CHICAGO — The PD-1 immune checkpoint inhibitor antibody nivolumab in combination with either sunitinib or pazopanib yielded encouraging antitumor activity with manageable toxicity in patients with metastatic renal cell carcinoma, according to study results presented at the ASCO Annual Meeting.
“Sunitinib has been shown to reverse VEGF-induced immune suppression and, in combination with an anti-PD-1 antibody, has shown synergistic activity in a murine renal cell carcinoma model,” Asim Amin, MD, PhD, a medical oncologist at Levine Cancer Institute at Carolinas HealthCare System, said during a presentation. “Combining VEGF TKIs to condition the tumor microenvironment making it more conducive for positive immune modulation by nivolumab modulation formed the basis of this trial.”
Amin and colleagues evaluated data from 53 patients. All patients in the dose escalation arms of the study had received at least one prior systemic therapy that could have included a TKI; however, patients assigned to the expansion cohort were treatment naive.
Researchers assigned 33 patients to nivolumab (BMS-936558, Bristol-Myers Squibb) plus 50 mg daily sunitinib (Sutent, Pfizer) daily for 4 weeks on and 2 weeks off. Seven patients received a 2-mg/kg starting dose of nivolumab every 3 weeks, and 26 received a 5-mg/kg escalated dose. Researchers assigned 20 patients to the 2-mg/kg starting dose of nivolumab, plus 800 mg daily pazopanib (Votrient, GlaxoSmithKline).
Seventeen patients in the sunitinib arm (52%) and nine in the pazopanib arm (45%) demonstrated a response. Of these responses, 41% in the sunitinib arm and 56% in the pazopanib arm were achieved by the first assessment at week 6.
The median duration of response was 37.1 weeks in the sunitinib arm and 30.1 weeks in the pazopanib arm. Fifty-nine percent of responders in sunitinib arm had ongoing responses, compared with 33% in the pazopanib arm. One patient in the sunitinib arm achieved a complete response.
Eleven patients assigned sunitinib (33%) and seven assigned pazopanib (35%) demonstrated stable disease.
Robust responses were observed across treatment groups regardless of 2-mg or 5-mg nivolumab doses, Amin said.
At 24 weeks, PFS rates were 78% in the sunitinib arm and 55% in the pazopanib arm.
Exploratory biomarker analyses showed no obvious association between baseline tumor PD-L1 expression and response; however, caution needs to be exercised during interpretation of these preliminary data due to the small number of patients, Amin said.
Four dose-limiting toxicities — three cases of increased aspartate aminotransferase/alanine aminotransferase levels and one case of fatigue — led to the pazopanib arm not proceeding to an expansion phase.
A majority of patients in both arms experienced a grade 3 to grade 4 adverse event (sunitinib, 82%; pazopanib, 70%). The most common severe adverse events in the sunitinib arm were elevated aspartate aminotransferase (18%), hypertension (15%) and hyponatremia (15%). The most common severe adverse events in the pazopanib arm were elevated aspartate aminotransferase (20%), elevated alanine aminotransferase (20%) and fatigue (15%).
One patient in the sunitinib arm experienced grade 3 to grade 4 pneumonitis.
Rates of hepatic grade 3 to grade 4 events in both arms, as well as renal adverse events in sunitinib arm, were higher than expected from monotherapy with either of the agents, Amin said.
Twelve patients in the sunitinib arm (36%) and five patients in the pazopanib arm (25%) discontinued a TKI or both study drugs on account of treatment-related adverse events.
“Nivolumab in combination with TKIs showed encouraging antitumor activity with a manageable toxicity profile,” Amin said. “The overall response rates were higher in combination therapy than have been seen with nivolumab or TKI monotherapy in renal cell carcinoma.”
For more information:
Amin A. Abstract #5010. Presented at: ASCO Annual Meeting; May 30-June 3, 2014; Chicago.
Disclosure: The researchers report consultant/advisory roles with, honoraria and research funding from, and stock ownership in Acceleron Pharma, AVEO, Bayer, Bristol-Myers Squibb, Dendreon, GlaxoSmithKline, Immatics, Jounce Therapeutics, MedImmune, Merck, Millennium, Novartis and Pfizer.