Axitinib plus pembrolizumab shows ‘unprecedented’ antitumour activity in advanced RCC
Combining axitinib with pembrolizumab results in an “unprecedented” objective response rate (ORR) in treatment-naïve patients with advanced renal cell carcinoma (RCC), results of an ongoing phase Ib trial have shown.
Among 52 patients treated with axitinib (5 mg BID) plus pembrolizumab (2 mg/kg Q3W), 38 (73 percent) achieved an objective response after a median follow-up of 20.4 months. This included four patients (8 percent) with a complete response and 34 patients (65 percent) with a partial response. [ASCO GU 2018, abstract 579; Lancet Oncol 2018, doi: 10.1016/S1470-2045(18)30081-0]
“More than 90 percent of patients experienced some degree of tumour shrinkage,” the investigators reported. “Among responders [n=38], median time to response was 2.8 months, and median duration of response was 18.6 months. Responses were observed in 18 [75 percent] of 24 patients with favourable-risk disease, and 18 [69 percent] of 26 patients with intermediate-risk or poor-risk disease.”
Median progression-free survival (PFS) was 20.9 months, while median overall survival was not reached.
“The antitumour activity of the combination treatment is unprecedented and superior to that expected from axitinib or PD-1 pathway inhibitor monotherapy,” the investigators noted.
In patients with advanced RCC, standard first-line treatment with sunitinib or pazopanib is associated with a median PFS of around 8–12 months, they added.
Other trials in patients with treatment-naïve metastatic RCC have reported a median PFS of 10–15 months with axitinib monotherapy, an ORR of 13 percent with nivolumab monotherapy, and a median PFS of 6 months and an ORR of 25 percent with atezolizumab monotherapy. [Lancet Oncol 2013;14:1233-1242; Lancet Oncol 2013;14:1287-1294; Clin Cancer Res 2016;22:5461-5471; Proc Am Soc Clin Oncol 2017;35(15 suppl):4505 (abstract); J Clin Oncol 2016;34:833-842] No data are available for pembrolizumab monotherapy in RCC.
In the current open-label study, adult patients who had undergone nephrectomy for advanced RCC (predominantly clear cell subtype) were recruited from 10 centres in the US. Eleven patients were enrolled in the dose-finding phase, while 41 patients were enrolled in the dose-expansion phase. The primary endpoint was investigator-assessed dose-limiting toxicity (DLT) during the first two treatment cycles (6 weeks) of the dose-finding phase to estimate the maximum tolerated dose and recommended phase II dose.
All 52 patients were analyzed together because they received the same dose and schedule of treatment. The results showed no unexpected toxicities.
During the 6-week observation period, three DLTs were reported, including transient ischaemic attack in one patient and completion of <75 percent of the planned axitinib dose due to treatment-related adverse event (TRAE) in two patients.
Grade 3/4 TRAEs occurred in 34 patients (65 percent). The most common grade ≥3 TRAEs were hypertension (n=12; 23 percent), diarrhoea (n=5; 10 percent), fatigue (n=5; 10 percent), and elevated alanine aminotransferase (n=4; 8 percent).
Based on the results of this trial, the US FDA granted Breakthrough Therapy Designation to the combination regimen as a first-line treatment for patients with advanced or metastatic RCC.