MUNICH – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the tyrosine kinase inhibitor axitinib (Inlyta) was associated with longer progression-free survival and higher objective response rates than was sunitinib as frontline therapy for patients with advanced renal cell carcinoma, investigators found.
The progression-free survival (PFS) benefit of the combination was seen both in the subset of patients with tumors expressing programmed death-1 ligand 1 (PD-L1) on at least 1% of their cells as well as in the overall study population, reported Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, on behalf of colleagues in the.
“This was very early on, at an interim analysis, showing a profound effect,” he said at a briefing prior to his presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.
“The results support this being a new first-line standard of care, and possibly a first-line option for advanced RCC based on these data,” he added.
Briefing discussant John Haanen, PhD, of the Netherlands Cancer Institute in Amsterdam, said that “based on preclinical data, it makes sense to combine angiogenesis inhibitors and immunotherapy, because we know angiogenesis, VEGF [vascular endothelial growth factor] especially impacts on the way the immune system can respond to the kidney cancer, and by taking away some of these negative effects of the VEGF by using an anti-VEGF drug, the immunotherapy may work better,” he said.
“This is the first study of a TKI plus and anti-PD-L1 drug showing an improved progression-free survival in this patient population,” he added.
On Oct. 18, the day before the start of ESMO 2018, Merck announced in apositive results of a phase 3 trial comparing axitinib in combination with a different checkpoint inhibitor, pembrolizumab (Keytruda), compared with sunitinib monotherapy. The press release, typically sparse on details, said that the trial met both primary endpoints of overall survival (OS) and PFS in the first-line treatment of advanced or metastatic RCC.
In the JAVELIN Renal 101 trial, investigators enrolled and randomized 886 patients, 873 of whom went on to treatment: 434 assigned to avelumab plus axitinib, and 439 to sunitinib.
A total of 560 patients were determined to be PD-L1-positive according to the Ventana assay: 270 assigned to the combination, and 290 assigned to sunitinib.
Avelumab was delivered 10 mg/kg intravenously every 2 weeks, and oral axitinib was given 5 mg twice daily over a 6-week cycle. Oral sunitinib was give 50 mg daily for 4 weeks, followed by 2 weeks off, for every cycle.
Median PFS by independent review in the PD-L1-positive patients, one of two primary endpoints, was 13.8 months in the avelumab/axitinib arm, vs. 7.2 months in the sunitinib arm. This translated into a stratified hazard ratio (HR) of 0.61 (P less than .001) favoring the combination.
The respective median PFS in the overall population was 13.8 vs. 8.4 months, respectively (HR, 0.69; P = .0001).
Objective response rates also were higher with the combination in both the PD-L1-positive population (55% vs. 26%), and in the overall population (51% vs. 26%). At the time of data cutoff, the median duration of response had not been reached in either treatment arm in either population.
The stratified odds ratio for response with avelumab/axitinib was 3.098 (P less than .001).
At the time of the data cutoff for this interim analysis, overall survival data were not mature. OS in the PD-L1-positive population, the second primary endpoint, will be reported at a later date, Dr. Motzer said.
The incidence of treatment-related adverse events was similar in the groups, at 95% of patients in the avelumab arm and 96% in the sunitinib arm. Grade 3 or 4 events occurred in 51% and 48% of patients respectively. Grade 3/4 hypertension was the highest-frequency event, occurring in 24% of patients on avelumab/axitinib vs. 15% on sunitinib.
Immune-related adverse events occurred in 38% of patients in the avelumab group, including hypothyroidism, liver function test abnormalities, adrenal insufficiency, acute kidney injury, colitis, and hepatotoxicity. Most of the events occurred in 1% or 2% of patients, except hypothyroidism, which occurred in 21%.
High-dose corticosteroids were administered to 11% of patients who experienced an immune-related adverse event.
“One of the beauties of this combination is really its tolerability,” said Viktor Grünwald, MD, of the West German Cancer Center in Essen, the invited discussant at the symposium.
“When it comes to toxicities, they are pretty much in the same range, which is really surprising,” he said.
He noted, however, that it’s still an open question whether the combination of avelumab and axitinib is better than sequencing of other agents, given the current absence of evidence of an OS or quality-of-life benefit for the combination.
At present, the best evidence supports the use of ipilimumab (Yervoy) and nivolumab (Opdivo), which provides a clinically relevant OS benefit in patients with intermediate and high-risk disease, and this therapy should remain the standard of care, Dr. Grünwald said.
“I do believe that there is a niche, in favorable-risk patients, for this specific combination [avelumab/axitinib],” he said.
The trial was sponsored by Pfizer as part of an alliance between Pfizer and Merck KGaA. Dr. Motzer disclosed consulting or advisory roles with Pfizer, Merck, and others, and research funding from Pfizer and others. Dr. Haanen disclosed financial compensation for advisory work he did for Pfizer, Merck, Sharpe & Dohme, and others, and grant support from Bristol-Myers Squibb, MSD, and Novartis. Dr. Grünwald disclosed honoraria for speaking and advising from MSD, and funding from Pfizer, MSD, and others.