Frontline Cabo/Nivo in RCC Supported by Risk Status, Metastasis Analyses

Rana McKay, MD

Associate Professor of Medicine

University of California San Diego​

San Diego, CA​

Targeted Oncology: Could you describe the updated data from the CheckMate 9ER trial (NCT03141177) in patients with metastatic renal cell carcinoma (RCC)?

RANA MCKAY, MD: The phase 3 CheckMate 9ER studywas a large study for patients with previously untreated advanced/metastatic RCC. Patients with any International Metastatic RCC Database Consortium risk factor were randomly assigned 1:1 to nivolumab [Opdivo] plus cabozantinib [Cabometyx] vs sunitinib [Sutent] and the dosing for cabozantinib was 40 mg—less than what we would traditionally use for monotherapy cabozantinib at 60 mg. The primary end point was progression-free survival [PFS]. Key secondary end points were overall survival [OS], response, and safety.

Updated data were presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium in January.¹ At the 55.6-month follow-up, data for PFS, OS, and response for the intent-to-treat population, not just the favorable-risk [group, were presented]. We’re continuing to see a benefit over time from a PFS standpoint and the delta between the Kaplan-Meier curves is holding steady; the curves aren't necessarily coming together. There's [over] 10% difference in PFS [rate at 48 months]. Median PFS was 16.4 months with cabozantinib/nivolumab compared with 8.4 with sunitinib, and the HR was 0.58 [95% CI, 0.49-0.70].

[Median] OS in the intent-to-treat population was 46.5 months with cabozantinib/nivolumab compared with 36 months with sunitinib; the HR was 0.77 [95% CI, 0.63-0.95]. This is the entire population. [For] just favorable risk, the HR [confidence interval] was overlapping. But there was a 10% delta from sunitinib [for OS at 48 months]. Objective response rate [ORR] was approximately 56% with the combination with a complete response rate of 14%. These early efficacy end points of response and PFS are impressive.

Then there was the breakout [of PFS and OS] by favorable, intermediate, and poor risk. I think the benefit is driven by the intermediate- and poor-risk patients where the HR was 0.56 for PFS and 0.73 for OS. For favorable risk, PFS was significant but then we started to see that HR trend above 1.0 for the favorable-risk OS. OS is challenging for favorable-risk patients, and I think the reason why over time the HR may drift is these patients tend to see multiple subsequent lines of therapy, which is going to color our ability to be able to assess the OS difference. They're going to get a second line, and some may get third and fourth lines as these are favorable-risk patients, and the longer they live, the more drugs they see. That's probably why we see the curves coming together.

Should patients with favorable-risk disease receive single-agent tyrosine kinase inhibitor (TKI) followed by immunotherapy?

What we've seen is in VEGF-TKI–exposed patients—the original studies of nivolumab/ipilimumab [Yervoy] in RCC were done in later-line settings; they weren't done in frontline. We were not seeing the durability of response and the depth of response, as opposed to using it in front line. When we look at the original CheckMate 025 data [NCT01668784] of nivolumab alone in the second line, the ORR was 25%.² The complete response rate was less than 10%. There's a question of durability with that regimen. In my practice, unless somebody has an autoimmune disease, I rarely use single-agent TKI.

Immunotherapy tends to work the best in RCC early and upfront. What we need to keep in mind is the favorable-risk subset analyses that we're doing for these studies were not powered to be able to assess differences in these subgroups. This is an exploratory exercise. Getting their first-line therapy right is important, which is why I tend to lean towards nivolumab/ipilimumab because that's where you have the opportunity to cure. If you use nivolumab later, we have not seen that same durability.

What adverse events (AEs) are of most concern with cabozantinib/nivolumab?

The safety profile from CheckMate 9ER showed diarrhea was the most common AE as any grade at 59%, and grade 3/4 at 7%.¹ Hand-foot syndrome, hypertension, fatigue, and hypothyroidism are the things to look out for. Aspartate aminotransferase [AST] and alanine aminotransferase [AST] increases [were seen] especially with cabozantinib: just under 30% any grade, grade 3/4 in 4% and 6% [for AST and ALT, respectively], so these are things to be mindful of. Overlapping toxicities are the things that we tend to struggle with in the clinic: the hepatitis, the diarrhea, and some of the endocrinopathies.

How does site of metastases impact outcomes with cabozantinib/nivolumab?

There was a post hoc exploratory analysis looking at PFS and OS by sites of metastases.³ Looking at for patients with liver, bone, or lung metastases, across the board, there was a benefit to cabozantinib/nivolumab independent of where the sites of metastases are. What’s striking is, though cabozantinib has a track record in the bone, how pronounced the PFS benefit is. It's almost approaching that of the patients with lung metastases. We know the patients with bone metastases do poorly but the PFS with nivolumab/cabozantinib approximates that of those with lung metastases for those patients with bone metastases. The HR was 0.38 [95% CI, 0.25-0.59]. It does seem to have efficacy independent of the sites of metastases.

REFERENCES:

1. Bourlon MT, Escudier B, Burotto M, et al. Nivolumab plus cabozantinib (N+C) vs sunitinib (S) for previously untreated advanced renal cell carcinoma (aRCC): Results from 55-month follow-up of the CheckMate 9ER trial. J Clin Oncol. 2024;42(suppl_4):362. doi:10.1200/JCO.2024.42.4_suppl.362

2. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-1813. doi:10.1056/NEJMoa1510665

3.Apolo AB, Powles T, Burotto M, et al. Nivolumab plus cabozantinib (N+C) versus sunitinib (S) for advanced renal cell carcinoma (aRCC): outcomes by baseline disease characteristics in the phase 3 CheckMate 9ER trial. J Clin Oncol. 2021;39(suppl 15):4553. doi:10.1200/JCO.2021.39.15_suppl.4553