Phase 3 RCC Data Reinforce Efficacy of Standard IO/TKI Doublets Across IMDC Risk Groups

In an interview with OncLive® regarding a State of the Science Summit™ on genitourinary cancer, Yousef Zakharia, MD, reviewed primary findings and updated data from 3 pivotal trials that reinforce the efficacy of standard first-line immuno-oncology (IO)/TKI doublets in metastatic clear cell renal cell carcinoma (ccRCC): the phase 3 KEYNOTE-426 study (NCT02853331) of pembrolizumab (Keytruda) plus axitinib (Inlyta), the phase 3 CheckMate-9ER study (NCT03141177) of cabozantinib (Cabometyx) plus nivolumab (Opdivo), and the phase 3 CLEAR study (NCT02811861) of pembrolizumab plus lenvatinib (Lenvima).

“We have 3 IO/TKI regimens showing consistent improvement in progression-free survival (PFS) across the International mRCC Database Consortium risk groups,” said Zakharia, who served as chair of the event. “An overall survival (OS) benefit [was] mainly [observed] in the intermediate- and poor-risk [patient populations]. However, all 3 of [these combinations] did not show an OS benefit in the favorable-risk [patient populations]. [Therefore], any of those IO/TKI regimens would be appropriate options for our patients with metastatic ccRCC.”

Zakharia, a medical oncologist, vice chair of the Genitourinary Malignancy Disease Group at the Mayo Clinic Comprehensive Cancer Center, and medical director of the Experimental Therapeutics Clinic at Mayo Clinic in Phoenix, Arizona, also highlighted long-term data expanding the use of checkpoint inhibitor–based regimens in more favorable-risk patients with ccRCC in a concurrent interview.

OncLive: What key findings from KEYNOTE-426 have supported the use of first-line pembrolizumab plus axitinib in ccRCC?

Zakharia: KEYNOTE-426 was a randomized clinical trial in first-line ccRCC where patients were randomly assigned to receive either pembrolizumab [at 200 mg every 3 weeks plus] 5 mg of axitinib twice daily or sunitinib [Sutent]. This was the first [trial investigating an] IO/TKI regimen to read out with the dual primary end points of PFS and OS in the intention-to-treat population. The important thing to remember here is that pembrolizumab was stopped at 2 years in this clinical trial but [treatment with] axitinib continued until disease progression or unacceptable toxicity. The overall outcome of this clinical trial remains in favor of pembrolizumab plus axitinib in the long term when it comes to PFS. For OS, we still lack OS positive signals [for the IO/TKI combination] in the favorable-risk patient population. However, in the intermediate- and poor-risk [subgroups], the combination of pembrolizumab and axitinib was superior to sunitinib in terms of OS.

How might long-term and biomarker data from the KEYNOTE-426 trial shape future clinical strategies?

The [most recent] data [from the study], which were presented at the 2024 ASCO Annual Meeting, were biomarker data. Investigators studied different aspects, including the T-cell signature, angiogenesis signature, and PD-L1 status. Patients who had enriched T-cell infiltration tended to do better with pembrolizumab plus axitinib as opposed higher angiogenesis gene expression was associated with improved clinical outcomes in the sunitinib arm, and PD-L1 CPS was negatively associated with OS within the sunitinib arm. This remains an investigational topic, and it’s not yet ready for prime time in the clinic. However, it’s a first step towards finding a good biomarker for metastatic kidney cancer, which we currently lack.

What insights from CheckMate-9ER inform the use of cabozantinib plus nivolumab in intermediate- and poor-risk metastatic ccRCC? What still needs to be known about the regimen’s benefit among favorable-risk patients?

CheckMate-9ER is another metastatic ccRCC trial where patients were randomly assigned to receive either cabozantinib plus nivolumab or sunitinib. In this clinical trial, [treatment with] both nivolumab and cabozantinib continued until disease progression and unacceptable toxicity with a primary end point of PFS per blinded review. A [total of] 651 patients [were enrolled onto the] clinical trial.

Similar to other [trials evaluating] IO/TKI regimens in the favorable-risk population, the PFS was superior with the combination compared with single-agent sunitinib. [However], OS was not superior in the favorable-risk population, as opposed to the intermediate- and poor-risk [populations], for whom both PFS and OS were superior with the doublet vs the single-agent TKI. The overall response rate [ORR] was 55.7% [95% CI, 50.1%-61.2%] with the combination.

At the 2024 Genitourinary Cancers Symposium, there was a presentation of a subgroup analysis [from CheckMate-9ER evaluating the efficacy of cabozantinib plus nivolumab] depending on whether the site of metastasis was in the liver, in the bone, or in the lungs. Relatively speaking, across the board, the benefit was in favor of the combination over sunitinib.

Long-term follow-up data continue to indicate that the combination of cabozantinib and nivolumab is superior to sunitinib, specifically in those patients with intermediate- and poor-risk disease. Whether we would still consider this regimen for favorable-risk patients or stick to a single-agent TKI remains an area of debate in the field. In my practice, I discuss [this question] on a case-by-case [basis], depending on the patient’s presentation.

What do findings from the CLEAR study indicate about the role for pembrolizumab plus lenvatinib in metastatic ccRCC?

The CLEAR study was a third trial of an IO/TKI combination using pembrolizumab plus lenvatinib vs lenvatinib plus everolimus vs sunitinib in metastatic ccRCC with the primary analysis comparing pembro lenvatinib vs sunitinib. Similar to the other studies, the OS benefit was in favor of the combination over sunitinib, mainly in the intermediate- and poor-risk [patient populations]. In the favorable-risk [patient population], there is still no OS signal for the combination vs sunitinib; however, the PFS and ORR outcomes are still in favor of the combination. The ORR [with the combination] was 71% [95% CI, 66.3%-75.7%] which I find interesting. However, this does not necessarily mean this combination is better than other IO/TKI combinations, as we cannot perform cross-trial comparisons.

Getting used to managing adverse effects is key for keeping patients on treatment for a long period of time, [particularly] using early interruption and dose reduction of the TKI. [This is] especially [important for] patients who experience grade 3/4 toxicity.