789P - Translational study and preliminary clinical trial of WX390 monotherapy in cancers with concurrence of PIK3CA and ARID1A mutations

Background

PIK3CA mutations are among the most frequent alterations in solid tumors. However, monotherapy with PI3Kα inhibitors has shown only modest efficacy for PIK3CA-mutated cancers, with an objective response rate (ORR) of less than 10%. Novel biomarkers of greater predictive value is needed. Meanwhile, genome-wide CRISPR/Cas9 screening indicated that cell lines with concurrent ARID1A and PIK3CA mutations showed exceptional dependency on PIK3CA, suggesting the co-mutation may serve as predictive biomarker in developing PI3Kα inhibitors. WX390 is a highly potent PI3Kα/mTOR dual inhibitor currently under clinical development in solid tumors.

Methods

Preclinical in vitro and in vivo models were utilized for inquiry of the efficacy of WX390 in PIK3CA and ARID1A co-mutants. We initiated a multicenter, open label, and single arm phase 2 trial of WX390 monotherapy in patients (pts) with platinum resistant ovarian clear cell carcinoma (OCCC) carrying PIK3CA mutation. WX390 was administered orally daily at 1.1mg qd.

Results

Co-occurence of PIK3CA and ARID1A mutation is a significant genetic event across human cancers (data from TCGA and MSK cohorts, N=51,561, Log₂ odds ratio=1.556, χ² P < 0.001). Co-mutation of ARID1A occurs in 18% of pts with PIK3CA mutations in pan-cancer, and 65.7% of pts with PIK3CA-mutated OCCC. The preclinical models with concurrent ARID1A and PIK3CA mutations showed more sensitive to WX390 treatment. Clinical efficacy of WX390 was shown in PIK3CA mutated platinum resistant OCCC. As of March 29, 2024, among the 17 efficacy-evaluable pts, the ORR was 30% (PIK3CA^mut-ARID1A^mut pts, N=3/10) vs 14.3% (PIK3CA^mut-ARID1A^wt pts, N=1/7). The 48-week PFS rate was 40% (PIK3CA^mut-ARID1A^mut pts) vs 14.3% (PIK3CA^mut-ARID1A^wt pts). The most common treatment related adverse events included hyperglycemia, diarrhea, and fatigue, similar to those reported with other PI3Kα inhibitors.

Conclusions

Co-occurring PIK3CA^mut- ARID1A^mut is highly prevalent in human cancers and may indicate enhanced response to WX390. WX390 had a manageable safety profile and encouraging efficacy in platinum resistant OCCC pts, especially for the PIK3CA^mut- ARID1A^mut sub-group. Further evaluation of efficacy and safety are ongoing.

Clinical trial identification

NCT06117540.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.