scholarly journals Exposure–response analyses of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma

2022 ◽  
Author(s):  
Anne-Gaëlle Dosne ◽  
Elodie Valade ◽  
Nele Goeyvaerts ◽  
Peter De Porre ◽  
Anjali Avadhani ◽  
...  
Keyword(s):  
Adverse Events ◽  
Urothelial Carcinoma ◽  
Objective Response ◽  
Locally Advanced ◽  
Hazard Ratio ◽  
Dose Titration ◽  
Efficacy And Safety ◽  
Exposure Response ◽  
Potential Biomarker ◽  
Metastatic Urothelial Carcinoma

Abstract Background Exposure–response analyses were conducted to explore the relationship between selected efficacy and safety endpoints and serum phosphate (PO4) concentrations, a potential biomarker of efficacy and safety, in locally advanced or metastatic urothelial carcinoma patients with FGFR alterations treated with erdafitinib. Methods Data from two dosing regimens of erdafitinib in a phase 2 study (NCT02365597), 6 and 8-mg/day with provision for pharmacodynamically guided titration per serum PO4 levels, were analyzed using Cox proportional hazard or logistic regression models. Efficacy endpoints were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Safety endpoints were adverse events typical for FGFR inhibitors. Results Exposure-efficacy analyses on 156 patients (6-mg = 68; 8-mg = 88) showed that patients with higher serum PO4 levels within the first 6 weeks showed better OS (hazard ratio 0.57 [95% CI 0.46–0.72] per mg/dL of PO4; p = 0.01), PFS (hazard ratio 0.80 [0.67–0.94] per mg/dL of PO4; p = 0.01), and ORR (odds ratio 1.38 [1.02–1.86] per mg/dL of PO4; p = 0.04). Exposure-safety analyses on 177 patients (6-mg = 78; 8-mg = 99) showed that the incidence of selected adverse events associated with on-target off-tumor effects significantly rose with higher PO4. Conclusions The exploratory relationship between serum PO4 levels and efficacy/safety outcomes supported the use of pharmacodynamically guided dose titration to optimize erdafitinib’s therapeutic benefit/risk ratio. Clinical trial registration number NCT02365597.

scholarly journals Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS)

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
P. Grivas ◽  
Y. Loriot ◽  
R. Morales-Barrera ◽  
M. Y. Teo ◽  
Y. Zakharia ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Locally Advanced ◽  
Significant Activity ◽  
Efficacy And Safety ◽  
Open Label ◽  
Pathway Gene ◽  
Metastatic Urothelial Carcinoma ◽  
Previously Treated

Abstract Background ATLAS evaluated the efficacy and safety of the PARP inhibitor rucaparib in patients with previously treated locally advanced/unresectable or metastatic urothelial carcinoma (UC). Methods Patients with UC were enrolled independent of tumor homologous recombination deficiency (HRD) status and received rucaparib 600 mg BID. The primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (loss of genome-wide heterozygosity ≥10%) populations. Key secondary endpoints were progression-free survival (PFS) and safety. Disease control rate (DCR) was defined post-hoc as the proportion of patients with a confirmed complete or partial response (PR), or stable disease lasting ≥16 weeks. Results Of 97 enrolled patients, 20 (20.6%) were HRD-positive, 30 (30.9%) HRD-negative, and 47 (48.5%) HRD-indeterminate. Among 95 evaluable patients, there were no confirmed responses. However, reductions in the sum of target lesions were observed, including 6 (6.3%) patients with unconfirmed PR. DCR was 11.6%; median PFS was 1.8 months (95% CI, 1.6–1.9). No relationship was observed between HRD status and efficacy endpoints. Median treatment duration was 1.8 months (range, 0.1–10.1). Most frequent any-grade treatment-emergent adverse events were asthenia/fatigue (57.7%), nausea (42.3%), and anemia (36.1%). Of 64 patients with data from tumor tissue samples, 10 (15.6%) had a deleterious alteration in a DNA damage repair pathway gene, including four with a deleterious BRCA1 or BRCA2 alteration. Conclusions Rucaparib did not show significant activity in unselected patients with advanced UC regardless of HRD status. The safety profile was consistent with that observed in patients with ovarian or prostate cancer. Trial registration This trial was registered in ClinicalTrials.gov (NCT03397394). Date of registration: 12 January 2018. This trial was registered in EudraCT (2017–004166-10).

Nivolumab monotherapy in patients with advanced platinum-resistant urothelial carcinoma: Efficacy and safety update from CheckMate 275.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4524-4524 ◽  
Author(s):  
Arlene O. Siefker-Radtke ◽  
Ari David Baron ◽  
Andrea Necchi ◽  
Elizabeth R. Plimack ◽  
Sumanta K. Pal ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Objective Response ◽  
Locally Advanced ◽  
Safety Data ◽  
Progression Free Survival ◽  
Efficacy And Safety ◽  
Open Label ◽  
Platinum Resistant ◽  
Metastatic Urothelial Carcinoma

4524 Background: In the open-label, single-arm, phase 2 CheckMate 275 trial, objective response rate (ORR) for patients (pts) with metastatic urothelial carcinoma (mUC) with nivolumab (NIVO) was 20.4% with minimum follow-up of 21.3 mo. Here, we report updated efficacy and safety data with minimum follow-up of 33.7 mo. Methods: Pts with platinum-resistant locally advanced or metastatic urothelial carcinoma received NIVO 3 mg/kg until disease progression or unacceptable toxicity. The primary endpoint was ORR by blinded independent review committee (BIRC) by RECIST v1.1 (including duration of response [DOR]). Secondary endpoints included progression-free survival (PFS) by BIRC, overall survival (OS), and ORR per investigator. Efficacy was evaluated in all treated pts and by tumor PD-L1 expression. Safety and PFS by investigator were exploratory endpoints. Results: ORR by BIRC was 20.7% (95% CI 16.1–26.1) including 18 (7%) complete responses (CR; with 1 additional CR since the last report; Table). ORR per investigator was similar (24.8%). Median DOR by BIRC was 20.3 mo (95% CI 11.5–31.3). Of 56 pts with best overall response (BOR) of CR or partial response (PR), 59% had a DOR ≥12 mo. Median PFS (mPFS) was 1.9 mo per BIRC (95% CI 1.9–2.3; Table) and 2.0 mo per investigator (95% CI 1.9–2.5). Median OS (mOS) was 8.6 mo (95% CI 6.1–11.3; Table). 12, 24, and 36-mo OS rates were 40%, 30%, and 22%. While efficacy was numerically higher in pts with tumor PD-L1 expression ≥1%, efficacy was observed in all pts (Table). Any-grade treatment-related adverse events occurred in 69% of pts (grade 3–4, 25%), mostly (59%) within the first 3 mo of initiating therapy. Conclusions: With long-term follow-up from CheckMate 275, NIVO continues to provide durable antitumor activity in pts with mUC. No new safety signals were noted. Clinical trial information: NCT02387996. [Table: see text]

The efficacy and safety of anlotinib in neoadjuvant treatment in locally advanced thyroid cancer: A single-arm phase II clinical trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 6069-6069
Author(s):  
Naisi Huang ◽  
Guohua Sun ◽  
Yulong Wang ◽  
Jiaying Chen ◽  
Qing Guan ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Thyroid Cancer ◽  
Adverse Events ◽  
Objective Response ◽  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Primary Treatment ◽  
Tumor Diameter ◽  
Efficacy And Safety ◽  
Advanced Thyroid Cancer

6069 Background: Surgery is the primary treatment for locally advanced thyroid cancer (TC). For some locally advanced TC, R0/R1 resection could not be achieved at initial diagnosis and neoadjuvant treatment would be an option. However, there is still little evidence regarding neoadjuvant treatment in locally advanced TC. Methods: This single-arm, phase 2 study investigated the efficacy and safety of Anlotinib (12mg orally daily, for two weeks on/on week off) for 2-6 cycles in patients with locally advanced TC in the neoadjuvant setting. Operable patients received surgery after neoadjuvant treatment. The primary endpoint was objective response rate (ORR). Results: A total of 13 patients were included and received an average of 3.5 cycles (range: 3-6 cycles) of Anlotinib treatment. 12 cases were papillary thyroid cancer, and 1 was follicular thyroid cancer. The ORR of Anlotinib was 76.9% with 10 partial response (PR), 2 stable disease (SD), and 1 progressive disease (PD). 8 PR and 1 SD patients received surgery after neoadjuvant treatment, of whom 8 had R0/1 resections and 1 had R2 resection. 2 PR patients refused to have surgery and the rest 2 patients were not operable. The R0/1 resection rate for intent to treat population was 61.5% and for per-protocol population was 72.7%. The maximum reduction in sum of tumor diameter was an average of 34.8% (range: 30.9%-45.5%) for PR patients. Most adverse events were grade 1 or 2. Common adverse events of all grade were hypertension (76.9%), hypertriglyceridemia (69.2%), proteinuria (53.8%), TSH increase (53.8%), cholesterol elevation (53.8%) and hand-foot syndrome (38.5%). The majority of adverse events discontinued after the neoadjuvant treatment stopped. Conclusions: Anlotinib demonstrated antitumor activity in the neoadjuvant treatment in locally advanced TC and the majority of patients achieved R0/1 resection. Adverse events were consistent with the known Anlotinib adverse event profile. These results suggest that Anlotinib neoadjuvant treatment represents a new option for locally advanced TC. Clinical trial information: NCT04309136.

A phase II study of RC48-ADC in HER2-positive patients with locally advanced or metastatic urothelial carcinoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4509-4509 ◽  
Author(s):  
Xinan Sheng ◽  
Ai-Ping Zhou ◽  
Xin Yao ◽  
Yanxia Shi ◽  
Hong Luo ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Phase Ii ◽  
Objective Response Rate ◽  
Response Rate ◽  
Phase Ii Study ◽  
Objective Response ◽  
Locally Advanced ◽  
Visceral Metastasis ◽  
Her2 Positive ◽  
Metastatic Urothelial Carcinoma

4509 Background: Urothelial carcinoma (UC) is the third largest cancer type with HER2 positive cancer. RC48-ADC is a novel humanized anti-HER2 antibody-drug conjugate (ADC). This study was to evaluate the activity of RC48-ADC in HER2-positive patients with locally advanced or metastatic urothelial carcinoma (mUC). Methods: This study is an open-label, multicenter, single-arm, non-randomized phase II study. Eligibility criteria include: histologically confirmed UC, HER2-positive (IHC 2+ or 3+), ECOG PS 0-1, treated with ≥1 prior systemic treatment. The patients received RC48-ADC treatment alone (2 mg/kg IV infusion, q2w) until disease progression, unacceptable toxicity, withdrawal, or study termination. The primary endpoint was objective response rate (ORR). Progress-free survival (PFS), overall survival (OS), and safety was also assessed. Results: Patient enrollment for this study was completed in November 2018. A total of 43 patients were enrolled, with a median age of 64 years old. At baseline, most patients (37/43) had visceral metastasis. Fourteen (32.6%) patients had received ≥ 2 lines treatment and 8 (18.6%) patients had prior immune checkpoint inhibitor (CPI) therapy in second line treatment. The objective response rate was 60.5% (95% CI: 44.4%, 75.0%) and the DCR was 90.7% (39/43). As of Jan 23, 2019, the median PFS for the overall study population was not yet reached, and the median PFS was 7.8 months (95% CI: 4.9, 10.7) for the 9 patients who started RC48-ADC prior to Jun 30, 2018. The ORR was 70.6% (12/17) in patients with HER2 FISH+ or IHC3+. The ORR was 64.9% (24/37) in patients with visceral metastasis and was 70.0% (14/20) in liver metastasis patients especially. The ORR was 64.3% in patients post to ≥ 2 lines treatment and 75.0% in patients post to immunotherapy. Common treatment-related AEs were leukopenia (51.2%), hypoesthesia (41.9%), alopecia (41.9%), neutropenia (37.2%), fatigue (34.9%), ALT increase (32.6%), and AST increase (32.6%); Most were Grade 1 or 2. Conclusions: RC48-ADC has demonstrated a clinically meaningful ORR of 60.5% in pretreated HER-2 positive mUC patients including those who underwent failure to the immunotherapy. Clinical trial information: NCT03507166.

scholarly journals Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma

JAMA Oncology ◽  
2017 ◽  
Vol 3 (9) ◽  
pp. e172411 ◽  
Author(s):  
Thomas Powles ◽  
Peter H. O'Donnell ◽  
Christophe Massard ◽  
Hendrik-Tobias Arkenau ◽  
Terence W. Friedlander ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Locally Advanced ◽  
Efficacy And Safety ◽  
Metastatic Urothelial Carcinoma

Primary results of EV-301: A phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated locally advanced or metastatic urothelial carcinoma.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 393-393
Author(s):  
Thomas Powles ◽  
Jonathan E. Rosenberg ◽  
Guru Sonpavde ◽  
Yohann Loriot ◽  
Ignacio Duran ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Interim Analysis ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Antibody Drug Conjugate ◽  
Free Survival ◽  
Phase Iii Study ◽  
Metastatic Urothelial Carcinoma

393 Background: Patients with locally advanced or metastatic urothelial carcinoma (la/mUC) have poor survival following progression after platinum-containing chemotherapy and PD-1/L1 inhibitor regimens. Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, a cell adhesion molecule highly expressed in urothelial carcinoma, with remarkable efficacy observed in a single-arm trial in this setting. This randomized phase III study (EV-301) was performed to confirm these findings. Methods: EV-301 (NCT03474107) is a global, open-label phase III study of EV vs chemotherapy conducted in patients with la/mUC who had received a prior platinum-containing chemotherapy and had disease progression during or after PD-1/L1 inhibitor treatment. Patients were randomized 1:1 to receive EV (1.25 mg/kg) on Days 1, 8, and 15 of each 28-day cycle or investigator choice of standard docetaxel, paclitaxel, or vinflunine chemotherapy. The primary endpoint was overall survival (OS); secondary endpoints included investigator-assessed progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) per RECIST v1.1, as well as safety/tolerability. A prespecified interim analysis, which tested OS at an adjusted 1-sided significance level of P = 0.00679, was performed when ≥285 deaths had occurred. The results of this interim analysis are presented here. Results: Overall, 608 patients with la/mUC were randomly assigned to EV (n=301) or chemotherapy (n=307). As of July 15, 2020, 301 deaths had occurred (EV, n=134; chemotherapy, n=167). After an 11.1 mo follow-up, median OS was significantly prolonged by 3.9 mo with EV compared with chemotherapy (median OS: 12.9 vs 9.0 mo, respectively; HR=0.70 [95% CI: 0.56-0.89], 1-sided P =0.001). Additionally, the OS benefit of EV was retained in the majority of prespecified subgroups. Progression-free survival also was improved with EV (5.6 mo) vs chemotherapy (3.7 mo) (HR=0.61 [95% CI: 0.50-0.75]; 1-sided P <0.00001). Both ORR and DCR were significantly higher with EV vs chemotherapy (40.6% vs 17.9% and 71.9% vs 53.4%, respectively; 1-sided P <0.001 each). Rates of treatment-related adverse events (TRAEs; 93.9% vs 91.8%), including serious TRAEs (22.6% vs 23.4%), were comparable between the EV and chemotherapy groups. Rates of grade ≥3 TRAEs were ~50% in both groups; decreased neutrophil count (13.4%) and white blood cell count (6.9%) were more common in the chemotherapy group, and maculo-papular rash (7.4%) was more common in the EV group. Conclusions: EV is the first therapy to show significant survival advantage over standard chemotherapy in patients with treatment-experienced la/mUC. With robust clinical benefit and a tolerable safety profile, EV is a new standard of care for this aggressive disease. Clinical trial information: NCT03474107.

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