Recap: Experts Discuss Treatment Methodologies in RCC

In conjunction with presentations from the 2022 International Kidney Cancer Symposium, experts convened to discuss best practices for patients with renal cell carcinoma (RCC). The experts discussed recent trial updates as well as different methods for treating patients with either non–clear cell RCC or clear cell RCC. Brian I. Rini, MD, professor of medicine in the Division of Hematology/Oncology at Vanderbilt University in Nashville, Tennessee, led the discussion.

The panel also included Matthew T. Campbell, MD, MS, associate professor in the Department of Genitourinary Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston; Hans Hammers, MD, PhD, the Eugene P. Frenkel, MD, Scholar in Clinical Medicine at UT Southwestern Medical Center in Dallas, Texas; Moshe Ornstein, MD, MA, a genitourinary oncologist at the Cleveland Clinic Taussig Cancer Center in Ohio; and Ulka Nitin Vaishampayan, MBBS, a professor of internal medicine at University of Michigan Medical School Health in Ann Arbor.

Non–Clear Cell RCC

To start the conversation, Rini asked his colleagues how they would typically treat patients with non–clear cell RCC. When given the option of an immunotherapy (IO)/tyrosine kinase inhibitor (TKI) combination or ipilimumab (Yervoy)/nivolumab (Opdivo), Hammers said he preferred to use IO monotherapy. However, he was open to a combination of a TKI and a PD-1 inhibitor, as more substantial response rates have been observed with such combinations.

Rini noted that he often chooses the TKI cabozantinib (Cabometyx) plus nivolumab, an IO agent. However, given the updated results from the phase 3 CLEAR trial (NCT02811861) of the combination of the TKI lenvatinib (Lenvima) and pembrolizumab (Keytruda), another IO agent, he may switch treatment strategies, he said.¹ “The data here [are] compelling, that papillary [disease (non–clear cell RCC)] does have a little less response than clear cell [RCC],” said Campbell. “If we have a [patient with] papillary [disease], we do like to molecularly profile and look for tumors that are potentially MET driven. Cabozantinib/nivolumab and lenvatinib/pembrolizumab are both excellent options for this patient group.”

However, Rini noted that he was wary to use cabozantinib, a MET inhibitor, on patients with papillary disease. Campbell countered, saying that cabozantinib has a unique mechanism of action and has the ability to target MET. Ornstein stated that cabozantinib can be a good treatment for this population; however, in the absence of IO, patients tend to not have improved response, so he will add nivolumab to make a combination therapy.

When discussing the use of an IO/TKI combination or single-agent therapy, Vaishampayan agreed that she too would use single-agent cabozantinib. Currently, she said she doesn’t believe up front combination therapy is needed, except for those with hereditary leiomyomatosis and RCC, whom she would treat with IO as well.

Rini asked if his colleagues would choose atezolizumab (Tecentriq) over nivolumab. Vaishampayan responded that she would use nivolumab over atezolizumab, but that she would prefer pembrolizumab over nivolumab. In a combination treatment, a PD-1 inhibitor would be ideal.

Hammers noted that in some cases, a patient’s insurance will not pay for a combination regimen but will allow the use of pembrolizumab monotherapy. When asked if he would use pembrolizumab to treat a patient with sarcomatoid disease, Hammers continued that he has seen effective responses to [pembrolizumab] in certain patients, so he would still lean toward the IO regimen.

Vaishampayan said that, in the future, debating the importance of IO therapy shouldn’t be a conversation. Different drug combinations and/or monotherapies need to be developed to better treat various diseases and MET [inhibition], she explained, pointing out that an IO agent used in combination with a TKI has shown “suboptimal” results in non–clear RCC, particularly in patients with papillary disease.

Unclassified disease was discussed next. Rini defined it as the incidence of renal cancer when the provider can’t determine what type. Ornstein said that in these situations, he treats patients as if they had sarcomatoid disease, giving IO/TKI combinations to generate those high response rates.

“A lot of these unclassified [diseases] are just clear cell [RCC] in hiding,” said Hammers. “That’s how I think about them, so IO tends to work better in unclassified [disease] than it does in papillary or chromophobe [RCC].” Ornstein asked Hammers if he would consider giving ipilimumab/nivolumab up front. Hammers said that the decision is determined by the tumor burden and whether a patient can afford to have continued disease progression.

On the treatment of unclassified diseases. Vaishampayan noted that she usually uses lenvatinib/pembrolizumab, which she believes helps the patient achieve the best response possible.

Next, Rini asked Ornstein about chromophobe cancer and his preferred treatment options.

“I send for next-generation sequencing, but I do give most of those patients lenvatinib and everolimus [Afinitor],” replied Ornstein.

Campbell agreed with this treatment combination. Currently, he noted, there are limited data on how to treat these patients. “Across all the different subgroups from different studies, there’s always a signal that chromophobes seem to be more responsive to mTOR,” Campbell said.

In conclusion, Hammers said that those with chromophobe disease need to have a VEGF inhibitor as part of their treatment, as IO cannot be relied on for [dissolution of disease].

Clear Cell RCC

Decision of Nephrectomy

For patients with clear cell RCC, debulking nephrectomy may be a viable treatment option. For a patient presenting with metastases, Vaishampayan said she might consider a nephrectomy and a lymph node removal. In addition, she said that she would add IO therapy up front. “The nephrectomy, whether it is a part of their treatment regimen or not, is sort of a secondary consideration after [it has been] established whether the patient will respond to and benefit from immune-based therapy,” she explained.

Hammers considers debulking nephrectomy for those patients who are bleeding from the tumor mass and may have lung nodules, he said. He doesn’t see an issue with removing the mass, as its removal can help improve the patient’s quality of life.

If a patient is healthy enough to withstand debulking nephrectomy, Vaishampayan usually encourages that it be done, she said. Additionally, data from the phase 3 SURTIME trial (NCT01099423), which investigated the use of immediate or deferred cytoreductive nephrectomy in those with clear cell RCC who were receiving sunitinib (Sutent), showed an improved median overall survival of 32.4 months (95% CI, 14.5-65.3) in the immediate surgery arm with sunitinib vs 15.0 months (95% CI, 9.3-29.5) in the delayed surgery arm.² “Now, with our systemic therapy being so much better, are we going to only improve that exponentially? The reality that we’re having so much discussion and controversy [around this]; the question needs to be answered,” said Vaishampayan.

Campbell cited the phase 3 CARMENA trial (NCT00930033), which studied sunitinib alone or after nephrectomy.³ The benefits shown in this trial included that fewer patients needed laparoscopic procedures when sunitinib was offered, which helped to defer nephrectomies.

When nephrectomy is deferred, that time can be used to conduct surveillance and to help determine the natural biology of a patient’s disease, Ornstein stated. He said that he will typically delay nephrectomy for 6 to 9 months and then revisit the possibility.

Stereotactic Body Radiotherapy

The conversation then shifted to when and how to use stereotactic body radiotherapy (SBRT). Vaishampayan said she uses it if she’s trying to delay systemic therapy if oligometastatic disease is involved. Hammers noted that he will use SBRT after ipilimumab/nivolumab treatment, intending it to target any breakout lesions not dismantled by therapy.

Ornstein wondered if it were possible for a patient receiving IO therapy to also receive SBRT. Hammers said he hadn’t seen many studies addressing toxicity in terms of IO treatment and SBRT. However, Campbell reported that SBRT could affect vertebral body metastasis, increasing risk of fracture. Such risk “must be taken very seriously when considering bone-modifying agents, because [fracture] can be devastating for patients. That’s an area where we don’t know how long after treatment to [give SBRT], and there are a lot of unanswered questions. That can be a complication of SBRT to the spine,” said Campbell.

TABLE. Leading Trials in Renal Cell Carcinoma^1,5,6

Frontline Treatment Options

Rini asked the panel members how they choose frontline treatment, and they responded that the International Metastatic RCC Database Consortium plays a role in how they make their choices.⁴ “If [patients] have sarcomatoid features, typically I would go with IO/IO [therapy],” said Vaishampayan. “If they have any other [risk factors]—liver metastases, brain metastases, bone metastases, etc—I tend to go with [an] IO/TKI combination, because of the high response rates. [I think of] the symptomatic nature of the disease: whether a patient has symptoms, impending symptoms, or pleural effusions that are constantly filling up every week. Those things will typically drive me toward using an IO/TKI regimen.”

Ornstein explained that he determines frontline therapy differently, tending to favor IO/TKI regimens but considering IO/IO if there are metastatic disease sites. If patients have pulmonary nodules, he noted that he will consider an IO/IO regimen. Currently, Ornstein said, he uses lenvatinib/pembrolizumab as his usual IO/TKI regimen, as more patients can tolerate the higher dosage. “If they can’t get 20 mg [of treatment], then I don’t think they should get that regimen,” he noted further.

If a combination regimen is involved—no matter what the specific agents are—patients will have overlapping toxicities, according to Ornstein. He said, however, that if a patient can withstand treatment and the resounding effects for 2, 4, or even 6 months, they will likely get 3 to 6 extra years of survival. That statement is “not rooted in data, necessarily, but the idea, the concept, is there,” he stressed. “I find that the first 2 to 4 months are when there are going to be more visits and more dose interruptions and modifications, but once we [get past] that time point, they’re in a much better place,” he said. “I wouldn’t necessarily say ‘cruise control,’ but it’s better.”

Campbell takes a different approach with his patients’ treatment, he said, often beginning lenvatinib at 18 mg. He explained that he likes to be flexible with the ability to increase or decrease dosages if necessary. Vaishampayan pointed out that dose intensity matters. Hammers said that in his practice, he prefers that his patients be on treatment for a certain number of days and then off treatment for a certain number as well (Table).^1,5,6

DISCLOSURE: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Editor's Note: This article was updated on 2/7/2023 and 2/9/2023 to correct errors in which mentions of lenvatinib were inaccurately transcribed as lenalidomide in 3 places, including once in reference to the CLEAR trial in the TABLE.

REFERENCES

1. Voss MH, Powles T, McGregor BA, et al. Impact of subsequent therapies in patients (pts) with advanced renal cell carcinoma (aRCC) receiving lenvatinib plus pembrolizumab (LEN + PEMBRO) or sunitinib (SUN) in the CLEAR study. J Clin Oncol. 2022;40(16 Suppl):abstr 4514. doi:10.1200/JCO.2022.40.16_suppl.4514
2. Bex A, Mulders P, Jewett M, et al. Comparison of immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: the SURTIME randomized clinical trial. JAMA Oncol. 2019;5(2):164-170. doi:10.1001/jamaoncol.2018.5543. Published correction appears in JAMA Oncol. 2019;5(2):271.
3. Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018;379(5):417-427. doi:10.1056/NEJMoa1803675
4. International mRCC Database Consortium [IMDC]. IMDC Online. Accessed December 20, 2022. https://bit.ly/3YE7wTW
5. Motzer RJ, Tannir NM, McDermott DF, et al. Conditional survival and 5-year follow-up in CheckMate 214: first-line nivolumab + ipilimumab (N+I) versus sunitinib (S) in advanced renal cell carcinoma (aRCC). Ann Oncol. 2021;32(Supp 5):S685-S687. doi:10.1016/j.annonc.2021.08.057
6. Choueiri TK, Powles TB, Albiges L, et al. Phase III study of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in previously untreated advanced renal cell carcinoma (aRCC) of IMDC intermediate or poor risk (COSMIC-313). Ann Oncol. 2022;33(Suppl 7):S808-S869. doi:10.1016/annonc/annonc1089