The Promise of Axitinib and Pembrolizumab Combination in Advanced Renal Cell Carcinoma

For patients with advanced renal cell carcinoma (RCC), current management typically includes a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), followed by immunotherapy with a programmed death receptor 1 (PD-1) inhibitor in appropriate patients. Based on previous studies, the potential combination of a TKI and PD-1 inhibitor has been associated with unacceptable toxicity. Axitinib is a VEGFR-TKI that is more selective than previous generations and is associated with a more tolerable safety profile. A phase Ib study examined the combination of axitinib (5 mg twice daily) with the PD-1 inhibitor pembrolizumab (2 mg/kg every 3 weeks) in 52 patients with advanced, clear-cell RCC who had not received prior systemic therapy.

At a median follow-up of 20.4 months, the combination of axitinib and pembrolizumab resulted in an objective response rate (ORR) of 73.1%, including a complete response in 4 (8%) patients. The median duration of response was 18.6 months, and estimated progression-free survival (PFS) was 20.9 months. Overall survival (OS) data are not yet mature. Eight patients with disease progression were still receiving treatment at data cutoff. In most patients, treatment beyond progression resulted in stable disease or slow progression, rather than regression.

The combination of axitinib and pembrolizumab was tolerable, with no unexpected toxicities. In the dose-finding stage there were 3 dose-limiting toxicities, including 1 patient with a transient ischemic attack, and 2 patients who were unable to complete ³75% of the planned dose due to grade 2/3 toxicity. Treatment-related adverse events (AEs) of grade 3 or higher occurred in 65.4% of patients, and immune-related AEs of grade ³3 occurred in 21.1% of patients. Importantly, liver function abnormalities and fatigue were lower with this combination than with previous TKI/PD-1 combinations investigated in RCC.

The investigators concluded that the combination of axitinib and pembrolizumab is safe and tolerable in treatment-naïve patients with advanced RCC and is associated with meaningful clinical benefit. A phase III trial investigating this combination in comparison to sunitinib in patients with treatment-naïve advanced RCC is underway. In a commentary accompanying this study, the authors highlighted the lack of effective combination therapies for advanced RCC and applauded the promising results seen with this combination. However, as this trial was limited to a highly selected population of patients with good prognostic features, it is not clear if similar results will be seen in the general population. Furthermore, additional studies will be needed to determine whether these impressive data are due to a synergistic effect from the combination, or similar results could be achieved  from sequential therapy.

Lancet Oncol. 2018 Feb 10 [Epub ahead of print].
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