Clinical Commentary: Finding the Most Beneficial Treatment in Metastatic RCC

Robert J. Motzer, MD

Kidney Cancer Section Head

Genitourinary Oncology Service

Jack and Dorothy Byrne Chair in Clinical Oncology

Memorial Sloan Kettering Cancer Center

New York, NY

Classifying Patients With Metastatic RCC

One of the questions that comes up in terms of characterizing or classifying patients with metastatic RCC is the risk systems that have been reported. The original risk system was the Memorial Sloan Kettering Cancer Center [MSKCC] risk system, which largely characterized outcomes for patients treated with cytokine therapy.¹ More recently is the International Metastatic RCC Database Consortium [IMDC] [risk model], which was produced not from patients who were treated with cytokines, but in a more modern era of patients treated with targeted therapy.² Both risk systems have been used extensively, and for the most part, they overlap.

In terms of assessing risk, [there are several] different risk factors including [the patient’s] Karnofsky performance status; time from diagnosis to treatment, which less than a year is a risk factor; and [their anemia status]. The platelets, neutrophils, and corrected calcium don’t qualify as risk groups. So 0 risk factors are classified as favorable risk, 1 to 2 [risk factors] are intermediate risk, and 3 or more are a poor risk.

Now [sarcomatoid features aren’t included in the risk factors for] a couple reasons. One is these were largely based on clinical characteristics that were done from large databases that didn’t necessarily have a pathology review. The other reason is that sarcomatoid features probably come out in about 10% of patients. It’s not a high proportion of patients, and I don’t think it was assessed in these risk groups as an independent risk factor. But it is seen in a relatively small proportion of patients.

However, it represents an aggressive tumor and is associated with a poor prognosis. Moreover, sarcomatoid features are not a type of kidney cancer, as they’re a variant and based on the appearance of the cells from the histologic specimen. The cells look spindle-like, and they look sarcomatoid. So 2 different variants are lumped together, and one is sarcomatoid and the other is rhabdoid.

Sarcomatoid can occur in any type of RCC histology. For example, you can get papillary RCC with sarcomatoid, and you can get chromophobe with sarcomatoid. So it’s seen in any histology, [and it is] basically a term for when a pathologist looks at the cells and they appear spindle shaped. When it occurs, the tumor is always classified as a grade 4, and it’s not specific histology. It’s independent of the IMDC and it hasn’t been accounted for, but it doesn’t differentiate itself from this IMDC system.

For patients with clear cell RCC with a sarcomatoid feature, our sense is those patients...have an aggressive histology, so they generally do bad. For the most part, they do overlap and fall into the poor-risk group here, but it’s mostly an outcome of these aggressive clinical features that they also display. The other thing with sarcomatoid is that it’s been a bit of an issue among the pathologists because it can occur in different quantities. You can have a tumor that’s got 5% of sarcomatoid features, and you can have one that’s 90%. It’s not that all sarcomatoid features are necessarily poor risk.

The other thing is that the grade and staging are primarily applicable to the primary kidney tumor. Once the tumor’s metastasized, for the most part, all the metastases may not have sarcomatoid features, but all the metastases have grade 4 features.

The tumor grade in terms of a Fuhrman grade is all based on the primary assessment but not the metastases. For your typical patients who have a kidney tumor resected, multiple small nodules, otherwise asymptomatic, the treatment approach that many of us use is surveillance in those patients. Many of those patients can have slowly progressive or stable disease for years with RCC, so surveillance is applicable to some patients; generally, it’s in patients with favorable-risk or small-volume disease.

Deciding on Treatment in the RCC Patient Population

The NCCN [National Comprehensive Cancer Network] guidelines for [deciding treatments for] patients with RCC have some difference between favorable, poor, and intermediate risk regarding the use of nivolumab [Opdivo] and ipilimumab [Yervoy].³ Evidence for [the use of these treatments] was primarily in the poor- and intermediate-risk groups. Outside the use of ipilimumab plus nivolumab, for the most part, the tyrosine kinase inhibitors [TKIs] and immunotherapy [IO] treatments are the same level of evidence for favorable, poor, and intermediate. Now if you are a proponent of ipilimumab and nivolumab, then the risk groups do make a difference. If you are more taken by the TKI-IO therapies, then the treatment is universal regardless of risk group.

But among the TKI-IOs, you have 3 different regimens to choose from without clear evidence of one over another. The axitinib [Inlyta] plus avelumab [Bavencio] treatment was also demonstrated to reach the primary end point of progression-free survival [PFS] in a phase 3 trial [NCT02684006] but did not reach the overall survival [OS] end point.⁴

It has not fallen into favor and use as much as the other PD-1 inhibitors plus TKIs because it was felt to possibly be less effective with a PD-L1 inhibitor than those with pembrolizumab [Keytruda] or nivolumab. [Some treatments] have been pushed off to the right as time goes by, including high-dose interleukin 2, which I think only a handful of people still give in the United States.

Efficacy in First-line Treatments for Metastatic RCC

[There are 4] phase 3 trials that defined first-line therapy for RCC that have readout in the last 5 years or so. Historically, kidney cancer was one of the cancers most resistant to treatment since it’s universally resistant to chemotherapy drugs. For the most part, when I was assigned to develop a kidney cancer program at [MSKCC] in 1988, the standard of care was cytokine therapies with interferon or interleukin 2. That remained the standard for very poor treatment up until sunitinib [Sutent] was approved in 2006.⁵

Sunitinib has become the standard of care for first-line therapy of RCC. Poziotinib is equivalent to our study and shows less toxicity, but the belief was that sunitinib has the strongest efficacy of these TKIs. So recently, 3 combinations were compared [with] sunitinib in large phase 3 trials that displaced sunitinib as the standard of care. [One such trial was] the [CheckMate 214 trial; NCT02231749] comparing ipilimumab and nivolumab vs sunitinib.

The primary end point [of this trial] was in the intermediate- and poor-risk groups.⁶ [This was done primarily] because patients with very aggressive tumors, like sarcomatoid features or poor-risk features, are deemed to do the best with these IO drugs. Patients with favorable risk generally do well for a very long time without progressing, and that’s why we picked that as a primary end point. [The combination] showed benefit in the primary analysis [with 12% complete response (CR) vs 3% and landmark OS of 24 months at 71% vs 61%].

The hallmark of the ipilimumab and nivolumab treatment is that there is a benefit in survival. The response rate, the PFS, and the initial analysis were better for sunitinib compared [with] ipilimumab-nivolumab in the favorable-risk group. That’s why ipilimumab-nivolumab is probably not the best choice for your favorable risk– group patients unless there’s a careful discussion with the patient.

The objective response rate was about 40% in the intent-to-treat group, which is not as high as the TKI-IO therapies that have been studied. The hallmark of ipilimumab and nivolumab is the fact that there’s durability in response and there seems to be a plateau in PFS around 20% to 30% for intermediate- or poor-risk patients treated with it. I think that we’re able to cure some patients with these intermediate- and poor-risk tumors with ipilimumab and nivolumab.

Regarding TKI-IO, there are a lot of suggestions that TKI and IO work together synergistically. The [KEYNOTE-426 trial; NCT02853331] was the first of the TKI-IO combinations that read out and showed a survival benefit.⁷ This trial is a one size fits all for patients with RCC, as it’s characterized by improvement in survival. The caveat around that though is we haven’t been able to see yet a plateau to the curve that suggests the durability we see of response in some [patients treated with] ipilimumab and nivolumab.

The 2 most recent trials were with cabozantinib [Cabometyx] and nivolumab from the [CheckMate] 9ER trial [NCT03141177] and lenvatinib [Lenvima] plus pembrolizumab from the CLEAR trial [NCT02811861]. Cabozantinib plus nivolumab is similar to axitinib and pembrolizumab, as it showed a high response rate, survival benefit, and a longer PFS than sunitinib [HR, 0.52; 95% CI, 0.43-0.64]. The CR rate is on the lower side compared [with] some of the other programs, [at 8% vs 5%], but some of that is subjective. For some people, the data from the CLEAR study [look] the best compared [with] any of the other studies.

Now there are some of real-world comparisons that I’m involved in as well. For the most part, though, the one that I’m involved in is ipilimumab and nivolumab compared [with] a TKI-IO. The only TKI-IO that’s been around long enough to look at survival or PFS comparisons in a real-world setting is axitinib and pembrolizumab. So because of that fact and that lenvatinib and pembrolizumab and cabozantinib and nivolumab are so new, the data [are] not mature. As time goes by, this will be a good opportunity for real-world studies, looking at these different combinations and how they fare in the real world. I think that’s going to be very important.

Effective Dosing in RCC

I think the point to remember is that the starting dose of lenvatinib is 20 mg in the combination [of lenvatinib plus pembrolizumab]. And it’s different than what we see with lenvatinib and everolimus because the starting dose is 18 mg. I think this 20-mg dose of lenvatinib plus pembrolizumab is important for patients with RCC.

In this program, 2 years of pembrolizumab are given first, [and] then the starting dose [of lenvatinib], particularly in first-line patients, is 20 mg, [and then dose] reduce to 14 mg, if you must. If a second dose reduction is needed, go to 10 mg, and then the third down to 8 mg.

I would say the sense is it’s important to start out high with 20 mg for efficacy, but many of the patients that I’ve treated for a long time wind up on 10 mg of lenvatinib over time [because] they have dose reductions for one reason or another.

Understanding the Differences for Locally Advanced RCC

Adjuvant pembrolizumab was entered into the NCCN guidelines for patients with locally advanced RCC and received a 2A recommendation. It is certainly an option for patients with stage II disease that have high-grade tumors or pretty much any patients with stage III disease. For the most part, sunitinib has been pushed down to being a category 3 recommendation.

When the VEGF-targeted therapies were approved, there was a lot of excitement from all of us that these could be the answer for adjuvant therapy. The first 5 trials looked at TKIs, but the last one, the EVEREST trial [NCT00071331], we haven’t heard from yet. And that was a cooperative group trial. For the most part, though, they have been disappointing for a TKI. The only study that met the primary end point was the S-TRAC trial [NCT00375674], which looked at sunitinib vs placebo.⁹

It did have a year of sunitinib therapy, and it met the primary end point of relapse-free survival [HR, 0.76; 95% CI, 0.59-0.98], and it is available because of that. [There are] issues around that, though, [because] 4 other trials with TKIs...didn’t show a benefit, including a very large one: the ASSURE trial [NCT00326898], which probably reflects more community use in the United States.

The S-TRAC [trial] was largely done at big centers around the world, and at MSKCC, we participated in that. I was the highest enroller globally for the S-TRAC trial, but the ASSURE trial was done through the cooperative groups. It probably reflects more real-world practice, and it didn’t show any benefit.

And the others that we did—PROTECT [NCT01235962], ATLAS [NCT01599754], and SORCE [NCT00492258]— [didn’t show any benefit with the TKI] as well. The other problem is that the sunitinib is toxic, and in a year of therapy, many patients did not do so well in terms of tolerability. It’s approved, but the data [are] conflicting. There was also considerable overlap in the patient population between the 3 major trials.

The S-TRAC trial tended to accrue patients that were higher risk, whereas with the ASSURE trial, there were some earlier-stage patients. That’s been one explanation of why, perhaps, the S-TRAC trial showed a positive benefit. But in a subset analysis from the ASSURE trial, where they looked at all the patients matching the population of the S-TRAC [trial], there was no benefit for sunitinib in there. So it’s conflicting data.

Managing AEs in RCC

In 2 of the trials, the PROTECT trial and the ASSURE trial, I treated about 100 patients with TKIs. The thing that was apparent to me, and apparent to others in the study, was that patients didn’t tolerate the TKI toxicity as well in the adjuvant setting.^10,11 They were not as accepting of toxicity in the adjuvant setting as they were in the setting of metastatic disease.

Many [patients exhibited] AEs in terms of skin toxicity and others. The patients would put up with it and try to manage it in the setting of metastatic disease, [but] they were simply intolerable in the adjuvant setting. There was a different scale of acceptability, and I think that was one of the problems with TKIs.

They have AEs, but in the setting of metastatic disease when they became available, people relied on them for the management of the metastatic disease. It’s a different story than if you’re cancer free, so I think tolerability is a real issue.

_REFERENCES

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_{8. 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}

_{9. Staehler M, Motzer RJ, George DJ, et al. Adjuvant sunitinib in patients with high-risk renal cell carcinoma: safety, therapy management, and patient-reported outcomes in the S-TRAC trial. Ann Oncol. 2018;29(10):2098-2104. doi:10.1093/annonc/mdy329}

_{10. Motzer RJ, Haas NB, Donskov F, et al; PROTECT investigators. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma. J Clin Oncol. 2017;35(35):3916-3923. doi:10.1200/JCO.2017.73.5324}

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