We demonstrated that EV-induced peripheral neuropathy may be a predictive factor for the effectiveness of EV treatment. To the best of our knowledge, this is the first study focusing on the effect of peripheral neuropathy on EV treatment in patients with advanced UC. Additionally, in patients who developed peripheral neuropathy, EV reduced nerve conduction velocity more markedly in the sensory nerves than in the motor and lower limbs than in the upper limbs, with the sural nerve, a sensory nerve in the lower limbs, being most affected. In clinical practice, our findings suggest the importance of paying attention to EV-induced peripheral neuropathy of the sural nerve for safe long-term use and maximizing the efficacy of EV treatment.
In addition to platinum-based chemotherapy, PD-1/L1 inhibitors are the standard of care for patients with advanced UC [7, 8]. Although first-line chemotherapy usually yields a high initial response rate and until PD-1/L1 inhibitors become available, the disease often acquires resistance rapidly [9, 10], and the overall 5-year survival rate is only 6% [11]. Recently, the PD-1 inhibitor pembrolizumab was shown to prolong the OS of patients with chemoresistant metastatic UC [12, 13] and has been approved as a second-line therapy in this setting. In addition, maintenance with the PD-L1 inhibitor avelumab significantly prolonged OS compared to best supportive care alone among advanced UC patients with no disease progression after first-line chemotherapy [14]. However, although immunotherapy is better tolerated than chemotherapy and is associated with a longer response duration, only a minority of patients achieve a response. Therefore, despite the clinical introduction of immune checkpoint inhibitors, advanced UC still progresses and generally remains incurable.
EV demonstrated a clinically significant OS benefit compared to standard chemotherapy in patients with advanced, previously treated UC in a randomized phase 3 EV-301 trial [2]. Subsequently, EV received regular approval from the United States Food and Drug Administration to treat adults with advanced UC who previously received platinum-based chemotherapy and PD-1/L1 inhibitors. Recently, the efficacy and safety of EV, with a median follow-up of 23.75 months from EV-301, were analyzed, and an ORR of 41.32% and DCR of 71.88% were reported [3]. In addition, median PFS and OS were indicated as 5.55 and 12.91 months, respectively. Furthermore, efficacy results in the Japanese subgroup of EV-301 were remarkably consistent with PFS and OS and confirmed ORR and DCR findings observed in the overall population [15]. These results are comparable to ours, indicating that EV treatment in a third-line setting is as effective as in real-world clinical trials.
Our study also revealed that patients with controlled disease had a significantly longer treatment duration and OS than those with uncontrolled disease. However, EV treatment was withdrawn in five (14.7%) of the 34 patients due to TRAEs. The reasons for withdrawal were peripheral neuropathy in two patients, skin rash in two, and febrile neutropenia in one. Safety data from the EV-301 trial also showed that TRAEs led to withdrawal in 13.5% of patients [2]. EV-related peripheral neuropathy is the most common TRAE that leads to interruption and withdrawal of treatment [2, 3]. Currently, no known methods exist to prevent or cure peripheral neuropathy [4]. Therefore, in clinical practice, early diagnosis of peripheral neuropathy is necessary to prevent it from becoming more severe and to ensure continued EV treatment for patients with efficacy.
EV consists of an antibody against Nectin-4, a transmembrane adhesion molecule that is highly expressed in UC cells and conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker [1]. MMAE is a potent anticancer microtubule-targeting agent that binds extensively to tubulin and microtubules, followed by the MMAE-mediated inhibition of microtubule-dependent axonal transport, leading to severe peripheral neuropathy [16]. NCS is a clinical practice tool for the detection of peripheral neuropathy. There is evidence to suggest that NCS data in asymptomatic patients receiving neurotoxic chemotherapy can predict the development or worsening of chemotherapy-induced peripheral neuropathy [17–19]. According to our NCS analysis, after one month of EV treatment, there was a more significant reduction in nerve conduction velocity in the sensory nerves than in the motor nerves. The lower limbs are more affected than the upper limbs. Interestingly, the sural nerve is the most commonly affected nerve in patients who develop peripheral neuropathy. However, NCSs are not used routinely for this purpose. Therefore, little is known about the electrophysiological effects of EV treatment on peripheral nerves. This study proposes that periodic NCS during EV treatment become standard practice in the future.
Recently, patients who experienced skin toxicity reported a higher ORR and longer PFS after EV treatment than those who did not experience skin toxicity [6]. Our data demonstrates that the objective response to EV treatment in patients with peripheral neuropathy was higher than in patients without. Additionally, patients who developed peripheral nerve diseases had more prolonged survival. The amount of MMAE released from EV upon uptake by cancer cells via Nectin-4 may be proportional to its therapeutic efficacy and the development of peripheral neuropathy. In addition, peripheral neuropathy developed at a median of 15 weeks after starting EV treatment. This suggests that patients who could tolerate EV treatment for a relatively long period were selected. However, the median observation period for patients without peripheral neuropathy was 4.2 months, which exceeded the median time of peripheral neuropathy onset. Based on this data, peripheral neuropathy may be considered as an on-target toxicity for the efficacy of EV treatment. To our knowledge, this is the first report to demonstrate an association between EV-related peripheral neuropathy and the therapeutic effects of EV treatment.
Our study had limitations, including a physician-reported response assessment and a small sample size. Additionally, the small sample size precluded multivariate analyses; thus, we could not account for the potential confounding factors. In addition, our NCS data may have been influenced by EV and previous chemotherapy and immunotherapy. Nonetheless, this is the first study to focus on the effect of peripheral neuropathy on EV treatment in patients with advanced UC. In clinical practice, our findings highlight the importance of monitoring the conduction velocity and paying attention to EV-induced neuropathy of the sural nerve for safe long-term use of EV treatment.