- |||||||||| Prolia (denosumab) / Amgen
Review, Journal: Diagnosis and Current Treatment of Aneurysmal Bone Cysts. (Pubmed Central) - Mar 7, 2024
Selective arterial embolization has significantly contributed to the development of effective treatments for these situations. Embolization or radiation, as well as denosumab therapy, are widely used as therapies for ABCs in anatomic locations where surgery would significantly increase morbidity.
- |||||||||| Enrollment change, Trial primary completion date: JaZ: Intensive Lipid-lowering in Patients With STEMI and NSTEMI (Germany on Target) (clinicaltrials.gov) - Mar 6, 2024
P=N/A, N=300, Not yet recruiting,
Embolization or radiation, as well as denosumab therapy, are widely used as therapies for ABCs in anatomic locations where surgery would significantly increase morbidity. N=1000 --> 300 | Trial primary completion date: Dec 2025 --> Apr 2026
- |||||||||| Krazati (adagrasib) / BMS, Lumakras (sotorasib) / Amgen
Review, Journal: Management of KRAS-mutated non-small cell lung cancer. (Pubmed Central) - Mar 6, 2024
New-generation inhibitors and different combination strategies are being developed in early-phase trials to overcome or delay the onset of resistance as well as to target non-G12C mutations. Owing to the biological heterogeneity of KRAS-mutant NSCLC, treatment will likely need to be individualized based on factors such as co-occurring mutations.
- |||||||||| Journal, Adverse events, Adverse drug reaction: Cardiovascular Adverse Drug Reactions of Anti-Calcitonin Gene-Related Peptide Monoclonal Antibodies for Migraine Prevention: An Analysis from the European Spontaneous Adverse Event Reporting System. (Pubmed Central) - Mar 6, 2024
However, hypertension with ERE, atrial fibrillation and myocardial infarction with GMB, as well as pallor, deep vein thrombosis, hot flush, and palpitations with FMB were not reported in the Summary of Product Characteristics (SmPCs). Considering this, more post-marketing analyses are needed to improve knowledge on the CV safety profiles of anti-CGRP-mAbs, especially for the last approved medication, EPT.
- |||||||||| Ibrance (palbociclib) / Pfizer
Journal: Targeted Liposomes Sensitize Plastic Melanoma to Ferroptosis via Senescence Induction and Coenzyme Depletion. (Pubmed Central) - Mar 6, 2024
The strategy involves the ratiometric coencapsulation of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor (palbociclib) and a ferroptosis inducer (auranofin) within cRGD peptide-modified targeted liposomes...The proof-of-concept was also demonstrated in the B16F10 tumor-bearing mice model. The current work offers a promising ferroptosis-targeting strategy for effectively treating heterogeneous melanoma by manipulating the cellular plasticity.
- |||||||||| Repatha (evolocumab) / Amgen, Astellas
New trial, Real-world evidence, Real-world: A Study Assessing Repatha (clinicaltrials.gov) - Mar 6, 2024
P=N/A, N=7000, Recruiting,
- |||||||||| Enrollment closed, Enrollment change, IO biomarker: MULTISARC: Molecular Profiling of Advanced Soft-tissue Sarcomas (clinicaltrials.gov) - Mar 5, 2024
P3, N=603, Active, not recruiting,
The current work offers a promising ferroptosis-targeting strategy for effectively treating heterogeneous melanoma by manipulating the cellular plasticity. Recruiting --> Active, not recruiting | N=960 --> 603
- |||||||||| KIYA-PREDICT (Section 6) - Mar 5, 2024 - Abstract #AACR2024AACR_9728;
Finally, ex vivo and in vivo responses to FDA approved ADC enfortumab vedotin were evaluated in a panel of bladder cancer PDX, with ex vivo and in vivo responses showing good concordance and expected modulation based on Nectin-4 expression levels. The combination of the KIYA-PREDICT
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen
Innovative mRNA strategies to encode CD19/CD3 T cell engagers in the treatment of B cell hematological malignancies (Section 3) - Mar 5, 2024 - Abstract #AACR2024AACR_9487;
Blinatumomab, a bispecific CD19/CD3 TCE, has shown remarkable efficacy in treating refractory or relapsed B-cell Acute Lymphoblastic Leukaemia (B-ALL), including cases resistant to conventional chemotherapy, leading to its global approval for B-ALL management...One candidate mRNA demonstrated an optimal "plateau" pharmacokinetic profile, achieving extensive target cell eradication over 20 days with a single low dose of 0.001 mpk in non-human primates.An investigator-initiated clinical study with mRNA encoding CD19/CD3 TCE is underway in relapsed and/or refractory acute lymphoblastic leukemia patients. The preliminary data from the on-going study showed ABO2015 with an acceptable safety profile, and activation of peripheral T cells was observed in one patient with low dose.These findings underscore the significant clinical potential of mRNA-encoded CD19/CD3 TCE in treating B-cell malignancies, heralding a paradigm shift in the clinical application of protein-based T cell engagers.
- |||||||||| Krazati (adagrasib) / BMS, Lumakras (sotorasib) / Amgen
Optimization of intermittent dosing strategies of KRAS G12C inhibitors in preclinical lung cancer model (Section 28) - Mar 5, 2024 - Abstract #AACR2024AACR_9403;
Overall, our findings suggest that the utilization of intermittent dosing regimens for selective KRASG12C inhibitors is a promising approach for improving clinical responses in lung cancers with KRAS mutations. Future experiments will aim to delineate MAPK pathway behavior in vivo and in vitro under pulsatile and continuous treatment, assess immunogenicity, and further characterize immune changes in the different treatment regimens, with the goal of designing more efficient cancer therapies utilizing selective KRAS inhibitors.
- |||||||||| tarlatamab (AMG 757) / Amgen
Impact of patient specific factors on exposures of tarlatamab, a half-life extended DLL3-directed bispecific T-cell engager in patients with advanced small cell lung cancer (Section 24) - Mar 5, 2024 - Abstract #AACR2024AACR_9373;
P1, P2
Future experiments will aim to delineate MAPK pathway behavior in vivo and in vitro under pulsatile and continuous treatment, assess immunogenicity, and further characterize immune changes in the different treatment regimens, with the goal of designing more efficient cancer therapies utilizing selective KRAS inhibitors. Overall, based on these analyses, no dose adjustment for tarlatamab is required based on age, sex, bodyweight, ethnicity, estimates of renal and hepatic function, prior lines of therapy, baseline disease status or emergence of ADA.
- |||||||||| Ibrance (palbociclib) / Pfizer, pfifteloxin (OBP-702) / Oncolys BioPharma, Telomelysin (suratadenoturev) / Oncolys BioPharma
Combination of CDK4/6 inhibitor promotes the antitumor effect of oncolytic adenovirus against canine breast cancer cells (Section 27) - Mar 5, 2024 - Abstract #AACR2024AACR_9321;
Our results suggest that telomerase-specific oncolytic adenoviruses have cytopathic effect against canine breast cancer cells via virus infection and replication. Furthermore, combination of CDK4/6 inhibitor may be a promising strategy for promoting the antitumor effect of oncolytic adenovirus against canine breast cancers.
- |||||||||| ADGN-121 / Aanastra, ADGN-123 / Aanastra
Selective deletion of the KRAS mutant gene with ADGN-123 and ADGN-121 peptide-RNA nanoparticles: A new strategy to overcome acquired resistance to KRASG12C and KRASG12D small molecule inhibitors (Section 27) - Mar 5, 2024 - Abstract #AACR2024AACR_9316;
Recently, KRASG12C inhibitors (sotorasib and adagrasib) have been approved and KRASG12D inhibitor MTRX-1133 has shown preclinical efficacy in KRASG12D mutated cancers...ADGN-121 was evaluated on ASPC-1 and PANC-1 generated clones resistance to MRTX-1133...ADGN treatments were well tolerated, with no signs of clinical toxicity detected after single or repeat administration.Our study provides a proof-of-concept that ADGN complexes can be applied to target driver mutations of cancers in vivo and permanently disrupt the oncogenic alleles, leading to major tumor regression. ADGN-123 and ADGN-121 constitute a potent alternative strategy to overcome resistance associated to small molecule inhibitors of KRASG12C and KRASG12D
- |||||||||| Ibrance (palbociclib) / Pfizer
Association of KAT6A expression with clinical outcomes in previously treated HR-positive and HER2-negative metastatic breast cancer (Section 45) - Mar 5, 2024 - Abstract #AACR2024AACR_9072;
Low tumor KAT6A mRNA expression identified patients with relatively greater benefit from addition of PAL to FUL especially in those with prior exposure to both chemo- and endocrine therapies. The data support further investigation of KAT6A and its related biomarkers and their association with CDK4/6 inhibitors and/or endocrine therapy in HR+/HER2-breast cancer patients and to test if a KAT6 inhibitor can enhance CDK4/6 inhibitor and/or endocrine therapy efficacy in tumors with high KAT6A expression.
- |||||||||| Genetic alterations and pharmacological response profiles from 10 cervical cancer cell lines (Section 16) - Mar 5, 2024 - Abstract #AACR2024AACR_8431;
A string of LoF alterations (CSMD2/CSMD3, ZNF717, CDC27) had been previously associated with poor response to radiation or to chemo-radiation, in tumors and are present in most CLs which are derived from resistant tumors. Future objectives are to validate the present biomarker findings in the context of a clinical platform trial.
- |||||||||| AZD8421 / AstraZeneca
Targeting the cell cycle with AZD8421, a potent and highly selective CDK2 inhibitor (Section 18) - Mar 5, 2024 - Abstract #AACR2024AACR_8375;
Monotherapy activity and combination benefit in vivo with standard of care agents was also observed in ovarian PDX models with elevated levels of CCNE1. AZD8421 is a potent and highly selective CDK2 inhibitor, with double digit nM potency in cells, as well as suitable physical and pharmacokinetic properties for progression into the clinic.
- |||||||||| Ibrance (palbociclib) / Pfizer, SRA515 / GSK, Verzenio (abemaciclib) / Eli Lilly
Targeting CDK4/6 and BET proteins for the treatment of RB+ and RB- osteosarcoma (Section 18) - Mar 5, 2024 - Abstract #AACR2024AACR_8364;
In-vivo efficacy of dual CDK46i+BETi is underway. This data provides rationale for further study of novel therapeutic options which may expand the clinical utility of CDK4/6i regardless of RB status.
- |||||||||| tagtociclib (PF-07104091) / Pfizer
PF-07104091, a first-in-class CDK2-selective inhibitor for the treatment of HR+/HER2- breast cancer and CCNE1high ovarian cancer (Section 18) - Mar 5, 2024 - Abstract #AACR2024AACR_8355;
Whole genome CRISPR KO and CRISPR activation screens in conjunction with CDK46 inhibition establish CDK2 KO as a primary sensitizer to CDK46 inhibition, and support Cyclin ECDK2 complexes as the driver of resistance to CDK46 inhibitors in ER+ breast models. PF-07104091 combined with CDK46 inhibitor Palbociclib or CDK4-selective inhibitor PF-0060 synergistically controls proliferation of ER+ BC cells in vitro and induces tumor regression in ER+ BC xenograft models, including PDX models with acquired resistance to CDK46 inhibitors and endocrine therapy.
- |||||||||| Lumakras (sotorasib) / Amgen
KRASG12C inhibition synergizes with checkpoint blockade in KRASG12C-mutated tumor model (Section 2) - Mar 5, 2024 - Abstract #AACR2024AACR_8210;
XPO7 was identified as a driver to change cell cycle landscape and merits as a therapeutic target combined with CDK4/6 inhibition in ESCC, which is beneficial to provide a novel treatment strategy. The successfully established CT26-KRASG12C model is a useful tool for investigating therapeutic strategies to combine KRASG12C inhibitors with immunotherapy.
- |||||||||| FMC-376 / Frontier Medicines
FMC-376 a dual inhibitor of ON and OFF states of KRASG12C is broadly active in PDX models of resistance (Section 26) - Mar 5, 2024 - Abstract #AACR2024AACR_8173;
In vivo profiling of FMC-376 against a panel KRASG12C mutant patient derived xenograft (PDX) models of NSCLC, CRC and PDAC, has demonstrated that dual inhibition of both ON and OFF KRASG12C leads to complete suppression and regression of tumors carrying a broad spectrum of known genomic and non-genomic (adaptive) drivers of clinical resistance to OFF state KRASG12C inhibitors. FMC-376 a clinical stage dual inhibitor of ON and OFF state KRASG12C has the potential to overcome limitations of single acting and OFF state KRASG12C inhibitors.
- |||||||||| Lumakras (sotorasib) / Amgen
Discovery of ACE-47228211, a highly potent and selective SOS1 inhibitor (Section 26) - Mar 5, 2024 - Abstract #AACR2024AACR_8172;
When combined with Sotorasib (5 mg/kg QD), a Kras G12C inhibitor, ACE-47228211 at 3 mg/kg exhibited synergistic effect similar to MRTX0920 at 50 mg/kg...The evaluation of ACE-47228211 in a safety panel of 87 targets and a kinase panel of >500 targets shows that this molecule has favorable selectivity and safety profiles. The molecule is currently in IND enabling stage of development.
- |||||||||| Ibrance (palbociclib) / Pfizer, Kisqali (ribociclib) / Novartis, Verzenio (abemaciclib) / Eli Lilly
Unveiling mechanisms of CDK4/6 inhibitor resistance in ER+ breast cancer models with acquired resistance (Section 24) - Mar 5, 2024 - Abstract #AACR2024AACR_8056;
These findings shed light on the shared pathways that drive CDK4/6 inhibitor resistance and provide insights into potential therapeutic targets for overcoming this resistance in breast cancer patients. Understanding these mechanisms is crucial for the development of more effective treatment strategies for CDK4/6 inhibitor-resistant cancers.
- |||||||||| Ibrance (palbociclib) / Pfizer, Kisqali (ribociclib) / Novartis, Verzenio (abemaciclib) / Eli Lilly
CDK4/6 therapy-induced senescence as a resistance mechanism-MiDAS touch (Section 24) - Mar 5, 2024 - Abstract #AACR2024AACR_8046;
This appears to be transient in nature as withdrawal of the drug results reacquisition of parental cell phenotype and drug-sensitivity. Targeting MiDAS pathway might be critical to improve efficacy of CDK4/6 inhibitors.
- |||||||||| MG132 / Jilin University, Dorothy M. Davis Heart and Lung Research Institute, Lumakras (sotorasib) / Amgen
Discovery and characterization of a KRASG12C/D/V degrader with potent anti-tumor activity in KRASmut-driven preclinical models (Section 46) - Mar 5, 2024 - Abstract #AACR2024AACR_7830;
Although the approval of Sotorasib in 2021 by the FDA partially addressed the needs of patients with KRASG12C mutant, other mutations, such as G12D and G12V, still lack effective target therapies...Meanwhile, using protease inhibitor MG132 or corresponding ligand pretreatment and VHLKD-AGS cell experiment confirmed that RD0255359-induced KRAS degradation was VHL and UPS dependent...Taken together, RD0255359 is a highly potent and selective KRASG12C/D/V degrader with favorable PK properties. It exhibits a promising therapeutic index in preclinical studies.
- |||||||||| Krazati (adagrasib) / BMS, Lumakras (sotorasib) / Amgen
KRAS inhibitor-based combinations in pancreatic cancer identified through Optim.AI (Section 46) - Mar 5, 2024 - Abstract #AACR2024AACR_7812;
Notably, we have identified KRAS inhibitor-based combinations that are distinctly different from wild type KRAS cell line. These preliminary findings could be used to drive precision medicine by identifying suitable biomarkers to potentially stratify pancreatic cancer patients and improve treatment outcomes.
- |||||||||| Lumakras (sotorasib) / Amgen
Blockade of CD24 sensitizes pancreatic cancer to Kras inhibitors (Section 47) - Mar 5, 2024 - Abstract #AACR2024AACR_7779;
KRAS, long considered an undruggable target, has been targeted by drugs including a KRASG12C inhibitor (G12Ci), AMG 510, which is approved for the treatment of KRASG12C-mutant non-small cell lung cancer (NSCLC)...Similar findings were observed in KRASG12D-driven PDAC model. Our findings identified a novel immune combination to improve the outcome of KRAS targeted therapy in PDAC.
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