乌鸦传媒

Adding an anti-interleukin (IL)-8 neutralizing antibody to nivolumab (Opdivo) produced preliminary clinical activity in a small trial primarily involving patients previously treated with PD-1/L1 inhibitors.

Five of 28 patients with advanced melanoma had objective responses to the combination. Responses also occurred in patients with non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). Across all doses evaluated, more than a third of 93 evaluable patients in the study obtained clinical benefit. Treatment with the drug, BMS-986253, plus nivolumab resulted in dose-dependent reductions in free serum IL-8 levels.

The combination was well tolerated, and no dose-limiting toxicities occurred, Ignacio Melero, MD, PhD, of the University of Navarra in Pamplona, Spain, reported during the Society for Immunotherapy of Cancer virtual meeting.

"Most of the patients included in this trial had received previous anti-PD-1 or PD-L1 therapy, and 25% of them also an anti-CTLA-4 antibody," said Melero. "From the perspective of safety, it was highly tolerable across all doses tested, and most of the safety profile was mainly due to the nivolumab.

"From the point of view of neutralizing IL-8, by increasing the doses and reducing the interval, we were able to downregulate levels of circulating free IL-8 to the point of having it almost in complete control. In looking at pre- and post-treatment biopsies, there was a clear tendency for a reduction in neutrophil infiltration in the tumor."

In response to a question from the virtual audience, Melero said the mechanism of action has not been completely elucidated. The antibody's effects on myeloid cells or an antiangiogenic effect might modify the vasculature to facilitate immune cell migration into the tumor microenvironment. "It could be a mixture of several of these things."

Press briefing moderator Mario Sznol, MD, of Yale Cancer Center in New Haven, Connecticut, asked whether an assay could be developed to identify tumors with high IL-8 expression and then target treatment to patients with those tumors.

Melero said studies involving in situ hybridization had shown that tumor cells are the primary source of IL-8. He did not elaborate on how that might be used to make more efficient use of the therapy.

In response to another question from the audience, Melero said investigators did not find a clear correlation between IL-8 expression and response to the neutralizing antibody, but he did not rule out the possibility, which will be examined more closely in ongoing studies.

Release of IL-8 by tumor cells by recruiting immunosuppressive cells to the tumor microenvironment and reducing effector T-cell antitumor activity. Elevated serum IL-8 is a and may have in patients treated with immunotherapy.

BMS-986253 is a fully human anti-IL-8 monoclonal antibody that binds IL-8 to prevent oncogenic signaling, said Melero. The antibody demonstrated safety as a single agent in a involving patients with advanced solid tumors, leading to a dose-escalation study involving patients with advanced cancers associated with IL-8 levels >10 pg/mL. Most of the patients had previously progressed during or after treatment with a PD-1/L1 inhibitor.

Investigators in the ongoing trial enrolled patients with advanced melanoma, NSCLC, RCC, squamous cell carcinoma of the head and neck, and urothelial carcinoma. Eligible patients had received at least one prior line of standard-of-care systemic therapy. Patients with melanoma had radiologic progression or recurrence during or after anti-PD-1/L1 therapy, alone or as part of a combination.

The primary objectives are safety and tolerability. Secondary objectives include pharmacokinetics, immunogenicity, changes in serum IL-8 levels, and preliminary investigator-assessed antitumor activity.

Patients initially were randomized to one of three doses of the anti-IL-8 antibody plus standard-dose nivolumab (N=49). Investigators subsequently enrolled patients into cohorts treated with the two higher doses of the antibody (N=71).

Treatment-related adverse events (TRAEs) occurred in 35% of patients, including grade 3/4 TRAEs in 5% of patients. The most common TRAEs were fatigue (9%), nausea (7%), rash (6%), pruritis (5%), and decreased appetite (5%).

BMS-986253 resulted in dose-dependent reductions in IL-8, reaching a maximum effect at the highest dose. The highest dose of the antibody (2,400 mg every 2 weeks) led to deep and durable suppression of IL-8, said Melero. The highest dose also reduced the density of tumor-associated neutrophils.

During the randomized dose-escalation phase, one partial response occurred in each of the two lower-dose cohorts and three occurred among patients treated with the highest dose. The sequential dose evaluations produced two additional partial responses in patients who received the 2,400-mg dose of the antibody.

Overall, seven of 93 evaluable patients from the randomized and nonrandomized cohorts had partial responses. In the subgroup of patients with advanced melanoma, five of 28 (17.5%) had partial responses. Stable disease occurred in 13 of 48 patients in the randomized cohorts and 15 of 45 in the sequential cohorts. Six patients in the melanoma subgroup had stable disease. The overall disease control rate (response plus stable disease) was 37.6% (35 of 93), including 39.3% in the melanoma subgroup (11 of 28).

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