Updates in Pharmacotherapy for Advanced Bladder Cancer: Four Recent Drug Approvals
Presentation by Lida Bighash, PharmD, BCOP
At the 2023 Meeting of the Oncology Nursing Society Metro Denver Chapter (MDONS), Dr. Lida Bighash from Denver Health provided pharmacy updates focused specifically on bladder cancer, which has seen several recent drug approvals. She began with a brief overview of bladder (urothelial) cancer, which is the 6th most common cancer diagnosis in the United States. She noted the 5-year relative survival of 77.9%, which drops substantively to 18% for disease that has spread beyond the bladder (i.e., metastatic urothelial cancer). A majority of bladder cancers are non-muscle invasive, and the major histological types are urothelial (90%), also called transitional cell cancers. Risk factors for bladder cancer include smoking and certain occupational chemical exposures. Treatment of bladder cancer varies depending on the extent of disease (Box 1) and may include surgery, chemotherapy, chemoradiotherapy, and more recently, immunotherapy.
Box 1. Overview of Bladder Cancer Treatment
Non-Muscle Invasive Disease
TURBT: Trans-urethral resection of bladder tumor (used for both diagnosis and treatment)
Intravesical therapy (using BCG or mitomycin)
Cystectomy (in selected patients)
Muscle Invasive Disease
Chemotherapy (cisplatin-based), followed by cystectomy
Chemoradiation
Adjuvant immunotherapy
Metastatic Disease
Systemic therapy
Adjuvant Treatment: Nivolumab
Nivolumab, a type of immunotherapy, was approved in 2021 in the adjuvant (post-surgery) setting, for patients at high risk for relapse after surgery. High risk patients include those whose tumors are classified as T3 or T4, and those with lymph node positive (LN+) disease. Patients who are candidates for nivolumab treatment may have received neoadjuvant (pre-surgery) cisplatin-based chemotherapy or not, and the therapy is indicated for up to one year. The mechanism of action of nivolumab is via inhibition of a tumor immune-suppressing pathway called the programmed death receptor (PD-1) pathway, which thereby promotes an effective anti-tumor immune response.
The approval for nivolumab in bladder cancer is based on the findings of the randomized, phase III clinical trial called CheckMate 247, which examined the efficacy of nivolumab versus placebo in 709 patients with muscle-invasive urothelial cell carcinoma who had undergone surgery. The study showed a significant benefit of nivolumab over placebo in disease -free survival (DFS), which was 20.8 months in the nivolumab arm and 10.8 months in the placebo arm. In addition, the proportion of patients alive and free of disease at 6 months was 74.9% and 60.3% in the nivolumab and placebo arms, respectively. Importantly, the benefit of nivolumab over placebo was seen in patients regardless of their programmed death ligand 1 (PD-L1) status. The principal side effects of this immunotherapy include immune-mediate adverse events such as dermatologic toxicities like rash which can have a median onset of 2 to 6 weeks, as well as diarrhea/colitis, hepatitis, thyroiditis, and pneumonitis, whose onset can vary from weeks to months after initial administration. For dermatologic toxicity, management may range from topical steroids and antihistamines to systemic corticosteroids. Other rare but serious complications such as pneumonitis can be managed with drug discontinuation or systemic corticosteroids.
Enfortumab Vedotin
Enfortumab Vedotin (EV) is an antibody-drug conjugate (ADC) type drug that is currently approved in the 2ndline, advanced/metastatic setting, and also more recently in combination with pembrolizumab (an immunotherapy agent) for patients who are not eligible for cisplatin, as a first-line treatment. The antibody portion of EV recognizes a molecule, nectin 4, that is highly expressed on bladder cancer cells. Upon binding the cancer cells, it releases its toxin, MMAE, which in turn kills the cancer cell. In the metastatic setting, the drug is indicated for use until unacceptable toxicity develops or until disease progression. Approval of EV is based upon the EV-301 trial, a large trial (608 patients) comparing EV with single agent chemotherapy in the second-line setting, as well as the smaller phase I/II, EV-103/Keynote-869 trial (45 patients) examining the use of EV in combination with pembrolizumab. Overall findings of these trials are summarized in Box 2.
Box 2. Enfortumab Vedotin (EV) in Bladder Cancer: Results of Key Clinical Trials
EV-301
608 patients, randomized to either EV or single-agent chemotherapy
Improvement in overall survival (OS) with EV: 12.9 months vs. 9.0 months
Improvement in progression-free survival (PFS) with EV: 5.6 months vs. 3.7 months
EV-103/Keynote-869
45 patients, received EV with pembrolizumab (an immunotherapy)
Overall response rate = 73.3%; Complete responses seen in 15.6%
Duration of response = 25.6 months; OS = 26.1 months
Results compare favorably with other agents in this treatment setting
Adverse events associated with EV, as observed in EV-301 included alopecia, peripheral neuropathy (~ 1/3 of patients), dermatologic toxicity such as pruritis (~33%), GI toxicity such as diarrhea (~24%), as well as reductions in blood cell counts (cytopenias such as anemia and neutropenia) and hyperglycemia (~6%). Cutaneous toxicities can be managed with zinc-containing agents, sunscreen, topical corticosteroids, and antihistamines. The potential for hyperglycemia and ocular toxicity with this agent also necessitates measures such as a baseline A1C level, and an ophthalmologic exam. Any new onset shortness of breath and/or dry cough should also be reported, as it could be indicative the rarer side effect of pneumonitis, which could necessitate discontinuation of EV.
Sacituzumab Govitecan
Sacituzumab govitecan (SG) is another ADC type drug that was approved for use in the 2nd line setting for patients with advanced or metastatic disease. The antibody portion of the drug recognizes a molecule called Trop2, which is expressed on the surface of bladder cancer cells. Upon binding and internalization into the cell, it releases a toxin called SN-38, a topoisomerase inhibitor that causes cell death. Approval of this agent was based on the TROPHY trial, a phase II study that assessed the efficacy of SG in 112 patients, with the main efficacy endpoints of overall response rate (ORR) and duration of response (DoR). Results showed a median overall survival (OS) of 10.9 months, which compares favorably to historical controls with single agent chemotherapy, which generally show a median OS of about 7 months. The ORR was found to be 27.7%. The principle adverse events with SG included diarrhea, nausea, fatigue, and neutropenia; about 10% of patients experienced diarrhea of grade 3 or higher and approximately one-third experienced grade 3+ neutropenia. Some additional considerations for SG mediated adverse events are listed in Box 3.
Box 3. Sacituzumab Govitecan (SG) Adverse Event Considerations
Neutropenia
More commonly observed in patients with a certain genetic predisposition (UGT1A1 homozygous and heterozygous) receiving SG.
Nausea and Vomiting
SG is a high emetic risk drug; a four-drug prophylactic regimen is recommended upfront.
Diarrhea
SG is associated with cholinergic responses such as abdominal cramping and salivation; can consider the use of atropine.
Infusion Reactions
Seen in about 35% of patients on SG; premedication with diphenhydramine, famotidine and acetaminophen is recommended.
Erdafitinib
This is an orally administered agent that is approved in the 2nd-line setting for bladder cancer that is positive for fibroblast-growth factor receptor (FGFR) 2 or 3 mutation or fusion, and patients have to have progressed after platinum-based chemotherapy and immunotherapy. The approval for erdafitinib is based on findings of the phase II BCL2001 trial, which showed a response rate of 40% with this agent. The drug is an inhibitor of the FGFR pathway, causing reduced signaling and reduced cancer cell viability in patients with this type of bladder cancer. Use of this drug is indicated until disease progression or unacceptable toxicity. The drug is initiated at a lower dose once daily and thereafter increased depending on serum phosphate levels; it can be taken with or without food and phosphate levels need to be monitored monthly, as about 75% or more will experience hyperphosphatemia. About one quarter of patients will also experience certain ocular toxicities such as dry eyes, and 75% experience dermatologic toxicities such as rash, nail changes, hand foot syndrome, and/or dry skin. As such, patients need to be appropriately educated about these potential toxicities so that they can be promptly reported and managed.
Summary
Summarizing, Dr. Bighash noted that treatment options have expanded for advanced/metastatic bladder cancer in recent years, and this has resulted in improved survival for patients. Antibody drug conjugates and FGFR pathway inhibitors provide new treatment options with distinct mechanisms of action. As use of these new agents increases across clinical practice, their distinct toxicity profiles also necessitate a careful monitoring and management strategy for adverse events, so that patients can remain on therapy as long as possible.
Speaker Disclosure Information: Dr Bighash listed no disclosures for this presentation.
You can view the full presentation from the 2023 MDONS Conference here: