The TORCH-2 study is a phase 1/2 open-label, dose escalation and expansion trial of Onatasertib in combination with tori in patients (pts) with advanced solid tumours (NCT04337463). Eligibility criteria included at least one measurable lesion, ECOG 0-1 and adequate organ function. Pts with prior PI3K/AKT/mTOR inhibitor therapy were excluded, regardless of PD-L1 expression. Onatasertib was administered 15mg orally once a day (QD) in combination with tori 240 mg, once every 21 days (Q3W), which is the recommended phase 2 dose for the combination based on previous data. Efficacy assessments were reported based on RECIST1.1 criteria. Results: As of Oct 20, 2023, 31 checkpoint inhibitor (CPI) naïve advanced CC pts who had at least prior 1 line of systemic chemotherapy were enrolled. Median age was 54 years. Baseline ECOG scores were 0 (11 pts) and 1 (20 pts); 29 pts had stage IV disease. There were 19 and 12 pts who had received 1 and ≥2 prior lines of systemic therapy, respectively. The median time from last prior systemic therapy was 16.7 months(m). The efficacy-evaluable population (30 CC pts) had an overall response rate (ORR; best response) of 53.3% (16/30, 3 responders unconfirmed), including 4 CR and 12 PR. The disease control rate was 86.7%. The median time to response was 1.4 months. Median progression free survival (PFS) and 24m PFS rate was 8.4 m and 31.0%, respectively. Median overall survival (OS) was not reach and 24m OS rate was 51.6%. The ORRs of PD-L1 positive, PD-L1 negative, and PD-L1 NA populations were 61.5% (8/13), 55.6% (5/9), and 37.5% (3/8), respectively. One CC pt with negative PD-L1 expression achieved CR and remains on treatment for over 3 years. Thirty pts (96.8%) had ≥ 1 TEAEs; 13 (41.9%) pts had grade ≥ 3 TRAEs. The most common grade ≥ 3 TRAEs included rash (12.9%), lymphocyte count decreased (9.7 %), and decreased platelet count (6.5%). Conclusions: Onatasertib in combination with tori is tolerable with encouraging response rate and disease stabilisation in CC pts at the RP2D combination dose, regardless of PD-L1 expression. Enrolment in the expansion cohort for CPI-treated CC is ongoing, and updated data will be presented. Clinical trial information: NCT04337463 .
Imlunestrant, an oral selective estrogen receptor degrader (SERD), as monotherapy and in combination with abemaciclib, in endometrioid endometrial cancer (EEC): Results from the EMBER phase 1a/1b study.
Authors: Yonemori Kan , Banda Kalyan , Boni Valentina , Sohn Joohyuk , Meniawy Tarek , Lombard Janine Margaret , Kaufman Peter A. , Richardson Debra L. , Bender Somme Laura , Matsumoto Koji , Giridhar Karthik , Garcia Saenz Jose Angel , Prenen Hans , Doger de Spéville Uribe Bernard , Dizon Don S. , García-Corbacho Javier , Li Yujia , Nguyen Bastien , Ismail-Khan Roohi , Neven Patrick
Published: June 2024

5589

Background: Imlunestrant is a next-generation oral SERD designed to deliver continuous estrogen receptor (ER) target inhibition aimed to improve outcomes for patients (pts) with ER+ cancers. In the first-in-human Phase 1a/1b EMBER trial (NCT04188548), imlunestrant showed favorable safety, pharmacokinetics, and clinical benefit in pre-treated pts with ER+ advanced breast cancer or EEC. Here, we report updated imlunestrant monotherapy data and the first clinical data of imlunestrant + abemaciclib in ER+ EEC pts from EMBER. Methods: Eligible pts had ER+ EEC previously treated with (or deemed inappropriate for) platinum-containing chemotherapy. Prior fulvestrant or aromatase inhibitor therapy was not allowed. In Phase 1a, pts received imlunestrant alone, and in Phase 1b, pts were randomized (1:1) to imlunestrant alone or with abemaciclib. Plasma samples were collected at baseline (all pts) and at cycle 2 (monotherapy pts) for ctDNA analysis (Guardant 360 assay) to correlate with clinical benefit. Primary endpoints were RP2D of imlunestrant monotherapy and in combination. Secondary endpoints included safety, tolerability, and overall response rate (ORR), clinical benefit rate (CBR: complete or partial response, or stable disease ≥24 weeks), and progression-free survival (PFS) using RECIST v1.1. Results: Overall, 72 pts were treated; 39 pts received monotherapy (33 at 400mg [RP2D] and 6 at 800mg po daily) and 33 pts received imlunestrant (29 at 400mg and 4 at 800mg po daily) + abemaciclib (150mg po twice daily). Baseline characteristics, safety, and preliminary efficacy are presented (Table). For monotherapy, the most common TEAEs (all grade/grade 3) were nausea (36%/3%), diarrhea (26%/0), urinary tract infection (26%/3%), and abdominal pain (21%/8%). For imlunestrant + abemaciclib, the most common TEAEs (all grade/grade 3) were diarrhea (88%/3%), nausea (67%/0), fatigue (49%/9%) and anemia (46%/12%). In the monotherapy arm, pts with deeper (≥ 50%) declines in ctDNA variant allele frequency had a higher CBR (4/7 vs 4/17). Conclusions: Imlunestrant, as monotherapy or with abemaciclib, appears safe and tolerable with preliminary evidence of efficacy in pts with metastatic ER+ EEC. Clinical trial information: NCT04188548 . [Table: see text]
Prospective evaluation of the effect of 3 days of post-chemotherapy dexamethasone on patient reported symptoms in gynecologic oncology patients treated with carboplatin and paclitaxel.
Authors: Hart Hayley , Morse Christopher , Krivak Thomas C. , Miller Eirwen Murray , Crafton Sarah , Wield Alyssa , Olawaiye Alexander , Amjad Ali Imran , Graham Emily , Li Tammy , English Heather , Kinzler Donna Marie , Nakayama John
Published: June 2024

5618

Background: Chemotherapy is associated with many adverse side effects including nausea, myalgia, and emotional stress. Some providers recommend three days of dexamethasone (supplemental dexamethasone) following chemotherapy in an effort to mitigate these toxicities. This study seeks to determine if supplemental dexamethasone affects patient-reported outcomes in patients receiving carboplatin and paclitaxel. Methods: Patients with gynecologic malignancies receiving carboplatin and paclitaxel every 3 weeks were eligible. In this prospective case-control study, patients receiving (cases) supplemental dexamethasone (8mg once daily x 3 days starting on post-chemotherapy day 1) were compared with those patients that did not receive delayed dexamethasone (controls). Decision for supplemental dexamethasone was based on provider’s discretion. The FACT-G7, a validated survey assessing the impact of chemotherapy on patients’ quality of life, was administered by telephone one week after each chemotherapy cycle for up to 6 cycles. Pain during post-chemotherapy days 1-3 was also assessed with an additional survey question. FACT-G7 composite score was our primary outcome of interest. The student’s t-test was used to compare the FACT-G7 and average pain scores between cases and controls at each survey point. Results: Fifty-two patients were enrolled, 26 received supplemental dexamethasone and 26 did not. At interim analysis, 94% of subjects have completed all 6 survey time points. The initial response rate was 98.0%. FACT-G7 scores (Table) were significantly higher, corresponding to less symptoms, in patients treated with supplemental dexamethasone after cycles 4-6. Pain scores in post-chemotherapy days 1-3 were lower following cycle 3 for the supplemental dexamethasone group (p=.0083). Conclusions: Supplemental dexamethasone after carboplatin and paclitaxel for patients with gynecologic malignancies improves patient-reported outcomes. This improvement was limited to cycles 4-6, suggesting possible mitigation of cumulative chemotherapy toxicities.[Table: see text]
The efficacy and safety of presurgical therapy with tislelizumab and axitinib for renal cell carcinoma with inferior vena cava tumor thrombus.
Authors: Wang Xuegang
Published: June 2024

e16508

Background: There is no currently consensus on presurgical therapy for renal cell carcinoma (RCC) with inferior vena cava (IVC) tumor thrombus. Tyrosine kinase inhibitor (TKI) combined with immune checkpoint inhibitor (ICI) had shown a survival benefit in metastatic RCC patients in clinical trials. However, the efficacy of presurgical therapy with combined ICI and TKI for nonmetastatic RCC with IVC tumor thrombus has not been adequately investigated. Methods: We retrospectively evaluated 7 patients of nonmetastatic RCC with IVC tumor thrombus treated with tislelizumab and axitinib as presurgical therapy and radical nephrectomy and tumor thrombectomy at the First Affiliated Hospital of Xiamen University from May 2020 to December 2022. All patients received combination therapy of tislelizumab and axitinib preoperatively for 3 cycles. The IVC tumor thrombus improvement by Mayo level and diameter were evaluated on magnetic resonance imaging (MRI), and clinical response of primary renal mass and adverse events (AEs) were evaluated using Response Evaluation Criteria in Solid Tumors 1.1 criteria and National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 criteria. Results: 7 RCC with IVC tumor thrombus patients received neoadjuvant tislelizumab combined axitinib, with a median age of 62 (50-72) years. 71.4% (5/7) were male, 71.4% (5/7) were diagnosed histologically with clear cell RCC, while 28.6% (2/7) were Type I papillary RCC. 57.1% (4/7) were Mayo level 2 tumor thrombus and 42.9% (3/7) were Mayo level 3. At follow-up after systematic therapy, 57.1% (4/7) patients had a reduction in Mayo level of tumor thrombus. The median decrease in thrombus dimeter and length was 5.3 (1.8-17.2) mm and 18.5 (4.4-41.5) mm, respectively. The overall response rate (ORR) in primary renal mass was 57.1% (4/7) with 4 partial responses (PR). Radical nephrectomy and thrombectomy were performed for all 7 patients at 1.5 months after finish of presurgical therapy, with 5 patients performed robotic surgery and 2 patients performed open surgery. 3 patients were planned to have hepatic vein clamping and liver mobilization but following treatment, neither of these manoeuvers was needed. The median operative time was 293 (240-322) minutes, the median blood loss was 1187 (750-2000) mL. The most common AE were all grade 1-2, only 1 patient occurred grade 4 liver function injury which did not affect normal operation after symptomatic treatment. During a median follow-up of 24.9 (14.0-45.0) months, only 1 patient had local IVC tumor thrombus metastasis, disease recovered stabilized after stereotactic radiotherapy. Conclusions: Presurgical therapy with tislelizumab and axitinib for RCC patient could be effective in reducing IVC tumor thrombus and were able to undergo easier radical surgery without serious AE.
Real-world data (RWD) with avelumab in patients (pts) with locally advanced or metastatic urothelial cancer (la-mUC): The AVEBLADDER study.
Authors: Sotelo Marta , Pelaez Mireia , Basterretxea Laura , Varga Estrella , Sánchez-Escribano Ricardo , Pujol Eduardo , Santander Carmen , Martinez-Kareaga Mireia , Arruti Ibarbia Mikel , Rodríguez Ledesma Inma , Álvarez-Fernández Carlos , Piedra Pablo , Calderero Veronica , Lainez Nuria , Verdun Aguilar Juan Antonio , Gil-Arnaiz Irene , Fernandez Ricardo , Mazas Cristina , Duran Ignacio
Published: June 2024

e16559

Background: Current standard of care for la-mUC pts who show no progression after platinum-based chemotherapy is maintenance with avelumab based on survival improvement (JAVELIN 100; Powles et al. NEJM 2020). However, the available RWD evidence on the use of avelumab in the E.U. is limited and there are concerns about the low uptake of this strategy based on figures from American series (Mamtani R et al; JAMA Netw Open 2023). We present here data on the use of avelumab in a large cohort of pts from different centres in Spain within the academic group GO NORTE. Methods: AVEBLADDER is a retrospective observational analysis in which clinical information was retrieved from pts treated across 14 centres in 13 provinces in Northern Spain. The study population included adult pts diagnosed with la/mUC (January 1, 2021-June 30, 2023) followed from date of diagnosis until death, loss to follow-up or end of study. Median overall survival (OS) was determined using the Kaplan-Meier method. Results: 419 pts were included. Median age was 71 [range 42-88]; 80% were males; 81% had primary bladder tumours and 94% predominant urothelial histology. Seventy three percent of pts had visceral/bony metastases and 59% were unfit for cisplatin. Most common 1st line treatment (tx) [88%] was platinum-based chemotherapy [median number of cycles 4]. Out of 369 pts who received platinum-based chemotherapy, non-progression (CR, PR or SD) was reported in 230 pts [62%], of whom only 85 pts [37%] received maintenance avelumab. Fifty-eight pts treated with avelumab were evaluable for response: 7 (10 %) achieved a CR, 12 (14%) PR, 22 (26%) SD and 17 (20%) PD. The most common reason for non-receiving avelumab in our series was lack of access/reimbursement according to country/region policy. Overall, 168 pts [40%] started 2nd line tx and atezolizumab was the most used agent, only 41 pts [24%] received third line tx. With a median follow-up of 11 months, 194 pts [46%] are still alive and median overall survival (OS) is estimated to be 28 months (95% CI 23-not reached) with maintenance avelumab vs 11 months (95% CI 9-13) for those who did not receive this drug. Conclusions: Despite the demonstrated improvement in OS for maintenance avelumab, its uptake in our series was low with roughly 40% of the pts. New policies and better access to the drug will most likely improve these figures and hopefully also the proportion of patients who progress to receive a third line where novel therapies are currently being implemented. AVEBLADDER is a study sponsored by GO NORTE a non-for-profit GU cooperative group.
Prognostic analysis of disitamab vedotin combined with PD-1 inhibitor first-line treatment in advanced urothelial carcinoma: A propensity score analysis.
Authors: Jiang Yupeng , Xu Chao , Zou Wen , Chen Minfeng , He Wei , Li Yuan , Feng Yeqian , Fan Songqing , Wu Lin , Wang Jingjing
Published: June 2024

e16565

Background: The combination of antibody-drug conjugates and PD-1 inhibitor has great prospects for first-line treatment of advanced urothelial carcinoma (UC). This real-world study explored the efficacy, safety, and prognostic biomarkers of disitamab vedotin (DV) combined with PD-1 inhibitor, and compared them with other first-line regimens without DV. Methods: Patients were enrolled retrospectively from July 2021 to December 2022 in two cancer centers. There were four first-line treatment regimens: DV (120-180mg) plus PD-1 inhibitor (Tislelizumab 200mg or Toripalimab 240mg) once every 3 weeks, chemotherapy (gemcitabine plus cisplatin/carboplatin) plus ICI, chemotherapy, and ICI. Then patients were classified into the DV group and No DV group. Treatment outcomes were compared between the two groups after 1:1 ratio PS matching adjusted for sex, PS score, stage, histological grade, and tumor location. In DV group, RNA-seq was used to analyze differential expressed genes (DEGs). Results: There are 63 patients enrolled with median age 68 years (44–90 years). The median follow-up time was 13 months (4–36 months). The 1-year overall survival and progression free survival (PFS) rates were 74.3% and 47%, respectively. There were 30 patients received DV plus ICI, 17 received chemotherapy plus ICI, 9 received chemotherapy, and 7 received ICI alone. PS score and first-line regimen containing DV are independent prognostic factors for PFS. After PS matching, there were 22 patients each in the DV group and No DV group. There were significant differences between the two groups in terms of objective response rate (81.8% vs.27.3%, p=0.003) and 1-year PFS rate (68.2% vs.33.5%, p=0.008) (Table). In safety, hematology and gastrointestinal toxicity were more likely to occur in the No DV group, while neurotoxicity and rash were more likely to occur in the DV group, and most of which were grade 1-2. In DV group, the top 5 most significantly DEGs between patients with long (>6 months) and short PFS (≤6 months)were SCGB1A1, AKR1C1, FAM205C, ACP7 and NLGN4X, and which are enriched in the pathway of cytoplasmic translocation and the function of ribosome. Conclusions: The first-line regimen of DV plus PD-1 inhibitor for patients with advanced UC was more effective and safer than the regimen without DV. The pathway of cytoplasmic translocation and the function of ribosome may be highly correlated to the effectiveness of the regimen of ADC plus ICI. [Table: see text]
TECIC bladder-sparing strategy for high-risk bladder cancer: Exploration and interim analysis of a multicenter, prospective, parallel controlled study (HSCRYO-104).
Authors: Jiang Haowen , Xu Chenyang , Chen Yiling , Zou Lujia , Zhang Limin , Jiang Shuai , Guo Jianming , Sheng Lu , Xu Bin , Luo Jianfeng
Published: June 2024

e16585

Background: To evaluate the efficacy and safety of transurethral resection of bladder tumors (TURBt) plus endoscopic cryoablation (ECA) combined with Immunotherapy and Chemotherapy (TECIC) as a bladder-sparing therapy in treating high-risk bladder cancer, and to explore the synergistic mechanism between cryoablation and antitumor immunity during the treatment. Methods: The HSCRYO-104 study was a multicenter, nonrandomized, parallel controlled clinical trial with a noninferiority design to evaluate the efficacy of the TECIC modality in treating high-risk non-muscle invasive bladder cancer and early muscle invasive bladder cancer (stage T2). The ratio of the EBCA group and the control group was set as 1:3. In the ECA group, patients received TURBt with immediate ECA at the resection site, and subsequent adjuvant chemoradiotherapy and immunotherapy. The control group was treated with radical cystectomy with pelvic lymphadenectomy and urinary diversion. The primary outcome was overall survival (OS), and secondary outcomes included progression free survival (PFS), in-situ recurrence and incidence of adverse events (AEs). Alterations in the tumor microenvironment were explored. Results: Between December 2021 and August 2023, the interim analysis and exploratory study was completed. A total of 106 patients received screening at four medical centers in Shanghai, and 103 patients were included (25 in the ECA group and 78 in the control group). The two groups were well-balanced at baseline. In the per-protocol analysis, three of the 24 patients in the EBCA group experienced in-situ recurrence and were treated by TURBt and ECA again. No progression or cancer-specific death was observed. Six of 74 patients in the control group died due to disease progression. The interim analysis found that the ECA group was noninferior to the control group in both OS and PFS, with a lower incidence of AEs, enhanced recovery after surgery and shorter hospital stay. Exploratory studies found a significant increase in the proportion of effector memory T cells and upregulation of cytokines (e.g., IL-7 and IL-15) in patients after cryoablation. Conclusions: The TECIC modality as a bladder preserving therapy achieved non-inferior short-term survival to the radical cystectomy with a better quality of life. This strategy has great potential for application in treating patients with bladder cancer. Clinical trial information: ChiCTR2200057679 .