Recap: Treatment Updates in Urothelial Cancer

At an Around the Practice program hosted by CancerNetwork^®, experts spoke about updates in the treatment of urothelial cancer based on recent research presented at the 2022 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU). The panel was led by Petros Grivas, MD, PhD, associate professor in the Division of Medical Oncology at the University of Washington (UW) School of Medicine, clinical director of the Genitourinary Cancers Program at UW Medicine, and associate professor of the Clinical Research Division at Fred Hutchinson Cancer Research Center in Seattle.

Additional experts were Shilpa Gupta, MD, director of genitourinary medical oncology at Taussig Cancer Center and co-leader of the Genitourinary
Oncology Program at Cleveland Clinic in Ohio; Peter H. O’Donnell, MD, associate professor of medicine at University of Chicago Medicine in Illinois; Thomas Powles, MBBS, MD, professor of genitourinary oncology, solid tumor research lead, and director of Barts Cancer Centre at St Bartholomew’s Hospital in London; and Guru P. Sonpavde, MD, director of bladder cancer at Dana-Farber Cancer Institute in Boston, Massachusetts.

Advances and Unmet Needs in Bladder Cancer

Grivas: What are the biggest advances being made [in urothelial cancer]? How has your practice changed in the last few years?

Powles: I don’t think we’ve made enough advances. Neoadjuvant chemotherapy has a 5% to 13% survival advantage, [which] is modest for 4 cycles of perioperative chemotherapy. We are on the cusp of massive changes, though, and maintenance avelumab [Bavencio] is a step in the right direction. [Still], it’s not the sum of our ambitions. The sum of our ambitions should be greater than [synchronizing] chemotherapy and immunotherapy. We have to develop better biomarkers and better drugs, and also move the [use of these] drugs to earlier in the disease. There’s a second generation of exciting biomarkers. The antibody-drug conjugates are making a big impact on where we are. I’m very positive about the [data for] adjuvant nivolumab [Opdivo], showing we can make differences in the perioperative setting.

Gupta: There’s a long way [to go], but [we’ve] made so many advances across the board. I would like to see more precision-based treatment for neoadjuvant approaches. We’ve known that different patients with different tissues and different subtypes respond differently to treatment, and we still offer blanket chemotherapy to our patients [in the neoadjuvant setting].

O’Donnell: [This space has seen] 8 approvals in the United States in the past 5 years. That’s amazing after decades of [almost] no development. That deserves to be pointed out, and all of us who treat urothelial cancer are gratified to have these additional tools. Now we have to learn how to use them, and we also have to learn to catch up to our colleagues in lung and breast cancer and molecularly subset our patients so that we can identify the right therapies for individual patients and not treat bladder cancers like [a
single] disease.

Sonpavde: It’s encouraging to see so many advances with antibody-drug conjugates, targeted agents like erdafitinib [Balversa], and the improved survival that has come with the [immunotherapy] switch maintenance strategy. There is clearly hope, but the main thing is that we don’t understand the biology well enough.Biomarkers have failed again and again. Drugs that are active in other similar cancers are somehow not that active in urothelial carcinoma. We need to do more work here. For example, chemotherapy-
plus-immunotherapy combinations have floundered. A lot of work needs to be done in understanding the tumor biology for us to make the huge advances.

Patient Treatment Strategy

Case

• A 73-year-old woman was diagnosed with metastatic urothelial cancer 6 months after receiving cystectomy for muscle-invasive disease.
• She has hypertension that is controlled through medication.
• She has three 1-cm lung metastases and pelvic lymph node metastases.
• Creatine clearance: 65 mL/min
• ECOG performance score: 1
  

Grivas: What would be your initial approach to treating this patient? Would you do any additional testing?

Sonpavde: This is a cisplatin-eligible patient with metastatic urothelial carcinoma, so the standard of care right now is to start with a cisplatin-based combination of chemotherapy, which would be the MVAC regimen [methotrexate, vinblastine sulfate, doxorubicin hydrochloride, and cisplatin]. MVAC would be reasonable, followed by switch maintenance avelumab [Bavencio] in patients who have stable or responding disease; about 75% of patients would be expected to have that. I would not do any other testing at the moment. It would be useful to do genomic profiling to have the FGFR3 status, especially in case you want to use an FGFR inhibitor for progressive disease. If the patient progresses on the platinum [therapy] without stability, you might want to go with the erdafitinib as an option in the second or even third line of treatment.

O’Donnell: [Given] the progression within 6 months post cystectomy, I’m already wondering if this patient is in a [poor] prognostic group. It’s not the quickest [time to progression] we see, but it’s rather quick for recurrence. I’m going to keep that in my mind as I watch this patient go through their frontline therapy.

Grivas: Would you talk about avelumab maintenance or any other testing, such as PD-L1, and how many cycles of chemotherapy would you administer?

Gupta: I assume the patient did not get neoadjuvant cisplatin-based chemotherapy. If the patient received that, then we would think about offering cisplatin again. But assuming the patient didn’t get that, I would also do gemcitabine followed by avelumab maintenance if [they’re] not progressing. There is no biomarker that would guide this approach, but we would like to get genomic testing for later. PD-L1 is a useless biomarker right now; because it doesn’t guide our frontline or subsequent-line therapy, I don’t specifically look for that.

Grivas: What are your thoughts on biomarkers in the frontline setting? Can you also discuss any trials that might be relevant to this situation?

Powles: At my university, we are doing a trial comparing 3 and 6 cycles of chemotherapy. My gut feeling is that there’s nothing magical about chemotherapy and maintenance therapy; it’s just that second-line immunotherapy is too late for most patients and first-line immunotherapy doesn’t get control of the disease enough. Therefore, the best way of getting people to have immunotherapy with a long enough [control] is to give chemotherapy, get in control, and then maintain that control. Six cycles of chemotherapy is probably too much. There are more patients who progress than respond between cycle 3 and cycle 6. Most of the responses happen early. By getting in control of the disease after 3 cycles and then [by administering] the immunotherapy directly after, we feel that it may be advantageous not just from a quality-of-life perspective, but [from] a survival benefit [perspective]. We may end up with more people getting curable responses with immune therapy.

The biomarker question you’ve asked is a difficult one. I would say that the PD-L1 story has been consistently inconsistent, but [tumor cell] expression appears to be more predictive than [immune cell] expression. [Also], tumor mutational burden [TMB] looks promising, but it’s a surrogate marker and has never been formally tested. There are a dozen different ways of measuring [TMB], and we’re likely to [get caught in all the same] traps as we did with PD-L1. There are a series of other markers, all of which are encouraging and promising but all exploratory in nature.

Grivas: [Let’s switch gears.] Can we discuss the JAVELIN 100 trial [NCT02603432] update that was presented at ASCO GU?

Powles: [The phase 3 JAVELIN 100 trial is] looking at patients who either have stable disease or responded to between 4 and 6 cycles of gemcitabine plus cisplatin or carboplatin as frontline therapy for advanced urothelial cancer.^1,2 A total of 700 patients were randomized. They started avelumab within 10 weeks of completion of chemotherapy and it was 1:1 randomization [vs best supportive care alone]. The hazard ratio for overall survival [OS] was initially at 0.69 [95% CI, 0.56-0.86; P = .001]. The more recent update with 3 years of follow-up has [yielded a hazard ratio of 0.76 [95% CI, 0.631-0.915; P = .0036]. The vast majority of patients received subsequent therapy. Common subsequent therapy was immunotherapy, suggesting this is an effective earlier treatment and is better than waiting for the cancer to come back.

My current approach is to treat patients with this strategy and to give [enfortumab] vedotin [Padcev] when progression [occurs]; it has become a straightforward pathway. In the patients with [complete response] in the control arm, progression-free survival [PFS] is 4 months, and this highlights the problem that bladder cancer is an aggressive disease, and you have to be in control. Imagine having friends or family with cancer and you aren’t a doctor, and you’ve been told that the chemotherapy has completely made the cancer disappear. Many people would expect 2 or 3 years or maybe a lifetime being cancer free; being told it will be back in 4 months is disappointing, [to say the least]. That underlines the shortcomings of chemotherapy, frankly.

Grivas: How long do you wait from the end of chemotherapy to begin avelumab maintenance?

Gupta: Based on the JAVELIN Bladder 100 trial, 4 to 10 weeks is the window [for beginning avelumab]. I scan patients after 3 cycles of chemotherapy to know what their response is, and then if the patient is tolerating chemotherapy very well and has no complications, I push until 6 cycles. If they’re having a hard time, then I try to get them to cycle 4 if possible. If not, then I move on to avelumab maintenance within 4 to 10 weeks.

Case (continued)

• Treatment was initiated with gemcitabine/cisplatin.
• She has a partial response.
• The CT scan showed a decrease in bladder mass and mildly improved nodal findings with no evidence of new disease.
• Maintenance avelumab was given at 800 mg intravenously every 2 weeks.

Grivas: How would you begin to treat this patient?

Sonpavde: Assuming the patient is negative for an FGFR3 mutation or fusion, I would usually go with enfortumab vedotin, which is approved and was shown to improve OS in a phase 3 trial [EV-301; NCT03474107].^3,4 To complete that sequence, sacituzumab govitecan [Trodelvy] is the other antibody-drug conjugate that’s available. I would use that in the fourth-line setting. In an FGFR3-altered patient, I tend to go with erdafitinib [Balversa] before enfortumab vedotin, although it’s not wrong to go with enfortumab before erdafitinib. I would choose erdafitinib first because [approval of this agent] is based on a trial that selected patients for FGFR3 mutations. This was a biomarker-targeted trial where the response rate was 40% and the median survival exceeded 1 year, around 13 months. With a drug that’s targeting a very specific gene like FGFR3 or FGFR2, you want to [begin treatment] early. Biologically, it makes more sense because this drug is not hitting other targets that much. If you go too late, that target might not be as relevant.

O’Donnell: I’m in agreement that when the [patient’s tumor is] FGFR negative, enfortumab vedotin is the drug to pick here. It’s the most active drug we have for urothelial cancer [in that setting], with response rates in the refractory setting as good as those of cisplatin combinations in the frontline setting. We want to move enfortumab vedotin earlier in the disease course [because you get just] 1 chance to treat a patient who’s progressing
after platinum and immunotherapy. The chance of a patient getting to the fourth line is rare. The [patient who is] FGFR positive is a more interesting debate. I would still pick enfortumab vedotin. I find enfortumab vedotin much easier to administer. [People might wonder why I don’t administer erdafitinib.] It’s a challenging drug to give because you must monitor the labs and the phosphorus, and give dose adjustments. The responses are not as rapid with erdafitinib, whereas with enfortumab vedotin, after a single infusion, patients are already getting better symptomatically.

Gupta: Our goal should be to try to get the patient through all lines of therapy, but erdafitinib is not a walk in the park by any means. Having said that, if a patient [with an FGFR alteration] has had significant neuropathy from a platinum-based regimen, then I would be hesitant to use enfortumab vedotin first. I would probably give that patient erdafitinib first because peripheral neuropathy is a big problem with enfortumab vedotin. If a patient is really struggling with peripheral neuropathy, then sacituzumab govitecan is also a reasonable option.

Grivas: Is there any scenario where you would give enfortumab vedotin regardless?

Powles: One needs to look at 2 or 3 outstanding points [regarding the results of EV-301]. [First], the initial control is fantastic, but the PFS curve goes right down. Unlike [with] immunotherapy, we’re not getting many durable remissions. The second point is that we need to be cautious about the way we give the drug, particularly with regard to the peripheral neuropathy and skin rash associated with more chronic therapy. The skin rash tends to occur quite quickly. All of these drugs have unique profiles for bladder cancer and become much more interesting to treat, but potentially it’s more difficult for patients if we get the management of these toxicities wrong. The skill level has gone up a lot. I’m excited about the results of [the phase 3 EV-302 trial (NCT04223856) of enfortumab vedotin plus pembrolizumab (Keytruda) in] the frontline setting; I think those are important.

Ongoing and Future Trials in Bladder Cancer

Grivas: Let’s transition into speaking about current trials, starting with the MAIN-CAV study [NCT05092958].

Gupta: The MAIN-CAV study is building upon the JAVELIN Bladder 100 backbone; it intensifies maintenance of avelumab further with the tyrosine kinase inhibitor cabozantinib [Cabometyx], which also targets the MET [receptor] and seems to be an active target. The key differences are that it allows any prior platinum [therapy consisting of] 4 to 6 cycles, and we limit the treatment duration to 2 years as opposed to indefinitely. The primary end point is OS, hypothesizing a 7-month improvement over avelumab [alone]. The trial just [became active].

Grivas: Can you discuss the PRESERVE 3 trial [NCT04887831]?

Snpavde: The PRESERVE3 trial tests an innovative idea of a drug called trilaciclib [Cosela], a CDK4/6 inhibitor. It’s FDA approved to prevent neutropenic complications from chemotherapy for small cell lung cancer. The idea is based on other data that this drug can arrest cell cycling and therefore prevent the myelotoxicity of chemotherapy. That’s how it works to prevent myelosuppression from chemotherapy in small cell lung cancer. It’s also been shown to arrest hematopoietic stem cells; therefore, it might protect hematopoietic stem cells from the cytotoxicity of chemotherapy, as well as enhance the immune system when given in combination with a PD-1 or a PD-L1 inhibitor to enhance the immune state. That’s been shown in translational studies and in animal models.

Grivas: Moving forward, which data are you most excited to see?

Sonpavde: The data to look forward to are, [first], from the CheckMate 901 trial [NCT03036098], which is comparing ipilimumab [Yervoy] and nivolumab [Opdivo] vs gemcitabine plus platinum–based [therapy] with the co-primary end points looking at cisplatin ineligible as well as PD-L1–high patients. It also has a substudy looking at gemcitabine and cisplatin plus or minus nivolumab, specifically looking at the cisplatin-eligible population. This might be a better partner for a PD-1 inhibitor than carboplatin-based chemotherapy. The [second trial to watch is EV-302], the enfortumab vedotin trial looking at
enfortumab vedotin and pembrolizumab vs gemcitabine platinum [therapy] followed by maintenance.

O’Donnell: We’re seeing many new targets, but the real chance for changing the course of this disease is in the perioperative setting. Once we’ve gotten to the metastatic space, we’re fighting an uphill battle, so I wonder about all these new agents we’re talking about.Enfortumab vedotin is among the most active agents and among the most exciting [treatments] that seem to be disrupting the landscape. It’ll be interesting to see how that translates to using things like enfortumab vedotin combinations, even in the perioperative [setting].

Gupta: I would echo what [my colleagues] said. There’s much excitement in the field. In the future, will we be able to spare patients chemotherapy if enfortumab vedotin plus pembrolizumab becomes the standard? Will we be able to intensify maintenance approaches with ongoing trials? The perioperative trials are of big interest. It remains to be seen what the ongoing phase 3 trials will show in the future.

References

1. Powles T, Park SH, Voog E, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med. 2020;383(13):1218-1230. doi:10.1056/NEJMoa2002788
2. Powles T, Park SH, Voog E, et al. Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (UC): long-term follow-up results from the JAVELIN Bladder 100 trial. J Clin Oncol. 2022;40(suppl 6):abstr 487. doi:10.1200/JCO.2022.40.6_suppl.487
3. FDA grants regular approval to enfortumab vedotin-ejfv for locally advanced or metastatic urothelial cancer. FDA. July 9, 2021. Accessed May 4, 2022. https://bit.ly/3vGxpG8
4. 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