Abequolixron Plus Docetaxel Shows Promising Efficacy in NSCLC and SCLC

Hossein Borghaei, DO, MS

Abequolixron (RGX-104) demonstrated early clinical activity when combined with docetaxel in heavily-pretreated patients with non–small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), according to interim study results announced in a press release from Inspirna.¹

Investigators in a phase 1/2 clinical trial (NCT02922764) reported an overall response rate (ORR) of 38% and a disease control rate (DCR) of 77% in 13 evaluable patients who received abequolixron plus docetaxel for second- or third-line NSCLC or second-line SCLC. The combination was well tolerated.

“The data thus far demonstrate that abequolixron is well tolerated in combination with full-dose docetaxel, while showing encouraging clinical activity suggesting that this drug candidate could be a valuable addition to a current standard-of-care chemotherapy in heavily-pretreated patients with lung cancer,” Hossein Borghaei, DO, MS, chief of the division of thoracic medical oncology at Fox Chase Cancer Center and principal investigator on the study, said in a statement.

Abequolixron is a small molecule liver X receptor agonist that targets apolipoprotein E pathway dysregulation and enhances antitumor immunity by inhibiting tumor angiogenesis, as well as depleting myeloid derived suppressor cells and activating cytotoxic T lymphocytes.

The phase 1/2 trial’s dose escalation portion administered different dose levels and schedules of abequolixron alone or combined with nivolumab (Opdivo), ipilimumab (Yervoy), docetaxel, or pembrolizumab (Keytruda)/carboplatin/pemetrexed (Alimta) in patients with advanced solid tumors and lymphoma.

The recommended phase 2 dose (RP2D) of abequolixron was determined to be 120 mg twice daily, 5 days on and 2 days off. In a phase 2 dose expansion cohort, 17 patients with NSCLC or SCLC were treated with the RP2D plus docetaxel. Thirteen of these patients were evaluable for response per RECIST 1.1 criteria: 5 patients with second- or third-line NSCLC and 8 patients with second-line SCLC. The 38% ORR consisted of 5 partial responses in patients, 4 who had NSCLC and 1 who had SCLC.

Of the 4 patients with NSCLC who responded, 2 had confirmed partial responses and 4 patients were on study treatment for over 19 weeks, including one with ongoing response at 37 weeks. For the 8 patients with SCLC, there were 5 patients who had a best response of stable disease, and 4 remained on therapy for at least 24 weeks without progression. One patient who had a best response of stable disease went on to have central nervous system progression at week 12 but stayed on therapy for 30 weeks without systemic progression.

All 17 patients were evaluated for safety. The most common treatment-related adverse event (AE) reported was fatigue, which occurred in 12 patients. The next most common AEs were diarrhea and nausea which each occurred in 9 patients, then a decrease in appetite in 8 patients, and neutropenia and weight loss each reported in 7 patients. In terms of grade 3 or 4 treatment-emergent AEs, there were 2 incidences of grade 4 neutropenia, 2 incidences of grade 3 fatigue, and 1 incidence each of diarrhea, nausea, and decreased appetite. All other AEs were grade 1 or 2.

The dose expansion cohort of the study is continuing to enroll patients with NSCLC. Another ongoing dose expansion arm of the study is evaluating abequolixron plus ipilimumab as second- or third-line treatment for endometrial cancer.

“These data, while early, clearly show the potential that abequolixron may have in driving deep responses in patients with heavily-pretreated lung cancer,” Masoud Tavazoie, MD, PhD, CEO of Inspirna, said in a statement. “We are excited to begin the new year by announcing these promising data for abequolixron and look forward to sharing more updates as we continue advancing our novel pipeline in difficult-to-treat cancers.”

_Reference:

_{1. Inspirna announces interim data from phase 1b/2 study of abequolixron (RGX-104) in relapsed or refractory lung cancer. Inspirna. January 5, 2023. Accessed January 6, 2023. https://bit.ly/3GqJNyb}