Fitting ADC Therapy Into the Treatment Paradigm in Advanced Bladder Cancer

Arlene O. Siefker-Radtke, MD

Professor

Department of Genitourinary Medical Oncology

Division of Cancer Medicine

The University of Texas MD Anderson Cancer Center

Houston, TX

At a live virtual event, Arlene O. Siefker-Radtke, MD, looked at the newer treatment strategies available for patients with advanced bladder cancer. In particular, Siefker-Radtke addresses how the antibody-drug conjugate (ADC) sacituzumab govitecan-hziy (Trodelvy) is a potent new therapy for patients with metastatic urothelial cancer. Importantly, she discusses how this therapy fits with other options for this patient population and what physicians should consider before turning to sacituzumab.

The Mechanism of Action

Sacituzumab is another [therapy that]...targets Trop-2 expression, which is found in a high percentage of patients with urothelial cancer, and as a result of this, we do not need to test for Trop-2 expression.¹ [Sacituzumab] brings the active metabolite of irinotecan, or SN-38, more directly to the tumor, but the linker is a little different. The linker is a hydrolysable linker, which does mean there could be some release of the irinotecan in the systemic circulation. That may account for why we see a few more [toxicities with this therapy], including more myelosuppression with this ADC. When they looked at activity [with this therapy] across tumor types that express TROP-2, the objective response rates [ORRs] appeared quite promising with a 31% ORR and a median overall survival [OS] of 16.3 months that also looked promising, especially when they started looking at cohorts of patients with urothelial cancer.¹ Sacituzumab received accelerated approval for patients with triple-negative breast cancer and was also granted accelerated approval on the basis of a phase 2 trial for patients with metastatic urothelial carcinoma.^2,3

Assessing the Trial Data

The phase 2 TROPHY-U-01 trial [NCT03547973] design took patients with metastatic urothelial cancer who progressed after prior platinum-based treatment or checkpoint inhibition [and gave them 10 mg/kg of sacituzumab on days 1 and 8 every 21 days].⁴ The primary end point was an [ORR] assessed by central review with multiple secondary objectives, including [OS] and duration of response [DOR]. In this trial, the patient characteristics were similar to what we’re observing in previously treated patients where we see a lot of visceral metastases, and in this trial 66% of patients had visceral metastases present. The majority [of patients] had an ECOG performance status of 1, which was probably due to their previous treatment, comorbid conditions, and the fact that these are elderly, frail individuals with a progressive disease.⁴

When we looked at the TROPHY-U-01 cohort 1 results, we saw promising response data with an ORR of 27.4% [95% CI, 19.5%-36.6%].⁴ Though this is a little bit lower compared to what was observed with enfortumab vedotin-ejfv [Padcev], keep in mind that there did seem to be a few more patients in this trial who received more lines of treatment, and some of them even had treatment with enfortumab vedotin. I think it’s hard to compare ORRs across clinical trials; we need randomized data to tell us what the ORR will be.

The median DOR [in this trial] was around 7.2 months [95% CI, 4.7-8.6], and a median OS that was getting close to a year [at 10.9 months (95% CI, 9.0-13.8)].⁴ There was a progression-free survival of 5.4 months [95% CI, 3.5-7.2], which I would argue is certainly promising in this population of [patients who had] previous chemotherapy and immune checkpoint inhibitor therapy. However, [sacituzumab] does have adverse events [AEs], and one of the notable AEs is the risk for neutropenia and neutropenic fever. The trial did not require [the use of] growth factor support, but about 30% of patients treated did receive growth factor support with this therapy. We also saw gastrointestinal AEs [of any grade] including diarrhea [65%], nausea [60%], and vomiting [30%], in addition to fatigue [52%] and alopecia [47%].⁴

Maximizing Treatment

My own strategy is to maximize the dose to get a maximal response whenever possible. [The risk of] neutropenia and neutropenic fevers [with sacituzumab] are real, and I tend to use it in patients who’ve had prior chemotherapy, immunotherapy, and enfortumab vedotin. I have started giving [these patients] growth factor support with the first cycle [of treatment]. I don’t wait for the neutropenic fever to develop, because these are often elderly, frail individuals with additional comorbid conditions and high rates of urinary tract infections. I personally favor giving growth factor support with [sacituzumab], and if I didn’t give growth factor support, and the patient had a neutropenic fever, I would likely consider giving the full dose the next cycle and then giving the growth factor support with it. I usually don’t [reduce the dosage] unless they develop neutropenia or neutropenic fever with the growth factor use. Now, if they were in the ICU [intensive care unit] for a long period of time with profound myelosuppression, on a case-by-case basis I might consider a dose reduction. But for most patients, I’m [going to give them] the full dose unless they develop neutropenia or neutropenic fever while receiving growth factor support.

Dosing and Toxicity Considerations with ADCs

[If the patient has] an FGF [fibroblast growth factor] mutation present, I typically do give erdafitinib [Balversa], sometimes even before enfortumab vedotin, but it depends on the patient. If the patient is diabetic, or I’m worried about [their risk of] neuropathy, or they have pre-existing neuropathy, then erdafitinib will delay the development of that neuropathy that I know [the patient is] likely to experience with enfortumab vedotin. If they have central serous retinopathy, then they’re not going to be a good candidate for erdafitinib, and I would choose one of the other options.

I do base [my treatment choices] on toxicity a bit, and we don’t have any data on sequencing erdafitinib with enfortumab vedotin or sacituzumab. I would argue all the above options are correct, whether you choose to give it before or after any [treatment], either the enfortumab vedotin [or] sacituzumab, and so forth. Looking at how to do the dose modifications for sacituzumab, we see [that for patients with] grade 4 neutropenia for more than 4 days, or those with grade 3 febrile neutropenia, that various guidelines…suggest reducing the dose of sacituzumab by 25% for the first dose reduction, and then administering growth factor support.⁵

If they haven’t had growth factor support and the neutropenia was mild, I’ll give the full dose with growth factor support in the second cycle. If neutropenia happens in the second cycle, I go down to a 50% dose reduction, but if it’s happening in the third cycle, despite growth factor support and despite the dose reductions, then sacituzumab may not be the right treatment for them. There’re also some guidelines regarding the nonhematologic toxicities [with sacituzumab], including severe diarrhea, and it’s a similar dose reduction schema.⁵ But I’ve also done strategies such as instead of getting day 1 and day 8 dosing, I’ll do day 1 every 2 weeks. [I also recommend to] watch for cirrhotic livers [in patients and see if they have a] Child-Pugh [class B score]. In those patients, I do not use enfortumab vedotin because it’s been challenging to give it even [if the patient has a] Child-Pugh [class A score] when starting with a dose reduction.

Another good reason to reach for sacituzumab first is if the patient has grade 2 neuropathy that is already impacting their proprioception by causing them significant symptoms, they’re not going to do well [with enfortumab vedotin]. Oftentimes, it will start quickly with it, and it’s also challenging if their diabetes is uncontrolled. But you’re trying to watch the glucose as a means of holding the dose, but you don’t know if it’s just from [what they ate] and then they didn’t take their insulin or other prescribed medications, or are they about to have that diabetic ketoacidosis that has been reported with enfortumab vedotin.⁶ We also see that enfortumab vedotin can sometimes cause myelosuppression, but at a much lower rate compared to sacituzumab, and there are some patients who have compromised bone marrows where it really is challenging to give an agent that causes myelosuppression. I think it’s wonderful that we now have several options that are still helping extend patients’ lives.

REFERENCES:

1. Loriot Y, Balar AV, Petrylak DP, et al. TROPHY-U-01 cohort 1 final results: a phase II study of sacituzumab govitecan (SG) in metastatic urothelial cancer (mUC) that has progressed after platinum (PLT) and checkpoint inhibitors (CPI). Ann Oncol. 2020;31(suppl 4):S1156. doi:10.1016/j.annonc.2020.08.2253

2. FDA grants regular approval to sacituzumab govitecan for triple-negative breast cancer. FDA. April 8, 2021. Accessed February 8, 2024. http://tinyurl.com/3awr3pz2

3. FDA grants accelerated approval to sacituzumab govitecan for advanced urothelial cancer. FDA. April 13, 2021. Accessed February 8, 2024. http://tinyurl.com/bdft7z8b

4. 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

5. Trodelvy. Prescribing information. Gilead; 2023. Accessed February 8, 2024. http://tinyurl.com/mu7wej3s

6. Atemnkeng F, Aguilar F, Gupta S, Chugh S, Klein M. Diabetic ketoacidosis and acute kidney injury associated with enfortumab vedotin for urothelial carcinoma: a case report. Kidney Med. 2023;5(12):100737. doi:10.1016/j.xkme.2023.100737