Adding 4-1BB Agonist to Pembrolizumab Safe, Effective Across Solid Tumors

Silas Inman @silasinman
Published: Sunday, Jun 05, 2016

Dr Anthony W. Tolcher

Anthony W. Tolcher, MD

The combination of the 4-1BB agonist utomilumab (PF-05082566) and the PD-1 inhibitor pembrolizumab (Keytruda) was safe and effective as a treatment for patients with advanced solid tumors, according to findings from a phase Ib study presented at the 2016 ASCO Annual Meeting.

In the dose escalation study, the overall response rate was 26% among 23 patients treated with the combination of utomilumab and pembrolizumab, including 2 complete responses, which were experienced by patients with renal cell carcinoma (RCC) and small cell lung cancer (SCLC). No dose-limiting toxicities were observed across all doses of utomilumab.

"Clinical activity was seen across a broad range of different tumors. There were 6 confirmed responses, 2 of which were complete responses, and these responses were very durable," said lead investigator Anthony W. Tolcher, MD, director of clinical research at South Texas Accelerated Research Therapeutics San Antonio. “The maximum-tolerated dose of utomilumab in combination with pembrolizumab is at least 5 mg/kg every 3 weeks given at standard dosing. No dose-limiting toxicities were observed for this combination across the entire dose range.”

Utomilumab is a fully humanized IgG2 monoclonal antibody agonist specific to 4-1BB (CD137), which is a costimulatory molecule on T-cells that enhances cytotoxic response and effector status. Upon binding to 4-1BB, the agonist antibody increases T cell proliferation while also enhancing the immune response. In preclinical studies, combining a 4-1BB agonist with a PD-1 inhibitor showed enhanced activity in melanoma and colon cancer models, Tolcher noted.

In the phase Ib study, pembrolizumab was administered at 2 mg/kg every 3 weeks concurrently with utomilumab at doses ranging from 0.45 mg/kg to 5.0 mg/kg. Dose escalation was determined by a time-to-event continuous reassessment method. Treatment was continued for a maximum of 32 cycles, which were indicated as 21 days, and dose-limiting toxicities were assessed during the first 2 cycles.

Of the 23 patients who received treatment, 14 were male (60.9%) and 9 were female (39.1%). Patients had received a median of 3 prior therapies. The primary types of cancer, which are known to be sensitive to PD-1 inhibitor, were non–small cell lung cancer (n = 6), RCC (n = 5), and head and neck cancer (n = 3). Other types of cancer included pancreatic cancer (n = 2), thyroid cancer (n = 2), SCLC (n = 1), colon cancer (n = 1), sarcoma (n = 1), thymoma (n = 1), and melanoma (n = 1).

"There was only 1 patient with melanoma. This study was initiated concurrently with the approval of nivolumab [Opdivo] and pembrolizumab, so a large number of melanoma patients were naturally getting those PD-1 therapies," said Tolcher.

In addition to the 6 confirmed responses, 1 patient with RCC and 1 with NSCLC had partial responses that were not yet confirmed, potentially increasing the overall response rate. Moreover, confirmed responses to the combination appeared durable, with most lasting greater than 6 months and half approaching the 2-year mark, said Tolcher. Five patients remained on therapy at the time of the analysis.

Most of the treatment-related adverse events (AE) that occurred were grade 1 or 2 in severity, including rash (39.1%), fatigue (34.8%), pruritus (17.4%), decreased appetite (13%), nausea (13%), pyrexia (13%), and dyspepsia (8.7%). The only treatment-related grade 3 AEs were adrenal insufficiency (n = 1) and hypokalemia (n = 1). None of the patients discontinued therapy as a result of treatment-related toxicity.

"Overall, there were no grade 3/4 toxicities in this population, at a frequency of greater than 15% of the population," said Tolcher. "The adrenal insufficiency is seen with anti–PD-1 therapy. There does not appear to be any evidence of synergistic or additive toxicity in this patient population."
In pharmacokinetic analyses of the study there was no evidence that the coadministration of pembrolizumab and utomilumab had any effect on the pharmacokinetic profiles for each drug or the development of anti–drug antibodies. "There were no overt drug interactions between these two biologics," said Tolcher.

There was a trend toward higher levels of activated, effector, and memory T cells when measured during cycle 5 for patients who responded to the combination versus those who did not. Additionally, a trend was noted toward an increase in CD8+ T cells and interferon gamma levels in responding patients versus those with progressive disease.

A number of clinical trials continue to assess utomilumab across a variety of settings for patients with solid and hematologic cancers. The agent is being explored with the OX40 agonist PF-04518600, the CD20 inhibitor rituximab, the anti-CCR4 agent mogamulizumab, and the PD-L1 inhibitor avelumab.
Tolcher AW, Sznol M, Hu-Lieskovan S, et al. Phase Ib study of PF-05082566 in combination with pembrolizumab in patients with advanced solid tumors. J Clin Oncol. 2016;34 (suppl; abstr 3002).
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