Soluble LAG-3 Protein Plus Pembrolizumab Shows Activity in PD-1 Resistant NSCLC

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Eftilagimod alpha, a soluble LAG-3 protein, showed antitumor activity in combination with pembrolizumab (Keytruda) in patients with non–small cell lung cancer (NSCLC) who were resistant to prior PD-1/PD-L1 therapy, according to a presentation at the 2023 European Lung Cancer Congress.¹

In part B of the multicenter phase 2 TACTI-002 trial (NCT03625323), which enrolled 36 patients who previously had a best response of progressive disease (PD) in first-line therapy for NSCLC, the objective response rate (ORR) was 8.3% (95% CI, 1.8-22.5). There was a disease control rate (DCR) of 33.3% (95% CI, 18.6-51.0%) and disease progression decelerated in 50% of patients. The combination also had a tolerable safety profile.

“What is important to see is that after the introduction of eftilagimod to pembrolizumab, patients presented on a shrinkage or deceleration of the tumor growth kinetics after a previous PD to immunotherapy,” stated Margarita Majem, MD, PhD, a faculty member in the department of medical oncology at the Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, in her presentation of the study results.

Eftilagimod alpha is a LAG-3 protein that functions as an MHC class II agonist rather than a LAG-3 agonist. It triggers activation of antigen-presenting cells (APCs) and CD8 T cells, which investigators hypothesized could lead to reverting PD-1 resistance that prevents patients from responding to immune checkpoint inhibitors such as pembrolizumab.

Between April 2019 and August 2021, 36 patients who had PD in the first line were enrolled in the TACTI-002 trial; 66.7% had received a PD-1/PD-L1 inhibitor with platinum-based chemotherapy and 33.3% had received PD-1/PD-L1 inhibitor monotherapy. The median age was 67 years (range, 46-84) and 61% were male. ECOG performance status was 0 in 33% of patients and 1 in 67% of patients. The majority (78%) had nonsquamous histology. Patients in all PD-L1 subgroups were enrolled, including 36.1% with tumor proportion score (TPS) less than 1%, 38.9% with TPS between 1% and 49%, and 16.7% with a TPS of 50% or higher.

Patients received 30 mg eftilagimod subcutaneously every 2 weeks for the first 8 cycles and every 3 weeks onward for a total of 1 year. They received 200 mg intravenous pembrolizumab every 3 weeks for 1 year, followed by 1 year of pembrolizumab alone. The primary end point was ORR; secondary end points included DCR, progression-free survival (PFS), overall survival (OS), and safety.

Three patients had a partial response. Nine patients had stable disease.

At a data cut-off of December 31, 2022, the median OS was 9.9 months (95% CI, 6.5-23.0) with 25 OS events (69.4%), with a 12-month OS rate of 44% and a 21-month OS rate of 39%. Majem said in her presentation that this compared favorably with historical data such as docetaxel’s 21-month OS rate of 10% to 15%, depending on histology, in this setting.^2,3 The median PFS was 2.1 months (95% CI, 1.9-2.1), and the 6-month PFS rate was 25%.

All 3 patients who responded had durable responses on treatment for over 18 months, and several patients with stable disease lasted beyond 6 months.1 Two of the 3 had PD-L1 expression of at least 50% and the third had positive PD-L1 expression. All 3 had secondary rather than primary resistance to first-line immunotherapy. Overall, patients with higher PD-L1 expression and secondary resistance had better PFS and OS outcomes in the trial.

In an exploratory analysis of tumor dynamics, 83.3% of patients had tumor growth kinetic shrinkage or deceleration after receiving eftilagimod. Out of 24 patients evaluated, 8 (33.3%) had shrinkage, 12 (50%) had deceleration, and only 4 (16.7%) had tumor acceleration.

In terms of safety and tolerability, the median exposure to eftilagimod and pembrolizumab was 2.8 months. No patients discontinued treatment due to adverse events (AEs), there were no fatal AEs, and no unknown immune-related AEs were reported. The most common treatment-emergent AEs were asthenia in 13.9% and pruritus in 11%, with no grade 3 asthenia and 1 grade 3 case of pruritus.

“In conclusion, the addition of an APC activator eftilagimod alpha administered together with anti–PD-1 therapy may reveal resistance to the previous anti–PD[-1/PD-L1] therapy, and these data support further clinical investigation of this innovative [chemotherapy]-free [dual immunotherapy] combination targeting both APCs and T cells in anti-PD[-1/PD-L1] resistant patient population,” Majem stated in her presentation.

_REFERENCES

_{1. Majem M, Forster M, Krebs 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: European Lung Cancer Congress 2023; March 29 to April 1, 2023; Copenhagen, Denmark. Abstract 11MO.}

_{2. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123-135. doi:10.1056/NEJMoa1504627}

_{3. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627-1639. doi:10.1056/NEJMoa1507643}