How to handle side effects of enfortumab vedotin + pembrolizumab

In the first-line treatment setting of patients with metastatic urothelial carcinoma, chemotherapy had been king for a long time. However, the EV-302/KEYNOTE-A39 study has recently established the combination of the Nectin-4–directed antibody-drug conjugate enfortumab vedotin (EV) and pembrolizumab as the new first-line standard.1 Patients with previously untreated locally advanced or mUC who were PD-(L)1-inhibitor–naïve were randomized to either EV plus pembrolizumab or platinum-based chemotherapy for six cycles. No maximum number of cycles had been defined for EV, while pembrolizumab was given for a maximum of 35 cycles. The population included individuals with performance status 0-2, although those with PS 2 had to meet certain criteria such as glomerular filtration rates >50mL/min and were thus highly selected. Progression-free survival (PFS) and overall survival (OS) constituted the dual primary endpoints.

This large study of 900 patients revealed an impressive difference for PFS that was double with EV plus pembrolizumab compared to traditional chemotherapy (12.5 vs. 6.3 months; HR, 0.45; p<0.00001). The curves started to separate early on. Similarly, the risk of death was reduced by 53% in the experimental arm, with median OS of 31.5 vs. 16.1 months (HR, 0.47; p<0.00001). OS benefits were consistent in the overall population regardless of cisplatin eligibility.

How can we pre-empt adverse events?

On the downside, EV plus pembrolizumab, as compared to chemotherapy, evokes more serious adverse events (AEs). Peripheral sensory neuropathy, pruritus, alopecia and rash occurred as the most frequent treatment-related AEs in the experimental arm. Among AEs of special interest, skin reactions occurred much more often with EV than with chemotherapy, which also applied to both sensory and motor peripheral neuropathy (Table). Moreover, the EV treatment was shown to cause ocular changes, particularly dry eye, and hyperglycemia the pathophysiology of which is unknown. With respect to pembrolizumab, treatment-emergent AEs of special interest were as expected.

Patient selection is a major pillar that helps to pre-empt problems. For example, EV plus pembrolizumab might need to be avoided in patients with poorly controlled diabetes or peripheral neuropathy. The trade-off for achieving an OS gain will be different in each case. It is important to remember that grade 2 peripheral neuropathy already affects the patient’s activities of daily life. Furthermore, we should know whether steroids have already been used to improve the patient performance status as this can have an impact on the efficacy of checkpoint inhibitors, and potentially also interfere with the efficacy of the combination. Generally, patients with ECOG performance status 2 must be very carefully selected.

The other major pre-emptive pillar is training on the ground. This involves anybody who might see the patient, including the oncology specialists and nurses, but indeed anybody who works in the emergency department or in primary care. The patients themselves need to be trained, as it is important to assure that they understand what to do in the event of a side effect. In case of toxicities grade ≥2, treatment should be paused, dose reduction should be considered, and the specifics of the AE should be dealt with.

Skin toxicity: watch out for dermatological emergencies

The skin rash caused by EV plus pembrolizumab is usually maculopapular and occurs in approximately two thirds of patients. Importantly, the assessment should involve inspection of the entire skin including the mucous membranes and eyes. Specifically, we should look for mouth ulcers and lymphadenopathy and ask the patients about systemic symptoms such as fever, because their risk of Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome and Stevens Johnson syndrome is increased. Inflammatory markers and full blood counts should be tested.

However, it is vital to do the basics, i.e. to exclude bites, skin infections or infestations and changes in the patients’ washing products, among others, instead of just assuming that the rash is treatment-related. The patient history should also include information about any previous therapies for the skin toxicity, as drugs such as antibiotics might compromise the oncologic treatment, particularly the checkpoint inhibitor component. Most units will know how to manage lower-grade skin reactions and have local algorithms in place. Dermatologists should be involved early if the patient has not responded to simple measures such as emollients and antihistamines, in case of mucosal involvement, and if more than one third of the skin is affected. If the causality is unclear, biopsies might be indicated. Red flag signs that call for the consultation of a dermatologist are pain, erythroderma, blisters and earlobe swelling, which can be a sign of DRESS syndrome that is a dermatological emergency. Patients need to be encouraged from the start to use products like oatmeal-based emollients, sunscreens when outside, and fragrance-free products.

Table: Adverse events of special interest related to enfortumab vedotin

Neuropathy & hyperglycemia

As the EV-related neuropathy is usually sensory, the patients should be asked direct questions such as “Do you have problems holding a pen or using a keyboard?”. Diabetic control needs to be checked; subtle increases in urinary symptoms might hint at a deterioration. Agents such as amitriptyline and gabapentin are usually effective, as well as local treatment with menthol cream 1-2%.

Regarding hyperglycemia, patient education as well as training of health care professionals is important. Symptoms including increased urinary frequency and fatigue should be checked at each visit. Diabetics should be encouraged to do home blood glucose monitoring more often, and diabetic nurse specialist teams can be involved in patient care. EV plus pembrolizumab treatment should be paused in case of blood glucose levels >250mg/dL. If steroid treatment is started for any other condition, it is important to know about it.

The key messages relate to education of anyone who might see the patient, multidisciplinary team involvement, and early intervention. Ideally, we should pre-empt problems before they start and make certain that there is a clear management pathway as soon as toxicities emerge. This way, dose reductions or temporary halts with the prospect of reinitiating this life-extending therapy are possible. However, we know that many patients with advanced urothelial carcinoma are not treated at all or are undertreated. Large real-world analyses from the USA and Denmark have shown that up to two thirds of patients did not even receive first-line treatment.2-4 This is most likely due to impaired access and decisions that are being made by members of the multidisciplinary team who are not specialized in treating metastatic urothelial carcinoma.

To learn more, don’t miss our roundtable session on prostate & urothelial cancer by Dr. Aurelius Omlin

References:
1 Powles TB et al: EV-302/KEYNOTE-A39: Open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC). Ann Oncol 2023; 34 (suppl_2): S1254-S1335
2 Bilen MA et al: Real-world (RW) treatment (Tx) patterns and clinical outcomes in patients (pts) with metastatic urothelial carcinoma (mUC) receiving first-line (1L) Tx: Results from IMPACT UC. Ann Oncol 2021; 32 (suppl_5): S678-S724
3 Morgans AK et al: Treatment patterns among patients with advanced urothelial carcinoma (aUC) in the USA. Ann Oncol 2021; 32 (suppl_5): S678-S724
4 Jensen JB et al: Treatment pattern and overall survival among patients with locally advanced or metastatic urothelial carcinoma: Results from a complete nationwide unselected real-world registry study in Denmark from 2010 to 2017: Ann Oncol 2021; 32 (suppl_5): S678-S724