Posted: Tuesday, July 27, 2021
The U.S. Food and Drug Administration (FDA) granted accelerated approval to sacituzumab govitecan-hziy (SG)1 for the treatment of patients with locally advanced or metastatic urothelial (bladder) cancer who have been previously treated with a platinum-containing chemotherapy regimen and either a PD-1 or PD-L1 inhibitor. Of note, this agent is indicated only after disease progression on prior treatment with a platinum-containing regimen and a checkpoint inhibitor. SG was also previously granted accelerated approval and then regular approval for patients with unresectable locally advanced or metastatic triple-negative breast cancer who have received two or more prior systemic therapies, at least one of them for metastatic disease.2
SG is an antibody-drug conjugate comprising a monoclonal antibody linked to a topoisomerase inhibitor, SN-38, targeting trophoblast surface antigen-2 (Trop-2).3 This protein is expressed on 80% to 90% of tumor cells in metastatic bladder cancer, and SG is the first advanced bladder cancer treatment to target the Trop-2 protein.
SG is the first advanced bladder cancer treatment to target the Trop-2 protein.
The approval of SG for this indication was based on final data from cohort 1 of the global phase II TROPHY-U-01 trial,4 in which treatment with SG was associated with an overall response rate of 27.7% in heavily pretreated patients with advanced bladder cancer who had experienced disease progression on platinum-based chemotherapy and an immune checkpoint inhibitor. This included a 5.4% complete response rate and a 22.3% partial response rate, with a median duration of response of 7.2 months.
According to Julia Batten, APRN, MSN, MPH, a nurse practitioner for the Genitourinary Oncology Program at Huntsman Cancer Institute at the University of Utah, “the ability to offer heavily pretreated patients an additional treatment option—which is relatively well tolerated and has a manageable toxicity profile—is a significant step toward extending lives in the face of a historically lethal cancer.”
Current Treatment Options
Until recently, the therapeutic landscape in metastatic bladder cancer after platinum-based chemotherapy and immune checkpoint inhibition has largely been dominated by enfortumab vedotin-ejfv (EV), erdafitinib, and certain chemotherapy regimens that were not given in previous lines of therapy.5 Both EV and erdafitinib have demonstrated objective response rates of approximately 40%, but most patients continue to experience disease progression on these therapies, and new agents are still needed.
The use of erdafitinib is limited to patients with an FGFR2/3 mutation or fusion. Still, EV, like SG, is also approved in patients with metastatic bladder cancer who have experienced disease progression on chemotherapy and immunotherapy.
However, according to Scott T. Tagawa, MD, MS, Professor of Medicine in the Division of Hematology & Medical Oncology at Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, NewYork Presbyterian Hospital, and principal investigator of the TROPHY study, SG is different. The unique mechanism of action and toxicity profile of SG allow for its use despite other treatment options in metastatic bladder cancer, without significant concerns about cross-resistance. Additionally, he added that common adverse events differ with each of these drugs, primarily neutropenia and diarrhea with SG, and rash and neuropathy with EV.
The unique mechanism of action and toxicity profile of SG allow for its use despite other treatment options in metastatic bladder cancer, without significant concerns about cross-resistance.
“For the average patient [with advanced bladder cancer], I would probably go with EV first, just due to the level of evidence,” said Dr. Tagawa. “But for a patient who’s fit enough for treatment but not fit enough for EV, I would skip EV and go to SG. Otherwise, I think the natural place for SG currently is after EV.”
The TROPHY-U-01 Trial
The open-label TROPHY-U-01 trial4 is evaluating SG in five cohorts: patients with metastatic urothelial cancer who experienced disease progression on platinum-based chemotherapy and checkpoint inhibition (cohort 1); those with metastatic urothelial cancer who were ineligible for platinum-based chemotherapy and experienced disease progression following checkpoint inhibition (cohort 2); those with metastatic urothelial cancer who never received checkpoint inhibitors but had disease progression on previous platinum-based therapy (cohort 3); those with metastatic urothelial cancer without prior systemic therapy in combination with cisplatin followed by SG and avelumab maintenance (cohort 4); and those with metastatic urothelial cancer without prior systemic therapy in combination with cisplatin and avelumab (cohort 5; ClinicalTrials.gov identifier NCT03547973).
Participants in the trial were given 10 mg/kg of SG on days 1 and 8 of a 21-day treatment cycle until loss of clinical benefit or intolerable toxicity. Among the 113 patients in cohort 1, the median progression-free survival was 5.4 months, and the median overall survival was 10.9 months.
Frequently reported adverse events (occurring in more than 25% of patients) included neutropenia, nausea, diarrhea, fatigue, hair loss, anemia, vomiting, constipation, decreased appetite, rash, and abdominal pain.
Nevertheless, according to Ms. Batten, SG has a “proven, predictable, and manageable safety profile,” as evidenced by the low rate of trial discontinuation due to treatment-related toxicities (6% of patients in cohort 1).
SG Dosing and Administration
“I tell my patients 2 weeks on, 1 week off,” noted Dr. Tagawa. The duration of treatment should be determined by the prescriber in collaboration with the patient and is based on factors such as tumor response and treatment tolerability.
The first infusion takes roughly 3 hours. If treatment is well tolerated, future infusions with SG should take about 1 to 2 hours.
Given the potential for infusion-related reactions, patients should be premedicated with an antipyretic such as acetaminophen, an H1 blocker such as diphenhydramine, and an H2 blocker such as cimetidine or famotidine. Corticosteroids (hydrocortisone at 50 mg or equivalent, oral or IV) may be administered prior to subsequent infusions for patients who have had an infusion reaction.
SG is considered to be moderately to highly emetogenic, so antiemetic prophylaxis to reduce or prevent nausea and vomiting is recommended (patients should either be given “take-home” medications with clear instructions for the prevention and treatment of nausea and vomiting, or a two- to three-drug regimen can be administered in the clinic). Ms. Batten advised clinicians to “consider treating anticipatory nausea with olanzapine in appropriate patients. If nausea and vomiting are persistent, a three-drug regimen may be used, such as a 5-HT3 inhibitor (ondansetron or palonosetron, or other agents according to local practices), an NK1-receptor antagonist (fosaprepitant or aprepitant), and dexamethasone (10 mg oral or IV).”
Patients should be monitored for symptoms of infusion reactions during and at least 30 minutes after each infusion. In the case of an infusion-related reaction, treatment may need to be paused or permanently stopped in the case of a life-threatening infusion-related reaction.
Adverse Effects of SG
The most common side effects of SG are nausea, diarrhea, fatigue, neutropenia, anemia, hair loss, vomiting, constipation, decreased appetite, rash, and abdominal pain or discomfort. SG can also cause serious side effects, including neutropenia, severe diarrhea, life-threatening infusion-related reactions, and allergic reactions.
Dr. Tagawa emphasized to JNCCN 360 that diarrhea and neutropenia are the most troublesome. Of note, the FDA label for SG includes a boxed warning for severe or life-threatening neutropenia and severe diarrhea. In the case of these serious side effects, patients may require medication support, dose reductions/interruptions, or treatment discontinuation.
“In terms of managing neutropenia, I generally use dose holds and reductions, although some [clinicians] jump into using growth factors. It’s not necessarily wrong versus right, but I would say it’s more within the guidelines to employ dose holds and dose reductions,” said Dr. Tagawa.
He added that the onset of diarrhea is typically within days after the infusion and is usually temporary. He counsels his patients to purchase antidiarrheal medicines before treatment (eg, loperamide) to have them on hand at home when needed.
“Not everyone is going to need antidiarrheal medication, but diarrhea is one of the more common adverse events seen with this drug across indications,” Dr. Tagawa told JNCCN 360. “It’s usually not something that happens to patients every day while they’re on the drug, but intermittently it can be significant, so recognizing it and intervening early can prevent it from becoming worse.”
Not everyone is going to need antidiarrheal medication, but diarrhea is one of the more common adverse events seen with this drug across indications.
Dr. Tagawa added that he discusses the potential risk of hair loss with his patients on SG. However, that he does not consider this quite as impactful a side effect as neutropenia or diarrhea in patients with advanced bladder cancer.
All patients should be closely monitored throughout their treatment and aggressively medically managed—including with dose holds, delays, and reductions—to prevent the need for treatment discontinuation and serious complications, Dr. Tagawa said. Of note, SG should not be re-escalated after dose reduction, as that was not allowed in the trials.
“Patients and their caregivers need to be informed that the goal of treatment with SG is to control their disease while ensuring safety and an acceptable quality of life,” said Ms. Batten. “This requires that they inform the care team as soon as they experience any new or worsening symptoms, so adverse events can be diagnosed and managed quickly to prevent them from becoming more severe or life-threatening.” However, she added, most adverse events with SG are predictable and manageable, resulting in a low treatment discontinuation rate.
Initiating and Monitoring Treatment
According to Ms. Batten, educating patients and caregivers about the mechanism of action of SG, potential side effects, drug administration, dosing frequency, and when to alert the clinical team about new symptoms or side effects are all critical to successful patient management.
Because neutropenia and diarrhea are included in the FDA boxed warnings, important points for patient education include the risk for reduced white blood cell counts, infection, and diarrhea with its separate risk for dehydration and electrolyte imbalances. Instruction on the appropriate use of antidiarrheal medications and antiemetics is also an important part of patient education, Ms. Batten added.
According to Dr. Tagawa, neutropenia and diarrhea can typically be managed by oncologists. The management of these adverse effects does not tend to require a multidisciplinary team (as opposed to EV and erdafitinib, which might require consults with ophthalmology or dermatology). In the event of grade 3/severe or grade 4/life-threatening diarrhea, consultation with a gastrointestinal specialist should be considered, along with inpatient management, Ms. Batten suggested.
Patients with advanced bladder cancer are usually familiar with intravenous therapy, so approaching that aspect of the conversation about starting therapy with SG is typically straightforward, according to Dr. Tagawa. “The part of the conversation that may be a little bit different would be the description of the toxicity profile: counseling patients on neutropenia, the danger of fever, and diarrhea,” he noted.
Dr. Tagawa conducts follow-ups with his patients on all treatment days (days 1 and 8 of every cycle) but routinely sees patients only on day 15 of cycle 1, and not day 15 of subsequent cycles. “Those with more severe toxicities than average may also be seen on day 15 of subsequent cycles, but that is not the most common scenario,” he noted. “I want to see and talk to patients and get labs to get an idea of their tolerance. I want to know how they are affected in terms of blood cell counts, but I also need to know about issues like diarrhea. We don’t want them having renal failure 2 weeks after severe but unreported diarrhea because they were dehydrated. These types of issues can happen, but they can be prevented if we pay attention.”
To optimize patient safety and appropriate management of adverse events, Ms. Batten urges providers to consider offering patients a “Treatment ID Card” for use in the event of any treatment-related toxicity. In that case, this card will inform outside providers, emergency department personnel, or members of other health-care facilities that the patient is receiving SG, with information on who should be contacted for additional management information.
According to the FDA, continued approval of SG in patients with locally advanced or metastatic bladder cancer will be contingent upon verification of clinical benefit in the confirmatory phase III TROPiCS-04 trial. The trial is currently enrolling patients with advanced urothelial carcinoma with prior treatment of platinum-based chemotherapy and immune checkpoint inhibitors. The study is comparing the overall survival of those receiving SG with those given the investigator’s choice of taxane or vinflunine chemotherapy (NCT04527991).
Scott T. Tagawa, MD, MS, has served as a consultant or advisor to Medivation, Astellas Pharma, Dendreon, Janssen, Genentech, Endocyte, Immunomedics, Karyopharm Therapeutics, AbbVie, Tolmar, QED, Amgen, Sanofi, Pfizer, Clovis Oncology, Novartis, Genomic Health, POINT Biopharma, Blue Earth Diagnostics, Seattle Genetics, AIkido Pharma, 4D Pharma, Clarity Pharmaceuticals, Gilead Sciences, Telix Pharmaceuticals, and Bayer; has received research funding from Lilly, Sanofi, Janssen, Astellas Pharma, Progenics, Millennium, Amgen, Bristol Myers Squibb, Dendreon, Rexahn Pharmaceuticals, Bayer, Genentech, NewLink Genetics, Inovio Pharmaceuticals, AstraZeneca, Immunomedics, Novartis, AVEO Oncology, Boehringer Ingelheim, Merck, Stem CentRx, Karyopharm Therapeutics, AbbVie, Medivation, Endocyte, Exelixis, Clovis Oncology, and POINT Biopharma; has received patent royalty from Immunomedics/Gilead; and has received reimbursement for travel, accommodations, and expenses from Sanofi, Immunomedics, and Amgen.
Julia Batten, APRN, MSN, MPH, has reported relationships with Astellas, AVEO Oncology, Bayer, EMD Serono, Exelixis, Pfizer, and Seattle Genetics.
- U.S. Food and Drug Administration. FDA grants accelerated approval to sacituzumab govitecan for advanced urothelial cancer. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sacituzumab-govitecan-advanced-urothelial-cancer. Accessed June 27, 2021.
- Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med 2021;384:1529–1541.
- Goldenberg DM, Stein R, Sharkey RM. The emergence of trophoblast cell-surface antigen 2 (TROP-2) as a novel cancer target. Oncotarget 2018; 9:28989–29006.
- 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;30;JCO2003489.
- Flaig TW, Spiess PE, Agarwal N, et al. NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer. Version 3.2021—April 22, 2021. Accessed June 27, 2021. To view the most recent version of these guidelines, visit org.