Promising Antitumor Activity and Tolerability Shown in Axitinib, Pembrolizumab Combo in Renal Cell Carcinoma

Michael Atkins, MD

The treatment combination of the tyrosine kinase inhibitor (TKI) axitinib (Inlyta) plus pembrolizumab was tolerable in 52 patients with treatment-naïve advanced renal cell carcinoma (RCC), and the combination demonstrated promising antitumor activity, according to the lead researcher from Georgetown Lombardi Comprehensive Cancer Center in Washington, DC.

“We were hoping that combining the two would result in synergistic antitumor effects,” said lead author Michael Atkins, MD, deputy director, Georgetown Lombardi Comprehensive Cancer Center.

The tolerability of this regimen contrasts with those of other clinical trials that combined checkpoint inhibitors with other less selective TKIs of the VEGF pathway. “What we saw in the total cohort of 52 patients was a very high degree of antitumor activity as manifest by partial and complete responses with a 73% objective response rate, including 8% complete responses,” said Atkins, the William M. Scholl Professor and Vice Chair, department of Oncology, Georgetown University School of Medicine.

Looking ahead, Atkins said that a number of large-scale studies comparing different combinations of VEGF receptor TKIs and checkpoint inhibitors with the VEGF receptor TKI sunitinib will be reporting their findings in the next 2 to 3 years. “Assuming that they show benefit similar to those observed in this trial, there will likely be a slew of new frontline treatment options to choose from for patients with advanced RCC.” But, he cautioned that the standard of care for first-line therapy in patients with kidney cancer could be changing, as the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) nears approval and “studies directly comparing VEGF receptor TKI plus checkpoint inhibitor combinations to first-line nivolumab plus ipilimumab immunotherapy have yet to be initiated.”

The study consisted of 2 phases—a dose-finding phase, in which 11 patients with previously untreated advanced renal cell carcinoma were enrolled between September 23, 2014, and March 25, 2015; and a dose-expansion phase, in which 41 patients were enrolled between June 3, 2015, and October 13, 2015.

Although using targeted therapy with VEGF receptor inhibitors such as axitinib has improved outcomes for patients with advanced RCC, resistance continues to pose a significant challenge. Durable responses have been observed when drugs that block the binding of the PD-1 receptor to its ligands have been administered in a few patients with advanced RCC whose disease progressed following VEGF receptor pathway-inhibitor therapy. Previous efforts to combine the standard first-line drugs, sunitinib and pazopanib, have been curtailed because of excessive toxicity.

The primary endpoint was dose-limiting toxicity during the first 2 treatment cycles (6 weeks) in the dose-finding phase to estimate the maximum tolerated dose. Secondary endpoints were adverse events (AEs), laboratory abnormalities, PD-L1 biomarker status, and pharmacokinetics.

At the data cutoff date, March 31, 2017, 25 (48%) patients were still on treatment; of these, 22 (88%) were receiving axitinib and pembrolizumab, and 3 (12%) were receiving pembrolizumab only. Eight (15%) patients had confirmed disease progression but were still receiving treatment. Twenty-seven (52%) patients discontinued both study treatments. The most common reason for discontinuing both study treatments were AEs (n = 10) and disease progression (n = 9).

Thirty (58%) patients discontinued axitinib because of AEs (n = 16), disease progression (n = 9), investigator discretion (n = 2), global deterioration of health status (n = 1), protocol violation (n = 1), and because the patient refused continued treatment for a reason other than an AE (n = 1). Twenty-seven (52%) patients discontinued pembrolizumab early because of AEs (n = 12), disease progression (n = 12), global deterioration of health status (n = 1), protocol violation (n = 1), and because of investigator discretion (n = 1).

Grade 3/4 treatment-related AEs (related to either axitinib or pembrolizumab, or both) occurred in 34 (65%) patients. The most common grade 3 or worse treatment-related AEs included hypertension (n = 12; 23%), diarrhea (n = 5; 10%), fatigue (n = 5; 10%), and increased alanine aminotransferase concentration (n = 4; 8%). The most common immune-related AEs (probably related to pembrolizumab) included diarrhea (n = 15; 29%), increased alanine aminotransferase concentration (n = 9; 17%) or aspartate aminotransferase concentration (n = 7; 13%), hypothyroidism (n = 7; 13%), and fatigue (n = 6; 12%). A total of 28 (54%) patients had treatment-related serious AEs. At data cutoff, 38 patients (73%; 95% CI, 59.0%-84.4%) achieved an objective response (complete or partial response).

In particular, fewer liver function test abnormalities or incidences of fatigue were reported in this study than in the previous studies, according to the researchers. For example, grade 3/4 elevated alanine aminotransferase was reported in 8% of patients in the study compared with 18% of patients treated with nivolumab plus sunitinib, 20% of patients treated with nivolumab plus pazopanib, and 60% to 70% of patients treated with pembrolizumab plus pazopanib.

The authors noted a number of potential confounding factors in their study. Notably, the patient population in this study might differ from the renal cell carcinoma population generally included in renal cell carcinoma clinical trials because all patients had previous nephrectomy (at a median of 2 years before enrollment), 75% had ECOG performance status 0, and very few patients had poor-risk disease. In addition, the researchers wrote, “The trial population had a more favorable prognostic population than typically included in front-line renal cell carcinoma trials and therefore cross-trial comparisons should be interpreted with caution.”

“These combination regimens involving VEGF receptor TKIs and checkpoint inhibitors appear to be tolerable and are effective in terms of response rate and progression-free survival,” said Atkins. “How these findings compare to a sequence of therapies—either VEGF targeted therapy followed by immunotherapy in sequence or more intensive immunotherapy, ie, nivolumab plus ipilimumab, followed by VEGF therapy, remains to be sorted out in future studies,” he concluded.

Reference:

Atkins MA, Plimack ER, Puzanov I, et al. Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomized, open-label, dose-finding, and dose-expansion phase 1b trial. Lancet Oncol. 2018;19(3):405-415. doi: 10.1016/S1470-2045(18)30081-0.