Rapid Progress Made With Late-Line Therapies in Metastatic Urothelial Cancer

With the emergence of immunotherapies, FGFR inhibitors, and antibody-drug conjugates (ADCs), the metastatic urothelial cancer treatment paradigm has dramatically evolved, according to Praful K. Ravi, MD, and even more approaches continue to emerge, showing encouraging efficacy in early-phase trials.

“Aside from the exciting enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) combination, other ADCs are being looked at,” Ravi explained. “We’re learning more about molecular subtyping in bladder cancer; for example, 15% may have a FGFR alteration while others may have a different alteration, such as HER2. With this said, ADCs targeting HER2 are still in early-phase trials. To date, [one that is furthest along] is sacituzumab govitecan-hziy (Trodelvy), which inhibits TROP-2, an antigen that is overexpressed in several tumors.”

In an interview with OncLive® during an Institutional Perspectives on Cancer webinar on Genitourinary Cancers, Ravi, who is an oncology fellow at Dana-Farber Cancer Institute, discussed recent advancements made with late-line therapies in advanced or metastatic urothelial cancer.

OncLive®: Could you outline some of the key updates with later-line treatment options in locally advanced or metastatic urothelial cancer?

Ravi: Prior to the JAVELIN Renal 101 trial, patients with advanced or metastatic urothelial cancer who are chemotherapy eligible or have not progressed within 12 months of neoadjuvant chemotherapy, would receive first-line chemotherapy. This would be a platinum-based chemotherapy such as gemcitabine/cisplatin or gemcitabine/carboplatin. Following progression on that, is the second-line space, which is where immunotherapies have been utilized.

Five agents have been approved; however, only 2 have phase 3 data: atezolizumab (Tecentriq) and pembrolizumab. Notably, only pembrolizumab demonstrated an overall survival (OS) benefit compared with second-line chemotherapy. Pembrolizumab had a 3-month benefit in median OS versus chemotherapy. With atezolizumab, no benefit in OS was observed. The response rate in the pembrolizumab trial was slightly higher compared with the atezolizumab trial, at least in the intent-to-treat populations.

Beyond immunotherapies, we have FGFR inhibitors. In the past 5 years, data have shown that some patients with advanced urothelial cancer have an alteration in FGFR; this signaling pathway appears to be altered in up to 20% of patients. These tumors are oncogene addicted; in other words, they are addicted to the pathway. As such, inhibiting this pathway is a rational way to try and treat these patients. That was the basis of erdafitinib (Balversa), which is a small molecule inhibitor. In a phase 2 trial of approximately 100 patients, the response rate in patients with an FGFR2 or FGFR3 alteration, which could be a mutation or a fusion, was 40%. This was fairly impressive, and the median duration response was [just under] 6 months.

An important thing to note with erdafitinib is that it does come with some on- and off-target toxicities. The on-target toxicity is hyperphosphatemia, which is an issue. You have to titrate the dose according to the phosphorus level within a couple of weeks because you expect the phosphorus level to be elevated; however, if it isn't, then you can increase the dose to 9 mg per day compared with 8 mg per day. The other important adverse effects (AEs) to note with the drug are the ophthalmologic complications, such as retinopathy and keratitis. Patients should at least have a baseline assessment with an ophthalmologist. The FDA actually recommends having these assessments periodically going forward; however, in practice, it's difficult to have this done. You can just monitor with symptoms or via an informal assessment with an Amsler Grid.

The third therapy is enfortumab vedotin, which is an ADC; I think of it as a targeted chemotherapy because it delivers the therapy to the tumor antigen. It is an antibody that targets Nectin-4, which is overexpressed in bladder cancer. This agent essentially links the antibody with a cytotoxic agent. It’s an effective way of getting the chemotherapy to the cancer cells and trying to avoid some AEs by delivering the chemotherapy to healthy cells, as well.

Enfortumab vedotin has received accelerated approval based on [results from] the EV-201 phase 2 study that were published earlier this year; this trial included 125 patients. The cohort that was studied here had received both platinum chemotherapy and an immune agent, so an anti–PD-1/PD-L1, [so these patients were being treated] in the third-line setting.

The response rate [with the agent] was 44%, which is quite impressive for this pretreated population. Approximately 12% of patients had a complete response [with the drug]; this suggests that the disease remains somewhat chemosensitive, but perhaps this is a better chemotherapy agent than platinum is in the space. It’s also a way of reducing the toxicity because some of the toxicities that you see with traditional platinum chemotherapy, you don’t see with enfortumab vedotin. However, you will see neuropathy; is very important to consider this before you start a patient on this drug, because they may have received previous platinum and you don't want them to experience more neuropathy with this drug.

The ADC is also now being studied in combination with pembrolizumab. A small, phase 1b study that was presented last year, which showed a response rate of 73% in the first-line setting, which is unprecedented in this kind of disease. However, this was a small, early-phase study, so we need more data to determine whether the [benefit is upheld in] larger studies. Another ongoing trial is assessing enfortumab vedotin with pembrolizumab and/or chemotherapy in the first-line setting; it just started accruing patients earlier this year. This trial will truly test whether the ADC can move into the frontline setting, rather than just the refractory setting.

With all these options to consider, how do you approach sequencing in practice?

You first need to ask yourself: ‘Is the patient platinum eligible and what is their previous history? Did they receive chemotherapy for localized disease in the neoadjuvant or adjuvant setting, and have they relapsed within 12 months?

If yes, then they have already been exposed to platinum chemotherapy, which would prompt you to move straight into the second-line agents. I would typically use pembrolizumab because it has an OS benefit and perhaps this would then be followed by enfortumab or, if they have an FGFR alteration, erdafitinib.

If the patient has not received any prior therapy, then the first key consideration is platinum eligibility. If they're eligible for any platinum, cisplatin in particular, then cisplatin-based chemotherapy should be the first line. You then have the recent JAVELIN Bladder 100 trial, suggesting that avelumab (Bavencio) maintenance in patients who respond or are stable [could be used] after that.

Beyond that, it’s difficult because if a patient already received avelumab maintenance after chemotherapy, should a different immune agent be given? Possibly not, and in that case, you may be tempted to consider a third-line agent or a different class of agents such as enfortumab vedotin or erdafitinib. It’s important to try and do some sort of tumor genomic profiling, either at diagnosis or when patients are getting past that first-line therapy because erdafitinib is approved for use post platinum.

In terms of patients who've received both platinum and immunotherapy, I believe enfortumab vedotin is the standard of care in the third-line setting if they don't have an FGFR alteration. Now, if the patient does have an FGFR alteration, the question of sequencing can be controversial here. Some have suggested that patients with a FGFR alteration may respond less well to immunotherapy because they have the so called “luminal tumors,” which may be less immune infiltrative; this was suggested in the erdafitinib trial. In the 22 patients who received erdafitinib had previously received immunotherapy and only 1 of them responded to the immunotherapy. The response rate to immunotherapy was 5% in these patients with an FGFR alteration.

However, some other data from the pembrolizumab and atezolizumab trials where they went back to look at those patients to see who had an FGFR alteration. They found that the response rate was similar regardless of whether the alteration was present or not. As such, I believe this is a controversial topic; we don't have an optimal way to sequence and we need to conduct more studies to figure this out.

Could you expand on the significance of the enfortumab vedotin approval in metastatic urothelial cancer?

This regulatory decision was based on data from the EV-201 study, a phase 2, single-arm study that included 125 patients, which showed a response rate of 44%. I believe this was an important accelerated approval because this agent could potentially be used to address an area of unmet need. No other standard-of-care options are really available for these patients.

However, this benefit still needs to be confirmed in a registrational phase 3 trial, EV-301. In this ongoing trial, patients who received prior platinum and immunotherapy are being randomized 1:1 to investigator’s choice of chemotherapy, which would be the standard of care, despite the fact that there is no real OS benefit with that, versus enfortumab vedotin.

If we see the OS benefit proven here, which I believe we most likely will based on the preliminary data, then it will be converted to a full approval.

What are some emerging agents that are generating excitement?

Sacituzumab govitecan has already received accelerated approval in triple-negative breast cancer for patients who have received 2 prior lines of chemotherapy. In bladder cancer, a basket study looked at the agent. This basket study included 45 patients with urothelial cancer who had received prior platinum therapy, some of which received a prior immune checkpoint inhibitor as well.

The response rate [observed with the agent] was 31%, which is in the ballpark of what we're seeing with enfortumab vedotin. Although this was a small study, we're now seeing a dedicated phase 2 trial called TROPHY U-01, which is being conducted in a similar manner to that of the enfortumab vedotin trial, where we hope to obtain good data. I imagine a similar kind of pathway for approval for sacituzumab in this disease.

Other emerging approaches are in the form of combinations, which is important because many patients with cancer tend to be comorbid and their disease might progress quickly. As such, we may not be able to get all the different lines of therapy in. Combining therapies may be a good strategy to see whether we get an additive effect or perhaps even synergy.

Studies are now trying to determine whether we can enhance the effect of immunotherapies in bladder cancer because we have some preclinical data suggesting that drugs may be able to reverse the immune suppressive microenvironment. One of these are small molecule inhibitors of receptor tyrosine kinases.

Data from the COSMIC-021 trial were presented during the 2020 ASCO Virtual Scientific Program; this trial studied the combination of cabozantinib (Cabometyx) and atezolizumab in patients who received prior platinum but no prior immunotherapy. This was a very small 30-patient, phase 1 study where investigators reported a response rate of approximately 30%; this was a little bit more than what you might expect from the 2 agents [when used as monotherapy]. Cabozantinib has a response rate of approximately 20% and that rate is about 13% with atezolizumab; this suggests an additive effect or potentially synergy with the combination.

This is promising but we will need to conduct larger studies, randomizing patients to atezolizumab plus cabozantinib versus atezolizumab alone to understand whether cabozantinib provides that intended additive effect.

Similarly, you've got sitravatinib and nivolumab (Opdivo). Sitravatinib is analogous to cabozantinib and it inhibits many pathways such as MET and VGEF. Investigators looked at combining sitravatinib with nivolumab in patients who had received prior PD-1/PD-L1 and platinum. This is important because you’re looking at immunotherapy after immunotherapy. In this early phase trial, the response rate was 39%, suggesting some promise with this strategy.

What is the take home message of your presentation?

Compared with 5 years ago, when the only approved therapy for advanced bladder cancer was chemotherapy, we now have a multitude of options. We have immunotherapies, and both pembrolizumab and atezolizumab with phase 3 data. We know that pembrolizumab has an OS benefit.

We also have molecular targeted therapies with an FGFR inhibitor, and we have ADCs. This is a very exciting time in urothelial cancer; we have more options available. Going forward, we need to figure out what the best treatment is for each patient. In the next 5 to 10 years, we also need to figure out what the best sequence of therapies is.