Scope of Treatment Sequencing Grows in Genitourinary Malignancies

Jonathan A. Chatzkel, MD

Checkpoint inhibitors have become staples of frontline and maintenance treatment for patients with metastatic renal cell carcinoma (mRCC) and advanced urothelial cancer, respectively, said Jonathan A. Chatzkel, MD, who added that the initial excitement seen with immunotherapy in those settings is now being seen with the second- and third-line use of antibody-drug conjugates (ADCs) and FGFR inhibitors in urothelial cancer.

“The standards of care in the treatment of metastatic bladder cancer and kidney cancer have changed dramatically over the past few years and are going to continue to change,” said Chatzkel, in an interview with OncLive® during an Institutional Perspectives in Cancer webinar on genitourinary malignancies, of which he was the chair.“In kidney cancer, doublet therapy has come into its own in the frontline setting. The question of which doublet is best for which patient is really a very tough question and depends on patient factors as well as which regimen the oncologist is most comfortable with.”

“In bladder cancer, maintenance immunotherapy has really come into its own. With tremendous OS [overall survival] benefit with maintenance avelumab [Bavencio], patients can benefit from this therapy. In later-line settings, enfortumab vedotin-ejfv [Padcev] and other ADCs [antibody-drug conjugates] have changed and will continue to change the space. It will be interesting to see whether therapies like enfortumab vedotin, sacituzumab govitecan-hziy [Trodelvy], and maybe even treatments like erdafitinib [Balversa] can move into the frontline setting as patients continue to benefit from these agents and clinicians continue to get more experience from them,” said Chatzkel.

In the interview, Chatzkel, an assistant professor of medicine, Division of Hematology and Oncology, University of Florida College of Medicine, University of Florida Health, discussed the key takeaways from the virtual meeting, which covered updates in first-line treatment options for metastatic urothelial cancer, as well as recommended treatments for patients with previously treated, locally advanced or metastatic urothelial cancer, and also newly diagnosed mRCC.

OncLive®: What have the IMvigor130 (NCT02807636) and JAVELIN Bladder 100 (NCT02603432)trials informed about the optimal use of immunotherapy in urothelial cancer?

Chatzkel: These are interesting trials because they look at where the best place to use immunotherapy is. The first study, IMvigor130, looks at using atezolizumab [Tecentriq] in combination with immunotherapy in the frontline setting, whereas JAVELIN Bladder 100 looks at using maintenance immunotherapy. These are certainly somewhat different approaches.

IMvigor130 was a large study that looked at patients with metastatic urothelial cancer and really looked at 3 different therapy pathways. The first was platinum-based therapy alone, which is the current standard of care, and the investigator was able to choose between cisplatin- and carboplatin-based therapy. The second treatment that was evaluated was the combination of platinum-based therapy with atezolizumab, and the third therapy that was looked at was atezolizumab alone in the first-line setting.

When you compared platinum-based chemotherapy vs platinum-based chemotherapy with atezolizumab, the median OS was 16.0 months with the combination vs 13.4 months with chemotherapy alone, but this did not meet statistical significance. The progression-free survival, on the other hand, was 8.2 months vs 3.6 months, respectively, and this did meet statistical significance. However, since the OS difference was not statistically significant between the 2 arms, a formal comparison was not initially carried out between atezolizumab alone and chemotherapy alone. This question was, however, looked at in an exploratory analysis where it was shown that patients who were PD-L1 positive and who could not get cisplatin did seem to benefit significantly from atezolizumab, which is certainly consistent with our current standard of care.

JAVELIN Bladder 100 really has significantly changed our current standards of care. This trial looked at the concept of maintenance immunotherapy. Maintenance immunotherapy is when we give immunotherapy, in this case avelumab, after patients responded to or at least had stable disease after 4 to 6 cycles of chemotherapy. In this study, there was quite a large and significant difference when patients received maintenance avelumab vs placebo. The OS increased from 14.3 months to 21.4 months, so this has been adopted into our current practice.

Now, it’s interesting to note that these 2 studies enrolled a different patient population. JAVELIN Bladder 100 is looking at the subset of patients who have a good response to chemotherapy, whereas IMvigor130 is looking at the whole group of patients treated with chemotherapy initially. JAVELIN Bladder 100 is looking at a group of patients who may have potentially different biology and may have slightly more indolent tumors, so that’s interesting to consider. Regardless, maintenance immunotherapy has really come into widespread practice.

The last study that we talked about was the combination of enfortumab vedotin and pembrolizumab [Keytruda] in the first-line setting. This trial looked at patients who were cisplatin ineligible. Now, this was quite a small study and only looked at about 45 patients, but interestingly, about 33 patients responded to therapy, with about half having a response lasting at least 2 years. This study has really piqued the interest in the community and has raised the question of whether this combination can be shown to be effective in larger studies, and whether this is going to further impact the standard of care.

Your colleague, Jess DeLaune, MD, of the University of Florida Health, spoke about updates in the treatment of patients with previously treated locally advanced or metastatic urothelial cancer. How have targeted agents helped fill the unmet need for patients who progress on chemotherapy and immunotherapy?

Dr DeLaune spent a good bulk of his time talking about the EV-201 trial [NCT03219333], which looked at enfortumab vedotin in the third-line space in patients who have progressed on chemotherapy, as well as checkpoint inhibitor therapy. This has traditionally been a tough space. Enfortumab vedotin, being an ADC, had generated a lot of excitement in the community, and this study really bore that out. About 42% of patients responded to this therapy, which is a pretty significant response. Enfortumab vedotin, in addition to some of these other new treatments, including sacituzumab govitecan, which is another ADC and the FGFR inhibitor erdafitinib have really brought a lot of new options to the table for patients with urothelial cancer that progressed on chemotherapy and on immunotherapy. This has really made a lot of difference for our patients and generated a lot of hope for the community.

Brian Ramnaraign, MD, also of the University of Florida Health, discussed available combinations in newly diagnosed metastatic RCC. Given the improved efficacy across the board with combinations in this setting, how do you distinguish between these regimens in practice?

There are a tremendous number of options for patients with kidney cancer, especially clear cell kidney cancer in the first-line setting. Dr Ramnaraign discussed the combination of cabozantinib [Cabometyx] and nivolumab [Opdivo], axitinib [Inlyta] plus pembrolizumab, and lenvatinib [Lenvima] and pembrolizumab, the latter of which we did not have a chance to discuss in our program, but that certainly has presented another new and very interesting options for patients. There’s a lot of agreement that a doublet makes sense for most patients. Single-agent TKI-based therapy has fallen out of favor except for a small portion of patients with very favorable-risk and indolent disease.

The second decision is whether the best option for a patient is a combination with 2 immunotherapy regimens such as ipilimumab [Yervoy] and nivolumab vs a TKI/immunotherapy combination. For most patients it’s going to come down to their comorbidities. For example, somebody with a significant history of say, Guillain-Barré syndrome may not be the best fit for dual immunotherapy. You may want to focus more on TKI-based therapy for that patient. In somebody with a severe history of autoimmune disease, you may even potentially want to consider a single- agent TKI. On the other hand, for patients with a history of severe uncontrolled hypertension, something like ipilimumab plus nivolumab may be a better option. In terms of whether the overall and complete responses are different between these studies, we don’t really know the answer to that.

The combination of lenvatinib and pembrolizumab did show a little bit of a higher overall response rate, but we can’t really compare across trials. Even though that number presented in the study was a little bit higher, we don’t know whether it’s truly different than what you could see with these other combinations.

Another thing that’s important is for the oncologist prescribing these drugs: What are they the most comfortable with? Each oncologist has their regimens that they’ve used the most and know how to advise the patients about the most and how to guide patients through the toxicity the best. That also comes into play. There’s a lot of different factors here. For most patients, any of these doublets are appropriate.