Truqap (capivasertib)

ERK and AKT signaling and their downstream target genes were regulated by CEACAM6 and thus the treatment with AKT inhibitor capivasertib or ERK inhibitor ulixertinib mitigated the CEACAM6-induced migration. These findings demonstrate that CEACAM6 is crucially involved in gallbladder cancer progression by promoting migration and inhibiting cell adhesion through ERK and AKT signaling providing specific options for treatment of CEACAM6-positive cancers.

P3, N=560, Recruiting, AstraZeneca

Outcomes in the Japan subgroup were broadly similar to those of the global population, supporting the clinical benefit of capivasertib-fulvestrant in treating HR-positive/HER2-negative advanced breast cancer that has progressed on, or after, an endocrine-based regimen.

P3, N=1017, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

This study provides pre-clinical evidence that AKT inhibitors combined with PI3K inhibitors, cisplatin, or vincristine exhibit additive/synergistic anti-MB activity, and lower doses could be used. The latter also applied to one MB line grown as spheroids, further supporting their future potential use.

P2; N=20; Not yet recruiting; Sponsor:Imperial College London

No abstract available

P2, N=120, Not yet recruiting, German Breast Group

The ZeptoCTC workflow represents a valuable tool in single cell cancer research, crucial for personalized medicine. It permits detailed analysis of key proteins and their activation status of targeted, cancer-driven signaling pathways in single cell samples, aiding in understanding tumor response, progression, and treatment efficacy beyond bulk analysis. The method significantly advances clinical investigations in cancer, improving treatment precision and effectiveness. The workflow will be applicable to protein analysis on other types of single cells like relevant in stem cell, neuropathology and hemopoietic cell research.

The addition of the rituximab further deepened the durability of capivasertib and venetoclax responses in a RCHOP refractory DLBCL in vivo models. These findings provide preclinical evidence for the rational treatment combination of AKT and BCL-2 inhibitors using capivasertib and venetoclax respectively alongside anti-CD20 antibody supplementation for treatment of patients with DLBCL.

P2, N=124, Recruiting, Alliance for Clinical Trials in Oncology | Trial completion date: Oct 2024 --> Jan 2028 | Trial primary completion date: Oct 2024 --> Jan 2026

The CAPItello-291 study is still ongoing, and more results are expected to be released in the future. Results from the CAPItello-291 study showed that capivasertib plus fulvestrant compared with placebo plus fulvestrant improved progression-free survival in participants with HR-positive/ HER2-negative advanced breast cancer whose cancer had grown or spread despite hormone therapy (with/without a CDK4/6 inhibitor).Clinical Trial Registration: NCT04305496 (CAPItello-291) (ClinicalTrials.gov).

Herein, we investigated combined blockade of the CDK4/6 and PI3K signaling with palbociclib, alpelisib, and capivasertib, which inhibit CDK4/6, PI3Kα, and AKT1-3, respectively...The AR antagonist enzalutamide was inactive against MDA-MB-453, MFM-223, and CAL148 cells and did not enhance the efficacy of either combination...Finally, treatment with palbociclib and the PDGFR inhibitor CP637451 arrested growth of MDA-MB-453 and MFM-223 cells to the same degree as palbociclib/capivasertib. These findings support testing the combination of CDK4/6 and AKT inhibitors in patients with LAR TNBC, and further investigation of PDGFR antagonists in this breast cancer subtype.

Frequent AEs associated with PI3K/AKT pathway inhibition occurred early and were manageable. The low rate of treatment discontinuations suggests that, when appropriately managed, these AEs do not pose a challenge to clinical benefit.

Patient-reported outcomes from CAPItello-291 demonstrated that capivasertib-fulvestrant delayed time to deterioration of GHS/QOL and maintained other dimensions of HRQOL (except symptoms of diarrhoea) similarly to fulvestrant. With the clinical efficacy and manageable safety profile, these exploratory results further support the positive benefit-risk profile of capivasertib-fulvestrant in this population.

The RMSD, RMSF, Rg, and SASA analyses showed that the G-SRC and G-AKT1 complexes were excellently stable compared to the control, dasatinib, and capivasertib, respectively. Furthermore, both of them exhibited significant interactions with the binding site residues of both proteins. In summary, this study indicates that these two molecules could be a potential ATP-competitive inhibitor of SRC and an allosteric inhibitor of AKT1.

P2, N=30, Active, not recruiting, AstraZeneca | Trial completion date: Jun 2024 --> Dec 2025

Capivasertib with fulvestrant was approved for patients whose tumors harbored PIK3CA/AKT1/PTEN alterations. Benefit-risk assessment in this subgroup was favorable based on a statistically significant and clinically meaningful improvement in PFS in the context of an acceptable safety profile including no evidence of a potential detriment in overall survival. By contrast, the benefit-risk was unfavorable in the biomarker-negative population.

P2, N=132, Recruiting, OHSU Knight Cancer Institute | Trial primary completion date: Dec 2024 --> Dec 2025

However, its use is associated with notable adverse events, including hyperglycemia, which may impact treatment outcomes. This case describes a patient with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) metastatic breast cancer and no prior history of diabetes who developed diabetic ketoacidosis (DKA) following capivasertib therapy.

Using a combination of functional and metabolic assays, we evaluated a panel of PC cell lines with different PTEN/PIK3CA status for their sensitivity to multi-node PAM inhibitors (PI3K/mTOR: gedatolisib, samotolisib) and single-node PAM inhibitors (PI3Kα: alpelisib; AKT: capivasertib; mTOR: everolimus). Gedatolisib, as a single agent and in combination with other therapies, reported promising preliminary efficacy and safety in various solid tumor types. Gedatolisib is currently being evaluated in a Phase 1/2 clinical trial in combination with darolutamide in patients with mCRPC previously treated with an AR inhibitor, and in a Phase 3 clinical trial in combination with palbociclib and fulvestrant in patients with HR+/HER2- advanced breast cancer.

Considering the recent approval of capivasertib for HR+/HER2- metastatic breast cancer (MBC) harboring PI3K-AKT pathway alts based on tissue NGS, we assessed the concordance of tissue and ctDNA NGS for PIK3CA, AKT1, PTEN as well as ESR1. We identified 367 HR+/HER2- MBC pts treated at MSK with tissue NGS by MSK-IMPACT within 60 days of ctDNA NGS by either Guardant360 or MSK-ACCESS, without intervening therapy... Tissue-ctDNA concordance for the detection of any oncogenic alteration was high for PIK3CA, AKT1, moderate for ESR1, and low for PTEN. More alts were detected in ctDNA for ESR1 and in tissue for PTEN, reflecting acquired ESR1 alts after estrogen deprivation and the current lack of ctDNA assay PTEN copy number loss detection. Additional correlative analyses (e.g.

P3, N=923, Active, not recruiting, AstraZeneca | Trial completion date: Mar 2024 --> Feb 2025 | Trial primary completion date: Mar 2024 --> Feb 2025

A recent study identified high rates of PI3K-AKT pathway mutations from the FLAURA and AURA3 osimertinib trials and pre-clinically validated that these mutations decreased osimertinib sensitivity in EGFR-mutated NSCLC. The AKT inhibitor capivasertib was found to overcome this resistance, providing important rationale for the development of AKT inhibitors in NSCLC.

Our study demonstrates a novel synthetic lethality interaction and unique mechanism between ARID1A loss and AKT inhibition, which may provide a therapeutic and mechanistic rationale for targeted therapy on patients with ARID1A-defective GC who are most likely to be beneficial to AZD5363 treatment.

P1/2, N=243, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

In conclusion, Capivasertib-fulvestrant therapy shows potential as an innovative therapeutic option for HR+ breast cancer but warrants additional research, especially in randomized control trials (RCT). It resulted in longer progression-free survival compared to fulvestrant alone. Its side effect profile is minimal.

It was recently FDA-approved in combination with fulvestrant to treat HR+, HER2-negative breast cancers with certain genetic alteration(s) activating the PI3K pathway. The results provide further evidence that increased mTORC1-driven translation functions as a mechanism of resistance to capivasertib monotherapy. Protein concentrations may offer additional insights for patient selection for capivasertib, even among genetically pre-selected patients.

Although multiple compounds have been developed, at present, there are just three inhibitors approved to target this pathway in patients with advanced ER-positive, HER2-negative breast cancer: everolimus (mTOR inhibitor), alpelisib (PIK3CA inhibitor), and capivasertib (AKT inhibitor). Herein, we review the common mechanisms of resistance to agents that target the PI3K/AKT/mTOR signalling pathway, elaborate on current management approaches, and discuss ongoing clinical trials attempting to mitigate this significant issue. We highlight the need for additional studies into AKT1 inhibitor resistance in particular.

Finally, we confirmed the synergistic effects of Lenvatinib and SAHA, or AZD5363 in primary liver cancer patient derived organoids. Collectively, these findings may enable the development of Lenvatinib combination therapies for HCC.

P2, N=140, Active, not recruiting, Queen Mary University of London | Unknown status --> Active, not recruiting | Trial completion date: Jun 2020 --> Jul 2024

P2; Trial completion date: Dec 2025 --> Jan 2027

By using multiple functional assays, a panel of BC cell lines was evaluated for their sensitivity to four different PAM inhibitors: gedatolisib (pan-PI3K/mTOR inhibitor), alpelisib (PI3Kα inhibitor), capivasertib (AKT inhibitor), and everolimus (mTORC1 inhibitor). These results indicate that inhibition of multiple PAM pathway nodes by a pan-PI3K/mTOR inhibitor like gedatolisib may be more effective at inducing anti-tumor activity than single-node PAM inhibitors. A global Phase 3 study is currently evaluating gedatolisib plus fulvestrant with and without palbociclib in patients with HR+/HER2- ABC.

P2, N=30, Recruiting, VA Office of Research and Development | Not yet recruiting --> Recruiting | Trial completion date: Nov 2027 --> Aug 2027 | Trial primary completion date: Nov 2026 --> May 2027

The results of the SOLAR-1 and CAPItello-291, highlight the benefit of the ɑ-selective phosphoinositide 3-Kinase Pathway inhibitor (PI3Ki) alpelisib and the AKT inhibitor (AKTi) capivasertib in patients with hormone receptor-positive (HR+)/Human Epidermal Growth Factor Receptor 2 (HER2)- negative metastatic breast cancer (mBC) that have PIK3CA/AKT1/PTEN tumour alterations. We have summarised the clinical data on the approved and discontinued agents targeting this pathway and have assessed the drugs development, successes, and failures. Finally, because of tumour heterogeneity, we emphasise the importance of reassessing the mutational status of PI3KCA in both metastatic tissue and blood at the time of disease progression to better tailor treatment for patients.

CX3CR1 inhibition blocks FGFR1 activation triggered by FGF9 and sensitizes PTEN-deficient prostate cancer to AKT inhibitor capivasertib. This study reveals the role of KLF5 acetylation in reprogramming CAFs and provides a rational for combined therapies using inhibitors of AKT and CX3CR1.

P1/2, N=159, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

In comparison to the standard drug Capivasertib, the phytochemical Kuwanon A emerges as a standout candidate based on computational analysis. This suggests its potential as an alternative to mitigate the limitations associated with the standard drug. The research aims to provide insights for future experimental validations and to stimulate the development of Kuwanon A as a novel, effective therapeutic agent for managing colorectal cancer.

P2, N=423, Active, not recruiting, University of Birmingham | Trial completion date: Sep 2023 --> Sep 2024 | Trial primary completion date: Sep 2023 --> Sep 2024

Combined capivasertib/enzalutamide was well tolerated but didn't significantly improve outcomes from abiraterone pre-treated mCRPC.

Furthermore, 5,7,4'-trimethoxyflavone was verified to bind to LRPPRC, STAT3, and CDK1, dissociating LRPPRC-JAK2-STAT3 and JAK2-STAT3-CDK1 interaction, leading to impaired tumorigenesis in 4-Nitroquinoline N-oxide induced ESCC mouse models and suppressed tumor growth in ESCC patient derived xenograft mouse models. In summary, this study suggests regulation of m6A modification by LRPPRC, and identifies a novel triplex target compound, suggesting that targeting LRPPRC-mediated JAK2/STAT3/MYC axis may overcome JAK2/STAT3/MYC dependent tumor therapeutic dilemma.

YBX1 is upregulated in ICC and promotes stemness and cisplatin insensitivity via the AKT/β-catenin axis. Our study describes a novel potential therapeutic target for improving ICC prognosis.