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Pablo, a 68-year-old vintager, spent his whole life on the vineyard harvesting Moscatel grapes and sun-drying them until they become the traditional las Pasas de Malaga. Now that he is retired, he prefers drinking the grapes as the sweet fortified Moscatel and Pedro Ximénez wines.
He was diagnosed with UCa of the bladder metastatic to the pelvic lymph nodes and lungs and was treated with first-line gemcitabine + cisplatin. At the end of chemotherapy, the CT scan revealed new and enlarging lung lesions. Treatment with pembrolizumab was started, but 6 months later he shows again progressive disease.
Assessment summary:
The patient started enfortumab vedotin (EV) with a very good response. 5 months after the start of treatment, the patient develops grade 2 peripheral neuropathy (PNP).
Pharmacological intervention is being started to manage the neuropathic pain.
Continue full dose EV without interruption
Reduce EV dose without interruption
Withhold EV until resolution to grade ≤1, then resume full dose
Withhold EV until complete resolution, then resume full dose
Switch to sacituzumab govitecan
Continue full dose EV without interruption
Reduce EV dose without interruption
Withhold EV until resolution to grade ≤1, then resume full dose
Withhold EV until complete resolution, then resume full dose
Switch to sacituzumab govitecan
Nervous system disorders are frequent adverse events (52% in clinical studies) in patients treated with enfortumab vedotin (EV) [1]. The most common neurologic adverse event is peripheral sensory neuropathy which developed in 38.7% of patients (very common, occurring in ≥1/10 patients). Other commonly seen adverse events are peripheral motor neuropathy, peripheral sensorimotor neuropathy, paraesthesia, hypoaesthesia, gait disturbance and muscular weakness. Very rarely (in ≥1/1000 to <1/100 patients) symptoms like demyelinating polyneuropathy, polyneuropathy, neurotoxicity, motor dysfunction, dysaesthesia, muscle atrophy, neuralgia, peroneal nerve palsy, sensory loss, skin burning sensation, burning sensation occurred. In clinical trials, the median time to onset of grade ≥2 peripheral neuropathy (PNP) was 4.6 months (range: 0.1-15.8 months).
In the case of Pablo, who developed the first event of grade 2 EV-associated PNP, by the rule and the product characteristics, withhold until grade ≤1 and resume treatment at the same dose level [2]. It is important to avoid higher grade PNP so that treatment can be restarted if still working and the patient remains in remission or at least stable. Also, higher grade PNP is interrupting the patient’s daily life and reduces quality of life significantly, and recovery is slow and full recovery is not guaranteed.
Just in general, for a recurrent grade 2 PNP, withhold until grade ≤1, then resume treatment reduced by 1 dose level [2]. It is also important to start medication to manage neuropathic pain if needed. For grade 1 PNP, no dose modification is indicated. In case of grade ≥3 PNP, permanently discontinue EV. It is important that patients are monitored for symptoms of new or worsening PNP, as these patients may require a delay, dose reduction or discontinuation of EV.
Of note and quite contra-intuitively, patients with CTCAE grade 1 PNP are described as asymptomatic by CTCAE and the PNP would only be captured when measuring the nerve conduction velocity [3]. CTCAE grade 2 PNP is described as follows: moderate symptoms, limiting instrumental activities of daily living. On the other hand, CTCAE grade 3 PNP includes severe symptoms, limiting self-care activities of daily living.