Patient Considerations for Using Dual Immunotherapy for RCC

Targeted Oncology: What is the significance of the CheckMate 214 trial (NCT02231749) in patients with advanced clear cell renal cell carcinoma (RCC), and how do you approach using this regimen?

TANNIR: This is the first trial that showed overall survival [OS] benefit for a combination that beat a single-agent TKI [tyrosine kinase inhibitor], sunitinib [Sutent].¹ Patients received nivolumab [Opdivo] plus ipilimumab [Yervoy] every 3 weeks for up to 4 cycles [of ipilimumab]. Even if the patient has bulky disease, even if a patient is symptomatic, we do not know which patients are going to respond to nivolumab/ipilimumab and which are going to respond to IO [immunotherapy] plus TKI. But initially when nivolumab/ipilimumab was investigated, the protocol asked to wait until they finish all 4 doses of ipilimumab, give all 4 cycles of nivolumab/ipilimumab, then scan them. If I see the patient has low-volume disease or intermediate-volume disease every 3 weeks and they’re still doing OK…I believe it is important to give all 4 doses of ipilimumab. I would [choose] nivolumab/ipilimumab because I want to see a response that’s durable.

But the downside—the advocates of IO/TKI would [point out] the progressive disease rate is 18% for the intent-to-treat population and 19% in intermediate-risk patients.² They are worried they may not be able to get the patient to a second line. We want the patient to get to a second, third, and fourth line. So…if the patient is symptomatic, I do the scans after 2 cycles. If they continue to have symptoms, especially if those symptoms worsen, and the scans show progressive disease, I am not going to go to the third and fourth cycle, because that’s a waste of time. Then I correct course and may go to a TKI. I learned that after we launched the CheckMate 214 trial 10 years ago.

What therapy would you prefer for patients with central nervous system (CNS) metastases?

Those patients were excluded from all these trials. Nivolumab/ipilimumab for RCC is different than nivolumab/ipilimumab for melanoma. [Data were] published in The New England Journal of Medicine [concerning] response rate in the brain.³ Brain metastases responded to nivolumab/ipilimumab in melanoma [at a rate of 57%], a very high response rate at the brain. The patients with metastatic melanoma with brain metastases given nivolumab/ipilimumab responded in the viscera, bone, and brain. That’s not the same with RCC. For somebody with brain metastases, it depends. Is it 1, 10, or 20 [lesions]? Are these small lesions in the brain without edema and without hemorrhage, and is the patient symptomatic or totally asymptomatic and neurologically intact?

I order MRI of the brain for patients with stage IV RCC, even if I’m not enrolling the patient in clinical trials. If there is a symptomatic or threatening brain metastases, we address it first and then I don’t have any problem giving them nivolumab/ipilimumab if they have brain metastases. Nivolumab/ipilimumab is not going to shrink these tumors in the brain, so I’ll take care of that with Gamma Knife or surgery if Gamma Knife is not appropriate…then go with systemic therapy. In patients who achieve a complete response [CR] with nivolumab/ipilimumab, unfortunately one of the relapse sites is the brain, so you have to deal with that. I’m very pleased with achieving a CR with nivolumab/ipilimumab, but I’m going have to keep an eye on whether they develop brain metastasis after achieving extracranial CR. But…we have the MRI-linac and can do Gamma Knife radiation therapy. I have several of these patients who are in CR with nivolumab/ipilimumab who had some brain metastases, were treated with a Gamma Knife, and they’ve gone 3 or 4 years without recurrence in the brain.

What other sites of metastasis can shape treatment selection?

At the American Society of Clinical Oncology Genitourinary Cancers Symposium in January, I [presented on] sites of metastasis, how the patients with different sites of metastases, lung, liver, and bone respond to nivolumab/ipilimumab.² Bone is one of those sites that respond less to nivolumab/ipilimumab compared with cabozantinib [Cabometyx] plus nivolumab.

But if we say that cabozantinib is active in patients with bone metastases, that doesn’t mean that lenvatinib [Lenvima] plus pembrolizumab [Keytruda] is not active in bone metastases. Patients with clear cell RCC that’s metastatic to the bone also respond to lenvatinib/pembrolizumab, and respond to nivolumab/ipilimumab. I have patients [with metastases in the] bone, liver, and lungs whose disease [has CR with] nivolumab/ipilimumab. What we do not have are data on who will respond to nivolumab/ipilimumab vs respond to IO/TKI.

Except…there is consensus among all the investigators in RCC for sarcomatoid [RCC]. Nivolumab/ipilimumab should be given to patients with sarcomatoid clear cell RCC.⁴ The CR rate with nivolumab/ipilimumab is 23%. Where survival traditionally with a single TKI for these patients is 13 or 14 months, it’s more than 4 years median OS, and 60% objective response rate [ORR], whereas if they don’t have sarcomatoid [RCC], the ORR is 42% in that intermediate/poor risk [group]. When you look at the IO/TKI, nothing compares. The percentage of patients with stage IV clear cell RCC who have any sarcomatoid, from focal sarcomatoid to 99% sarcomatoid…[is] 10% to 15%. It’s not trivial, so that’s an important point.

_References:

_{1. Albiges L, Tannir NM, Burotto M, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020;5(6):e001079. doi:10.1136/esmoopen-2020-001079}

_{2. Tannir NM, Escudier B, McDermott DF, et al. Nivolumab plus ipilimumab (NIVO + IPI) vs sunitinib (SUN) for first-line treatment of advanced renal cell carcinoma (aRCC): long-term follow-up data from the phase 3 CheckMate 214 trial. J Clin Oncol. 2024;42(suppl 4):363. doi:10.1200/JCO.2024.42.4_suppl.363}

_{3. Tawbi HA, Forsyth PA, Algazi A, et al. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N Engl J Med. 2018;379(8):722-730. doi:10.1056/NEJMoa1805453}

_{4. Rini BI, Signoretti S, Choueiri TK, et al. Long-term outcomes with nivolumab plus ipilimumab versus sunitinib in first-line treatment of patients with advanced sarcomatoid renal cell carcinoma. J Immunother Cancer. 2022;10(12):e005445. doi:10.1136/jitc-2022-005445}