Cabozantinib/Nivolumab Combination Findings Further Inform RCC Care

Adam E. Singer, MD, PhD

Longer follow-up data from the phase 3 CheckMate 9ER trial (NCT03141177) has further solidified past findings with other TKI and immunotherapy combinations, showing that patients with favorable-risk renal cell carcinoma (RCC) do not experience the same benefit as those with intermediate- and poor-risk disease, according to Adam E. Singer, MD, PhD.

Singer noted that the findings from CheckMate 9ER with cabozantinib (Cabometyx) plus nivolumab (Opdivo) were similar to those from the phase 3 KEYNOTE-426 trial (NCT02853331) of axitinib (Inlyta) and pembrolizumab (Keytruda), and the phase 3 CLEAR study (NCT02811861) of lenvatinib (Lenvima) and pembrolizumab in a few ways. For example, all 3 trials showed that the combination regimens were superior to sunitinib (Sutent) in terms of progression-free survival (PFS), overall survival (OS), and overall response rate (ORR) in the intention-to-treat (ITT) populations.^1-3

“It’s interesting that [there were] similar findings across the trials [demonstrating that] the IMDC favorable-risk category [groups did not experience an] improvement in OS compared with sunitinib,” Singer added in an interview with OncLive®. “None of the 3 trials [showed] that in the favorable-risk subgroup. Nevertheless, the response rates were higher in the combination arms in all 3 trials.”

In the interview, Singer highlighted findings from CheckMate 9ER, detailing how cabozantinib plus nivolumab compares with other regimens in terms of efficacy and safety. In a concurrent interview, he detailed how he selects between currently available TKI/immuno-oncology therapeutic approaches and immunotherapy monotherapy regimens when treating patients with RCC.

Singer is a health sciences clinical instructor of Medicine and division lead for kidney cancer in the Division of Hematology/Oncology at UCLA Health in Torrance.

OncLive: What were key findings from the CheckMate 9ER trial and how have they influenced the RCC treatment paradigm?

Singer: CheckMate 9ER was a randomized phase 3 trial in which patients with metastatic clear cell RCC were randomly assigned to the combination of cabozantinib and nivolumab, the intervention arm, or sunitinib monotherapy, the control arm. Data showed that the combination of cabozantinib and nivolumab significantly improved PFS and OS for the ITT population. The ORR was also significantly higher with cabozantinib and nivolumab than sunitinib monotherapy.

This finding held up for the IMDC intermediate- and poor-risk subgroups, but for the IMDC favorable-risk subgroup, PFS was borderline in terms of a significant improvement, with [a trend favoring the doublet vs sunitinib observed]—the HR was 0.72. [Additionally], the OS was not significantly different in the favorable-risk population. The 5-year analysis was presented at the 2024 Genitourinary Cancers Symposium and showed that these findings, which were seen on the initial analysis, have [been] maintained over time.

How does the cabozantinib/nivolumab regimen compare with other currently available combination regimens?

For the first-line setting, there are multiple options to choose from. Three of them are combinations of VEGFR/TKI [inhibitors]—axitinib, cabozantinib, or lenvatinib—and an immunotherapy checkpoint inhibitor—pembrolizumab or nivolumab. The 3 TKI/IO combinations are axitinib/pembrolizumab, cabozantinib/nivolumab, and lenvatinib/pembrolizumab. Additionally, there’s one [approach] which is dual immunotherapy with ipilimumab [Yervoy] and nivolumab.

What’s interesting is that these combinations tend to be more tolerable than sunitinib monotherapy, and this was formally analyzed in data from CheckMate 9ER presented at the 2024 ASCO Annual Conference; [data] showed that patients are able to spend more time on therapy with the cabozantinib/nivolumab combination than sunitinib monotherapy.

Furthermore, there appears to be a post-discontinuation benefit. Patients who went off sunitinib on average started their next line of therapy sooner than patients who went off cabozantinib/nivolumab. There appears to be a bit of benefit after discontinuation, which may be attributable to the immunotherapy component because the half-lives are so long—we think that there may continue to be effect after stopping the drug.

What are the most significant challenges in managing toxicities observed with these regimens?

The adverse effect [AE] profiles are fairly similar in terms of what we see, with the caveat of axitinib, which tends to cause fewer AEs than lenvatinib or cabozantinib, but the kinds of AEs it causes are all the same. These are on-target VEGFR inhibition AEs, as well as some off target effects from other kinases that these drugs target. AEs such as diarrhea, nausea, anorexia, hypertension, and fatigue are very common. Hypothyroidism can occur, and proteinuria and dysphonia are somewhat common. Hand-foot syndrome is [also] something we see—cabozantinib tends to cause this more often than the other agents.

But in general, we see higher rates of AEs with these drugs, and that’s just for the TKI component—when you add in the immunotherapy component, the AEs observed with nivolumab or pembrolizumab are [similar to what is seen when] these drugs are used [in] any cancer. The AE profiles of these drugs have been well characterized in the past and continue to be characterized. Immune-mediated AEs, thyroid issues, pruritus, diarrhea, [and additional] AEs that have been well characterized are seen.

References

1. Choueiri TK, Eto M, Motzer R, et al. Lenvatinib plus pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study. Lancet Oncol. 2023;24(3):228-238. doi:10.1016/S1470-2045(23)00049-9
2. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma: 5-year analysis of KEYNOTE-426. J Clin Oncol. 2023;41(suppl 17):LBA4501. doi:10.1200/JCO.2023.41.17_suppl.LBA4501
3. Powles T, Burotto M, Escudier B, et al. Nivolumab plus cabozantinib versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended follow-up from the phase III randomised CheckMate 9ER trial. ESMO Open. 2024;9(5):102994. doi:10.1016/j.esmoop.2024.102994