Abequolixron (RGX-104), a first-in-class liver-X receptor (LXR) agonist, in combination with docetaxel, has shown promising preliminary efficacy and tolerability in patients with advanced/metastatic non-squamous non-small cell lung cancer (NSCLC) who have progressed on prior therapies. These findings from the phase 1/2b RGX-104-001 trial, were presented at the 2024 SITC Annual Meeting, potentially offering a new treatment avenue for patients with limited options. The study suggests that abequolixron may enhance the benefit of docetaxel in later-line settings.
Efficacy Outcomes
The RGX-104-001 trial evaluated the combination of abequolixron and docetaxel in patients with recurrent advanced/metastatic NSCLC who had previously received immune checkpoint inhibitors and platinum-based therapy. The evaluable population (n = 15) achieved an overall response rate (ORR) of 53%. In the intention-to-treat (ITT) population (n = 21), the ORR was 38%. The median duration of response (DOR) was 5.8 months, and the median progression-free survival was 3.3 months in the ITT population.
According to Dr. Abdul Rafeh Naqash, assistant professor at the University of Oklahoma Health Sciences College of Medicine, the observed ORR with the combination is notably higher than what is typically seen with docetaxel monotherapy in similar settings. "We would expect approximately a 15% to 20% ORR with docetaxel [alone] in the second- and third-line [settings in this population]," he noted. The data suggest that abequolixron may add clinical benefit to docetaxel in this patient population.
Safety Profile
The safety data from the trial indicated that the combination of abequolixron and docetaxel was generally well-tolerated. The most common grade 1/2 treatment-emergent adverse effects (TEAEs) were fatigue (52%), nausea (43%), and diarrhea (38%). Grade 3 or higher TEAEs included neutropenia (14%), fatigue (10%), nausea (10%), and dyspnea (10%). Importantly, the study did not observe significant immune-related toxicities, which is a concern when using immune-modulating drugs in later-line settings after prior chemoimmunotherapy.
Future Directions
The encouraging results from the RGX-104-001 trial have led to the planning of a randomized phase 2 trial. This trial will investigate abequolixron plus docetaxel versus docetaxel alone in patients with recurrent advanced/metastatic NSCLC who have received prior treatment with an immune checkpoint inhibitor plus platinum-based therapy. The phase 2 trial will also incorporate the collection of blood- and tissue-based biomarkers to correlate with clinical efficacy outcomes, including assessment of the tumor microenvironment, peripheral blood inflammatory markers, and APOE levels.
Dr. Naqash emphasized the importance of randomized trials in evaluating novel drug combinations. "Randomized studies should be a standard to help us understand whether a novel drug is adding benefit to a SOC drug," he stated. He also acknowledged the limitations of single-arm studies and the need for robust data to confirm the benefits of new agents in combination with established therapies like docetaxel.
Implications for NSCLC Treatment
For patients with NSCLC who have exhausted first-line treatment options, subsequent options are often limited, particularly for those without driver mutations. Chemotherapy remains a standard approach, but it is associated with significant toxicities. The combination of abequolixron and docetaxel represents a potential strategy to expand on the benefit of chemotherapy while mitigating some of its adverse effects. The planned phase 2 trial will provide further insights into the efficacy and safety of this combination and its potential role in improving outcomes for patients with advanced NSCLC.
