Buparlisib Treatment Begins in Combination With AN0025 and Atezolizumab for Advanced Solid Tumors

The investigational combination of the oral pan-PI3K inhibitor and oral EP4 antagonist buparlisib (AN2025) and AN0025 with or without atezolizumab (Tecentriq) has been administered for the first time in a patient with a locally advanced or metastatic solid tumor in a phase 1a clinical trial, according to a press release from Adlai Nortye.¹

In addition to targeting PI3K mediated tumorigenesis, buparlisib can also resolve immunosuppression in the tumor microenvironment. PIK3CA alterations are found in roughly 13% of solid tumors and are especially prevalent in patients with cervical, breast, endometrial, ovarian, urothelial, and colorectal cancers, as well as head and neck squamous cell carcinoma (HNSCC).

"Results from preclinical studies of the triple combination of buparlisib, AN0025 and an anti-PD1 antibody have demonstrated encouraging antitumor activity. We believe that this triple combination potentially could develop into a novel anti-cancer immune therapy by exquisitely and systemically targeting the suppressive tumor microenvironment and thus permitting enhanced host immune responses against the tumor." said Dr. Lars Birgerson, MD, PhD, chief medical officer of Adlai Nortye, in a press release.

The agent has already demonstrated a 20% reduction in the risk of death in patients with recurrent or metastatic HNSCC treated in the phase 3 BURAN study of buparlisib in combination with paclitaxel compared with paclitaxel monotherapy (NCT04338399). The study is actively assessing overall survival (OS) as its primary end point along with the secondary end points of progression-free survival (PFS), overall response rate (ORR), health-related quality of life, safety and tolerability, and pharmacokinetics (PK).²

Similarly, in the open-label, multicenter study (NCT04975958), the safety, PK, and preliminary efficacy of buparlisib is being investigated either in a doublet combination with AN0025 or triplet combination with atezolizumab added. The coprimary end points are dose-limiting toxicities and the number of patients with adverse events (AEs) or serious AEs. The secondary end points of the study include ORR, PFS, duration of response, and OS. Efficacy will also be assessed in the subgroup of patents with PIK3CA mutations.³

Patients are eligible to enroll in the study if they are aged 18 years or older with an ECOG performance status of 0 or 1, life expectancy of at least 3 months, and have been histologically diagnosed with locally advanced and nonresectable or metastatic disease that is measurable, adequate laboratory tests, and available tumor tissue. In terms of prior therapy, patients were required to have received at least 1 prior systemic therapy, but no more than 4 lines of therapy for advanced disease.

The study is currently recruiting patients at Hope Cancer Center in New Jersey.

"We expect to identify the recommended phase II dose of this phase I clinical trial in the second half of 2022 as a step in a planned development program to bring this therapy to patients worldwide,” said Birgerson, in the press release.

_References:

_{1. Adlai Nortye announces first patient dosed in phase I clinical trial of AN2025 and AN0025 in combination with atezolizumab for advanced solid tumors. News release. Adlai Nortye. September 7, 2021. Accessed September 8, 2021. https://bit.ly/3nkehKp}

_{2. Soulieres D, Faivre SJ, Dreyer K, et al. The BURAN study of buparlisib (AN2025) in combination with paclitaxel compared to paclitaxel alone, in patients with recurrent or metastatic head and neck squamous cell carcinoma. J Clin Oncol. 20201;39(suppl 15). doi: 10.1200/JCO.2021.39.15_suppl.TPS6090}

_{3. Double/triple combinations of AN2025, AN0025 and atezolizumab in advanced solid tumors. Clinicaltrials.gov. Accessed September 8. 2021. https://bit.ly/2X6FrJR}