Durvalumab/Metformin Combination May Be Effective in HNSCC

Joseph M. Curry, MD,

Promise has been shown with anti-PD-L1 immune checkpoint inhibition for the treatment of squamous cell carcinoma of the head and neck (HNSCC). Metformin also alters immunity within the tumor microenvironment, however, clinical benefit has yet to be observed.

A single-center phase 1 trial (NCT03618654) looked at durvalumab, an anti-PD-L1 antibody, with or without metformin. Patients were randomized 3:1 to receive either the combination or durvalumab monotherapy. Additionally, mage analysis algorithms were employed for CD8-positive & FoxP3-positive T-cell counts and respective distances.

In total, 32 patients were evaluable, with 37.5% of them having a primary site pathological response. Additionally, CD8-FOXP3 distance was greater in those who responded.

Principle study investigator Joseph M. Curry, MD, a professor with specialties in head and neck surgery, Head and Neck Oncology, and Otolaryngology at Jefferson University Hospital, discussed the efficacy of durvalumab in combination with metformin for the treatment of HNSCC during an interview with Targeted Oncology^TM.

TARGETED ONCOLOGY™: Can you give an overview of spatial distribution of CD8-positive and FoxP3-positive in a window of opportunity for durvalumab plus metformin trial in squamous cell carcinoma of the head and neck?

Immune checkpoint inhibitors have been a popular and exciting development because of the efficacy they've shown in head and neck cancer, specifically within head and neck cancer, anti-PD-1 therapy. So, both pembrolizumab and nivolumab, have been approved for the treatment of recurrent and metastatic head neck cancer and squamous cell carcinoma because of the effects of efficacy that they've shown in a number of clinical trials. And in fact, after the initial approval, they've moved up in the algorithm such that pembrolizumab is now included in first line therapy for metastatic and inoperable disease. And so, these therapies have really expanded what we think of as options in terms of non-surgical therapies. And in terms of this specific clinical trial, they've also expanded how we approach disease, which is in some cases operable, looking at neoadjuvant strategies for the use of immune checkpoint inhibitors.

Can you explain the design of your pilot study and the methods used to conduct the study?

This is a trial looking at patients with head and neck squamous cell carcinoma, who were treated in a window of opportunity or treated prior to therapy with one dose of immune checkpoint inhibitor for the PD-1, PD-L1 axis specifically, what we use was a drug called durvalumab. Use for anti-PD-L1 inhibition. What we did was treat patients in a randomized fashion, either with single agent durvalumab or durvalumab combined with metformin in a 4-week window prior to surgery. They got standard doses of metformin if randomized to that arm, and they got a single dose of durvalumab prior to surgery.

What are the results?

Before treatment, and then right before surgery, patients underwent either a diagnostic biopsy and then the surgical resection specimen. And those two were compared for differences after therapy. What we're looking for were increased recruitment of immune cells, or changes, predictable of response. We did actually see substantial changes in some of the immune cells, particularly looking at FOXP3- positive lymphocytes, which are generally considered to be regulatory or suppressive T cells, and then also CD8-positive T cells, which are generally considered to be in the effector class. which helped carry out the immune response against the tumor.

What we saw were changes in concentrations, but also changes in distances. We measured this both in the actual leading edge of the tumor and in the stroma adjacent to the tumor. We could see differences between the HPV positive and HPV negative samples that were included from patients in the trial. And we could also see a number of different changes in response to therapy. There were a lot of different movements of lymphocytes into or out of the tumor microenvironment. And most critically, what we saw was actually some changes that suggested or some preoperative findings that suggested or predicted response later on, meaning greater distances between the immune cells was important because we think that closer distances can contribute to more suppression by regulatory T cells. And then subsequently, we also saw higher concentrations of some of the T cells in the microenvironment, on the tumor side, in responders as well. And so, so those are some of the key findings that we saw with changes in the microenvironment.

What do you hope other physicians will take away from this research?

We hope that this to provide some preliminary data that can allow us, or provide insight or a method, to hopefully look in the future at methods and techniques that we can use to predict response to immune checkpoint inhibitors. Here we've studied durvalumab, but it is open to be studied in other immune checkpoint inhibitors and of course, needs to be validated in a larger study.

_REFERENCE:

_{Curry J, Alnemri A, Sussman S, et al. Spatial distribution of CD8+ and FoxP3+ in a window of opportunity for durvalumab (MEDI4736) plus metformin trial in squamous cell carcinoma of the head and neck (HNSCC). Ann. Oncol. 2021;32(5):787.}