MIAMI — A novel combination of therapeutic agents may have activity in advanced renal cell carcinoma (RCC), according to preliminary results of a new study.
In a small pilot cohort of 11 treatment-naive patients with advanced RCC, researchers found that axitinib (Inlyta, Pfizer) plus pembrolizumab (Keytruda, Merck) was well tolerated at standard doses and exhibited substantial antitumor activity.
"Agents that block the [planned death] PD-1/PD1 interaction have shown efficacy in patients who progressed on [vascular endothelial growth factor receptor (VEGFR)] pathway inhibitor therapy," said lead author Toni K. Choueiri, MD, clinical director, Lank Center for Genitourinary Oncology, the Dana Farber Cancer Center, Boston, Massachusetts.
"Pembrolizumab has shown antitumor activity in several malignancies, including some small studies in [RCC]," explained Dr Choueiri, who presented the findings of this study here at the 14th International Kidney Cancer Symposium (IKCS).
Axitinib, a VEGFR inhibitor, is already approved for second-line treatment of advanced RCC. Pembrolizumab, a humanized monoclonal antibody, blocks binding of the immune-checkpoint receptor PD-1 to its ligands (PD-L1/2). It has been approved for use in melanoma and non–small cell lung cancer.
"Our hypothesis was that the combination regimen of axitinib and pembrolizumab might provide a clinical benefit in treatment-naive patients with advanced RCC compared to axitinib or VEGF pathway-directed therapy alone," said Dr Choueiri.
The current trial is an ongoing, open-label, multicenter phase 1b study, with the main objective of assessing the safety and tolerability of this combination and estimating the maximum tolerated dose (MTD).
"We are reporting now the results from the dose-finding phase," Dr Choueiri told attendees.
Signs of Efficacy
As of September 11, 2015, 11 patients (8 men; mean age, 61 years) were enrolled in the study.
Enrollment criteria including having clear-cell advanced RCC, primary tumor resection, a measurable lesion, Eastern Cooperative Oncology Group Performance Status score 0/1, no uncontrolled hypertension, and no prior systemic therapy. Axitinib was administered orally at a starting dose of 5 mg twice daily, beginning on day 7. Pembrolizumab 2 mg/kg was administered intravenously on day 1 of 3-week cycles. The MTD was estimated by the modified toxicity probability interval method, and tumors were assessed per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1.
Dose-limiting toxicity was defined as any of the following that occurred during the first 6 weeks: grade 4 neutropenia or thrombocytopenia, grade 3 or higher neutropenia infection, thrombocytopenia with bleeding, febrile neutropenia, nonhematologic toxicities that were grade 3 or higher toxicity, or not being able to complete 75% or more of axitinib dosing or 2 infusions of pembrolizumab during the treatment-related toxicity phase.
To date, 3 patients have had dose-limiting toxicities. "One patient has a transient ischemic attack, and 2 patients received less than 75% of planned axitinib dosing because of toxicity," said Dr Choueiri.
Efficacy was not the primary endpoint of the study, but six of the 11 patients had confirmed partial response, and the rest had stable disease. After 7.4 months, nine patients continue receiving treatment without progression, with two patients ending treatment because of toxicity.
Common all-grade adverse events were diarrhea and hypothyroidism (n = 6 each) and arthralgia, fatigue, and headache (n = 4 each). In addition, two patients had increased alanine aminotransferase and aspartate aminotransferase.
Grade 3/4 adverse events included headache, increased alanine aminotransferase and aspartate aminotransferase, hyperuricemia, and acute cholecystitis.
The MTD was determined to be 5 mg axitinib and 2 mg/kg pembrolizumab.
Dr Choueiri concluded that the combination was well tolerated at standard doses of each drug. "We have enrolled 41 additional patients in the cohort that we hope to be reporting on in the future," he said.
Sabina Signoretti, MD, an associate professor of pathology at Harvard Medical School in Boston, Massachusetts, who was approached by Medscape Medical News for an independent comment, explained the data are "quite encouraging."
"The drugs are already approved and available, and axitinib is approved for renal cancer," she said. "That makes it very translatable into the clinical setting."
However, she cautioned that these are very early data, there was toxicity, and follow-up is very early. "There are all of the caveats that go with very early studies," Dr Signoretti said. "We will have to wait for the updated results to have a better idea."
14th International Kidney Cancer Symposium (IKCS). Presented November 7, 2015.