Ibrilatazar Shows Survival Improvement in Advanced Squamous NSCLC

The objective response rate of the efficacy evaluable population was 52.0% and was composed entirely of partial responses; 32.0% of patients experienced stable disease as best response, with an additional 16.0% experiencing disease progression.

Ibrilatazar (ABTL0812), an oral agent that induces cytotoxic autophagy, elicited enhanced survival outcomes when added to chemotherapy in patients with advanced squamous non–small cell lung cancer (NSCLC), according to preliminary results from the phase 1/2a ENDOLUNG trial (NCT03366480) published in Lung Cancer.¹

Data from the trial revealed that among patients treated with ibrilatazar in the efficacy analysis population (n = 25), the median overall survival (OS) was 22.5 (95% CI, 9.5-not calculable [NC]) months, which more than doubled the historical control of 11.3 months (95% CI, 9.5-14.8) found in the phase 3 KEYNOTE-407 trial (NCT02775435) published in The New England Journal of Medicine.² Additionally, the median OS in the intention-to-treat population (n = 40) of the ENDOLUNG trial was 18.4 months (95% CI, 9.5-NC).

Additionally, the median progression-free survival (PFS) between the intention-to-treat and efficacy analysis populations were both 6.2 months (95% CI, 4.4-8.8), with a similar median duration of response (DOR) of 5.1 months (95% CI, 3.9-8.5).

Furthermore, the objective response rate (ORR) of the efficacy evaluable population was 52.0% (95% CI, 34.2%-65.9%) and was composed entirely of partial responses. A total of 32.0% of patients experienced stable disease as best response, with an additional 16.0% experiencing disease progression. The disease control rate (DCR) was 84.0% (95% CI, 63.9%-95.5%).
"Squamous cell lung cancer is one of the lung cancer subtypes with the fewest therapeutic options and the poorest prognosis. That’s why it is especially relevant that a new molecule like ibrilatazar, with a different mechanism of action, has shown promising antitumor activity,” lead study author Joaquim Bosch-Barrera, MD, PhD, medical oncologist at ICO Girona and researcher from the Dr. Josep Trueta Biomedical Research Institute of Girona (IDIBGI), said in a news release on the study findings.³ “This molecule targets the PI3K pathway and autophagy, making it a very attractive and innovative therapeutic target. Ibrilatazar also demonstrated a favorable tolerability profile in combination with chemotherapy in this study."

The open label phase 1/2a trial enrolled patients with a histological diagnosis of stage III squamous NSCLC ineligible for radical radiotherapy and assigned them to receive ibrilatazar plus intravenous carboplatin and paclitaxel using a 3 + 3 design. Patients were initially given a starting dose comprising 1300 mg of ibrilatazar 3 times daily, with de-escalation dose levels comprising 1000 mg, 650 mg, and 500 mg 3 times daily. Inpatient de-escalation was not permitted.

Additionally, intravenous carboplatin given at area under the curve 5 and paclitaxel at 175 mg/m² were given every 21 days for a maximum of 8 cycles. Patients received ibrilatazar until disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision.

Patients in the intent-to-treat population had a median age of 66 years (range, 49-76), and 90.0% were male. All patients were Caucasian, with 2 reporting as Hispanic or Latino. Additionally, 67.5% had formerly smoked; most had either stage IVa (30.0%) or stage IVb (50.0%) cancer; and 37.5%, 37.5%, and 7.5% received prior chemotherapy, radiation therapy, and surgery, respectively.

The primary end point of the trial was ORR. Secondary end points included PFS, DOR, OS, and safety.

Among patients in the safety analysis (n = 40), 97.5% experienced adverse effects (AEs), with 55% experiencing AEs of grade 3 or higher. A total of 25% of patients experienced AE-related treatment discontinuation, with AEs leading to death in 4 patients. The 4 fatal AEs included single instances of general physical health deterioration, pulmonary embolism, septic shock, and sudden death.

References

1. Bosch-Barrera J, Estévez-García P, Martín-Martorell P, et al. ENDOLUNG trial, part II. A phase II study of the Akt/mTOR inhibitor and autophagy inducer ibrilatazar (ABTL0812) in combination with paclitaxel/carboplatin in patients with squamous non-small cell lung cancer. Lung Cancer. 2025;201:108105. doi:10.1016/j.lungcan.2025.108105
2. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non–small-cell lung cancer. N Engl J Med. 2018;379(21):2040-2051. doi:10.1056/NEJMoa1810865
3. AbilityPharma’s IBRILATAZAR (ABTL0812) doubles overall survival in patients with squamous non-small cell lung cancer. News release. AbilityPharma. June 5, 2025. Accessed June 6, 2025. https://tinyurl.com/yc3an6vj