Study EV-103: Update on durability results and long term outcome of enfortumab vedotin + pembrolizumab in first line locally advanced or metastatic urothelial carcinoma (la/mUC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4528-4528
Author(s):  
Terence W. Friedlander ◽  
Matthew I. Milowsky ◽  
Mehmet Asim Bilen ◽  
Sandy Srinivas ◽  
Rana R. McKay ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Objective Response ◽  
Locally Advanced ◽  
Unmet Need ◽  
First Line ◽  
Antibody Drug Conjugate ◽  
Durable Response ◽  
Long Term Outcome ◽  
Metastatic Urothelial Carcinoma

4528 Background: Significant unmet need remains for people with cisplatin-ineligible (cis-ineligible) locally advanced or metastatic urothelial carcinoma (la/mUC). In the first-line (1L) setting, carboplatin-based regimens have demonstrated poor tolerability, modest objective response rate (ORR) and limited durability. PD-1/PD-L1 inhibitors demonstrate durable responses; however, only a minority of pts achieve a response (ORR 24-29%). Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) delivering the microtubule-disrupting agent monomethyl auristatin E (MMAE) to targeted tumor cells expressing Nectin-4. EV has shown an overall survival benefit versus chemotherapy in previously treated la/mUC. Preclinical studies show that ADCs utilizing MMAE can induce immunogenic cell death and may enhance antitumor immunity. Clinical data suggests the combination of EV + pembrolizumab (P) may have the potential to induce greater antitumor activity compared to either agent alone. Preliminary data on EV + P was previously presented, and the FDA granted breakthrough therapy designation to EV + P for the treatment of pts with 1L cis-ineligible la/mUC in Feb 2020. Here we report updated data with 24.9 months median follow-up. Methods: This multi-cohort EV-103 study (NCT03288545) evaluates the safety/activity of EV + P (Dose Escalation/Cohort A). This report highlights 1L cis-ineligible pts treated with 3-week cycles of EV 1.25 mg/kg (Days 1, 8) and P (Day 1). Endpoints include safety/tolerability, investigator response per RECIST v1.1, DOR, PFS, and OS. Results: As of 13 Oct 2020, the median follow-up for the 45 1L la/mUC pts (median age 69 yrs [51-90]) was 24.9 months. The median number cycles of EV + P was 9 (range 1-34). The most common treatment-related adverse events were peripheral sensory neuropathy (56%, 4% ≥G3), fatigue (51%, 11% ≥G3), and alopecia (49%). There was one death reported as possibly related to study treatment (multiple organ dysfunction syndrome) per investigator assessment. Confirmed ORR is 73.3% (95% CI: 58.1, 85.4) including 17.8% CR and an ORR of 57.1% (8/14) in pts with liver metastasis. The median DOR was 25.6 months (95% CI: 8.3, -). Fifty-three percent of the responders had DOR at 24 months. Additionally, the DCR is 93.3%, the median PFS is 12.3 months (95% CI: 8.0, -), and the median OS is not reached. The OS rate at 24 months is 56.3% (95% CI: 39.8, 69.9). Conclusions: EV + P, a platinum-free option, continues to demonstrate promising activity with a durable response profile in 1L cis-ineligible pts with la/mUC. The safety profile is manageable and stable over time with no new safety signals. Cohort K of EV-103 in cis-ineligible pts with la/mUC is actively randomizing pts to EV monotherapy or EV + P to evaluate the contribution of each agent. Clinical trial information: NCT03288545.

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.

scholarly journals Nivolumab Alone and With Ipilimumab in Previously Treated Metastatic Urothelial Carcinoma: CheckMate 032 Nivolumab 1 mg/kg Plus Ipilimumab 3 mg/kg Expansion Cohort Results

2019 ◽  
Vol 37 (19) ◽  
pp. 1608-1616 ◽  
Author(s):  
Padmanee Sharma ◽  
Arlene Siefker-Radtke ◽  
Filippo de Braud ◽  
Umberto Basso ◽  
Emiliano Calvo ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Urothelial Carcinoma ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Locally Advanced ◽  
Open Label ◽  
Duration Of Response ◽  
Metastatic Urothelial Carcinoma

PURPOSE CheckMate 032 is an open-label, multicohort study that includes patients with unresectable locally advanced or metastatic urothelial carcinoma (mUC) treated with nivolumab 3 mg/kg monotherapy every 2 weeks (NIVO3), nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks (NIVO3+IPI1), or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks (NIVO1+IPI3). We report on the expanded NIVO1+IPI3 cohort and extended follow-up for the NIVO3 and NIVO3+IPI1 cohorts. METHODS Patients with platinum-pretreated mUC were enrolled in this phase I/II multicenter study to receive NIVO3, NIVO3+IPI1, or NIVO1+IPI3 until disease progression or unacceptable toxicity. Primary end point was investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, including duration of response. RESULTS Seventy-eight patients were treated with NIVO3 (minimum follow-up, 37.7 months), 104 with NIVO3+IPI1 (minimum follow-up, 38.8 months), and 92 with NIVO1+IPI3 (minimum follow-up, 7.9 months). Objective response rate was 25.6%, 26.9%, and 38.0% in the NIVO3, NIVO3+IPI1, and NIVO1+IPI3 arms, respectively. Median duration of response was more than 22 months in all arms. Grade 3 or 4 treatment-related adverse events occurred in 21 (26.9%), 32 (30.8%), and 36 (39.1%) patients treated with NIVO3, NIVO3+IPI1, and NIVO1+IPI3, respectively. Grade 5 treatment-related pneumonitis occurred in one patient each in the NIVO3 and NIVO3+IPI1 arms. CONCLUSION With longer follow-up, NIVO3 demonstrated sustained antitumor activity alone and in combination with ipilimumab. NIVO1+IPI3 provided the greatest antitumor activity of all regimens, with a manageable safety profile. This result not only supports additional study of NIVO1+IPI3 in mUC, but demonstrates the potential benefit of immunotherapy combinations in this disease.

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]

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

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17113-e17113 ◽  
Author(s):  
Huayan Xu ◽  
Xinan Sheng ◽  
Xieqiao Yan ◽  
Zhihong Chi ◽  
Chuanliang Cui ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Phase Ii ◽  
Objective Response ◽  
Locally Advanced ◽  
Good Effect ◽  
Visceral Metastasis ◽  
Antibody Drug Conjugate ◽  
Her2 Positive ◽  
Open Label ◽  
Metastatic Urothelial Carcinoma

e17113 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 benefit from the treatment of RC48-ADC.The 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, one-arm, non-randomized phase II trial. Eligibility criteria include: histologically confirmed urothelial carcinoma, HER2-negasitive (IHC 0 or 1+), ECOG PS 0-1, treated with ≥1 prior systemic treatment. The patients received RC48-ADC treatment alone (2mg/kg IV infusion, q2w) until disease progression, unacceptable toxicity, withdrawal, or study termination. The primary objectives were activity (ORR) and safety. Progress-free survival, disease control rate and overall survival will also be assessed. Results: As of February 2020, 8 patients were enrolled in the study. The median age was 65 years old. At baseline, most patients (6/8) had visceral metastasis. 6 (75%) patients had received≥2 lines treatment and 4 (50%) patients had prior immune checkpoint inhibitor (CPI) therapy in second line treatment. The objective response rate was 25% (2/8) and the DCR was 75% (6/8). The ORR was 33.3% (2/6) in patients with visceral metastasis and was 50.0% (2/4) in liver metastasis patients. The ORR was 33.3% (2/6) in patients post to ≥ 2 lines of treatment and 25% (1/4) in patients post to immunotherapy. Common treatment-related AEs were AST increase (62.5%), ALT increase (50.0%), nausea (50.0%), leukopenia (37.5%), fatigue (37.5%), vomiting (37.5%), hypoesthesia (25.0%), alopecia (25.0%), and neutropenia (25.0%). Most of these AE were Grade 1 or 2. The AE of Grade 3 was neutropenia (12.5%). The SAE was CPK increased (12.5%). Conclusions: The study showed that RC48-ADC was safety and the ORR was 25% in HER-negative patients with locally advanced or metastatic urothelial carcinoma. Clinical trial information: NCT04073602.

First Report of Oncological Outcome and Prognostic Analysis in a First-Line Setting of Short Hydration Gemcitabine and Cisplatin Chemotherapy for Patients with Metastatic Urothelial Carcinoma

Oncology ◽  
2021 ◽  
pp. 1-10
Author(s):  
Taku Naiki ◽  
Takashi Nagai ◽  
Yosuke Sugiyama ◽  
Toshiki Etani ◽  
Satoshi Nozaki ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Risk Index ◽  
Objective Response ◽  
Oncological Outcome ◽  
Nutritional Risk ◽  
First Line ◽  
Prognostic Analysis ◽  
Nutritional Risk Index ◽  
Metastatic Urothelial Carcinoma ◽  
Gemcitabine And Cisplatin

<b><i>Objectives:</i></b> The aim of the study was to examine the effectiveness of a modified-short hydration gemcitabine and cisplatin (m-shGC) regimen for patients with metastatic urothelial carcinoma (mUC) and to assess the efficacy of a geriatric nutritional risk index (GNRI) with regard to prognosis. <b><i>Patients and Methods:</i></b> From January 2016 to July 2020, 68 patients with mUC underwent first-line m-shGC therapy with 70 mg/m<sup>2</sup> cisplatin and 1,000 mg/m<sup>2</sup> gemcitabine (days 1, 8, and 15), with 2,050 mL fluid replaced on the first day of each 28-day cycle. Prior to the start of treatment, the serum neutrophil-to-lymphocyte ratio (NLR), and levels of albumin and C-reactive protein (CRP) in serum, as well as body heights and weights were measured. Patients were grouped according to GNRI &#x3c;92 (low) or ≥92 (high). The analysis of data was done retrospectively. <b><i>Results:</i></b> Median follow-up was found to be 12.9 (range 1.7–50.2) months and the objective response rate (ORR) was 54.4% after m-shGC treatment. The ORR was significantly different when high and low-GNRI groups were compared (ORR: 28.0 vs. 69.8% in low- vs. high-GNRI groups). Median overall survival (OS) was calculated as 8.6 (95% confidence interval [CI]: 5.4–21.3) and 34.5 (95% CI: 20.5–NA) months for low- and high-GNRI groups, respectively (<i>p</i> &#x3c; 0.0001). Unlike for NLR and CRP, univariate and multivariate analyses revealed that low GNRI and visceral metastases were significant prognostic factors for short OS. <b><i>Conclusions:</i></b> First-line m-shGC showed a survival benefit for mUC, with GNRI a useful prognostic biomarker.

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