Despite high rates of toxicity and a patient death, a first-line tyrosine kinase inhibitor/immunotherapy combination of axitinib and avelumab for the treatment of metastatic renal cell carcinoma (mRCC) exhibits promising antitumor activity, suggested findings from a phase Ib clinical trial (abstract 4504) presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 2–6 in Chicago.
“The safety profile of the combination of avelumab plus axitinib appears manageable and consistent with those agents administered as monotherapy, and early encouraging antitumor activity was observed,” reported Toni K. Choueiri, MD, of the Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, and Brigham and Women’s Hospital in Boston. “The confirmed ORR of 58.2% for the combination of avelumab and axitinib suggests efficacy beyond single-agent activity and is consistent with response data from other anti–PD-1/PD-L1 plus angiogenesis inhibitor combinations.”
PD-L1 expression on immune cells at or exceeding 1% and 5% levels were associated with higher response rates, he noted.
Axitinib is a VEGFR-tyrosine kinase inhibitor that is approved by the US Food and Drug Administration (FDA) for second-line treatment of advanced RCC. Avelumab is a fully human monoclonal antibody immunotherapy that targets PD-L1 and has been approved by the FDA for treating patients with metastatic Merkel cell carcinoma and advanced urothelial cell carcinoma following platinum-based chemotherapy.
Patients with mRCC have a daunting prognosis with an 8% 5-year survival rate. Among patients with treatment-naive advanced RCC, axitinib has a manageable safety profile and a median progression-free survival time of 10.1 months, compared with 6.5 months for sorafenib, Dr. Choueiri said.
The JAVELIN Renal 100 study was undertaken to assess the safety and tolerability of first-line avelumab plus axitinib, and to evaluate this regimen’s antitumor activity. The researchers enrolled 55 patients with a median age of 60 years (42–76), of whom all but one patient received treatment. Most participants (76%) were men.
More than half (56%) of patients had dose reductions; four patients (7%) received less than 90% of the planned avelumab dose. Of the 54 participants, 32 had confirmed objective tumor responses according to RECIST v1.1 criteria, for an objective response rate (ORR) of 58.2%.
“Disease control was achieved in 78.2% of patients,” Dr. Choueiri reported. “Forty-five patients experienced tumor shrinkage and 34 experienced shrinkage of 30% or more.”
Adverse events were reported for nearly all (96%) participants (49% experienced grade 3 toxicities and 9% experienced grade 4 toxicities). The most frequent adverse event was diarrhea (affecting 56% of participants; 3.6% had grade 3 diarrhea). Hypertension (47%; 29% grade 3), dysphonia (45.5%; none were grade 3), fatigue (45.5%; 3.6% grade 3), and hand-foot syndrome (31%; 7.3% grade 3) were also reported.
Immune-related adverse events affected 31% of participants, though only 5.5% experienced grade 3 toxicity and none experienced grade 4. One patient died of an immune-related adverse event (myocarditis).
The findings support pursuit of an ongoing phase III clinical study of efficacy and safety of the combination compared with sunitinib in treatment-naive clear cell mRCC, Dr. Choueiri said.
He disclosed consultancy and advisory board relationships with several drug companies, including Merck, which developed avelumab.