Checkpoint Inhibitors Demonstrate Broad Reach in GU Cancers

Rohit Jain, MD, MPH

Maintenance therapy with avelumab (Bavencio) has resulted in prolonged overall survival (OS) for patients with metastatic urothelial carcinoma following frontline chemotherapy, Rohit Jain, MD, MPH, said, adding that ongoing research efforts are evaluating the utility of immunotherapy in earlier lines of treatment and ways of overcoming immunotherapy resistance in this population.

“[The advances made in metastatic urothelial carcinoma have been] very dramatic, and it is good for us and the patients because we are seeing good responses with more tolerability [from] the treatment. The landscape will significantly change as these drugs are being used more in the frontline setting, as well as in the muscle invasive and non–muscle invasive settings,” said Jain, an assistant member in the Department of Genitourinary Oncology at Moffitt Cancer Center, in an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on genitourinary malignancies.

The virtual meeting covered updates in the first- and later-line settings of metastatic urothelial carcinoma, as well as the optimization of treatment decisions in newly diagnosed renal cell carcinoma (RCC) and remaining questions regarding risk stratification in metastatic castration-resistant prostate cancer (mCRPC).

In the interview, Jain, who chaired the event, discussed the nuances of treatment selection for patients with platinum-eligible vs -ineligible metastatic urothelial carcinoma, the current state of immunotherapy in this disease, and factors to consider during the decision-making process in RCC and mCRPC.

OncLive^®: How has the treatment landscape of metastatic urothelial carcinoma grown since the introduction of immunotherapy in the second-line setting?

Jain: When the immunotherapy era started in 2015 and 2016, the immunotherapy drugs were approved for bladder cancer in the second-line setting, which was very exciting. Patients were having more durable responses, and we were prolonging OS. Subsequently, we have seen enfortumab vedotin-ejfv [Padcev] and sacituzumab govitecan-hziy [Trodelvy], which are 2 new antibody-drug conjugates [ADCs] that have changed the landscape further, along with the addition of erdafitinib [Balversa], which is an FGFR inhibitor.

What factors should be considered when selecting treatment for patients with platinum-eligible vs -ineligible disease?

We look at, in a general sense, whether the patient can get chemotherapy or not, which is defined by [their] performance [status]. If a patient is very frail and uses a lot of assistance in their daily living activities, they [receive] a performance score of 3. Those patients are not usually good candidates for chemotherapy because of the toxicity [they’ll experience]. Those patients, as well as those with significant renal dysfunction or other medical comorbidities, are considered platinum ineligible. In general, [patients with platinum-ineligible disease] will go for palliative care or hospice.

When we look at the platinum-eligible population, these patients are candidates for chemotherapy. Those patients are defined as cisplatin eligible or cisplatin ineligible. We all use the Galsky criteria, which is a combination of the performance status, hearing loss, neuropathy, [New York Heart Association] class III heart failure [status], and, most of all, renal dysfunction. If a patient doesn’t have any of these criteria and they are fit, they are cisplatin eligible. If they have any of those criteria, they are considered cisplatin ineligible.

Those who are platinum- and cisplatin-eligible should get cisplatin and gemcitabine or dose-dense MVAC [methotrexate, vinblastine, doxorubicin, cisplatin, and G-CSF or pegylated G-CSF] as their chemotherapy regimen.

When we talk about cisplatin-ineligible patients, that is an area that is still moving a lot. Initially, we had immunotherapy with pembrolizumab [Keytruda] or atezolizumab [Tecentriq] approved as monotherapy in this setting. [This indication] was later changed to a PD-L1–high population. The recent combination trials [demonstrated] that [combining immunotherapy with] chemotherapy in the first [year of treatment] plays a significant role for these patients. If the patients can get chemotherapy, that is how we should treat them. Right now, the overall consensus is to give carboplatin plus gemcitabine in the first-line setting to patients with cisplatin-ineligible bladder cancer if they are eligible [for chemotherapy].

We also look at PD-L1 status. If patients have PD-L1–low disease and have a high volume of metastases, [we give] carboplatin plus gemcitabine. If they have PD-L1–high disease, we can discuss immunotherapy. Still, we feel that even in patients with PD-L1–high status, that immunotherapy may not be the best choice if they also have a high volume of metastases.

We are moving toward chemotherapy first, followed by maintenance treatment with avelumab. In a very small subset of patients with PD-L1–high disease and a high volume of metastases or lymph node metastases, immune monotherapy with atezolizumab or pembrolizumab would be appropriate.

[The landscape is] still moving, and we have other clinical trials ongoing. Hopefully they will help us further [treatment options] in this specific patient population.

How did the data from the phase 3 JAVELIN Bladder 100 trial (NCT02603432) affect the treatment paradigm of metastatic urothelial carcinoma?

JAVELIN Bladder 100 was a landmark trial because it changed practice. [It affected] how we were treating patients who were getting 4 or 6 cycles of chemotherapy depending on tolerability and response. If patients had a good response [to chemotherapy], we observed them. Once they progressed, they used to get second-line immunotherapy. However, with the response we were seeing in the salvage setting, we looked at whether we could move [immunotherapy] earlier as a maintenance therapy. That’s where the JAVELIN Bladder 100 data play a significant role.

[JAVELIN Bladder 100] was a randomized phase 3 global trial that [enrolled] patients who received chemotherapy with cisplatin plus gemcitabine or carboplatin plus gemcitabine and had a complete response [CR], partial response, or stable disease and randomized them to avelumab [n = 350] or best supportive care [n = 350]. The primary end points were OS in all-comers and the PD-L1–positive population.

We saw that the median OS in all-comers was [21.4] months [with avelumab] vs 14.3 months [with supportive care], with a hazard ratio of 0.69. When we looked at the PD-L1–positive population, the median OS with avelumab was not reached yet vs 17.1 months with best supportive care. So, in the overall population and the PD-L1–positive population, we see significant responses [with avelumab], especially in the PD-L1–high population. Patients who get the maintenance treatment live longer, so that is why [the findings from JAVELIN Bladder 100] were [practice] changing.

When we looked at the subgroup analysis, OS was maintained [irrespective of] the chemotherapeutic [agent used]. That is why [JAVELIN Bladder 100] was a landmark, phase 3 trial that has clearly shown that waiting for patients to progress after chemotherapy is not a good idea. As soon as patients have a response [to chemotherapy], they should be started on maintenance treatment [with avelumab] as soon as possible.

Beyond supportive care, what is the standard treatment for patients with metastatic disease who are ineligible for chemotherapy?

For those patients who are ineligible for chemotherapy, the standard is usually immunotherapy. Immunotherapy has generally been considered more tolerable compared with chemotherapy, although [immunotherapy confers] its own immune-related toxicities. If a patient would like to get treated and the provider feels that an immune monotherapy could be an option for them, that is the current recommendation. If a patient is platinum ineligible, they can get immune monotherapy with atezolizumab or pembrolizumab irrespective of their PD-L1 status.

Could some of the novel agents that are currently approved in later-line settings make optimal combination partners for immunotherapy?

One question is: What should we do after immunotherapy? What happens in the immunotherapy-resistant population? If we look at all-comers, the response rates are between 25% and 30% [with immunotherapy], so the remaining 70% of patients are experiencing disease progression. Here, the ADCs play a significant role because we’ve seen, based on data from EV-103 [NCT03288545], response rates of 70% with enfortumab vedotin plus pembrolizumab. There is some synergistic activity [between the ADCs and immunotherapies]. Further clinical trials will help us see whether these responses are maintained and if we can further increase response rates, change the tumor microenvironment, and turn non-responders into responders.

During the IPC meeting, Jad Chahoud, MD, MPH, of Moffitt Cancer Center, discussed considerations for choosing systemic therapy in RCC. How do you select treatment for these patients?

In [metastatic] RCC, the first-line setting is evolving very fast. We have a couple of good treatment options with comparable response rates and CR rates. In the community, it becomes quite challenging [to determine] which [regimen] to use. I divide patients up by their [International Metastatic RCC Database Consortium Risk Score] to see whether they have favorable- vs intermediate- or poor-risk disease. In patients with favorable-risk scores, the options include pembrolizumab plus axitinib [Inlyta], nivolumab [Opdivo] plus cabozantinib [Cabometyx], and lenvatinib [Lenvima] plus pembrolizumab. Any of these 3 [doublets] is appropriate in the favorable-risk setting. [We have to consider] what other medical comorbidities the patients have, how much hypertension they have, and what their ejection fraction is. All those things come into play because all these TKIs have significant cardiotoxicity. Which drug will we stop first? Then, by stopping the TKI, will the toxicity reverse [itself]?

In the intermediate- and poor-risk populations, we also have nivolumab and ipilimumab [Yervoy]. We have to look at comorbidities, whether the patient is on antihypertensives, and whether their hypertension is controlled or uncontrolled. That will help us see whether a TKI is appropriate in the frontline setting or whether the dual checkpoint inhibitor combination should be given. Secondly, [we have to consider] the sites of metastases, especially if the patient has spinal metastases. Sometimes a checkpoint inhibitor wouldn’t be good because of a phenomenon called pseudo-progression, which is a flare up where the spinal metastasis can increase in size and cause more symptoms.

All these criteria come into play because it is a gray zone; [the choice between regimens] is not black and white. [Treatment selection] depends on which combination the provider is comfortable with and what medical conditions the patient has.

Finally, Jingsong Zhang, MD, PhD, of Moffitt Cancer Center, discussed recent updates in mCRPC during the IPC meeting. Based on available data, what is known about risk stratification in this disease state, and how does risk translate into treatment decisions?

It’s a good question because the answer is not clear. Every clinical trial had their own ways of defining high-risk vs low-risk [mCRPC]. If we look at CHAARTED [NCT00309985] vs LATITUDE [NCT01715285] vs STAMPEDE [NCT00268476], there is not a clear-cut definition of high-risk vs low-risk mCRPC.

I suggest that if the patient has significant disease burden, they should be considered high risk. If the patient has lymph node metastases, they should be considered low risk. Based upon that, treatment should be given [accordingly].

We have novel antiandrogen [agents] like apalutamide [Erleada], abiraterone acetate [Zytiga], and enzalutamide [Xtandi]. All of these agents are approved in the hormone-sensitive prostate cancer [HSPC] setting and all are appropriate [treatment options]. The idea behind HSPC [treatment] is to be as aggressive as possible. Irrespective of a low vs a high volume of metastases, patients are candidates for antiandrogen therapy with these agents. Depending on how the patient is feeling, what other medical conditions they have, patients should receive these novel antiandrogens with androgen deprivation therapy if appropriate. If a patient has a high volume of metastases, they are also a good candidate for chemotherapy based on the CHAARTED trial.