Physical, but not laboratory, treatment-related adverse events are associated with favorable outcomes of enfortumab vedotin for advanced urothelial carcinoma: A landmark analysis

doi:10.21203/rs.3.rs-4620148/v1

Download PDF

Research Article

Physical, but not laboratory, treatment-related adverse events are associated with favorable outcomes of enfortumab vedotin for advanced urothelial carcinoma: A landmark analysis

https://doi.org/10.21203/rs.3.rs-4620148/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background

While the occurrence of immune-related adverse events has been recognized as a prognostic marker in patients receiving immune checkpoint inhibitors, the prognostic significance of treatment-related adverse events (trAEs) in patients undergoing antibody–drug conjugates such as enfortumab vedotin (EV) is controversial.

Methods

We reviewed 106 patients with advanced urothelial carcinoma who were treated with EV therapy at 10 institutions between 2021 and 2023. Associations of clinical parameters with overall survival and progression-free survival were assessed using the Cox proportional hazards model. For the assessment of trAEs, landmark analysis was conducted to minimize immortal time bias.

Results

Of 106 patients, 55 (51.9%) experienced disease progression and 44 (41.5%) died during the follow-up period. Any grade and grade ≥ 3 trAEs occurred in 94 (88.7%) and 44 (41.5%) patients, respectively. Common trAEs included skin disorders (74.5%), gastrointestinal disorders (62.3%), fatigue (50.0%), peripheral neuropathy (36.8%), and hematological disorders (37.7%). One patient died of interstitial pneumonia (grade 5). According to landmark analysis using 88 patients who survived for two months or more, trAEs were significantly associated with longer survival. Furthermore, when trAEs were classified into “physical trAEs” such as skin disorders and “laboratory trAEs” such as hematological disorders, the former were associated with longer survival while the latter were associated with shorter survival.

Conclusions

Physical, but not laboratory, trAEs are associated with favorable outcomes of EV therapy for advanced urothelial carcinoma. Both managing trAEs and utilizing them as prognostic markers are key points in the use of antibody–drug conjugates such as EV.

adverse event

enfortumab vedotin

immortal time bias

landmark analysis

urothelial carcinoma

Enfortumab vedotin (EV) is a novel antibody–drug conjugate which delivers monomethyl auristatin E to nectin-4-expressing cells [1–3]. Urothelial carcinoma (UC) has been considered as a good target for EV because it highly expresses nectin-4 [2,3]. In 2021, EV was approved for advanced UC given that the EV-301 trial showed its superiority to non-platinum-based chemotherapy after platinum-based chemotherapy and immune checkpoint inhibitors (ICIs) such as pembrolizumab [1]. While the survival time of advanced UC has been significantly prolonged since the advent of pembrolizumab in 2017, EV and other new agents are expected to further prolong survival [4,5]. Recently, clinical outcomes of EV in real-world patients with advanced UC have increasingly been reported [6–19]. However, albeit its promising antitumor activity, EV has the unique complication profile due to its mechanism of action, including skin disorders, peripheral neuropathy, interstitial pneumonia, and so on [20–23]. Therefore, the management of treatment-related adverse events (trAEs) is a key point in treating patients with EV [24].

The occurrence of immune-related adverse events has been recognized as a prognostic marker in patients treated with ICIs [25,26], whereas the prognostic significance of trAEs in patients treated with antibody–drug conjugates such as EV is controversial. Despite many reports on EV in real-world patients [6–23], few studies have investigated the prognostic impact of trAEs on outcomes of EV [20]. This might be partly because trAEs are likely to be underreported in the real-world setting compared to the clinical trial setting [27]. This study aimed to assess the prognostic significance of trAEs in advanced UC treated with EV by conducting a detailed evaluation of trAEs and using landmark analysis.

Patients and treatments

This retrospective multi-institutional study was approved by the Institutional Review Board of the Graduate School of Medicine and Faculty of Medicine, The University of Tokyo (approval number: 10565), as well as that of each participating institution. An opt-out approach was used to obtain informed consent from patients.

We retrospectively reviewed 106 patients with advanced UC who were treated with EV at 10 institutions between December 2021 and December 2023. The cohort included 39 patients who were analyzed in our previous study [9]. EV was administered at a dose of 1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle [1]. Dose reduction was determined according to the institutional policy or the physicians’ discretion considering the patient’s condition.

Endpoints, follow-up, and statistical analysis

Endpoints of this study included overall survival (OS), progression-free survival (PFS), and treatment responses. PFS was defined as the time from the initiation of EV to disease progression or death, whichever occurred first. OS was defined as the time from the initiation of EV to death. Treatment responses, including disease progression, objective response rate (ORR), and disease control rate (DCR), were assessed according to Response Evaluation Criteria in Solid Tumours version 1.1. The incidence and severity of trAEs were assessed using the Common Terminology Criteria for Adverse Events version 5.0. All patients underwent evaluations every 1–3 months that included routine blood tests, chest X-ray, and computed tomography. Follow-up information was obtained as of May 2024.

OS and PFS were estimated using the Kaplan–Meier method and compared using the log-rank test when needed. Associations of clinical parameters, including pretreatment factors and posttreatment trAEs, with OS and PFS were assessed using the Cox proportional hazards model. For the assessment of prognostic significance of trAEs, landmark analysis was used to minimize immortal time bias. All statistical analyses were performed using JMP Pro version 17.0.0 (SAS Institute). P < 0.05 was considered significant.

Analyses of the whole population

Table 1 shows patients’ characteristics in the whole population (n = 106). Similarly to the EV-301 trial [1], about a third (32.1%) of the patients had liver metastasis. Two patients had not received platinum-based chemotherapy due to hemodialysis and allergy to platinum-containing agents. The median number of cycles of EV therapy was 4 (interquartile range [IQR]: 2–7). Dose reduction was carried out in 35 (33.0%) of the patients mainly due to the occurrence of trAEs.

Table 1

Patients’ characteristics in the whole population (n = 106)
Parameter	Value
Age, years, median (IQR)	72 (63–77)
Sex, no. (%):
Male	75 (70.8)
Female	31 (29.2)
ECOG PS, no. (%):
0	56 (52.8)
1	39 (36.8)
2	6 (5.7)
3	5 (4.7)
Primary tumor site, no. (%):
Bladder	49 (46.2)
Upper urinary tract	42 (29.6)
Both	15 (14.2)
Resection of primary site, no. (%)	63 (59.4)
Lymph node metastasis, no. (%)	71 (67.0)
Visceral metastasis, no. (%):	81 (76.4)
Lung metastasis, no. (%)	49 (37.7)
Bone metastasis, no. (%)	34 (32.1)
Liver metastasis, no. (%)	34 (32.1)
Prior treatment lines, no. (%):
1^†	2 (1.9)
2	78 (73.6)
≥3	26 (24.5)
Prior platinum-based regimen, no. (%):
GC	48 (45.3)
GCa	29 (27.4)
GC + GCa	12 (11.3)
ddMVAC	12 (11.3)
ddMVAC + GC	2 (1.9)
ddMVAC + GCa	1 (0.9)
None^†	2 (1.9)
Prior ICI regimen, no. (%):
Pembrolizumab	72 (67.9)
Avelumab	24 (22.6)
Avelumab + Pembrolizumab	6 (5.7)
Nivolumab	4 (3.8)
Cycles of EV therapy, median (IQR)	4 (2–7)
ddMVAC, dose-dense methotrexate/vinblastine/doxorubicin/cisplatin; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EV, enfortumab vedotin; GC, gemcitabine/cisplatin; GCa, gemcitabine/carboplatin; ICI, immune checkpoint inhibitor; IQR, interquartile range
^†, Platinum-based chemotherapy was not conducted due to hemodialysis (n = 1) and allergy to platinum-containing agents (n = 1).

Figure 1 illustrates Kaplan-Meier curves depicting PFS, OS, and treatment responses in the whole population. Of 106 patients, 55 (51.9%) experienced disease progression and 44 (41.5%) died during the median follow-up of 5 (IQR: 2–11) months. Median OS and PFS were 13 and 5 months, respectively. The ORR and DCR were 44.3% and 71.7%, respectively, which were comparable to those of the EV-301 trial (ORR: 40.6%; DCR: 71.9%) [1].

Supplementary Table 1 shows univariable and multivariable Cox proportional hazard regression analyses of pretreatment factors for OS and PFS. Eastern Cooperative Oncology Group Performance Status ≥ 1 and bone metastasis were identified as independent predictors of shorter OS and PFS. However, liver metastasis was not associated with OS or PFS even in univariable analyses.

Profile of trAEs

Table 2 shows a summary of trAEs in the whole population (n = 106). Any grade and grade ≥ 3 trAEs occurred in 94 (88.7%) and 44 (41.5%) patients, respectively. Relatively common (> 10%) trAEs included skin disorders (74.5%), gastrointestinal disorders (62.3%), fatigue (50.0%), peripheral neuropathy (36.8%), hematological disorders (37.7%), eye disorders (17.0%), and hyperglycemia (14.2%). Grade ≥ 4 trAEs occurred in five (4.7%) patients: water blister (grade 4); Stevens-Johnson syndrome (grade 4); neutropenia with anorexia (grade 4); neutropenia (grade 4); myelodysplastic syndrome accompanied with thrombocytopenia (grade 4); and interstitial pneumonia (grade 5). The last two trAEs occurred in the same patient, who developed thrombocytopenia and interstitial pneumonia simultaneously. The former required repeated platelet transfusion and turned out to be myelodysplastic syndrome by bone-marrow biopsy. The latter required steroid pulse therapy, and the patient eventually died of an exacerbation of interstitial pneumonia.

Table 2. Summary of trAEs in the whole population (n = 106).

trAE	Any grade	Grade ≥ 3
Skin disorders, no. (%):	79 (74.5)	14 (13.2)
Rash	61 (57.5)	7 (6.6)
Pruritus	52 (49.1)	5 (4.7)
Alopecia	41 (38.7)	0 (0)
Dry skin	34 (32.1)	0 (0)
Water blister	13 (12.3)	1 (0.9)
Stevens-Johnson syndrome	2 (1.9)	2 (1.9)
Gastrointestinal disorders, no. (%)	66 (62.3)	8 (7.5)
Nausea	48 (45.3)	4 (3.8)
Dysgeusia	35 (33.0)	0 (0)
Vomiting	7 (6.6)	0 (0)
Constipation	26 (24.5)	1 (0.9)
Diarrhea	18 (17.0)	4 (3.8)
Peripheral neuropathy, no. (%):	39 (36.8)	5 (4.7)
Peripheral sensory neuropathy	35 (33.0)	5 (4.7)
Peripheral motor neuropathy	20 (18.9)	3 (2.8)
Eye disorders, no. (%):	18 (17.0)	0 (0)
Blurred vision	15 (14.2)	0 (0)
Dry eye	7 (6.6)	0 (0)
Keratitis	5 (4.7)	0 (0)
Fatigue, no. (%)	53 (50.0)	6 (5.7)
Interstitial pneumonia, no. (%)	6 (5.7)	3 (2.8)^*
Other physical disorders, no. (%)^†	10 (9.4)	1 (0.9)
Hematological disorders, no. (%):	40 (37.7)	17 (16.0)
Anemia	33 (31.1)	12 (11.3)
Neutropenia	11 (10.4)	6 (5.7)
Febrile neutropenia	2 (1.9)	2 (1.9)
Thrombocytopenia	5 (4.7)	1 (0.9)
Hyperglycemia, no. (%)	15 (14.2)	3 (2.8)
Other laboratory disorders, no. (%)^‡	7 (6.6)	4 (3.8)
Any trAEs, no. (%):	94 (88.7)	44 (41.5)
Physical trAEs	92 (86.8)	30 (28.3)
Laboratory trAEs	49 (46.2)	22 (20.8)

trAE, treatment-related adverse event

^*, Including a grade 5 case.

^†, Seizure (grade 3; n = 1), edema (grade 1 and 2; n =2), nail change (grade 1; n =2), arthralgia (grade 2; n = 1), vertigo (grade 2; n = 1), urinary tract pain (grade 2; n = 1), hematuria (grade 1; n = 1), headache (grade 1; n = 1), fever (grade 1; n = 1), and oral mucositis (grade 1; n = 1), including overlaps.

^‡, Myelodysplastic syndrome accompanied with thrombocytopenia (grade 4; n = 1), hypercalcemia (grade 3; n = 2), hyponatremia (grade 3; n = 1), hyperkalemia (grade 2; n = 1),　hypoparathyroidism (grade 2; n = 1), and elevated liver enzymes (grade 2; n = 1).

Landmark analysis

To assess the prognostic significance of trAEs, landmark analysis was conducted to minimize immortal time bias: only patients who survived for two months or more (n = 88) were included in the analysis [26]. Of 88 patients, 46 (52.3%) experienced disease progression and 35 (39.8%) died, during the median follow-up of 7 (IQR: 4–13) months.

Overall, the occurrence of any trAEs was significantly associated with longer OS and PFS (Figures 2A and 2B). Supplementary Figure 1 illustrates Kaplan-Meier curves according to respective types of trAEs. A significant correlation between the occurrence of trAEs and longer survival was observed in skin disorders for OS (Supplementary Figure 1A) and peripheral neuropathy for OS and PFS (Supplementary Figures 1E and 1F). A non-significant trend for longer survival was also observed in skin disorders for PFS (Supplementary Figure 1B) and gastrointestinal disorders for OS (Supplementary Figure 1C). To the contrary, the occurrence of hematological disorders was significantly associated with shorter OS and PFS (Supplementary Figures 1M and 1N).

Based on the above observations, trAEs were classified into “physical trAEs”, such as skin disorders, gastrointestinal disorders, peripheral neuropathy, eye disorders, fatigue, and interstitial pneumonia, and “laboratory trAEs”, such as hematological disorders and hyperglycemia. Physical trAEs were significantly associated with longer OS and PFS (Figures 2C and 2D), whereas laboratory trAEs were significantly associated with shorter OS (Figure 2E) and showed a non-significant trend for shorter PFS (Figure 2F).

Supplementary Table 2 shows univariable and multivariable Cox proportional hazards regression analyses, including the occurrence of trAEs, for OS and PFS, using landmark analysis. For OS, bone metastasis, non-occurrence of any trAEs, non-occurrence of physical trAEs, and occurrence of laboratory trAEs were identified as independent predictors of shorter survival. For PFS, bone metastasis, non-occurrence of physical trAEs, and occurrence of laboratory trAEs were identified as independent predictors of shorter survival, whereas non-occurrence of any trAEs was not. Again, liver metastasis was not associated with OS or PFS even in univariable analyses.

For reference, Supplementary Figure 2 illustrates Kaplan-Meier curves depicting OS and PFS according to trAEs and their grades. There were no significant differences in survival between grade ≥ 3 and grade ≤ 2 trAEs both for any trAEs and categorized (physical/laboratory) trAEs.

The present study assessed the prognostic significance of trAEs in advanced UC treated with EV using landmark analysis. In the whole population (n = 106), oncological outcomes and trAE profile of EV therapy in this study were in line with those in the EV-301 trial [1]. Subsequent landmark analysis (n = 88) showed that the occurrence of any trAEs was significantly associated with longer survival. Furthermore, when trAEs were classified into “physical trAEs” such as skin disorders and “laboratory trAEs” such as hematological disorders, the former were associated with longer survival while the latter were associated with shorter survival. This study is the first to propose the concept of categorized (physical/laboratory) trAEs for antibody–drug conjugates such as EV.

While the occurrence of immune-related adverse events has been recognized as a prognostic marker in patients receiving ICIs [25,26], the prognostic significance of trAEs in patients undergoing antibody–drug conjugates has not been fully elucidated. Vlachou et al. reviewed 56 patients with advanced UC undergoing EV and reported that the response rate was higher in patients with cutaneous toxicity (or skin disorders) than in those without (57.7% versus 24.0%, P = 0.0145) [20]. Although the study did not conduct multivariable analysis or landmark analysis due to the small sample size, it was the first report demonstrating an association between EV-related cutaneous toxicity and response. Our study validated the concept of the study by a more comprehensive assessment of trAEs and by minimizing immortal time bias using landmark analysis.

Mechanisms underlying the association between physical trAEs (especially, skin disorders) and better prognosis remain unclear. As nectin-4 is normally expressed in epidermal keratinocytes and skin appendages, as well as in the urothelium, monomethyl auristatin E can be delivered into nectin-4-expressing normal tissues, such as the epidermis and epithelium of sweat glands and hair follicles, which eventually causes skin disorders [24]. Skin and tumor cells might show a similar reaction to EV according to the level of nectin-4 expression per each patient, skin reactions could be a surrogate marker of survival and treatment responses in patients treated with EV. While skin disorders have been reported as common trAEs of EV, severe skin disorders such as Stevens-Johnson syndrome have been highlighted [20,21]. Meanwhile, mild trAEs such as alopecia are likely to be underreported in the real-world setting. Alopecia is not life-threatening (highest grade = 2) but is cosmetically impactful, especially for female patients, which should thus be taken into account in clinical practice [27]. The present study also found that other physical trAEs such as peripheral neuropathy were associated with better prognosis. To the contrary, hematological disorders were associated with worse prognosis. This might reflect the host’s vulnerability to monomethyl auristatin E rather than affinity to nectin-4 and might thus be negatively correlated with effectiveness of EV.

Aside from trAEs, several pretreatment factors were assessed in this study. Notably, liver metastasis was not associated with survival even in univariable analyses, which has been recognized as a strong poor prognosticator for advanced UC both in pre-ICI [28] and post-ICI [29] eras. Actually, this is in line with the result of the EV-301 trial that the benefit of EV was observed both in patients with and without liver metastasis [1].

The limitations of this study included its retrospective design and relatively small sample size. Nevertheless, this is the first comprehensive assessment of prognostic significance of trAEs in patients treated with EV using landmark analysis. Given that EV has recently been approved as first-line treatment for advanced UC in combination with pembrolizumab [30], the drug will be more widely used in the real-world setting. Results of this study will provide additional insight for both clinicians and patients who will use EV in clinical practice.

The occurrence of trAEs is a predictor of longer survival in advanced UC treated with EV. Furthermore, when trAEs are classified into two categories, physical, but not laboratory, trAEs are associated with favorable outcomes of EV more strongly. Not only managing trAEs but also utilizing them as prognostic markers will be key points in the use of antibody–drug conjugates such as EV in the near future.

Acknowledgments

We thank Ms. Yuki Ikemori from Nihon University for helping with data collection.

Author contributions

S Taguchi and T Kawai contributed to the conception, study design, analysis, interpretation of data, and drafted the first manuscript. Y Ambe, K Kishitani, M Noda, T Kaneko, J Miyakawa, Y Nakamura, H Hoshina, D Obinata, K Yamaguchi, S Kakutani, Y Furuya, Yujiro Sato, Y Adachi, K Sugimoto, K Sato, M Tabata, T Tanaka, K Nara, J Kamei, Y Akiyama, Yusuke Sato, Yuta Yamada, A Niimi, and D Yamada contributed to acquisition of data. Y Uemura contributed to the analysis and interpretation of data. T Takada, Sayuri Takahashi, Yukio Yamada, H Miyazaki, Y Enomoto, H Nishimatsu, T Fujimura, H Fukuhara, T Nakagawa, Satoru Takahashi, and H Kume supervised the study, helped to draft the manuscript and were involved in revising it critically for important intellectual content. All authors read and approved the final manuscript.

Funding

We received no funding/grant support for this study.

Data availability

The dataset analyzed in this study is available from the corresponding author upon reasonable request.

Conflict of interest

None declared.

Ethical approval

This study was approved by the Institutional Review Board of the Graduate School of Medicine and Faculty of Medicine, The University of Tokyo (approval number: 10565), as well as that of each participating institution.

Informed Consent

An opt-out approach was used to obtain informed consent from patients.

Powles T, Rosenberg JE, Sonpavde GP et al (2021) Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med 384:1125–1135.
Challita-Eid PM, Satpayev D, Yang P et al (2016) Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models. Cancer Res 76:3003–3013.
Chu CE, Sjöström M, Egusa EA et al (2021) Heterogeneity in NECTIN4 Expression Across Molecular Subtypes of Urothelial Cancer Mediates Sensitivity to Enfortumab Vedotin. Clin Cancer Res 27:5123–5130.
Taguchi S, Kawai T, Nakagawa T et al (2022) Improved survival in real-world patients with advanced urothelial carcinoma: A multicenter propensity score-matched cohort study comparing a period before the introduction of pembrolizumab (2003–2011) and a more recent period (2016–2020). Int J Urol 29:1462–1469.
Taguchi S, Kawai T, Nakagawa T, Kume H (2024) Latest evidence on clinical outcomes and prognostic factors of advanced urothelial carcinoma in the era of immune checkpoint inhibitors: a narrative review. Jpn J Clin Oncol 54:254–264.
Koshkin VS, Henderson N, James M et al (2022) Efficacy of enfortumab vedotin in advanced urothelial cancer: Analysis from the Urothelial Cancer Network to Investigate Therapeutic Experiences (UNITE) study. Cancer 128:1194–1205.
Zschäbitz S, Biernath N, Hilser T et al (2023) Enfortumab Vedotin in Metastatic Urothelial Carcinoma: Survival and Safety in a European Multicenter Real-world Patient Cohort. Eur Urol Open Sci 53:31–37.
Mamtani R, Tsingas K, Parikh RB et al (2024) Real-world use, dose intensity, and adherence to enfortumab vedotin in locally advanced or metastatic urothelial cancer. Urol Oncol 42:177.e1–177.e4.
Taguchi S, Kawai T, Ambe Y et al (2023) Enfortumab vedotin versus platinum rechallenge in post-platinum, post-pembrolizumab advanced urothelial carcinoma: A multicenter propensity score-matched study. Int J Urol 30:1180–1186.
Fukuokaya W, Koike Y, Yata Y et al (2024) Real world evidence of enfortumab vedotin in patients with advanced urothelial cancer: A multicenter observational study. Int J Urol 31:342–347.
Uemura K, Ito H, Jikuya R et al (2024) Enfortumab vedotin prolongs overall survival in metastatic urothelial carcinoma following pembrolizumab therapy in real-world data. Int J Urol 31:678–684.
Hara T, Matsushita Y, Harada K, Fujimoto N, Fujisawa M, Miyake H (2024) Clinical outcomes in patients with advanced urothelial carcinoma treated with enfortumab vedotin: A retrospective multicenter study in Japan. Int J Urol 31:696–698.
Miyake M, Nishimura N, Oda Y et al (2024) Enfortumab vedotin following platinum-based chemotherapy and immune checkpoint inhibitors for advanced urothelial carcinoma: response, survival and safety analysis from a multicentre real-world Japanese cohort. Jpn J Clin Oncol 54:329–338.
Minato A, Kimuro R, Ohno D et al (2023) Efficacy and Tolerability of Enfortumab Vedotin for Metastatic Urothelial Carcinoma: Early Experience in the Real World. Anticancer Res 43:4055–4060.
Minato A, Furubayashi N, Nagata Y et al (2024) Prognostic Impact of Histologic Subtype and Divergent Differentiation in Patients with Metastatic Urothelial Carcinoma Treated with Enfortumab Vedotin: A Multicenter Retrospective Study. Curr Oncol 31:862–871.
Endo Y, Akatsuka J, Takeda H et al (2024) Real-World Insights into Efficacy and Safety of Enfortumab Vedotin in Japanese Patients with Metastatic Urothelial Carcinoma: Findings, Considerations, and Future Directions. Curr Oncol 31:759–768.
Hirasawa Y, Adachi T, Hashimoto T et al (2024) Comparison of the efficacy of enfortumab vedotin between patients with metastatic urothelial carcinoma who were treated with avelumab or pembrolizumab: real-world data from a multi-institutional study in Japan. J Cancer Res Clin Oncol 150:182.
Kawahara T, Hasizume A, Uemura K et al (2023) Administration of Enfortumab Vedotin after Immune-Checkpoint Inhibitor and the Prognosis in Japanese Metastatic Urothelial Carcinoma: A Large Database Study on Enfortumab Vedotin in Metastatic Urothelial Carcinoma. Cancers (Basel) 15:4227.
Morikawa T, Naiki T, Sugiyama Y et al (2024) C-Reactive Protein Is a Potential Prognostic Marker in Patient with Advanced or Metastatic Urothelial Carcinoma Treated with Enfortumab Vedotin: A Multi-Center Retrospective Study. Cancers (Basel) 16:1725.
Vlachou E, Matoso A, McConkey D et al (2023) Enfortumab Vedotin-related Cutaneous Toxicity and Radiographic Response in Patients with Urothelial Cancer: A Single-center Experience and Review of the Literature. Eur Urol Open Sci 49:100–103.
Guerrois F, Thibault C, Lheure C et al (2022) Life-threatening skin reaction with Enfortumab Vedotin: Six cases. Eur J Cancer 167:168–171.
Taoka R, Kamada M, Izumi K et al (2024) Peripheral neuropathy and nerve electrophysiological changes with enfortumab vedotin in patients with advanced urothelial carcinoma: a prospective multicenter cohort study. Int J Clin Oncol 29:602–611.
Yoon S, Shin SJ, Kim HC et al (2022) Enfortumab vedotin-related pneumonitis is more common than expected and could lead to acute respiratory failure. Eur J Cancer 174:81–89.
Lacouture ME, Patel AB, Rosenberg JE, O'Donnell PH (2022) Management of Dermatologic Events Associated With the Nectin-4-directed Antibody-Drug Conjugate Enfortumab Vedotin. Oncologist 27:e223–e232.
Kawai T, Taguchi S, Nakagawa T et al (2022) Impact of immune-related adverse events on the therapeutic efficacy of pembrolizumab in urothelial carcinoma: a multicenter retrospective study using time-dependent analysis. J Immunother Cancer 10:e003965.
Nara K, Taguchi S, Buti S et al (2024) Associations of concomitant medications with immune-related adverse events and survival in advanced cancers treated with immune checkpoint inhibitors: a comprehensive pan-cancer analysis. J Immunother Cancer 12:e008806.
Taguchi S (2024) Editorial comment from Dr Taguchi to Real world evidence of enfortumab vedotin in patients with advanced urothelial cancer: A multicenter observational study. Int J Urol 31:348.
Taguchi S, Nakagawa T, Hattori M et al (2013) Prognostic factors for metastatic urothelial carcinoma undergoing cisplatin-based salvage chemotherapy. Jpn J Clin Oncol 43:923–928.
Taguchi S, Kawai T, Nakagawa T et al (2021) Prognostic significance of the albumin-to-globulin ratio for advanced urothelial carcinoma treated with pembrolizumab: a multicenter retrospective study. Sci Rep 11:15623.
Powles T, Valderrama BP, Gupta S et al (2024) Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med 390:875–888.

No competing interests reported.

SupplementaryFigure1.pdf
Supplementary Figure 1. Kaplan-Meier curves according to respective types of trAEs, using landmark analysis (n = 88): (A) OS and (B) PFS according to skin disorders; (C) OS and (D) PFS according to gastrointestinal disorders; (E) OS and (F) PFS according to peripheral neuropathy; (G) OS and (H) PFS according to eye disorders; (I) OS and (J) PFS according to fatigue; (K) OS and (L) PFS according to interstitial pneumonia; (M) OS and (N) PFS according to hematological disorders; and (O) OS and (P) PFS according to hyperglycemia. OS, overall survival; PFS, progression-free survival; trAE, treatment-related adverse event ^*, Statistically significant
SupplementaryFigure2.pdf
Supplementary Figure 2. Kaplan-Meier curves depicting (A) OS and (B) PFS according to any trAEs and their grades, (C) OS and (D) PFS according to physical trAEs and their grades, and (E) OS and (F) PFS according to laboratory trAEs and their grades, using landmark analysis (n = 88). OS, overall survival; PFS, progression-free survival; trAE, treatment-related adverse event ^*, Statistically significant
SupplementaryTable1.docx
SupplementaryTable2.docx

Download PDF

Version 1

posted

You are reading this latest preprint version

Physical, but not laboratory, treatment-related adverse events are associated with favorable outcomes of enfortumab vedotin for advanced urothelial carcinoma: A landmark analysis

Status:

Version 1

Abstract

Background

Methods

Results

Conclusions

Figures

Introduction

Materials and methods

Patients and treatments

Endpoints, follow-up, and statistical analysis

Results

Analyses of the whole population

Discussion

Conclusions

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1