CADTH Reimbursement Review

Enfortumab Vedotin (Padcev)

Sponsor: Seagen Canada Inc.

Therapeutic area: Locally advanced or metastatic urothelial carcinoma

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Introduction

Bladder cancer is the fifth most common cancer in Canada, with approximately 12,200 cases, resulting in an estimated 2,600 deaths in 2020. Urothelial carcinoma (UC) is the most common type of bladder cancer, accounting for 90% to 95% of cases.^1-4 Urothelial cancer typically arises in the bladder but may develop in any location lined with urothelium, including the renal pelvis, ureter, urethra, and prostatic urethra.⁵ Age, tobacco use, chemical carcinogens, family history, arsenic exposure, and use of indwelling catheters are known risk factors for bladder cancer. Bladder cancer is more common in males, although the reason is unknown.^6-9 The most common presentation of UC is visible or microscopic hematuria. Other symptoms of UC include painful urination, back or flank pain, fatigue, and unexplained weight loss.⁴ Approximately 15% of patients have locally advanced or metastatic UC at presentation.¹⁰ In Canada, the 5-year net survival rate for bladder cancer is 75%; however, there are no Canadian-specific survival statistics for locally advanced or metastatic UC patients. The estimated 5-year relative survival for patients with metastatic disease is approximately 6.4%,⁷ and up to 15% when treated with contemporary regimens.^11,12

Standard of care for locally advanced or metastatic UC consists of platinum-based chemotherapy, mainly gemcitabine plus cisplatin. In cisplatin-ineligible patients, gemcitabine plus carboplatin is recommended.¹⁰ Recently, avelumab was granted a conditional listing by CADTH for the first-line maintenance treatment of locally advanced or metastatic UC in patients whose disease has not progressed following first-line platinum-based induction chemotherapy.¹³ In patients who progress following platinum-based chemotherapy, treatment with checkpoint inhibitor (CPI) immunotherapy, preferably pembrolizumab, is recommended as second-line systemic therapy.^14,15 Following failure of platinum chemotherapy and CPIs, or when CPIs are unavailable, salvage chemotherapy with taxanes is recommended, with paclitaxel or docetaxel preferred for most patients.¹⁰

Enfortumab vedotin is an antibody-drug conjugate (ADC) consisting of a fully human immunoglobulin G1Κ antibody and the microtubule-disrupting drug monomethyl auristatin E (MMAE). It acts via a protease-cleavable linker directed against nectin-4,¹⁶ which is an adhesion protein located on the surface of UC cells. Non-clinical data suggest that enfortumab vedotin binds cells expressing nectin-4, resulting in internalization of the ADC–nectin-4 complex and intracellular release of MMAE via proteolytic cleavage, inducing apoptosis through a disrupted microtubule network.¹⁷ The MMAE released through cellular apoptosis can further diffuse into nearby cells expressing low levels of nectin-4, resulting in cytotoxic cell death.¹⁸

Enfortumab vedotin is currently under review by Health Canada for the treatment of patients with locally advanced or metastatic UC who have previously received a programmed death receptor 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor and who have received a platinum-containing chemotherapy in the neoadjuvant, adjuvant, locally advanced, or metastatic setting or who are not eligible for cisplatin-containing chemotherapy.¹⁸

The Health Canada Notice of Compliance was expected on November 2, 2021. Enfortumab vedotin has not been previously reviewed by CADTH.

The objective of the current review is to perform a systematic review of the beneficial and harmful effects of enfortumab vedotin in patients with locally advanced or metastatic UC who have previously received a platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient groups who responded to CADTH’s call for patient input and from a clinical expert consulted by CADTH for the purpose of this review.

Patient Input

One patient advocacy group, Bladder Cancer Canada (BCC) provided input for the review of enfortumab vedotin in patients with locally advanced or metastatic UC. Bladder Cancer Canada is a nationally registered Canadian charity and is the first and only Canadian patient advocacy organization dedicated to bladder cancer issues. Supported by a Medical Advisory Board and a Medical Research Board consisting of the top bladder cancer specialists across Canada, its mission is to help bladder cancer patients and their support teams address the day-to-day issues of this disease; increase awareness among the public and medical community; and fund research into the diagnosis, treatment, and elimination of the disease. The organization’s vision is patient support, awareness, and research to create a world where bladder cancer is “just a memory.”

The information provided by BCC was gathered through an online survey and telephone interviews conducted between May 27 and June 11, 2021. Most survey respondents were from Canada, with a small number from the US. Telephone interviews with 2 patients from Canada who had experience with enfortumab vedotin were also conducted in June 2021. In total, 38 patients diagnosed with stage II or higher muscle-invasive bladder cancer (MIBC), of whom one-third reported living with locally advanced or metastatic bladder cancer, and 6 caregivers completed the survey.

Many patients and caregivers reported that symptoms of bladder cancer including fatigue, lack of sleep, and loss of strength and stamina were problematic but manageable, while some patients indicated that having bladder cancer has had a minimal impact on their day-to-day lives. Additional symptoms including blood in the urine, pain in the abdomen and bones, decreased mobility and difficulty and/or pain when urinating were also commonly reported. Frequent need for urination and loss of control, urostomy and catheter management, and urinary tract infections were the most commonly reported issues related to continence that affect the day-to-day life of patients and result in the need for additional planning, discomfort, and time lost. Financial impacts related to the costs of catheters and urostomy supplies that are not covered by some provincial governments were reported to strain the already limited financial resources of patients and caregivers.

Patients reported experiencing a number of side effects with current treatments, including fatigue, constipation, low blood cell count, loss of appetite, neuropathy, nausea, vomiting, hair loss, insomnia, diarrhea, and mouth sores. While most patients identified minimal barriers to accessing treatment for their bladder cancer; some mentioned they did have difficulties due to travel distances, treatment costs, unavailability of treatment in Canada, no access to a physician, and the need for time off work to receive treatment. Two patients had experience with enfortumab vedotin through a clinical trial. Patients noted that side effects of treatment with enfortumab vedotin were temporary and manageable compared to previous treatments received. When asked what key benefits provided by enfortumab vedotin have been important to them as patients, they said that the treatment has given them their “life back again” — allowing them to resume activities that they enjoy. Patients with experience with enfortumab vedotin emphasized the importance of publicly funded access to this treatment.

Overall, patients and caregivers expressed a desire for fewer and less-severe side effects than those experienced with current bladder cancer treatments, as well as treatments that induce remission or are curative. Specifically, patients described an ideal treatment as one that would slow or stop disease progression, recurrence and spread; reduce pain, fatigue, and impaired sexual function; increase energy levels and strength; improve mental health, continence, and urination control; and result in fewer or no infections and avoidance of surgery.

Clinician Input

Input From Clinical Experts Consulted by CADTH

In patients with incurable locally advanced or metastatic UC, the clinical expert identified an unmet need for an effective third-line treatment option after progression with platinum chemotherapy and a PD-1 or PD-L1 inhibitor. The mainstay of treatment for incurable patients is cytotoxic platinum-based chemotherapy with gemcitabine with or without cisplatin. Maintenance avelumab was reported to show an overall survival (OS) benefit and is likely to become a funded standard of care. Pembrolizumab is now a funded second-line standard of care in Canada following demonstration of a survival benefit after progression despite first-line chemotherapy, displacing second-line taxane therapy. The only options following immunotherapy are paclitaxel and docetaxel, which are associated with modest response rates and treatment duration; enfortumab vedotin would therefore provide a new alternative to taxane therapy. The clinical expert noted that identifying patients who would respond to enfortumab could not be done, and that patients at this stage are typically under the care of expert medical oncologists, who would be able to identify progressive disease to initiate new treatment. Response to treatment would rely on improvement in symptoms, which would be assessed before treatment and/or evidence of objective tumour shrinkage on imaging. The clinical expert also stated that there are additional adverse events (AEs) with enfortumab vedotin that may require assessment by ophthalmologists or dermatologists.

Clinician Group Input

Two clinicians from the Ontario Health (Cancer Care Ontario) Genitourinary Cancer Drug Advisory Committee (DAC) and a group of 17 Canadian physicians who treat bladder cancer and who, with the support of BCC, provided input for this review. The DAC provides timely evidence-based clinical and health-system guidance on drug-related issues in support of Ontario Health’s mandate, including the Provincial Drug Reimbursement Programs and the Systemic Treatment Program. The group of Canadian physicians represents the specialty from across Canada in both academic and community settings and shares BCC’s goal of improving the management of bladder cancer.

The clinicians agreed that a standard of care for patients with advanced urothelial cancer post–platinum chemotherapy and post-immunotherapy is an unmet need in these patients. Enfortumab vedotin is indicated in a third-line setting. Alternative third-line options would be non-platinum chemotherapy, for which there is little evidence of efficacy and for which the toxicity rate is much higher, or fibroblast growth-factor receptor gene (FGFR)-targeted therapy, which would not be favoured due to the lack of FGFR testing in Canada. The experts agreed that enfortumab vedotin will redefine the current treatment paradigm as there are no other beneficial therapies in this setting other than taxanes, which are associated with significant toxicity, Offering enfortumab vedotin to all eligible patients would provide them with hope for improved life expectancy with tolerable side effects. The clinician group stated that patients would be assessed for toxicity and clinical progression every month throughout treatment, with imaging every 2 to 3 months. Blood work should be performed before each treatment cycle, and patients should be seen by their treating oncologist following each cycle. Patients with disease that has metastasized to the bones should also have a bone scan. The clinician group noted that decisions to discontinue treatment should be made in consultation with the patient and would include progressive disease, worsening symptoms, severe AEs, deterioration to end of life, dose-limiting toxicity resulting in intolerable adverse effects such as significant neuropathy, and patient wishes to discontinue treatment for any number of personal reasons.

Although no marked experience with enfortumab vedotin was mentioned, the clinicians consider this drug of great importance in the management of bladder cancer, filling an unmet need for patients requiring treatment following progression on platinum-based chemotherapy and immunotherapy. The approval of enfortumab vedotin would give medical oncologists an option to offer to patients with advanced urothelial cancer that has progressed on first- and second-line therapy. Enfortumab vedotin offers significant OS benefits compared to taxane chemotherapy, with tangible benefits for patients. Enfortumab vedotin would offer a longer life expectancy with preservation of quality of life (QoL) as the drug is generally well tolerated. For a patient population with such a poor prognosis, the inclusion of enfortumab vedotin in the treatment algorithm has the potential to significantly improve the outcomes associated with bladder cancer.

Drug Program Input

Input was obtained from the provinces (ministries of health and/or cancer agencies) participating in CADTH reimbursement reviews. The Provincial Advisory Group (PAG) noted that taxanes (paclitaxel and docetaxel) are the most relevant comparators in this setting and are funded and available in all provinces. They noted that an updated algorithm for metastatic UC would help jurisdictions navigate funding as there are now several therapies available for multiple lines of treatment, increasing the complexity of funding.

The PAG identified several factors that could affect implementation. The main concerns of the PAG involved indication creep; they were interested to know if patients who have not received previous platinum-based chemotherapy, or those who did but did not receive PD-1 or PD-L1 inhibitors, should be treated with enfortumab vedotin. The clinical expert explained that these patients would not generally be eligible; however, there would be instances in which these patients may receive enfortumab vedotin. Additionally, the PAG was interested in whether patients who discontinue immunotherapy due to toxicity should be offered enfortumab vedotin before disease progression, and if patients currently being treated with taxanes or alternative chemotherapies should be switched to enfortumab vedotin at the time of public funding or wait until their disease progresses. The clinical expert noted that initiation of enfortumab vedotin should follow the criteria of Study EV-301, in which patients who discontinued CPI treatment due to toxicity were eligible provided they had evidence of disease progression following discontinuation, and that if current treatment options are working, there would be no reason to switch to enfortumab vedotin until disease progression. However, this is up to the treating physician, as well as the patient.

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

Study EV-301 was a global, open-label, phase III randomized controlled trial (RCT) comparing enfortumab vedotin to standard salvage chemotherapy regimens in adults with locally advanced or metastatic UC who had received a platinum-containing chemotherapy and who had experienced disease progression or relapse during or following treatment with PD-1 or PD-L1 inhibitors. Patients were randomized 1:1 to receive enfortumab vedotin (n = 301) 1.25 mg/kg on days 1, 8, and 15 of every 28-day cycle, or standard chemotherapy consisting of paclitaxel, docetaxel, or vinflunine (n = 307) on day 1 of each 21-day cycle until disease progression. The primary end point of the EV-301 study was OS, with secondary end points of progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), and health-related quality of life (HRQoL).¹⁷

Baseline characteristics of the EV-301 trial were well balanced between treatment arms; however, the study may have enrolled a healthier group of patients with a younger median age and lower Eastern Cooperative Oncology Group Performance Status (ECOG PS) compared to the Canadian population. Study EV-301 patients were mostly White (51.6%) and male (77.3%), with a median age of 68 years. Most patients had an ECOG PS of 1 (59.9%) and metastatic disease (95.2%).¹⁷

Efficacy Results

In the final primary efficacy analysis of EV-301, the median OS was 12.88 months (95% confidence interval [CI], 10.58 to 15.21) in the enfortumab vedotin arm, and 8.97 months (95% CI, 8.05 to 10.74) in the chemotherapy arm. Enfortumab vedotin was associated with a statistically significantly prolonged OS compared to chemotherapy (hazard ratio [HR] = 0.702; 95% CI, 0.556 to 0.886; P = 0.00142).¹⁷ Results for all sensitivity and subgroup analyses were consistent with the primary analysis.

The secondary end point of PFS was in line with the primary end point. Enfortumab vedotin was associated with a statistically significantly prolonged PFS compared to chemotherapy (HR = 0.615; 95% CI, 0.505 to 0.748; P < 0.00001), with a median PFS of 5.55 months (95% CI, 5.32 to 5.82) in the enfortumab vedotin arm and 3.71 months (95% CI, 3.52 to 3.94) in the chemotherapy arm.¹⁷ Sensitivity and subgroup analyses for PFS were consistent with the overall analysis.

Health-related quality of life, a secondary outcome of EV-301, was assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EuroQol 5-Dimensions 5-Levels questionnaire (EQ-5D-5L). In the enfortumab vedotin arm, change in scores from baseline to week 12 for functional scales of the EORTC QLQ-C30 ranged from 2.17 (standard deviation [SD] = 16.20) for emotional functioning to −5.12 (SD = 23.80) for social functioning. In the chemotherapy arm, change from baseline scores at week 12 ranged from 3.27 (SD = 18.06) in emotional functioning to −9.15 (SD = 26.29) in role functioning. For symptom scores in the enfortumab vedotin arm, the change from baseline at week 12 ranged from 5.77 (SD = 32.56) for appetite loss to −6.96 (SD = 26.26) for pain, while in the chemotherapy arm, scores ranged from −1.63 (SD = 27.90) for insomnia to 6.64 (SD = 22.56) for fatigue. For the EQ-5D-5L, the mean change from baseline to week 12 for the EuroQol Visual Analogue Scale (EQ VAS) was −1.8 (SD = 16.6) for enfortumab vedotin and −5.3 (14.5) for the chemotherapy arm.¹⁷

The ORR was a secondary outcome in EV-301. The confirmed ORR was 40.6% compared to 17.9% for the chemotherapy arm, which was statistically significantly in favour of enfortumab vedotin (P < 0.001). Totals of 4.9% and 35.8% of patients achieved a confirmed complete response (CR) and partial response (PR), respectively, in the enfortumab vedotin arm compared to 2.7% and 15.2%, respectively, in the chemotherapy arm. Results for sensitivity and subgroup analyses for ORR were comparable to those of the primary analysis.¹⁷

Harms Results

The overall incidence of treatment-emergent adverse events (TEAEs) was consistent between enfortumab vedotin (98.0%) and taxane chemotherapy arms (||||||); however, there were imbalances in the specific TEAEs experienced in each arm, with differences of 5% or greater for enfortumab vedotin in 15 preferred term TEAEs. The incidence of serious adverse events (SAEs) was higher in the enfortumab vedotin arm compared to taxane chemotherapy (46.6% versus ||||), with acute kidney injury occurring most frequently in the enfortumab vedotin arm (6.4% versus ||||||) and febrile neutropenia occurring most frequently with taxane chemotherapy (1.4% versus ||||). Withdrawals due to adverse events (WDAEs) and TEAEs resulting in death were similar between the enfortumab vedotin and taxane chemotherapy arms (17.2% versus ||||||, and 7.1% versus ||||, respectively). The most common reason for WDAEs was peripheral sensory neuropathy, which occurred in 2.4% and |||||| of patients in the enfortumab vedotin and taxane chemotherapy groups, respectively.

The incidence of notable harms, including infusion-related reactions (IRRs), ocular disorders, skin reactions, and peripheral neuropathy, was generally more frequent in the enfortumab vedotin arm than the chemotherapy arm. Infusion-related reactions were the least frequently occurring group of notable harms in 9.1% versus |||| of patients in the enfortumab vedotin and taxane chemotherapy arms, respectively. Drug eruption was the most common IRR with enfortumab vedotin (5.7% versus ||||||), while general systemic IRRs were most frequent in the taxane chemotherapy arm (1.4% versus ||||). Incidence of treatment-emergent ocular disorders was higher in the enfortumab vedotin arm compared to the taxane chemotherapy arm (28.0% versus ||||||, respectively), the most frequent being increased lacrimation (10.1% versus ||||, respectively), dry eye (6.4% versus ||||||, respectively), and conjunctivitis (6.4% versus ||||, respectively). Skin reactions were more frequent in the enfortumab vedotin arm (53.7%) compared to the taxane chemotherapy arm (||||). The most frequently occurring skin reactions were rash (16.9% versus ||||||), maculopapular rash (16.9% versus ||||||), stomatitis (9.1% versus ||||||), and drug eruption (8.8% versus ||||). Peripheral neuropathy events occurred in 50.3% and |||||| of patients in the enfortumab vedotin and taxane chemotherapy arms, respectively. The majority of notable harms were of mild to moderate severity.

Critical Appraisal

Study EV-301 was a phase III, open-label RCT. In general, patients in the 2 treatment arms did not differ with regard to baseline disease or treatment characteristics, indicating that randomization was successful. The reviewers and the clinical expert consulted by CADTH agreed that the open-label design was appropriate; however, they noted that this could increase the risk of bias in the reporting of outcomes such as response, HRQoL, and AEs, which are subjective in measurement and interpretation. The primary end point of OS is objective, and therefore unlikely to be affected by biases of open-label study designs. Secondary end points of PFS and ORR are subjective, and therefore subject to potential bias. Reporting of patient-rated outcomes, such as symptom reduction and HRQoL, as well as some of the harms outcomes, may have been biased or influenced by the patient or investigator’s knowledge of treatment assignment. All study outcomes were investigator-assessed and did not include full evaluation through an independent review committee to mitigate the biases associated with the open-label study design. Discontinuation rates were higher in the chemotherapy arm compared with the treatment arm (81.4% versus 92.8%, respectively) while the rate of discontinuation due to disease progression was nearly identical (58.8% versus 58.6%, respectively), which may reflect the open-label design, given that the proportion of discontinuations due to patient and physician decision was higher in the chemotherapy arm. The study was stopped early for efficacy based on a statistically significant OS result in favour of enfortumab vedotin. Trials that stop early for benefit may show a higher or better treatment-effect estimate in the intervention group; however, given that the primary end point of the study, OS, was not subjective, the review team’s concerns were minor. Still, the decision to conduct the primary analysis using an information fraction of only 68.6% raises the possibility of an increased and notable risk of overestimation.

In discussions with the clinical expert consulted by CADTH, the inclusion and exclusion criteria for EV-301 were generally as expected for patients with locally advanced or metastatic UC. However, the expert hypothesized that the patients included in the trial may reflect a “less sick” population than would be seen in the real world, and noted that the median age of 68 implies a younger study population than would be expected. Additionally, the clinical expert considered the ECOG PS of patients to be unreflective of patients at this stage of disease, as most patients would not be ECOG PS 0 or 1 (0: 40.1%, 1: 59.9%). The chosen comparator of standard chemotherapy generally aligns with the recommended standard-of-care guidelines in Canada; however, vinflunine is not available as a treatment option in Canadian clinical practice, and any aggregate results for the chemotherapy arm should therefore consider the proportion of patients that may have received this treatment. The clinical expert noted that this may not affect efficacy outcomes but would affect the results for safety. Given the known differences in safety profiles of enfortumab vedotin, taxanes, and vinflunine, any safety results must be interpreted with caution and may not be generalizable. The high rate of dropouts in completion of the patient-reported outcome (PRO) measures should also be taken into account when interpreting the results.

Indirect Comparisons

No indirect evidence that matched the inclusion and exclusion criteria of this review was included in the sponsor’s submission to CADTH or identified in the literature search.

Other Relevant Evidence

No long-term extension studies or other relevant studies were included in the sponsor’s submission to CADTH.

Conclusions

Enfortumab vedotin is a first-in-class treatment that has been studied in patients who have received a prior PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy and demonstrated a statistically significant improvement in OS and PFS compared to chemotherapy in this patient population. Enfortumab vedotin was also associated with a clinically meaningful ORR compared to chemotherapy for a single-drug therapy, which is an important consideration for this stage of disease. The ORR results are in line with the survival benefit seen for OS. Both measures are important to patients, but the effect of the clinically meaningful ORR on improvement in cancer symptoms is uncertain. Given the open-label design, the PFS and ORR results must be interpreted with caution. Enfortumab vedotin was not associated with any major improvement or deterioration in HRQoL in the pivotal study; however, because of high patient-attrition rates, the effect of enfortumab vedotin on HRQoL remains uncertain.

Overall, despite the similar rates of TEAEs between the enfortumab vedotin and chemotherapy arms, any interpretation of the comparative results must take into consideration the individual safety profiles of the study treatments, particularly for taxanes, as vinflunine is not available in Canada. Generally, the rate of specific TEAEs was higher for enfortumab vedotin compared to taxane therapies. Compared to taxane chemotherapy, enfortumab vedotin was also associated with more SAEs and symptomatic notable harms, including ocular disorders, skin reactions, and peripheral neuropathy. Despite the feedback from 2 patients in the patient group input who noted that side effects of treatment with enfortumab vedotin were temporary and manageable, enfortumab vedotin was hypothesized by the clinical expert to be more toxic than current therapeutic options, which may explain the lack of improvement in QoL.

Overall, enfortumab vedotin provides an effective third-line treatment option, extending survival and demonstrating good clinical response after progression with platinum chemotherapy and a PD-1 or PD-L1 inhibitor. However, there were several limitations in the generalizability of results given the stage of disease, as well as potential safety concerns.

Introduction

Disease Background

Bladder cancer is the fifth most common cancer in Canada, with approximately 12,200 cases, resulting in an estimated 2,600 deaths in 2020. Urothelial carcinoma is the most common type of bladder cancer, accounting for 90% to 95% of cases.^1-4 Urothelial cancer typically arises in the bladder but may develop in any location lined with urothelium, including the renal pelvis, ureter, urethra, and prostatic urethra.⁵ Age, tobacco use, chemical carcinogens, family history, arsenic exposure, and use of indwelling catheters are known risk factors for bladder cancer. Bladder cancer is more common in males, although the reason is unknown.^6-9

Urothelial carcinoma can be characterized as non–muscle-invasive bladder cancer (NMIBC), MIBC, or metastatic based on the extent of invasion into the wall of the bladder (Figure 1). Approximately 70% to 80% of newly diagnosed patients present with NMIBC.¹⁹ However, superficial bladder tumours often recur, and a subset of these patients progress to develop high-grade muscle-invasive urothelial cancer. Nearly 40% to 50% of patients with early-stage MIBC will relapse after initial treatment. Approximately 15% of patients present with locally advanced or metastatic disease.¹⁰ In Canada, the 5-year net survival for bladder cancer is 75%; however, there are no Canadian-specific survival statistics for locally advanced or metastatic UC patients. The estimated 5-year relative survival rate for patients with metastatic disease is approximately 6.4%,⁷ and up to 15% when treated with contemporary regimens.^11,12

Figure 1: Stages of Urothelial Carcinoma

Source: Berdik (2017).²⁰ Reprinted by permission from Springer Nature Limited: Springer Nature, Berdik, C., Unlocking bladder cancer, Nature, 551:S34-S35, 2017. https://www.nature.com/articles/551S34a.

The most common presentation of UC is visible or microscopic hematuria. Other symptoms of UC include painful urination, back or flank pain, fatigue, and unexplained weight loss.⁴ Coupled with numerous imaging and clinical tests, including urinalysis, cystoscopy, and urine cytology, diagnosis is confirmed with a high-quality transurethral resection of the bladder tumour (TURBT), which also confirms the pathology and extent of the disease. If the tumour is determined to be NMIBC, localized chemotherapy is initiated. If it is determined to be MIBC, additional laboratory tests (complete blood count, and blood chemistry), imaging (X-ray, CT, and MRI), and biomarker testing (PD-L1 and FGFR) are recommended.^4,14

Standards of Therapy

Standard of care for locally advanced or metastatic UC consists of platinum-based chemotherapy. In patients who are eligible for cisplatin-based chemotherapy, the preferred regimen is gemcitabine plus cisplatin. In select cases in which more aggressive treatment is needed, dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin is used. Routine assessment of cisplatin eligibility consists of creatinine clearance of greater than 60 mL/min, an ECOG PS of less than 1, absence of hearing loss greater than grade 2 (per Common Terminology Criteria for Adverse Events), absence of neuropathy of greater than grade 2, and absence of New York Heart Association grade III or IV heart failure. In these patients, gemcitabine plus carboplatin is recommended.¹⁰ Recently, CADTH granted a conditional listing to avelumab for first-line maintenance treatment of locally advanced or metastatic UC in patients whose disease has not progressed following first-line platinum-based induction chemotherapy.¹³ Although it did not receive a positive recommendation from CADTH,²¹ pembrolizumab may be used in a first-line setting in cisplatin-ineligible patients with advanced UC.¹⁰

In patients who progress following platinum-based chemotherapy, treatment with CPI immunotherapy, preferably pembrolizumab, is recommended as second-line systemic therapy.^14,15 Alternative CPI regimens include nivolumab, avelumab, and erdafitinib, if available.¹⁴ Following failure of platinum chemotherapy and CPIs, or when CPIs are unavailable, salvage chemotherapy with taxanes; paclitaxel or docetaxel are preferred in most patients. Alternatively, re-treatment with previously unused chemotherapy and immunotherapy regimens can be used, following a prolonged response to initial chemotherapy.¹⁰

Drug

Enfortumab vedotin is an ADC consisting of a fully human immunoglobulin G1Κ antibody and a microtubule-disrupting drug, MMAE, that acts via a protease-cleavable linker directed against nectin-4¹⁶ adhesion proteins on UC cell surfaces. Non-clinical data suggest that enfortumab vedotin binds nectin-4–expressing cells, resulting in internalization of the ADC–nectin-4 complex and intracellular release of MMAE via protolytic cleavage, and inducing apoptosis through a disrupted microtubule network.¹⁷ When released through cellular apoptosis, MMAE can further diffuse into nearby cells expressing low levels of nectin-4, resulting in cytotoxic cell death.¹⁸

Enfortumab vedotin is administered via IV infusion and must be reconstituted and diluted with 2.3 mL or 3.3 mL of sterile water for injection before administration from 20 mg and 30 mg vials, respectively. Enfortumab vedotin is administered over 30 minutes through an IV line, is not to be administered as an IV push or bolus, and is not to be co-administered with other drugs.¹⁸

Enfortumab vedotin is approved by Health Canada for the treatment of adult patients with unresectable locally advanced or metastatic UC who have previously received a platinum-containing chemotherapy and PD-1 or PD-L1 inhibitor therapy.¹⁸

A Health Canada Notice of Compliance was granted on October 29, 2021. Enfortumab vedotin has not been previously reviewed by CADTH.

In 2019, enfortumab vedotin was approved by the FDA under accelerated approval for treatment of adult patients with locally advanced or metastatic UC who have previously received a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy.¹⁷ In 2021, the European Medicines Agency accepted an application for a marketing authorization for enfortumab vedotin as an accelerated assessment.²²

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups.

One patient advocacy group, BCC, provided input for the review of enfortumab vedotin in locally advanced or metastatic UC. A nationally registered Canadian charity, BCC and is the first and only Canadian patient advocacy organization dedicated to bladder cancer issues. Supported by a Medical Advisory Board and a Medical Research Board consisting of the top bladder cancer specialists across Canada, its mission is to help bladder cancer patients and their support teams address the day-to-day issues of this disease; increase awareness among the public and medical community; and fund research into the diagnosis, treatment, and elimination of the disease. The organization’s vision is patient support, awareness, and research to create a world where bladder cancer is “just a memory.”

The information provided by BCC was gathered through an online survey and telephone interviews conducted between May 27 and June 11, 2021. Most survey respondents were from Canada, with a small number from the US. Additionally, telephone interviews with 2 patients from Canada who had experience with enfortumab vedotin were conducted in June 2021. In total, 38 patients diagnosed with stage II or higher MIBC, of which one-third reported living with locally advanced or metastatic bladder cancer, and 6 caregivers completed the survey.

Many patients and caregivers reported that symptoms of bladder cancer, including fatigue, lack of sleep, and loss of strength and stamina were problematic but manageable, while some patients indicated that having bladder cancer has had a minimal impact on their day-to-day lives. Blood in the urine, pain in the abdomen and bones, decreased mobility and difficulty or pain when urinating were also commonly reported symptoms. Frequent need for urination and loss of control, urostomy and catheter management, and urinary tract infections were the most commonly reported issues related to continence that affect the day-to-day lives of patients and result in the need for additional planning, discomfort, and time lost. Financial impacts related to the costs of catheters and urostomy supplies that are not covered by some provincial governments were reported to strain the already limited financial resources of patients and caregivers.

Patients described experiencing a number of side effects with current treatments, including fatigue, constipation, low blood cell count, loss of appetite, neuropathy, nausea, vomiting, hair loss, insomnia, diarrhea, and mouth sores. Most patients reported encountering minimal barriers to treatment for their bladder cancer; however, some mentioned they did have difficulties due to travel distances, treatment costs, unavailability of treatment in Canada, no access to a physician, and the need to take time off work to receive treatment. Two patients had experience with enfortumab vedotin through a clinical trial. Patients noted that the side effects of treatment with enfortumab vedotin were temporary and manageable compared to previous treatments received. When asked what key benefits from enfortumab vedotin have been important to them as patients, they reported that the treatment has given them their “life back again” — allowing them to resume the activities that they enjoy. Patients with experience with enfortumab vedotin emphasized the importance to publicly funded access to this treatment.

Overall, patients and caregivers hoped for fewer and less-severe side effects than those experienced with current bladder cancer treatments, as well as treatments that induced remission or were curative. Specifically, patients described the ideal treatment as one that would slow or stop disease progression, recurrence and spread, reduce pain, fatigue, and impaired sexual function; increase energy levels and strength; improve mental health, continence, and urination control; and result in fewer or no infections and avoidance of surgery.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 1 clinical specialist with expertise in the diagnosis and management of urothelial cancer.

Unmet Needs

The clinical expert stated that there is a need for an effective third-line treatment option after progression with platinum chemotherapy and a PD-1 or PD-L1 inhibitor. Currently these patients are offered either a trial of monotherapy taxane chemotherapy, targeted therapy (if next-generation sequencing is available and actionable mutations are found), or best supportive care. The clinical expert highlighted that, at this point, survival is short (usually less than 12 months), and it is questionable whether these approaches influence the natural history of the disease. At this stage of disease, current treatment should reduce tumour burden, in turn reducing cancer symptoms and prolonging length of life. Ideally, treatment would improve both survival and QoL for these patients as well.

Place in Therapy

Initially, bladder cancer is treated superficially with intravesical therapies, but often it progresses to muscle-invasive disease that requires more definitive therapy with cystectomy (with or without perioperative cisplatin-based chemotherapy) or chemoradiation. The clinical expert noted that patients may then develop incurable local recurrence or, in most cases, distant metastases, while some patients present with de novo incurable metastatic disease.

The clinical expert noted that the mainstay of treatment for incurable patients is cytotoxic platinum-based chemotherapy with gemcitabine with or without cisplatin (or carboplatin), which improves OS but is not curative. For the small minority of patients with absolute contraindications to chemotherapy, the clinical expert stated that the safest alternative is immunotherapy, provided PD-L1 is overexpressed. Enfortumab could be considered, however, it has the potential for serious toxicities comparable to those associated with chemotherapy, and it is unclear why enfortumab would be preferred. Patients with true contraindications or severe immune-mediated toxicity due to PD-1or PD-L1 inhibitors could be considered for enfortumab therapy.

Second-line chemotherapy consists of single-drug paclitaxel, docetaxel, or vinflunine, and only has modest activity. However, vinflunine is not approved or available in Canada. Pembrolizumab is now a funded second-line standard of care in Canada following demonstration of a survival benefit after progression despite first-line chemotherapy, displacing second-line taxane therapy. In patients without evidence of progressive disease after first-line treatment with gemcitabine and platinum-based chemotherapy, maintenance therapy with avelumab was reported to show an OS benefit and is likely to become a funded standard of care. It was also suggested by the clinical expert that avelumab maintenance therapy may be considered a form of second-line therapy, as there is no evidence to support re-treatment with other PD-1 or PD-L1 inhibitors following progression. The clinical expert emphasized that primary chemotherapy should continue to be the standard of care until comparative data are available.

According to the clinical expert, there is a need for a more effective third-line treatment options given the use of pembrolizumab as second-line treatment. The clinical expert stated that patients are often in good health following treatment with immunotherapy and are good candidates for additional systemic therapy; however, the only options in these patients are paclitaxel and docetaxel, which have modest response rates and treatment durations. The clinical expert acknowledged that the targeted agent erdafitinib is available from the sponsor for patients whose tumours express aberrations in FGFR genes. It was also noted that only 25% of incurable, locally advanced, or metastatic UC patients have tumours with eligible FGFR aberrations, and next-generation sequencing of tumours is required for confirmation. The clinical expert also noted that erdafitinib is not currently funded for this indication.

The clinical expert noted that enfortumab vedotin has only been studied in patients with progressive cancer and appears to be associated with high objective tumour response rates in metastatic UC; current data would therefore not support its use in the absence of disease progression. The clinical expert also expressed a high level of interest in the use of enfortumab vedotin earlier in the natural history of metastatic UC, adding that the drug may eventually have a role in perioperative adjuvant therapy.

Patient Population

The clinical expert suggested that the population under consideration would be incurable locally advanced or metastatic urothelial cancer, and that misdiagnosis is highly unlikely. Virtually all incurable patients will have progressed despite platinum-based chemotherapy and PD-1 or PD-L1 inhibitor therapy. The clinical expert noted that there is no way to assess which patients will most likely respond to treatment, and that no special tests are required. Patients are typically under the care of expert medical oncologists, and that symptoms and cross-sectional imaging make it easy to identify disease progression. The expert did note that some patients on immunotherapy may experience pseudo-progression, but most oncologists would not switch treatment until unequivocal progression despite immunotherapy was observed.

The clinical expert noted that the patients least likely to respond to treatment are those with poor functional status.

Assessing Response to Treatment

The clinical expert stated that there are no differences in disease characteristic or predictors of response to enfortumab among urothelial cancer patients. Instead, those with signs or symptoms of disease progression despite prior platinum-based chemotherapy and PD-1 or PD-L1 inhibitors currently have the greatest need. Response to treatment would rely on improvement in symptoms, which would be assessed before treatment and/or evidence of objective tumour shrinkage on imaging (i.e., every 3 months).

Discontinuing Treatment

The clinical expert suggested that discontinuation of treatment would be warranted in the event of disease progression despite treatment, a severely reduced functional status, or intolerable side effects.

Prescribing Conditions

The clinical expert noted that patients with incurable locally advanced or metastatic UC are typically under the care of expert medical oncologists, and that enfortumab can be administered by trained staff in an outpatient clinic. The expert emphasized that enfortumab may cause adverse ocular effects such as keratitis, and assessment and monitoring by an ophthalmologist may be required. Additionally, rash due to treatment with enfortumab may require assessment by a dermatologist.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups.

Two clinicians from the Cancer Care Ontario Genitourinary Cancer DAC and a group of 17 Canadian physicians who treat bladder cancer, with the support of BCC, provided input for this review. The DAC provides timely evidence-based clinical and health-system guidance on drug-related issues in support of Cancer Care Ontario’s mandate, including the Provincial Drug Reimbursement Programs and the Systemic Treatment Program. The group of Canadian physicians represents the specialty from across Canada in both academic and community settings and shares BCC’s goal of improving the management of bladder cancer.

The clinicians agreed that there was no standard of care for patients with advanced urothelial cancer post–platinum chemotherapy and post-immunotherapy, representing an unmet need in these patients. Enfortumab vedotin is indicated in the third-line setting, and the experts agreed that enfortumab vedotin will redefine the current treatment paradigm, with alternative third-line treatment options consisting of non-platinum chemotherapy (i.e., taxanes, for which there is little evidence of efficacy and for which the toxicity rate is much higher) or FGFR-targeted therapy (which would not be favoured for the reasons of unavailability of FGFR testing in Canada), becoming fourth-line options. The clinician groups indicated that offering enfortumab vedotin to all eligible patients would provide them with hope for improved life expectancy with tolerable side effects. The clinician group stated that, throughout treatment, patients would be seen by their treating oncologist following each cycle and would be assessed for toxicity and clinical progression every month, with imaging every 2 to 3 months. Blood work should be performed before each treatment cycle. One clinician group noted that patients with disease that has metastasized to the bones should also have a bone scan. The clinician groups noted that decisions to discontinue treatment should be made in consultation with the patient, and generally be based on progressive disease, worsening symptoms, dose-limiting toxicity resulting in intolerable severe AEs such as significant neuropathy, patient wishes to discontinue treatment for personal reasons, and deterioration to end of life.

Although no marked experience with enfortumab vedotin was mentioned, the clinician groups consider this drug of great importance in the management of bladder cancer, filling an unmet need for patients requiring treatment following progression on platinum-based chemotherapy and immunotherapy and giving medical oncologists an additional option to offer patients with advanced urothelial cancer that has progressed on first- and second-line therapy. The clinician groups believe that enfortumab vedotin would offer a longer life expectancy with preservation of QoL, as the drug is generally well tolerated. The clinician groups also noted that, for a patient population with such a poor prognosis, the inclusion of enfortumab vedotin in the treatment algorithm has the potential to significantly improve the outcomes associated with bladder cancer.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may affect their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 2.

The PAG noted that taxanes (paclitaxel and docetaxel) are the most relevant comparators in this setting and are funded and available in all provinces. The group noted that an updated algorithm for metastatic UC would help jurisdictions navigate funding as several therapies are now available for multiple lines of treatment, increasing the complexity of funding.

Clinical Evidence

The clinical evidence included in the review of enfortumab vedotin is presented in 3 sections. The first section, the systematic review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. The second section includes indirect evidence selected from the literature that met the selection criteria specified in the review. No indirect treatment comparisons were submitted to CADTH by the sponsor. The third section includes sponsor-submitted long-term extension studies and additional relevant studies that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of enfortumab vedotin 1.25 mg/kg for the treatment of patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy in the neoadjuvant, adjuvant, locally advanced, or metastatic setting or who are not eligible for cisplatin-containing chemotherapy.

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 3. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

The systematic review protocol was established before the granting of a Notice of Compliance from Health Canada.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the Peer Review of Electronic Search Strategies checklist.²³

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) via Ovid and Embase (1974–) via Ovid. All Ovid searches were run simultaneously as a multi-file search. Duplicates were removed using Ovid deduplication for multi-file searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was enfortumab vedotin. Clinical trials registries searched included the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform (ICTRP) search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Appendix 1 provides detailed search strategies.

The initial search was completed on July 22, 2021. Regular alerts updated the search until the meeting of CADTH pan-Canadian Oncology Drug Review Expert Committee on November 10, 2021.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist.²⁴ Included in this search were the websites of regulatory agencies (US FDA and European Medicines Agency). Google was used to search for additional internet-based materials. See Appendix 1 for more information on the grey literature search strategy.

These searches were supplemented by reviewing bibliographies of key papers and through contacts with appropriate experts. In addition, the sponsor of the drug was contacted for information regarding unpublished studies.

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies for inclusion, and differences were resolved through discussion. A focused literature search for network meta-analyses dealing with UC was run in MEDLINE All (1946–) on July 22, 2021. No limits were applied.

Findings From the Literature

A total of 105 studies were identified from the literature for inclusion in the systematic review (Figure 2). The included study is summarized in Table 4. A list of excluded studies is presented in Appendix 2.

Figure 2: Flow Diagram for Inclusion and Exclusion of Studies

Description of Studies

One study was included in the review. Study EV-301 was a global, open-label, phase III RCT comparing enfortumab vedotin to standard salvage chemotherapy regimens in adults with locally advanced or metastatic UC who had received a platinum-containing chemotherapy and who had experienced disease progression or relapse during or following treatment with PD-1 or PD-L1 inhibitors. The design of EV-301 is shown in Figure 3.

Figure 3: Schematic Overview of the EV-301 Study

OS = overall survival; PD = progressive disease; PFS1 = progression-free survival on study therapy; PFS2 = progression-free survival on subsequent therapy.

Source: EV-301 Clinical Study Report.¹⁷

The primary objective of EV-301 was to compare the OS of patients with locally advanced or metastatic UC treated with enfortumab vedotin to those treated with chemotherapy. It was conducted in 19 countries, with 11 sites in Canada accounting for 52 patients.¹⁷

Key eligibility criteria for EV-301 are summarized in Table 4. Briefly, eligible patients included adults with histologically or cytologically confirmed urothelial carcinoma previously treated with a platinum-containing regimen (cisplatin or carboplatin) in the metastatic or locally advanced, neoadjuvant, or adjuvant setting and must have experienced radiographic progression or relapse during or after a CPI (anti–PD-1 or anti–PD-L1) for locally advanced or metastatic disease.¹⁷

Patients were randomized 1:1 via interactive response technology to either arm A, which consisted of enfortumab vedotin (n = 301), or arm B, which consisted of various chemotherapy regimens (n = 307). Prior to randomization, investigators selected docetaxel, vinflunine, or paclitaxel to be used in the event a patient was randomized to arm B, with a maximum of 35% of patients receiving vinflunine. Patients were stratified according to ECOG PS (0 versus 1), regions of the world (Western Europe versus US versus rest of world) and liver metastasis (yes versus no). To maintain trial integrity, aggregate analyses or summaries by randomized treatment assignment were limited and documented before the primary hard database lock. Interim analysis was conducted externally by an independent data analysis centre and the results were reviewed by an independent data monitoring committee. The data cut-off date for the primary analysis of EV-301 was July 15, 2020, and database lock took place on September 15, 2020.¹⁷

Any subgroup results for patients receiving vinflunine in arm B will not be discussed in this report as vinflunine is not available in Canada. Vinflunine was only offered as a choice of comparator in countries where it is approved for UC.¹⁷

Populations

Inclusion and Exclusion Criteria

Inclusion and exclusion criteria for the EV-301 trial are summarized in Table 4. Patients were required to have histologically or cytologically confirmed UC with locally advanced or metastatic UC at baseline and an ECOG PS of 0 or 1. Patients must have received a platinum-containing regimen (cisplatin or carboplatin) in the metastatic or locally advanced, neoadjuvant, or adjuvant setting. In line with current guidelines, if the platinum regimen was administered in the adjuvant or neoadjuvant setting, patients must have progressed within 12 months of completion. Finally, patients must have received treatment with, and experienced radiographic progression or relapse during or after, a CPI for locally advanced or metastatic disease. Patients were excluded if they had received prior chemotherapy with any study therapies in the control arm.¹⁷

Investigators were free to terminate a patient’s involvement in the study if they felt that the patient’s clinical condition warranted discontinuation, and each patient was free to discontinue or withdraw from the study at any time for any reason. All patients who discontinued study treatment were to remain in the study and continue to be followed for 30 days after their last dose for safety assessments, and every 3 months for survival status and progression on subsequent therapy or if the patient specifically withdrew consent for contact. If a patient was discontinued for ongoing AEs or unresolved laboratory results, the patient was followed up until the event was stabilized or no longer clinically significant.¹⁷

Baseline Characteristics

Baseline characteristics for the EV-301 study are summarized in Table 5. Baseline characteristics were well balanced between enfortumab vedotin and chemotherapy arms. Patients were mostly White (52.8% versus 50.5%, respectively) and male (79.1% versus 75.6%, respectively). The median age was 68 years in each treatment arm, with 64.1% and 63.8% aged 65 years or older in the enfortumab vedotin and chemotherapy arms, respectively. Patients were stratified by ECOG PS, geographic region, and presence of liver metastases. Geographic region varied, with most patients living in the rest of the world category (43.8%), followed by Western Europe (41.9%), and the US (14.3%). Most patients had an ECOG PS of 1 (60.1% versus 59.6% in the enfortumab vedotin and chemotherapy arms, respectively), and metastatic disease at baseline (96.3% versus 94.1%, respectively), of whom 30.9% of all patients had liver metastases, while most patients had metastases to the viscera (77.7% versus 81.7%, respectively). A total of 27 patients had mismatched stratification (19 on liver metastasis and 8 on ECOG PS), which was accounted for using sensitivity analyses.¹⁷

Totals of 277 patients (92.0%) and 284 patients (92.5%) in the respective enfortumab vedotin and chemotherapy arms underwent prior procedures for primary cancer; the most common being TURBT (n = 318, 52.3%). Prior radiation therapy was received by 32.7% of patients overall — 96 (31.9%) in the enfortumab vedotin arm and 103 (33.6%) in the chemotherapy arm). The majority of patients received 2 prior lines of therapy in the locally advanced or metastatic setting (74.1% versus 77.5%, respectively). Most patients received cisplatin-based platinum regimens (64.1% versus 61.9% in the enfortumab vedotin and chemotherapy arms, respectively), and pembrolizumab was the most commonly received PD-1 or PD-L1 inhibitor received (48.5% versus 46.9%, respectively). In patients with prior CPI therapy, progressive disease was the most common best overall response, occurring in 50.7% of patients overall.¹⁷

Interventions

Enfortumab Vedotin

Enfortumab vedotin was administered via IV infusion at a dose of 1.25 mg/kg over 30 minutes on days 1, 8, and 15 of every 28-day cycle until radiological disease progression per investigator assessment, or other discontinuation criteria were met, or upon study termination or completion. Enfortumab vedotin was not administered as an IV push or bolus. Weight-based dosing was calculated using the patient’s actual body weight on day 1 of each cycle. Doses were based on 100 kg for individuals weighing > 100 kg. The maximum dose of enfortumab permitted was 125 mg. Enfortumab vedotin was supplied by Astellas in single-use glass vials containing white, lyophilized powder for reconstitution. Each vial contained 30 mg of the study drug.¹⁷

Patients were observed during administration and for at least 60 minutes following the infusion during the first 3 cycles for redness, swelling, pain, and infection. Patients experiencing enfortumab vedotin IRRs may have received premedication before subsequent infusion, including pain medication, antihistamines, and corticosteroids 30 to 60 minutes before each infusion. If anaphylaxis occurred, treatment was immediately and permanently discontinued. If toxicities or AEs occurred on day 1 of any cycle and enfortumab vedotin could not be administered, the start of the cycle may have been delayed. If toxicities occurred on days 8 or 15 of any cycle and required the dose to be held for 3 days or longer, the dose(s) were to have been eliminated, rather than delayed. If a patient only received enfortumab vedotin on day 1 and needed to skip days 8 and 15, the patient could resume the next cycle as early as day 22 (new day 1), if the toxicity had resolved by then.¹⁷

Dose reduction to 1 mg/kg and to 0.75 mg/kg was allowed depending on the type and severity of toxicity. Patients with a dose reduction may have been re-escalated, provided the toxicity did not require discontinuation of the study drug. If the toxicity recurred, re-escalation was not permitted. Patients with grade 2 or higher corneal AEs were not permitted to re-escalate the dose. Dose interruptions for other enfortumab vedotin-associated toxicity were permitted at the discretion of the site investigator.¹⁷

Dose interruptions may have lasted up to 8 weeks (2 cycles). Dose interruptions for patients who were deriving clinical benefit from treatment may have been extended beyond 8 weeks if toxicity did not require permanent discontinuation. The schedule for response assessments was not adjusted in the event of dose interruption.¹⁷

For patients with hyperglycemia, blood glucose was assessed before each dose of study drug. The study drug was withheld in patients with blood glucose levels exceeding 250 mg/dL (13.9 mmol/L). Treatment discontinuation was required if blood glucose levels exceeded 500 mg/dL (27.8 mmol/L) and was considered related to enfortumab vedotin.¹⁷

Docetaxel, Paclitaxel, or Vinflunine

Local product labels and institutional guidelines were followed for the administration of chemotherapy agents.¹⁷

Docetaxel was administered as an IV infusion on day 1 of every 21-day cycle after all procedures and assessments had been completed, including the required premedication according to the local standard of care before day 1. Docetaxel was administered at 75 mg/m² over a 1-hour infusion, and patients were observed during administration and at least 30 minutes following the first 3 cycles. Patients were pre-medicated with corticosteroids, such as dexamethasone 16 mg per day orally for 3 days starting 1 day before docetaxel administration to reduce the incidence and severity of fluid retention and hypersensitivity reactions.¹⁷

Vinflunine was administered as an IV infusion on day 1 of every 21-day cycle at a dose of 320 mg/m² after all procedures and assessments had been completed. Patients were observed during administration and for at least 30 minutes following the first 3 cycles.¹⁷

Paclitaxel was administered as an IV infusion on day 1 of every 21-day cycle at a dose of 175 mg/m² after all procedures and assessments had been completed. Paclitaxel was administered over 3 hours and patients were observed for at least 30 minutes following the first 3 cycles. Patients treated with paclitaxel were pre-medicated to prevent severe hypersensitivity; this may have consisted of dexamethasone 20 mg orally approximately 12 and 6 hours before paclitaxel, diphenhydramine 50 mg intravenously 30 to 60 minutes before paclitaxel, and cimetidine (300 mg) or ranitidine (50 mg) intravenously 30 to 60 minutes before paclitaxel, as determined by the investigator.¹⁷

Switching between chemotherapies during study treatment was not permitted. Dose modifications for chemotherapy regimens were considered according to local product labels. Transfusions or growth factors were used for hematologic toxicities of grade 3 or higher with chemotherapy, following institutional guidelines.¹⁷

Prior and Concomitant Therapy

Prior medication was considered medication with at least 1 dose taken before the date of the first dose of the study drug.²⁶ Concomitant drug therapies were those medications or therapies with at least 1 dose taken between the date of the first dose and the date of the last dose of the study drug plus 30 days.^17,26 Overall, 99.3% of enfortumab-treated and 99.7% of chemotherapy-treated patients were using concomitant drug therapies.¹⁷

Patients in the enfortumab vedotin arm who were concomitantly receiving strong CYP3A4 inhibitors or P-glycoprotein inhibitors were to be closely monitored for adverse reactions.¹⁷

In the chemotherapy arm (treatment with docetaxel, vinflunine, or paclitaxel), concomitant use of drugs that strongly inhibit or induce CYP3A4 were to be avoided. Additionally, medicinal products that prolong the QT-QTc interval were to be avoided in patients receiving vinflunine, and caution was to be exercised when paclitaxel was administered with strong inhibitors or inducers of CYP2C8.¹⁷

Subsequent Anticancer Therapy

Subsequent anticancer therapies included all systemic therapies and radiation, palliative radiation, and other therapies that irradiate or affect either target or non-target lesions. A total of 108 enfortumab-treated patients (35.9%) and 118 chemotherapy-treated patients (38.4%) received subsequent anticancer therapy after discontinuation of study treatment. The most common subsequent anticancer therapy was paclitaxel for both treatment arms (19 patients [6.3%] in the enfortumab vedotin arm and 18 patients [5.9%] in the chemotherapy arm).¹⁷

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 6. These end points are further summarized in the following section. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 4.

The primary outcome of the EV-301 trial was OS, defined as the time from randomization to the date of death from any cause.¹⁷

The secondary outcomes of EV-301 included PFS, ORR, duration of response (DOR), DCR, and HRQoL via the EORTC QLQ-C30 and EQ-5D-5L. For response outcomes, patients were evaluated based on investigator assessment according to Response Evaluation Criteria in Solid Tumours Version 1 (RECIST 1.1). Secondary outcomes were defined as follows:¹⁷

• Progression-free survival on study therapy (PFS1) was defined as the time from the date of randomization until the date of radiological disease progression (per RECIST 1.1), or until death from any cause.

• ORR was defined as the proportion of patients with complete or partial objective response based on the RECIST 1.1 per the investigator.

• DCR was defined as the proportion of patients with a complete or partial objective response, or a stable disease based on RECIST 1.1.

• DOR was defined as the time from the date of the first response CR or PR according to RECIST 1.1 (whichever is recorded first) that is subsequently confirmed as assessed by the investigator to the date of radiological progression or date of death for patients who achieved CR or PR.

• HRQoL and PRO parameters were measured by the EORTC QLQ-C30 and EQ-5D-5L instruments. Detailed information on the scoring and validity of the EORTC QLQ-C30 and EQ-5D-5L is provided in Appendix 4.

  • The EORTC QLQ-C30 is a generic tool developed to assess the QoL of cancer patients. The tool yields the following scales: Global Health Status/QoL, functional scales, symptom scales or items, and financial impact. Outcome scores are computed using a linear transformation of the raw score such that scores range from 0 to 100. A higher score represents a higher (“better”) level of functioning, or a higher (“worse”) level of symptom.

  • The EQ-5D-5L is a generic, preference-based measure that indirectly measures the utility for health and generates an index-based summary score based upon societal preference weights. The EQ-5D-5L consists of 6 items that cover 5 main domains (mobility, self-care, usual activities, pain and discomfort, and anxiety or depression) and the EuroQol Visual Analogue Scale (EQ VAS) for health status.

Exploratory end points in EV-301 of interest included:¹⁷

• Progression-free survival on subsequent therapy (PFS2), defined as the time from randomization to subsequent disease progression after initiation of new anticancer therapy, or death from any cause, whichever occurred first. Following PFS1, patients entered the long-term follow-up period and were followed per institutional guidelines (but not less than every 3 months from the date of the follow-up visit) for survival and progression status on subsequent therapy.

• A health care resource utilization (HCRU) questionnaire focused on unplanned use of health care resources related to clinical events or AEs in patients assigned to treatment arms. Data on the incidence of emergency room visits, hospitalizations, and outpatient (either primary care or specialist) office visits were collected via the HCRU tool. Date and length of each hospitalization were collected.

Safety end points included AEs, laboratory tests, vital signs, electrocardiograms, and ECOG PS. All AEs were coded using the Medical Dictionary for Regulatory Activities by system organ class and preferred term and graded using the National Cancer Institute Common Terminology Criteria for Adverse Events. An AE was considered “serious” if, in the view of either the investigator or sponsor, it resulted in death; was life-threatening (resulted in persistent or significant disability or incapacity or substantial disruption of the ability to conduct normal life functions); resulted in a congenital anomaly or birth defect; required inpatient hospitalization (except for planned procedures as allowed per study); or led to prolongation of hospitalization (except if prolongation of planned hospitalization is not caused by an AE), hospitalization for treatment/observation/examination caused by an AE, or other medically important events.¹⁷

Statistical Analysis

Sample Size and Power Calculation

The sample size calculation for EV-301 was based on the primary end point of OS. Assuming a 10% dropout rate, the estimated sample size was 600 patients, resulting in 85% power to detect a statistically significant difference at an overall 1-sided type I error rate of 0.025. Assuming an HR of 0.75 (the median OS values in enfortumab vedotin arm and chemotherapy arm were 10.7 months and 8 months, respectively), the final analysis was planned for when 439 death events had occurred, and 1 interim analysis was conducted at 285 death events (65% of planned events).¹⁷

The planned sample size also provided more than 90% power to detect statistically significant differences on secondary end points including PFS1 (assuming median PFS1 values in the enfortumab vedotin and chemotherapy arms were 6 months and 4 months, respectively), and ORR and DCR (assuming a 15% treatment difference between enfortumab vedotin and chemotherapy for both ORR and DCR).¹⁷

Interim and Final Analyses

The study design was a sequential group design with 2 planned analyses: 1 interim analysis and 1 final (primary) analysis. The interim analysis was to be performed after 285 deaths (65%), while the final analysis was to be performed after 439 death events. The interim analysis was conducted externally by an independent data analysis centre and the results reviewed by an independent data monitoring committee. At the interim analysis, OS was tested at the 1-sided 0.00541 significance level for efficacy according to the O’Brien-Fleming boundary as implemented by a Lan-DeMets alpha spending function. Secondary end points of PFS1, ORR, and DCR were tested sequentially when primary OS was rejected using the hierarchical gatekeeping procedure. The familywise type I error rate for this study was strongly controlled at 0.025 (1-sided) according to the multiplicity adjustment rule. The ORR and DCR were tested following rejection of both OS and PFS1 and the significance level of both ORR and DCR was 0.025.¹⁷

Predetermined early termination based on statistically significant OS results favouring enfortumab vedotin was suggested by the independent data analysis centre at the interim analysis.^17,26

Multiplicity Adjustment

Multiplicity adjustment was incorporated within the interim and final analysis of the primary end point (OS), and between the primary and the selected secondary end points (PFS1, ORR, and DCR) using the familywise type I error rate at 2.5% (1-sided). The primary end point of OS was to be tested at both the interim and final analysis according to the O’Brien-Fleming boundary according to the Lan-DeMets method via East v6.5. As stated above, secondary outcomes were tested hierarchically if OS was rejected. The significance level of PFS1 at the interim and final analysis were to be based on the Pocock boundary following the Lan-DeMets method.¹⁷

Boundaries for OS and PFS1 were updated based on actual observed information fractions at the interim. Because study enrolment was completed in January 2020, and based on the definition of the response evaluable set (RES), the ORR and DCR analyses were ready after enrolment completion. Following the pre-specified multiplicity procedure, the ORR was to be tested once on the interim data (i.e., data per interim analysis cut-off) and was only to be tested when both OS and PFS1 were rejected either at interim or final analysis. The ORR analysis was to apply the interim data cut-off date when it was performed at the final analysis. The ORR test P value was to be compared to the significance level 0.025. Testing on DCR was similar to the testing on ORR, but DCR was to be tested only when ORR was rejected.¹⁷

Efficacy Analyses

All randomized patients were analyzed according to the treatment to which they were randomized. Efficacy analyses were conducted on the full analysis set (FAS) and RES. Imaging for both arms was performed at baseline and every 56 ± 7 days from the first dose of study treatment throughout the study until PFS1 was documented by radiological disease progression or the patient was lost to follow-up, died, withdrew study consent, or started a subsequent anticancer therapy. Images were analyzed for radiologic disease progression by study site investigator. Independent review of all or a sample of scans may have been considered following completion of PFS1 analyses.¹⁷

Descriptive statistics including the number of patients, mean, SD, median, minimum, and maximum were used for continuous variables. Frequencies and percentages are displayed for categorical data based on the number of patients with no missing data. Kaplan–Meier survival curves are displayed for time-to-event variables and median survival time was estimated with 2-sided 95% CIs. All nominal comparisons were made using 2-sided test at an alpha = 0.05 significance level.¹⁷

In the event of missing or partial dates, if the imputed date was after minimum (death date, cut-off date), minimum (death date, cut-off date) was used as imputed date.²⁶

Missing or partial start and stop dates of AEs and concomitant medication were imputed using the following algorithm:²⁶

• Imputation rules for partial or missing stop dates:

  • If the month and year are present, then impute as the last day of that month.

  • If only the year is present, impute as December 31 of that year.

  • If the stop date is entirely missing, assume the event or medication is ongoing.

• Imputation rules for partial or missing start dates are summarized in Table 7.

The imputed dates were used to determine whether an AE is or is not treatment-emergent. Listings of AEs and concomitant medications presented the actual partial dates; imputed dates were not shown.²⁶

In the case of a partial starting date of subsequent anticancer therapy, the date was imputed to the first day of the month but not earlier than the last dosing date of the study drug. A month and year must have been present, or the date remained missing.²⁶

Patients with missing baseline variable were excluded from the analysis of change from baseline.²⁶

Patients who did not satisfy the criteria to be counted as responders or for whom data were insufficient to determine or confirm a response under the RECIST 1.1 guidelines were to be considered nonresponders in the final analysis of response rates. No imputation of data was done to determine individual patient response.²⁶

Primary Efficacy End Point Analyses

The analysis population for the primary end point of OS was the FAS. Overall survival was defined as the time from the date of randomization until the documented date of death from any cause. Patients who were still alive at the data cut-off date (July 15, 2020) were censored at the last known alive date or at the analysis cut-off date, whichever is earlier. Overall survival (in days) was calculated as (date of death or censored) – (date of randomization) + 1.¹⁷

The distribution of OS was estimated for each treatment arm using Kaplan–Meier methodology, and the primary analysis comparing arm A and arm B was conducted using the log-rank test stratified by ECOG PS (0 versus 1), region (US, Western Europe, or the rest of world) and liver metastasis status (yes versus no) per interactive response technology. The stratified Cox proportional hazards model was used to estimate the HR and the corresponding 95% CIs with the same stratification factors as used for stratified log-rank test.¹⁷

Sensitivity Analyses

Sensitivity analysis for the primary end point of OS included:¹⁷

• OS analysis based on unstratified log-rank test.

• Imbalance in the use of subsequent anticancer therapy (including subsequent use of enfortumab vedotin) may have potentially biased the inference in OS. The following methods were to be used to assess the impact of the use of subsequent anticancer therapy on OS:

  • Rank-preserving structural failure time method. This method was to assess the impact on patients in arm B who took enfortumab vedotin as a subsequent therapy by reconstructing the patients’ survival durations, as if they had never received enfortumab vedotin.

  • Inverse probability of censoring weights (IPCW) method. Patients who took subsequent therapy were censored at the time of sequent anticancer therapy but were weighted according to their probability of taking subsequent therapy.

To assess the potential impact of COVID-19, the following sensitivity analyses may have been conducted:¹⁷

• same as OS primary analysis, except those patients who died from COVID-19 were censored at the death date

• same as OS primary analysis, but patients who died from of COVID-19 were excluded from the analysis.

An ad hoc sensitivity analysis using the actual stratification factors was conducted to account for any mismatched stratification factors at baseline.¹⁷

Secondary Efficacy End Point Analyses

Secondary efficacy end points of PFS1, ORR, DOR, and DCR were assessed by the investigator. Response and progression were evaluated using RECIST 1.1.¹⁷ Progression-free survival on study therapy was assessed in the FAS and was a secondary end point of the EV-301 trial. Formal statistical comparison of arm A (enfortumab vedotin) and arm B (chemotherapy) was performed per the planned multiplicity adjustment rule. Values for PFS were estimated using the Kaplan–Meier method, and the stratified Cox proportional hazard model was used to estimate HRs and 95% CIs using the same stratification factors as those used for OS. Sensitivity analyses for PFS1 included analysis based on the unstratified log-rank test, sensitivity analysis on FAS when removing the censoring of progressive disease or death events occurring after missing 2 consecutive tumour assessments, and sensitivity analyses to assess the potential impact of COVID-19 as detailed for OS. Secondary end point analyses of ORR and DCR were conducted in the RES using the stratified Cochran-Mantel-Haenszel test. Both ORR and DCR including 95% CIs were estimated for each treatment arm. Formal statistical comparison of enfortumab vedotin and chemotherapy was conducted according to the planned multiplicity adjustment rule only. Additional sensitivity analysis for ORR and DCR included the comparison of ORR and DCR regardless of confirmation. For patients with confirmed CR or PR from the analysis of ORR, the distribution of DOR was estimated using the Kaplan–Meier method for each treatment arm.¹⁷

Health-related quality of life was a secondary end point of the EV-301 trial and was measured using the EORTC QLQ-C30 and EQ-5D-5L.¹⁷ For the EORTC QLQ-C30, instrument completion rate at each analysis was reported. Completion rate (i.e., unadjusted) at each analysis visit was calculated as the number of patients meeting the minimum requirements for scoring at least 1 domain of the instrument divided by the number of patients in the FAS population. The compliance rate (adjusted) at each analysis visit was calculated among patients who were expected to have PRO assessments. The following was provided:¹⁷

• number and percent of patients with all EORTC QLQ-C30 questions completed

• number and percent of patients for whom at least 1 subscale of EORTC QLQ-C30 can be calculated (minimum requirements for scoring of the instrument)

• number and percent of patients with at least 1 question completed on the EORTC QLQ-C30.

Means and change from baseline at each scheduled assessment were reported for each of the EORTC QLQ-C30 subscales. The analyses included data from the baseline assessment through the last available data for all patients in the FAS. Change from baseline in the Global Health Status (a 2-item QoL subscale of the EORTC QLQ-C30) score for enfortumab vedotin and chemotherapy at week 12 was analyzed using a restricted maximum likelihood–based repeated measures approach (mixed model for repeated measures [MMRM]). The week 12 time point was selected to minimize the impact of missing data given that the median of PFS1 for the chemotherapy arm was 4 months. Analysis of the EORTC QLQ-C30 was based on observed data (i.e., data collected at each time point without carrying forward previous values). Only patients with a baseline and at least 1 post-baseline score were included in the analysis. Data from a limited number of PRO assessments may have been used in case of substantial dropout (i.e., analysis was to be limited to time points at which at least 10% of subjects had non-missing data in both treatment arms) by week 12.¹⁷

For the EQ-5D-5L, instrument completion and compliance rates at each analysis visit were reported. Completion rate (i.e., unadjusted) at each analysis visit was calculated as the number of patients for whom either the utility index or EQ VAS score could be calculated (minimum requirements for scoring of the instrument) divided by the number of patients in the FAS population. The compliance rate (adjusted) at each analysis visit was calculated among patients who were expected to have PRO assessments. The following were provided:¹⁷

• the number and percent of patients with all questions completed (i.e., all 5 items and EQ VAS)

• the number and percent of patients for whom either the utility index or the VAS score could be calculated (minimum requirements for scoring of the instrument)

• the number and percent of patients with at least 1 question completed on the EQ-5D-5L or EQ VAS.

The completion and compliance rates by treatment arm at each analysis visit were also provided graphically by means of a line graph. Descriptive characteristics of the EQ-5D-5L were summarized from baseline assessment through the last available data. The frequency and the percentage of reported problems for each level for each dimension were provided. All time point data were included and summarized. Scores for the EQ VAS were summarized by treatment arm at each visit using descriptive statistics.¹⁷

Due to a potential data integrity issue for electronic reporting at site 39004, sensitivity analysis for the MMRM analysis for the EQ-5D-5L, as well as the EORTC QLQ-C30 and for the mean change from baseline for each of the domains for the EORTC QLQ-C30, was conducted by removing the data from site 39004.^17,26

Changes to Planned Analyses

For PRO outcomes, the pre-specified analysis approach created a week-by-week cut-off that started in the midpoint of each week and carried forward into the midpoint of the following week, which unintentionally created a mismatch that artificially lowered the calculation of compliance rates, particularly at the week 12 time point. As a result, questionnaire completion and compliance rates and the analyses for EORTC QLQ-C30 and EQ-5D were also assessed in ad hoc analyses that aligned the windows for the start and end of each week.¹⁷

Subgroup Analyses

Pre-specified subgroup analyses for OS, PFS1, and ORR were conducted to determine if the treatment effect was consistent across the following subgroups: age (younger than 65 versus 65 or older and younger than 75 versus 75 or older), sex (male versus female), region (Western Europe versus US versus rest of world), ECOG PS (0 versus 1), liver metastasis (yes versus no), pre-selected control therapy (paclitaxel versus docetaxel versus vinflunine), primary tumour site (upper tract versus bladder or other), prior lines of systemic therapy (1 to 2 lines versus 3 or more lines), and best response to prior CPI (responder versus nonresponder). Treatment-effect estimates and 95% CIs were provided.^17,26

Exploratory Efficacy Analyses

The FAS was used for the analysis of PFS2 for each treatment arm following the Kaplan–Meier methodology. Enfortumab vedotin and chemotherapy were compared using log-rank tests stratified by ECOG PS (0 versus 1), region (US, Europe, and the rest of world) and liver metastasis status (yes versus no) per interactive response technology. The stratified Cox proportional hazards model was used to estimate the HR and the corresponding 95% CI.¹⁷

Incidences of HCRU, including emergency room visits, hospitalizations, and outpatient (either primary care or specialist) office visits, were summarized by treatment arm by each visit. The duration of hospital stays was also summarized by treatment arm using descriptive statistics (mean, SD, median, minimum, and maximum).¹⁷

Treatment Discontinuation and Follow-Up

Following discontinuation, patients had a follow-up visit 30 days after their last dose of study drug for safety assessments. If a patient discontinued the study drug before PFS1, the patient entered the post-treatment follow-up period and continued imaging assessments every 56 days until PFS1 was documented or a subsequent anticancer treatment was initiated, whichever occurred first. Following PFS1, patients entered the long-term follow-up period and were to be followed at a minimum of every 3 months from the date of the follow-up visit for survival status and progression status on subsequent therapy (i.e., PFS2). Patients were followed until PFS2 was documented or the patient started another anticancer treatment, whichever occurred first. Following PFS2, patients entered the survival follow-up period and were followed for survival status every 3 months until death, loss to follow-up, withdrawal of study consent, or study termination by sponsor. Patients were eligible to continue receiving treatment until they met a discontinuation criterion or upon study termination or completion, whichever occurred first.¹⁷

Safety Analyses

All safety analyses were presented as the number and percentage of patients by treatment arm and overall, for the safety analysis set. All AEs, TEAEs, and SAEs recorded on treatment, including those within 30 days from the last study treatment, were summarized by number and percentage of patients reporting AEs. Summary tables include patient counts as opposed to AE counts.¹⁷

Adverse events of special interest (AESIs), such as IRRs, ocular toxicity, skin reactions, and peripheral neuropathy, were summarized by treatment arm and overall and classified by sponsor-specific query (SSQ), customized medical query, or standard Medical Dictionary for Regulatory Activities query (SMQ) and preferred term. Time to onset of a specific AESI was calculated as time from the first dose of study drug to the start of the first TEAE that met the respective search criteria.¹⁷

Analysis Populations

The following analysis populations were defined in Study EV-301:¹⁷

• The FAS consisted of all randomized patients. This analysis set is in compliance with the intent-to-treat principle that includes all randomized patients. The FAS was the primary analysis set for efficacy analyses except for response-related efficacy end points. Demographic and baseline characteristics were summarized for the FAS.

• The safety analysis set consisted of all patients who received any amount of study drug and was used for safety analyses. Patients were analyzed based on actual treatment received.

• The RES was defined as all patients in the FAS who had measurable disease (according to RECIST 1.1) as determined by the investigator at baseline. The RES was used for primary efficacy analysis of response-related end points (e.g., ORR and DCR). Patients were analyzed by assigned treatment.

Protocol Amendments and Deviations

Three substantial amendments were made to the study protocol. A total of 128 patients were randomized under the original protocol, and 480 were randomized under the second version of the protocol incorporating Amendment 1. At the time of the interim analysis, no patients had been enrolled under the third or fourth versions of the protocol, which incorporated Amendments 2 and 3.¹⁷

The first amendment included some additional exclusion criteria for the EV-301 population that were not outlined in the original study protocol, many of which were related to contraindications or hypersensitivities on the product labels of the comparators. Additional changes included hematology, biochemistry, and pregnancy tests in women of childbearing potential, as well as concomitant medication assessments included at follow-up visits. Amendment 2 increased the number of death events in the final and interim analyses to increase the power of the study from 80% to 85%. Amendment 3 included a crossover extension phase that was added to the design of the study.^17,25,26 Overall, none of the protocol amendments affected the conduct or integrity of the study, nor did they affect the patients’ safety.

As of the cut-off date, 33 patients — 21 (7.0%) in the enfortumab vedotin arm and 12 (3.9%) in the chemotherapy arm — had 1 or more major protocol deviations. The most frequent protocol deviation involved patients entering the study despite not satisfying the entry criteria. This occurred in 8 patients in the enfortumab vedotin arm (2.7%) and 9 patients in the chemotherapy arm (2.9%).¹⁷

Eight patients (2.7%) in the enfortumab vedotin arm compared to 2 patients (0.7%) in the chemotherapy arm developed withdrawal criteria during the study but were not withdrawn. Four patients (1.3%) in the enfortumab vedotin arm received the wrong treatment or incorrect dose; 1 received weight-based dosing rather than weight-capped dosing and 3 had a total dose ± 10% of the recommended dose. Last, 1 patient (0.3%) in each arm received excluded concomitant treatments.¹⁷

Results

Patient Disposition

Study EV-301 was a randomized, open-label, phase III clinical trial. Table 8 summarizes the disposition of enrolled patients. A total of 745 patients were screened for eligibility and 608 were randomized to receive enfortumab vedotin (n = 301) or chemotherapy (n = 307). As of the data cut-off date, 56 patients (18.6%) in the enfortumab vedotin arm and 22 patients (7.2%) in the chemotherapy arm remained on the study drug. A greater proportion of patients in the chemotherapy arm discontinued from the study compared to the enfortumab vedotin arm (92.8% versus 81.4%, respectively), most due to patient withdrawal (8.8% versus 5.0%, respectively) and physician decision (7.2% versus 2.3%, respectively). The most common reasons for treatment discontinuation in both treatment arms were disease progression (177 patients [58.8%] in the enfortumab vedotin arm and 180 patients [58.6%] in the chemotherapy arm) and AEs (42 patients [14.0%] in the enfortumab vedotin arm and 46 patients [15.0%] in the chemotherapy arm).¹⁷

Exposure to Study Treatments

Exposure to study treatments is summarized in Table 9. The median duration of treatment with enfortumab vedotin was 4.99 months (range = 0.5 to 19.4), and 3.45 (range = 0.2 to 15.0) months for the chemotherapy arm, with individual median durations of treatment of 2.23 months, 3.68 months, and 3.91 months for patients treated with docetaxel, paclitaxel, and vinflunine, respectively.¹⁷

The median relative dose intensities were 80.73% for the enfortumab vedotin arm and 97.36% for the chemotherapy arm. The median relative dose intensities for docetaxel, paclitaxel, and vinflunine were 98.17%, 96.71%, and 92.54%, respectively.¹⁷

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported.

Overall Survival

At the pre-planned interim analysis, a total of 299 death events had occurred. The independent data analysis centre then informed the sponsor that the efficacy boundary for OS had been crossed and recommended stopping the study for efficacy based on an August 20, 2020, data snapshot, with a July 15, 2020, data cut-off. For OS at the interim, the HR for enfortumab vedotin versus chemotherapy was 0.70 (95% CI, 0.56 to 0.89). The study database was subsequently locked on September 15, 2020 (data cut-off, July 15, 2020) for primary efficacy analysis, and the protocol was amended to allow for patients in the chemotherapy arm to cross over to receive enfortumab vedotin therapy (Protocol Amendment 3).¹⁷

In the final primary efficacy analysis (Table 10), a total of 301 (68.6%) of the planned 439 death events occurred in the FAS with 11.1 months of follow-up. The HR for the enfortumab vedotin versus chemotherapy was 0.702 (95% CI, 0.556 to 0.886) in favour of enfortumab vedotin. The median OS was 12.88 months (95% CI, 10.58 to 15.21) in the enfortumab vedotin arm and 8.97 months (95% CI, 8.05 to 10.74) in the chemotherapy arm (P = 0.00142). The OS rate was 77.9% versus 69.5% and 51.5% versus 39.2% for enfortumab vedotin and chemotherapy arms at 6 and 12 months, respectively.¹⁷ Figure 4 summarizes OS in a Kaplan–Meier plot.

Figure 4: Kaplan–Meier Plot of Overall Survival (Full Analysis Set)

CI = confidence interval; HR = hazard ratio.

Source: EV-301 Clinical Study Report.¹⁷

Sensitivity Analysis

Pre-specified sensitivity analyses evaluating the effect of various censoring rules on OS are summarized in Table 11. Results for all sensitivity analyses (rank-preserving structural failure time method, IPCW method, and ad hoc sensitivity by stratification factors) were consistent with the primary analysis, with all methods demonstrating statistically significant improvements in OS compared to chemotherapy. For the rank-preserving structural failure time method, only 4 patients from the chemotherapy arm received subsequent therapy with enfortumab vedotin, and the results are similar. Results for the IPCW method were based on the 95 patients (31.6%) in the enfortumab vedotin arm the and 102 patients (33.2%) in the chemotherapy arm who received subsequent therapy as of the data cut-off date. Results for the IPCW method varied most from the primary analysis, with a HR of 0.630 (95% CI, 0.435 to 0.912) for enfortumab versus chemotherapy. The median OS was 17.87 months (95% CI, 11.63 to not evaluable) for enfortumab vedotin, and 10.32 months (95% CI, 8.31 to 15.67) for chemotherapy (P = 0.001). Results for sensitivity analyses based on actual stratification factors were also comparable to those of the primary analysis as there was only a total of 14 patients in the enfortumab vedotin arm and 13 patients in the chemotherapy arm with mismatched stratification at baseline.¹⁷

Subgroup Analysis

Subgroups of interest outlined in the review protocol (Table 3) for OS in the FAS are summarized in Table 12. Across subgroups of interest, results were mostly consistent with the overall population. The subgroups of patients with an ECOG PS of 0, primary tumour site of the upper tract, patients with 3 or more prior lines of systemic therapy, and responders to prior CPI were favoured over chemotherapy (HR = 0.810 [95% CI, 0.530 to 1.240], HR = 0.848 [95% CI, 0.567 to 1.269], HR = 0.875 [95% CI, 0.466 to 1.644], and HR = 0.630 [95% CI, 0.338 to 1.174], respectively);¹⁷ however, there was a small number of patients within these subgroups.

Progression-Free Survival

Progression-Free Survival on Study Therapy

Progression-free survival was a secondary end point of EV-301; the results are summarized in Table 13 and by Kaplan–Meier plot in Figure 5. Enfortumab vedotin was associated with a statistically significantly prolonged PFS compared to chemotherapy (HR = 0.615; 95% CI, 0.505 to 0.748). The median PFS1 was 5.55 months (95% CI, 5.32 to 5.82) in the enfortumab vedotin arm, and 3.71 months (95% CI, 3.52 to 3.94) in the chemotherapy arm (P < 0.00001). The 6- and 12-month PFS rates for enfortumab vedotin and chemotherapy were 44.0% and 28.2%, and 21.7% and 8.3%, respectively.¹⁷

Figure 5: Kaplan–Meier Plot of PFS1, Investigator Assessment (Full Analysis Set)

CI = confidence interval; HR = hazard ratio.

Source: EV-301 Clinical Study Report.¹⁷

Sensitivity Analysis

Pre-specified sensitivity analyses evaluating the effect of various censoring rules on PFS are summarized in Table 30. Sensitivity analyses were comparable to the primary analysis of PFS1, with an HR for PFS for enfortumab vedotin versus chemotherapy of 0.616 (95% CI, 0.507 to 0.749) in favour of enfortumab vedotin.¹⁷

Subgroup Analysis

Subgroups of interest outlined in the review protocol (Table 3) for PFS in the FAS are summarized in Table 31. Results of the subgroup analyses were consistent with the overall PFS1 observed, ranging from HR = 0.511 to HR = 0.716 for subgroups of interest, including ECOG PS, liver metastasis, primary tumour site, prior lines of systemic therapy, and best response to prior CPI.¹⁷

Progression-Free Survival on Subsequent Therapy

Progression-free survival on subsequent therapy was defined as the time from randomization to subsequent disease progression after initiation of new anticancer therapy, or death from any cause, and was an exploratory end point of EV-301. Results for PFS2 are summarized in Table 32 of Appendix 3.¹⁷

Health-Related Quality of Life

EORTC QLQ-C30

Health-related quality of life as assessed by the EORTC QLQ-C30 was a secondary outcome of EV-301. At baseline, 90.7% and 88.6% of patients completed the EORTC QLQ-C30 in the enfortumab vedotin and chemotherapy arms, respectively. Completion and compliance rates for the EORTC QLQ-C30 generally diminished with each visit (Figure 7, Appendix 3).¹⁷

Results of the EORTC QLQ-C30 functional and symptom scales from baseline to week 12 are summarized in Table 14. Following ad hoc adjustments (due to mismatched data entry and visit schedule), the mean baseline Global Health Status scores for the adjusted analysis were 63.83 (19.89) in the enfortumab vedotin arm and 64.58 (19.19) in the chemotherapy arm. The change from baseline to week 12 by MMRM in the FAS (n = 227 in enfortumab vedotin arm and n = 193 in chemotherapy arm) was −2.825 (standard error = 1.348) in the enfortumab vedotin arm, and −4.996 (standard error = 1.479) in the chemotherapy arm (P = 0.2429). Results of the sensitivity analysis excluding 1 study site were similar to the base-case MMRM.¹⁷

In the enfortumab vedotin arm, mean change from baseline scores from the EORTC QLQ-C30 ranged from −0.92 (SD = 15.76) in cognitive functioning to −5.12 (SD = 23.80) in social functioning, with an increase of 2.17 (SD = 16.20] in the emotional functioning score. In the chemotherapy arm, reduction in score from baseline to week 12 ranged from −0.49 (SD = 16.66) in cognitive functioning to −9.15 (SD = 26.29) in role functioning, with an increase of 3.27 (SD = 18.06) in emotional functioning.

For enfortumab vedotin, a decrease in symptom burden from baseline to week 12 was observed for nausea and vomiting (−0.39 [SD = 16.73]), insomnia (−3.67 [SD = 30.06]), constipation (−6.04 [SD = 27.99]), and financial difficulties (−0.26 [SD = 20.36]) scores, with the largest numerical improvement in reduction of self-reported pain (−6.96 [SD = 26.26]), while increases were demonstrated in other symptom scales. Conversely, improvements in insomnia (−1.63 [SD = 27.90]) and constipation (−0.98 [SD = 24.13]) scores occurred from baseline to week 12 in the chemotherapy arm, while the other symptom scores worsened.¹⁷ In an additional analysis provided to CADTH, enfortumab vedotin was favoured over chemotherapy in reduction of reported pain symptoms (−5.73; 95% CI, −10.80 to −0.66). Improvement in appetite loss favoured the chemotherapy arm (7.29; 95% CI, 0.90 to 13.69).²⁷

EuroQol 5-Dimensions 5-Levels Questionnaire

At baseline, 91.0% and 89.9% of patients completed the EQ-5D-5L in the enfortumab vedotin and chemotherapy arms, respectively. Completion and compliance rates for the EQ-5D-5L decreased over time, with a notable decrease after week 12 (Figure 8, Appendix 3).¹⁷

Descriptive results from the EQ-5D-5L are summarized in Table 15. Mean EQ VAS scores at baseline were 68.2 (SD = 18.1) and 68.3 (SD = 18.8) in the enfortumab vedotin and chemotherapy arms, respectively. A reduction of −1.8 (SD = 16.6) in mean EQ VAS scores was reported from baseline to week 12 in the enfortumab vedotin arm compared to −5.3 (SD = 14.5) in the chemotherapy arm.¹⁷

Clinical Response Outcomes

Overall Response Rate and Disease Control Rate

Results for the secondary end points of EV-301, ORR, DCR, and other clinical response outcomes per RECIST 1.1 according to the investigator are summarized in Table 16. In patients with measurable disease, the confirmed ORR was statistically significant in favour of enfortumab vedotin, with an ORR of 40.6% for the enfortumab vedotin arm and 17.9% for the chemotherapy arm (stratified 1-sided P < 0.001). Totals of 14 patients (4.9%) and 8 patients (2.7%) achieved a CR, and 103 (35.8%) versus 45 (15.2%) achieved a PR in the enfortumab and chemotherapy arms, respectively.¹⁷

The confirmed DCR was statistically significant in favour of enfortumab vedotin, with a DCR of 71.9% in the enfortumab arm and 53.4% in the chemotherapy arm (1-sided P value < 0.001).¹⁷

Of the 117 patients in the enfortumab vedotin arm who achieved a confirmed CR or PR, the time to response was 1.87 months, while in the 53 patients who received chemotherapy, the time to response was 1.91 months.¹⁷

Sensitivity Analysis

Results for the sensitivity analysis of ORR and DCR regardless of confirmation of best overall response are summarized in Table 33. While still in favour of enfortumab vedotin versus chemotherapy (50.7% versus 28.4%; 1-sided P value < 0.001), the proportion of patients with unconfirmed ORR were higher than the primary analysis for ORR. Sensitivity analysis results for DCR were comparable to those for the primary analysis.¹⁷

Subgroup Analysis – ORR

Subgroups of interest outlined in the review protocol (Table 3) for OS in the FAS are summarized in Table 34. Across subgroups of interest, the treatment effect was consistent with the overall analysis, with all subgroups favouring enfortumab vedotin.¹⁷

Duration of Response

The DOR for patients with confirmed CR or PR is summarized in Table 17 and Figure 6. Duration of response was similar between treatment arms, with a median DOR of 7.39 months (95% CI, 5.59 to 9.46) versus 8.11 months (95% CI, 5.65 to 9.56) for enfortumab vedotin and chemotherapy, respectively.¹⁷

Figure 6: Kaplan–Meier Plot of Duration of Response, Investigator Assessment (All Patients With Confirmed Complete or Partial Response)

CI = confidence interval; CR = complete response; DOR = duration of response; PR = partial response.

Source: EV-301 Clinical Study Report.¹⁷

Health Care Resource Utilization

Measures of HCRU, an exploratory outcome in the EV-301 study, are summarized in Table 18. No notable differences in specific HCRU measures were observed between enfortumab vedotin and chemotherapy.¹⁷

Harms

Only those harms identified in the review protocol are reported. Specific harms associated with vinflunine are not presented.

Adverse Events

Overall, 98.5% of patients experienced at least 1 TEAE — 290 (98.0%) in the enfortumab vedotin arm and 288 (99%) in the chemotherapy arm (Table 19). The most common TEAEs in the enfortumab vedotin were alopecia (47.0%), decreased appetite (40.9%), fatigue (36.1%), diarrhea (34.8%), peripheral sensory neuropathy (34.5%), and pruritus (34.5%). The most common TEAEs for taxane chemotherapies included alopecia (||||||), fatigue (||||||), peripheral sensory neuropathy (||||||), and anemia (||||).¹⁷

The incidence of TEAEs, including decreased appetite, diarrhea, pruritis, nausea, constipation, dysgeusia, pyrexia, dry skin, rash, maculopapular rash, decreased weight, asthenia, abdominal pain, increased aspartate aminotransferase, and hyperglycemia, were each at least 5% higher in the enfortumab vedotin than in the taxane chemotherapy arm, while anemia, decreased neutrophil count, peripheral edema, arthralgia, myalgia, and decreased white blood cell count were at least 5% higher with taxane chemotherapy than with enfortumab vedotin.¹⁷

The TEAEs resulting in dose reduction or dose interruption are summarized in Table 35 and Table 36 of Appendix 3. Of all patients with TEAEs, 101 (34.1%) and 81 (27.8%) in the enfortumab vedotin and chemotherapy arms (including vinflunine), respectively, experienced TEAEs that led to a dose reduction (Table 35), while 180 (60.8%) and 85 (29.2%) in the enfortumab vedotin and chemotherapy arms, respectively, experienced a TEAE leading to a dose interruption (Table 36). In the enfortumab vedotin arm, the most common TEAEs resulting in a dose reduction were peripheral sensory neuropathy (7.4%) and maculopapular rash (4.4%). In the chemotherapy arm, the most common TEAEs resulting in dose reduction were peripheral sensory neuropathy (6.2%) and fatigue (4.1%). In the enfortumab vedotin arm, the most common TEAEs leading to dose interruption were peripheral sensory neuropathy (15.5%) and fatigue (6.1%). In the chemotherapy arm, the most common TEAEs leading to dose interruption were decreased neutrophil count (3.8%) and anemia (3.4%).¹⁷

A least 1 grade 3 or higher TEAE was experienced by 403 patients (68.7%) — 210 (70.9%) with enfortumab vedotin, and |||||||||||| with taxane chemotherapy (|||||| for docetaxel, and |||| for paclitaxel) (Table 20). For enfortumab vedotin, the most common grade 3 or greater TEAEs (occurring in at least 5% of patients) were maculopapular rash (7.4%), hyperglycemia and decreased neutrophil count (7.1%, each), fatigue (6.8%), anemia (6.4%), and decreased appetite (5.4%). The most frequent grade 3 or higher TEAEs with docetaxel were decreased neutrophil count (||||), anemia (||||),decreased white blood cell count (||||), and febrile neutropenia (||||). The most frequent grade or higher 3 TEAEs with paclitaxel were decreased neutrophil count (||||), anemia (||||), and febrile neutropenia (||||||).¹⁷

Some imbalances across treatment arms were evident between the incidence rates of grade or greater 3 TEAEs. The taxanes were associated with a higher grade or greater decreased neutrophil counts (|||| versus 7.1%), anemia (|||| versus 6.4%), febrile neutropenia (|||| vs 1.4%) and decreased white blood cell counts (|||||| versus 1.4%) compared to enfortumab vedotin, while the incidence of grade or greater maculopapular rash and hyperglycemia was higher in the enfortumab vedotin arm compared to taxane chemotherapies (7.4% versus 　|　; and 7.1% versus ||||, respectively) (Table 20).¹⁷

Serious Adverse Events

The incidence of SAEs is summarized in Table 21. The overall incidence of treatment-emergent SAEs was similar between the enfortumab vedotin (46.6%) and taxane chemotherapy arms (||||). The most common SAEs in the enfortumab vedotin arm were acute kidney injury (6.4%), malignant neoplasm progression (4.1%), and pneumonia (4.1%). The most common SAEs in the taxane chemotherapy arm were febrile neutropenia (||||||) and pneumonia (||||).¹⁷

Withdrawals Due to Adverse Events

As of the July 15, 2020, data cut-off, a total of 51 patients (17.4%) in the enfortumab vedotin arm, and |||||||||| in the taxane chemotherapy arm withdrew from treatment due to TEAEs. The most common reason for a WDAE in both arms was peripheral sensory neuropathy, which occurred in 2.4% and |||| of patients in the enfortumab vedotin and taxane chemotherapy arms, respectively.¹⁷

Mortality

Treatment-emergent AEs resulting in death during the study are summarized in Table 23. Overall, 21 patients (7.1%) in the enfortumab vedotin and |||||||||| patients in the taxane chemotherapy arms experienced a TEAE leading to death, with malignant neoplasm progression the most common TEAE leading to death in both arms.¹⁷

As of the July 15, 2020, data cut-off date, 130 patients (43.9%) in the enfortumab vedotin arm and 161 patients (55.3%) in the chemotherapy arm (including those who received vinflunine) died. The most common cause of death on study was disease progression.¹⁷

Notable Harms

Infusion-Related Reactions

Infusion-related reactions by preferred term are summarized in Table 24. Overall, 27 patients (9.1%) in the enfortumab vedotin arm and |||||||||||||||||||| in the taxane chemotherapy arm experienced an IRR.

The majority of the IRRs were grades 1 or 2, with 4 grade 3 events, all in the enfortumab vedotin arm (1 event of drug hypersensitivity and 3 events of drug eruption), considered related to enfortumab vedotin. One case of drug eruption in the enfortumab vedotin arm was considered serious, while 2 events consisting of extravasation and infusion-related reaction were considered serious in the chemotherapy arm (including the vinflunine-treated patients).¹⁷

Ocular Disorders

Ocular disorders were considered AEs of special interest for this review. The incidence of treatment-emergent ocular disorders was higher in the enfortumab vedotin arm and is summarized in Table 25. Ocular disorders were experienced by 83 patients (28%) in the enfortumab vedotin arm and 21 patients (||||)in the chemotherapy arm (taxanes). In the enfortumab vedotin and taxane chemotherapy arms, 71 patients (24.0%), and |||||||||| patients experienced an event in the category of any dry eye, respectively. Blurred vision was experienced by 18 patients (6.1%) in the enfortumab vedotin arm and |||||||| of patients in the taxane chemotherapy arm. Three grade 3 events were reported by 3 patients; 2 in the enfortumab vedotin arm that were considered serious (1 event each of conjunctivitis and blepharitis) and 2 in the chemotherapy arm (lacrimation increased and visual impairment). One patient in the enfortumab vedotin arm withdrew from treatment because of conjunctivitis.¹⁷

In patients who experienced an event, the median time to onset was 1.9 months in the enfortumab vedotin arm and 0.5 months in the chemotherapy arm (including vinflunine).¹⁷

Skin Reactions

Table 26 summarizes skin reactions in the safety analysis set. In the enfortumab vedotin arm, 159 patients (53.7%) experienced any rash or serious cutaneous adverse reactions, compared to |||||||||| in the taxane chemotherapy arm. The most common rash per sponsor-specific or customized medical queries in the enfortumab vedotin compared to the taxane chemotherapy arm were rash (16.9% versus ||||, maculopapular rash (16.9% versus ||||), and drug eruption (8.8% versus ||||). The most frequent severe cutaneous adverse reactions (SMQ) were stomatitis (9.1% versus ||||), drug eruption (8.8% versus ||||), and conjunctivitis (6.4% versus ||||). Grade 1 or 2 skin reactions occurred in 112 (39%) patients in the enfortumab vedotin arm, and 56 (19%) patients in the chemotherapy arm (including vinflunine-treated patients).¹⁷

In the enfortumab vedotin arm, 42 patients reported grade 3 events, including stomatitis (0.7%), drug eruption (2.7%), and conjunctivitis, blister, dermatitis bullous, skin exfoliation, and toxic skin eruption (0.3% each), and 1 patient experienced grade 4 dermatitis bullous that was considered related to treatment. Fourteen (4.7%) patients in the enfortumab vedotin arm experienced skin reactions that were considered serious, while 12 patients experienced a skin reaction that led to withdrawal of treatment (4 rash maculopapular, 2 drug eruption, 2 dermatitis bullous, and 1 patient each with rash, rash erythematous, conjunctivitis, and toxic skin eruption). In the overall chemotherapy arm (including vinflunine-treated patients), 2 patients reported grade 3 events: drug eruption and mouth ulceration (0.3% each), and only 1 patient discontinued treatment due to drug eruption. Twenty-four patients (8.1%) in the enfortumab vedotin arm and 2 patients (0.7%) in the chemotherapy arm experienced skin reactions that led to a dose reduction, while 33 patients (11.1%) in the enfortumab vedotin arm and no subjects in the chemotherapy arm experienced events that led to a dose interruption.¹⁷

In patients who experienced an event, median time to onset was 0.5 months in the enfortumab vedotin arm and 0.7 months in the chemotherapy arm.¹⁷

Peripheral Neuropathy

Table 27 summarizes the incidence of peripheral neuropathy in the safety analysis set. A total of 149 patients (50.3%) and |||||||||| patients in the enfortumab vedotin and taxane chemotherapy arms experienced an event of any peripheral neuropathy, of which 139 patients (47%) and |||||||||| patients in the enfortumab vedotin and chemotherapy arms, respectively, experienced any sensory peripheral neuropathy, and 33 patients (11.1%) and |||||||| experienced motor events.

A total of 23 peripheral neuropathy events were grade 3 (15 in the enfortumab vedotin arm and 8 in the overall chemotherapy arm), with 6 patients in the enfortumab vedotin arm and 2 patients in the chemotherapy arm experiencing peripheral neuropathy that was considered serious. Fourteen patients in the enfortumab vedotin arm and 8 patients in the chemotherapy arm reported peripheral neuropathy events that resulted in treatment withdrawal.¹⁷

In patients who experienced a neuropathy event, the median time to onset in the enfortumab vedotin arm was 2.5 months compared to 0.8 months in the chemotherapy arm. For grade 2 or higher events, the median time to onset was 4.3 months in the enfortumab vedotin arm and 1.8 months in the chemotherapy arm.¹⁷