Background: Oncogenic hyperactivation of the PI3K pathway is common in multiple cancers, with preclinical data showing that CDK4/6 inhibitors sensitise PIK3CA mutant cancers to PI3K inhibitors. We report the activity of the P+T in solid tumors with PI3K pathway activation, along with the PD biomarker analysis. Methods: We previously reported the dose escalation phase identifying 125mg P given 3-weeks-on, 1-week-off in combination with T 2mg as the recommended phase 2 dose (R2PD, Lim, ASCO 2017). We report the results in solid tumors with confirmed activating mutations (mts) in the PI3K pathway, from dose escalation and expansion, with no prior exposure to CDK4/6 or PI3K pathway inhibitors. PD studies include analyses of platelet-rich plasma (PRP) and paired tumour biopsies. Results: 20 pts (median age 61, range 34-72) were treated at the doublet RP2D, M/F 7/13, with a median 4 prior treatments (range 2-11). Tumour types included colorectal, breast, lung, endometrial,oligodendroglioma and head and neck cancers. Durable disease control occurred in 3 patients with ER+ advanced breast cancer with responses lasting >6 months including 1 pt with a H1047R PIK3CAmt with an ongoing RECIST PR>36 cycles, 2 pts with PIK3CAmt colorectal cancer had RECIST SD for >5 months, and 1 patient with a PIK3CGmt anaplastic oligodendroglioma had clinical and radiological benefit lasting 5.5 months. Treatment was well tolerated with predictable G1-2 adverse events (AEs). G3 toxicities of neutropenia (n=6), thrombocytopenia (2), rash (2), mucositis (1) and raised transaminases (1 each) were all transient with no G4/5 AEs. Significant decreases in tumour pRb, and pAKT and pGSK3ß in PRP, confirmed modulation of both CDK4/6 and PI3K pathways at R2PD. Conclusions: Doublet P+T is well tolerated at the combination RP2D, with PD evidence of PI3K and CDK4/6 modulation in both plasma and tumor. Promising preliminary anti-tumor activity is seen in a mixed histology cohort selected for activating PIK3 mutations. Clinical trial information: NCT02389842