Abequolixron/Docetaxel Produces Durable Responses in Recurrent Advanced NSCLC

The first-in-class liver-X receptor abequolixron (RGX-104) in combination with docetaxel generated preliminary efficacy signals and was well tolerated in the second- and third-line settings in patients with advanced/metastatic nonsquamous non–small cell lung cancer (NSCLC), according to Abdul Rafeh Naqash, MD. Data from the phase 1/2b dose-escalation and -expansion RGX-104-001 trial (NCT02922764) investigating this combination in this patient population were presented at the 2024 SITC Annual Meeting.

“Novel drugs and appropriate clinical trial designs are ways to move the needle to help patients achieve what we want for them, [which is] to live longer and better,” Naqash said in an interview with OncLive^®.

Findings from the study demonstrated that patients in the evaluable population (n = 15) achieved an overall response rate (ORR) of 53%; the ORR in the intention-to-treat (ITT) population (n = 21) 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.

Safety data showed that 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%).

In the interview, Naqash discussed the patient population enrolled in this study, key efficacy data with abequolixron plus docetaxel, and the potential implications of these trial’s findings within the current NSCLC treatment paradigm, in which docetaxel monotherapy is a standard of care (SOC) in later-line settings.

The findings from the RGX-104-001 trial support the continued development of a randomized phase 2 trial, which will investigate abequolixron plus docetaxel vs docetaxel in patients with recurrent advanced/metastatic NSCLC who have received prior treatment with an immune checkpoint inhibitor plus platinum-based therapy.

Naqash is an assistant professor at the University of Oklahoma Health Sciences College of Medicine in Oklahoma City and part of the TSET phase 1 program at the University of Oklahoma Health Stephenson Cancer Center.

OncLive: What criteria were used to select the patient population enrolled in RGX-104-001?

Naqash: The key eligibility criteria for this study were nonsquamous NSCLC, meaning primarily adenocarcinomas that were metastatic or advanced in stage, or locally advanced and unresectable, meaning patients [with disease that was] nonmetastatic but unresectable who had received some form of therapy in the stage IIIB [setting] and went on to receive [abequolixron and docetaxel] in combination. Patients should have had disease progression after checkpoint [inhibitor–based] therapy because checkpoint inhibitor therapy plus chemotherapy or checkpoint inhibitor therapy alone is the SOC [in the first line].

[The trial] also included patients who might have received targeted therapies in previous lines. Patients who had received neoadjuvant taxanes—if they were surgically resectable when they were diagnosed—should have had at least a 6-month progression-free interval since their last taxane dose. In that context, we worry about giving taxanes in the less-than-6-month period [because] the chances of getting a benefit [with another taxane] in the later setting are lower.

[Patients also needed to have] measurable disease per RECIST 1.1 criteria and a good ECOG performance status of 0 or 1. [The trial allowed patients with] treated brain metastases without evidence of new or enlarging lesions.

How did the efficacy outcomes with abequolixron plus docetaxel in this trial compare with outcomes historically seen with docetaxel monotherapy in this population?

There was promising preliminary efficacy in the second- and third-line settings [for the combination in patients with] nonsquamous NSCLC with an ORR of 38% [in the ITT population] and a median DOR of 5.8 months. Eight patients had a partial response. Four patients had tumors with stable disease.

We would expect approximately a 15% to 20% ORR with docetaxel [alone] in the second- and third-line [settings in this population]. [These trial data are] interesting because numerically, even though it was not a randomized trial, the combination [of docetaxel and abequolixron] seemed to confer enough clinical benefit [to suggest] that the experimental agent, abequolixron, adds benefit to docetaxel in the second-line setting and beyond.

What has been seen regarding the safety profile of abequolixron plus docetaxel?

From a physician’s standpoint, we always try to be careful about toxicity management. [When adding a drug to a treatment regimen], even if it’s an immune modulator, different effects can happen in the immune system. [Patients] could have a combination of chemotherapy-related and immune-related AEs. Thankfully, we didn’t see a lot of that [in the RGX-104-001 trial]. In the context of this study, we saw that the most common grade 2 or lower treatment-related AEs were fatigue, nausea, and diarrhea.

We didn’t see febrile neutropenia. We didn’t see significant or obvious grade 3 or higher immune toxicities, which is good because we worry when patients have baseline immune toxicities when they discontinue first-line chemoimmunotherapies for lung cancer. In the second- and third-line settings, when we put them on another immune-modulating drug, we worry about the tendency of cross reactivity and whether another drug in the later-line setting will reactivate the immune system enough where they have further enhancement of toxicity. Thankfully, we didn’t see that.

What are the next steps for evaluating immune-related biomarkers in this study?

The collection of both blood- and tissue-based biomarkers is being done per the protocol in the study, but none of [those findings have] been reported yet. Perhaps down the line, we will see more of those data.

The encouraging results from the study will likely result in [further research, such as the] phase 2 randomized trial that is being planned in the recurrent advanced/metastatic NSCLC setting. That trial will likely [collect] more biomarker data, both from the peripheral blood and from tissue. [In the phase 2 trial, investigators will likely evaluate] the tumor microenvironment, peripheral blood–based inflammatory markers, and APOE levels [in order to] correlate those with clinical efficacy outcomes.

How might future data from the phase 2 trial support the use of abequolixron in patients with later-stage NSCLC?

[This phase 2 trial is] being planned. We are all excited about that because for patients with NSCLC, even though we have good first-line regimens, the moment those regimens are exhausted, if [the tumors have] no driver mutations, [subsequent] options are limited. Then patients start getting chemotherapy, which most patients are not excited about. [Abequolixron plus docetaxel] is not a chemotherapy-free regimen, but if we can try to expand on the benefit of chemotherapy with an immune modulator [like] abequolixron, [this agent] would probably balance out some of the AEs we tend to see with chemotherapy. We need more attractive treatment options in the second- and third-line settings for patients with NSCLC so we can try to extend patients’ quality of life and survival to help them live longer and better without significant toxicities.

More work needs to be done to find the right combinations. [Regimens] that work in preclinical settings may not necessarily work in human beings. I work as a phase 1 trialist in drug development, and as excited as I am about clinical trials and novel drugs, being cautiously optimistic is an important aspect of drug development. Having appropriate clinical trial designs is another extremely important aspect.

One [feature of the phase 2 trial that] I appreciate is its randomized design [comparing] abequolixron plus docetaxel vs docetaxel alone. Randomized studies should be a standard to help us understand whether a novel drug is adding benefit to a SOC drug. The data we have [so far with abequolixron] are interesting and exciting, [but it has been evaluated in] a single-arm study at this point. We have seen time and again other combinations [with docetaxel] have efficacy and benefit in the single-arm setting, but then when we do a randomized study, [the novel agents] do not add much benefit [to docetaxel].

In our line of work, we call docetaxel this old dog that is always on guard and doesn’t seem to go away after you conduct randomized studies. Hopefully, we’ll see more positive results with the [phase 2 randomized] study we’re planning to conduct. However, appropriate, randomized clinical trials to take drug development forward and help us understand the level of benefit a novel agent is adding to a SOC therapy are extremely important.

Reference

Mita MM, Mita AC, Desai P, et al. Abequolixron ( RGX-104 ), a first-in-class oral immunotherapy targeting the liver-X receptor (LXR), in combination with docetaxel in recurrent advanced/metastatic non-small cell lung cancer (NSCLC). Presented at: 2024 SITC Annual Meeting; November 6-10, 2024; Houston, TX. Abstract 657.