First-line Eftilagimod Alpha Plus Pembrolizumab Generates Favorable ORR in PD-L1–Negative HNSCC

Treatment with eftilagimod alpha (IMP321) plus pembrolizumab (Keytruda) in the first line led to clinically meaningful responses in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) and a PD-L1 combined positive score (CPS) of less than 1, with over half of patients still on treatment at 6 months, according to data from cohort B of the randomized phase 2b TACTI-003 trial (NCT04811027).¹

Findings presented during the July ESMO Virtual Plenary showed that patients in the PD-L1–negative population (n = 31) experienced an overall response rate (ORR) of 35.5% (95% CI, 19.2%-54.6%) per RECIST 1.1 criteria, which included a complete response (CR) rate of 9.7% and a partial response (PR) rate of 25.8%. Best responses of progressive disease (PD; 41.9%) and stable disease (SD; 22.6%) were also observed. The disease control rate (DCR) was 58.1% (95% CI, 39.1%-75.5%).

Efficacy analysis according to iRECIST criteria showed an ORR of 38.7%, with best responses of CR in 9.7% of patients, PR in 29.0%, SD in 25.8%, and PD in 35.5%. The DCR was 64.5% (95% CI, 45.4%-80.8%). Notably, responses were observed regardless of human papillomavirus status in patients with oropharynx primary tumors.

At a data cutoff date of March 11, 2024, approximately 60% of patients had experienced tumor shrinkage following treatment with eftilagimod alpha plus pembrolizumab. Notably, a single patient did develop early pseudo progression, which later resulted in a durable response. This patient has continued on treatment for over 14 months. Further assessment of tumor response dynamics over time revealed that 71% of patients remained on treatment for at least 4 months, and approximately 50% of patients remained on treatment for over 6 months.

“This response rate compares very favorably to historical results, where a response rate in the region of 5% would be expected,” lead study author Robert Metcalf, MBChB, MRCP, PhD, an honorary consultant in medical oncology at the Christie National Health Service Foundation Trust, in Manchester, United Kingdom, stated during an oral presentation of the data. “Based on the encouraging response rates and the high unmet clinical need, particularly for the PD-L1 CPS population, further investigation of this combination is warranted.”

Unlike other LAG-3–targeted agents, which are typically drug antagonists targeting T cells, eftilagimod alpha is a soluble LAG-3 fusion protein and MHC Class II agonist. The agent activates antigen-presenting cells, leading to an increase in activated CD4- and CD8-positive T cells and accordingly bolstering immune responses. Eftilagimod alpha has demonstrated signals of activity in the second-line head and neck squamous cell carcinoma (HNSCC) setting when combined with pembrolizumab (Keytruda), which is the current standard of care for the recurrent or metastatic PD-L1–positive population.

At the 2023 ASCO Annual Meeting, data from part C of the phase 2 TACTI-002 trial (NCT03625323)showed that patients with HNSCC unselected for PD-L1 expression who were treated with second-line eftilagimod alpha plus pembrolizumab (n = 37) achieved an ORR of 29.7% (95% CI, 15.9%-47.0%), comprising a 13.5% complete response rate and a 16.2% partial response rate.² Additionally, data from cohort A of the trial were presented at the 2023 ESMO Congress and showed an ORR of 31.3% (95% CI,16.1%-50.0%) in patients with first-line, non–small cell lung cancer (NSCLC) and PD-L1 tumor proportion score (TPS) of less than 1%.3 In both cohorts, responses were observed irrespective of CPS and TPS.¹

TACTI-003 is a multicenter, randomized, open-label phase 2b study evaluating a soluble LAG-3 fusion protein combined with an anti–PD-1 inhibitor as first-line therapy in relapsed/metastatic HNSCC. The trial comprised 2 cohorts. In cohort A, patients with a CPS of 1 or greater were randomly assigned 1:1 to receive either 400 mg of intravenous pembrolizumab plus 30 mg of subcutaneous eftilagimod alpha every 2 weeks for the first 3 months, followed by every 3 weeks thereafter for up to 2 years; or up to 2 years of pembrolizumab alone. In cohort B, all patients with a CPS of less than 1 received pembrolizumab plus eftilagimod alpha.

During follow-up, PFS and/or OS data were obtained across all cohorts. Radiological assessments were performed every 9 weeks for 36 weeks, after which they were performed every 12 weeks and assessed locally by an investigator. Randomization was stratified according to CPS (1 to 19 vs ≥ 20) and ECOG performance score (PS; 0 vs 1).

The study’s primary end point was ORR by RECIST 1.1 criteria, and key secondary end points included progression-free survival, overall survival, ORR according to iRECIST, time to response, duration of response, safety, immunogenicity, and quality of life.

A total of 33 patients were enrolled onto cohort B from 14 sites across 6 countries between April 2022 and October 2023. Of these, 31 were deemed efficacy evaluable. The median age of patients was 64 (range, 23-83). The majority of patients were male (74.2%) had an ECOG PS of 1 (67.7%) and were ex-smokers (61.3%).Primary tumors were located in the oropharynx (35.5%), larynx (32.3%), oral cavity (29.0%), and hypopharynx (3.2%). Regarding baseline disease status, 61.3% of patients had metastatic-only disease, followed by local and metastatic disease (22.6%), and local-only disease (16.1%).

The median treatment exposure was 23.7 weeks (range, 0.1-63.3) for eftilagimod alpha and 22.1 weeks (range, 0.1-63.1) for pembrolizumab.

Regarding safety, Metcalf reported that “This combination of eftilagimod alpha and pembrolizumab is safe and well tolerated, with no new safety signals seen [in the current analysis].”

Any-grade treatment-emergent adverse effects (TEAEs) were reported in 72.7% of patients in the safety population (n = 33). Notably, only 15.2% of patients experienced grade 3 or higher TEAEs, Metcalf noted, adding that TEAEs leading to treatment discontinuation were reported in 9.1% of patients. Immune-mediated AEs were observed in 39.4% of patients, 30.4% and 9.1% of which were grade 1/2 and grade 3, respectively. Local injection site reactions occurred in 18.2% of patients, all of which were grade 1.

The most frequently observed TEAEs included fatigue (21.2%), weight loss (18.2%), hypothyroidism (18.2%), pyrexia (15.2%), arthralgia (15.2%), gamma-glutamyl transferase increase (15.2%), and anemia (15.2%).

References

1. Metcalf R, Laban S, Kristensen C, et al. Eftilagimod alpha (soluble LAG-3) and pembrolizumab in first-line recurrent or metastatic head and neck squamous cell carcinoma: Primary results from cohort B (CPS less-than 1) of the TACTI-003 study. Presented at the 2024 ESMO Virtual Plenary Meeting; July 11, 2024.
2. Doger de Spéville B, Felip E, Forster M, et al. Final results from TACTI-002 Part C: A phase II study of eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab in patients with metastatic 2nd line head and neck squamous cell carcinoma unselected for PD-L1. J Clin Oncol. 2023;41(suppl 16):6029. doi:10.1200/JCO.2023.41.16_suppl.6029
3. Carcereny E, Felip E, Majem M, et al. Combining the antigen-presenting cell activator eftilagimod alpha (soluble LAG-3) and pembrolizumab: Overall survival data from the first line non-small cell lung carcinoma (NSCLC) cohort of TACTI-002 (phase II). Ann Oncol.2024;35(suppl 2):S755-S851.doi: 10.1016/S0923-7534(23)01943-9