(UroToday.com) On the second day of the American Society for Clinical Oncology (ASCO) Genitourinary Cancer Symposium 2022, Dr. Flaig presented in a session highlighting novel therapies in bladder cancer and their toxicities. Following presentations from Dr. Tolcher and Dr. Tagawa highlighting the basic principles of tumor antigen targeting with antibody-drug conjugates and the current (and future) indications for these agents in urothelial carcinoma (UC), Dr. Flaig presented on the management of toxicity associated with these novel systemic agents.
In this context, he began by emphasizing a number of key points. First, among the approved antibody-drug conjugates (enfortumab vedotin and Sacituzumab govitecan) have specific toxicity profiles. Second, the targeted therapy erdafitinib has important adverse events which are critical to follow. Finally, there are emerging immune-oncologic combinations including these agents with immune checkpoint inhibitors which may also contribute to important toxicity which clinicians must be comfortable managing.
Dr. Flaig first began with a discussion of antibody-drug conjugates. While discussed in more detail by other speakers, he emphasized that both the specific therapeutic payload and the target are important in the toxicity profile. To this end, enfortumab vedotin (EV) targets Nectin-4 with a payload of MMAE while Sacituzumab govitecan (SG) targets Trop-2 with a payload of SN-38. Among this, first discussing EV, he emphasized that skin reactions occur in more than half of patients and may be grade 3-4 in 13%, including fatal reactions. Skin toxicity manifests with erythematous, scaly, pruritic papules on the chest, likely in part because Nectin-4 has expression in normal cutaneous tissue. Treatment can begin with topical steroids and antihistamines and should involve dermatology in severe cases.
Further, peripheral neuropathy is common (>50%), though severe, grade 3-4 events are uncommon (4%). Hyperglycemia and diabetic ketoacidosis are relatively uncommon (7% grade 3-4) but require monitoring of blood glucose and holding of EV when these reach 250 mg/dL. Pneumonitis, ocular disorders, and infusion site extravasation are other important adverse events of EV.
Considering SG next, he emphasized that most available safety data come from its use in breast cancer. Neuropenia is relatively common, occurring in more than 60% of patients and being grade 3-4 in more than 40%. Febrile neutropenia, including leading to death, may occur in 7% of patients. Diarrhea is also common (>60%) but is less commonly (12%) severe, grade 3-4 event. Nausea and vomiting similarly occur in more than 60% of patients but reach grade 3-4 severity in 4%. However, 2 or 3 anti-nauseants may be required. Finally, grade 3-4 hypersensitivity may occur in 2% of patients and thus premedication is recommended. UGT1A1 alterations may predispose to marrow toxicity in patients receiving SG: if homozygous of UGT1A1*28 (seen in approximately 10-15%), rates of grade 3-4 neutropenia are 67% while for those who are heterozygous or wildtype, rates are 46%. Thus, it is critical to closely monitor patients with a known reduction in UGT1A1 activity and consider this among patients who have early or unusually severe toxicity.
Moving next to a discussion of erdafitinib, Dr. Flaig emphasized that hyperphosphatemia is a key adverse events. It’s necessary both to restrict phosphate intake to 600-800 mg daily and also to start at an 8mg dose with subsequent up-titration to 9mg among those patients who do not have a phosphate level rise about 5.5 mg/dL. Additionally, ocular disorders may be clinically important as these led to dose interruption and reductions in 9% and 14% of patients, respectively. Erdafitinib can cause central serous retinopathy/retinal pigment epithelial detachment. As a result, it is important to obtain monthly ophthalmologic evaluations during the first four months of therapy, followed by every 3 months thereafter and for-cause at any point if patients develop visual symptoms.
Other common adverse events include stomatitis, fatigue, diarrhea, onycholysis, and hand foot syndrome.
Dr. Flaig further noted that there are numerous emerging therapeutic combinations in this disease space including multiple immune checkpoint inhibitor combinations. In terms of combining standard cytotoxic chemotherapy (gemcitabine and cisplatin) with pembrolizumab, phase II data in the neoadjuvant setting showed that significant toxicity was observed using the usual gem-cis dosing following an initial pembrolizumab lead-in. Instead, a split-dose regime of gemcitabine-cisplatin without pembrolizumab lead-in was subsequently employed instead. When combining the ADC EV with pembrolizumab, there are emerging phase I data which suggest that peripheral sensory neuropathy, fatigue, and alopecia are relatively common (~50%). Further “there was one death reported as possible related to study treatment (multiple organ dysfunction syndrome)”.
In closing, Dr. Flaig highlighted that there are several new and emerging therapies in bladder cancer which have important, unique, and specific toxicity profiles which must be both considered in treatment selection and carefully monitored during therapy. The toxicity of novel combination therapy approaches will require careful study to optimize the efficacy and toxicity balance.
Presented by: Thomas W. Flaig, MD, University of Colorado Anschutz Medical Campus