1094 - Multi-Center Phase I Study of Concurrent Paxalisib and Radiation Therapy in Patients with Solid Tumor Brain Metastases (BM) or Leptomeningeal Metastases (LM) Harboring PI3K Pathway Mutations

B. S. Imber^1,2, R. Kotecha³, M. H. Blau⁴, J. Friend⁵, R. J. Young⁶, M. Offin⁷, R. Michelle⁸, E. Diamond⁸, and J. T. Yang⁹; ¹Early Drug Development Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, ²Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, ³Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, ⁴Department of Radiation Oncology, University of Washington, Seattle, WA, ⁵Kazia Therapeutics, Sydney, NSW, Australia, ⁶Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, ⁷Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, ⁸Memorial Sloan Kettering Cancer Center, New York, NY, ⁹New York University School of Medicine, New York, NY

Purpose/Objective(s): Partial or whole-brain RT is a standard of care for solid tumor BM and LM. However, tumors harboring PI3K pathway mutations have poorer CNS control after RT alone. Combining RT with paxalisib, a CNS-penetrant small molecule PI3K/mTOR inhibitor, may overcome this relative radioresistance and improve outcomes. Materials/

Methods: This is a multi-center (n=3 institutions), open-label, phase I study (NCT04192981) of concurrent paxalisib with partial or whole brain RT (30 Gy in 10 fractions) for patients with BM or LM harboring PI3K pathway alterations. Part A was a 3+3 dose escalation cohort of paxalisib at 45, 60 or 75mg daily for 2 weeks with concurrent RT to establish the maximum tolerated dose (MTD). Part B was a dose expansion cohort at the established MTD to further validate safety and early efficacy. CNS response was assessed using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria.
Results: From 3/2020-2/2024, a total of 21 patients (76% female, median age 58y) were enrolled. Most patients (n=18) had BM, and 3 had LM. The most common histology was breast (n=10, 48%) followed by lung, rectal and endometrial (all n=2, 10%). PIK3CA mutations were the most common pathway alteration (n=15, 71%) followed by PTEN deletion (n=3, 14%). Part A enrolled 12 patients of which 9 were evaluable (3 did not complete protocol therapy). There were no dose-limiting toxicities (DLTs) at 45mg paxalisib daily, and 2 patients had DLT at 60mg: 1 with grade 3 nausea and emesis and 1 with grade 4 enterocolitis and neutropenia. Subsequently, 9 additional patients were enrolled during Part B at the established MTD of 45mg, of which 1 withdrew consent prior to completion of study interventions. No additional DLTs were observed during Part B. In total, there were 14 evaluable patients who received 45 mg/day concurrently with RT, two of whom died of intercurrent extracranial progression prior to CNS restaging, and one who recently completed protocol therapy. Of the 11 with at least one follow-up MRI, there was robust response signal. At 1-month post-treatment, 6/11 (55%) had partial response (PR) and the remaining 5/11 (45%) had stable disease. To date, best CNS response is 72% PR (8/11) and 27% SD (3/11).
Conclusion: A MTD of 45 mg/day has been confirmed for paxalisib with concurrent brain RT for patients with BM and/or LM demonstrating PI3K pathway alterations. Given significant unmet need for this population, this novel therapeutic combination warrants further investigation given promising signal of activity.