Treatment with the first-line combination of pembrolizumab and lenvatinib led to durable anti-tumor activity in patients with non–clear cell renal cell carcinoma.
The latest data from the phase 2 KEYNOTE-B61 trial (NCT04704219) showed that lenvatinib (Lenvima) plus pembrolizumab (Keytruda) elicited durable anti-tumor activity as a first-line treatment for patients with non–clear cell renal cell carcinoma (nccRCC).1
Findings shared during the 2023 ASCO Annual Meeting showed that, as of the data cutoff of November 7, 2022, the objective response rate (ORR) in the overall study population was 49% (95% CI, 41%-57%), and best responses included complete response (CR, 6%; n = 9), partial response (PR, 44%; n = 69), stable disease (SD, 33%; n = 52), progressive disease (11%; n = 17), not evaluable (0.6%; n = 1), and not available (6%; n = 10). The positive antitumor activity was observed across histologic subtypes.
Immunotherapy-based combinations, such as lenvatinib plus pembrolizumab, are considered the frontline standard of care in patients with ccRCC. For instance, the phase 3 CLEAR trial (NCT02811861) investigating lenvatinib plus pembrolizumab, lenvatinib plus everolimus (Afinitor), or sunitinib (Sutent) monotherapy in patients with previously untreated advanced RCC found that the median progression-free survival (PFS) was longest in the pembrolizumab arm, at 23.9 months vs 14.7 months in the everolimus arm and 9.2 months in the sunitinib arm.2 “However, these combinations are not well characterized in non-ccRCC,” lead study author, Chung-Han Lee, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, New York, and colleagues, wrote in a presentation of the KEYNOTE-B61 data.1
To address this unmet need, the investigators conducted the single-arm KEYNOTE-B61, which is the largest trial to evaluate the activity of an immune checkpoint inhibitor combination in patients with non–clear cell disease. The initial analysis of this trial showed a confirmed ORR of 47.6% (95% CI, 36.4%-58.9%) in the 82 patients with at least 24 weeks of follow-up.3
Eligible patients for enrollment in KEYNOTE-B61 included those with histologically confirmed non-ccRCC and locally advanced or metastatic disease who had received no prior systemic therapy, had measurable disease per RECIST v1.1 criteria, and a Karnofsky Performance Status score of at least 70%.1
In the updated analysis, 158 patients were enrolled and received intravenous pembrolizumab at 400 mg every 6 weeks for a maximum of 18 cycles plus oral lenvatinib at 20 mg daily. Patients underwent tumor assessment 12 weeks from treatment initiation, then every 6 weeks for 54 weeks, then every 12 weeks thereafter.
The primary end point of this trial was ORR by blinded independent central review (BICR) and per RECIST v1.1. Key secondary end points included clinical benefit rate (CBR), disease control rate (DCR), duration of response (DOR), and PFS by BICR and per RECIST v1.1; overall survival (OS); and safety and tolerability.
Of the entire study population, the median age was 60.0 years (range, 24-87). In total, 58.8% (n = 93), 18.4% (n = 29), 13.3% (n = 21), 3.8% (n = 6), and 5.7% (n = 9) of patients had papillary, chromophobe, unclassified, translocation, or other histology, and 12.0% (n = 19) of patients had known sarcomatoid features. At screening, sites of metastases included lymph nodes (64.6%; n = 102), lung (34.2%; n = 54), bone (31.0%; n = 49), liver (19.6%; n = 31), and abdominal cavity (12.7%; n = 20). A total of 44.3% (n = 70) and 55.7% (n = 88) of patients had favorable-risk and intermediate/poor-risk disease per International Metastatic RCC Database Consortium risk criteria. Regarding PD-L1 status, 58.9% (n = 93) of patients had a combined positive score (CPS) of at least 1, 31.6% (n = 50) of patients had a CPS of less than 1, and 9.5% (n = 15) had unknown status.
When stratified by histology, the best ORRs were 54%, 28%, 52%, 67%, and 56% in patients with papillary, chromophobe, unclassified, translocation, and other histology, respectively.
In the entire trial population, the DCR was 82% (95% CI, 75%-88%) and the CBR, defined as CR, PR, or SD for at least 6 months, was 72% (95% CI, 64%-78%).
Overall, 88.0% (n = 139) of patients experienced a reduction in tumor burden. Across all histologies, 91.4% (n = 85), 72.4% (n = 21), 95.2% (n = 20), and 86.7% (n = 13) of patients experienced a tumor burden reduction in the papillary, chromophobe, unclassified, and translocation/other subgroups.
In patients with a confirmed objective response, the median DOR was not reached ([NR] range, 1.5+ to 15.3+). Responses continued for at least 12 months in 74.6% of responders. As of the data cutoff date, 92 patients were still receiving the study treatment, including 55 responders.
The estimated 12-month PFS rate was 62.8% (95% CI, 54.2%-70.1%), with a total of 62 events (39.2%) observed. The median PFS was 17.9 months (95% CI, 13.5-NR). The 12-month OS rate was 82.2% (95% CI, 75.1%-87.5%), with a total of 35 events (22.2%) observed. The median OS was NR.
In all, 99.4% (n = 157) of patients experienced any-grade adverse effects (AEs), and 65.2% (n = 103) of patients experienced grade 3 to 5 AEs. Treatment-related adverse effects (TRAEs) occurred in 94.3% (n = 149) of patients, with 51.3% (n = 81) of patients having TRAEs of grade 3 to 5. A total of 34.2% (n = 54) and 72.2% (n = 114) of patients required dose reductions of lenvatinib or treatment interruption because of AEs. Additionally, 15.8% (n = 25) required treatment discontinuation because of a TRAE, including pembrolizumab discontinuation (10.8%; n = 17), lenvatinib discontinuation (8.9%; n = 14), and discontinuation of both study drugs (3.2%; n = 5). Eight patients died during the study, although no deaths were attributed to TRAEs.
The most common TRAEs of any grade were hypertension (57.0%), diarrhea (43.7%), hypothyroidism (36.7%), palmar-plantar erythrodysesthesia (28.5%), dysphonia (27.8%), proteinuria (27.8%), fatigue (26.6%), decreased appetite (23.4%), nausea (23.4%), asthenia (20.3%), weight decrease (18.4%), stomatitis (17.7%), arthralgia (16.5%), mucosal inflammation (14.6%), pruritus (13.3%), increased aspartate aminotransferase (12.0%), increased alanine aminotransferase (10.8%), hyperthyroidism (10.8%), and dysgeusia (10.1%).
“Results from this study support the use of pembrolizumab plus lenvatinib as first-line treatment for patients with non-ccRCC, regardless of histology,” the study authors concluded.
“A new benchmark is certainly set. The combination of nivolumab [Opdivo] and cabozantinib [Cabometyx], however, appears similarly promising, at least in non-chromophobe variant histologies. But of course, [the phase 2 CA209-9KU trial (NCT03635892)] was a much smaller study, and not all patients [received the combination] in the first line,” Manuela Schmidinger, MD, of the Medical University of Vienna in Austria, said in a discussion of the KEYNOTE-B61 data. “We should probably go for immunotherapy/TKI combinations in non-ccRCC, despite the lack of a phase 3 trial, at least in the non-chromophobe subtype.”