Addition of eftilagimod alpha to pembrolizumab may revert resistance to anti-PD-1/PD-L1 therapy

Final results of the phase II TACTI-002 trial show signs of efficacy with the combination of eftilagimod alpha and pembrolizumab in patients with predominantly PD-L1 negative/low second-line non-small cell lung cancer after confirmed progression on first-line anti-PD1/PD-L1 therapy. Effects are durable and the combination of eftilagimod alpha and pembrolizumab was well-tolerated.

Eftilagimod alfa (efti) is a soluble LAG-3 protein that targets a subset of MHC class II molecules to mediate antigen presenting cells (APC) and subsequent CD8 T-cell activation. Stimulating APCs and subsequent T cell recruitment with efti may revert PD-1/PD-L1 resistance. At ELCC 2023, final results from part B of the TACTI-002 trial were presented, assessing second-line PD-1/PD-L1-resistant non-small cell lung cancer (NSCLC) patients treated with efti plus pembrolizumab.

Study design

Patients with metastatic NSCLC unselected for PD-L1 expression and with resistance to first-line PD-1/PD-L1 inhibitor-based therapy were enrolled. Patients were treated with efti (30 mg subcutaneously Q2W for eight 3-week cycles and then Q3W up to one year) in combination with pembrolizumab (200 mg IV Q3W up to two years). Primary endpoint was objective response rate (ORR) as per iRECIST. Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and tolerability. Post-hoc analysis included tumour growth kinetics (TGK). Imaging was performed every 9 weeks and locally evaluated. PD-L1 tumour proportion score (TPS) was assessed using the IHC 22C3 kit.

Results

Between April 2019 and August 2021, 36 patients were enrolled in the study. Median age of the participants was 67 years and 61.1% were male. The ECOG performance status was 0 or 1 in respectively 33% and 67% of patients. Most patients (77.8%) had non-squamous histology. PD-L1 expression levels (TPS) were <1% for 36.1% of patients, 1-49% for 38.9% of patients and ≥50% for 16.7% of participants. Patients previously received a PD-1/PD-L1 inhibitor alone or in combination with a checkpoint inhibitor (33.3%) or combined with platinum-based chemo (66.7%) as first-line therapy. Median treatment exposure was 2.8 months for both efti and pembrolizumab. The objective response rate and disease control rate was 8.3% and 33.3%, respectively. Median OS was 9.9 months and median PFS was 2.1 months. The 6-month PFS rate was 25% and the 6-, 12- and 21-month OS rates were 72%, 44% and 39%, respectively. Efficacy was durable with all three responders on treatment for more than 18 months. Overall, patients with high PD-L1 expression and with secondary resistance had better ORR, PFS and OS compared to patients with PD-L1 negative expression and primary resistance. Furthermore, a tumour growth kinetics analysis was performed on patients with data available on the same lesions from prior failed therapy and post-baseline. After addition of efti, 83.3% of patients had post-efti treatment initiation tumour growth kinetic shrinkage (33.3%) or deceleration (50.0%) after previous disease progression. Most common treatment-emergent adverse events were asthenia (13.9%, only grade 1 and 2) and pruritus (11%, one case of grade 3). There were no treatment discontinuations due to adverse events and no grade 5 toxicity.

Conclusion

The addition of APC activator eftilagimod alpha administered subcutaneously with anti-PD-1 therapy may revert resistance to anti-PD-1/PD-L1 therapy. These data support further clinical investigation of this innovative chemotherapy-free I-O/I-O combination targeting both APCs (efti) and T-cells (anti-PD-1) in PD1/PD-L1 resistant patients.

Reference

Majem Tarruella M, et al. Final data from a phase II study (TACTI-002) of eftilagimod alpha (soluble LAG-3) & pembrolizumab in 2nd line metastatic NSCLC pts resistant to PD-1/PD-L1 inhibitors. Presented at ELCC 2023; Abstract 11MO.