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Tumor cell line panel composition and growth inhibition sensitivity (GI50) to AZD8835.

Details on PK / PD / efficacy modeling in BT474 xenograft model

The PIK3CA gene, encoding the p110α catalytic unit of PI3Kα, is one of the most frequently mutated oncogenes in human cancer. Hence, PI3Kα is a target subject to intensive efforts in identifying inhibitors and evaluating their therapeutic potential. Here, we report studies with a novel PI3K inhibitor, AZD8835, currently in phase I clinical evaluation. AZD8835 is a potent inhibitor of PI3Kα and PI3Kδ with selectivity versus PI3Kβ, PI3Kγ, and other kinases that preferentially inhibited growth in cells with mutant PIK3CA status, such as in estrogen receptor–positive (ER+) breast cancer cell lines BT474, MCF7, and T47D (sub-μmol/L GI50s). Consistent with this, AZD8835 demonstrated antitumor efficacy in corresponding breast cancer xenograft models when dosed continuously. In addition, an alternative approach of intermittent high-dose scheduling (IHDS) was explored given our observations that higher exposures achieved greater pathway inhibition and induced apoptosis. Indeed, using IHDS, monotherapy AZD8835 was able to induce tumor xenograft regression. Furthermore, AZD8835 IHDS in combination with other targeted therapeutic agents further enhanced antitumor activity (up to 92% regression). Combination partners were prioritized on the basis of our mechanistic insights demonstrating signaling pathway cross-talk, with a focus on targeting interdependent ER and/or CDK4/6 pathways or alternatively a node (mTOR) in the PI3K-pathway, approaches with demonstrated clinical benefit in ER+ breast cancer patients. In summary, AZD8835 IHDS delivers strong antitumor efficacy in a range of combination settings and provides a promising alternative to continuous dosing to optimize the therapeutic index in patients. Such schedules merit clinical evaluation. Mol Cancer Ther; 15(5); 877–89. ©2016 AACR.

Supplementary Figure from A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors

Purpose:To characterize safety and tolerability of the selective PI3Kβ inhibitor AZD8186, identify a recommended phase II dose (RP2D), and assess preliminary efficacy in combination with abiraterone acetate or vistusertib.Patients and Methods:This phase I open-label study included patients with advanced solid tumors, particularly prostate cancer, triple-negative breast cancer, and squamous non–small cell lung cancer. The study comprised four arms: (i) AZD8186 monotherapy dose finding; (ii) monotherapy dose expansion; (iii) AZD8186/abiraterone acetate (with prednisone); and (iv) AZD8186/vistusertib. The primary endpoints were safety, tolerability, and identification of the RP2D of AZD8186 monotherapy and in combination. Secondary endpoints included pharmacokinetics (PK), pharmacodynamics, and tumor and prostate-specific antigen (PSA) responses.Results:In total, 161 patients were enrolled. AZD8186 was well tolerated across all study arms, the most common adverse events being gastrointestinal symptoms. In the monotherapy dose-finding arm, four patients experienced dose-limiting toxicities (mainly rash). AZD8186 doses of 60-mg twice daily [BID; 5 days on, 2 days off (5:2)] and 120-mg BID (continuous and 5:2 dosing) were taken into subsequent arms. The PKs of AZD8186 were dose proportional, without interactions with abiraterone acetate or vistusertib, and target inhibition was observed in plasma and tumor tissue. Monotherapy and combination therapy showed preliminary evidence of limited antitumor activity by imaging and, in prostate cancer, PSA reduction.Conclusions:AZD8186 monotherapy had an acceptable safety and tolerability profile, and combination with abiraterone acetate/prednisone or vistusertib was also tolerated. There was preliminary evidence of antitumor activity, meriting further exploration of AZD8186 in subsequent studies in PI3Kβ pathway–dependent cancers.

Supplementary Data from A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors

Five to ten percent of ER+ metastatic breast cancer (MBC) tumors harbor somatic PTEN mutations. Loss of function of this tumor-suppressor gene defines a highly aggressive, treatment-refractory disease for which new therapies are urgently needed. This Phase I multipart expansion study assessed oral capivasertib with fulvestrant in patients with PTEN-mutant ER+ MBC. Safety and tolerability were assessed by standard methods. Plasma and tumor were collected for NGS and immunohistochemistry analyses of PTEN protein expression. In 31 eligible patients (12 fulvestrant naive; 19 fulvestrant pretreated), the 24-week clinical benefit rate was 17% in fulvestrant-naive and 42% in fulvestrant-pretreated patients, with objective response rate of 8% and 21%, respectively. Non-functional PTEN was centrally confirmed in all cases by NGS or immunohistochemistry. Co­mutations occurred in PIK3CA (32%), with less ESR1 (10% vs 72%) and more TP53 (40% vs 28%) alterations in fulvestrant-naive versus fulvestrant-pretreated patients, respectively. PTEN was clonally dominant in most patients. Treatment-related grade ≥3 adverse events occurred in 32% of patients, most frequently diarrhea and maculopapular rash (both n = 2). In this clinical study, which selectively targeted the aggressive PTEN-mutant ER+ MBC, capivasertib plus fulvestrant was tolerable and clinically active. Phenotypic and genomic differences were apparent between fulvestrant-naive and -pretreated patients.Trial registration number for the study is NCT01226316.

Background: In the PAKT study, addition of the oral AKT inhibitor capivasertib to 1st-line paclitaxel therapy for metastatic TNBC resulted in significantly longer progression-free survival (PFS; primary endpoint; Schmid, J Clin Oncol 2020). The stratified PFS hazard ratio was 0.74 (95% CI, 0.50-1.08; one-sided P=0.06; predefined significance level of 0.10, one-sided; median PFS 5.9 vs 4.2 months with capivasertib vs placebo). Overall survival (OS) results were immature at the primary analysis with 53% of events but suggested long OS with capivasertib (HR, 0.61; 95% CI, 0.37-0.99; two-sided P=0.04). Here we report final results. Methods: This double-blind, placebo-controlled, randomised phase II trial, recruited women with untreated, metastatic TNBC. Total of 140 patients were randomly assigned (1:1) to paclitaxel 90mg/m2 (days 1, 8, 15) with either capivasertib (400mg twice daily) or placebo (days 2-5, 9-12, 16-19) every 28 days until disease progression or unacceptable toxicity. The primary endpoint was PFS. Secondary endpoints included OS in the ITT population and in patients with and without PIK3CA/AKT1/PTEN-alterations. Results: With a median F/U of 40.0 months, median OS was longer in the capivasertib arm (19.1 vs 13.5 months, stratified HR 0.70, 95% CI 0.47-1.05, p=0.085). In contrast to the earlier analysis, no meaningful differences were seen in terms of benefit with capivasertib between patients with or without alterations of PIK3CA/AKT1/PTEN. Median OS numerically favoured capivasertib vs placebo both in the PIK3CA/AKT1/PTEN-altered (stratified HR 0.58, 95% CI 0.21-1.58, p=0.290) and PIK3CA/AKT1/PTEN non-altered subgroup (stratified HR 0.74, 95% CI 0.47-1.18, p=0.207). The safety profile of capivasertib plus paclitaxel was unchanged. Conclusions: Final OS results show a numerical trend favouring capivasertib; effects were observed regardless of PIK3CA/AKT1/PTEN alterations. Consistent with the previously observed PFS benefit, these findings support further evaluation of first-line Capivasertib plus paclitaxel for metastatic TNBC in the ongoing Capitello290 randomised phase III trial in patients with and without PIK3CA/AKT1/PTEN alterations. Citation Format: Peter Schmid, Jacinta Abraham, Stephen Chan, Adrian Murray Brunt, Gia Nemsadze, Richard D Baird, Yeon Hee Park, Peter Hall, Timothy Perren, Robert C Stein, László Mangel, Jean-Marc Ferrero, Melissa Phillips, John Conibear, Javier Cortes, Andrew Foxley, Elza de Bruin, Robert McEwen, Myria Nikolaou, Daniel Stetson, Brian Dougherty, Aaron Prendergast, Max McLaughlin-Callan, Matthew Burgess, Cheryl Lawrence, Hayley Cartwright, Kelly Mousa, Nicholas Turner, Duncan Wheatley. Mature survival update of the double-blind placebo-controlled randomised phase II PAKT trial of first-line capivasertib plus paclitaxel for metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-11.

Purpose:Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ER+ breast cancer, but it has administration and pharmacokinetic limitations. Pharmacodynamic data suggest complete ER degradation is not achieved at fulvestrant's clinically feasible dose. This presurgical study (NCT03236974) compared the pharmacodynamic effects of fulvestrant with AZD9496, a novel, orally bioavailable, nonsteroidal, potent SERD, in treatment-naïve patients with ER+ HER2− primary breast cancer awaiting curative intent surgery.Patients and Methods:Patients were randomized 1:1 to receive AZD9496 250 mg twice daily from day 1 for 5–14 days, or fulvestrant 500 mg on day 1. On-treatment imaging-guided core tumor biopsies were taken between day 5 and 14 and compared with pretreatment diagnostic biopsies. The primary objective was to compare the effects of AZD9496 and fulvestrant on ER expression. Secondary objectives included changes in progesterone receptor (PR) and Ki-67 pharmacokinetic/pharmacodynamic relationships and safety.Results:Forty-six women received treatment (AZD9496 n = 22; fulvestrant n = 24); 35 paired biopsies were evaluable (AZD9496 n = 15; fulvestrant n = 20). The least square mean estimate for ER H-score reduction was 24% after AZD9496 versus 36% after fulvestrant treatment (P = 0.86). AZD9496 also reduced PR H-scores (−33.3%) and Ki-67 levels (−39.9%) from baseline, but was also not superior to fulvestrant (PR: −68.7%, P = 0.97; Ki-67: −75.4%, P = 0.98). No new safety findings were identified.Conclusions:This was the first presurgical study to demonstrate that an oral SERD affects its key biological targets. However, AZD9496 was not superior to fulvestrant at the dose tested.

Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ERPatients were randomized 1:1 to receive AZD9496 250 mg twice daily from day 1 for 5-14 days, or fulvestrant 500 mg on day 1. On-treatment imaging-guided core tumor biopsies were taken between day 5 and 14 and compared with pretreatment diagnostic biopsies. The primary objective was to compare the effects of AZD9496 and fulvestrant on ER expression. Secondary objectives included changes in progesterone receptor (PR) and Ki-67 pharmacokinetic/pharmacodynamic relationships and safety.Forty-six women received treatment (AZD9496This was the first presurgical study to demonstrate that an oral SERD affects its key biological targets. However, AZD9496 was not superior to fulvestrant at the dose tested.

Background: Estrogen receptor positive (ER+) breast cancer is routinely treated with endocrine therapies targeting the ER axis. However, primary and secondary resistance ultimately limits the use of these agents. Fulvestrant (FULV) is the first-in-class selective ER degrader (SERD) clinically effective in patients with ER+ breast cancer, both naïve and resistant to tamoxifen and aromatase inhibitors. FULV has low oral bioavailability, and its dose-dependent pharmacodynamic (PD) activity and clinical efficacy is limited by the currently approved maximal feasible dose (MFD) of 500 mg, which is administered monthly as two intramuscular injections. AZD9496 is an orally bioavailable, nonsteroidal, selective and potent degrader and antagonist of ER in preclinical models. This pre-surgical, window of opportunity study (NCT03236974) compared PD changes and the PD/pharmacokinetic (PK) relationships of AZD9496 with FULV in patients with newly diagnosed ER+ HER2- breast cancer awaiting curative intent surgery.Methods: In this open-label, multicenter study, patients were randomized 1:1 to receive oral AZD9496 250 mg BID from Day 1 for 5-14 days or FULV 500 mg administered intramuscularly on Day 1 only. On-treatment image-guided core tumor biopsies were taken between Days 5 and 14. The primary objective was to compare the effects of AZD9496 and FULV on ER expression in tumor tissue using pre-dose biopsies as baseline. Secondary objectives were changes in progesterone receptor (PR) and Ki-67 biomarkers, AZD9496 and FULV plasma concentrations during treatment, and safety. Immunohistochemistry was used to determine ER and PR H-scores, and Ki-67 index, and treatment effects were compared using an analysis of covariance model. Blood samples for PK analysis were taken at on-treatment biopsy and 1-2 hours afterwards. Adverse events (AEs) were monitored from screening through to a follow-up visit 28 days after the last study dose.Results: Of the 49 women enrolled, 46 received treatment (AZD9496 n=22; FULV n=24) and of these, 35 paired biopsies were evaluable (AZD9496 n=15; FULV n=20). The least square mean estimate for the reduction in ER H-score after AZD9496 treatment was 24% (80% CI: 34.4, 14.3), and after FULV treatment was 36% (44.9, 27.7), with a least square mean difference between AZD9496 and FULV of 12% (p=0.86). AZD9496 was not superior to FULV in terms of ER modulation at the tested dose. AZD9496 also reduced PR H-scores and Ki-67 levels from baseline (by 33.3% and 39.9%, respectively). These effects were not statistically superior to FULV at the tested dose (PR: -68.7%, p=0.97; Ki 67: 75.4%, p=0.98).Plasma exposure of AZD9496 (AUC -40%, Cmax -25%) was lower than predicted based on PK data from the previous phase 1 study, whereas FULV exposure was consistent with historical data. No clear exposure-response relationship for plasma concentration at biopsy and PD markers for AZD9496 or FULV were observed.The median treatment duration of AZD9496 was 9.5 days (range: 6-15), and the relative dose intensity was 100% (range: 90-125); no patients discontinued AZD9496. AZD9496 and FULV were both well tolerated, and no new safety findings were identified. No grade ≥3 toxicities or serious AEs occurred. Conclusion: AZD9496 250 mg BID reduced ER, PR and Ki-67 expression, and as such, is the first pre surgical study to demonstrate an oral SERD impacting its key biological targets. These reductions were not superior to the FULV clinically approved dose, which performed as expected based on historical data. Pre-surgical studies represent an important method to test the proof of mechanism of novel SERDs early in clinical development. Citation Format: John FR Robertson, Abigail Evans, Stephan Henschen, Cliona Kirwan, Ali Jahan, Laura Kenny, J. Michael Dixon, Peter Schmid, Ashutosh Kothari, Omar Mohamed, Peter A Fasching, Kwok-Leung Cheung, Rachel Wuerstlein, Danielle Carroll, Teresa Klinowska, Justin PO Lindemann, Alexander MacDonald, Richard Mather, Rhiannon Maudsley, Michele Moschetta, Myria Nikolaou, Martine P Roudier, Tinnu Sarvotham, Gaia Schiavon, Diansong Zhou, Li Zhou, Nadia Harbeck. A pre-surgical, window of opportunity study comparing the novel oral SERD AZD9496 with fulvestrant in patients with newly diagnosed ER+ HER2- primary breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-04-01.

2538Background: Knowledge of the success rates in obtaining baseline and on treatment tumour biopsies with sufficient evaluable tumour tissue is valuable in guiding strategies for evaluation of PD ...

The PIK3CA gene, encoding the p110α catalytic unit of PI3Kα, is one of the most frequently mutated oncogenes in human cancer. Hence, PI3Kα is a target subject to intensive efforts in identifying inhibitors and evaluating their therapeutic potential. Here, we report studies with a novel PI3K inhibitor, AZD8835, currently in phase I clinical evaluation. AZD8835 is a potent inhibitor of PI3Kα and PI3Kδ with selectivity versus PI3Kβ, PI3Kγ, and other kinases that preferentially inhibited growth in cells with mutant PIK3CA status, such as in estrogen receptor–positive (ER+) breast cancer cell lines BT474, MCF7, and T47D (sub-μmol/L GI50s). Consistent with this, AZD8835 demonstrated antitumor efficacy in corresponding breast cancer xenograft models when dosed continuously. In addition, an alternative approach of intermittent high-dose scheduling (IHDS) was explored given our observations that higher exposures achieved greater pathway inhibition and induced apoptosis. Indeed, using IHDS, monotherapy AZD8835 was able to induce tumor xenograft regression. Furthermore, AZD8835 IHDS in combination with other targeted therapeutic agents further enhanced antitumor activity (up to 92% regression). Combination partners were prioritized on the basis of our mechanistic insights demonstrating signaling pathway cross-talk, with a focus on targeting interdependent ER and/or CDK4/6 pathways or alternatively a node (mTOR) in the PI3K-pathway, approaches with demonstrated clinical benefit in ER+ breast cancer patients. In summary, AZD8835 IHDS delivers strong antitumor efficacy in a range of combination settings and provides a promising alternative to continuous dosing to optimize the therapeutic index in patients. Such schedules merit clinical evaluation. Mol Cancer Ther; 15(5); 877–89. ©2016 AACR.