Approaches to Urothelial Care Call for Nuanced AE Management
Avelumab, erdafitinib, and enfortumab vedotin-ejfv are 3 critical drugs in the treatment of urothelial cancer with distinct safety profiles, according to a presentation at the 6th Annual School of Nursing Oncology™ Meeting.
New targeted therapies, immunotherapies, and antibody-drug conjugates for the treatment of urothelial cancer (UC) have accentuated the importance of the oncology nurse’s role in patient education and symptom management, according to Laura Wood, MSN, RN, OCN.1
“Nurses play a critical role in providing education to patients and caregivers,” Wood said in an interview with Oncology Nursing News®, “ensuring that AEs [adverse effects] and irAEs [immune-related AEs] are identified early so appropriate interventions can be initiated, while…provid[ing] emotional support [to patients] as they navigate the cancer journey.”
A former oncology nurse specialist at the Taussig Cancer Center, Wood summarized what she had said at the 6th Annual School of Nursing Oncology about avelumab (Bavencio), erdafitinib (Balversa), and enfortumab vedotin-ejfv (Padcev), underscoring their uniqueness and the best ways to manage their AEs.
Avelumab is the current standard of care maintenance treatment for patients with locally advanced or metastatic UC that has not progressed with frontline platinum-based chemotherapy. The drug was approved for patients who have received prior treatment with at least 1 line of platinum-based chemotherapy. Approval was granted based on positive results from the JAVELIN Bladder 100 trial (NCT02603432),2 which compared the efficacy of avelumab plus best supportive care (BSC) against BSC alone.
An analysis of long-term outcomes found that the 30-month overall survival (OS) rate with avelumab (n = 350) was 43.7% compared with 33.5% for BSC (n = 350). In addition, the median progression-free survival (PFS) was 5.5 months vs 2.1 months (HR, 0.54; P <.001) in the experimental and control arms, respectively, and the 30-month PFS rate was 19.3% vs 6.3%, respectively.
“Nurses need to be aware that this treatment is available [and] that it is an approved option for patients who are doing well and benefiting from first-line platinum-based chemotherapy,” Wood said. “They also need to know that it requires premedication for the first 4 infusions due to the potential for an infusion-related reaction. That is unique compared to the other checkpoint inhibitors we use in oncology.”
As of August 2022, National Comprehensive Cancer Network (NCCN) guidelines suggest that patients with locally advanced or metastatic disease who are cisplatin-eligible receive cisplatin-based combination chemotherapy followed by avelumab maintenance therapy or dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) with growth factor support for 3 to 6 cycles, followed by avelumab maintenance therapy.3
Patients who are cisplatin-ineligible may receive gemcitabine plus carboplatin chemotherapy followed by avelumab maintenance therapy. They may also receive atezolizumab (Tecentriq) or pembrolizumab (Keytruda) if their tumors express PD-L1 and they are ineligible for platinum-based chemotherapy regardless of PD-L1 expression. They may also receive gemcitabine with or without paclitaxel .
For second-line treatment, the preferred agent is pembrolizumab (category 1 post-platinum). Alternatives to pembrolizumab include immune checkpoint inhibitors nivolumab (Opdivo) and avelumab and monotherapy with erdafitinib or enfortumab vedotin. Paclitaxel, docetaxel, and gemcitabine are also viable options included in the NCCN guidelines.
Depending on treatment history, the following sequential therapies may also be useful: ifosfamide, doxorubicin, and gemcitabine (IAG); gemcitabine/paclitaxel; gemcitabine/cisplatin; and ddMAC with growth support factor.
Erdafitinib is approved for patients with locally advanced or metastatic UC that is susceptible to FGFR3 or FGFR2 genetic alterations and that has progressed during or following at least 1 line of platinum-based chemotherapy—including within 12 months of neoadjuvant or adjuvant therapy.
To determine whether a patient is eligible for erdafitinib, the therascreen FGFR RGQ RT-PCR Kit or the formalin-fixed, paraffin-embedded (FFPE) test may be used.4
“Tumor testing is required,” Wood stressed. “There’s biomarker testing involved, and [erdafitinib] is approved for patients who have progressed during or following frontline platinum-based chemotherapy. [It] remains a mainstay in our treatment plan within 12 months of neoadjuvant or adjuvant therapy.” What makes the medication unique, she added, is that with it “there is the potential for dose titration.”
The starting dose for erdafitinib is 8 mg once daily (two 4-mg tablets). After patients have been taking erdafitinib for 14 to 21 days, the dose may be increased to 9 mg daily (three 3 mg tablets) provided that patients can tolerate it and their serum phosphate levels are normal.3
Nurses should note that erdafitinib can increase a patient’s phosphorus levels, putting them at risk of hyperphosphatemia.
“Again, we’re looking at sequential therapy,” Wood said. “One of the unique [AEs] is the potential for an increased phosphorus level, and that is something we do not normally include in our laboratory panels. But it is critical to monitor for that…[and to] educate patients about a low-phosphorus diet.”
Patients should restrict phosphate intake to 600 mg to 800 mg daily. However, if serum phosphate exceeds 7.0 mg/dL, it may be appropriate to add an oral phosphate binder until levels are below 5.5 mg/dL.
Erdafitinib is also associated with ocular toxicities. According to the package insert, 19% of patients experienced all-grade dry eye with the agent, 17% experienced blurred vision, 6% cataracts, and 5% keratitis. However, the percentage of patients who experienced grade 3 or greater ocular toxicities was much smaller: 1% (dry eye), 0% (blurred vision), 2% (cataracts), and 3% (keratitis).
Moreover, 25% of patients experienced serous retinopathy/retinal pigmen epithelial detachment (CSR/RPED). The median onset time to first occurrence was 50 days.
The last drug Wood discussed was enfortumab vedotin. As she explained in the interview, the agent “is an antibody-drug conjugate [that] targets Nectin-4 protein on UC cells.” As it binds “with the Nectin-4 protein, the linker dissolves, and the microtubular payload is released, leading to cell cycle arrest and apoptosis,” she said.
The drug is indicated for adults with locally advanced or metastatic disease who have had previous PD-1 or PD-L1 inhibition and platinum-based chemotherapy. To be given enfortumab vedotin, patients must be ineligible for cisplatin-containing chemotherapy and must have received at least 1 prior line of therapy.5
The recommended dose for enfortumab vedotin is 1.25 mg/kg, and the maximum dose is 125 mg/kg. It is administered intravenously over 30 minutes on days 1, 8, and 15 of a 28-day cycle.
Nurses should be aware that this agent can cause severe or life-threatening cutaneous AEs, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). These reactions typically occur during the first treatment cycle but may also occur later.
The drug also comes with a warning for skin reactions, hyperglycemia and diabetic ketoacidosis, pneumonitis, peripheral neuropathy, ocular disorders, dry eye symptoms, blurred vision, increased lacrimation, conjunctivitis, and infusion site extravasation.
Patients should be told about the risk of infusion-site reactions, hyperglycemia, pneumonitis, and vision changes and advised to use artificial tears to prevent or treat dry eye. Moreover, baseline assessments and continued monitoring for peripheral neuropathy are advised.
On the Horizon
According to Wood, a few investigative therapies with promising efficacy and safety profiles. One of them is N-803, a mutant IL-15–based immunostimulatory fusion protein complex.
At the 2022 ASCO Annual Meeting, findings from the ongoing phase 2/3 QUILT-3.032 trial (NCT03022825) showed that among 160 patients with carcinoma in situ or papillary Bacillus Calmette-Guérin (BCG)–unresponsive non–muscle invasive bladder cancer, the complete response was 71% (95% CI, 60.1%-80.5%). The median duration of response was 26.6 months, and the OS rate was 100% at a 2-year data cutoff.6
Based on findings from the QUILT-3.032 trial, a biologics license application has been filed with and accepted by the FDA. The decision date has been set for May 23, 2023.7
Wood also highlighted Trop-2, a biomarker that is gaining traction in UC. In May 2021, the FDA granted accelerated approval to sacituzumab govitecan (Trodelvy) based on phase 2 findings from the TROPHY U-01 trial (NCT03547973).
Data showed a viable response among patients with pretreated metastatic UC who received the Trop-2-directed antibody-drug conjugate. In a single cohort of 133 patients with a median of 3 prior lines of therapy, the objective response rate was 27%, and a measurable disease decrease was observed in 77%. Median PFS was 5.4 months, and median OS 10.9 months.8
Continued approval is contingent on findings from the confirmatory phase 3 TROPiCS-04 trial (NCT04527991).9
In her presentation Wood noted that nurses should encourage patient participation in clinical trials. She also urged nurses to give continued attention to biomarker testing in order to help facilitate potential clinical trial enrollment.
- Wood L. Novel approaches to renal and urothelial cancers. Presented at: 6th Annual School of Nursing Oncology; July 29-30, 2022; San Diego, CA.
- Powles T, Park SH, Voog E, et al. Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (UC): long-term follow-up results from the JAVELIN Bladder 100 trial. J Clin Oncol. 2022;40(suppl 6):487. doi:10.1200/JCO.2022.40.6_suppl.487
- NCCN. Clinical Practice Guidelines in Oncology. Bladder cancer, version 2.2022. Accessed August 9, 2022. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf
- Balversa. Prescribing information. Janssen Products, LP; 2019. Accessed August 10, 2022. https://bit.ly/2X67iEm
- Padvec. Prescribing information. Astellas Pharma US, Inc.; 2019. Accessed August 10, 2022. https://bit.ly/3JObQJ1
- Chang SS, Chamie K, Gonzalgo ML, et al. Positive efficacy and safety phase 3 results in both CIS and papillary cohorts BCG-unresponsive nonmuscle invasive bladder cancer (NMIBC) after IL-15RαFc superagonist N-803 (Anktiva) and BCG infusion. J Clin Oncol. 2022;40(suppl 6):431. doi:10.1200/JCO.2022.40.6_suppl.431
- ImmunityBio announces FDA acceptance of biologics license application for N-803 in BCG-unresponsive non-muscle-invasive bladder cancer carcinoma in situ. News release. ImmunityBio. July 28, 2022. Accessed August 10, 2022. https://bit.ly/3zmRnX8
- Tagawa ST, Balar AV, Petrylak DP, et al. TROPHY-U-01: a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors. J Clin Oncol. 2021;39(22):2474-2485. doi:10.1200/JCO.20.03489
- FDA grants accelerated approval to sacituzumab govitecan for advanced urothelial cancer. News release. FDA. April 13, 2021. Accessed August 10, 2022. https://bit.ly/3tgxmgy