ipatasertib (RG7440) / Roche, Pfizer - LARVOL DELTA

AKT inhibitors for advanced metastatic breast cancer: Meta-analysis of their efficacy and safety across hormone receptor (HR) and HER2 status-based subtypes (ESMO Asia 2025) - "Background: Trials combining novel AKT inhibitors, Capivasertib and Ipatasertib, within the standard therapy (SoC) of breast cancer have reported variable results across its subtypes. AKT inhibitors demonstrated favourable clinical response in the HR+/HER2- subtype when combined with endocrine therapy (fulvestrant), as well as in PI3K/AKT-altered subgroups within both HR+ and TNBC subtypes. Future trials should prioritize the enrolment of participants with PI3K/AKT alterations or other targetable molecular vulnerabilities to better assess their therapeutic potential."

Metastases • Retrospective data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2

Outcomes with first-line treatments for patients with locally advanced or metastatic triple negative breast cancer eligible for anti-PD-(L)1 therapy: A systematic literature review of randomized trials (SABCS 2025) - "Adding atezolizumab to taxane-based chemotherapies (7.2-7.5 vs. 5.3-6.4 months)—but not gemcitabine-carboplatin or capecitabine (4.2 vs. 3.6 months)—resulted in a significant PFS benefit...There were also statistically significant improvements in PFS with molecular subtyping-based treatments and a numerical improvement in PFS when replacing nab-paclitaxel with sacituzumab govitecan (SG) combined with immunotherapy...Conversely, trials evaluating the addition of oleclumab, nivolumab, or ipatasertib to chemotherapy and/or immunotherapy did not significantly improve PFS.Median OS ranged from 10.7-32.8 months across trials; most showed no significant differences between treatment arms... This review indicates an evolving treatment landscape, with the adoption of regimens with atezolizumab, toripalimab, pembrolizumab, and SG being associated with improved efficacy in patients with PD-(L)1-eligible LA/mTNBC. Specifically, the most recent publication revealed that SG in..."

Clinical • Metastases • Review • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Morpheus-TNBC: A Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Patients With Metastatic or Locally Advanced Breast Cancer (clinicaltrials.gov) - P1/2 | N=792 | Recruiting | Sponsor: Hoffmann-La Roche | N=580 ➔ 792 | Trial completion date: May 2028 ➔ Sep 2030 | Trial primary completion date: May 2028 ➔ Sep 2030

Enrollment change • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • PD-L1 • PIK3CA

Genomic biomarkers of response to ipatasertib in hormone receptor-positive, HER2-negative metastatic breast cancer (SABCS 2025) - "This study aimed to identify genomic biomarkers in circulating tumor DNA (ctDNA) that are associated with differences in response to ipatasertib combination therapy. TAKTIC was a phase Ib trial evaluating ipatasertib with fulvestrant or an aromatase inhibitor (Arms A/B), or fulvestrant plus palbociclib (Arm C) in patients with HR+/HER2– MBC with disease progression after ≥1 prior line of metastatic therapy. Genomic biomarkers detected in ctDNA correlated with PFS on ipatasertib therapy in this heavily pretreated population with HR+/HER2- MBC. Activating alterations in FGFR1, ERBB2, EGFR, and ESR1 were linked with inferior PFS, and triplet therapy prolonged treatment benefit in patients with PI3K pathway mutant disease. These exploratory findings are hypothesisgenerating and require clinical and preclinical validation to inform personalized AKT inhibitor treatment."

Biomarker • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • AKT1 • CDK4 • EGFR • ER • FGFR1 • HER-2 • PIK3CA • PTEN

Addition of ipatasertib to dual anti-HER2 maintenance therapy in HER2-positive metastatic breast tumors with PIK3CA mutations: the phase 1b SOLTI-1507 IPATHER trial. (PubMed, Clin Cancer Res) - P1 | "These results support ipatasertib plus HP as a safe and promising maintenance strategy for HER2-positive breast tumors harboring PIK3CAmut."

Journal • P1 data • Breast Cancer • Cardiovascular • HER2 Breast Cancer • HER2 Positive Breast Cancer • Ischemic stroke • Oncology • Pneumonia • Solid Tumor • HER-2 • PIK3CA

Enhanced expression of CXCL1 in renal cell carcinoma facilitates tumor cell malignancy via PI3K/AKT-dependent mechanisms. (PubMed, Oncol Lett) - "Finally, the AKT-specific inhibitor GDC-0068 was shown to reverse the promoting effects of CXCL1 on the malignant behaviors of RCC cells. Taken together, the findings of the present study have shown that CXCL1 exhibits high expression patterns in RCC tissues and may serve diverse functions in facilitating various aspects of RCC advancement."

IO biomarker • Journal • B Cell Lymphoma • Genito-urinary Cancer • Lymphoma • Microsatellite Instability • Oncology • Renal Cell Carcinoma • Solid Tumor • BAX • CD4 • CXCL1 • MSI

PRKG1 hinders myogenic differentiation and predicts response to AKT inhibitor ipatasertib in Rhabdomyosarcoma. (PubMed, Nat Commun) - "Here, we evaluate the activity of pan-AKT inhibitors Ipatasertib, ATP-competitive, and Miransertib, allosteric inhibitor, in RMS cell lines and fusion-positive/negative patient-derived xenografts (PDX). The antitumor activity of Ipatasertib is dose-dependent, reaching an effective intra-tumor concentration when administered at 25 mg/kg daily. This study unveils the role of PRKG1 in myogenesis and highlights the potential of PRKG1 as a clinical biomarker for Ipatasertib therapy in RMS."

Journal • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor

Morpheus Lung: A Study Of Multiple Immunotherapy-Based Treatment Combinations In Participants With Metastatic Non-Small Cell Lung Cancer (Morpheus- Non-Small Cell Lung Cancer) (clinicaltrials.gov) - P1/2 | N=314 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Nov 2026 ➔ Nov 2025

Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PD-L1

Precision oncology in rare tumors: Efficacy of molecularly guided treatment in the ROME trial (ESMO 2025) - P2 | "The most frequently used TT regimen was ipilimumab plus nivolumab (12 patients, 37.5%), followed by nivolumab, pemigatinib, ipatasertib, and vemurafenib plus cobimetinib (3 each). Conclusions MTB-guided treatment was feasible and led to superior clinical outcomes compared to SoC in patients with rare cancers. These findings support the integration of rare tumor types into precision oncology trials using molecularly driven, tumor-agnostic approaches."

Clinical • Anal Carcinoma • Brain Cancer • Carcinosarcoma • Glioblastoma • Melanoma • Mesothelioma • Neuroendocrine Tumor • Oncology • Sarcoma • Solid Tumor

Study of Chemotherapy Plus Ipatasertib for People With Solid Tumors With PTEN/AKT Mutations, A ComboMATCH Treatment Trial (clinicaltrials.gov) - P2 | N=33 | Recruiting | Sponsor: National Cancer Institute (NCI) | Active, not recruiting ➔ Recruiting

Enrollment open • Oncology • Solid Tumor • AKT2

VIRMA-mediated SHQ1 m6A modification enhances liver regeneration through an HNRNPA2B1-dependent mechanism. (PubMed, Acta Pharm Sin B) - "The upregulation of Shq1 enhanced the proliferation ability of cells, which was attenuated by the specific AKT inhibitor ipatasertib...Downregulation of Shq1 inhibited the PI3K/AKT pathway, thereby suppressing cell proliferation and cell cycle progression, ultimately impeding liver regeneration. In summary, our results demonstrate that VIRMA plays a critical role in promoting liver regeneration by regulating m6A modification, providing valuable insights into the epigenetic regulation during liver regeneration."

Journal • HNRNPA2B1 • HNRNPAB • VIRMA

Computational evaluation of AKT2 mutations reveals R274H and R467W as potential drivers of protein instability and inhibitor resistance in cancer therapy. (PubMed, PLoS One) - "Molecular docking revealed that R274H, in kinase domain, disrupts key hydrogen bonds with THR292 and GLU279, leading to more flexible binding pocket and significantly reduced binding affinity for Capivasertib and Ipatasertib. These findings suggest that these mutations may contribute to inhibitor resistance by weakening inhibitor interactions and destabilizing the protein-inhibitor complex. This study underscores the importance of genetic screening in optimizing cancer treatment and highlights the need for mutation-specific therapeutic strategies targeting AKT2."

Journal • Oncology • AKT2

NCI-MATCH: Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial) (clinicaltrials.gov) - P2 | N=6452 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Dec 2025 ➔ Dec 2026

Biomarker • Trial completion date • Trial primary completion date • Bladder Cancer • Brain Cancer • Breast Cancer • Cervical Cancer • Colon Cancer • Colorectal Cancer • Endometrial Cancer • Esophageal Cancer • Gastric Cancer • Genito-urinary Cancer • Glioblastoma • Glioma • Head and Neck Cancer • Hematological Malignancies • Hormone Receptor Positive Breast Cancer • Kidney Cancer • Liver Cancer • Lung Cancer • Lymphoma • Melanoma • Multiple Myeloma • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Refractory Ovarian Cancer • Renal Cell Carcinoma • Skin Cancer • Solid Tumor • Thyroid Gland Carcinoma • Uterine Cancer • CD4 • MSI

Efficacy and safety of systemic therapies following progression on CDK4/6 inhibitors in patients with HR+/HER2- metastatic breast cancer: a systematic review and network meta-analysis. (PubMed, EClinicalMedicine) - "Sapanisertib plus fulvestrant provided the greatest PFS benefit (HR 0.34, 95% CI 0.14-0.82) but had a high discontinuation rate (>15%). Among the approved therapies, ribociclib plus ET (HR 0.57, 95% CI 0.39-0.84), capivasertib plus fulvestrant (HR 0.62, 95% CI 0.51-0.75), and elacestrant (HR 0.70, 95% CI 0.55-0.89) demonstrated superior efficacy...Ipatasertib and alpelisib showed the greatest benefits in patients with PI3K/PTEN/AKT alterations. Antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan and sacituzumab govitecan, outperformed standard chemotherapy, albeit with higher toxicity...Grant Assignment Decree No. 1369 adopted on 01.09.2023 by the Italian Ministry of University and Research (MUR)."

Journal • Retrospective data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Comprehensive genomic profiling to guide personalized targeted and immunotherapy in gastrointestinal tumors: Subgroup analysis of the ROME trial (ESMO-GI 2025) - P2 | "Funding: Erlotinib, Pertuzumab, Vemurafenib, Trastuzumab Emtansine, Alectinib, Vismodegib, Cobimetinib, Atezolizumab, Trastuzumab, Ipatasertib (GDC-0068), Entrectinib and Pralsetinib were provided by Roche; Everolimus, Lapatinib, Alpelisib were provided by Novartis, Palbociclib and Talazoparib were provided by Pfizer, Ipilimumab and Nivolumab were provided by Bristol Myers Squibb (BMS); Brigatinib was provided by Takeda Pharmaceutical Co.; Ponatinib, Itacitinib (INCB039110), Pemigatinib (INCB054828) were provided by Incyte; Selpercatinib was provided by Eli Lilly; Tepotinib was provided by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945). CGP with MTB-guided TT may identify patients with GI cancer who benefit from targeted therapies not routinely available in clinical practice. The roles of TMB and potential disease-specific thresholds deserve further investigation."

IO biomarker • Tumor mutational burden • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA • TMB

Pharmacokinetics, safety and tolerability of ipatasertib in combination with palbociclib and fulvestrant in patients with advanced breast cancer in a phase Ib study. (PubMed, Front Pharmacol) - P1 | "This study indicated a DDI between ipatasertib and palbociclib, leading to increased ipatasertib exposure. The combination regimen of ipatasertib 300 mg with palbociclib and fulvestrant had a notable and manageable safety profile, that is generally consistent with the known risks of each individual study drugs in patients with HR + HER2-breast cancer."

Journal • P1 data • PK/PD data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CYP3A4 • HER-2

AFT-50 EndoMAP: A Study of Targeted Agents for Patients With Recurrent or Persistent Endometrial Cancer (clinicaltrials.gov) - P1/2 | N=148 | Recruiting | Sponsor: Alliance Foundation Trials, LLC. | Trial completion date: Oct 2026 ➔ Oct 2027 | Trial primary completion date: Oct 2025 ➔ Oct 2026

IO biomarker • MSI-H • MSi-H Companion diagnostic • PARP Companion diagnostic • PD(L)-1 companion diagnostic • Trial completion date • Trial primary completion date • Endometrial Cancer • Oncology • Solid Tumor

AKT Inhibitor, Ipatasertib, With Endocrine and CDK 4/6 Inhibitor for Patients With Metastatic Breast Cancer (TAKTIC) (clinicaltrials.gov) - P1 | N=77 | Active, not recruiting | Sponsor: Massachusetts General Hospital | Trial completion date: Dec 2024 ➔ Jul 2026

Trial completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Akt Inhibitors Sensitize Pancreatic Cancers to Radiation Therapy by Enhancing Oxidative Stress, Reversing EMT, and Reprogramming the Immune Microenvironment (ASTRO 2025) - "Akt inhibitors (capivasertib or ipatasertib), singly or in combination with capecitabine, were evaluated for their radiation sensitization potential, using capecitabine-radiation as the standard-of-care reference for comparisons. Collectively, our results suggest that inhibition of Akt signaling sensitizes pancreatic cancers to radiation therapy by amplifying radiation-induced oxidative stress and abrogating the pro-survival signaling drive downstream of constitutively active mutant Kras. This also reverses EMT and reprograms the immunosuppressive tumor microenvironment to a more immunogenic phenotype that may be primed for further enhancement by targeted immunotherapies. Taken together, these results suggest that Akt inhibition may be a promising strategy for sensitization of pancreatic cancer to radiation therapy via multiple orthogonal mechanisms that include EMT reversal and immune reprogramming."

IO biomarker • Oxidative stress • Oncology • Pancreatic Cancer • Solid Tumor • AKT1S1 • CDH1 • KRAS • NQO1 • PD-L1 • SNAI1 • SNAI2

Prostate Cancer Biomarker Enrichment and Treatment Selection (clinicaltrials.gov) - P2 | N=200 | Active, not recruiting | Sponsor: Canadian Cancer Trials Group | Trial primary completion date: Jun 2025 ➔ Oct 2024

Biomarker • Trial primary completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

RAS pathway inhibitors combined with targeted agents are active in patient-derived spheroids with oncogenic KRAS variants from multiple cancer types. (PubMed, Cancer Res Commun) - "Vertical inhibition of the RAS/MEK/ERK pathway by targeting SHP2 or SOS1 and the downstream kinases MEK (trametinib) or ERK (temuterkib) was highly effective. Inhibition of upstream tyrosine receptor kinases with nintedanib in combination with batoprotafib or BI-3406 was also effective, and in combination with sotorasib, demonstrated synergy in spheroids harboring KRAS G12C. Dual inhibition of the RAS/MEK/ERK and PI3K/AKT/mTOR pathways by batoprotafib or sotorasib with either the mTORC1/2 inhibitor sapanisertib or the AKT inhibitor ipatasertib demonstrated combination activity, primarily in spheroids harboring KRAS G12C. The BCL-2 inhibitor venetoclax in combination with sotorasib, batoprotafib or BI-3406 resulted in additive and synergistic cytotoxicity. Lastly, concurrent inhibition of the KRAS pathway with sotorasib and batoprotafib demonstrated combination activity in spheroids containing KRAS G12C."

Journal • Oncology • KRAS

Study of Chemotherapy Plus Ipatasertib for People With Solid Tumors With PTEN/AKT Mutations, A ComboMATCH Treatment Trial (clinicaltrials.gov) - P2 | N=33 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Active, not recruiting

Enrollment closed • Oncology • Solid Tumor • AKT2

Pharmacokinetics, safety and tolerability of ipatasertib in combination with palbociclib and fulvestrant in patients with advanced breast cancer in a Phase Ib study (Frontiers) - "The PK analysis showed that the area under the concentration-time curve from time 0 to 24 hours at steady state (AUC0-24,ss) and the maximum observed plasma concentration at steady state (Cmax,ss) of ipatasertib increased by 68% and 49%, respectively, when ipatasertib was coadministered with palbociclib and fulvestrant compared to administration of ipatasertib alone. A similar trend was observed for M1 with AUC0-24,ss and Cmax,ss increased by 20% and 14%, respectively, when ipatasertib was coadministered with palbociclib and fulvestrant compared to administration of ipatasertib alone."

P1 data • PK/PD data • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

Study of Chemotherapy Plus Ipatasertib for People With Solid Tumors With PTEN/AKT Mutations, A ComboMATCH Treatment Trial (clinicaltrials.gov) - P2 | N=33 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Aug 2025 ➔ Aug 2026 | Trial primary completion date: Aug 2025 ➔ Aug 2026

Trial completion date • Trial primary completion date • Oncology • Solid Tumor • AKT2

New therapeutic targets in pleural mesothelioma: Combined AKT and mTOR inhibition using Ipatasertib and Sapanisertib synergistically inhibits proliferation and viability (DGT 2025) - "Combined treatment with Ipatasertib and Sapanisertib had a strong synergistic effect in all cell lines and primary cells from two PM patients, even in Cisplatin-resistant cells. Results Our study demonstrates recurrent activation of AKT kinases by copy number gain and upregulated expression in PM. Pharmacological AKT and mTOR inhibition is a promising therapeutic alternative in mesothelioma."

Malignant Pleural Mesothelioma • Mesothelioma • Pleural Mesothelioma • Solid Tumor • AKT2