Immunotherapy Combinations Appear Efficacious in Long-Term Follow-up of Advanced RCC

Nivolumab (Opdivo) in combination with ipilimumab (Yervoy) sustained survival benefit over time as treatment of patients with poor- to intermediate-risk advanced renal cell carcinoma (RCC), according to long-term follow-up from the phase 3 CheckMate 214 study, which was presented during the 2020 European Society of Medical Oncology (ESMO) Virtual Congress.

This immunotherapy-based regimen received its approval from the FDA in April 2018 for the treatment of patients with intermediate- and poor-risk advanced RCC based on the findings from CheckMate 214. The co-primary end points of the study included investigator-assessed objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) in previously untreated patients with intermediate- and poor-risk metastatic RCC. Secondary end points aimed to evaluate the ORR, OS, and PFS among the intent-to-treat (ITT) patient population in the study.

The study randomized patients 1:1 to receive either the combination regimen or sunitinib (Sutent), and the updated findings of the CheckMate 214 study represent 4 years of follow-up in this patient population. To date, this is the longest follow-up for a phase 3 study of an immunotherapy-based combination as treatment of patients with previously untreated advanced RCC.

In an interview with Targeted Oncology, Laurence Albiges, MD, PhD, medical oncologist, chair Genitourinary group, and vice chair, Department of Cancer Medicine, Gustave Roussy Institute, discussed the updated findings for the combination of nivolumab and ipilimumab as treatment of patients with intermediate- and poor-risk advanced RCC.

TARGETED ONCOLOGY: What sort of magnitude of benefit have we seen so far with the combination of nivolumab and ipilimumab?

Albiges: The CheckMate 214 trial has been previously reported and what is being presented this is more as extended follow up. The magnitude of benefit that was initially reported was on the primary end point population of patients with first-line metastatic clear cell RCC (ccRCC) with intermediate- and poor-risk disease, which accounted for about 80% of our patient population. This trial was positive for OS, and what we have now presented at ESMO is the extended follow-up with a minimum follow-up of 48 months. We have results both on the primary end point population, intermediate and poor, but also of course, in the ITT population.

TARGETED ONCOLOGY: What were the findings in the primary population?

Albiges: What we're seeing is a benefit across the different endpoint that has been analyzed with a sustained OS benefit of 0.65 with the intermediate- and poor-risk population. We also see a benefit in terms of PFS as well as the ORR. It is to say that this benefit is seen also through the response rate of patients achieving complete responses. About 11% of patients achieved a complete response, and these data are very consistent over time, meaning that patients that derived benefit are still having this benefit with long follow-up of about 4 years.

TARGETED ONCOLOGY: What did we see in the ITT population with this combination?

Albiges: I think this piece is very important as well as the trial is positive for primary end point of OS in the ITT population as well. The hazard ratio (HR) is 0.69 as well. This is very strong data, and I think it provides a lot of insight. We have to look closely to all the different sub-populations, including patients with low risk. For the first time, the OS HR in the low risk patient population is below 1. However, it is to be said that sunitinib, which was the comparator arm of the trial, derived better results in terms of both ORR and PFS in the low risk population.

TARGETED ONCOLOGY: Were there any new safety signals with the longer follow-up?

Albiges: There were no new safety signals, but we should emphasize that the vast majority of toxicity occurred within the first 6 months with this approach. With a longer follow-up, we have no new toxicity being reported.

TARGETED ONCOLOGY: How have these data changed your practice, particularly in regard to those with favorable risk disease?

Albiges: These data are providing us long-term activity information. The doublet is being used in patient with intermediate- and poor-risk population in France where I work, but I think it is important to also understand that there's a lot of translational and biomarker work that helps to define those patients that will derive benefit from this doublet. Some trials, such as the bionic trials presented at ESMO, actually tried to look at gene expression profiling to better define if a patient should be allocated to doublet or single agent. This is a lot of work ongoing, and for the moment, nivolumab plus ipilimumab is 1 of our standards of care in first-line treatment for patients with intimidate and poor risk.

TARGETED ONCOLOGY: These data are the longest follow-up from a phase 3 study of an immunotherapy-based regimen, but this isn’t the only combination regimen like this regimen under investigation. With 3 other FDA-approved combination regimens and the positive data from the CheckMate-9ER study, how has this impacted your frontline treatment approach?

Albiges: I think you're right when you stress the fact that the long follow-up is something that is very clinically relevant for all physicians, that we are treating patients with this disease. What we want to see in our patient is a great magnitude of benefit in terms of OS that is sustained over time with a good quality of life. Therefore, having these very long-term data is important to us. It is great that we have the opportunity to select within 1 patient between having a doublet immunotherapy approach or a VEGF tyrosine kinase inhibitor plus immunotherapy strategy. This is something that we discuss for each patient based on the clinical presentation, based on the existing comorbidities or symptoms related to the disease, and therefore, we actually define our strategy within each patient individually. However, having the choice between those different approaches is important, and while we were talking here about ccRCC, we should have in mind that there are also other tumor types, such as non-clear cell, where we still need to move the field forward.

TARGETED ONCOLOGY: What are your final thoughts in regard to these data?

Albiges: For the first time, these trials are loading to provide insight on a subpopulation that is patients who did not have prior nephrectomy. It's the first time that we now have nivolumab plus ipilimumab a benefit being investigated in this sub-population. It is very interesting to see that in a subset of patient that have a very dismal prognosis, and we see a clear benefit in favor of nivolumab plus ipilimumab over sunitinib for those patients who did not have prior surgery. On top of the great HR that is being reported in this population, we also see tumor shrinkage on the primary, meaning that those patients with a doublet of nivolumab plus ipilimumab see a reduction in their primary tumor that is more than 30% with the doublet in 35% of patients versus 20% only with sunitinib single agent.

I think it is very reassuring. We're in the era of CARMENA. We want to prioritize systemic treatment in patients who require systemic treatment, of course. We can tell our patients that the primary is likely to respond as well, we're not dealing with progressive disease on the primary, and that the magnitude of benefit is also seen in the sub-population of very at-risk disease.