Truqap

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01EX27 Mechanism of action Capivasertib is a potent, selective inhibitor of the kinase activity of all 3 isoforms of serine/threonine kinase AKT (AKT1, AKT2 and AKT3).‍​‍‍‍​‍‍‍‍‍‍‍‍​‍ AKT is a pivotal node in the phosphatidylinositol 3-kinase (PI3K) signalling cascade regulating multiple cellular processes including cellular survival, proliferation, cell cycle, metabolism, gene transcription and cell migration. AKT activation in tumours is a result of upstream activation from other signalling pathways, mutations of AKT, loss of Phosphatase and Tensin Homolog (PTEN) function and mutations in the catalytic subunit of PI3K (PIK3CA). Capivasertib inhibits the phosphorylation of AKT substrates such as glycogen synthase kinase 3-β (GSK3β) and proline rich AKT substrate of 40 kilodaltons (PRAS40). Capivasertib reduces growth of a range of cell lines derived from solid tumours and haematological disease. Multiple breast cancer cell lines were sensitive to capivasertib monotherapy. Within cell lines showing greater sensitivity to capivasertib there was an enrichment of PIK3CA or AKT1 mutations, or loss of PTEN. Some cell lines lacking such mutations were also sensitive to capivasertib. In vivo, monotherapy , capivasertib inhibits growth of human cancer xenograft models representative of different tumour types including ER + and triple negative breast cancer models with PIK3CA , AKT1 mutations, PTEN loss and HER2 amplification, mutant xenograft models and triple negative breast cancer xenograft models. Combined treatment with capivasertib and fulvestrant demonstrated a greater anti-tumour response in a range of human breast cancer PDX models representative of different breast cancer subsets. This included models without detectable mutations or alterations in PIK3CA , PTEN or AKT , as well as models with mutations or alterations in PIK3CA , PTEN or AKT . Cardiac Electrophysiology Based on an exposure-response analysis of data from 180 patients with advanced solid malignancies who received capivasertib doses from 80 to 800 mg, the predicted QTcF prolongation was 3.87 ms at the mean steady state C max following 400 mg twice daily. No clinically relevant effect of capivasertib on QT prolongation associated with pro-arrhythmic effect was observed at the recommended dose of 400 mg twice daily. Clinical efficacy CAPItello‑291 was a randomised, double-blind, placebo-controlled study that enrolled 708 patients, designed to demonstrate the efficacy and safety of Truqap in combination with fulvestrant in adult females, pre- or post-menopausal, and adult males with locally advanced (inoperable) or metastatic HR positive and HER2 negative breast cancer of whom 289 patients had tumours with one or more eligible PIK3CA/AKT1/PTEN alterations following recurrence or progression on or after aromatase inhibitor (AI) based treatment. Patients were excluded if they had more than 2 lines of endocrine therapy for locally advanced (inoperable) or metastatic disease, more than 1 line of chemotherapy for locally advanced (inoperable) or metastatic disease, prior treatment with AKT, PI3K, mTOR inhibitors, fulvestrant and/or other SERDs, clinically significant abnormalities of glucose metabolism (defined as patients with diabetes mellitus Type 1 or Type 2 requiring insulin treatment, and/or HbA1c ≥ 8.0% (63.9 mmol/mol)), history of clinically significant cardiac disease, and symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy. Patients were randomised 1:1 to receive either 400 mg of Truqap (N=355) or placebo (N=353) given twice daily for 4 days followed by 3 days off treatment each week of 28‑day treatment cycle. Fulvestrant 500 mg was administered on cycle 1 days 1 and 15 and then at day 1 of a 28‑day cycle. Peri/pre-menopausal women were treated with an LHRH agonist. Randomisation was stratified by presence of liver metastases, prior treatment with CDK4/6 inhibitors and geographical region (region 1: US, Canada, Western Europe, Australia, and Israel vs region 2: Latin America, Eastern Europe, and Russia vs Region 3: Asia). Treatment was administered until disease progression, death, withdrawal of consent, or unacceptable toxicity. A tumour sample was collected prior to randomisation to determine PIK3CA/AKT1/PTEN alteration status retrospectively by central testing. Demographic and baseline characteristics were well balanced between arms. Of the 708 patients, the median age was 58 years (range 26 to 90); female (99%); White (57.5%), Asian (26.7%), Black (1.1%); Eastern Cooperative Oncology Group (ECOG) performance status 0 (65.7%), 1 (34.2%), 21.8% were pre/peri menopausal. All patients received prior endocrine-based therapy (100% aromatase inhibitor (AI)-based treatment and 44.1% received tamoxifen). Prior treatment with CDK4/6 inhibitor was reported in 70.1% of patients. Chemotherapy for locally advanced (inoperable) or metastatic disease was reported in 18.2% of patients. Patient demographics for those in the PIK3CA/AKT1/PTEN -altered subgroup were generally representative of the overall study population. The dual primary endpoints were investigator assessed progression free survival (PFS) in the overall population and PFS in the PIK3CA/AKT1/PTEN -altered subgroup per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. The key secondary endpoints of overall survival (OS) and objective response rate (ORR) will be formally analysed at future data cut offs. At the time of primary analysis, the median duration of follow-up for PFS in the overall population was 13 months (range: 0 to 25 months) in censored patients. The study demonstrated statistically significant improvement in PFS for patients receiving Truqap plus fulvestrant compared to patients receiving placebo plus fulvestrant, in both the overall population and the PIK3CA/AKT1/PTEN -altered subgroup (see table 9). An analysis of PFS in the 313 (44%) patients whose tumours did not have a PIK3CA/AKT1/PTEN alteration showed a HR of 0.79 (95% CI: 0.61, 1.02), indicating that the difference in the overall population was primarily attributed to the results seen in the population of patients whose tumours have a PIK3CA/AKT1/PTEN alteration. PFS results by investigator assessment were supported by consistent results from a blinded independent central review (BICR) assessment. The investigator-assessed ORR in patients receiving Truqap plus fulvestrant and placebo plus fulvestrant was 22.9% and 12.2%, respectively, in the overall population and 28.8% and 9.7%, respectively, in the altered subgroup. A prespecified interim analysis of OS (DCO 15 April 2024, 59% of patients had died) showed a HR of 0.88 (95% CI: 0.65, 1.19) in the PIK3CA/AKT1/PTEN -altered subgroup. Efficacy results are presented in Table 9 and Figure 1. Table 9 Progression-free survival, by investigator assessment in the PIK3CA/AKT1/PTEN - altered subgroup PIK3CA/AKT1/PTEN altered subgroup N = 289 Truqap plus fulvestrant N = 155 Placebo plus fulvestrant N = 134 Number of PFS events – n (%) 121 (78.1) 115 (85.8) Median PFS months (95% CI) 7.3 (5.5, 9.0) 3.1 (2.0, 3.7) Hazard ratio (95% CI) a 0.50 (0.38, 0.65) p-value b < 0.001 a Stratified Cox proportional hazards model. A hazard ratio < 1 favours capivasertib + fulvestrant. For the Overall population, log-rank test and Cox model stratified by presence of liver metastases (yes vs no), prior use of CDK4/6 inhibitors (yes vs no) and geographic region (Region 1: United States, Canada, Western Europe, Australia, and Israel, Region 2: Latin America, Eastern Europe and Russia vs Region 3: Asia). For the altered population, the log rank test and Cox model stratified by presence of liver metastases (yes vs no), and prior use of CDK4/6 inhibitors (yes vs no). b Stratified log-rank test. Figure 1 – Kaplan-Meier plot of progression-free survival – CAPItello‑291 (investigator assessment, PIK3CA/AKT1/PTEN -altered subgroup)