Tivumecirnon Plus Pembrolizumab Shows Activity in Checkpoint Inhibitor–Exposed Recurrent/Metastatic HNSCC

Jameel Muzaffar, MD

The addition of tivumecirnon (FLX475) to pembrolizumab (Keytruda) elicited responses and was well tolerated in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) who were previously exposed to an immune checkpoint inhibitor, particularly those with human papillomavirus (HPV)–positive disease, according to data from the phase 2 FLX475-02 trial (NCT03674567).

Findings presented at the 2024 AACR Annual Meeting showed that at a median follow-up of 14.8 months (range, 2.2-40.1), all evaluable patients (n = 32) experienced a confirmed overall response rate (ORR) of 15.6% (95% CI, 6%-32%), which was comprised entirely of partial responses. The stable disease (SD) and progressive disease (PD) rates were 31.3% and 53.1%, respectively. Notably, the unconfirmed ORR was 25% (95% CI, 11%-43%).

Among subjects with HPV-positive HNSCC (n = 18), tivumecirnon plus pembrolizumab elicited a confirmed ORR of 22.2% (95% CI, 9%-46%). The SD and PD rates in this population were 27.8% and 50%, respectively, and the unconfirmed ORR was 38.9% (95% CI, 18%-65%).

"For patients [with HSNCC] who have [progressed on] checkpoint blockers, there's really no standard of care,” lead study author Jameel Muzaffar, MD, said in an interview with OncLive^®. “Therefore, having these newer combinations come up and show such promising responses is encouraging. It tells us that we're going in the right direction.”

Muzaffar is an instructor in the Department of Medicine at the Duke University School of Medicine and Duke Cancer Institute in Durham, North Carolina.

Tivumecirnon is a selective CCR4 antagonist devised to inhibit the infiltration of immunosuppressive regulatory T cells (Treg) into the tumor microenvironment. FLX475-02 is evaluating the agent as monotherapy and in combination with pembrolizumab in patients with advanced cancer. Data presented at the 2024 AACR Annual Meeting focused on a phase 2 cohort of patients with HNSCC who previously received an immune checkpoint inhibitor.

All patients in the HNSCC cohort received 100 mg of oral tivumecirnon once per day in combination with 200 mg of intravenous pembrolizumab once every 3 weeks.

The primary end point was ORR per RECIST v1.1 criteria. Progression-free survival (PFS) also served as a key secondary end point.

In the cohort of 32 evaluable patients with recurrent/metastatic HNSCC, the median age of was 58 years (range, 34-77). The majority of the subjects were male (94%) and had an ECOG performance status of 0 (53%). Patients had primary tumor sites that included oropharynx (56%), not oropharynx (41%), and unknown (3%). Sixty-nine percent of patients had a PD-L1 combined positive score (CPS) of at least 1%, 9% had a PD-L1 CPS of less than 1%, and PD-L1 CPS was unknown in 22% of patients.

Patients had undergone a median of 3 (range, 1-6) prior lines of therapy, and the majority (69%) received at least 3 prior lines of therapy. Notably, 34% of patients responded to prior treatment with a checkpoint inhibitor, 29% had SD, 34% had PD, and 3% had an unknown response.

Additional data showed that the median PFS in the overall cohort was 2.2 months (95% CI, 2.0-6.0). For the HPV-positive subgroup, the median PFS was 2.9 months (95% CI, 2.7-7.3). The median duration of response duration of response was 4.8 months (range, 1.3-8.8) and 5.5 months (range, 2.7-7.3) for the overall and HVP-positive populations, respectively.

In the overall population, patients with a PD-L1 CPS of at least 1% (n = 23), the confirmed and unconfirmed ORRs were 17.4% (95% CI, 5%-39%) and 30.4% (95% CI, 13%-53%), respectively. Those with a PD-L1 CPS of less than 1% (n = 3), the confirmed and unconfirmed ORRs were both 33% (95% CI, 0.8%-99%).

In the HPV-positive population, those with a PD-L1 CPS of at least 1% (n = 10) the confirmed and unconfirmed ORRs were 30% (95% CI, 7%-65%) and 60% (95% CI, 26%-88%). In those with a PD-L1 CPS of less than 1% (n = 3), the confirmed and unconfirmed ORRs were both 33.3% (95% CI, 0.8%-91%).

Regarding safety, serious treatment-emergent adverse effects (TEAEs) occurred in 43.8% of the overall population. TEAEs leading to discontinuation and death occurred in 12.5% and 15.6% of patients, respectively.

The most common TEAEs reported in at least 15% of patients included QT prolongation (any-grade, 53.1%; grade 3/4, 6.3%), dyspnea (34.4%; 6.3%), fatigue (31.3%; 0%), anemia (28.1%; 6.3%), nausea (25.0%; 0%), constipation (21.9%; 0%), cough (18.8%; 0%), dysphagia (18.8%; 6.3%), hypercalcemia (18.8%; 6.3%), decreased weight (18.8%; 0%), COVID-19 (15.6%; 0%), diarrhea (15.6%; 0%), headache (15.6%; 0%), hypophosphatemia (15.6%; 3.1%), and productive cough (15.6%; 0%).

Additionally, 6.3% of patients experienced serious treatment-related AEs (TRAEs); however, TRAEs did not lead to discontinuation or death in any patients. The most common any-grade TRAEs reported in at least 10% of patients included QT prolongation (43.8%), fatigue (15.6%), nausea (15.6%), and pruritus (12.5%). Additionally, 6.3% of patients experienced grade 3/4 QT prolongation.

Muzaffar and colleagues concluded by noting that the data derived from patients with checkpoint inhibitor–exposed, recurrent/metastatic HNSCC justify further evaluation of tivumecirnon plus pembrolizumab in this patient population.

“The combination has [lower] toxicity. That also helps us in the long run because these patients have had [prior] chemotherapy or radiation,” Muzaffar said. “Although [these patients] are susceptible to the toxic effects of the therapy that we're giving them, overall, given the ORR with the lower toxicity, this is a very encouraging regimen, which we will plan to develop further in this population.”

Reference

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.