Lenvatinib Plus Pembrolizumab Demonstrates Antitumor Activity in Metastatic ccRCC

Chung-Han Lee, MD, PhD

In patients with metastatic clear cell renal cell carcinoma (RCC) who had progressed on prior PD-1 or PD-L1 immune checkpoint inhibitor therapy, the combination of lenvatinib (Lenvima) and pembrolizumab (Keytruda) achieved antitumor responses, according to results from a phase 2 trial (NCT02501096).¹

Results presented during the 202- Internation Kidney Cancer Symposium showed that the doublet elicited an objective response rate (ORR) of 53.8% (95% CI, 43.8-63.7) by investigator review per immune-related RECIST (irRECIST) criteria at week 24. Moreover, 52 patients experienced a confirmed partial response (PR), while 3 patients had a confirmed complete response (CR), translating to an ORR of 52.9% (95% CI, 42.8-62.8) by independent imaging review (IIR) and irRECIST. The ORR was also found to be 52.9% (95% CI, 42.8-62.8) when evaluated by IIR and RECIST v1.1 criteria.

“The combination of lenvatinib and pembrolizumab demonstrated antitumor activity in patients with metastatic clear cell RCC who had progressed on prior anti–PD-1 therapy,” lead study author Chung-Han Lee, MD, PhD, a medical oncologist specializing in genitourinary cancers at Memorial Sloan Kettering Cancer Center (MSK) said in a virtual poster presentation during the meeting. “Efficacy was maintained regardless of prior anti-VEGF or prior nivolumab [Opdivo] plus ipilimumab [Yervoy] therapy.”

In May 2016, the VEGF inhibitor lenvatinib was approved by the FDA or use in combination with everolimus (Afinitor) in patients with advanced RCC following previous antiangiogenic therapy. Data from preclinical research has indicated the addition of the agent to pembrolizumab resulted in enhanced clinical activity versus single-agent lenvatinib or PD-1/PD-L1 monotherapy.^2,3 “This has suggested a role for lenvatinib in immune modulation,” said Lee.

In the multicenter, open-label, phase 2 trial, investigators set out to examine lenvatinib plus pembrolizumab in patients with RCC whose disease has progressed following immune checkpoint inhibition. A total of 104 patients were enrolled on the RCC cohort. In order to be eligible to participate, patients had to have metastatic clear cell RCC who had measurable, progressive disease per RECIST v1.1 criteria that was confirmed at least 4 weeks following checkpoint inhibition.

Patients were given oral lenvatinib at a daily dose of 20 mg with intravenous pembrolizumab administered at a dose of 200 mg every 3 weeks. The primary end point of the trial was ORR at week 24, while key secondary end points included ORR, progression-free survival (PFS), and overall survival (OS), as well as safety and tolerability.

The median age was 60 years. The majority of patients, or 77%, were male and 77% had undergone prior nephrectomy. Forty-five percent of patients had an ECOG performance status of 0, while 55% had a status of 1. With regard to risk, 36% were determined to have favorable

risk per MSK Cancer Center (MSKCC) criteria, 42% were intermediate risk, and 22% were poor risk. Per the International Metastatic RCC Database Consortium risk criteria, 17%, 59%, and 24% of patients had favorable, intermediate, and poor risk, respectively. Additionally, 42% of patients had PD-L1–positive tumors, while 41% did not; 16% of patients did not have that information available.

More than half of patients (60%) had received 2 or more previous anticancer regimens, and 59% had received 1 prior VEGF-targeted treatment. All patients had prior anti–PD-1/PD-L1 therapy; 65% had anti–PD-1/PD-L1 therapy and anti-VEGF treatment and 37% had received nivolumab plus ipilimumab. In 92% of patients, anti–PD-1/PD-L1 treatment had been their most recent therapy received.

Results showed that in the subset of patients who had received prior treatment with anti–PD-1/PD-L1 therapy and VEGF inhibition (n = 68), the ORR was 60.3% (95% CI, 47.7-72.0) per investigator review and 51.5% (95% CI, 39.0-63.8) per IIR and irRECIST criteria and IIR and RECIST v1.1 criteria. In those who did not receive prior immunotherapy plus VEGF treatment (n = 36), the ORRs were 52.8% (95% CI, 35.5-69.6) and 55.6% (38.1-72.1), respectively.

In the subgroup of patients who received previous nivolumab/ipilimumab (n = 38) the ORR with lenvatinib/pembrolizumab per investigator review was 50.0% (95% CI, 33.4-66.6); per IIR and irRECIST and RECIST v1.1 criteria, the ORR was 55.3% (95% CI, 38.3-71.4).

Patients who did not receive prior nivolumab/ipilimumab (n = 66) experienced an ORR of 62.1% (95% CI, 49.3-73.8) with lenvatinib/pembrolizumab per investigator review; per IIR, irRECIST, and RECIST v1.1 criteria, the ORR was 51.5% (95% CI, 38.9-64.0) in these patients.

“The ORRs were similar regardless of whether patients were treated with VEGF-targeted therapies or prior nivolumab plus ipilimumab,” said Lee.

Moreover, the median time to response to lenvatinib/pembrolizumab was 2.1 months per investigator review, 2.6 months per IIR and iRECIST criteria, and 2.7 months per IIR and RECIST v1.1 criteria.

The majority of patients who received lenvatinib plus pembrolizumab experienced tumor shrinkage, with 7 patients reporting an 100% reduction in target lesions by IIR per RECIST v1.1 criteria. Notably, these responses were found to be durable.

Overall, the median PFS with lenvatinib/pembrolizumab was 10.8 months (95% CI, 7.8-13.6) by IIR per RECIST v1.1 criteria, and 11.8 months (95% CI, 9.5-17.7) per irRECIST criteria. The median OS reported with the doublet had not yet been reached (95% CI, 16.7–not reached [NR]).

In patients who received prior anti-VEGF treatment, the median PFS with lenvatinib/pembrolizumab was 9.4 months (95% CI, 7.4-13.1), while the median OS was NR (95% CI, 16.7–NR). In those who did not receive previous VEGF inhibition, neither the median

PFS (95% CI, 9.5–NR) or the median OS (95% CI, 14.9–NR) had been reached. In patients who previously received nivolumab plus ipilimumab, the median PFS was 11.1 months (95% CI, 5.5–NR) and the median OS was 14.9 months (95% CI, 13.1–NR). In those who did not receive prior treatment with the immunotherapy doublet, the median PFS was 10.4 months (95% CI, 7.6-15.8) and the median OS had not yet been reached (95% CI, NR–NR).

The median duration of treatment on the trial was 8.3 months. The median percent of intended dose for lenvatinib was 73% and the median number of pembrolizumab administrations was 12. Additionally, the median lenvatinib dose intensity was reported to be 14.59 mg/day.

With regard to safety, 99% (n = 103) reported treatment-related toxicities with lenvatinib/pembrolizumab; 60% (n = 62) of patients experienced effects that were grade 3 or 4 in severity. Specifically, five grade 4 treatment-related adverse effects (TRAEs) were reported and included increased aspartate aminotransferase, increased lipase, diverticulitis, large intestine perforation, and myocardial infarction. Two grade 5 toxicities, upper gastrointestinal hemorrhage and sudden death, were also reported.

Fifteen patients experienced toxicities that resulted in treatment discontinuation. Sixty-four patients required a dose reduction of lenvatinib, while 45 patients required a dose reduction of pembrolizumab.

The TRAEs reported in 20% or more of patients who received the combination included fatigue (55%, any grade; 5%, grade 3), diarrhea (46% and 8%, respectively), proteinuria (38% and 10%), hypertension (38% and 21%), hypertension (38% and 21%), dysphonia (37% and 0%), stomatitis (33% and 0%), nausea (32% and 2%), decreased appetite (31% and 0%), arthralgia (30% and 1%), palmar-plantar erythrodysesthesia syndrome (26% and 0%), hypothyroidism (25% and 0%), and headache (23% and 0%).

“In this population, no new safety signals were seen,” concluded Lee. “To further investigate the efficacy of this regimen, a phase 3 trial in the first-line setting is currently ongoing.”

In the multicenter, randomized, open-label phase 3 CLEAR trial (NCT02811861), investigators are comparing the safety and efficacy of lenvatinib plus everolimus and lenvatinib plus pembrolizumab versus sunitinib (Sutent) as frontline treatment in patients with advanced RCC.⁴

_References:

_{1. Lee, C-H, Shah AY, Hsieh JJ, et al. Phase 2 trial of lenvatinib + pembrolizumab for progressive disease after PD-1/PD-L1 immune checkpoint inhibitor in metastatic clear cell renal cell carcinoma: results by independent imaging review and subgroup analyses. Presented at: IKCS 2020 Virtual Experience; November 6-7, 2020; Virtual. https://bit.ly/32lG5Td.}

_{2. Kato Y, Tabata K, Kimura T, et al. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PLoS One. 2019;14(2):e0212513. doi:10.1371/journal.pone.0212513}

_{3. Kimura T, Kato Y, Ozawa Y, et al. Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model. Cancer Sci. 2018;109(12):3993-4002. doi:10.111/cas.13806}

_{4. Lenvatinib/everolimus or lenvatinib/pembrolizumab versus sunitinib alone as treatment of advanced renal cell carcinoma (CLEAR). ClinicalTrials.gov. Updated July 31, 2020. Accessed November 6, 2020. https://clinicaltrials.gov/ct2/show/NCT02811861.}