Piqray (alpelisib)

P2, N=51, Not yet recruiting, Novartis Pharmaceuticals

Overall, alpelisib combined with capecitabine demonstrated modest antitumor activity in a molecularly selected subset of patients with metastatic colorectal cancer. However, frequent treatment-limiting toxicities may limit the future clinical applicability of this regimen and highlight the need for improved toxicity management and optimized patient selection.

Alpelisib plus paclitaxel was tolerable and pharmacologically feasible with a defined RP2D but showed limited efficacy in PIK3CA-altered GC.

Treatment paradigms have advanced from non-targeted options, such as fulvestrant monotherapy or everolimus-based combinations, to precision medicine strategies, including inhibitors of the PI3K/AKT pathway, oral selective estrogen receptor degraders (SERDs), and novel ER-modulating agents, often guided by biomarkers and molecular surveillance... Early second-line standards, including fulvestrant and alpelisib for PIK3CA-mutated tumors, established the basis for biomarker-guided treatment in hormone receptor-positive, HER2-negative metastatic breast cancer...Elacestrant improved progression-free survival in ESR1-mutated disease in the EMERALD trial, capivasertib plus fulvestrant demonstrated significant benefit in tumors harboring AKT/PIK3CA/PTEN pathway alterations in CAPItello-291, and inavolisib plus palbociclib and fulvestrant achieved both progression-free and overall survival improvement in PIK3CA-mutated patients with early relapse in INAVO120... Post-CDK4/6i management increasingly relies on NGS-guided precision approaches, integrating pathway-specific therapies and ctDNA surveillance to tailor sequencing based on resistance profiles, prior ET response, and tumor heterogeneity. Future investigations into novel ER degraders and multi-targeted combinations hold potential to further optimize algorithms, extend non-chemotherapy options, and enhance survival in HR+/HER2- mBC.

Collectively, these findings identify E545A as a functionally active and therapeutically consequential PIK3CA variant. Our study expands the current understanding of PIK3CA-driven oncogenic diversity beyond canonical hotspot mutations and underscores the need for variant-resolved stratification to improve the efficacy of PI3K-targeted therapies.

Our findings highlight the potential of cisplatin-alpelisib treatment in a subset of HGSOC patients with PIK3CA overexpression, mediated either through gene amplification or transcriptional modulation, reflecting the wider application of alpelisib in PIK3CA-non-mutated ovarian cancer.

These findings establish selective CDK4 inhibition as a therapeutically active and mechanistically rational strategy in prostate cancer and support AU2-94 as a candidate for further preclinical and clinical development, including in combination regimens for advanced and therapy-resistant disease.

This study highlights the need for further investigation into the efficacy of pathway inhibitors in managing TSC-related lipomas in vivo and offers a potential treatment avenue for patients suffering from recurrent lipomatosis.

P1/2, N=435, Active, not recruiting, Stemline Therapeutics, Inc. | Recruiting --> Active, not recruiting

In BCs with alterations in the AKT/PIK3CA pathway, capivasertib, alpelisib, and inavolisib have recently improved progression-free survival (PFS). Inavolisib (GC0077) differs from the other drugs targeting this pathway by its high potency and tolerability when combined with endocrine therapy, mostly with fulvestrant, and a CDK4/6 inhibitor. Its recent use in the first-line combined treatment for advanced HR+/HER2-negative BC has shown a PFS benefit compared to placebo in the INAVO120 trial, suggesting its role as a valid treatment option in PIK3CA-mutated patients. Further studies are warranted to confirm these results in terms of prolonging efficacy and maintaining durable responses - with a manageable safety profile - in clinical practice.

Methods We derived a novel PDX from a patient with hormone receptor negative, HER2-positive IBC refractory to neoadjuvant chemotherapy with Docetaxel, Carboplatin, Trastuzumab, and Pertuzumab (TCHP)...We performed short-tandem repeat (STR) profiling, plotted tumor growth curves for mice treated with alpelisib/everolimus vs. untreated, and immunohistochemistry (IHC), and performed clinical genomic assays...Conclusion We established a PDX of a HER2-positive IBC tumor with a PIK3CA hotspot mutation (H1047R) refractory to TCHP. Targeting the PI3K/mTOR pathway may be useful to overcome resistance in HER2-positive IBC with a H1047R mutation in PIK3CA.

Collectively, our analysis describes the driver genes and mutation characteristics in SCC. The multi-cohort and network-based framework employed in this study identifies candidate hub genes that warrant further clinical investigation in cervical cancer.