During a Targeted Oncology case-based roundtable event, Arlene Siefker-Radtke discussed the second-line treatment options for a patient with urothelial carcinoma and the EV-301 trial of enfortumab vedotin.
Targeted OncologyTM: What do the National Comprehensive Cancer Network (NCCN) guidelines indicate for a patient like this?
SIEFKER-RADTKE: According to the NCCN guidelines, multiple second-line treatments could be considered [for cases such as this]. The preferred regimen is pembrolizumab [Keytruda], but several other alternative preferred regimens are also listed, including erdafitinib [Balversa] and enfortumab vedotin [Padcev], and other checkpoint inhibitors, including nivolumab [Opdivo] and avelumab [Bavencio]. Other [treatment approaches include the use of] single-agent taxanes or possibly going back to chemotherapy if needed in certain situations.1
Three [immune therapy] agents are currently FDA approved [for the treatment of bladder cancer] in the second-line setting. As you may recall, there were 2 additional approvals [for this indication]: atezolizumab [Tecentriq] and durvalumab [Imfinzi]. However, these agents did not have phase 3, that is, level 1 evidence confirming [their clinical benefit in this setting], so they were voluntarily withdrawn for this indication.
Thus, we currently have 3 agents as options for the second-line treatment [of bladder cancer]. We have nivolumab, for which FDA approval was based on data from a phase 2 single-arm trial that enrolled 270 patients, showing an objective response rate [ORR] of around 20.7% and a median OS [of 8.6 months]. Adverse events [AEs] of grade 3 to 4 occurred in around 24% of patients.2-4
The other immune checkpoint inhibitors [approved for this indication] led to similar outcomes. [In 249 patients treated with] avelumab, the ORR was 17%, and the median duration of response [DOR] was similar in nivolumab [20.3 months] and avelumab [20.5 months], but a little longer with pembrolizumab [29.7 months].5
[Compared with] chemotherapy with a single-agent taxane, or vinflunine [Javlor] in Europe, [pembrolizumab led to] improvements in the ORR and overall survival [OS] and had a better toxicity profile. [These findings are considered] level 1 evidence in this setting.
So some people have asked [whether there are] differences in outcomes between these treatment groups, but these treatments appear to be similar. Variability in the patient populations and study eligibility criteria might account for observed differences between these 3 agents, all of which appear to be effective [second-line treatments for bladder cancer], but currently, the level 1 evidence favors pembrolizumab.
How does enfortumab vedotin factor into previously treated metastatic bladder cancer?
The NCCN guidelines for postchemotherapy and post–immuno-oncology [IO] treatment list enfortumab vedotin as one of the preferred regimens, and this recommendation is due to level 1 evidence from a clinical trial. We also see that erdafitinib [is a recommended regimen in this setting] based on data from a phase 2 trial design. A variety of other regimens [are also recommended], including chemotherapy combination regimens that we have used historically, as well as, intriguingly, this new one, sacituzumab govitecan [Trodelvy].6
Enfortumab vedotin received FDA approval for treatment of patients with metastatic urothelial cancer who have had prior chemotherapy and immune checkpoint inhibition therapy. The use of enfortumab vedotin [for this indication is categorized as level 1 evidence in the NCCN]. Enfortumab vedotin is a targeted chemotherapy agent that uses an antibody that targets Nectin4, a molecule commonly expressed on urothelial cancer tumors. Anywhere from 80% to 90% of patients with bladder cancer have NECTIN4 expression on their tumors, and therefore, you do not need to test for NECTIN4 expression to give this treatment.
The payload carried by the antibody is the taxane monomethyl auristatin E, which was much too toxic to the liver as a non-targeted therapy. However, it is very effective when targeted directly to the tumor with an antibody. Once the antibody binds to the tumor cell, a protease cleavable linker releases the monomethyl auristatin E inside the tumor, resulting in cell death.
What data support this treatment?
[The phase 2 component of the] EV-201 clinical trial [NCT03474107] looked at 2 patient cohorts. Cohort 1 consisted of patients who had received prior platinum-base chemotherapy and a PD-L1 inhibitor; cohort 2 consisted of patients who had received prior treatment with a PD-L1 inhibitor but who were platinum naive. Enfortumab vedotin was given [in 28-day cycles] as a weekly dose on days 1, 8, and 15.
[Accelerated approval for enfortumab vedotin] for treatment of bladder cancer in the post-platinum, post-immune checkpoint inhibitor setting was based on data from this phase 2 trial. The ORRs to enfortumab vedotin and some of these other targeted agents [were higher than any] we had previously seen in the post-frontline cisplatin setting. [In the EV-201 trial] the ORR was 44%, the median DOR was 7.6 months, and median OS was 12.4 months. The finding of a median OS of 12.4 months was remarkable in a third-line, post-chemotherapy, post-IO setting. As we all recall, historically we only achieved survival of about 1 year with front-line cisplatin-based chemotherapy. So it is truly an achievement to have the second-, third-, and additional-line treatments for urothelial cancers show such high response rates and good median OS.
In cohort 2 of the trial, which was a cisplatin-unfit cohort comprising patients who were not eligible for platinum-based therapy, the ORR was around 51%, the median duration of response was 13.8 months, and the median OS was 16 months. Some people say, “Does that mean that we should not give cisplatin?” However, these findings could just reflect of the use of additional agents or the potential for long, durable survival in this population of patients who were not eligible for standard of care-based therapy.
The phase 3 EV-301 trial evaluated the primary end point of OS following treatment with enfortumab vedotin in a post-platinum, post-checkpoint inhibitor cohort. The results [of EV-301], which were published in the New England Journal of Medicine, showed improvements in median overall survival and progression-free survival compared with single-agent taxane therapy.
What is the toxicity profile of enfortumab vedotin?
Furthermore, data from the EV-301 trial showed that enfortumab vedotin had a toxicity profile that was similar to, if not better than, a taxane, as this therapy could be used as a long-term treatment.7 We now have FDA approval for enfortumab vedotin for the treatment of locally advanced or metastatic bladder cancer.
The phase 3 trial [EV-301] trial enrolled patients with urothelial cancer, including those with squamous differentiation or mixed cell types, who had evidence of radiographic progression after prior treatment with platinum-containing chemotherapy and a prior immunotherapy. Enrolled patients were randomly allocated to receive enfortumab or a single-agent taxane, as the trial evaluated several end points, the primary one being OS.
[In the trial, patients who received enfortumab had a median OS of 12.8 months]. This survival benefit is something that we had never achieved before in a third-line setting for bladder cancer and was much better than that observed in patients who received a single-agent taxane. Median survival in patients who got single-agent taxane was about 9 months, which was surprisingly long in this third-line setting.8 However, the trial cohort may have been enriched for patients who had benefited from prior immune checkpoint inhibition therapy.
However, toxicity is a challenge with any type of chemotherapy or targeted agent, including enfortumab. An appreciable proportion of patients who received enfortumab had AEs, including peripheral neuropathy [35%], pruritus [32%], fatigue [31%], and poor appetite [31%].8 Many patients will have a poor appetite or just lose weight, which may, in part be due to a direct drug-related toxicity on the liver or the GI tract. This toxicity may induce the development of sores along the GI tract or disruption of the mucosal layer, contributing to diarrhea. When these AEs occur, withholding the drug usually results in improvement, even for peripheral neuropathy, although sometimes you have to reduce the dose or even take a break from treatment.
There are also some treatment-related AEs of special interest [for enfortumab], especially skin reactions. Nectin4 expression is found in the skin, and, thus, there is potential for skin toxicity. In animal models, the dose-limiting toxicities were diarrhea and skin reactions, such as peeling of the skin or bullous lesions of the skin. If you see a patient with peeling of the skin or bullous lesions of the skin, [which] almost look like bullous pemphigoid, that could be a sign that you are reaching a dose-limiting toxicity. So it is time to hold the therapy until the skin reaction heals and then resume treatment, if feasible. [However,] patients with skin reactions often require a dose reduction. This could be done either by dosing 2 weeks out of 3, so skipping that third weekly dose, or by reducing the dose of the therapy while maintaining the original treatment schedule of dosing 3 weeks out of 4.
There is also evidence of organ dysfunction, especially abnormal hepatic function [associated with enfortumab]. Monomethyl auristatin E is metabolized to a much higher extent in the liver than in the kidneys. [Enfortumab] monoclonal antibodies are taken up by the reticuloendothelial system and broken down in the liver, which can lead to toxic liver effects. In fact, the FDA package insert for enfortumab cautions against using this enfortumab in patients with moderate to severe liver function. So [enfortumab might not be the best therapy] for patients with a Child Pugh score of B or C.
We had a death in one of our earliest patients treated with enfortumab vedotin. This patient had a cirrhotic nodular liver and their glucose level went up [to 253 mg/dL] just before the second dose. That is why [monitoring glucose levels is] recommended for patients receiving enfortumab.
Are there any scenarios where treatment needs to be adjusted?
[Enfortumab therapy] should be withheld in a patient whose glucose is above 250 mg/dL because this could be a dose-limiting toxicity. The patient who passed away had a glucose level just barely above [250 mg/dL], but this individual was not diabetic. Notably this patient also experienced diarrhea and developed bullous [skin lesions] and peeling skin, a presentation that made some of us wonder if this could be Stevens-Johnson syndrome. I think that high doses and off-target drug activity introduced the drug into the skin, resulting in disruption of the skin. So be cautious in patients with cirrhotic livers; [even in patients with] mild to moderate liver dysfunction you should consider starting treatment at a reduced dose.
One of the benefits of [enfortumab] is that it is not associated with myelosuppression, and, therefore, you do not need to use as much growth factor support in [patients who receive] this therapy. I have yet to use growth factor [in this setting], so enfortumab is easier on the bone marrow and works particularly well in patients with bone metastases.
I have been very impressed by the sclerotic changes in the bone [that occur in some patients who receive enfortumab]. If a patient has sclerotic changes and bone pain is improved, that is a sign of treatment response. Sometimes, [as part of this treatment response,] the bone scan will show increased interval activity due to an osteoblastic reaction, resulting in the sclerotic lesions.
Are there other therapies to consider for a patient like this?
Sacituzumab govitecan is another novel antibody-drug conjugate therapy that works by delivering a toxic payload of irinotecan directly into the tumor, thereby minimizing [drug-related] toxicity. [Sacituzumab govitecan’s] high drug-to-antibody ratio enables a high concentration of payload to be directed into the cancer cell, where it is released through hydrolysis. Sacituzumab govitecan’s antibody is directed toward Trop-2 expression, which is present in about 80% of urothelial carcinoma tumors. Given this high prevalence of expression, testing for Trop-2 expression is not required before using sacituzumab govitecan.
Sacituzumab govitecan has significant activity across multiple tumor types and is already approved for the treatment of patients with breast cancer. [Furthermore, this agent] has a very good toxicity profile and in a phase 2 trial, patients with metastatic epithelial cancer treated with sacituzumab govitecan had an ORR of around 30%, a median progression-free survival of 7.3 months, and a median OS of 16.3 months. [Based on these data, sacituzumab govitecan] received accelerated approval for triple-negative breast cancer and fast track designation for urothelial cancer, and a phase 3 trial of sacituzumab govitecan treatment for urothelial cancer is ongoing.
What data support the use of sacituzumab govitecan?
The [phase 2, two-arm] TROPHY-U-01 trial [NCT03547973] included a cohort composed of 100 patients with metastatic urothelial cancer who had progressed following platinum-based therapy and checkpoint inhibitor therapy.9 [At the time this trial was undertaken] accelerated approval for enfortumab had been granted, so standard-of-care therapies might have included enfortumab as well as erdafitinib.
Sacituzumab govitecan was given to patients at a dose of 10 mg/kg on days 1 and 8 of each 21-day cycle.9,10 Dosing sacituzumab govitecan on a 3-week schedule, in this way, improved its tolerability, enabling continued treatment for many months to achieve durable activity and responses [as have been seen for enfortumab vedotin]. So if the patients were benefiting and not having significant toxicity, they continued this therapy.
The primary end point of TROPHY-U-01 was the objective response rate as assessed by central review; secondary end points were duration of response, PFS, and OS.9,10
[Trial patients tended to be older]; 23% were over the age of 75 and heavily pretreated, and the median number of prior anticancer regimens was 3. [Commonly used] prior therapies included carboplatin and cisplatin and, in total, 72% of patients had an [ECOG] performance status of 1.
[However,] I have heard oncologists argue that when you are enrolling patients with a performance status of 1, you are probably getting those with a performance status of 2 because we are so eager to find novel therapies for these patients. [In total, 62% of the trial patients had] visceral metastases, including 28% with liver metastases and those typically have a poor prognosis even with immune checkpoint inhibitor treatment in the second-line setting. The Bellmunt risk score indicates that many trial patients had multiple risk factors, which indicates a poor prognostic.
The ORR for patients was 31%, [which I think is a very good response rate in this heavily pretreated patient cohort].
Some have said, “Well, this is lower than [the response rate for] enfortumab vedotin.” It is numerically lower, but it is not a head-to-head comparison. The lower response rate may reflect the heavily pretreated nature of the TROPHY-U-01 cohort, which may have included many patients with prior erdafitinib or enfortumab treatment. The trial’s complete response rate was around 5%, the partial response rate was around 22%, and the median DOR was 7.2 months. Median OS in the trial was 10.9 months, which is truly remarkable [in this heavily pretreated cohort]. Keep in mind that in trials of frontline carboplatin therapy for metastatic disease, carboplatin did not always achieve a median survival of 10.9 months.
What is the toxicity profile for sacituzumab govitecan?
Sacituzumab govitecan has toxicity, and good management of that toxicity can help keep patients on treatment longer. [Sacituzumab govitecan] has a different toxicity profile from that of enfortumab vedotin but is not associated with neuropathy, so it could be a good option for patients who have preexisting neuropathy and cannot tolerate taxane-based therapy. [However, sacituzumab govitecan] can lead to neutropenia, which was seen in 46% of patients, including 34% of grade 3 or 4.
Trial patients experienced other AEs of grade 3 or 4, including anemia [14%], leukopenia [17%], lymphopenia [7%], and neutropenic fevers [10%].10 Diarrhea was also a common AE in trial patients; however, the diarrhea was a little different from that associated with enfortumab vedotin. [In patients treated with enfortumab vedotin], diarrhea typically occurs toward the end of the cycle and is a sign of mucosal toxicity, whereas with sacituzumab, it can occur on the day of or the day following the infusion. I think this is because irinotecan can induce diarrhea as well as decreased appetite and hair loss.
1. NCCN. Clinical Practice Guidelines in Oncology. Bladder Cancer, version 1.2022. Accessed February, 17, 2022. https://bit.ly/3Hyb3tf
2. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18(3):312-322. doi:10.1016/S1470-2045(17)30065-7
3. Galsky MD, Saci A, Szabo PM, et al. Nivolumab in patients with advanced platinum-resistant urothelial carcinoma: efficacy, safety, and biomarker analyses with extended follow-up from CheckMate 275. Clin Cancer Res. 2020;26(19):5120-5128. doi:10.1158/1078-0432.CCR-19-416
4. Patel MR, Ellerton J, Infante JR, et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol. 2018;19(1):51-64. doi:10.1016/S1470-2045(17)30900-2
5. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015-1026. doi:10.1056/NEJMoa1613683
6. Bellmunt J, Necchi A, de Wit R, et al. Pembrolizumab (pembro) versus investigator’s choice of paclitaxel, docetaxel, or vinflunine in recurrent, advanced urothelial cancer (UC): 5-year follow-up from the phase 3 KEYNOTE-045 trial. J Clin Onc. 2021;39(suppl 15): 4532-4532. doi:10.1200/JCO.2021.39.15_suppl.4532
7. Petrylak DP, AV Balar, O’Donnell PH, et al. EV-201: Results of enfortumab vedotin monotherapy for locally advanced or metastatic urothelial cancer previously treated with platinum and immune checkpoint inhibitors. J Clin Onc. 2019;37(suppl 4):4505-4505. doi:10.1200/JCO.2019.37.18_suppl.LBA4505
8. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 2021;384(12):1125-1135. doi:10.1056/NEJMoa2035807
9. Loriot Y, Basar VA, Petrylak DP, et al. LBA24 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). Annals of Oncology. 2020;31(suppl 4): S1142-S1215. doi:10.1016/annonc/annonc32
10. 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 Aafter platinum-based chemotherapy and checkpoint inhibitors. J Clin Onc. 2021;39(22): 2474-2485. doi:10.1200/JCO.20.03489