Investigators Look to Translate Positive Results of Eftilagimod Alpha Combination to NSCLC

Wade T. Iams, MD

Clinicians tasked with treating patients with non–small cell lung cancer (NSCLC) have seen a number of advances in recent years, with the FDA approving antibody-drug conjugates, immune checkpoint inhibitors, combination regimens, and more in the space. Investigators are now hoping to add an additional therapeutic option to the treatment paradigm of NSCLC with the development of the novel agent eftilagimod alpha (IMP321).

Eftilagimod alpha is a first-in-class, soluble lymphocyte activation gene-3 (LAG-3) protein fused to a human IgG backbone.¹ It targets a subcategory of MHC class II molecules to mediate the activation of antigen-presenting cells such as dendritic cells and monocytes, aiding in the recruitment of natural killer cells and T cells. The agent is classified as an MHC class II agonist, not a LAG-3 antagonist.¹

“There are various monoclonal antibodies that target LAG-3; [nivolumab/]relatlimab [Opdualag] may be the most familiar,” said Wade T. Iams, MD, an assistant professor of medicine at Vanderbilt University Medical Center, in Nashville, Tennessee, in an interview with OncologyLive^®. “But LAG-3 is also expressed on antigen-presenting cells. Eftilagimod alpha is unique in that it’s not a monoclonal antibody [but rather a] soluble LAG-3 molecule and it can act on antigen-presenting cells to prime MHC-II mediated antigen presentation upstream of T cells.”

Eftilagimod alpha is being evaluated for patients with NSCLC in both the first- and second-line settings in the phase 2 TACTI-002 trial (NCT03625323).

Eftilagimod Alpha Exhibits Efficacy in Multiple Tumor Types

Preceding the initiation of TACTI-002, eftilagimod alpha displayed activity and a low level of toxicity in patients with advanced renal cell carcinoma in a phase 1 trial (NCT00351949). The first-in-human trial enrolled 21 patients with advanced renal cell carcinoma. Patients received eftilagimod alpha at doses ranging from 0.050 mg to 30 mg twice per week for a total of 6 subcutaneous injections.²

At doses above 6 mg, eftilagimod alpha induced sustained CD8 T-cell activation and increased the presence of long-lived effector-memory CD8 T cells in all patients. Patients treated at a dose of 6.25 mg or 30 mg (n =8) experienced a 78% mean change in terms of CD8-positive, CD69-positive T cells. There was also a significant increase in the presence of circulating activated CD8-positive T cells displaying the activation markers CD69, CD38, and HLA-DR in most (n = 7) of the patients in this group (P = .016).

Patients who received eftilagimod alpha at a dose greater than 6 mg experienced stable disease at a significantly greater rate than the 11 patients who received lower doses (P = .015). Moreover, no clinically significant treatment-related adverse events (AEs) were reported among any of the 21 evaluable patients. Most grade 1 injection site AEs occurred at the 30-mg dose level and included erythema (n = 8), nodule (n = 2), and pain (n = 2). Study authors concluded that eftilagimod alpha was a prime candidate to make up a component of first-line combination regimens.

Eftilagimod alpha was later evaluated in combination with the PD-1-targeted immunotherapy pembrolizumab (Keytruda) in the phase 1 TACTI-mel study (NCT02676869). The trial enrolled patients with unresectable or metastatic melanoma. A total of 24 patients were treated with the combination. Part A of the study was the dose escalation portion and part B was dose confirmation.³

Patients in part A received eftilagimod alpha at a dose of 1 mg (n = 6), 6 mg (n = 6), or 30 mg (n = 6). In part B, patients were treated with the agent at a dose of 30 mg (n = 6). Eftilagimod alpha was administered via subcutaneous injection every 2 weeks for approximately 6 months, beginning at pembrolizumab cycle 5. All patients received pembrolizumab 2 mg/kg intravenously every 3 weeks.

In part A, the overall response rate (ORR) was 33%, including 2 patients who achieved a complete response. The disease control rate (DCR) was 55.6% and the median progression-free survival (PFS) was 4.7 months.

In part B, the ORR was 50% and the DCR was 83%. The median PFS and median duration of response (DOR) could not be calculated, as all responses were ongoing for at least 1 year.

Regarding safety, no dose-limiting toxicities were observed. No AEs led to treatment discontinuation, and serious AEs were reported in 6 patients overall. In part B, the most common treatment-related AEs of any grade included fatigue (83.3%), injection site erythema (66.7%), rash (66.7%), and arthralgia (66.7%).

Investigators determined the recommended phase 2 dose to be 30 mg administered every 2 weeks for a maximum of 12 months. They noted that the combination of eftilagimod alpha plus pembrolizumab induced long-term tumor responses and a long-term increase in circulating activated CD8 and CD4 T cells without clinically significant toxicity.

“In combination with pembrolizumab, which is more of a cytotoxic T-cell stimulatory agent at the site of cytotoxic T-cell tumor interactions, eftilagimod alpha works upstream at the antigen-presenting cell and T-cell interface to increase the overall immune response,” Iams said. “[It is] synergistic in combination with pembrolizumab.”

TACTI-002 Trial Details

Study authors are looking to translate the positive results obtained with the eftilagimod alpha plus pembrolizumab combination in melanoma to NSCLC with the initiation of TACTI-002. The TACTI-002 study is a nonrandomized, open-label trial that will evaluate the safety and efficacy of eftilagimod alpha plus pembrolizumab among patients with NSCLC and metastatic head and neck cancer squamous cell carcinoma (HNSCC).

Investigators theorized that the stimulation of the dendritic cell network and the subsequent T-cell recruitment caused by eftilagimod alpha could help combat resistance to anti–PD-1 agents. The multicenter trial is aiming to enroll approximately 189 patients and encompasses 3 experimental arms: first-line NSCLC (part A), second-line NSCLC (part B), and HNSCC (part C).⁴

Patients in each arm will be treated with the same regimen. Eftilagimod alpha is being given at a dose of 30 mg every 2 weeks for the first eight 3-week cycles and then every 3 weeks starting at cycle 9 via a subcutaneous injection. Pembrolizumab is administered intravenously at a dose of 200 mg every 3 weeks.

The primary end point of the trial is ORR per RECIST criteria up to 24 months. Secondary end points include safety, time to response, DOR, and PFS.

Early findings from TACTI-002 have been promising. As of the July 1, 2022, data cutoff, 114 patients with treatment-naïve NSCLC had been enrolled in part A of the trial. The median age of these patients was 67 years (range, 44-85) and all but 1 patient had metastatic disease. Most patients were men (73.7%), had an ECOG performance status of 1 (62.3%), and had nonsquamous histology (63.2%).¹

The median duration of treatment with eftilagimod alpha was 24.7 weeks (range, 1-58), and 24.2 weeks (range, 0.1-103.3) with pembrolizumab. Two years of treatment was completed by 6 patients, and 24 patients remained on treatment at the data cutoff.

Preliminary data from the trial showed that patients in part A experienced an ORR of 40.4% (95% CI, 31.3%-50.0%), including 1 patient with a complete response, per RECIST criteria. Additionally, 32.5% of patients achieved stable disease, the median PFS was 6.6 months (95% CI, 4.6-9.3), and the 6-month PFS rate was 56.2%. The median DOR was 21.6 months (95% CI, 17.3-30.0).⁵

Additional findings from the study showed that the benefit observed with eftilagimod alpha treatment was consistent across PD-L1 subgroups. Patients with a PD-L1 tumor proportion score (TPS) of less than 1% (n = 32), 1% to 49% (n = 38), and at least 50% (n = 20) experienced an ORR of 31.3% (95% CI, 16.1%-50.0%), 44.7% (95% CI, 28.6%-61.7%), and 55% (95% CI, 31.5%-76.9%), respectively. The median PFS was 4.2 months (95% CI, 3.6-6.1), 8.3 months (95% CI, 4.4-15.7), and 16.7 months (95% CI, 4.0-16.8), respectively. Notably, among 58 patients with a PD-L1 TPS of at least 1%, the ORR was 48.3% (95% CI, 35%-61.8%).

In terms of safety, the most common AEs related to study treatment included pruritus (20.2%), asthenia (19.3%), and rash (13.2%). Grade 3 or greater AEs occurred in 12.3% of patients, and 10.5% experienced serious AEs. Treatment discontinuation due to AEs was observed at a rate of 9.6%, and 3 patients died.

Eftilagimod alpha displayed an encouraging response rate across all PD-L1 subgroups and was very well tolerated, the study authors wrote. Further late-stage development of the agent is warranted.^1,5

“We’re hoping that in the second-line [NSCLC] cohort, we can see similar results with improved ORR, PFS, and overall survival,” Iams said. “The second-line setting is a very crowded space [in terms of] novel agents being evaluated for patients with relapsed NSCLC. It’s a very high area of need. There’s huge interest in the field for other strategies that could have less toxicity [than the standard of care] and trying to salvage that long-term durable disease control. We’re all hoping that some of the strategies in the relapsed NSCLC setting can provide patients still with more opportunity for durable disease control.”

Considering the positive findings from part A of the trial, the FDA granted a fast-track designation to eftilagimod alpha plus pembrolizumab for the frontline treatment of patients with stage IIIB/IV NSCLC with a PD-L1 TPS of at least 1%. The designation was granted on October 4, 2022, and will allow for the expedited review and potential future approval of the combination by the FDA.⁶

References

1. Iams WT, Felip E, Majem M, et al. Combining the antigen-presenting cell activator eftilagimod alpha (soluble LAG-3) and pembrolizumab: efficacy 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; November 8-12, 2022; Boston, MA.
2. Brignone C, Escudier B, Grygar C, Marcu M, Triebel F. A phase I pharmacokinetic and biological correlative study of IMP321, a novel MHC class II agonist, in patients with advanced renal cell carcinoma. Clin Cancer Res. 2009;15(19):6225-6231. doi:10.1158/1078-0432.CCR-09-0068
3. Atkinson V, Khattak A, Haydon A, et al. Eftilagimod alpha, a soluble lymphocyte activation gene-3 (LAG-3) protein plus pembrolizumab in patients with metastatic melanoma. J Immunother Cancer. 2020;8(2):e001681. doi:10.1136/jitc-2020-001681
4. Combination study with soluble LAG-3 fusion protein eftilagimod alpha (IMP321) and pembrolizumab in patients with previously untreated unresectable or metastatic NSCLC, or recurrent PD-X refractory NSCLC or with recurrent or metastatic HNSCC (TACTI-002). ClinicalTrials.gov. Updated June 13, 2022. Accessed November 16, 2022. https://clinicaltrials.gov/ct2/show/NCT03625323
5. Felip E, Majem M, Doger B, et al. A phase II study (TACTI-002) in first-line metastatic non–small cell lung carcinoma investigating eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab: updated results from a PD-L1 unselected population. J Clin Oncol. 2022;40(suppl 16):9003. doi:10.1200/JCO.2022.40.16_suppl.9003
6. Immutep receives FDA fast track designation for LAG-3 therapeutic eftilagimod alpha for first line non-small cell lung cancer. News release. Immutep Limited. October 4, 2022. Accessed November 16, 2022. bit.ly/3C5MuTD