Background: Taselisib (GDC-0032) is a next-generation PI3K inhibitor with increased anti-tumor activity against PIK3CA mutant (MT) cancers. Taselisib is an orally bioavailable, potent, and selective inhibitor of Class I PI3K alpha, delta, and gamma isoforms, with 30-fold less inhibition of the PI3K beta isoform relative to the PI3K alpha isoform. Preclinical data show that taselisib has enhanced activity against PI3K alpha isoform (PIK3CA) MT breast cancer cell lines and enhanced antitumor activity when combined with letrozole. Clinical data with single-agent taselisib also showed increased tumor shrinkage in patients with PIK3CA MT breast cancer as compared to patients with PIK3CA wildtype (WT) breast cancer.

Material and Methods: A Phase 1b dose escalation study was conducted with evaluation of taselisib doses ranging from 6-9 mg QD in combination with letrozole 2.5mg QD in a modified 3+3 design. A dose expansion cohort was conducted with taselisib 6 mg QD. Safety and tolerability of GDC-0032 was assessed, as well as pharmacokinetics (PK), pharmacodynamic (PD) assessment by FDG-PET, and anti-tumor activity by RECIST.

Results: As of 31 January 2014, 28 patients were enrolled onto this study with the completion of dose escalation and the dose expansion cohort. No dose limiting toxicities (DLTs) were observed at either the 6 mg (n = 20) or 9 mg (n = 8) dose levels. Adverse events (AEs) assessed by the investigator as related to taselisib in ≥10% of patients (any grade) included diarrhea, nausea, stomatitis, fatigue, rash, decreased appetite, hyperglycemia, dysgeusia, mucosal inflammation, vomiting, muscle spasms, asthenia, dry mouth, dry skin, pruritus, and aspartate aminotransferase increased. Grade 3 and 4 adverse events assessed by the investigator as drug-related and occurring in greater than one patient included diarrhea (14%), hyperglycemia (7%), and mucosal inflammation (7%). No apparent PK interactions were observed between taselisib and letrozole. The median number of prior systemic therapies was six, and promising efficacy data has been observed in these heavily pretreated patients. Metabolic partial responses via FDG-PET (≥ 20% decrease in mean SUVmax) were observed in 11 out of 18 patients assessed (61%). Confirmed partial responses by RECIST have been observed at both the 6mg and 9mg taselisib dose levels. For patients with measurable disease at baseline, the overall response rate of 38% was observed in patients with PIK3CA MT breast cancer and 9% in patients with PIK3CA WT breast cancer. Updated data on safety, PD, efficacy, and biomarker correlates will be presented.

Conclusions: The combination of taselisib and letrozole is a well-tolerated regimen with promising preliminary efficacy in PIK3CA MT breast cancer patients. This preliminary Ph1b clinical data is consistent with taselisib preclinical and single-agent clinical data showing increased anti-tumor activity for taselisib in PIK3CA MT breast cancer as compared to PIK3CA WT breast cancer. Taselisib is being further investigated in the neoadjuvant setting in combination with letrozole in the LORELEI study in patients with untreated hormone receptor-positive breast cancer.

Citation Format: Cristina Saura, Jasgit Sachdev, Manish R Patel, Andres Cervantes, Dejan Juric, Jeffrey R Infante, Donald Richards, Sandra Sanabria, Xuyang Lu, Joseph Ware, Timothy R Wilson, Hema Parmar, Jerry Y Hsu, Mafalda Oliveira, Eric P Winer, Daniel D Von Hoff, Jose Baselga, Ian E Krop. Ph1b study of the PI3K inhibitor taselisib (GDC-0032) in combination with letrozole in patients with hormone receptor-positive advanced breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD5-2.