Tivumecirnon Plus Pembrolizumab Displays Activity and Tolerability in HNSCC


Jameel Muzaffar, MD, discusses findings from the phase 2 portion of the FLX475-02 study examining tivumecirnon plus pembrolizumab in HNSCC.

Jameel Muzaffar, MD

Jameel Muzaffar, MD

The investigational selective CCR4 antagonist tivumecirnon (formerly FLX475) demonstrated efficacy with a tolerable safety profile when combined with pembrolizumab (Keytruda) in the treatment of patients with head and neck squamous cell carcinoma (HNSCC) who previously received a checkpoint inhibitor, according to Jameel Muzaffar, MD.

During the 2024 AACR Annual Meeting, Muzaffar and coauthors presented findings from the phase 2 portion of the phase 1/2 FLX475-02 trial (NCT03674567), which examined tivumecirnon plus pembrolizumab in patients with recurrent or metastatic HNSCC who previously received checkpoint inhibition therapy. At a median follow-up of 14.8 months (range, 2.2-40.1), the overall response rate (ORR) was 15.6% (95% CI, 6%-32%) among response-evaluable patients (n = 32); all responses were partial. Additionally, patients with HPV-positive tumors (n = 18) experienced an ORR of 22.2% (95% CI, 9%-46%) and a median progression-free survival of 2.9 months (95% CI, 2.0-10.3).

“We have a patient population which is difficult to treat, and we’ll keep trying,” Muzaffar said. “We’ll keep improving as we go. A conference like AACR gives us a wonderful opportunity to present our study and get more information out there.”

In an interview with OncLive®, Muzaffar, the clinical director of the head and neck medical oncology program at Duke Cancer Institute, outlined the rationale of the FLX475-02 study and highlighted the key safety and efficacy findings of the trial. Muzaffar is also an instructor in the Department of Medicine at Duke University School of Medicine in Durham, North Carolina.

OncLive: What was the rationale for initiating the FLX475-02 study?

Muzaffar: The HNSCC population is an area [where there is a] big unmet need. We don’t have effective treatment options, especially for patients who have received a checkpoint inhibitor before and have become resistant to it. Tregs are heavily involved in mediating that resistance [and] tivumecirnon blocks CCR4, which prevents the migration of the Tregs into the tumor. We’re trying to decrease the Tregs and increase the T-effector cells in the tumor microenvironment of these patients. Then, we’re going to combine [tivumecirnon] with a checkpoint blocker and in this case we used pembrolizumab. Our goal was to see if we reduce the Treg population, does the checkpoint blocker become more effective?

What were the key data fromFLX475-02 that you presented at the 2024 AACR Annual Meeting?

Thirty-two patients [with] HNSCC which had metastasized [were enrolled]. All patients [had received] multiple lines of therapy and had been treated with a checkpoint inhibitor before. Patients [were treated with] tivumecirnon which is an oral medication—they took 1 pill every day—and pembrolizumab was given once every 3 weeks. Results were stratified based on HPV-positive and HPV non-positive [status] as well as on the CPS scores of patients.

Interestingly, overall there was a signal [of efficacy]; the response rate was approximately 16% in this patient population. This is a good number because all these patients have become resistant to checkpoint inhibition. Also interestingly, the response rate was higher in the HPV-positive population [at] approximately 23%. Some patients also had durable responses lasting 1 to 2 years and some patients are still being followed.

This combination had minimal toxicity and one of the main [adverse effects] was QTc prolongation. Decreasing the dose took care of that issue and most patients with QTc [prolongation had intervals] become normal again, and they were able to complete the treatment. The tolerance was very high with minimal adverse effects.

What are some potential future directions of this research?

This is a small study involving only 32 patients, but due to the signal present, we will look at the survival data which is still being collected, [and] we are going to look at the tumor microenvironment. We are looking at the pathology of the patients who responded and seeing what is going on at the level of the tumor microenvironment and that is going to help us to develop our next study.

There is a possibility that we may have a bigger phase 3 study looking very deeply into the HPV-positive patient population. In the past couple of decades, smoking has become less [common] in this population, so the HPV-[positive] population is increasing. That area is not just an unmet need at this time, but is also going to keep growing. That is something we need to work on very closely, and we believe that this combination has a role in treating this group of patients, especially when they have become resistant to checkpoint blockers.

What is your primary take-home message for colleagues on findings from FLX475-02?

For patients with HNSCC who have failed checkpoint blockers, there’s no standard of care, and having these newer combinations show such promising responses is very encouraging. It tells us that we’re going in the right direction and at the same time the combination has much less toxicity. That also helps us in the long run because these patients have received chemotherapy and radiation so they’re very susceptible to the toxic effects of the therapy that we’re giving them. Overall, given the response rate and the lower toxicity seen, this is a very encouraging regimen which we will plan to develop further in this population.


Muzaffar J, Kirtane K, Redman R, et al. Phase 2 study of oral CCR4 antagonist FLX475 (tivumecirnon) plus pembrolizumab in subjects with head and neck squamous cell carcinoma (HNSCC) previously treated with checkpoint inhibitor. Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract CT226.

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