Zhang Discusses Factors Influencing Frontline Therapy for Advanced RCC

Tian Zhang, MD, MHS (MODERATOR)

Associate Professor

Harold C. Simmons Comprehensive Cancer Center

The University of Texas Southwestern Medical Center

Dallas, TX

Event region: Texas

CASE SUMMARY

The patient is a 61-year-old man with an active lifestyle and a history of low-volume, indolent, metastatic clear cell renal cell carcinoma (RCC). After left nephrectomy and adrenalectomy, he was observed based on his preference and the low volume and indolence of disease.

Three years after surgery, continued indolent growth and increased total tumor burden (new paratracheal lymph nodes [2 × 1.5 cm] and more than 10 pulmonary nodules) were seen on CT scan. A lung biopsy confirmed metastatic RCC (mRCC). Laboratory results were within normal limits, and ECOG performance status was 0.

DISCUSSION QUESTION

• How does risk status influence your frontline decision-making for a patient with mRCC?

ZHANG: Does risk status influence your first-line decision-making for a patient like this? This is very much a favorable-risk disease, but what if [it] was borderline favorable/intermediate?

RODNEY: Yes. The first 3 options [in the poll] I would pick or have no issue with across the board. I will typically look at ipilimumab [Yervoy]/nivolumab [Opdivo] in the intermediate- to high-risk group, at least [according to] the NCCN [National Comprehensive Cancer Network guidelines].¹

That does include most of the patients, so I look at the risk categories in making the decision. [For] favorable-risk [disease], I think about the first 3 options.

ZHANG: What are your thoughts if he had borderline [anemia and]
his hemoglobin [level] was 11.5 g/dL? At that borderline intermediate status, would you pick something different for him?

RODNEY: You would have both time and a patient, in terms of getting a response. The IO [immunotherapy] combination of ipilimumab/nivolumab is a reasonable choice in that patient population.

DISCUSSION QUESTION

• What else drives your selection of first-line therapy?

LAZO: We have the good fortune to have a lot of different regimens we can use now, a difference from even 5 years ago. We know from the nature of RCC [that] sometimes patients have a very different disease progression, and some of them can be favorable candidates who can be placed on active surveillance.

The regimen that we use will depend on a lot of different things, including the patient’s performance status, the age of the patient, patient preference, how they tolerate it, sometimes insurance issues, and familiarity with our regimens. I chose cabozantinib [Cabometyx] and nivolumab. But in patients with higher-risk [disease], I usually use lenvatinib [Lenvima] and pembrolizumab [Keytruda]. It depends on a lot of different circumstances.

ZHANG: All options are available, and you think about the patient in front of you.

RODNEY: Dr Lazo, do you have a certain experience that leads you to the lenvatinib/pembrolizumab combination, even though they all cross the same territory?

LAZO: I have treated a few patients with lenvatinib and pembrolizumab, and they have a good tolerance and acceptable disease response. I don’t know what your experience is, but for the most part, it is well tolerated. It depends on the patient population. In South Texas, our population is older…so we need to choose something that is not going to hurt them too much.

GUO: I use the IMDC [International Metastatic RCC Database Consortium] for risk stratification.² In the first line, I’m using lenvatinib and pembrolizumab a lot more in the past year, and before that I used IO/IO and axitinib [Inlyta] plus pembrolizumab a lot more. The reason is [that] the new data show a much higher response rate and CR [complete response] rate and we have had more experience managing the adverse events [AEs] and dose adjustment for lenvatinib.³ Also, the AEs of immunotherapy with IO/IO, if you have one of the bad cases, can be challenging to manage.

ZHANG: What tips somebody from IO/IO to VEGF TKI [tyrosine kinase inhibitor]/IO?

GUO: I rarely use IO/IO. If I feel the need to treat, I use lenvatinib/pembrolizumab.

DISCUSSION QUESTION

• What do you think of the longer-term results of the CheckMate 9ER (NCT03141177) trial?

ZHANG: We would love to hear…what your thoughts are now that we have more follow-up and longer-term follow-up [data] showing sustained overall survival [OS] improvement [From the Data⁴].

DALAL: I don’t think there is any surprise here. We do expect this kind of separation compared with TKI monotherapy. If you look at any IO/TKI combinations, the data would be similar.

ZHANG: Do you use cabozantinib/nivolumab in this setting, or would it translate into any of the VEGF TKIs/IOs?

LUU: I have used cabozantinib/nivolumab not in clear cell RCC but in non–clear cell RCC.

DASGUPTA: I would expect cabozantinib/nivolumab to have won over sunitinib [Sutent]. It is more modern, and it’s a combination. When we were using sunitinib, it was so toxic that I never had good luck using it. I am not surprised by the data; I would have expected [them]. I have not used it myself; I haven’t had the chance to. I have been more of a lenvatinib/pembrolizumab [user] so far. But [I have] nothing against this.

ZHANG: What do you all think about having this stability of the hazard ratio [HR, 0.70; 95% CI, 0.56-0.87] for OS?⁴

In [findings from] many of these phase 3 trials, as we get more and more follow-up, some of these hazard ratios trend up a little. Do you read into that? Or do you think what we expected initially, and now that we have cleaner data, more real events, we’re still expect[ing] this hazard ratio?

RODNEY: It seems like what I would expect. The biggest unmet answer comes into the comparison of things that we want to pick compared with the trial [results], which [are against] sunitinib. Until there is a definitive winner, it does come down to the factors measured in terms of individual experience, access to therapy, AEs, and the issues of patient satisfaction with frequency of treatment or access to the oral therapies vs not [having access].

DISCUSSION QUESTION

• How do the PFS [progression-free survival] and OS results from the CheckMate 9ER follow-up affect your choice of treatment?

ZHANG: There are some discussions [that] as you get more follow-up, you also get more events and cleaner data overall. Early on, if our median follow-up was only at 18 months, for example, we’d get more modeling, and we are [now] seeing the effect of more events.

ZHANG: It would be great to hear from you all…about the PFS vs OS hazard ratios. Do you think about this in the favorable-risk population and whether to use that VEGF TKI/IO combination vs single-agent TKI?

MAZHARUDDIN: The data are good. [Cabozantinib/nivolumab] is somewhat comparable [with] the other IO/TKI combinations.

ZHANG:[Looking at the] intention-to-treat [population] vs breaking out by IMDC risk groups, do you care that the favorable-risk population hasn’t shown separation? Do you use cabozantinib/nivolumab in this favorable-risk population?

MAZHARUDDIN: In that favorable-risk population, I typically use the IO/TKI combination because I don’t have other great options in that scenario. In general, I don’t use a lot of nivolumab/cabozantinib, but in favorable-risk [disease], I would use IO/TKI.

ZHANG: Why do you not use too much nivolumab and cabozantinib?

MAZHARUDDIN: [It requires] dosing every 2 weeks vs every 3 weeks [for other IO/TKI regimens]. The outpatients get tired.

RODNEY: It does come down to both access and convenience issues. It would be great to see a separation between the different competitors of what we would like to use, but of all 3, it does come down to individual nuances of AEs as well as the access and availability of the patient to receive the care.

DISCUSSION QUESTION

• What are your thoughts on the outcomes for continued TKI after the IO is stopped in the CheckMate 9ER follow-up?

ZHANG: Do you think that there is anything to read into here, with the majority of patients receiving cabozantinib monotherapy after they have stopped nivolumab?⁴ This was just presented at ASCO GU [2023 American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco, California].

XIONG: This is the first time I have looked at this data curve, but it is interesting to look at the comments. I have patients [with favorable-risk disease] who tend to stop TKI[s] and continue immunotherapy. But in this study, it is the opposite. This probably reflects what we experience in clinical practice, especially for patients in the favorable- or intermediate-[risk] prognostic group, though we expect the patients to be on treatment for 2 years or longer. So that is not a surprise to me.

ZHANG: This was a prespecified cutoff of the immunotherapy, but you are telling us in your practice you would rather stop the VEGF TKI component, the oral treatment, and continue their immunotherapy?

XIONG: My impression of TKIs is that they tend to cause everyday AEs, sometimes ones that are grade 2. But they are everyday and bothersome, like diarrhea, which leads to some malnutrition status in my patients. If these patients have some complications, I tend to stop TKI but continue immunotherapy. With immunotherapy, if you have complications, it can be bad. But if you don’t, [there are sometimes] no AEs at all.

ZHANG: It is important to know that the treatment density of the oral therapies can cause ongoing toxicities, whereas if [patients] are 2 years into their immunotherapy, sometimes we are not seeing so many long-term AEs, although those immune complications can occur at any point.

_References

_{NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 3.2023. Accessed June 12, 2023. https://bit.ly/3tcwJXG}

_{International mRCC Database Consortium. IMDC. Accessed May 18, 2023. https://bit.ly/3JaLIZI}

_{Motzer R, Alekseev B, Rha SY, et al; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716}

_{Burotto M, Powles T, Escudier B, et al. Nivolumab plus cabozantinib vs sunitinib for first-line treatment of advanced renal cell carcinoma (aRCC): 3-year follow-up from the phase 3 CheckMate 9ER trial. J Clin Oncol. 2023;41(suppl 6):603. doi:10.1200/JCO.2023.41.6_suppl.603}