Conference Coverage

Enoblituzumab plus pembrolizumab shows promise for select solid tumors



– Combination enoblituzumab and pembrolizumab showed acceptable safety and encouraging antitumor activity in select patients with B7-H3-expressing non–small-cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), and other solid tumors in a phase 1 dose-escalation and expansion study.

Of note, the combination showed activity in patients anticipated to be poorly responsive to checkpoint inhibitor therapy alone, Charu Aggarwal, MD, of the University of Pennsylvania, Philadelphia, reported at the annual meeting of the Society for Immunotherapy of Cancer.

In all, 133 patients were treated weekly with 3, 10 or 15 mg/kg intravenous doses of the investigational anti-B7-H3 monoclonal antibody enoblituzumab plus 2 mg/kg intravenous doses of the programmed death-1 (PD-1) inhibitor pembrolizumab every 3 weeks (the standard dose at the time) for up to 1 year in the open-label dose-escalation study. Of those, 85% experienced treatment-related adverse events (AEs), and 27.1% experienced grade 3 or higher AEs, Dr. Aggarwal said.

These AEs were mostly infusion-related reactions typically seen with the first dose, and they were not usually cumulative, she said, noting that the rates of immune-related adverse events were less than 5%, about 7% of patients discontinued treatment because of a drug-related AE, and 1 treatment-related death due to pneumonitis occurred.

“No maximum tolerated dose was reached,” she added. “What I want to emphasize is that this is a combination immunotherapy approach, and what we found was that despite a combination approach, the nature, rate, and incidence of immune-related adverse events was not different than what is expected compared to single-agent [therapy] alone.”

Patients were then divided into disease-specific dose-expansion cohorts and the SCCHN and NSCLC cohorts were further stratified based on whether or not they had prior exposure to PD-1 inhibitor therapy.

Antitumor activity was noted in anti-PD-1-naive SCCHN patients, and objective responses were also seen in NSCLC patient with tumor programmed death-ligand 1 (PD-L1) expression of less than 1% and patients with checkpoint inhibitor–refractory urothelial carcinoma.

“We saw a 33.3% response rate in IO [immunotherapy]-naive head and neck cancer patients, and a 35.7% response rate in patients with PD-L1-negative immunotherapy-naive non–small-cell lung cancer patients,” she said.

No objective radiographic responses were seen in the IO-exposed SCCHN patients, but a few were seen in the other tumor cohorts, she noted.

“What was more interesting is this prolonged and high level of stable disease that we found in patients who had been previously treated with IO and had actually experienced significant clinical and radiographic progression then experienced stability with this combination,” she said, noting that “a fair amount of stable disease” was also seen in the IO-naive SCCHN and NSCLC patients.

In the immunotherapy-naive SCCHN patients, responses were seen regardless of human papillomavirus status, and four are still on treatment. One had a confirmed complete response.

“The majority of our patients on our trial and in this cohort were B7-H3-positive, she said, adding that the responses that were seen, including in those with stable disease, were “sustained and durable.”

Responses were similar in the immunotherapy-naive NSCLC patients who were PD-L1 negative, she said.

“Responses were seen irrespective of histology ... and many of these patients are still on treatment,” she added, noting that most were B7-H3-positive, which “seems to select our patients who have an even higher response rate of about 45%.”

The responses in that cohort also occurred early, were durable, and are sustained, and some patients remain on treatment and “are enjoying the clinical benefit afforded by this combination,” she said.

The findings are notable, because B7-H3 is highly expressed in many solid tumors, and monotherapy with enoblituzumab, which targets B7-H3 and is engineered to enhance antibody-dependent cell-mediated cytotoxicity, has demonstrated antitumor activity with an acceptable safety profile in patients with selected solid tumors.

In this study it was combined with pembrolizumab to test the hypothesis that coordinated engagement of both innate and adaptive immunity via the targeting of two distinct members of the B7 family could achieve greater antitumor activity than either agent alone, she explained.

The results “benchmark favorably” versus prior experience with PD-1 agents; pembrolizumab and nivolumab each lead to activity of about 13%-16%, she said.

“We acknowledge that our study has very small numbers. Nevertheless, these are encouraging data ... in this very tough-to-treat population,” Dr. Aggarwal said, adding that “further investigation of enoblituzumab with an anti-PD-1 molecule is warranted in both head and neck and lung cancer patients, perhaps including in combination with chemotherapy.”

Further, given the expression patterns of B7-H3 on a wide variety of solid tumors, further investigation of this combination ... is warranted in other tumor types, including in both checkpoint-naive and -treated populations, she concluded.

This study was sponsored by MacroGenics. Dr. Aggarwal reported receiving consulting fees from BMS.

SOURCE: Aggarwal C et al., SITC 2018 Abstract O24.

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