Axitinib Plus Pembrolizumab Shows Promise in Treatment-Naïve Advanced RCC

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Previous use of PD-1 checkpoint inhibitors combined with VEGF-tyrosine kinase inhibitors resulted in excess toxicity in patients.
Previous use of PD-1 checkpoint inhibitors combined with VEGF-tyrosine kinase inhibitors resulted in excess toxicity in patients.

Axitinib plus pembrolizumab combination therapy was found tolerable in patients with treatment-naïve advanced renal cell carcinoma (RCC), and it shows promising antitumor activity in this patient population, a study published in Lancet Oncology has shown.

Previous studies in which PD-1 checkpoint inhibitors were combined with VEGF-tyrosine kinase inhibitors (TKIs) has led to excess toxicity in patients, thereby halting further development. However, a team led by Michael B. Atkins, MD, of Georgetown-Lombardi Comprehensive Cancer Center in Washington, DC, sought to determine if combining axitinib, a more selective VEGF inhibitor, with the anti-PD-1 pembrolizumab could generate antitumor activity in patients with treatment-naïve advanced RCC.

The study was conducted in 2 phases: a dose-finding phase to estimate maximum tolerated dose, then a dose-expansion phase to further establish safety and determine preliminary efficacy. Eligibility patients were 18 years or older; had RCC, predominantly clear cell subtype, with the primary tumor resected and at least 1 measurable lesion; Eastern Cooperative Oncology Group performance status 0-1; controlled hypertension; and no previous systemic therapy for RCC.

For the dose-finding phase, the researchers enrolled 11 patients between September 23, 2014, and March 25, 2015 ( Identifier: NCT02133742), then an additional 41 patients were enrolled between June 3, 2015, and October 13, 2015, for the dose-expansion phase.

Patients received axitinib 5 mg orally twice daily with pembrolizumab 2 mg/kg IV every 3 weeks. Assessments for safety were conducted in all patients after having received at least 1 dose of axitinib or pembrolizumab. Assessments for antitumor activity were conducted in patients who received the study treatment and had an adequate baseline tumor assessment. Investigator-assessed dose-limiting toxicity during the first 2 cycles (6 weeks) — the primary end point — was used to estimate the maximum tolerated dose and recommended phase 2 dose.

Patients in both phases were analyzed together. Among the 11 patients in the 6-week dose-finding phase, 3 dose-limiting toxicities were reported (transient ischemic attack in 1 patient, treatment-related toxicity after receiving less than 75% of the planned axitinib dose in 2 patients). Twenty-five patients were still receiving the study treatment at the data cutoff date (March 31, 2017).

Grade 3 or worse treatment-related adverse events were reported in 34 (65%) patients, the most common were: hypertension (12 [23%]), diarrhea (5 [10%]), and increased ALT concentration (4 [8%]). The most common potentially immune-related, probably to pembrolizumab, adverse events were: diarrhea (15 [29%]), increased ALT concentration (9 [17%]) or AST concentration (7 [13%]), hypothyroidism (7 [13%]), and fatigue (6 [12%]). Twenty-eight (54%) patients experienced treatment-related serious adverse events. At data cutoff, 38 (73%) patients achieved complete or partial response.

The researchers report that a phase 3 trial comparing axitinib plus pembrolizumab with sunitinib monotherapy is ongoing ( Identifier: NCT028553331).


Atkins MB, Plimack ER, Puzanov I, et al. Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial [published online February 10, 2018]. Lancet Oncol. doi: 10.1016/S1470-2045(18)30081-0
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