Pembrolizumab paired with immunostimulator is safe and tolerable



CHICAGO – Combining an immunostimulatory agent with the PD-1 checkpoint inhibitor pembrolizumab appeared quite safe and very tolerable, in a small phase Ib study.

There were some signs of efficacy against a variety of solid tumors, as well as biomarker trends showing immune activity.

In the phase Ib trial, researchers combined escalating doses (0.45-5.0 mg/kg) of PF-2566, an investigative immunostimulatory agent, with the anti–PD-1 checkpoint inhibitor pembrolizumab at 2 mg/kg, with both drugs given intravenously once every 3 weeks for a maximum of 32 cycles. A primary objective of the trial was to determine a maximum tolerated dose. Secondary objectives were to assess safety and tolerability and to determine any antitumor responses.

Dr. Anthony Tolcher

Dr. Anthony Tolcher

PF-2566 (Utomilumab/PF-05082566) is a monoclonal agonist targeting 4-1BB, a “costimulatory molecule that’s induced upon T-cell receptor activation and ultimately enhances cytotoxic T-cell response and effector status,” said Dr. Anthony Tolcher of the START Center for Cancer Care, San Antonio, at the annual meeting of the American Society of Clinical Oncology.

Eligible patients were 18 years or older, had a performance status of 0-1, and had advanced or metastatic solid tumors that had progressed on standard therapy or for which no standard therapy was available. They could not have had any form of immunosuppressive therapy in the 2 weeks prior to registration, a monoclonal antibody in the 2 months before the first dose, or any symptomatic or progressing central nervous system primary malignancies. Prior pembrolizumab was permitted.

Twenty-three patients (14 males) were heavily pretreated with a median of three prior therapies (range 0-9) for a variety of cancers, including six non–small-cell lung, five renal cell, three head and neck, and two each pancreatic and thyroid cancers.

Good safety and tolerability profiles

The most prevalent treatment-emergent adverse events (AEs) were fatigue, rash, cough, nausea, and decreased appetite, affecting 7-10 patients each. All were grade 1/2 except for one grade 3/4 case of fatigue and three cases of grade 3/4 anemia among the 23 patients. Most treatment-related AE’s were grade 1/2, largely fatigue (n = 8) and rash (n = 9). There was one case each of grade 3 adrenal insufficiency and hypokalemia. No patient discontinued the trial because of a treatment-related toxicity. Dr. Tolcher noted that adrenal insufficiency has been reported previously with the use of PD-1 inhibitors. “There does not appear to be any evidence of synergistic or additive toxicity in this patient population,” he said.

Neither drug affected the pharmacokinetics of the other drug or the development of antibodies to the other drug. The maximum tolerated dose of PF-2566 was at least 5 mg/kg every 3 weeks when combined with pembrolizumab 2 mg/kg. No dose-limiting toxicity was observed across the PF-2566 dosing range. And there were no treatment-emergent AEs of clinical relevance.

Pharmacodynamics and efficacy

By day 1 of cycle 5, “there [was] a trend toward increasing numbers of activated CD8 [cytotoxic] T cells in patients who ultimately responded or had a complete response, compared to those that had stable disease or progressive disease. The same actually applies to the effector memory T cells,” Dr. Tolcher said but was careful to point out that the sample sizes were small and it was only a trend. Similarly, circulating levels of gamma-interferon, often used as a biomarker of activated T cells, were higher at 6 and 24 hours post dose in cycle 5 for those patients who ultimately had partial or complete responses, compared with those with progressive or stable disease.

Among the 23 patients, there were two confirmed complete responses and four partial responses as well as one unconfirmed partial response. If responses occurred, they often were durable past 1 year and even out close to 2 years.

Dr. David Spigel

Dr. David Spigel

The strengths of this study were that it enrolled heavily pretreated patients and there were no drug-drug interactions, no dose-limiting toxicities, and no treatment-related AE’s leading to discontinuation, “so in general a very well-tolerated immunotherapy combination,” said discussant Dr. David Spigel of the Sarah Cannon Research Institute in Nashville, Tenn. There were also some durable responses, and he said it was interesting to see that there were some blood biomarkers that correlated with responses.

“It was hard for me to find any weaknesses to this,” Dr. Spigel said, beside the fact that it was a small study. “So what does this change?” He said the combination of pembrolizumab and PF-2566 looks promising in light of some sustained responses in refractory tumors and its safety profile. For the future, expansion trial cohorts are still needed to confirm activity and safety, especially hepatic safety based on trial results with similar drugs, and PF-2566 is already being tested with rituximab in lymphoma and with an anti-CCR4 compound (mogamulizumab).