Lenvatinib/Pembrolizumab Yields Greater Clinical Benefit vs Sunitinib Regardless of Biomarker Subtypes in ccRCC

Toni Choueiri, MD

Regardless of patient biomarker subtype, lenvatinib (Lenvima) plus pembrolizumab (Keytruda) produced greater clinical benefit vs sunitinib (Sutent) in advanced clear cell renal cell carcinoma (RCC) when the primary end point of progression-free survival (PFS) and secondary end point of objective response rate (ORR) of the phase 3 CLEAR trial (NCT02811861) were examined.

Findings from a biomarker analysis of CLEAR presented at the 2024 ASCO Annual Meeting revealed that PFS consistently favored lenvatinib plus pembrolizumab vs sunitinib regardless of mutation status of RCC driver genes. A PFS benefit was observed in patients with mutated VHL (HR, 0.48; 95% CI, 0.39-0.58), PBRM1 (HR, 0.51; 95% CI, 0.34-0.78), SETD2 (HR, 0.58; 95% CI, 0.34-1.01), BAP1 (HR, 0.47; 95% CI, 0.26-0.86), and KDM5C (HR, 0.48; 95% CI, 0.24-0.98),which were the most frequently mutated genes.

Additionally, patients with wild-type disease also experienced a PFS benefit with the combination vs sunitinib, including those with wild-type VHL (HR, 0.53; 95% CI, 0.34-0.82), PBRM1 (HR, 0.48; 95% CI, 0.34-0.67), SETD2 (HR, 0.46; 95% CI, 0.34-0.62), BAP1 (HR, 0.48; 95% CI, 0.35-0.64), and KDM5C (HR, 0.49; 95% CI, 0.37-0.65).

“We initially reported as part of the study [PFS by] PD-L1 immunohistochemistry [IHC] using the combined positive score [CPS] cutoff of 1 and at that time the benefit was consistent. But here we looked at PD-L1 [IHC CPS] as a continuous variable in the lenvatinib/pembrolizumab arm [n = 219; P = .2301] vs the sunitinib arm [n = 222; P = .0670] and there is no difference; we cannot use PD-L1 here to pick 1 treatment vs another,” Toni Choueiri, MD, said in a presentation of the findings. Choueiri is director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, co-leader of the Kidney Cancer Program at Dana-Farber/Harvard Cancer Center, and the Jerome and Nancy Kohlberg Chair and Professor of Medicine at Harvard Medical School in Boston, Massachusetts.

Additionally, gene signature scores were not associated with PFS outcomes for the lenvatinib plus pembrolizumab arm. However, Choueiri noted that “when we look at single-agent sunitinib, not surprisingly, 2 out of 3 angiogenesis signatures—notably the angiogenesis (P < .1) and the microvessel density (P < .1)—were associated with better outcomes to the VEGF TKI sunitinib, and this is another validation, one of many. On the other hand, 2 other signatures—proliferation (P < .1) and MYC (P < .1)—were associated with worse outcomes with sunitinib and worse prognosis.”

PFS by gene signature scores in each treatment arm were examined by 1 T-cell inflamed (GEP), 2 immuno-oncology (monocytic myeloid-derived suppressor cells and granulocytic myeloid-derived suppressor cells), 3 angiogenesis (angiogenesis, microvessel density, and Angio36), and 7 pan-cancer signatures. The signatures for pan-cancer were proliferation, MYC, RAS, WNT, stroma/epithelial-mesenchymal transition/TBFβ, glycolysis, and hypoxia.

Patients treated with combination of lenvatinib plus pembrolizumab also experienced a longer PFS vs sunitinib regardless of having a high or low signature. The most prominent benefit was reported in the angiogenesis-low (HR, 0.39; 95% CI, 0.27-0.57), GEP-low (HR, 0.41; 95% CI, 0.24-0.68), MYC-high (HR, 0.42; 95% CI, 0.30-0.60), Angio36-low (HR, 0.44; 95% CI, 0.31-0.63), RAS -low (HR, 0.44; 95% CI, 0.30-0.64), and hypoxia-low (HR, 0.44; 95% CI, 0.30-0.65) subgroups.

“[Regarding] the primary end point of PFS, the combination is active irrespective of PD-L1 IHC. It’s active and improved PFS and response rates vs sunitinib regardless of RCC driver gene mutation status or gene signature subgroups,” Choueiri said.

Evaluating Biomarkers in CLEAR

CLEAR enrolled adult patients with advanced clear cell RCC who did not receive prior systemic anticancer therapy for RCC. Patients had a Karnofsky performance of at least 70 and were stratified by geographic region (Western Europe and North America vs rest of the world) and Memorial Sloan Kettering Cancer Center (MSKCC) risk category (favorable, intermediate, or poor). Patients were then randomly assigned 1:1 to receive lenvatinib 20 mg daily plus pembrolizumab 200 mg every 3 weeks vs lenvatinib 18 mg daily plus everolimus (Afinitor) 5 mg daily vs sunitinib 50 mg daily given for 4 weeks on and 2 weeks off. This biomarker analysis of the study solely focused on the lenvatinib plus pembrolizumab and sunitinib arms.

At baseline, PD-L1 expression was evaluated in 441 patients via the IHC pharmDx assay, gene alteration was evaluated in 380 patients via the whole-exome sequencing ImmunoID NeXT platform, and gene expression was evaluated in 388 patients via the RNA-sequencing ImmunoID NeXT platform.

“[When examining] the full analysis set [of] 355 [patients in] the combination [arm] and 357 [patients receiving] sunitinib and comparing it with the PD-L1, whole exome sequencing DNA,and RNA sequencing [analysis sets], there wasn’t a major difference in baseline characteristics [regarding] risk factor by MSKCC or International Metastatic RCC Database Consortium [(IMDC) criteria] or PD-L1 [CPS]. Even more importantly, when you look at activity in terms of PFS and response rate, there is also no difference between the total clinical set and the biomarker set.”

In the full analysis set, regarding clinical outcomes, patients achieved a median PFS of 23.9 months (95% CI, 20.8-27.7) in the lenvatinib plus pembrolizumab arm vs 9.2 months (95% CI, 6.0-11.0) in the sunitinib arm (HR, 0.48; 95% CI, 0.39-0.58). The ORR was 71% vs 37%, respectively. Additionally, by MSKCC risk evaluation, patients had favorable- (27%), intermediate- (64%), and poor- (9%) risk disease in both the lenvatinib plus pembrolizumab and sunitinib arms. By IMDC risk evaluation, patients had favorable- (31% vs 35%), intermediate- (59% vs 54%), and poor- (9% vs 10%) risk disease in the combination vs sunitinib arms, respectively. Patients had a PD-L1 CPS less than 1 (32% vs 29%), 1 or greater (30% vs 33%), or not available (38% vs 38%), respectively.

ORR Analysis and Further Data

Trends observed with ORR were similar to those seen with PFS, as the ORR was higher for the combination vs sunitinib irrespective of the 5 gene mutations examined and gene signatures across high/low subgroups.

Lenvatinib plus pembrolizumab led to a superior ORR vs sunitinib among patients with mutated VHL (80.3% vs 38.6%), PBRM1 (80.0% vs 34.4%), SETD2 (85.4% vs 48.8%), BAP1 (58.8% vs 36.7%), and KDM5C (85.7% vs 37.9%), respectively. The ORRs also favored the combination vs sunitinib in patients with wild-type VHL (65.6% vs 37.3%), PBRM1 (72.7% vs 40.0%), SETD2 (72.4% vs 35.1%), BAP1 (78.9% vs 38.4%), and KDM5C (73.9% vs 38.2%), respectively.

Molecular subtypes included in the CLEAR analysis were informed by analyses of RCC datasets from Merck as well as analyses of the phase 3 JAVELIN Renal 101 study (NCT02684006) and phase 3 IMmotion 151 study (NCT02420821), which Choueiri noted were both examining VEGF/immunotherapy combinations vs sunitinib.

“Tumors of patients with IMDC favorable- and intermediate- risk [disease] were enriched in the angiogenesis and angiogenesis/stromal clusters,” Choueiri highlighted. “On the other hand, the poor-risk [tumors] were enriched in the proliferative cluster and [tumors that were] PD-L1–positive were enriched in the immune proliferative cluster. But does that mean that the combination of lenvatinib/pembrolizumab would be better in some clusters or perhaps the same as sunitinib? The answer is no. Looking at response rates, PFS, and this RCC specific cluster signature, the combination of lenvatinib/pembrolizumab remains superior to sunitinib in all the clusters tested.”

Across all molecular subtype clusters, the median PFS in the combination arm (n = 192) was 24.3 months (95% CI, 18.6-28.6) compared with 9.4 months (95% CI, 6.0-11.1) in the sunitinib arm (n = 196). Numerically higher tumor responses and longer PFS were observed across all 5 molecular subtypes: angiogenesis/stromal, angiogenesis, immune/proliferative, proliferative, and stromal/proliferative.

“The combination of lenvatinib/pembrolizumab showed clinical benefit over sunitinib in patients with first-line advanced clear cell RCC regardless of all the biomarkers we tested; this is the first test,” Choueiri said. “PFS analysis confirmed the superiority of the combination irrespective of PD-L1 IHC. When we look at the top gene mutations [and] the signature the [results show the] same [trend] whether the signatures are cancer signatures in general or kidney cancer-specific molecular subtypes.”

Reference

Motzer RJ, Porta C, Eto M, et al. Biomarker analyses in patients with advanced renal cell carcinoma (aRCC) from the phase 3 CLEAR trial. J Clin Oncol. 2024;42(suppl 16):4504. doi:10.1200/JCO.2024.42.16_suppl.4504