Pembrolizumab plus lenvatinib: A standard of care in first-line treatment of advanced RCC
31 Mar 2025
byProf. Viktor Grünwald, University Hospital Essen, Essen, Germany
Therapeutic advancements based on immuno-oncology (IO) combinations have revolutionized the treatment landscape for renal cell carcinoma (RCC). In particular, front-line use of immune checkpoint inhibitors combined with tyrosine kinase inhibitors (TKIs) offers superior survival benefits compared with TKI monotherapy or IO-IO combinations. At the 10th Annual Scientific Meeting of the Hong Kong Society of Uro-Oncology (HKSUO) (Uro- Oncology Asia 2025), Professor Viktor Grünwald of the University Hospital Essen, Essen, Germany, presented recent data supporting the broad antitumour activity of pembrolizumab plus lenvatinib in patients with clear- and non-clear-cell RCC histologies.
IO combinations: Standard first-line options
Clear-cell RCC (ccRCC), the most common histological subtype of RCC, accounts for 75–80 percent of RCC cases. [Nat Rev Nephrol 2020;16:435-451] International clinical practice guidelines recommend various IO combinations as first-line systemic treatment for advanced and metastatic ccRCC, especially for patients with intermediate/poor International Metastatic RCC Database Consortium (IMDC) risk criteria. [Ann Oncol 2024;35:692-706; EAU Guidelines 2024] The IMDC categorizes patients with metastatic RCC into favourable, intermediate, or poor risk groups, enabling doctors to better predict a patient’s prognosis and guide treatment decisions accordingly. [J Clin Oncol 2009;27:5794-5799; Lancet Oncol 2013;14:141-148]
IO-TKI fared better than IO-IO or TKI monotherapy for efficacy
Two distinct types of IO combination regimens, IO-IO and IO-TKI, are available for first-line treatment of metastatic RCC. “In key clinical trials, these IO combinations were superior to single-agent sunitinib on several outcomes, demonstrating improved median overall survival [OS, approximately 47–54 vs 29 months], better objective response rates [ORRs, approximately 40–71 vs 30 percent], and impressive 5-year OS rates [approximately 42–48 vs 20 percent],” pointed out Grünwald. [ESMO Open 2024;9:102994; Eur Urol 2023;84:449-454; J Clin Oncol 2023;41:abstract LBA4501; J Clin Oncol 2024;42:1222-1228; Ann Oncol 2024;35:1026-1038; Hammers HJ, et al, IKCS 2021, abstract E39]
“Furthermore, IO-TKI combinations delivered better survival efficacy than IO-IO combination vs sunitinib,” he continued. “With the IO-TKI combinations, the progression-free survival [PFS] benefit was evident early on with immediate separation of the survival curves, whereas this benefit was apparent only after a year of treatment with the dual IO combination. This also translates to an initial robust OS benefit detectable in the OS curves for the IO-combinations.” [ESMO Open 2024;9:102994; Eur Urol 2023;84:449-454; J Clin Oncol 2024;42:1222-1228; Ann Oncol 2024;35:1026-1038]
A network meta-analysis found that pembrolizumab plus lenvatinib provides a similar OS and trend of improvement in PFS and response outcomes to most other frontline treatments for advanced RCC. [Grünwald V, et al, ASCO GU 2024, abstract 482]
ARON-1 RW study: Longer OS, lower primary progression with IO-TKI
In the absence of head-to-head prospective trials comparing IO-IO vs IO-TKI combinations, real-world (RW) data can provide insights into how these therapies perform in routine clinical practice in a broader range of patients, including those often not included in highly selective clinical trial populations. The ARON-1 project, an ongoing RW database, was designed to create a global network of uro-oncologists to share insights on immunotherapy and other treatments for genitourinary tumours.
Within the ARON-1 project, one of its studies collected and analyzed RW data on first-line use of IO combinations in patients with metastatic RCC. The retrospective analysis included 729 patients, of whom 86 percent had ccRCC. Median follow-up duration was 18.1 months. [Target Oncol 2023;18:559-570]
Among the 616 patients with intermediate/poor IMDC risk, median OS was significantly longer with IO-TKI compared with dual IO therapy (55.7 vs 29.7 months; p=0.045). (Figure 1) [Target Oncol 2023;18:559-570]. Although this observation is of interest, retrospective analyses remain prone to known and unknown confounders, which impact outcome data and render medical interpretation of such comparisons complex.
Another analysis of ARON-1 investigated the prevalence and clinicopathological characteristics of primary refractory (Pref) patients, a subgroup whose disease progresses despite first-line treatment.
“The highest rate of primary progression was observed in patients treated with nivolumab plus ipilimumab [27 percent], whereas the lowest rate was reported for pembrolizumab plus lenvatinib [10 percent]. Patients with primary progression on contemporary therapies have poor survival,” noted Grünwald. This observation from routine practice is in line with clinical trial data. Among 1,709 patients included in the analysis, 19 percent were Pref. Median OS in these patients was significantly lower than in patients who responded to therapy (7.6 vs 55.7 months; p<0.001), with respective 2-year OS rates of 27 and 77 percent. [Target Oncol 2024;19:893-903]
CLEAR study: New data
In the open-label, randomized, phase III CLEAR study, pembrolizumab plus lenvatinib (n=355) significantly improved PFS and OS vs sunitinib (n=357) in patients with previously untreated advanced RCC. [N Engl J Med 2021;384:1289-1300] A post hoc analysis of the CLEAR study was performed to explore efficacy outcomes according to baseline prognostic features. [Int J Cancer 2025;156:1326-1335]
Tumour shrinkage by organ site
The most common metastatic sites in the pembrolizumab plus lenvatinib and sunitinib arms, respectively, were lung (71.0 and 63.9 percent), lymph node (45.6 and 43.7 percent), bone (22.5 and 24.9 percent), and liver (17.7 and 19.6 percent). Greater depth and breadth of tumour shrinkage were observed in target lesions across all four sites for patients in the pembrolizumab plus lenvatinib vs sunitinib arm. [Int J Cancer 2025;156:1326-1335]
Delayed organ tumour progression
In addition to tumour shrinkage, longer time to organ-specific progression was observed with pembrolizumab plus lenvatinib vs sunitinib: lung (hazard ratio [HR], 0.48; 95 percent confidence interval [CI], 0.36–0.62), lymph node (HR, 0.63; 95 percent CI, 0.46–0.85), bone (HR, 0.40; 95 percent CI, 0.25–0.63), and liver (HR, 0.52; 95 percent CI, 0.32–0.84). [Grünwald V, et al, ASCO 2024, abstract 4524]
Lower tumour burden at progression
At the time of overall disease progression, median decreases in sums of target lesion diameters were greater with pembrolizumab plus lenvatinib vs sunitinib (-48.1 vs -17.4 percent). “Therefore, even as patients start progressing on pembrolizumab plus lenvatinib, they are still in a better state compared with baseline,” emphasized Grünwald. [Grünwald V, et al, ASCO 2024, abstract 4524]
Efficacy irrespective of tumour burden
Patients in the pembrolizumab plus lenvatinib arm were grouped into quartiles according to baseline tumour burden (Q1: ≤34.72 mm; Q2: >34.72 to ≤60.06 Q4: >108.56 mm) and efficacy outcomes were compared among the four categories. “Median PFS [27.6, 25.3, 27.7 and 22.1 months, respectively] and objective response rates [ORRs; 75.3, 80.0, 72.8 and 71.3 percent, respectively] were similar across all groups irrespective of tumour burden. Additionally, lower tumour burden was associated with more complete responses, which can be useful when setting patient expectations regarding treatment responses,” noted Grünwald. [Grünwald V, et al, ASCO GU 2024, abstract 364]
OS benefit maintained across subgroups
An earlier exploratory subgroup analysis of the CLEAR study data showed that OS results generally favoured pembrolizumab plus lenvatinib over sunitinib, irrespective of metastatic lesions (lung, bone or liver) at baseline, prior nephrectomy, or sarcomatoid features. [Front Oncol 2023;13:1223282]
Broad activity in rare RCC subtypes
Rare RCC histologic subtypes, which are collectively called non-clear-cell RCC (nccRCC), include papillary, chromophobe, and translocation RCC, among others. [Nat Rev Nephrol 2020;16:435-451]
KEYNOTE-B61 study
The prospective, single-arm, phase II KEYNOTE-B61 study (n=158) evaluated pembrolizumab plus lenvatinib as first-line treatment for patients with advanced nccRCC. After a median follow-up of 22.8 months, an updated analysis showed an overall ORR of 50.6 percent and a complete response rate of 8.2 percent. [Voss M, et al, ASCO GU 2024, abstract 2]
“Deep tumour responses were reported across the different histological subtypes,” said Grünwald. The overall reduction in tumour burden was 88.6 percent, and rates in the papillary, unclassified, chromophobe, and translocation/ other subgroups were 96.6, 95.0, 84.0, and 93.3 percent, respectively. (Figure 2) [Voss M, et al, ASCO GU 2024, abstract 2]
“Median PFS was 17.9 months [range, 15.1–22.1 months], which is comparable to the PFS observed for this regimen [23.9 months] in the CLEAR study,” highlighted Grünwald. (Figure 3) [Voss M, et al, ASCO GU 2024, abstract 2; N Engl J Med 2021;384:1289-1300]
Summary
RW evidence indicates that first-line use of IO-TKI combinations are effective in patients with advanced RCC and offers an activity profile, which is distinct from IO-IO. Pembrolizumab plus lenvatinib demonstrated survival benefits and broad antitumour activity vs sunitinib alone irrespective of baseline prognostic features. The combination also showed efficacy in rare subtypes of RCC, making it a suitable first-line treatment option for patients with advanced nccRCC subtypes.
