ADCs and TKIs Plus Immunotherapy Signal the Future of Urothelial Carcinoma and RCC

Benjamin Garmezy, MD

Antibody-drug conjugates (ADCs) and TKIs combined with immunotherapy and other emerging agents are improving response rates in patients with urothelial cancer and renal cell carcinoma (RCC) respectively, explained Benjamin Garmezy, MD, in an interview with OncLive^® following a State of the Science Summit™ on genitourinary cancers, which he chaired.

“What will be exciting to see over the next few years is how these ADCs that are already FDA approved are going to partner with other current drugs that we can use to treat this disease, such as immunotherapy,” Garmezy said.

In the interview, Garmezy, the assistant director of genitourinary research at Sarah Cannon Research Institute at Tennessee Oncology, discussed the positive trajectory of ADCs and immunotherapy in urothelial carcinoma, highlighting the importance of considering individual patient eligibility for treatments like first-line chemotherapy. He also broke down treatment sequencing strategies in RCC and underscored the importance of testing for biomarkers in every patient with metastatic disease to better guide treatment decisions.

OncLive^®: What was the primary focus of your presentation on later-line therapies for metastatic urothelial carcinoma?

Garmezy: My goal was to highlight advances made with later-line treatments for patients with urothelial carcinoma. I discussed options for patients who had progressed after frontline therapies or after frontline treatment with chemotherapy followed by immunotherapy maintenance. [Those options include] FGFR inhibition for patients based on a genetic sequencing report, the new class of ADCs that have been FDA approved, and other emerging therapeutics in that area.

How has the standard of care for progressive urothelial malignancies evolved over time?

There has been a ton of activity in recent years with new FDA approvals. Historically, we treated these patients with chemotherapy, and then recently, with a lot of novel immune checkpoint inhibition, which was the mainstay. In the past few years, we have started to see approvals take off with FGFR inhibition, as well as with the new ADCs. We now have 2 FDA-approved ADCs with different targets, 1 for TROP2 and 1 for nectin-4. These are great for our patients and have really revolutionized care for patients with a tumor type that is historically difficult to treat.

What does the future look like for ADCs in the treatment of patients with urothelial cancer?

ADCs have had a huge effect and they are only going to make a larger footprint as we move forward. Right now, we are able to salvage patients with high response rates to ADCs in this highly refractory setting. More importantly, we are seeing options outside of traditional chemotherapy for patients who may not be candidates for chemotherapy, [including those] who are unable to tolerate cisplatin, for instance, as well as patients who may have autoimmune conditions and cannot receive immune therapies.

Where are ADCs ultimately going to end up? [Combinations of ADCs and immune therapy] may even make chemotherapy less important as a frontline treatment for these diseases. It is hard to ignore the fact that we even have other ADCs that are now entering larger phase trials that are seeking their own FDA approvals, particularly those targeting HER2. HER2-directed ADCs [act differently from] how we treat HER2 in other disease types, such as breast cancer.

You see HER2 expression on cells in a much patchier and less uniform distribution of expression when you do immunohistochemistry [IHC]. That was important when we started asking: Why do some therapies in this space work and some do not? How does the creation of a molecule and compound allow us to see whether it is going to be efficacious? Cleavable linkers vs non-cleavable linkers may matter. The actual payload attached to the ADC likely matters, as some seem to be more immunogenic than others—at least in preliminary signals.

We cannot speak definitively yet because we do not have large enough data sets. However, there is an interesting story around the monomethyl auristatin E payload and its synergy with immune therapy and how that may look going forward, whether in current FDA-approved ADCs with enfortumab vedotin-ejfv [Padcev] or in novel ADCs that are under development right now. These developing agents are targeting HER2 or additional proteins that are overexpressed in urothelial cancer.

How has recent progress with immunotherapy improved urothelial carcinoma treatment?

That is a complicated question, because [some of that progress has been] walked back by the FDA. Immunotherapy is incredibly vital, but we do not have perfect biomarkers in urothelial cancer. There are trends in patients with high PD-L1 combined positive scores [CPS], but those without those biomarkers may still respond to immunotherapy.

In the clinic, you could have a patient who may not be platinum eligible for a variety of reasons. When discussing platinum eligibility, having that option for an immunotherapy mechanism that you can deliver in clinic to most patients has been a lifesaver in this disease. [This is especially true for] the elderly population that probably cannot tolerate some of our more aggressive chemotherapies, as well as those patients who have other reasons [that render them ineligible], such as [impaired] renal function, which is all too common and means they are unable tolerate platinum. Immunotherapy, either in the frontline or in a salvage setting post chemotherapy, is critical.

How effective are ADCs across urothelial carcinoma subtypes?

The amount of expression on some of these targets is not only seen in the conventional urothelial subtype. You also see it in patients with papillary disease, those with mixed histologies, and those with sarcomatoid carcinoma. These patients often have TROP2 expression or nectin-4 expression, and these ADCs can be important here. In traditional neuroendocrine subtypes and small-cell subtypes of urothelial cancer that are much less common, ADCs like sacituzumab govitecan-hziy [Trodelvy] and enfortumab vedotin may not be the best options. However, in those other subtypes where there is expression [of those targets], these therapies can be deployed.

Pedro Barata, MD, MSc, of Tulane Medical Center, spoke about frontline therapies for metastatic urothelial carcinoma. How do treatment options vary for patients with platinum eligibility vs ineligibility?

The changing dynamics of what we view as platinum eligibility is a discussion that was continued at the 2022 ASCO Annual Meeting. If patients are eligible to receive cisplatin, that means their glomerular filtration rate [GFR] is above 50 mL/min to 60 mL/min. If their GFR is a bit on the lower side, you can use split-dose cisplatin, which can be done in the community [setting] as well as in a traditional academic center.

With cisplatin, we need to ask: How is the patient’s hearing function? How is their heart function? What is their New York Heart Association heart failure class? Do they have residual neuropathy? Those are all important questions. If [a patient is] not cisplatin eligible, then we start asking ourselves whether they are carboplatin eligible. In these patients, hearing issues are a little less common; we can take a patient with a GFR [as low as] 30 mL/min and give them carboplatin.

A much larger subset of patients is eligible to receive frontline carboplatin. With [avelumab (Bavencio)], a new immunotherapy maintenance option, getting patients on chemotherapy with carboplatin and gemcitabine and then giving them immunotherapy maintenance if they have a response or stable disease is an excellent option.

In a patient who is unable to receive carboplatin because of renal failure or some other issue, getting them on immunotherapy up front is the clear option and a worthy one. In the future, we will have FDA-approved [ADC and immunotherapy] combinations for those patients, but [we are] not there yet.

What efforts can be made to improve immunotherapy and targeted therapy for those with urothelial cancer?

The biggest thing that we need to do as a community is sequence all patients with metastatic disease. There are a reasonable number of patients with FGFR mutations that we do not capture because we are not looking. Erdafitinib [Balversa] is an active drug in this population. It does have its own toxicities that are unique. As an oral therapy, [the agent is] not necessarily easier than some of these ADC infusions and chemotherapy infusions; however, it is an important treatment option for patients because it does have a different [safety] profile that may be tolerable when other therapies are not options for patients. That is essential.

It is also essential that we offer immunotherapy to all our patients, even if there may be [cases] that gives us pause, [such as] those with low-level historic autoimmune conditions who do not have active autoimmune problems. We can discuss checkpoint inhibitors with those patients and do shared decision-making. Some of our patients with metastatic urothelial cancer are going to want the option to receive these therapies and [may choose to] take a bit of a risk of reactivating some of those diseases. It is imperative that we do not take the decision out of the hands of those patients who are on the fence about whether they will be a candidate for immunotherapy.

Your colleague, Daniel Vaena, MD, of the West Cancer Center and Research Institute, spoke on later-line therapies for RCC. What sequencing strategies may be useful in this setting?

This is an interesting discussion, and as a community, we are still trying to figure out how to sequence these RCC therapies. We have multiple up-front regimens of immunotherapies plus TKIs, and we also have an immunotherapy plus immunotherapy regimen. We all [know how to sequence standard-of-care treatments]. When we give ipilimumab [Yervoy] plus nivolumab [Opdivo] up front, we sequence with a single-agent TKI, then perhaps with a TKI plus everolimus [Afinitor] or a different TKI in that third-line setting. We go down the line like that.

However, it gets a lot more complicated when we are talking about patients who have received an immunotherapy plus a TKI in the front line. [For example,] if a patient received [first-line] pembrolizumab [Keytruda] plus axitinib [Inlyta], cabozantinib [Cabometyx] plus nivolumab, or pembrolizumab plus lenvatinib [Lenvima], then in the second line, it is probably important to provide that TKI.

Some data show that cabozantinib is highly active after other TKIs. However, we also know that the TKIs outside of cabozantinib can be just as important post TKI therapy. Look at the data for tivozanib [Fotivda]. Some patients [who previously received] axitinib still have a reasonable chance at [achieving] a durable response with tivozanib. I like to highlight that 1 [example] specifically because axitinib and tivozanib are VEGF-heavy TKIs, and cabozantinib and lenvatinib have those other TAM kinase receptor targets as well, which may also be important for salvage TKI treatment.

It is a complicated discussion. Lenvatinib plus everolimus is still an important combination that we can offer our patients as mTOR inhibition post immunotherapy/TKI failure if they have not seen pembrolizumab plus lenvatinib up front. It is an interesting question. We still do not have all the answers. Ultimately, some of these patients are going to see many lines of therapy with a changing of TKIs.

An interesting research question that we are challenged with in clinic is: Post progression on immunotherapy plus TKI therapy, do we continue the immunotherapy? That may be answered soon. A couple of large, active phase 3 trials are trying to answer this question; these trials are enrolling patients. We will have data in the future, but right now, it is still a complicated question for our patients.

Kathryn Beckermann, MD, PhD, of Vanderbilt University Medical Center, spoke on adjuvant and frontline treatments for RCC. What is the need for biomarkers in this landscape?

Biomarkers are going to be essential in adjuvant RCC. In the [phase 3 KEYNOTE-564 study (NCT03142334)], most patients fell into a very similar profile, the pT3 N0 profile. Patients who have more aggressive disease than that are going to be great candidates for adjuvant immunotherapy, and the those who did not meet that profile [in the trial] were not the ones deriving the benefit when you look at the survival analysis and the Kaplan-Meier curves.

Ideally, it would be wonderful if we had something as simple as a PD-L1 or a CPS cutoff. Unfortunately, we do not [have this cutoff] in this disease type, and we know that patients without those biomarkers still respond.

There has been some discussion about how we should look at signatures. Is there an immunogenic signature that we can use, like the ones we use in panels of RNA or DNA mutations, to highlight immunogenic signatures vs angiogenic signatures? Are those patients with immunogenic signatures perhaps going to do better with immunotherapy?

We can employ a biomarker test post nephrectomy to see who is going to be most served by taking on the potential toxicity of 1 year of immunotherapy, with its potential for a life-altering adverse effect, and who would not necessarily be helped by the therapy. This is probably years away. Ideally, however, we can figure this out as a community so that we can better deploy these therapies, not just using pathology grading, but using the biology of the tumor itself to help guide us. 

What is your main message for colleagues regarding the current state of genitourinary cancers?

Right now, we have so many clinical trial options, both at community centers, as well as at academic centers across the country, for patients with novel targets. If we do not look for novel targets, whether through genetic sequencing, IHC staining, or other forms of staining from pathology groups, we are not going to be able to identify those patients, and it is going to be harder to push the field forward.

HER2 is the best example of that in bladder cancer. There is a large subset of patients with [bladder cancer and] HER2 expression. Until we start staining and can better describe how we look at that staining, we are going to have the same issues and failures in the HER2 population that we have had in the past.

It is also important that we continue to sequence every patient with metastatic disease, so we get a better understanding of both prognostic significance as well as potential therapeutic options for those patients in later-line settings.