The first-line combination of pembrolizumab and eftilagimod alpha elicited a 40.4% (95% CI, 31.3%-50.0%) overall response rate by immune RECIST criteria in the intent-to-treat population in patients with advanced non–small cell lung cancer, according to updated findings from the phase 2 TACTI-002 trial.
The first-line combination of pembrolizumab (Keytruda) and eftilagimod alpha (efti; IMP321) elicited a 40.4% (95% CI, 31.3%-50.0%) overall response rate (ORR) by immune RECIST (iRECIST) criteria in the intent-to-treat (ITT) population in patients with advanced non–small cell lung cancer (NSCLC), according to updated findings from the phase 2 TACTI-002 trial (NCT03625323) that were presented during the 2022 SITC Annual Meeting.1
The ORR comprised 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). The median duration of response (DOR) was 21.6 months (95% CI, 17.3-30.0).
When assessed by RECIST 1.1 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 11.4% of patients were not evaluable.
“We did see deep and durable responses across subgroups; there did appear to be a step-wise benefit by PD-L1 score from 0%, to 1% to 49%, to greater than 50%,” lead study author Wade T. Iams, MD, assistant professor of medicine in the Division of Hematology Oncology at Vanderbilt University Medical Center in Nashville, Tennessee, said in a presentation during the meeting. “The combination of eftilagimod alpha and pembrolizumab is safe and tolerable, and there are ongoing studies in late-stage development for this combination.”
Efti is a soluble LAG-3 protein that binds to a subset of MHC 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 result in more potent antitumor responses when paired with pembrolizumab vs what has been reported with pembrolizumab alone.
In October 2022, the FDA granted a fast track 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 1.1 criteria, had an ECOG performance status of 0 to 1, and available tumor tissue for central PD-L1 testing. Patients were unselected for PD-L1 status. The 3 parts comprised the combination in the first-line setting where patients were unselected for PD-L1 (part A; n = 114), in the second-line setting for patients resistant to PD-1/PD-L1–based therapy (part B; n = 36), and in second-line head and neck squamous cell carcinoma after platinum-based therapy (part C; n = 39).
The findings from part A were presented during the 2022 SITC Annual Meeting. Here, efti was administered every 2 weeks plus pembrolizumab every 3 weeks for 8 cycles followed by efti and pembrolizumab both given every 3 weeks for 9 cycles for 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 1.1 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 7.0 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 (94.7%) were current or former smokers, as well as had metastatic disease (99.1%). Squamous histology was reported in 35.1% of patients.
A total 35.6% and 42.2% of patients had a PD-L1 TPS less than 1% and between 1% and 49% by central assessment only, respectively. Additionally, 34.3% and 38.9% had 1% and 1% to 49% of PD-L1 TPS by central and local assessment, respectively. A total 22.2% and 26.9% of patients had PD-L1 TPS 50% or higher 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 1.1 criteria.
Response rates improved with increasing PD-L1 TPS. For example, in those with a PD-L1 <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 PD-L1 TPS 1% to 49% (n = 38) and a 55.0% ORR (95% CI, 31.5%-76.9%) in those with PD-L1 TPS ≥50% (n = 20). In patients whose tumors had PD-L1 TPS ≥1% (n = 58), the ORR was 48.3% (95% CI, 35.0%-61.8%).
The disease control rates (DCRs) in patients whose tumors have PD-L1 TPS <1%, between 1% and 49%, ≥50%, and ≥1% were 65.6% (95% CI, 46.8%-81.4%), 78.9% (95% CI, 62.7%-90.5%), 80.0% (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 PD-L1 TPS ≥50%, 8.3 months (95% CI, 4.4-15.7) in those with PD-L1 TPS 1%-49%, 4.2 months (95% CI, 3.6-6.1) in PD-L1 TPS <1%, and 9.3 months (95% CI, 6.1-15.7) in PD-L1 TPS >1%.
The median treatment exposure for the combination was 24.7 weeks (range, 1-58.0) and 24.2 weeks (range, 0.1-103.3) for maintenance pembrolizumab. Six patients completed the 2 years of treatment while 24 were still on therapy at the data cutoff date.
The safety profile was consistent with prior reports of the combination. Grade 3 or higher adverse effects (AEs) 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.
Any-grade AEs 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.
Through biomarker assessments, investigators found that interferon-gamma and CXCL 10/IP were significantly elevated at 3 and 6 months compared with baseline levels.
Data from part B of the trial were presented during the 2022 World Conference on Lung Cancer. Here, efti plus pembrolizumab showed encouraging PFS and OS in the second-line setting in patients with NSCLC who progressed on anti–PD-1/anti–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%.