Pembrolizumab/Cabozantinib Shows Encouraging Preliminary Efficacy in mRCC


Pembrolizumab plus cabozantinib showed promising activity with an objective response rate of 65.8%, median progression-free survival of 10.45 months, and median overall survival of 30.81 months in metastatic renal cell carcinoma.

Elaine T. Lam, MD FACP

Elaine T. Lam, MD FACP

The combination of pembrolizumab (Keytruda) and cabozantinib (Cabometyx) led to promising preliminary efficacy and a manageable toxicity profile in patients with metastatic renal cell carcinoma (mRCC), according to findings from a phase 1/2 trial (NCT03149822).1

Among the 38 patients evaluable for response, the overall response rate (ORR) was 65.8% (95% CI, 49.9%-78.8%) with 78.6% as first-line therapy and 58.3% as second-line therapy. The median progression-free survival (PFS) at a median follow-up of 23.5 months was 10.45 months (95% CI, 6.25-14.63). At this time point, the median overall survival (OS) was 30.81 months (95% CI, 24.2-not reached).

The disease control rate (DCR) was 97.4% (95% CI, 86.5%-99.9%), and the median duration of response (DOR) was 8.3 months (interquartile range, 4.6-15.1). Overall, pembrolizumab plus cabozantinib was comparable in this patient population with other available checkpoint inhibitor-tyrosine kinase inhibitor combinations.

“The combination of pembrolizumab and cabozantinib had a safety profile that was similar to other immune checkpoint inhibitor and tyrosine kinase inhibitor combinations. The recommended phase 2 dose was standard dosing of both agents, [and] the combination of pembrolizumab and cabozantinib showed encouraging responses both in treatment-naive and pre-treated patients with RCC,” Elaine T. Lam, MD FACP, professor of medicine at the University of Colorado Anschutz Medical Campus in the Department of Medicine and Division of Medical Oncology, told Targeted Oncology, in an interview.

In phase 1, the dose-escalation portion of the trial, a standard 3+3 design was utilized, and in phase 2, the dose-expansion part, a Simon 2-stage design was used. Patients were treated with a fixed dose of pembrolizumab at 200 mg by intravenous infusion each 21-day cycle for up to 35 cycles in the first course and could resume a second course of up to an additional 17 cycles of pembrolizumab if they had disease progression following completion of the first course of treatment. Cabozantinib was also given to patients orally once a day on a continuous basis at a dose of 40 mg orally once daily or 60 mg orally once daily in phase 1 and at the recommended phase 2 dose (RP2D) in phase 2.2

“Different immune checkpoint inhibitor and VEGFR tyrosine kinase inhibitor combinations have been approved for the treatment of patients with metastatic renal cell carcinoma. We performed this phase 1/2 study to evaluate the safety and effectiveness of pembrolizumab and cabozantinib,” said Lam.

Patients were eligible for enrollment if they had mRCC with clear-cell or non-clear cell histology, adequate organ function, an ECOG performance status of 0-1, and no prior exposure to pembrolizumab or cabozantinib. Investigators assessed the primary end point of ORR at the RP2D, and the secondary end points of safety, DCR, DOR, PFS, and OS.1,2

Forty-five patients were enrolled between October 2017 and August 2020, including 8 patients in phase 1 and 37 patients in phase 2.1 The trial took place across 5 sites within the University of Colorado/UCHealth system.

There were 40 patients treated at the RP2D who were evaluable for PFS and OS. Further, 38 patients were evaluable for response. Among all patients, 38 (84%) had clear cell RCC and 7 (16%) had non-clear cell RCC. A total of 4 patients (8.9%) had sarcomatoid differentiation, and 30 patients (67%) had prior exposure to a checkpoint inhibitor and/or VEGFR therapy. Further, the median age of all patients was 61 years (range, 54-69), and most patients were male (73.3%), White (88.9%), and non-Hispanic (84.4%).

Three patients remained on study treatment at the time of data analysis. Forty-two patients discontinued treatment due to progression (62%), AEs (33%), or other reasons (5%).

For safety, the most common grade 1 or 2 treatment-related adverse events (TRAE) included diarrhea (71%), anorexia (62%), dysgeusia (62%), weight loss (62%), and nausea (60%), and the most common grade 3/4 TRAEs included hypertension (20%), hypophosphatemia (18%), alanine transaminase elevation (11%), diarrhea (9%), and fatigue (7%). Only 1 grade 5 TRAE was observed, which was reversible posterior encephalopathy syndrome and related to treatment with cabozantinib.

Fourteen patients had TRAEs which led to discontinuation of study, including immune-mediated pancreatitis, immune-mediated hepatitis, intolerable diarrhea, elevated liver function tests, immune-mediated myocarditis, immune-mediated nephritis, immune-mediated rash, reversible posterior leukoencephalopathy syndrome, venous thromboembolism and renal infarcts, and osteonecrosis of the jaw. Moreover, 28 of 40 patients (70%) given treatment with the RP2D required dose reduction of cabozantinib at a median of 4 cycles (range, 1–38).

“Pembrolizumab and cabozantinib treatment in patients with metastatic RCC demonstrated encouraging preliminary efficacy and a manageable toxicity profile comparable with other available immune checkpoint inhibitor-tyrosine kinase inhibitor combinations. However, this is a small study that has not been validated in larger clinical trials, so cannot be considered a standard of care,” explained Lam.

  1. Kessler ER, Callihan E, Hu J, et al. A Phase I/II Clinical Trial of Pembrolizumab and Cabozantinib in Metastatic Renal Cell Carcinoma. Cancer Res Commun. 2023;3(6):1004-1012. Published 2023 Jun 8. doi:10.1158/2767-9764.CRC-23-0060
  2. Study of pembrolizumab and cabozantinib in patients with metastatic renal cell carcinoma. Updated October 17, 2023. Accessed January 5, 2024.
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