Extended Follow-Up Confirm Efficacy of First-Line Pembrolizumab/Lenvatinib Combo in Advanced Non–Clear Cell RCC


Frontline pembrolizumab plus lenvatinib continues to show benefit vs historical controls in advanced non–clear cell renal cell carcinoma.

Martin H. Voss, MD

Martin H. Voss, MD

Patients with advanced non–clear cell renal cell carcinoma (RCC) given pembrolizumab (Keytruda) plus lenvatinib (Lenvima) in the first-line setting continued to experience durable clinical benefit and a manageable safety profile vs historical controls, according to follow-up data from the phase 2 KEYNOTE-B61 trial (NCT04704219).1

Findings from the single-arm trial, which were presented during the 2024 Genitourinary Cancers Symposium, showed that with the longer follow-up, the updated objective response rate (ORR) was 50.6% (95% CI, 42.6%-58.7%) in the overall population. The disease control rate (DCR) was 82.3% (95% CI, 75.4%-87.9%), and the clinical benefit rate (CBR) was 71.5% (95% CI, 63.8%-78.4%). Additionally, the median duration of response (DOR) was 19.5 months (range, 1.5+ to 23.5+).

“Updated efficacy and safety results continue to support pembrolizumab plus lenvatinib as a first-line treatment option for patients with advanced non–clear cell RCC,” lead study author Martin H. Voss, MD, clinical director of the Genitourinary Medical Oncology Service at Memorial Sloan Kettering Cancer Center, and coinvestigators wrote in the poster that was presented during the meeting.

In August 2021, the FDA approved the combination of pembrolizumab and lenvatinib as a first-line treatment for patients with advanced clear cell RCC, based on findings from the phase 3 CLEAR/KEYNOTE-581/E7080-G0000-307 trial (NCT02811861).2

In the prospective, phase 2 KEYNOTE-B61 trial, investigators evaluated the regimen in 158 patients with advanced non–clear cell RCC.3 Initial data, which included a median follow-up of 15 months, showed an ORR of 49.4% (95% CI, 41.3%-57.4%), with 74.6% of responders still in response at 1 year or longer. The 1-year progression-free survival (PFS) and overall survival (OS) rates were 62.8% and 82.2%, respectively. Responses were also observed in the papillary RCC (53.8%), chromophobe RCC (27.6%), unclassified RCC (52.4%), translocation RCC (66.7%), and other histology (55.6%) subgroups.3

In the results presented at the 2024 Genitourinary Cancers Symposium, investigators showcased data with a median time from first dose to the data cutoff—July 5, 2023—of 22.8 months (range, 16.6-27.6).1

To be eligible for enrollment, patients must have had histologically confirmed locally advanced or metastatic non–clear cell RCC who did not receive prior systemic treatment, had measurable disease as per RECIST v1.1 criteria, and a Karnofsky performance score of 70% or more. Tumor tissue samples also must have been available.

Pembrolizumab was administered at 400 mg intravenously every 6 weeks for up to 18 cycles or approximately 2 years; lenvatinib was given orally at 20 mg daily. Patients had their disease assessed 12 weeks from allocation, followed by every 6 weeks for 54 weeks, and then every 12 weeks.

The primary end point was ORR as per RECIST v1.1 criteria by blinded independent central review (BICR); secondary end points were CBR, DCR, DOR, and PFS per RECIST v1.1 criteria by BICR, OS, and safety.

All patients who received at least 1 dose of study treatment were evaluable for efficacy and safety, and investigators assessed DOR in those who achieved a complete or partial response (PR).

Treatment is ongoing in 45.6% of patients (n = 72). A total 54.4% of patients discontinued therapy (n = 86) due to disease progression (35.4%), adverse events (AEs; 13.3%), patient decision (1.9%), physician decision (1.3%), and non-study anti-cancer treatment (0.6%).

Regarding baseline characteristics, the median age was 60 years (range, 24-87) and patients either had papillary (58.9%), chromophobe (18.4%), unclassified (12.7%), translocation (3.8%), or other histology, which included medullary and other histology subtypes (6.3%). Twelve percent of patients had sarcomatoid features present, broken down by papillary (21.1%), chromophobe (26.3%), unclassified (31.6%), or other (21.1%). Most patients had International Metastatic Renal Cell Carcinoma Database Consortium intermediate- or poor-risk disease (64.6%). Patients either had a PD-L1 combined positive score (CPS) of under 1 (31.6%), at least 1 (59.5%), or missing (8.9%).

Additional efficacy findings showed that the complete response (CR) rate was 8.2%, the PR rate was 42.4%, and 31.6% of patients had stable disease (SD); 20.9% of patients had SD lasting at least 6 months. A total 10.8% of patients had progressive disease and 7.0% of responses were not evaluable.

Responses were also evaluated by histology. The ORRs were 53.8% (CR rate, 10.8%; PR rate, 43.0%) in papillary RCC, 34.5% (all PRs) in chromophobe RCC, 50.0% (all PRs) in unclassified histology, 66.7% (CR rate, 16.7%; PR rate, 50.0%) in translocation RCC, and 60.0% (CR rate, 20.0%; PR rate, 40.0%) in other histologies.

The ORRs with pembrolizumab/lenvatinib were similar across the prespecified patient subgroups but were lowest in those with PD-L1 CPS under 1 (34.0%; 95% CI, 21.2%-48.8%) and in chromophobe RCC (20.0%; 95% CI, 0.5-71.6%).

The overall reduction in tumor burden was 88.6%; these rates were 96.6%, 95.0%, 95.0%, 84.0%, and 93.3% in the papillary, unclassified, chromophobe, and translocation/other subgroups, respectively. One hundred and forty-eight patients had a baseline and at least 1 postbaseline assessment.

The median PFS and OS in the overall patient population was 17.9 months (95% CI, 15.1-22.1) and not reached (NR; 95% CI, NR-NR). The 12- and 18-month PFS rates were 63.9% and 48.1%, respectively; the 12- and 18-month OS rates were 81.6% and 72.5%, respectively.

PFS and OS data were also included for the papillary and chromophobe histology subgroups. In the papillary subgroup, the median PFS and OS was 17.5 months (95% CI, 13.5-20.7) and NR (95% CI, 24.7-NR), respectively. The 12- and 18-month PFS rates were 67.1% and 46.0%, respectively; the 12-month OS rate was 82.8% and the 18-month OS rate was 71.8%. For the chromophobe subgroup, the median PFS was 26.2 months (95% CI, 6.7-NR) and the median OS was NR (95% CI, 20.9-NR). The 12-month PFS rate was 56.5% and the 18-month PFS rate was 51.4%; the 12- and 18-month OS rates were 82.8% and 75.9%, respectively.

Regarding safety, nearly all patients experienced an AE (99.4%); 70.9% had a grade 3 to 5 AE. A total 26.6% of patients discontinued any treatment, which was due to pembrolizumab (20.9%) lenvatinib (19.6%), or both (9.5%). Serious AEs occurred in 42.4% of patients, and 9 patients died because of AEs.

Any-grade and grade 3/4 treatment-related AEs (TRAEs) occurred in 95.6% and 21.5% of patients, respectively. TRAEs that led to any treatment discontinuations occurred in 21.5% of patients; these were pembrolizumab-only discontinuations in 15.2%, lenvatinib-only in 12.7%, and both drug discontinuations in 4.4% of patients. Serious AEs that were treatment related occurred in 24.7% of patients.

Any-grade and grade 3 to 5 immune-mediated AEs were reported in 58.2% and 9.5% of patients, respectively. These required systemic corticosteroids in 13.9% of patients at either a high (≥40 mg/day of prednisone or equivalent) or low starting dose (<40 mg/day of prednisone or equivalent; 7.0% each).

Furthermore, any-grade TRAEs that occurred in at least 10% of patients were hypertension (56.3%), diarrhea (45.6%), hypothyroidism (40.5%), proteinuria (30.4%), fatigue (29.1%), palmar-plantar erythrodysesthesia syndrome (29.1%), dysphonia (27.8%), decreased appetite (25.9%), nausea (25.3%), decreased weight (21.5%), asthenia (20.9%), stomatitis (19.0%), arthralgia (17.1%), pruritis (15.2%), mucosal inflammation (14.6%), increased aspartate aminotransferase (12.7%), increased alanine aminotransferase (12.0%), vomiting (12.0%), hyperthyroidism (12.0%), dry mouth (10.8%), dysgeusia (10.1%), and rash (10.1%).

Editor's Note: Dr Voss cited clinical support by Merck & Co., Inc; medical writing and/or editorial assistance by ApotheCom, which was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.; and research funding by Merck Sharp & Dohme.


  1. Voss MH, Gurney H, Atduev V, et al. First-line pembrolizumab plus lenvatinib for non–clear cell renal carcinomas (nccRCC): extended follow-up of the phase 2 KEYNOTE-B61 study. J Clin Oncol. 2024;42(suppl; abstr 2).
  2. Motzer R, Alekseev B, Rha S-Y, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi: 10.1056/NEJMoa2035716.
  3. Albiges L, Gurney H, Atduev V, et al. Pembrolizumab plus lenvatinib as first-line therapy for advanced non-clear-cell renal cell carcinoma (KEYNOTE-B61): a single-arm, multicentre, phase 2 trial.Lancet Oncol. 2023;24(8):881-891. doi: 10.1016/S1470-2045(23)00276-0
Related Videos
Karl Semaan, MD, MSc
Bradley McGregor, MD, discusses findings from a phase 1b study of abemaciclib  in clear cell renal cell carcinoma.
Toni K. Choueiri, MD
Neil J. Shah, MBBS
Sumanta Kumar Pal, MD, FASCO, chair, Kidney and Bladder Cancer Disease Team; co-director, Kidney Cancer Program; professor, vice chair, Academic Affairs, Department of Medical Oncology & Therapeutics Research, City of Hope
Vivek Subbiah, MD
Marijo Bilusic, MD, PhD
Joshua Linscott, MD
Petros Grivas, MD, PhD
Sujith Samarasinghe, MD