CTNI-07 - Phase I study of paxalisib and radiotherapy for CNS disease harboring PI3K pathway mutations: pilot analysis of circulating tumor DNA for patient eligibility confirmation and post-treatment response

Friday, November 17, 2023

7:30 PM – 9:30 PM PT

Location: Exhibit Hall A/B

Poster Presenter(s)

Brandon S. Imber

Memorial Sloan Kettering Cancer Center
New York, New York, United States

Author(s)

VR

Vignesh Ravichandran

Memorial Sloan Kettering Cancer Center
New York, United States
PR

Pavitra Rao

Memorial Sloan Kettering Cancer Center
New York, United States
HC

Hilary Casanova

Memorial Sloan Kettering Cancer Center
New York, United States
JF

John Friend

Kazia Therapeutics
Sydney, Australia
JS

Jeremy Simpson

Kazia Therapeutics
Sydney, New South Wales, Australia
LP

Luke Pike

Memorial Sloan Kettering Cancer Center
New York, New York, United States
MZ

Melissa Zinovoy

Memorial Sloan Kettering Cancer Center
New York, United States
RM

Ryan Mitchell

Memorial Sloan Kettering Cancer Center
New York, United States
CC

Christina Chacko

Memorial Sloan Kettering Cancer Center
New York, United States
Rupesh Kotecha

Miami Cancer Institute, Baptist Health South Florida
Miami, Florida, United States
SS

Somica Somai

Memorial Sloan Kettering Cancer Center
New York, United States
Adrienne Boire

Memorial Sloan Kettering Cancer Center
New York, New York, United States
IG

Igor Gavrilovic

Memorial Sloan Kettering Cancer Center
New York, New York, United States
Anna F. Piotrowski

Memorial Sloan Kettering Cancer Center
New York, New York, United States
Jessica A. Wilcox

Memorial Sloan Kettering Cancer Center
New York, New York, United States
Rachna Malani

University of Utah/Huntsman Cancer Institute
Salt Lake City, Utah, United States
RY

Robert J. Young

Memorial Sloan Kettering Cancer Center
New York City, New York, United States
MO

Michael Offin

Memorial Sloan Kettering Cancer Center
New York, New York, United States
Eli Diamond

Memorial Sloan Kettering Cancer Center
New York, New York, United States
JY

Jonathan T. Yang

University of Washington
Seattle, United States

Introduction: Radiotherapy (RT) is effective for brain metastases (BM) or leptomeningeal disease (LMD), but disease control is poor for tumors harboring PI3K pathway alterations (PI3Kalt). We hypothesized that combining RT with paxalisib, a CNS-penetrant PI3K/mTOR inhibitor, offers therapeutic synergy. The role of plasma circulating tumor DNA (ctDNA) to confirm study eligibility and response monitoring is unclear.

Methods: This is a multi-institutional, phase I trial of concurrent paxalisib and whole brain RT (30 Gy in 10 fractions, NCT04192981) for CNS disease. To establish eligibility, patients had documented PI3Kalt performed using institutional tumor targeted sequencing (MSK-IMPACT) of primary or metastatic tumors (eligibility sequencing). Plasma ctDNA was collected at baseline and 3-, 6- and 9-months post-treatment and sequenced using institutional plasma ctDNA targeted sequencing platform (MSK-ACCESS). Our objectives were to a) determine PI3Kalt concordance between eligibility sequencing and baseline ctDNA and b) analyze quantitative post-treatment plasma ctDNA dynamics.

Results: Between 3/2020-5/2023, 15 patients were enrolled to receive daily paxalisib (45mg, n=11 or 60mg, n=4) and WBRT. Twelve were treated for BM and 3 for LMD. Eligibility sequencing was determined a median of 8.1months (range: 2.4-38.6) pre-study enrollment and the most common PI3Kalt were PIK3CA (n=7), INPP4B (n=2), INPPL1 (n=1) and PIK3CG (n=1), and PTEN copy number alterations (homdel n=2). Baseline ctDNA was sequenced from 13/15 patients (18 samples: baseline=13, 3-months=4 and 6-months=1). We confirmed 100% of PIK3CA mutations using baseline ctDNA. One breast cancer BM patient demonstrated significant variant allele frequency reduction from 50% (baseline) to 0.1% (3-months post-treatment) for two tracked PIK3CA mutations (p.E545K and p.A1066V), which correlated with a partial response per RANO-BM.

Conclusions: For patients on genomically-driven targeted therapy and RT combination trials, alterations detected using plasma ctDNA, especially PIK3CA, may be used to rapidly assess eligibility. Serial ctDNA collection may serve as a potential response biomarker with further validation.