Eftilagimod Alpha Combination Demonstrates Durable Responses in Frontline NSCLC

Wade T. Iams, MD

Investigators from phase 2 TACTI-002 trial (NCT03625323) reported deep and durable responses for the immunotherapy combination of pembrolizumab (Keytruda) and eftilagimod alpha (efti; IMP321) in patients with advanced non–small cell lung cancer (NSCLC). Updated findings from the trial were presented during the Society for Immunotherapy of Cancer (SITC) 37th Annual Meeting & Pre-Conference Programs in Boston, Massachusetts.¹

The first-line combination elicited a 40.4% (95% CI, 31.3%-50.0%) overall response rate (ORR) by immune RECIST (iRECIST) criteria in the intention-to-treat (ITT) population. The ORR was comprised of a 0.9% complete response (CR) rate and a 39.5% partial response (PR) rate. Additionally, 32.5% of patients had stable disease (SD), 15.8% of patients had progressive disease (PD), and 11.4% of patients were not evaluable (NE) (FIGURE¹). The median duration of response (DOR) was 21.6 months (95% CI, 17.3-30.0).

When assessed by RECIST v1.1 criteria, the ORR in the ITT population was 38.6% (95% CI, 29.6%-48.2%) and included a 0.9% CR rate and a 37.8% PR rate. The SD and PD rates were 32.5% and 17.5%, respectively. A total of 11.4% of patients were NE.

“We did see deep and durable responses across subgroups; there did appear to be a stepwise benefit by PD-L1 score from 0% to [between] 1% to 49% to greater than 50%,” lead study author Wade T. Iams, MD, said in a presentation during the meeting. Iams is an assistant professor of medicine in the Division of Hematology and Oncology at Vanderbilt University Medical Center in Nashville, Tennessee. “The combination of eftilagimod alpha and pembrolizumab is safe and tolerable, and there are ongoing studies in latestage development for this combination,” he said.

Efti is a soluble LAG-3 protein that binds to a subset of major histocompatibility complex class II molecules and mediates antigen-presenting cell and CD8 T-cell activation in patients. T cells are recruited by stimulating the dendritic cell network, which has the potential to produce more potent antitumor responses when paired with pembrolizumab vs what has been reported with pembrolizumab alone.

In October 2022, the FDA granted a fasttrack designation to efti for use in combination with pembrolizumab as a frontline treatment for patients with stage IIIB/IV NSCLC with a PD-L1 tumor proportion score (TPS) of at least 1%, based on earlier findings from the TACTI-002 trial.²

In the 3-part, international, open-label trial, patients with NSCLC had measurable disease per RECIST v1.1 criteria, had an ECOG performance status of 0 to 1, and submitted available tumor tissue for central PD-L1 testing. Patients were unselected for PD-L1 status. The trial used the combination in the first-line setting where patients were unselected for PD-L1 (part A; n = 114), the second-line setting for patients resistant to PD-1/PD-L1–based therapy (part B; n = 36), and the second-line setting for patients with head and neck squamous cell carcinoma who had received platinum-based therapy (part C; n = 39).

The findings from part A were presented during the SITC 37th Annual Meeting & Pre-Conference Programs. In this part, efti was administered every 2 weeks and pembrolizumab administered every 3 weeks for 8 cycles, followed by both efti and pembrolizumab given every 3 weeks for 9 cycles up to 1 year. Maintenance pembrolizumab was given every 3 weeks for 16 cycles up to 1 year. Patients were followed for progression-free survival (PFS) and overall survival (OS).

The primary end point was ORR by iRECIST criteria, and secondary end points were ORR by RECIST v1.1 criteria, DOR, safety, PFS, OS, and pharmacokinetics/ pharmacodynamics. The data cutoff date for part A was July 1, 2022.

Part A comprised 114 patients from 18 sites across 6 countries between March 2019 and November 2021, and the minimum follow-up was 7 months. The median time since diagnosis was 1.5 months.

Regarding baseline characteristics for part A, the median age was 67 years (range, 44-85), 26.3% of patients were female, and 62.3% of patients had an ECOG performance status of 1. Most patients were current or former smokers (94.7%) and had metastatic disease (99.1%). Squamous histology was reported in 35.1% of patients.

A total of 35.6% and 42.2% of patients had a PD-L1 TPS of less than 1% and between 1% and 49% by central assessment only, respectively. Additionally, 34.3% and 38.9% of patients had a PD-L1 TPS of 1% and between 1% and 49% by central and local assessment, respectively. A total of 22.2% and 26.9% of patients had a PD-L1 TPS of 50% or greater by central and central plus local assessment, respectively. Additional data showed that in the efficacy evaluable population (n = 101), the ORR was 45.5% (95% CI, 35.6%-55.8%) by iRECIST criteria and 43.6% (95% CI, 33.7%- 53.8%) by RECIST v1.1 criteria.

Response rates improved with increasing PD-L1 TPS. For example, in those with a PD-L1 TPS of less than 1% (n = 32), the ORR was 31.3% (95% CI, 16.1%-50.0%), compared with a 44.7% ORR (95% CI, 28.6%-61.7%) in those with a PD-L1 TPS of 1% to 49% (n = 38) and a 55% ORR (95% CI, 31.5%-76.9%) in those with a PD-L1 TPS of 50% or greater (n = 20). In patients whose tumors had a PD-L1 TPS of 1% or greater (n = 58), the ORR was 48.3% (95% CI, 35.0%-61.8%).

The disease control rates (DCRs) in patients whose tumors had a PD-L1 TPS of less 1%, between 1% and 49%, 50% or greater, and 1% or greater were 65.6% (95% CI, 46.8%-81.4%), 78.9% (95% CI, 62.7%-90.5%), 80% (95% CI, 56.3%-94.3%), and 79.3% (95% CI, 66.7%-88.8%), respectively.

Furthermore, response rates were similar in those with squamous (37.5%; 95% CI, 22.7%-54.2%) and nonsquamous (40.3%; 95% CI, 28.9%-52.5%) histology. The DCRs were 82.5% (95% CI, 67.2%-92.7%) and 66.7% (95% CI, 54.6%-77.3%), respectively.

Overall, the median PFS was 6.6 months (95% CI, 4.6-9.3) and the 6-month PFS rate was 56.2%. Iams noted that PFS was improved proportionally to PD-L1 expression levels. The median PFS was 16.7 months (95% CI, 4.0-16.8) in those with a PD-L1 TPS of 50% or greater, 8.3 months (95% CI, 4.4-15.7) in those with a PD-L1 TPS between 1% and 49%, 4.2 months (95% CI, 3.6-6.1) in those with a PD-L1 TPS of less than 1%, and 9.3 months (95% CI, 6.1-15.7) in those with a PD-L1 TPS of 1% or greater.

The median treatment exposure for the combination was 24.7 weeks (range, 1-58) and 24.2 weeks (range, 0.1-103.3) for maintenance pembrolizumab. Six patients completed the 2 years of treatment, whereas 24 were still on therapy at the data cutoff date.

The safety profi le was consistent with prior reports on the combination. Adverse effects (AEs) of Grade 3 or above occurred in 12.3% of patients, and serious AEs occurred in 10.5% of patients. AEs that led to treatment discontinuation occurred in 9.6% of patients, and AEs that led to death occurred in 3 patients.

AEs of any grade by preferred term were pruritus (20.2%), asthenia (19.3%), rash (13.2%), diarrhea (10.6%), and fatigue (10.5%). Grade 3 diarrhea and fatigue were reported in 1 patient each.

Data from part B of the trial were presented during the International Association for the Study of Lung Cancer 2022 World Conference on Lung Cancer in Vienna, Austria. Here, efti plus pembrolizumab showed encouraging PFS and OS in the second-line setting in patients with NSCLC who showed progression on anti–PD-1/ PD-L1 therapy. The median OS was 9.7 months, and the 18-month OS rate was 36.5%.³ The 6-month PFS rate was 25%.

_REFERENCES:

_{1. Iams W, Felip E, Majern M, et al. Combining the antigen-presenting cell activator eftilagimod alpha (soluble LAG-3) and pembrolizumab: effi cacy results from the 1st line non-small cell lung cancer cohort of TACTI-002 (phase II). Abstract presented at: Society for Immunotherapy of Cancer 37th Annual Meeting & Pre-Conference Programs; November 8-12, 2022; Boston, MA. Abstract 1470.}

_{2. Immutep receives FDA fast track designation for LAG-3 therapeutic eftilagimod alpha for fi rst line non-small cell lung cancer. News release. Immutep. October 4, 2022. Accessed November 11, 2022. h ps://bit.ly/3C5MuTD}

_{3. Immutep reports new positive interim data from its phase II study of LAG-3 candidate, eftilagimod alpha, in 2nd line PD-X refractory NSCLC. News release. Immutep. August 1, 2022. Accessed November 10, 2022. h ps://bit.ly/3JnIWPU}