Case Studies Illustrate the Importance of Nuanced Treatment Discussions in Advanced RCC

Hans Hammers, MD, PhD

Given the various frontline combination treatment options available for patients with metastatic renal cell carcinoma, choosing the appropriate therapy for each individual can present a challenge, according to Hans Hammers, MD, PhD.

“Balanced discussions with patients about the pros and cons of [different frontline combination] regimens are important. [In the patient] cases we chose, we can see some differences there, [which highlighted] some of the main ongoing discussions in the field,” Hammers said in an interview with OncLive^® following a State of the Science Summit™ on bladder cancer and RCC, which he chaired.

In the interview, Hammers outlined 3 patient cases presented during the meeting, detailing how each patient’s disease presented and how clinicians proceeded with treatment. Hammers also highlighted factors that could help inform these decisions and ongoing research within the RCC landscape.

Hammers is a professor in the Department of Internal Medicine and a member of the Division of Hematology and Oncology at the Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center in Dallas, Texas. He is also the inaugural Eugene P. Frenkel, MD, Scholar in Clinical Medicine.

Patient Case 1

Hammers: The first case is that of a young gentleman. He was 48 years old at the time of diagnosis and had a large left renal mass, and he was also found to have large metastatic lesions in the liver. This was all biopsy confirmed and was a case of clear cell RCC.

He was seen in urology, was deemed to be unresectable, and was sent to medical oncology. This was in 2017, just around the time when immune checkpoint inhibitors became available. He had access to nivolumab [Opdivo] plus ipilimumab [Yervoy], and he was started on that therapy.

When we discussed treatment, he expressed his biggest wish was to buy some time to see his son graduate. We also talked about some of the adverse effects [AEs associated with treatment]. The alternative to immune checkpoint inhibitors at the time would have been just a single-agent TKI.

He was started on immunotherapy and received 2 doses of nivolumab/ipilimumab. When he presented for the third [dose], we saw that he had very significant elevations in his kidney function tests in the sense of autoimmune nephritis. He was started with immune suppression. Therefore, several questions arose around this [patient]. What was the role of cytoreductive nephrectomy for this patient? There was certainly a reason why he was sent from urology to us. The takeaway message here is when in doubt, give systemic therapy. This has really been the message and the trend over the past few years.

In [a patient such as] this young gentleman, I would say the trend is to give immune checkpoint inhibitors with a PD-1 and CTLA-4 inhibitor combination, since the long-term outcome is more favorable with this regimen. However, the AE portfolio is that of autoimmune disease. He required significant immune suppressive therapy with 2 different immune suppressive agents, [including] prednisone and mycophenolic acid. Despite that, he had a very significant treatment effect, particularly in his liver metastases, but also in his primary.

After 1 year of therapy and 6 months of immune suppression, he maintained very deep response, and he underwent surgical consolidation. There was no evidence of any metastatic cells in the liver though there were some residual viable tumor [cells] in the kidney primary. He is now more than 5 years out, without any evidence of recurrence, and in total, he received only 2 infusions of immune checkpoint inhibition.

The summation is that patients can do really well on this particular therapy. Sometimes you can get treatment refractory autoimmune AEs, but they don't necessarily take away from the benefit from this therapy overall.

Patient Case 2

This was a 66-year-old female [who was in an outpatient facility with significant pulmonary infiltrates, which caused respiratory distress. She was brought from an outside institution to UT Southwestern where she was diagnosed with [widespread] metastatic RCC with a very large left renal mass and numerous lung deposits with an inflammatory halo around them and significant oxygen requirements. I saw her at the time in the hospital as a consultant, and it was very clear that that she needed to start systemic therapy right away.

[This patient] started on lenvatinib [Lenvima] and pembrolizumab [Keytruda], and she had significant benefit from lenvatinib early on with reduction in oxygen requirements. [Because of this], she could leave the hospital and she started pembrolizumab as outpatient [treatment]. More than a year later, she had a very deep response to this therapy, but she developed polymyalgia rheumatica. Some of the questions [that arose at the meeting] were around how to manage that. [She] took a treatment break from immunotherapy and from the TKI to see which [treatment] contributed most [to the AE]. Did she have an immune-mediated AE or was it more TKI therapy driven? If [the AE] was mostly driven by the TKI, then we would restart [pembrolizumab], and if it was mostly driven by the immunotherapy, then we may give her a few more doses now that she's on lower levels of prednisone to consolidate.

We also talked about surgical consolidation. Her tumor was felt by urology to be highly avascular, almost like a flaccid bag, that they felt could be reduced with minimal interventional surgery. We also talked in general terms about radiation in some patients [with those types of tumors]. She did uniquely well, again with some complications, and we will see where that goes.

Patient Case 3

We had a third case of a patient who progressed shortly after initial treatment with adjuvant immunotherapy. This was a 64-year-old patient in 2018. This patient was participating in an adjuvant clinical trial for grade 3 clear cell RCC. He was on the PD-L1 inhibitor atezolizumab [Tecentriq], and he was only exposed to [atezolizumab] for roughly 6 months. However, he had inflammatory AEs that he did not tolerate, so he left the study.

A few months later, he had progressive disease with multiple deposits in the abdomen that continued to enlarge. He was rechallenged with nivolumab plus ipilimumab, leading to a significant shrinkage of these lesions and loss of enhancement. He received the full 2 years of immunotherapy. He is now almost 5 years out from that therapy and is doing well with no need for any further immunotherapy.

In that context, we discussed the potential appetite for surgical intervention or radiation with lesions that were partially close to the bowels, with the suggestion that they should be treated systemically.

This is another example of patients who progressed on prior PD-L1 or PD-1 therapeutic exposure where treatment with a CTLA-4 inhibitor can drive some benefit. This is a situation that is going to become more important as we learn more about how these patients do on adjuvant pembrolizumab, for example.

Among these 3 cases, what stands out as the most controversial areas that have yet to be settled with level 1 evidence?

An ongoing debate and where the data are now coming in are regarding long-term outcomes with some of these therapies. The 2 main categories of therapies [in the frontline setting include] dual checkpoint inhibition and the combination of a PD-1 inhibitor with a TKI. In the presentations prior to these cases, we touched upon some of these [data]. We got some long-term follow-up data at the 2023 ASCO Annual Meeting. I would say there was sobering data on the PD-1/TKI combinations when indirectly compared with the phase 3 CheckMate 214 trial [NCT02231749]. Unfortunately, we never had a direct head-to-head comparison of these [combinations] in the United States. However, the Europeans are now engaging in a trial to be a little bit more definitive.

The cases that we had showed a little bit of the difference in [the types of patients we see]. You can overtly progress on dual immune checkpoint inhibition; 20% of patients do. A treatment like that would have been the wrong choice for the patient who was in the hospital and needed a response so she could leave the hospital. [This is different] from somebody who walks into our office [such as the patient in the first case study]. Yes, the patient had metastases in the liver, but there were no major liver abnormalities. He was doing well and was a young patient who wanted to invest in a potential long-term outcome.

There are some practitioners who stick with 1 [type of combination] or the other, but there are some clinical criteria that can help us to decide which one to go with.

Looking toward the future, are there any ongoing or planned trials that you would like to highlight?

We are all waiting for the results coming in on HIF-2α inhibitors; they’re certainly positioned to change the treatment landscape. This is a completely new class of drug that is uniquely well tolerated, and in patients with conducive biology, can lead to prolonged responses with a unique quality of life. The AEs primarily surround anemia. It is a new class of drugs that's coming either as a single agent, potentially in the form of [belzutifan (Welireg)] from a pivotal phase 3 trial [NCT04195750], or in combination with a TKI.

Triplet therapies are also being tested. For example, lenvatinib with a CTLA-4 inhibitor [quavonlimab] and pembrolizumab, or with belzutifan and pembrolizumab, [are being evaluated vs lenvatinib plus pembrolizumab in the phase 3 MK-6482-012 trial (NCT04736706)]. These trials have just accrued, so it will be years from now until we know [the results], but triplet therapy is in the works; we will see how that goes.

One triplet therapy trial included the combination of cabozantinib [Cabometyx] with nivolumab and ipilimumab in the phase 3 COSMIC-313 trial [NCT03937219]; unfortunately, [this triplet] had excessive toxicity and may not be an option. I don't think it will be widely used if it were to be approved because of punishing liver toxicity. However, efforts are being made to find agents that are combinable, with reasonable toxicity and, hopefully, good long-term outcome.