Posted: Tuesday, February 9, 2021
Treatment options for locally advanced or metastatic urothelial carcinoma have primarily been limited to two categories of systemic agents, namely cytotoxic agents such as platinum drugs1-3 and anti–PD-1 or anti–PD-L1 checkpoint inhibitors such as pembrolizumab4 or atezolizumab.5 (A targeted therapy, erdafitinib, is also an option for urothelial carcinoma with susceptible genetic alterations.) However, in December 2019, another systemic treatment, an antibody-drug conjugate—enfortumab vedotin-ejfv (Padcev)—was granted accelerated approval by the U.S. Food and Drug Administration in patients previously treated with both platinum agents and checkpoint inhibitors.6
Clarifying the indication for enfortumab vedotin, Jonathan E. Rosenberg, MD, Chief of the Genitourinary Oncology Service at Memorial Sloan Kettering Cancer Center in New York City, explained that “approval of enfortumab vedotin was issued based on the population of patients in the EV-201 trial7 who had received a platinum-containing chemotherapy regimen and an immune checkpoint inhibitor.” However, in an interview with JNCCN 360, he added that although the approved setting is actually third line, some patients are not eligible for first-line cisplatin treatment and may receive immunotherapy in the first line. Those patients were treated in Cohort 2 of EV-201, and the data will be reported in 2021.7 “In clinical practice, enfortumab vedotin might also be used in those patients in the second line after the immune checkpoint inhibitor, but such use is thus far off-label treatment,” Dr. Rosenberg observed.
A Targeted Antibody-Drug Conjugate
Enfortumab vedotin comprises a fully human monoclonal antibody connected by a protease-cleavable linker with the microtubule-disrupting agent monomethyl auristatin E (MMAE). Enfortumab vedotin targets Nectin-4, a transmembrane protein involved in oncogenic cellular processes. It is highly expressed in urothelial carcinomas, with moderate expression in normal human skin.8
ROLE OF NECTIN-4
We haven’t seen any differences in response or outcomes based on differing Nectin-4 expression at this time, so the relative levels don’t seem to matter. That’s where we are now, although that may change as data and information evolve.
Although the target of enfortumab vedotin is Nectin-4, treatment eligibility does not require high expression or even measurement of tumoral Nectin-4. “In the initial trial [ie, the phase I study9],” Dr. Rosenberg said, a tumor biopsy was submitted for every patient. When Nectin-4 levels were measured, more than 95% of patients had high expression on their tumors. “The researchers also found that patients with very low levels of Nectin-4 exhibited responses to enfortumab vedotin in the phase I trial, so Nectin-4 expression was not predictive.” The investigators dropped the requirement for high Nectin-4 expression, and Nectin-4 levels were not measured in subsequent trial phases.
Dr. Rosenberg said: “We haven’t seen any differences in response or outcomes based on differing Nectin-4 expression at this time, so the relative levels don’t seem to matter. That’s where we are now, although that may change as data and information evolve.”
Response Rate Versus Durability of Response
In the phase II EV-201 study, the average survival rate for patients treated with enfortumab vedotin was about 1 year.7 In the absence of enfortumab vedotin, survival in this setting “is more like 6 to 9 months,” noted Dr. Rosenberg. “The median time with treatment was 6 or 7 months, but there are rare patients for whom enfortumab vedotin can be effective for several years. Those patients are outliers, but for them, this treatment has changed the natural course of their disease,” he continued. “We have to remember that even though the response rate with enfortumab vedotin is around 40%—higher than with any other options—not every response is durable.” In contrast, he pointed out, when an immune checkpoint inhibitor is given to a patient whose disease is platinum-refractory, the response rate may be in the 20% range, but this can be quite durable.
Considerations Before Starting Treatment
Patients with locally advanced or metastatic urothelial carcinoma may present with disease-related symptoms, such as acute kidney injury or abdominal pain,” explained Mali Amirault, NP, Nurse Practitioner at the University of Colorado, specializing in genitourinary oncology. [Editor’s Note: Ms. Amirault has recently accepted a new position at Massachusetts General Hospital in Boston.]
Even though enfortumab vedotin is not used in the front-line setting, “our patients have had a generally good performance status. The advantage of an antibody-drug conjugate is that it is tolerated better than standard chemotherapy. Therefore, even a patient with a performance status of 2 could be eligible,” Ms. Amirault told JNCCN 360. “The cytotoxic component of the antibody-drug conjugate does not affect the body in the same way as standard infusional chemotherapy. As long as patients don’t have significant peripheral neuropathy (greater than grade 2) at baseline, they may be eligible, and enfortumab vedotin should be well tolerated.”
Performance status can be quite variable in the third-line setting. Many patients are not eligible for treatment at all, Dr. Rosenberg acknowledged. In addition, some patients are symptomatic and may have difficulty with any treatment. On the other hand, “patients who previously received immune checkpoint inhibitors are often in pretty good shape because those agents are generally well tolerated,” he said.
General Eligibility for Treatment
- Neuropathy: The cytotoxic component of enfortumab vedotin—MMAE—is neurotoxic. Patients with neuropathy at baseline—associated with previous cisplatin therapy or diabetes—may experience worsening sensory and motor neuropathy. “That is something we assess and ask about at every visit,” said Dr. Rosenberg. Patients with severe neuropathy at baseline may not be good candidates for enfortumab vedotin. “That said, when we hold or reduce the dose of enfortumab vedotin, the neuropathy often improves. Also, the neuropathy from enfortumab vedotin often is described as numbness rather than burning, pain, or tingling. Paresthesias frequently improve with time or supportive medications, but in my experience, the numbness seems to remain for a longer period.”
Ms. Amirault described a similar approach. “Before starting enfortumab vedotin, we want to make sure that any peripheral neuropathy—perhaps as a result of prior platinum therapy—is on the mild side. During my assessment, I might ask ‘Do you have trouble holding a pen? Do you have trouble writing? Did you button your shirt today? Did you tie your shoes? Can you hold a utensil and bring it to your mouth, or do you sometimes drop it?’ I have found that such specific questions will elicit more useful information than asking, ‘Do you have numbness or tingling in your fingers and/or toes?’”
- Ocular Issues: Before patients start treatment with enfortumab vedotin, Ms. Amirault suggests referral to an ophthalmology consult because the antibody-conjugate target is Nectin-4, and it is expressed in the skin, eye, and bladder cancer cells. Ocular side effects include dry eye and/or blurry vision.
- Skin and Fatigue: Dermatologic side effects, such as discoloration, maculopapular rash, and pruritus, are also common with enfortumab vedotin. If any of these side effects are observed at baseline, they will likely worsen with enfortumab vedotin. Of note, patients who received an immune checkpoint inhibitor before enfortumab vedotin may have developed a skin rash or fatigue with previous treatment. However, by the time enfortumab vedotin is initiated, “those side effects have probably resolved or have been deemed mild enough to move forward,” Ms. Amirault pointed out. If a patient has hepatitis or some other significant adverse effect associated with a PD-1 or PD-L1 inhibitor, “it will need to be addressed before considering enfortumab vedotin.”
- Hepatic or Renal Dysfunction: Because enfortumab vedotin clears through the liver, patients with moderate to severe liver dysfunction are not good candidates for this treatment.10 In contrast, patients with renal dysfunction are eligible to receive enfortumab vedotin.
- Hyperglycemia: Both Dr. Rosenberg and Ms. Amirault emphasized that enfortumab vedotin should not be initiated in patients with uncontrolled diabetes, defined as a blood sugar higher than 250 mg/dL.
“Hyperglycemia is a significant, although idiosyncratic, issue,” said Dr. Rosenberg. “A number of cases of severe hyperglycemia have been reported in patients treated with enfortumab vedotin. They were more common in patients with a higher body mass index and elevated glucose at baseline, but not always,” he noted. Checking hemoglobin A1c at baseline is recommended. For patients with values of 7% or higher, referral to an endocrinologist is recommended “to get the A1c under better control.”
- Anemia: “Pay attention to the baseline hemoglobin before starting enfortumab vedotin,” Dr. Rosenberg advised. “Anemia is likely during treatment, so you may need to consider transfusion before initiating treatment.” The [EV-2017] trial didn’t enroll patients with hemoglobin lower than 9 g/dL, so caution is recommended in that situation.”
Neuropathy seems to be cumulative, and the risk for those symptoms increases the longer the patient remains on treatment.
Thorough patient education is critical before starting treatment. “Our pharmacist and I educate patients and their families about when side effects are likely to occur,” explained Ms. Amirault. For instance, “it is fairly rare to hear about skin issues or serious fatigue during the first cycle (ie, in the first month of treatment). However, some of these side effects may begin to emerge during the second cycle. Neuropathy seems to be cumulative, and the risk for those symptoms increases the longer the patient remains on treatment.”
Administration of Enfortumab Vedotin: Best Practices
Placement of a port is not mandatory but may be wise, particularly if the patient has poor peripheral IV access.
Because of the potential for extravasation at the administration site, the placement of a port is appropriate in patients receiving enfortumab vedotin. “It isn’t always necessary,” Dr. Rosenberg observed, “but the key is the expertise of the infusion nursing team.” Enfortumab vedotin is not a vesicant, he explained, “but it is a significant irritant; substantial, local reactions have been observed, although not at the level of seriousness seen with doxorubicin, for example.” Placement of a port is not mandatory, Dr. Rosenberg said, but may be wise, particularly if the patient has poor peripheral IV access.
Those who administer enfortumab vedotin are cautioned to check the catheter’s position to ensure blood return in the vein, Ms. Amirault advised. Moreover, because extravasation may occur with enfortumab vedotin, the catheter should be placed in the forearm rather than the hand. Because the dosing schedule for enfortumab vedotin is weekly for 3 weeks with 1 week off, “almost all of our patients receive a port, and none have regretted getting it,” she reported.
At the University of Colorado, patients undergo laboratory tests, including a comprehensive metabolic panel and complete blood cell count, before each infusion. “Neither premedication nor IV hydration is standard,” Ms. Amirault noted, “so the infusion—which takes about 30 minutes—is relatively quick.”
In most cases, patients also review side effects with the nurse practitioner before moving on to the infusion center. “Specifically, red flags comprise worsening peripheral neuropathy; blood sugar higher than 250 mg/dL; fever; severe fatigue (which tends to get cumulatively worse); or itchy skin that causes the patient distress,” she said.
Placement of a port is not mandatory but may be wise, particularly if the patient has poor peripheral IV access.
Adverse Events and Management
- Neuropathy: To manage neuropathy, “we might start by recommending a capsaicin ointment or cream. Unfortunately, those types of topical treatments don’t seem to be particularly effective,” Ms. Amirault acknowledged. In terms of systemic treatment for neuropathy, gabapentin is the first drug of choice. “If gabapentin is not effective or sufficient, we may be able to consider pregabalin,” she said. “And, doses can certainly be held or reduced if neuropathy does not respond to other interventions.”
- Fatigue: Fatigue is common with advanced disease, older age, and cancer treatment. The best advice often seems counterintuitive, Ms. Amirault observed, in that patients are encouraged to move rather than simply to rest. “I might suggest walking for 10 minutes three times a day. Even if the patient has to nap after a walk, staying active seems to be helpful.” Additionally, patients should be encouraged to integrate conventional good-health recommendations, such as getting restful sleep; staying well hydrated; maintaining bowel hygiene; and eating nutritious, balanced meals that include sufficient protein. All of this will contribute to improved energy and well-being.
Nectin-4 is expressed in the skin, so dermatologic issues are “on-target off-target” toxicities.
- Skin: Skin toxicity may become an issue during treatment with enfortumab vedotin, cautioned Dr. Rosenberg. Most patients experience some level of dermatologic toxicity—itching, rash, red skin—“but most of that is mild.” Nectin-4 is expressed in the skin, so dermatologic issues are “on-target off-target” toxicities, he told JNCCN 360. For most mild cases, moisturizers and topical steroids will often improve the situation. “If the skin does not respond to these types of measures, we will send the patient promptly for a dermatology consult because severe skin toxicities have been reported,” he said.
Ms. Amirault echoed Dr. Rosenberg’s experience. The majority of patients treated with enfortumab vedotin develop some degree of “itchy, dry skin, which can hinder one’s quality of life.” Similar to the management of other drug-related rashes, “we might start with a histamine-1 or histamine-2 blocker as well as a hydrating lotion. “I prefer to use formulations that are supplied in tubs rather than via a pump,” she commented. “We might also try a topical steroid, and if that doesn’t work, a low-dose oral steroid. For darkening or skin discoloration, we might try a urea cream,” she said.
- Eyes: According to Dr. Rosenberg, a few patients treated with enfortumab vedotin develop keratoconjunctivitis. “These issues have responded well to the use of steroid eye drops and holding the dose,” he reported. “No patient in my experience had to discontinue enfortumab vedotin treatment because of ocular toxicity.”
Dose Delay or Reduction
In general, Ms. Amirault noted that if side effects are emerging or worsening, “we might decide to skip or delay the next weekly dose and restart once the issue has improved. On the other hand, if skipping a dose does not result in change or improvement, we might decide to reduce the next dose.”
Dose reductions are initiated in 20% increments. Therefore, she explained, the starting dose of 1.25 mg/kg of enfortumab vedotin would be initially reduced to 1 mg/kg, then to 0.75 mg/kg, and then to 0.5 mg/kg. “After that, we would discontinue treatment.”
According to Dr. Rosenberg, the next steps for patients with advanced, metastatic bladder cancer who stop responding to enfortumab vedotin depend on functional status. Some patients whose tumors harbor a mutation of the fibroblast growth factor receptor genes (FGFR3 or FGFR2)—about 15% to 20% of the population—may consider the targeted tyrosine kinase inhibitor erdafitinib.11 If a patient is not eligible for targeted therapy but is fit and interested in further treatment, chemotherapy, such as a taxane,4 pemetrexed,12,13 or gemcitabine,14 may be an option. [Editor’s Note: The NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer14 indicate that a taxane may be used as a radiation sensitizer when fractionated radiation is applied with palliative intent in this setting (category 2B).]
Some research has suggested that enfortumab vedotin may affect the tumor microenvironment, Dr. Rosenberg told JNCCN 360, and “anecdotally, some patients have responded to treatment with an immune checkpoint inhibitor after enfortumab vedotin, even when the disease progressed on a checkpoint inhibitor in an earlier setting.” This is an area of unmet need, and various approaches are being studied.
Another antibody-drug conjugate, sacituzumab govitecan, which is approved in breast cancer,15 has been associated with a response rate of about 33% and a progression-free survival of about 5 to 6 months in this third-line bladder cancer setting.16 The two antibody-drug conjugates, ie, enfortumab vedotin and sacituzumab govitcan, have different targets and different mechanisms.
“Based on the reported toxicity profiles, sacituzumab govitecan seems more ‘chemotherapy-like’ and is associated with more cytopenias and more gastrointestinal issues compared with enfortumab vedotin, which may be associated with a higher incidence of neuropathy,” Dr. Rosenberg observed. “The two agents seem to have different toxicity profiles, which is good because we might be able to consider both in sequence.”
Currently, in patients who are not eligible for first-line cisplatin treatment, “we have a clinical trial17 exploring the combination of pembrolizumab plus enfortumab vedotin,” Dr. Rosenberg said. “So far, the response rate seems to be about 70%, with progression-free survival of about 12 months, which is unprecedented. On its own, pembrolizumab is associated with a progression-free survival of 2 to 3 months, so in a good way, something is going on when enfortumab vedotin is added.” There is also a large ongoing phase III trial (ClinicalTrials.gov identifier NCT04223856) looking at the treatment of patients in the first line and does not require that patients are ineligible for cisplatin. The combination of pembrolizumab plus enfortumab vedotin is being compared with standard first-line chemotherapy, namely gemcitabine plus a platinum agent.
A smaller trial, exploring cohorts of EV-103 (NCT03288545), is comparing first-line enfortumab vedotin alone versus enfortumab vedotin plus pembrolizumab. “We are trying to determine how much of the response is due to enfortumab vedotin because we’ve never given it to previously untreated patients,” Dr. Rosenberg explained.
For most patients, the toxicity profile of enfortumab vedotin is relatively mild but “similar to any cytotoxic agent; however, there is a subset for whom it can be a rocky road,” commented Dr. Rosenberg. In those patients, adverse effects such as neuropathy and skin toxicity can be severe. Clinicians also need to be vigilant about hyperglycemia, which, when present, can be severe and linked to extreme insulin resistance. Although It is quite rare, Dr. Rosenberg noted, “some of those patients may need treatment in the ICU. If they improve, they probably should not restart treatment with enfortumab vedotin.”
Bladder cancer is an aggressive cancer, stressed Ms. Amirault. It has generally been treated aggressively with cytotoxic agents, such as cisplatin, which are challenging. “The cytotoxic agent in enfortumab vedotin, MMAE, is so potent that we cannot use it on its own. However, combining it with a targeted antibody allows it to work on tumor cells without as much collateral damage as systemic chemotherapy,” she explained. Moreover, the MMAE component is so potent that efficacy is often maintained with substantial dose reductions. “What we’ve noticed,” she said, “is that even before confirmation of response on imaging at 3 months, patients may experience amelioration of their pain or improved kidney function on enfortumab vedotin.” Confirming this observation, Dr. Rosenberg concluded: “In my experience, disease-related symptoms often improve nicely when treatment with enfortumab vedotin is initiated.”
Even before confirmation of response on imaging at 3 months, patients may experience amelioration of their pain or improved kidney function on enfortumab vedotin.
Jonathan E. Rosenberg, MD, has served as a consultant for Seattle Genetics, Astellas, Bayer, Lilly, Boehringer Ingelheim, Merck, EMD Serono, Pfizer, BMS, GSK, Mirati, AstraZeneca, Janssen, Roche, and Genentech.
Mali Amirault, NP, reported no conflicts of interest.
- von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 2000;18:3068–3077.
- De Santis M, Bellmunt J, Mead G, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol 2012;30:191–199.
- Bellmunt J, von der Maase H, Mead GM, et al. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup Study 30987. J Clin Oncol 2012;30:1107–1113.
- Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 2017;376:1015–1026.
- Powles T, Durán I, van der Heijden MS, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2018;391:748–757.
- National Institutes of Health. National Cancer Institute. Enfortumab vedotin approved for recurrent bladder cancer. Jan. 14, 2020. Available at https://www.cancer.gov/news-events/cancer-currents-blog/2020/enfortumab-vedotin-bladder-cancer-fda-approval. Accessed November 4, 2020.
- Rosenberg JE, O’Donnell PH, Balar AV, et al. Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/programmed death ligand 1 therapy. J Clin Oncol 2019;37:2592–2600.
- Challita-Eid PM, Satpayev D, Yang P, et al. Enfortumab vedotin antibody-drug conjugate targeting Nectin 4 is a highly potent therapeutic agent in multiple preclinical cancer models. Cancer Res 2016;76:3003–3013.
- Rosenberg J, Sridhar SS, Zhang J, et al. EV-101: A phase I study of single-agent enfortumab vedotin in patients with Nectin-4—positive solid tumors, including metastatic urothelial carcinoma. J Clin Oncol 2020;38:1041–1049.
- Enfortumab vedotin-ejfv (Padcev). FDA prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761137s000lbl.pdf. Accessed November 28, 2020.
- National Institutes of Health. National Cancer Institute. Targeted drug erdafitinib benefits some patients with advanced bladder cancer. August 9, 2019. Available at https://www.cancer.gov/news-events/cancer-currents-blog/2019/erdafitinib-advanced-bladder-cancer. Accessed November 4, 2020.
- Sweeney CJ, Roth BJ, Kabbinavar FF, et al. Phase II study of pemetrexed for second-line treatment of transitional cell carcinoma of the urothelium. J Clin Oncol 2006;24:3451–3457.
- Galsky MD, Mironov S, Iasonos A, et al. Phase II trial of pemetrexed as second-line therapy in patients with metastatic urothelial carcinoma. Invest New Drugs 2007;25:265–270.
- Flaig TW, Spiess PE, Agarwal N, et al. NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer. Version 6.2020—July 16, 2020. Accessed November 29, 2020. To view the most recent version of these guidelines, visit NCCN.org.
- National Institutes of Health. National Cancer Institute. Sacituzumab govitecan approved for metastatic triple-negative breast cancer. Available at https://www.cancer.gov/news-events/cancer-currents-blog/2020/fda-sacituzumab-govitecan-triple-negative-breast-cancer. Accessed November 11, 2020.
- Tagawa ST, Faltas BM, Lam ET, et al. Sacituzumab govitecan in previously treated metastatic urothelial cancer. 2019 GU Cancers Symposium. Abstract 354.
- Rosenberg JE, Flaig TW, Friedlander TW, et al: Study EV-103: preliminary durability results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma. 2020 Genitourinary Cancers Symposium. Abstract 441.