Safety profile of enfortumab vedotin plus pembrolizumab in locally advanced or metastatic urothelial carcinoma: a multicenter Japanese cohort study.

(Purpose) Enfortumab vedotin has been available as a third-line treatment for advanced urothelial carcinoma in Japan since December 2021. While the treatment is expected to improve the outcome of advanced urothelial carcinoma, concerns regarding adverse events do exist. We report here our initial experience of the use of enfortumab vedotin as a third-line therapy in patients with advanced urothelial carcinoma. (Patients and Methods) We retrospectively evaluated the efficacy and adverse events of enfortumab vedotin treatment, as a third line therapy, in patients who had failed platinum-containing chemotherapy and immune checkpoint inhibitor therapy in our institution from January 2022 to January 2023. Efficacy was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), and duration of response (DOR). Safety was evaluated for treatment-related adverse events using the Common Terminology Criteria for Adverse Events (CTCAE) ver. 4.0. (Results) In this study, sixteen patients were investigated. The median age was 70 years (45-93 years); all patients had previously received platinum-containing chemotherapy with cisplatin or carboplatin, eleven having been treated with pembrolizumab, and 5 with avelumab, as sequential immune checkpoint inhibitors. As for efficacy, the median observation period was 9.27 months (4.03-16.6 months). The treatment response rate included 2 complete response (CR) (12.5%), 5 partial response (PR) (31.3%), and 5 stable disease (SD), out of 16 patients. The ORR and DCR were 43.8% and 75.0%, respectively. The median PFS was 7.77 months (3.67-not reached). The median time to response was 1.87 months (0.47-2.80 months) and the median DOR was 7.93 months (0.73-13.1 months). Eight patients (50%) discontinued treatment due to disease progression. As for safety, the incidence of treatment-related adverse events (TRAE) was 93.8%, and that of Grade 3 or higher TRAE was 56.3%. Four out of 16 patients (25%) underwent dose reduction due to TRAE. Among all grades, skin reactions were the most common in 12 patients (75%), followed by dysgeusia, alopecia, neutropenia, and anorexia. Neutropenia (including febrile neutropenia) was the most common Grade 3 or higher TRAE in five patients (31.3%), followed by skin reactions, anorexia, and anemia. Two of the patients, who observed skin reactions, developed severe rash and Stevens-Johnson syndrome, which eventually led to treatment discontinuation. The median time from enfortumab vedotin administration to onset of skin reaction was 9 days (5-18 days), with most cases occurring in the first cycle. (Conclusions) Enfortumab vedotin is an effective treatment option in real clinical practice. However, adverse events, including skin reactions, should be carefully monitored.

Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV‑201): a multicentre, single-arm, phase 2 trial

SummaryLocally advanced or metastatic urothelial cancer is an aggressive form of cancer with high recurrence rates and low survival. Nectin-4 is a cell adhesion molecule commonly expressed in several tumors, including high expression in urothelial cancer. Enfortumab vedotin is an antibody–drug conjugate composed of an anti-Nectin-4 humanized monoclonal antibody linked to the microtubule disrupting agent, monomethyl auristatin E. In this phase I study (NCT03070990), Japanese patients with locally advanced/metastatic urothelial cancer treated with prior chemotherapy, or ineligible for cisplatin, were randomized 1:1 to receive 1.0 mg/kg (Arm A) or 1.25 mg/kg (Arm B) enfortumab vedotin on Days 1, 8, and 15 of each 28-day cycle. Assessing the pharmacokinetic and safety/tolerability profiles of enfortumab vedotin were primary objectives; investigator-assessed antitumor activity (RECIST v1.1) was a secondary objective. Seventeen patients (n = 9, Arm A; n = 8, Arm B) received treatment. Pharmacokinetic data suggest a dose-dependent increase in enfortumab vedotin maximum concentration and area under the concentration–time curve at Day 7. Enfortumab vedotin was well tolerated across both doses. Dysgeusia and alopecia (n = 9 each) were the most common treatment-related adverse events. Regardless of attribution, grade ≥ 3 adverse events occurring in ≥2 patients were anemia and hypertension (n = 2 each). One patient achieved a confirmed complete response (Arm A) and five achieved confirmed partial responses (n = 3, Arm A; n = 2, Arm B). Objective response and disease control rates were 35.3% and 76.5%, respectively. In Japanese patients with locally advanced/metastatic urothelial cancer, enfortumab vedotin is well tolerated with preliminary antitumor activity and a pharmacokinetic profile consistent with prior reports.

Cutaneous reactions with enfortumab vedotin: A case series and review of the literature

PURPOSELocally advanced or metastatic urothelial carcinoma is an incurable disease with limited treatment options, especially for patients who were previously treated with platinum and anti–programmed death 1 or anti–programmed death ligand 1 (PD-1/L1) therapy. Enfortumab vedotin is an antibody–drug conjugate that targets Nectin-4, which is highly expressed in urothelial carcinoma.METHODSEV-201 is a global, phase II, single-arm study of enfortumab vedotin 1.25 mg/kg (intravenously on days 1, 8, and 15 of every 28-day cycle) in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum chemotherapy and anti–PD-1/L1 therapy. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by blinded independent central review. Key secondary end points were duration of response, progression-free survival, overall survival, safety, and tolerability.RESULTSEnfortumab vedotin was administered to 125 patients with metastatic urothelial carcinoma. Median follow-up was 10.2 months (range, 0.5 to 16.5 months). Confirmed objective response rate was 44% (95% CI, 35.1% to 53.2%), including 12% complete responses. Similar responses were observed in prespecified subgroups, such as those patients with liver metastases and those with no response to prior anti–PD-1/L1 therapy. Median duration of response was 7.6 months (range, 0.95 to 11.30+ months). The most common treatment-related adverse events were fatigue (50%), any peripheral neuropathy (50%), alopecia (49%), any rash (48%), decreased appetite (44%), and dysgeusia (40%). No single treatment-related adverse events grade 3 or greater occurred in 10% or more of patients.CONCLUSIONEnfortumab vedotin demonstrated a clinically meaningful response rate with a manageable and tolerable safety profile in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum and anti–PD-1/L1 therapies.

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.

e16574 Background: Enfortumab vedotin (EV), a fully human monoclonal antibody directed against Nectin-4 delivering intracellular monomethyl auristatin E (MMAE) to tumor cells, demonstrated superior overall survival (OS) with manageable safety/tolerability over standard chemotherapy in patients (pts) with previously treated locally advanced or metastatic urothelial carcinoma (la/mUC) in the pivotal EV-301 trial. EV-301 findings led to approval in 41 countries. As EV monotherapy has not been studied in a Chinese population, EV-203 (NCT04995419) assessed efficacy, safety/tolerability, and pharmacokinetics (PK) of EV in pts with la/mUC in China. Methods: In this single-arm, open-label, phase 2 study, Chinese pts with la/mUC previously treated with platinum-based chemotherapy and PD-1/L1 inhibitor therapy received EV 1.25 mg/kg via intravenous infusion on days 1, 8, and 15 of each 28-d cycle at 6 centers. Pts had Eastern Cooperative Oncology Group performance status 0–1 and were excluded if they had preexisting grade ≥2 sensory/motor neuropathy, active central nervous system metastases, clinically significant toxicity associated with prior treatment, or history of uncontrolled diabetes mellitus. Two study centers enrolled pts for a PK cohort. Primary endpoints were confirmed objective response rate (ORR; by Response Evaluation Criteria in Solid Tumors v1.1) by independent review committee (IRC) and PK parameters of antibody–drug conjugate (ADC), total antibody (TAb), and unconjugated MMAE. Secondary endpoints included investigator-assessed confirmed ORR; investigator-/IRC-assessed duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS); OS; and safety/tolerability. Results: A total of 40 Chinese pts were enrolled; 15 were in the PK cohort. Confirmed ORR by IRC was 37.5% (n/N=15/40; 95% CI: 22.7–54.2); best overall response was complete response for 1 (2.5%) pt and partial response for 14 (35.0%) pts. Investigator-assessed ORR was 42.5% (n=17). DCRs were 82.5% (n=33) by investigator and 72.5% (n=29) by IRC. Median DOR by investigator and IRC were not reached. Median PFS were 4.24 mo by investigator and 4.67 mo by IRC. Median follow-up time was 6.5 mo and median OS was not reached. Most treatment-related adverse events (TRAEs) were grade 1–2. Two pts discontinued EV due to TRAE (acute coronary syndrome and hyperglycemia/rash). Serum ADC and TAb concentrations peaked at end of EV infusion; MMAE concentrations had median peak 2–3 d post dose. Minimal ADC, TAb, and MMAE accumulation were observed with repeat EV dosing. Conclusions: EV-203 results show EV has a favorable benefit–risk profile, demonstrating meaningful clinical activity with a manageable safety profile, in pts with previously treated la/mUC in China. EV data are consistent with those from the global population in phase 2–3 EV trials of la/mUC. No new safety signals were identified. Clinical trial information: NCT04995419 .

6017 Background: Globally, HNCs accounted for an estimated 932,000 new cases and 467,000 deaths in 2020. Nectin-4 is expressed in a majority of HNCs. Given the poor prognosis (median survival < 1 y) of recurrent/metastatic disease in patients (pts) with head and neck squamous cell carcinoma, effective treatments are needed. Targeting Nectin-4 with an antibody–drug conjugate (ADC) may be a novel strategy. Enfortumab vedotin (EV) is a Nectin-4 directed ADC approved for treatment of adults with locally advanced or metastatic (la/m) urothelial carcinoma previously treated with platinum-containing chemotherapy and PD-1/L1 inhibitor based on survival benefit shown in the phase 3 EV-301 trial. Use of EV for HNC is investigated in EV-202 (NCT04225117). Methods: In this multicohort, open-label phase 2 study, pts with previously treated la/m solid tumors not amenable to curative-intent treatment and Eastern Cooperative Oncology Group performance status 0–1 were enrolled into tumor-specific cohorts. For the HNC cohort, pts must have progressed/relapsed/discontinued treatment for toxicity after 1 platinum-based therapy for la/m disease and no more than 2 lines of cytotoxic therapy in the la/m setting. Unless contraindicated, pts must have received a programmed cell death protein 1/ligand 1 (PD-1/L1) inhibitor (based on PD-1/L1 expression). Pts received EV 1.25 mg/kg intravenously on days 1, 8, and 15 of a 28-d cycle until disease progression/discontinuation criteria were met. Primary endpoint was confirmed objective response rate (ORR; per RECIST v1.1) per investigator assessment. Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety/tolerability. Results: As of April 11, 2022, a total of 46 pts were in the HNC cohort; median follow-up was 9.33 mo. Median age was 65 y, 87% of pts were men, and most had received ≥2 lines of systemic therapy in the metastatic setting. Histology at diagnosis was squamous cell carcinoma for 45 (97.8%) pts and “other” for 1 pt. ORR was 23.9% (n = 11). Median DOR was not reached. DCR was 56.5% (n = 26). Median time to response was 1.74 mo. Median PFS and OS were 3.94 and 5.98 mo, respectively. Common adverse events (AEs) were fatigue, alopecia, and peripheral sensory neuropathy (28.3% for each; n = 13). Grade ≥3 AEs occurring in > 1 pt were anemia (n = 3), decreased neutrophil count (n = 2), and malignant neoplasm progression (disease progression of HNC; n = 2). Of treatment-related AEs of special interest for EV, skin reactions occurred in 45.7% of pts, peripheral neuropathy in 32.6%, and hyperglycemia in 4.3%. Conclusions: In pts with heavily pretreated HNC, antitumor activity of EV monotherapy and tolerability, with manageable adverse events, was observed, consistent with that in previously studied populations with advanced urothelial carcinoma. Further investigation of EV activity in HNC is warranted. Clinical trial information: NCT04225117 .

Real-world evidence regarding enfortumab vedotin for unresectable or metastatic urothelial carcinoma is scarce, particularly in Japan. We investigated real-world data focusing on patient background, previous treatments, response, survival and adverse events in patients receiving enfortumab vedotin. A multicentre database was used to register 556 patients diagnosed with metastatic urothelial carcinoma from 2008 to 2023; 34 patients (6.1%) treated with enfortumab vedotin were included. Best radiographic objective responses were evaluated using the Response Evaluation Criteria in Solid Tumors (v1.1) during treatments. Overall survival and progression-free survival were estimated (Kaplan-Meier method). Toxicities were reported according to the Common Terminology Criteria for Adverse Events, version 5.0. The relative dose intensity, which could impact oncological outcomes, was calculated. The median number of enfortumab vedotin therapy cycles was 5. The best objective response to enfortumab vedotin was partial response, stable disease and progressive disease in 19 (56%), 5 (15%) and 10 (29%) patients, respectively. The median overall survival and progression-free survival after the first enfortumab vedotin dose were 16 and 9months, respectively. No significant relationship was observed between survival outcomes after enfortumab vedotin initiation and the enfortumab vedotin relative dose intensity. The median overall survival from first-line platinum-based chemotherapy initiation was 42months. Twenty-six (76%) patients experienced any grade of enfortumab vedotin-related toxicities; eight (24%) experienced Grades 3-4 toxicities, the most common being skin toxicity (any grade, 47%; Grades 3-4, 12%). Here, we report real-world evidence for enfortumab vedotin therapy in Japan. Tumour responses and safety profiles were comparable with those of clinical trials on this novel treatment.

Background/AimThe impact of steroid premedication on the efficacy and cutaneous toxicity of enfortumab vedotin (EV) in advanced urothelial carcinoma (UC) is unclear.Patients and MethodsWe retrospectively analyzed consecutive patients with advanced UC who received EV after the failure of platinum-based chemotherapy and immune checkpoint inhibitors from December 2021 to November 2024.ResultsTwenty-eight patients (male, n=16; median age, 71 years) were enrolled. Dexamethasone 6.6 mg was administered intravenously prior to EV in six (21.4%) patients. There were no differences in the overall response and disease control rates between patients with and without steroid premedication (p=0.653 and p>0.99, respectively). The progression-free survival was not significantly associated with or without steroid premedication (not estimable vs. 4.3 months, p=0.501). There were no marked differences in the incidence of all grades of EV-related cutaneous adverse events (AEs) between patients with and without steroid premedication (33.3% vs. 45.5%, p=0.673). There was no significant difference in the incidence of grade ≥3 EV-related cutaneous AEs between the patients with and without steroid premedication (16.7% vs. 36.4%, p=0.630). Multivariate analysis revealed that a performance status ≥2 was an independent prognostic factor for progression-free survival (hazard ratio=4.653, 95% confidence interval=1.263-17.140, p=0.021), and steroid premedication was not (p=0.869).ConclusionIn EV treatment, steroid premedication did not affect clinical outcomes. The incidence and severity of EV-related cutaneous toxicity tended to improve in patients who received steroid premedication, although no significant differences were observed.

The clinical outcomes associated with cutaneous toxicity and changes in the renal function of patients receiving enfortumab vedotin (EV) for advanced urothelial carcinoma (UC) is unclear. We retrospectively analyzed the relationship between clinical outcomes and EV-related cutaneous toxicity, and the influence on the renal function in 58 patients with advanced UC who received EV after the failure of platinum-based chemotherapy and immune checkpoint inhibitors from December 2021 to July 2023. There were no differences in the overall response and disease control rates between patients with any grade of EV-related cutaneous toxicity and without (p=0.605 and p>0.99, respectively) nor of grade ≥3 (p>0.99 and p=0.173, respectively). Progression-free survival was not significantly associated with EV-related cutaneous toxicity of any grade (5.4 vs. 5.6 months, p=0.557) nor of grade ≥3 (2.7 vs. 5.6 months, p=0.053). Overall survival was not significantly associated with EV-related cutaneous toxicity of any grade (11.8 vs. 8.9 months, p=0.389), nor of grade ≥3 (4.6 vs. 11.4 months, p=0.168). The incidence of EV-related cutaneous toxicity of any grade was significantly higher in patients with any grade of ICI-related cutaneous toxicity (88.9% vs. 36.7%, p=0.008). There was no significant difference in the serum creatinine levels after EV treatment (p=0.211). Divided into two groups according to their renal function, using a serum creatinine cut-off of 2 mg/dl, there were no significant changes after EV treatment in either group (p=0.187 and p=0.938). EV-related cutaneous toxicity did not affect clinical outcomes, although it occurred in patients who experienced immune checkpoint inhibitor-related cutaneous toxicity. EV did not affect renal function.

Enfortumab Vedotin–related Cutaneous Toxicity and Radiographic Response in Patients with Urothelial Cancer: A Single-center Experience and Review of the Literature

LB906 Characterization of cutaneous adverse events to enfortumab vedotin

Background: Platinum-containing chemotherapy is the standard first-line treatment of advanced urothelial carcinoma (UC). After the failure of the first-line treatment, emerging anti-PD-1/L1 therapies yield rather low response rates. RC48-ADC is a novel HER2-targeting antibody-drug conjugate (ADC). We aimed to evaluate the efficacy and safety of RC48-ADC in patients with HER2-positive locally advanced or metastatic UC. Methods: This is a phase 2, open-label, multi-centre, single-arm study of RC48-ADC at 2·0 mg/kg intravenously once every two weeks in patients with HER2-positive (immunohistochemical status 3+ or 2+ by central lab) locally advanced or metastatic UC who had failed with at least one line systemic chemotherapy. The primary endpoint was objective response rate (ORR) assessed by blinded independent review committee (BIRC)- per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1·1. The secondary endpoint included progression-free survival, duration of response, disease control rate, overall survival and safety. Findings: From 28 December 2017 to 28 November 2018, 43 patients were enrolled and treated with RC48-ADC. The median follow-up was 11·8 months. The confirmed ORR as assessed by BIRC was 51·2% (95% CI: 35·5%, 66·7%). Similar responses were observed in prespecified subgroups, such as those with liver metastasis and those previously treated with anti-PD-1/L1 therapies. Median progression-free survival was 6·9 months (95% CI: 5·3, 8·3). Median overall survival was 13·9 months (95% CI: 9·0, NE). The most commonly treatment-related adverse events (TRAEs) were hypoaesthesia (60·5%), alopecia (55·.8%), and leukopenia (55·8%). No Grade 4 or Grade 5 TRAE had occurred. Twenty-four (55·8%) patients experienced Grade 3 TRAEs, including hypoaesthesia (18·6%) and neutropenia (14·0%). Interpretation RC48-ADC manifested clinically meaningful efficacy and a manageable safety profile in patients with HER2-positive locally advanced or metastatic UC who were previously treated with platinum-containing chemotherapy and/or anti-PD-1/L1 therapies. Clinical Trial Registration: This study is registered with ClinicalTrials.gov, number NCT03507166. Funding Statement: RemeGen, Ltd., funded the study and provided the study drug. This work was also supported by grants from Natural Science Foundation of China (81672696) and Beijing Municipal Administration of Hospitals' Ascent Plan (DFL20181101). Declaration of Interests: JG is the member of the advisory board/consultant of MSD, Roche, Pfizer, Bayer, Novartis, Simcere, Shanghai Junshi Bioscience, Oriengene. JF are employees and shareholders of RemeGen, Ltd. All the other authors declare no conflict of interest. Ethical Approval Statement: All the patients provided written informed consent before joining the study. The study protocol was approved by a relevant institutional review board or ethics committee of each study centre. The study was compliant with the Declaration of Helsinki and Good Clinical Practice guidelines.

Enfortumab vedotin (EV) is an antibody drug conjugate approved for advanced urothelial cancer, consisting of a monomethyl auristatin E payload linked to a human monoclonal antibody targeting nectin-4. No validated biomarker predictive of or correlated with response exists for EV. Cutaneous toxicity is among the most common EV-related toxicities and typically emerges in early cycles. This retrospective experience of patients with urothelial cancer treated with EV monotherapy evaluated whether EV-related cutaneous toxicity correlated with improved outcomes including progression-free (PFS) and overall (OS) survival and overall response rate (ORR). Patients treated with EV monotherapy at Johns Hopkins were identified, and baseline characteristics, treatment, and toxicity details were extracted through chart review. Univariable Cox hazard ratios (HRs) were calculated for assessing the effect of baseline patient characteristics and cutaneous toxicity in PFS and OS. Based on the univariable analysis and known risk factors, all subsequent analyses were adjusted for: Eastern Cooperative Oncology Group performance status, visceral metastases at baseline, gender as well as EV dose, and weight to account for dosing differences. Multivariable Cox proportional HRs were used for comparing PFS and OS between patients with and without cutaneous toxicity, assessing toxicity and EV dose as a time-dependent variables. Adjusted p-values were calculated to compare ORR and disease control rate (DCR) between groups using the Poisson regression model. Of the 78 patients analyzed, 42 (53.8%) experienced EV-related cutaneous toxicity that appeared early during treatment (median time to occurrence 0.5 months from EV initiation). Cutaneous toxicity correlated with significantly improved OS [HR, 0.48; 95% confidence interval (CI), 0.25, 0.9; P = 0.0235], ORR (68.3% vs. 20.7%, P = 0.0033) and DCR (82.9% vs. 48.3%, P = 0.0122). Median PFS was numerically longer in the cutaneous toxicity group (6.3 vs. 1.7 months), although no significance was achieved in the multivariable analysis (HR, 0.62; 95% CI: 0.35, 0.108; P = 0.0925). In this retrospective study, EV-related cutaneous toxicity was associated with improved patient outcomes. Confirming this observation and understanding its mechanism could lead to discovery of a new clinical biomarker of EV response that can emerge in the first cycle.