bluuebunny/crossref_metadata_2025 huggingface dataset:
A randomized, non-comparative, phase II study of maintenance OSE2101 vaccine alone or in combination with nivolumab (nivo) or FOLFIRI after induction with FOLFIRINOX in patients (Pts) with advanced pancreatic ductal adenocarcinoma (aPDAC): First interim results of the TEDOPAM GERCOR D17-01 PRODIGE 63 STUDY.
Authors: Hilmi Marc , Mitry Emmanuel , Turpin Anthony , Bouché Olivier , Metges Jean-Philippe , Ghiringhelli François , Trouilloud Isabelle , Roth Gaël , Baumgaertner Isabelle , Borg Christophe , Ammarguellat Hanifa , Guillet Marielle , Rinaldi Yves , Lecomte Thierry , Louvet Christophe , Lambert Aurélien , Hautefeuille Vincent , Garcia-Larnicol Marie-Line , Henriques Julie , Neuzillet Cindy
Published: June 2022

4148

Background: OSE2101 is a multiple neoepitope vaccine restricted to HLA-A2 positive Pts. This study aimed to assess the efficacy and safety of OSE2101 ± anti-PD1 nivo as maintenance therapy in Pts with aPDAC after FOLFIRINOX induction chemotherapy. Methods: TEDOPaM-PRODIGE 63 was initially a 3-arm, open-label, randomized, non-comparative phase II study. Pts with aPDAC, HLA-A2 positive (blood) and no progression after 8 cycles of (modified) FOLFIRINOX were randomized 1:1:1 to receive FOLFIRI (standard Arm A), OSE2101 (subcutaneous injection on D1 Q3W x 6 doses then Q8W until M12 then Q12W up to M24, experimental Arm B) or OSE2101 + nivo (360 mg IV on D1 Q3W x 6 then 480 mg Q4W up to M24, experimental Arm C). FOLFIRI was reintroduced at disease progression in Arms B and C. Primary endpoint was overall survival (OS) rate at 12 months (M12) (Fleming two-stage design, H0: 25%; H1: 50%, one-sided alpha: 2.5%, power: 90%). 156 Pts were planned. Results: Following the occurrence of 2 tumor flares in Arm C, an Independent Data Monitoring Committee (IDMC) recommended to continue FOLFIRI as backbone in experimental Arm B and stop Arm C. Interim analysis results refer to 29 randomized Pts: 9/10/10 in Arm A/B/C, respectively. Median age was 63 years, 52% were men, 55% had ECOG PS 0, and 83% were metastatic. Best response to induction FOLFIRINOX was partial response in 48% and stable disease in 52%. With a median follow-up of 23 months, M12-OS rate was 44%, 40%, and 30% in Arm A, B and C. Other efficacy results are summarized in Table below. No OSE2101-related toxicity of grade ≥ 3 (G≥3) were observed in Arm B; 1 G3 cytokine-release syndrome (OSE2101-related) and 2 tumor flares (nivo-related) leading to death were observed in Arm C. Conclusions: Maintenance OSE2101 monotherapy showed a favorable safety profile and encouraging time to strategy failure warranting further evaluation. OSE2101 + nivo was associated with poorer outcomes leading to close Arm C. Following IDMC recommendation, the study is ongoing with the new design (maintenance FOLFIRI vs. FOLFIRI + OSE2101). Clinical trial information: NCT03806309. [Table: see text]
Evaluation of somatic and germline variants in patients with small bowel adenocarcinoma reveals clinically actionable targets.
Authors: Wei Deng , Liu Si , Li Xiaomo , Ma Tonghui
Published: June 2022

4159

Background: Small bowel adenocarcinoma (SBA) is a rare gastrointestinal cancer with a poor prognosis and limited treatment options. Because the treatments for colorectal cancer showed limited efficacy in SBA, the NCCN guide strongly encourages SBA patients to participate in clinical trials. In this study, we aimed to explore clinically actionable variants in a large cohort of patients with SBA to assist oncologists to select the matched trials for patients. Methods: To explore therapeutic targets in 84 Chinese SBA patients, a deep sequencing panel (OncoPanscan, Genetron health) was used to characterize somatic alterations including point mutations, indels, copy number alterations, gene fusions as well as pathogenic germline variants. Results: Recurrent somatic mutations included TP53 (57%), KRAS (56%), APC (31%), SMAD4 (21%), MDM2 (13%), CTNNB1 (12%), KMT2C (12%), SOX9 (12%), ARID2 (12%), FAT3 (11%), FBXW7 (10%), SPTA1(10%) and PIK3CA (10%). Of the entire cohort, we observed five activating PIK3CA mutations (R108H; G364R; E542K; E545K, n = 2) which may be sensitive to FDA-approved PIK3CA inhibitor alpelisib. Additionally, patients with loss-of-function mutation in NF1 (n = 2), STK11 (n = 1) and PTEN (n = 1) can be targeted with MEK inhibitor selumetinib and mTOR inhibitor everolimus, respectively. Except for one V600E mutation, all mutations in BRAF are either type 2 (L597R, n = 1) or type 3 (N581S, n = 1; D594N, n = 4) which were sensitive to MEK inhibitor trametinib. We also found four type 2 MAP2K1 activating mutations (K57E, K57N, and F53L) which can be targeted by trametinib. Furthermore, oncogenic ERBB2/HER2 mutations were seen in 4 patients including S310F (n = 1), V842I (n = 2) and V777L (n = 1). We also found one patient harbored ERBB2/HER2 high magnification amplification. These five patients were candidates for HER2-targeted therapy clinical trials. Interestingly, one IDH1 mutation (R132C) carrier in our cohort might benefit from ivosidenib. In addition, we observed targetable gene amplification of MDM2 (n = 2) and FGF3/4/19 (n = 2). There were two patients with MLH1 loss-of-function germline mutations that may benefit from immunotherapy. Among 78 patients with available MSI status, three were designated as microsatellite instability. The median TMB of microsatellite stable patients was 2.82 mutations/Mb. Lastly, we observed five deleterious germline mutations, three for SBDS, one each for APC and ERCC5. Taken together, at least 33 (39%) patients in our cohort harbored actionable genetic alterations. Conclusions: Through comprehensive genomic characterization of Chinese SBA patients, we identified actionable variants of multiple signaling pathways in plenty. NGS profiling results can guide physicians to enroll a significant portion of SBA patients in genomically-matched clinical trials.
Final clinical results of pivotal trial of IL-15RαFc superagonist N-803 with BCG in BCG-unresponsive CIS and papillary nonmuscle-invasive bladder cancer (NMIBC).
Authors: Chamie Karim , Chang Sam S. , Gonzalgo Mark , Kramolowsky Eugene V. , Sexton Wade J. , Bhar Paul , Reddy Sandeep K. , Soon-Shiong Patrick
Published: June 2022

4508

Background: Patients with NMIBC CIS unresponsive to BCG have limited treatment options. N-803 (Anktiva) is a mutant IL-15-based immunostimulatory fusion protein complex (IL15RaFc) that promotes proliferation and activation of natural killer (NK) cells and CD8+ T cells, but not regulatory T cells. Phase 1b data in BCG-naïve patients with NMIBC demonstrate that intravesical administration of N-803 with BCG induced complete response in all patients, without recurrences for the study duration of 24 months. Pembrolizumab was approved in 2020 with a 41% complete response (CR) rate in a single arm phase 2 trial of 96 patients. We report data on 160 subjects from an open-label, 3 cohort multicenter study (QUILT 3.032) of intravesical BCG plus N-803 in patients with BCG-unresponsive high-grade NMIBC (NCT03022825). Methods: All treated patients received intravesical N-803 plus BCG, consistent with the standard induction/maintenance treatment schedule. The primary endpoint for Cohort A (CIS) is incidence of CR of CIS at any time. The primary endpoint for Cohort B (Papillary) is disease-free rate (DFS) at 12 months. Results: To date, we enrolled 160 patients (83 CIS, 77 Papillary). In the overall population, median age is 72.3 years, 81% male, with mean number of prior TURBT = 4. Median number of prior BCG doses = 12. CIS patients have a CR rate of 71% (59/83), with a mediation duration of CR of 24.1 months in responders; 91% avoided cystectomy and 96% 24 month bladder cancer specific progression free survival (defined as progression to MIBC). Papillary patients have a 57% 12 month DFS rate, 48% 24 month DFS rate, and 95% avoided cystectomy. Median time to cystectomy in responders (N = 4) is 12.9 months versus 7.8 in non-responders (N = 8) for a 5.1 month delay in cystectomy. PK data shows no systemic levels of N-803; activity is confined to the bladder. Low grade treatment related AEs (grade 1-2) include dysuria (22%), pollakiurua (19%), hematuria (18%), fatigue (16%), and urgency (12%), all other AEs were seen at 7% or less. No treatment related grade 4 or 5 AE were seen. No SAE's were considered treatment related. No immune related SAE's have been seen. Conclusions: In 160 patients with BCG-unresponsive NMIBC, there is a 99% bladder cancer specific overall survival at 2 years. In CIS patients 71% CR rate with 24.1 months median duration of response, and 53% DFS rate at 18 months in Papillary disease. Cystectomy was avoided in over 90% of patients with 2 years of follow-up. The efficacy and safety profile of N-803+BCG exceeds that of other available intravesical and systemic options for BCG-unresponsive NMIBC. Clinical trial information: NCT03022825.
Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): Analysis of progression after first subsequent therapy in KEYNOTE-426.
Authors: Powles Thomas , Plimack Elizabeth R. , Stus Viktor , Waddell Tom , Gafanov Rustem , Pouliot Frédéric , Nosov Dmitry , Melichar Bohuslav , Soulieres Denis , Borchiellini Delphine , Vynnychenko Ihor , McDermott Raymond S. , Azevedo Sergio Jobim , Tamada Satoshi , Kryzhanivska Anna , Li Chenxiang , Burgents Joseph E. , Molife L. Rhoda , Rini Brian I. , Bedke Jens
Published: June 2022

4513

Background: The randomized, open-label, phase 3 KEYNOTE-426 study (NCT02853331) met its primary and key secondary end points of improved OS, PFS, and ORR with pembro + axi versus sunitinib as first-line treatment for patients with advanced ccRCC. Extended follow-up (42.8-mo median follow-up) continued to show the superior efficacy of pembro + axi versus sunitinib in this patient population. We describe the results of PFS2 for all randomly assigned patients and across IMDC risk categories. Methods: Treatment-naive patients with advanced ccRCC, Karnofsky Performance Status Scale score ≥70% and measurable disease per RECIST v1.1 were randomly assigned 1:1 to receive pembro 200 mg IV every 3 weeks for up to 35 doses (̃2 y) + axi 5 mg orally twice daily or sunitinib 50 mg orally once daily on a 4-wk on/2-wk off schedule. The end point of this exploratory analysis was PFS2, defined as time from randomization to progression after first subsequent therapy or any-cause death. The Kaplan-Meier method was used to estimate PFS2 and hazard ratios were estimated using a Cox regression model. Results: Of 861 patients, 432 were assigned to receive pembro + axi; 429, to sunitinib. Median time from randomization to the database cutoff date (January 11, 2021) was 42.8 mo (range, 35.6-50.6). Overall, 47.2% of patients (204/432) in the pembro + axi arm and 65.5% of patients (281/429) in the sunitinib arm received ≥1 line of subsequent anticancer therapy. For patients who received subsequent therapy, anti–PD-1/PD-L1 agents were the first subsequent treatment for 11.3% of patients (23/204) in the pembro + axi arm and 54.8% of patients (154/281) in the sunitinib arm. In the pembro + axi arm, 82.8% of patients (169/204) received a VEGF/VEGFR inhibitor as first subsequent therapy, as did 43.4% (122/281) in the sunitinib arm. PFS2 results are displayed in the Table. Conclusions: In this exploratory analysis, PFS2 was longer for patients randomized to pembro + axi compared to sunitinib. Results were consistent across IMDC risk groups. These data support use of pembro + axi for the first-line treatment of patients with advanced ccRCC. Clinical trial information: NCT02853331. [Table: see text]
A phase II study of RC48-ADC in HER2-negative patients with locally advanced or metastatic urothelial carcinoma.
Authors: Xu Huayan , Sheng Xinan , Zhou Li , Yan Xieqiao , Li Siming , Chi Zhihong , Cui Chuanliang , Si Lu , Tang Bixia , Mao Lili , Lian Bin , Wang Xuan , Bai Xue , Li Juan , Guo Jun
Published: June 2022

4519

Background: RC48-ADC is a novel humanized anti-HER2 antibody-drug conjugate (ADC). A phase II clinical study showed that RC48-ADC has a good effect on locally advanced or metastatic urothelial carcinoma with HER2-positive expression that failed standard chemotherapy. In the study, some patients with HER2-postive immunohistochemistry (IHC 2+) but negative FISH test still benefited from the treatment of RC48-ADC.This study was to evaluate the activity and safety of RC48-ADC in HER2-negative patients with locally advanced or metastatic urothelial carcinoma. Methods: This study is an open-label, single-center, single-arm, phase II trial. Eligibility criteria include: histologically confirmed urothelial carcinoma, HER2-negasitive (IHC 0 or 1+), ECOG PS 0-1,and treated with ≥1 prior systemic treatment. Patients received RC48-ADC 2mg/kg q2w until disease progression, unacceptable toxicity, withdrawal of consent, or study termination. The primary objectives were activity (ORR) and safety. Second objectives included progress-free survival, disease control rate and overall survival. Results: As of February 2022(date cutoff),19 patients were enrolled. The median age was 64 years old(range:36-77). At baseline, there were 6 patients with HER2(IHC 0), and 13 patients with HER2(IHC 1+).Most patients (13/19) had visceral metastasis. 15(79%) patients had received≥2 lines treatment.At date cutoff, 19 patients were assessable for response. The objective response rate was 26.3% (95% CI:9.1%,51.2%) and the DCR was 94.7% (18/19). The mPFS was 5.5months (95% CI:3.9,6.8) and mOS was 16.4months (95% CI:7.1,21.7).All of the 6 patients with HER2(0) were SD in the study. The ORRs were 38% (5/13) in patients with HER2(IHC 1+),31% (4/13) in visceral metastasis,17% (1/6) in liver metastasis patients,27% (4/15) in patients post to ≥ 2 lines of treatment. Common treatment-related AEs were leukopenia (52.6%), hypoesthesia (47.4%),alopecia (47.4%), AST increase (42.1%), ALT increase (42.1%), and neutropenia (42.1%), fatigue (42.1%),nausea (26.3%), vomiting (15.8%).Most of these AEs were Grade 1 or 2. The AE of Grade 3 was neutropenia (10.5%). The SAE was CPK increased (5.3%). Conclusions: This study showed that RC48-ADC was safe and the ORR was 26.3% in HER-negative patients with locally advanced or metastatic urothelial carcinoma. The enrollment was completed and data will be updated later. Clinical trial information: NCT04073602.
Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) compared to computed tomography (CT) for advanced renal cell carcinoma (RCC).
Authors: Pathmanathan Shivanshan , Tariq Arsalan , Gan Chun Loo , Pearce Adam , Rhee Handoo , Kyle Samuel , Raveenthiran Sheliyan , Wong David , McBean Rhiannon , Marsh Philip , Goodman Steven , Dhiantravan Nattakorn , Esler Rachel , Dunglison Nigel , Navaratnam Anojan , Yaxley John , Thomas Paul , Pattison David A. , Goh Jeffrey C. , Roberts Matthew
Published: June 2022

4540

Background: There is emerging role of the use of PSMA PET in RCC. Herein, we report our experience in use of PSMA PET in recurrent or metastatic RCC in Brisbane, Australia. Methods: Patients (pts) who underwent PSMA PET and conventional diagnostic CT for metastatic or recurrent RCC between 2015 and 2020 at three institutions were identified. Retrospective chart reviews were conducted using standardized collection template. The outcomes included percentage of patients who had a change in management secondary to PSMA PET findings, comparison of metastasis detection for PSMA PET vs. CT, and biopsy histology of PSMA avid sites. Results: 42 PSMA PET were performed in 40 patients. 10 pts (25%) and 30 pts (75%) had PSMA PET in the metastatic disease and recurrent disease setting, respectively. Table 1 highlights demographics. Overall, 12 pts (30%, n=3 metastatic, n=9 recurrent) had a change in management following PSMA PET. In the metastatic disease group, 2 pts (20%) underwent initial systemic therapy (after histological confirmation) due to higher burden of disease shown with PSMA PET than CT, while systemic therapy was changed for 1 pt (10%). In the recurrent disease group, PSMA improved delineation of suspected recurrence (compared to CT) resulting in resection rather than surveillance (n=4; 13%) or change in surgical approach for resection (n=1; 3%). PSMA PET distribution showed more metastatic sites than CT leading to systemic therapy rather than resection of recurrence (n=2; 7%), while absent PSMA activity for suspected recurrence on CT led to surveillance rather than resection (n=2; 7%). PSMA PET detected more sites of metastases compared with conventional scan in 6 pts (60%) with metastatic disease and in 9 pts (30%) with recurrent disease. 26 pts had biopsy of PSMA avid sites. Majority of pts had confirmed recurrence of clear cell renal carcinoma (n= 22; 85%). Other histology included sarcomatoid renal cell carcinoma (n=2; 8%), carcinoid (n=1; 4%), and urothelial cancer (n=1; 4%). In 2 instances, biopsy/resection was performed of a suspected recurrence on CT that was not PSMA avid, and neither showed malignancy. Conclusions: PSMA PET detected more accurately metastatic and recurrent disease, with high pathological concordance, to result in change in management for 30% of patients. Prospective study is warranted to further investigate the utility of PSMA PET scan in advanced RCC.[Table: see text]
Activity of tivozanib in non-clear cell renal cell carcinoma (nccRCC): Subgroup analysis from a phase 2 randomized discontinuation trial.
Authors: Barata Pedro C. , Allman Kim , Asnis-Alibozek Aviva G. , Kasturi Vijay , Pal Sumanta K.
Published: June 2022

4542

Background: Non-clear cell renal cell carcinoma (nccRCC) is a blanket term for a collection of heterogenous and biologically diverse RCC histologies including (but not limited to) papillary, chromophobe and unclassified subtypes. Tivozanib is a selective VEGFR tyrosine kinase inhibitor with demonstrated activity in RCC with clear cell component. Here we report efficacy of tivozanib in a histologically diverse nccRCC subset included in a phase 2 study. Methods: We conducted a subgroup analysis of patients with nccRCC enrolled in the study 201 (NCT00502307), a phase 2 randomized discontinuation trial of tivozanib in patients with RCC who had no prior VEGF targeted treatment. Clinical outcomes including overall response rate (ORR), disease control rate (DCR, defined by CR+PR+SD), and progression free survival (PFS) were examined. Safety outcomes for all patients are reported in the original publication (Nosov, JCO 2012). Results: Of the 272 patients enrolled, 46 (16.9%) patients had nccRCC. [11 (4%) papillary, 2 (0.7%) chromophobe, 2 (0.7%) collecting duct, and 31 (11.4%) unclassified/mixed]. Of the 46 nccRCC patients, the ORR was 17.4% by investigator (INV) review and 15.2% by independent radiology review (IRR). The DCR was 80.4% by INV and IRR. The median PFS was 6.7 months (204 days) (95%CI: 125-366 days) by IRR (Figure 1). Of note, 14 patients with SD after 16 weeks on tivozanib were randomized to 12 weeks of placebo and may have progressed during that timeframe before unblinding and resuming tivozanib. Safety was not analyzed by histology but there were no new safety signals and was consistent with tivozanib labelling in the ITT population. Conclusions: Tivozanib demonstrated activity and a favorable safety profile in patients with nccRCC. This data adds to the body of evidence supporting VEGFR TKI use in advanced RCC including in non-clear cell histologies. Clinical trial information: NCT00502307. [Table: see text]
Variation in recurrence rate and overall survival (OS) outcomes by disease stage and incremental impact of time to recurrence on OS in localized renal cell carcinoma (RCC).
Authors: Haas Naomi B. , Bhattacharya Rituparna , Song Yan , Rogerio Jackie , Zhang Su , Carley Christopher , Anderson Annika , Signorovitch James , Sundaram Murali
Published: June 2022

4543

Background: Prior research shows that post-nephrectomy recurrence is correlated with significantly increased mortality in patients (pts) with intermediate-high (int-high) risk and high risk RCC. However, no study has quantified the incremental OS associated with increased time to recurrence (ToR). Additionally, limited evidence is presented on the variation of recurrence rate and OS by stage of RCC. Methods: The SEER-Medicare database (2007–2016) was used in this retrospective observational study. Post-nephrectomy pts with newly diagnosed, int-high risk (pT2 N0 high grade, pT3 N0 any grade) or high-risk (pT4 N0 any grade, pT any N1 any grade) RCC were identified and stratified based on tumor stage and grade. Grade was defined based on Furhman grading system and was reported in SEER Registry. Post-nephrectomy recurrence free rates and OS by disease stage were described using Kaplan-Meier analyses. OS from nephrectomy in pts with recurrence vs pts without recurrence was compared by disease stage. Multivariable regression analysis was used to quantify the incremental OS associated with increased ToR post-nephrectomy in all pts with recurrence. Results: 643 pts met the inclusion criteria (269 with vs 374 without recurrence; median follow-up: 23 months). The mean age was 75.5 years (yrs), 61% male, and 86% white. Results presented in the table showed wide variance in 5-yr recurrence-free rate in int-high risk group (28%-63%) and indicated substantial risk of disease recurrence in all subgroups of int-high risk pts. Among those with T3 Grade 1-2, T3 Grade 3, and T3 Grade 4 disease, pts with recurrence had significantly higher risk of death than those without (all ps<0.05;). Results for pts with T2 and T4 disease were not presented due to small sample size. Multivariable regression analysis indicated that 1 additional yr of ToR was associated with 0.73 additional yrs (8.8 additional months) of OS post nephrectomy (95% CI: 0.40, 1.05 yrs; p<0.001). Conclusions: The non-trivial recurrence rates observed in pts with T3 Grade 1-2 and T3 Grade 3 RCC highlighted the substantial risk of recurrence and unmet needs in the int-high risk RCC patients. This study also confirms the incremental nature of the association of ToR and OS in patients with int-high and high risk localized RCC. These findings highlight the need for effective early intervention with adjuvant treatments in int-high and high risk post-nephrectomy RCC pts. [Table: see text]
Outcomes with novel combinations in nonclear cell renal cell carcinoma (nccRCC): ORACLE study.
Authors: Kilari Deepak , Szabo Aniko , Ghatalia Pooja , Rose Tracy L , Dong Huaying , Weise Nicole , Zhuang Tony Z. , Alloghbi Abdurahman , Jain Rohit K. , Alva Ajjai Shivaram , Tripathi Abhishek , Basu Arnab , Davis Nancy B. , Brundage James , Emamekhoo Hamid , Zakharia Yousef , Koshkin Vadim S , Bilen Mehmet Asim , Heath Elisabeth I. , McKay Rana R.
Published: June 2022

4545

Background: Despite recent advances in the treatment of clear cell RCC, there is a paucity of data to guide management of nccRCC due to the heterogeneity and rarity of these tumors. The clinical activity of combination therapies (including IO-IO, IO-VEGF, VEGF-mTOR) in subtypes of advanced nccRCC is unknown. Methods: In this multicenter retrospective analysis, we evaluated the efficacy of combination systemic therapies in patients with nccRCC. Eligible patients included those with nccRCC as determined by local genitourinary pathology review and receipt of one of three combination regimens during any line treatment (IO-IO, IO-VEGF, mTOR-VEGF). The primary endpoint was objective response rate (ORR) assessed by investigator review. Secondary endpoints were progression- free survival (PFS), disease control rate (DCR), and overall survival (OS). Results: Among 128 included patients, median age was 57 years; 66% were male and 65% white. Histologies included papillary (37%), unclassified (33%), chromophobe (16%), translocation (9%), and other (5 %). Among all patients, 69% had prior nephrectomy; 80% were IMDC intermediate/poor risk; 20% had sarcomatoid and/or rhabdoid differentiation, 27% and 29% had liver and bone metastasis respectively and 63% received combination treatment as first line. Comparison of outcomes based on treatment regimen, line of treatment and subtype is shown in the table. Median PFS and OS were longer with IO/IO and IO/VEGF compared to VEGF/ mTOR at 8.5, 9.5 and 3.7 months and 24.4, 18.2 and 15.4 months respectively. Conclusions: Antitumor activity was observed with novel combinations in nccRCC in both frontline and later line setting. Optimal management of nccRCC remains an unmet need and prospective data is warranted to guide treatment selection for this population. [Table: see text]
Phase Ib study of anti-PD-L1 monoclonal antibody socazolimab in combination with nab-paclitaxel as first-line therapy for advanced urothelial carcinoma.
Authors: Duan Rong , Liu Yixun , Hu Xuechun , Cui Chuanliang , Si Lu , Sheng Xinan , Liu Zhi , Xiang Ping , Yan Xieqiao , Li Siming , Zhou Li , Li Juan , Li Yu Jie , Ng Rachel , Dai Xiang Rong , Li Benjamin Xiaoyi , Chi Zhihong , Xiao Jun , Guo Jun , Tang Bixia
Published: June 2022

4563

Background: PD-1/PD-L1 immune checkpoint inhibitors (ICIs)0have demonstrated activity in the postplatinum and platinum-ineligible settings for advanced urothelial carcinoma (aUC). As only around 30% of patients with aUC can tolerate platinum standard treatment, first-line ICIs combined with non-platinum drugs have certain research value. Therefore we assessed the safety and efficacy of anti-PD-L1 monoclonal antibody Socazolimab in combination with nab-paclitaxel as first line therapy in aUC (NCT04603846). Methods: This is a multi-center,single-arm, phase Ib study which enrolled aUC patients with treatment-naive or first recurrence more than 6 months after the end of adjuvant chemotherapy in China. Eligible patients received Socazolimab (5mg/kg) and nab-paclitaxel (260mg/m2) every 3 weeks. Primary endpoint was to investigate the safety and tolerability of nab-paclitaxel in combination with Socazolimab. Second endpoints were the objective response rate (ORR) and progression-free survival (PFS). Results: 20 patients were enrolled, including 5 renal pelvis urothelial carcinoma, 8 bladder urothelial carcinoma, and 7 ureteral carcinoma. The median age was 69 years. As of January 14, 2022, the median follow-up time was 5.49 months. Median number of treatment cycles was 6.5 cycles. No patients had dose limiting toxicity. Among the 17 patients who had received at least one tumor assessment, 8 patients achieved partial responses. ORR was 52.94% (95% CI, 27.81-77.02). DCR was 88.24% (95% CI, 63.56-98.54). Median PFS was 8.18 months (95% CI, 5.32-13.60). Adverse reactions related to the study drug were mainly Grade 1-2. Common adverse reactions included rash (6/20,30%), increased alanine aminotransferase (6/20, 30%), increased γ-glutamyltransferase (4/20, 20%),sinus bradycardia (4/20, 20%), increased aspartate aminotransferase (4/20, 20%),pruritus (3/20, 15%). Grade 3 or higher treatment-related adverse events occurred in 4 (20%) patients, mainly Grade 3 increases in alanine aminotransferase (2/20, 10%). No confirmed treatment-related deaths occurred, and no treatment-related deaths occurred, and no new safety signals were observed. Conclusions: Socazolimab combined with nab-paclitaxel as first-line treatment was effective and well-tolerated in Chinese patients with advanced urothelial carcinoma, warranting phase II trials. Clinical trial information: NCT04603846.
Assessment of a HER-2 scoring system and its correlation of HER2-targeting antibody-drug conjugate therapy in urothelial carcinoma.
Authors: Lei Huizi , Ling Yun , Yuan Pei , Guo Jun , Sheng Xinan , Zhou Ai-Ping , Ying Jianming
Published: June 2022

4572

Background: Human epidermal growth factor receptor 2 (HER2) overexpression is related to many tumor treatments. RC48-ADC, a novel humanized anti-HER2 antibody conjugated with monomethyl auristatin E, has shown a promising efficacy in patients with HER2-positive locally advanced or metastatic urothelial carcinoma (mUC). The characteristic expression and scoring systems of HER2 have existed in breast cancer, gastric cancer for many years, but not in UC. We aimed to explore the expression pattern of HER2 in UC and develop a validated HER2 scoring system. Methods: A total of 137 patients and 43 patients in two studies of cohort 1 and cohort 2 were enrolled, respectively. The patients of the cohort 2 were enrolled in the open-label, multicenter, phase II study of RC48-ADC. Formalin-fixed paraffin-embedded urothelial cancer samples were tested for HER2 status using the fluorescence in situ hybridization (FISH) PathVysion HER2 DNA probe kit (PathVysion, Abbott Molecular, USA). Immunohistochemistry (IHC) was performed using the Ventana Benchmark XT (Ventana Medical Systems, USA). The 2018 ASCO/CAP HER2 scoring system of breast cancer was adopted and modified to score HER2 expression level in UC. Results: The expression rate of HER2 (IHC 2+/3+) was 24.1% (33/137). In HER2 IHC status 3+ or 2+ patients, the HER2 amplified rate was 31% (13/42). The objective response rates in RC48-ADC treatment patients with IHC 3+, IHC 2+ and FISH +, IHC 2+ and FISH - were 58.8%, 66.7% and 40%, respectively. Heterogeneity of HER2 protein expression was 55.5% (15/27) and the objective response rate had no significant difference between patients with tumor heterogeneity and homogeneity. Conclusions: The modified HER2 testing scoring system could be applied to UC to determine which patient might benefit from anti-HER2-ADC treatment. There was a trend towards a better benefit for patients with HER2 amplification and the tumor heterogeneity did not influence the drug efficacy.
Novel use of ctDNA to identify muscle-invasive and non-organ-confined upper tract urothelial carcinoma.
Authors: Huelster Heather L , Green Elizabeth A. , Soupir Alex C. , Rose Kyle M. , Katende Esther N. , Naidu Shreyas U , Gilbert Scott Michael , Manley Brandon J. , Poch Michael Adam , Sexton Wade J. , Yu Alice , Spiess Philippe E. , Du Pan , Jia Shidong , Kim Il-Jin , Tan Lu , Wang Liang , Li Roger
Published: June 2022

4587

Background: Upper tract urothelial carcinoma (UTUC) is an aggressive cancer for which use of neoadjuvant chemotherapy (NAC) is limited by suboptimal clinical staging prior to nephroureterectomy. Detection of circulating tumor DNA (ctDNA) is associated with locally advanced and metastatic urothelial carcinoma of the bladder and may help identify UTUC patients who would benefit from NAC. Here we examine the feasibility and utility of plasma ctDNA in the diagnosis of non-organ confined high-risk UTUC. Methods: Patients with high-grade cTa-T2 UTUC without radiographic evidence of metastatic disease undergoing up-front radical nephroureterectomy (RNU) were prospectively accrued for pre- and post-operative plasma collection. Blood was collected preoperatively on the day of surgery, and plasma and buffy coat were processed for extraction of cell-free DNA and genomic DNA, respectively. FFPE tumor samples from RNU were used for tissue genomic DNA extraction. Targeted next-generation sequencing (NGS) was used for variant profiling. ctDNA positivity was defined as the presence of plasma cell-free DNA variants concordant with tissue-based variants. Results: NGS analyses of matched FFPE and plasma samples were successfully performed for all 19 accrued UTUC patients. Alterations in the TERT promoter (74%), TP53 (58%), FGFR3 (53%), myc amplification (53%), and ATM (42%) were demonstrated in urothelial tumor tissue. Matched plasma ctDNA showed prevalent alterations in the TERT promoter (42%), TP53 (42%), PIK3CA (37%), ATM (32%) and CD274 (26%). Nine patients (47%) had detectable plasma ctDNA mutations concordant with tumor-specific variants using the targeted NGS panel. All patients with detectable preoperative ctDNA had advanced staging (≥pT2 or ≥pN1) and lymphovascular invasion on final pathology, resulting in a 90% sensitivity. The panel was 100% specific with no patients with pTis, pTa, pT1 and pN0 having detectable concordant ctDNA mutations. Concordant plasma ctDNA was detected in four of nine patients postoperatively. Two of three (67%) who developed metastatic disease had detectable ctDNA while neither of the two who developed non-muscle-invasive bladder recurrences did. Conclusions: Prospective ctDNA analysis using a targeted NGS panel can be used to predict muscle-invasive and non-organ-confined UTUC preoperatively. Detectable postoperative ctDNA may indicate residual disease and predate clinical recurrence.
Cohort study of patients with oligorecurrent prostate cancer: Oncological outcomes of patients treated with salvage lymph node dissection via PSMA radioguided surgery.
Authors: Knipper Sophie , Mehdi Irai Mehrdad , Simon Ricarda , Koehler Daniel , Rauscher Isabel , Eiber Matthias , van Leeuwen Fijs WB , van Leeuwen Pim , de Barros Hilda , van der Poel Henk G. , Budaeus Lars , Steuber Thomas , Graefen Markus , Tennstedt Pierre , Heck Matthias , Horn Thomas , Maurer Tobias
Published: June 2022

5009

Background: Prostate-specific membrane antigen (PSMA) positron-emission tomography (PET) allows detection of small and/or atypically localized metastatic prostate cancer (PCa) lesions. In a subset of patients with recurrent oligometastatic PCa salvage surgery with PSMA-targeted radioguidance (PSMA-RGS) may be of value. We aimed to evaluate the oncological outcomes of salvage PSMA-RGS for oligo-recurrent PCa and determine predictive preoperative factors of improved outcomes. Methods: In this cohort study within two tertiary care centers, patients with biochemical recurrence (BCR) after radical prostatectomy (RP) and imaging with PSMA PET receiving salvage PSMA-RGS between 2014 and 2020 were analyzed. Kaplan-Meier and multivariable Cox regression models adjusted for various parameters were used to test for BCR-free survival (BFS) and therapy-free survival (TFS) differences. Postoperative complications were classified according to Clavien-Dindo. Results: Overall, 364 patients were assessed. At PSMA-RGS, median (IQR) age and preoperative PSA was 67 (61-71) years and 1.0 (0.5-1.9) ng/ml. Metastatic soft-tissue lesions from PCa metastases could be removed in 343 (94.2%) patients. Within three months from surgery, 24 (6.6%) patients suffered from Clavien-Dindo complications grade III-IV. During follow-up, 225 patients experienced BCR and 121 patients received further therapy. Median follow-up for patients who did not experience BCR and who did not receive further therapy was 10.8 months and 10.3 months, respectively. Median (IQR) BFS and TFS was 7.8 (5.4-10.5) and 35.5 months (25.9-45.9 months). At two years of follow-up, BFS rate was 31.9% and TFS rate was 58.0%. In multivariable analyses, higher preoperative PSA (HR: 1.1), higher number of PSMA-avid lesions on preoperative imaging (HR: 1.2) and multiple (pelvic plus retroperitoneal) localizations (HR: 1.9), as well as retroperitoneal localization (HR: 2.0) of lesions in PSMA PET imaging were independent predictors of BCR after PSMA-RGS. Limitations are the retrospective design and lack of a control group. Conclusions: As salvage surgery in oligo-recurrent PCa currently constitutes an experimental treatment approach careful patient selection is mandatory based on life expectancy, low PSA values and low number of PSMA PET avid lesions located in the pelvis. Further studies are needed to confirm our findings and define the oncological value of salvage surgical procedures in oligo-recurrent PCa.
Prostate-specific membrane antigen PET response associates with radiographic progression-free survival following stereotactic ablative radiation therapy in oligometastatic castration-sensitive prostate cancer.
Authors: Sutera Philip , Deek Matthew , Guler Ozan Cem , Hurmuz Pervin , Reyhan Mehmet , Rowe Steven P. , Hrinivich William , Ren Lei , Kiess Ana Ponce , Song Daniel Y. , Oymak Ezgi , Pienta Kenneth J. , Pomper Martin , Feng Felix Y , Ozyigit Gokhan , Tran Phuoc T. , Phillips Ryan , Onal Huseyin Cem
Published: June 2022

5011

Background: Emerging data suggest metastasis-directed therapy (MDT) improves outcomes in patients with oligometastatic castration-sensitive prostate cancer (omCSPC). Prostate-specific membrane antigen positron emission tomography (PSMA-PET/CT) can detect occult metastatic disease and has been proposed as a biomarker for treatment response. Herein we identify and validate a PSMA-PET biomarker for clinical outcomes following MDT in omCSPC. Methods: This was an international multi-institutional retrospective study of two completely independent cohorts of men with omCSPC, defined as ≤3 lesions, treated with metastasis-directed stereotactic ablative radiation therapy (SABR) who underwent PSMA-PET/CT prior to and 3-6 months after treatment. Pre- and post-SABR PSMA-PET/CT standardized uptake value (SUV) was measured for all lesions and PSMA response defined discretely using a cutpoint of ≥ 30% decrease in SUVmax. PSMA-PET response was correlated with lesion local control (LLC), radiographic progression-free survival (rPFS) defined using conventional and PET imaging, and metastasis-free survival (MFS) defined by conventional imaging alone. Results: A total of 131 patients with 261 treated metastases were included in the analysis, with median follow-up of 29 months (IQR 18.5-41.3). Following SABR, 78.4% of lesions experienced a partial or complete PSMA response. Multivariable analysis demonstrated SUV response significantly associated with improved LLC (HR = 9.97, 95%CI 3.92-25.4; p < 0.01). Patients with PSMA response in all lesions experienced significantly better rPFS (HR = 0.49, 95%CI 0.26-0.92; p = 0.03) compared to their counterparts and this maintained significance within both the discovery (p < 0.01) and validation (p = 0.01) cohorts. Within the discovery cohort, patients with PSMA response in all lesions also experienced significantly improved MFS (HR = 0.24, 95%CI 0.07-0.85; p = 0.03); analysis of the independent validation cohort is ongoing. Conclusions: Following SABR, PSMA-PET response is a robust and externally validated radiographic biomarker for rPFS and appears to be associated with MFS pending validation. This approach holds promise for guiding clinical management of omCSPC.
Piflufolastat F 18-PET/CT in patients with prostate cancer: An analysis of OSPREY (cohorts A and B) standardized uptake value (SUV) results stratified by PSA and Gleason score.
Authors: Gorin Michael A. , Rowe Steven P. , Pienta Kenneth J. , Carroll Peter R. , Pouliot Frederic , Probst Stephan , Saperstein Lawrence , Preston Mark , Alva Ajjai Shivaram , Patnaik Akash , Stambler Nancy , Siegel Barry A. , Morris Michael J.
Published: June 2022

5024

Background: The OSPREY clinical trial was a phase 2/3 prospective study of prostate specific membrane antigen (PSMA) PET/CT using piflufolastat F 18. Piflufolastat F 18 (aka 18F-DCFPyL or PyL) is a novel PSMA-targeting radiopharmaceutical approved for imaging of PCa pts both at initial staging and for disease recurrence. Here we describe SUV results by biopsy status, baseline PSA levels, and Gleason score (GS). Methods: Piflufolastat F 18-PET/CT was evaluated in men with NCCN high-risk PCa scheduled to undergo radical prostatectomy with pelvic lymphadenectomy (RP-PLND) (Cohort A) and men with radiologically suspected recurrent/metastatic PCa (Cohort B). A single IV dose of 9 mCi (333 MBq) of piflufolastat F 18 was administered followed by PET/CT acquisition 1-2 hours later. Piflufolastat F 18 uptake in various lesion locations as defined by maximum and peak SUV (SUVmax, SUVpeak) were determined by three blinded, independent central readers for each tissue (e.g., bone, lymph nodes (LN), soft tissue). To measure SUVs, the reader placed a volume of interest (VOI) on each identified lesion. SUVmax was defined as the maximum single-voxel SUV within the VOI. SUVpeak within the VOI was defined as the average SUV within a fixed-sized VOI (1 cm diameter sphere), representing the cluster with the highest average SUV. Results: 345 men underwent piflufolastat F 18-PET/CT. Cohort B (n = 93evaluable) SUVmax and SUVpeak were significantly higher for biopsy positive (+)(one biopsy lesion/pt) when compared to biopsy negative (-) lesions from bone and LN. SUVpeak for biopsied bone and LN (Cohort B) appeared to increase with rising baseline PSA. In high-risk PCa pts, SUVpeak for prostate (Cohort A; n = 252 evaluable) increased with baseline PSA and were highest for GS 9-10 (Table). Conclusions: Piflufolastat F 18-PET/CT uptake was significantly higher in biopsy + lesions and increased with baseline PSA. Prostate SUVpeak was highest for GS 9-10. Clinical trial information: NCT02981368. [Table: see text]
Progression patterns by types of metastatic spread, prostate-specific antigen (PSA), and clinical symptoms: Post-hoc analyses of ARAMIS.
Authors: Morgans Alicia K. , Sweeney Christopher , Wallis Christopher J.D. , Halabi Susan , Armstrong Andrew J. , Verholen Frank , Ortiz Jorge A. , Schmall Anja , Srinivasan Shankar , Grimm Marc-Oliver
Published: June 2022

5044

Background: Darolutamide (DARO), a highly potent and structurally distinct androgen receptor inhibitor, prolonged metastasis-free survival by nearly 2 years and reduced the risk of death by 31% vs placebo (PBO) with a favorable tolerability profile in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) in ARAMIS. We present post-hoc analyses of ARAMIS to evaluate the association between metastatic progression with prostate-specific antigen (PSA) and clinical progression and to describe the distribution of metastatic progression between groups. Methods: Pts with nmCRPC were randomized 2:1 to DARO (n=955) or PBO (n=554) while continuing androgen-deprivation therapy. Descriptive analyses were performed using the primary data cutoff (Sept 3, 2018) for the double-blind period. Post-baseline metastases were based on central review of conventional radiographic imaging every 16 weeks. PSA and pain progression were defined per primary analysis ( N Engl J Med. 2019;380:1235-46). Results: Metastatic progression was observed in 13.6% of DARO and 28.5% of PBO pts. Most pts had isolated progression as bone (DARO 46%, PBO 39%) or lymph node (32%; 40%) metastasis (Table). Pts with radiographic progression had shorter median time from initial diagnosis to study treatment (DARO 72.9, PBO 74.4 months) vs the overall ARAMIS population (86.2, 84.2 months). Of all pts with metastatic progression, baseline PSA levels (ng/mL) were similar in DARO (12.6) and PBO pts (15.1); DARO pts had lower median PSA before metastasis (16.7) vs PBO pts (48.0) and median absolute/relative PSA decrease from baseline of -0.7/-3.2% vs an increase for PBO pts of 29.5/181%. PSA progression before metastasis was observed in 55.6% (160/288) of pts, occurring in fewer DARO (45.4%) vs PBO pts (63.9%) (treatment difference 18.5%; nominal 95% CI 6.5%–30.6%). The median time between PSA progression and metastasis was 7.0 months with DARO vs 5.6 months with PBO. Pain progression before metastatic progression was rare and similar between groups (DARO 16.9%, PBO 17.7%). Conclusions: DARO significantly reduced risk of metastatic progression and improved overall survival vs PBO without changing the pattern of metastatic progression. Many pts with nmCRPC experienced metastatic progression without PSA progression, and pain progression was rare. These results support the use of imaging with PSA monitoring to properly identify disease progression in pts with nmCRPC. Clinical trial information: TBC. [Table: see text]
Predictors of overall survival among Black South African men treated with androgen-deprivation therapy for metastatic prostate cancer.
Authors: Pumpalova Yoanna S , Ramakrishnan Adarsh , Minkowitz Shauli , Doherty Sean , Singh Elvira , Pentz Audrey , Chen Wenlong Carl , Neugut Alfred I. , Rebbeck Timothy , Joffe Maureen
Published: June 2022

5046

Background: Men in sub-Saharan Africa (SSA) are disproportionately affected by prostate cancer (PCa), and many have metastatic disease (mPCA) at presentation. In SSA, androgen deprivation therapy (ADT) is the first-line treatment for mPCa, and often the only available therapy. Treatment failure and death is common. We identified predictors of overall survival (OS) in Black South African (SA) men with mPCa on ADT. Methods: We performed a retrospective analysis of prospectively gathered data from men diagnosed with mPCA (3/22/2016 - 10/30/2020) at Chris Hani Baragwanath Hospital in Johannesburg, which was also a study site for the concurrent Men of African Descent and Carcinoma of the Prostate study. We included men with mPCA treated with ADT (received at least 1 dose of luteinizing hormone-releasing hormone agonist and/or had surgical castration), who had ≥1 PSA level drawn ≥12 weeks after ADT start. OS was defined from ADT start to death. PSA progression (PSA-P) definition was adapted from PCWG 3. Cox regression models were used to identify predictors of OS. PSA-P was treated as a time-dependent covariate. Results: Of 200 men with mPCa, we excluded 6 who did not receive ADT and 41 without sufficient data for PSA-P analysis. Of 153 men, 26.8% were <65 years old and 12% had a family history of PCa. Median PSA at diagnosis was 71.5 ng/mL (interquartile range (IQR) 20.7-432.6), median alkaline phosphatase level (ALP) 108 IU/L (79-224) and median hemoglobin (Hb) 13 g/dL (IQR 10-15). Median PSA nadir was 2.8 ng/mL (IQR 0.55-17.93). The rate of PSA-P at 1- and 2-years was 12.1% [95%CI 5.9-17.8] and 37.5% [95%CI 26.1-47.2]. The median follow-up was 2.75 years, and the 3-year OS was 61.9% [95%CI 52.7-72.6]. Cox proportional hazard ratio (HR) models of risk factors for OS are shown in Table 1. PSA-P was a strong predictor of OS. Men with PSA nadir >4ng/mL after ADT start had a HR for death of 3.77 [1.86-7.62]. Men with ALP >150 IU/L and those with Hb <13.5g/dL at diagnosis were also at higher risk for death (HR 3.09 [1.64-5.83] and HR 2.00 [1.28-6.56] respectively). Conclusions: Among Black men in SA treated with ADT for mPCA, PSA-P strongly predicts OS. In this cohort, high ALP and anemia at diagnosis, and PSA nadir >4ng/mL after ADT start are associated with higher risk for death. These factors can be used identify high risk men with mPCA, for whom early treatment escalation to chemotherapy should be considered. [Table: see text]