Lenvatinib/Pembrolizumab Maintained Beneficial Outcomes When Evaluated by Tumor Size in RCC

Lenvatinib (Lenvima) plus pembrolizumab (Keytruda) demonstrated efficacy irrespective of tumor burden in patients with advanced renal cell carcinoma (RCC) in the overall patient population of the phase 3 CLEAR study (NCT02811861), according to data presented at the 2023 Genitourinary Cancers Symposium.¹

In an evaluation of 322 patients enrolled on the CLEAR trial, it was found that patients with the highest tumor burden had a median overall survival (OS) of 39.5 months (95 CI, 32.1-48.7), and OS improved with lower tumor volume, with 3-year OS rates ranging from 55.6% in the highest burden subgroup to 73.0% in the lowest burden subgroup.

“With extended follow-up of the CLEAR study, progression-free survival [PFS], OS, and objective response rate [ORR] benefits with lenvatinib plus pembrolizumab were observed across patients with [advanced] RCC irrespective of their baseline tumor size,” Viktor Grünwald, MD, a professor for Interdisciplinary Genitourinary Oncology at the University Hospital Essen in Essen, Germany, said in a presentation of the data.

Investigators shared that they had an interest in exploring the connection between tumor burden at treatment initiation and subsequent clinical outcomes. Therefore, to delve into this data, investigators examined the mature efficacy dataset from the CLEAR study with a data cut-off of July 31, 2022, providing a 4-year median follow-up time for the exploratory and post-hoc analysis.

Notably, the final prespecified OS analysis of CLEAR was reported at the 2023 ASCO Annual Meeting and showed that the median OS was 53.7 months (95% CI, 48.7-not estimable [NE]) with lenvatinib plus pembrolizumab (n = 355) vs 54.3 months (95% CI, 40.9–NE) with sunitinib (Sutent; n = 357; HR, 0.79; 95% CI, 0.63-0.99; P = .0424).²

Additionally, the ORR was 71.3% (95% CI, 66.6%-76.0%) with the combination vs 36.7% (95% CI, 31.7%-41.7%) with sunitinib and the complete response rates (CRs) were 18.3% and 4.8%, respectively. Finally, the median progression-free survival was 23.9 months (95% CI, 20.8-27.7) with lenvatinib plus pembrolizumab vs 9.2 months (95% CI, 6.0-11.0) with sunitinib (HR, 0.47; 95% CI, 0.38-0.57; P < .0001).²

Results from the Subgroup Analysis by Lesion Size

Looking into this mature dataset, investigators evaluated the exploratory subgroup of patients assigned to the treatment arm from the CLEAR trial. They then sorted patients into quartiles in conjunction with the size off their target lesion. Q1 (n = 81) included patients with a lesion 34.72 mm or less, Q2 (n = 80) included patients with lesion greater than 34.72 mm and up to 60.06 mm, Q3 (n = 81) evaluated patients with a lesion between 60.06 mm and 108.56 mm, and Q4 (n = 80) included patients with lesions greater than 108.56 mm. It was also noted that IMDC risk group was not a stratification factor, and therefore, relevant data were derived programmatically.¹

The overall response by tumor size was 75.3% (95% CI, 65.9%-84.7%) in Q1, 80.0% (95% CI, 71.2%-88.8%) in Q2, 72.8% (63.2%-82.5%) in Q3, and 71.3% (95% CI, 61.3%-81.2%) in Q4. This included CRs (29.6%; 22.5%; 11.1%; and 2.5%) near-CRs (19.8%, 20.0%, 24.7%, and 8.8%), and other partial responses (25.9%; 37.5; 3.0%; and 60.0%). Stable disease rates were 16.0% in Q1, 16.3% in Q2, 11.1% in Q3, and 18.8% in Q4. The progressive disease rates were 7.4%, 1.3%, 9.9%, and 3.8%, respectively.

Furthermore, the median PFS for patients treated within cohorts Q1, Q2, Q3, and Q4 was 27.6 months (95% CI, 13.1-35.9), 25.3 months (95% CI, 16.6-37.0), 27.7 months (95% CI, 16.7-42.2), and 22.1 months (95% CI, 12.7-25.9), respectively.

Enrollment in CLEAR By Quartiles

The median age of patients included in the study was 63.0 years (range, 34-78), 64.0 (36-84), 64.0 (39-80), and 64.5 (38-88), in patients across quartiles 1, 2, 3, and 4, respectively. Furthermore, 54.3%, 60.0%, 56.8%, and 60.0% of patients were from Western Europe or North America across this groups of patients, and 45.7%, 40.0%, 43.2%, and 40.0% of patients were from the rest of the world, respectively. When looking to MSKCC prognostic risk group, patients had favorable vs intermediate and poor risk in Q1 (32.1% vs 67.9%), Q2 (32.5% vs 67.5%), Q3 (25.9% vs 74.1%), and Q4 (8.8% vs 91.3%).

Looking at IMDC risk groups across quartiles, 40.7%, 58.0%, and 1.2% of patients had favorable, intermediate, or poor risk disease in Q1; 30.0%, 68.8%, and 1.3% in Q2; 34.6%, 65.4%, and 0.0% in Q3; and 6.3%, 93.8%, and 0% in Q4. Notably, 9.9%, 8.8%, 4.9%, and 6.3% of patients had sarcomatoid features, respectively.

Further, 25.9% and 32.1%; 37.5% and 28.8%; 37.0% and 34.6%; and 23.8% and 33.8% of patients had PD-L1 expression greater than or equal to 1 vs less than 1, respectively. A total of 87.7%, 88.8%, 76.5%, and 38.8% of patients, respectively, had a prior nephrectomy.

“Taken together, these results further support lenvatinib plus pembrolizumab as a first-line treatment for patients with [advanced] RCC, irrespective of baseline tumor size,” Grünwald concluded.

References

1. Grünwald V, Motzer RJ, Haanen JB, et al. Subgroup analyses of efficacy outcomes by baseline tumor size in the phase 3, open-label CLEAR trial. J Clin Oncol. 2024;42(suppl 4):364. doi:10.1200/JCO.2024.42.4_suppl.364.
2. Motzer RJ, Porta C, Eto M, et al. Final prespecified overall survival (OS) analysis of CLEAR: 4-year follow-up of lenvatinib plus pembrolizumab (L+P) vs sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC). J Clin Oncol. 41, 2023 (suppl 16):4502. doi:10.1200/JCO.2023.41.16_suppl.4502