Treatment with zanzalintinib plus nivolumab (Opdivo) demonstrated early antitumor activity and safety in patients with untreated advanced or metastatic clear cell renal cell carcinoma (ccRCC), though the addition of relatlimab (Opdualag) to this doublet did not appear to increase responses or survival outcomes after a shorter period of follow-up, according to Jad Chahoud, MD, MPH.1
Patients in the dose expansion cohort of the phase 1 STELLAR-002 trial (NCT05176483) showed a confirmed overall response rate of 63% (95% CI, 46%-77%) in the doublet arm (n = 40) compared with 40% (95% CI, 25%-57%) in the triplet arm. Confirmed complete responses (CR) and confirmed partial responses (PR) were achieved in 8% and 55%, respectively, in the doublet arm. These respective rates were observed in 3% and 38% of patients in the triplet arm.
“In our dose escalation cohort, we identified the dose and the safety, and we also saw some signals and patients with [ccRCC]. Patients with prostate cancer and patients with colorectal cancer [CRC] had some initial responses, even on the dose escalation cohort, and that helped us to move forward with the dose expansion cohorts,” Chahoud said in an interview with OncLive®.
In the interview, Chahoud explained the background and the impetus for evaluating zanzalintinib plus nivolumab with or without relatlimab in the STELLAR-002 study, the design of the study, and the key efficacy and safety data from the study.
Chahoud is an associate member in the Department of Genitourinary Oncology and the medical director of IPOP at Moffitt Cancer Center in Tampa, Florida.
OncLive: What was the background and rationale of the STELLAR-002 study?
Chahoud: STELLAR-002 is a phase 1, multiple-arm, dose escalation, cohort expansion trial trying to look at a new VEGF TKI, zanzalintinib, that has a shorter half-life, which usually helps a lot with the management of a lot of the multi-TKI toxicities. [The agent is being evaluated] in combination with nivolumab, either alone or in combination with relatlimab, which is a LAG-3 inhibitor. [The study] has multiple arms beyond the dose expansion, [including] multiple genitourinary cohorts. We presented the clear cell cohorts of nivolumab plus zanzalintinib alone and zanzalintinib plus nivolumab and relatlimab.
Going back to the thought process of [the trial], most currently approved frontline therapies for ccRCC are a combination of immuno-oncology [IO] plus VEGF TKIs or an IO/IO combination; no triplet [regimens] have been approved.
What were the key methods and design of the study?
The dose escalation [phase was a] regular dose-finding cohort, looking at the combination of nivolumab plus zanzalintinib and nivolumab plus relatlimab plus zanzalintinib. [Our goal is to identify and] take the optimal dose into those expansion cohorts that are in ccRCC or non-ccRCC, [as well as] other cancers, like prostate cancer and CRC.2 At [the 2025 ASCO Annual Meeting, we presented data from both] the dose escalation and nonrandomized dose escalation ccRCC cohort. Patients were enrolled onto the first arm [and treated with] nivolumab plus zanzalintinib every 4 weeks. The other arm was nivolumab plus relatlimab plus zanzalintinib, [administered] every 4 weeks. Each cohort enrolled 40 patients. The cohorts were enrolled sequentially and were not open at the same time.
Within the dose escalation, what we could reconfirm is the safety of the combination. We found that [both] the doublet and the triplet [were] tolerable and safe. We found the optimal dosing, was nivolumab at 480 mg every 4 weeks, and zanzalintinib at 100 mg [once daily]; the triplet [comprised] nivolumab plus relatlimab [at a fixed dose of 480 mg each] every 4 weeks with zanzalintinib at 60 mg [once daily]. That took us to the other expansion cohorts, [where we focused] more on the clear cell cohorts.
The patient characteristics reflect [a typical] real-world patient population that we see in our clinic.1 [In the doublet arm,] the median age was 68 years, and patients ranged in age from 48 years to 81 years. The IMDC risk group was representative of real-world data, with 75% of patients [in the doublet arm] being in the intermediate or poor risk group, and the other 25% in the favorable risk group.
The [study’s] primary end point was safety and ORR, and the key secondary end point was progression-free survival [PFS].
What were the key efficacy data from the dose expansion cohort?
Looking at the clinical efficacy [in the dose expansion cohort,] we saw an ORR of 63% with the nivolumab/zanzalintinib doublet; 8% achieved CRs, and 55% achieved PRs.1 Interestingly, in this arm, only 5% of patients had disease progression. We also had an additional patient who switched [to a] confirmed PR after the data cutoff.
Interestingly, the ORR with the triplet was lower at 40%, with only 3% [of patient achieving a] CR, and [38% showing a] PR. There are still 5 patients who [may achieve a] confirmed PR with longer follow-up. We’ve [also] had longer median follow-up time with the doublet, at 20.1 months vs 15.9 months for the triplet.
The disease control rate [among] partial responders, complete responders, and patients who had stable disease was 90% [95% CI, 76%-97%]. The median time to treatment response was also in line with [our expectations for] IO/TKIs, with a median time to ORR of 2.1 months in the doublet arm and 3.6 months in the triplet [arm]. The median duration of response [DOR] was not reached in either cohort; interestingly, the 12-month DOR rate was [73.4% in the doublet arm and 74.1% in the triplet arm]. [Furthermore,] we saw a median PFS of 18.5 months [95% CI, 9.5-not evaluable (NE)] in the doublet cohort and 13.0 months [95% CI, 7.4-NE] in the triplet cohort.
What should be known about the safety profile of zanzalintinib plus nivolumab with or without relatlimab in ccRCC?
From a safety standpoint, patients had treatment-emergent adverse effects [TEAEs] in both arms, which is what we would expect from IO/TKIs. We expected grade 3/4 toxicities, with hypertension, diarrhea, and [lower rates] of palmar-plantar erythrodysesthesia, nausea, and vomiting. The median time on treatment was 16.1 months [range, 0.5-24.8] with the doublet vs 10.9 months [range, 0.5-17.1] with the triplet. The main reason for [treatment] discontinuation on the doublet arm was [related] to disease progression.
References
- Chahoud J, McGregor BA, Torras OR, et al. Zanzalintinib (zanza) + nivolumab )nivo) ± relatlimab (rela) in patients (pts) with previously untreated clear cell renal cell carcinoma (ccRCC): results from an expansion cohort of the phase 1b STELLAR-002 study. J Clin Oncol. 2025;43(suppl 16):4515. doi:10.1200/JCO.2025.43.16_suppl.4515
- Garmezy B, O’Neill B, Shah NJ, et al. Zanzalintinib (zanza) + nivolumab (nivo) ± relatlimab (rela) in patients (pts) with advanced solid tumors: results from two dose-escalation cohorts of the phase 1b STELLAR-002 study. J Clin Oncol. 2025;43(suppl 16). doi:10.1200/JCO.2025.43.16_suppl.3101