- |||||||||| FDA event, Journal: An Expedition on Synthetic Methodology of FDA-approved Anticancer Drugs (2018-2021). (Pubmed Central) - Jan 30, 2024
The review comprises the key structural features, approval times, target selectivity, mechanisms of action, therapeutic indication, formulations, and possible synthetic approaches of these approved drugs. These crucial details will benefit the scientific community for futuristic new developments in this arena.
- |||||||||| Lumakras (sotorasib) / Amgen, BMS-986466 / BridgeBio, BMS
Journal: Discovery of 1H-pyrazolo[3,4-b]pyrazine derivatives as selective allosteric inhibitor of protein tyrosine phosphatase SHP2 for the treatment of KRAS-mutant non-small cell lung cancer. (Pubmed Central) - Jan 23, 2024
In this study, we used the previously reported SHP2 allosteric inhibitor IACS-13909 as a lead drug for structural derivation and modification, and synthesized three SHP2 inhibitors...Furthermore, the combination therapy of compound 4b and KRAS inhibitor sotorasib would play a strong synergistic effect against NCI-H358 cells...Molecular docking study predicted that compound 4b bound to the allosteric site of SHP2 and formed H-bond interactions with key residues Thr108, Glu110, Arg111, and Phe113. In summary, this study aims to provide new ideas for the development of SHP2 allosteric inhibitors for the treatment of KRAS mutant non-small cell lung cancer.Communicated by Ramaswamy H. Sarma.
- |||||||||| Krazati (adagrasib) / BMS, Avastin (bevacizumab) / Roche, Lumakras (sotorasib) / Amgen
Review, Journal: KRASG12C mutant lung adenocarcinoma: unique biology, novel therapies and new challenges. (Pubmed Central) - Jan 23, 2024
Similar to other target therapies, clinical administration of KRASG12C inhibitors (sotorasib and adagrasib) resulted in acquired resistance due to various genetic changes not only in KRAS but in other oncogenes as well. Recent clinical studies are aiming to increase the efficacy of G12C inhibitors by novel combination strategies.
- |||||||||| Lumakras (sotorasib) / Amgen
Journal: Sotorasib is a pan-RASG12C inhibitor capable of driving clinical response in NRASG12C cancers. (Pubmed Central) - Jan 18, 2024
Structural and reciprocal mutagenesis studies suggested that differences in isoform-specific binding are mediated by a single amino acid: Histidine-95 in KRAS (Leucine-95 in NRAS). A patient with NRASG12C colorectal cancer treated with sotorasib and the anti-EGFR antibody panitumumab achieved a marked tumor response, demonstrating that sotorasib can be clinically effective in NRASG12C-mutated tumors.
- |||||||||| Lumakras (sotorasib) / Amgen, Tarlox (tarloxotinib bromide) / Pathos
Trial termination: Tarlox and Sotorasib in Patients With KRAS G12C Mutations (clinicaltrials.gov) - Jan 17, 2024
P1/2, N=5, Terminated,
A patient with NRASG12C colorectal cancer treated with sotorasib and the anti-EGFR antibody panitumumab achieved a marked tumor response, demonstrating that sotorasib can be clinically effective in NRASG12C-mutated tumors. Active, not recruiting --> Terminated; Study drug was discontinued by manufacturer for business reasons.
- |||||||||| Preclinical, Journal: In situ modeling of acquired resistance to RTK/RAS-pathway-targeted therapies. (Pubmed Central) - Jan 16, 2024
We additionally modeled resistance to targeted therapies including the KRAS inhibitors adagrasib and sotorasib, the MEK inhibitor trametinib, and the farnesyl transferase inhibitor tipifarnib. These studies highlight the tractability of in situ resistance assays to model acquired resistance to targeted therapies and provide a framework for assessing the extent to which synergistic drug combinations can target acquired drug resistance.
- |||||||||| Vectibix (panitumumab) / Amgen, Takeda, Lumakras (sotorasib) / Amgen
Journal: Combating KRASG12C Inhibitor Resistance. (Pubmed Central) - Jan 15, 2024
Findings from the phase III CodeBreaK 300 trial indicate that adding the EGFR inhibitor panitumumab to sotorasib bests standard care for chemorefractory KRASG12C colorectal cancer. Joint SHP2 blockade is another approach that shows signs of activity in reversing acquired KRASG12C inhibitor resistance, according to preliminary phase I data.
- |||||||||| Lumakras (sotorasib) / Amgen
Journal: Sotorasib in KRAS mutated lung cancer - Authors' reply. (Pubmed Central) - Jan 14, 2024
Joint SHP2 blockade is another approach that shows signs of activity in reversing acquired KRASG12C inhibitor resistance, according to preliminary phase I data. No abstract available
- |||||||||| Lumakras (sotorasib) / Amgen
Journal, Real-world evidence, Real-world, Metastases: Sotorasib in KRASp.G12C mutated advanced NSCLC: Real-world data from the Italian expanded access program. (Pubmed Central) - Jan 8, 2024
No abstract available Real-world data from the Italian EAP confirm the tolerability and effectiveness of sotorasib in patients with KRASp.G12C-mutated advanced NSCLC and highlight the value of the national ATLAS network as source of real-world evidence driving the clinical management of NSCLC patients.
- |||||||||| Lumakras (sotorasib) / Amgen
Journal: Brief report on the efficacy of sotorasib in KRAS-Mutated NSCLC patients with brain metastases. (Pubmed Central) - Jan 8, 2024
Real-world data from the Italian EAP confirm the tolerability and effectiveness of sotorasib in patients with KRASp.G12C-mutated advanced NSCLC and highlight the value of the national ATLAS network as source of real-world evidence driving the clinical management of NSCLC patients. While sotorasib may have some intracranial activity, a multidisciplinary approach to BM therapy is still warranted, as are future studies with larger patient samples, controls, and extended follow-up.
- |||||||||| Krazati (adagrasib) / BMS, Lumakras (sotorasib) / Amgen
Retrospective data, Review, Journal: 1Outcomes Following KRAS Inhibitor Treatment in Patients with KRAS-Mutated Solid Tumors: A Systematic Review and Meta-analysis. (Pubmed Central) - Jan 7, 2024
This study provided a comprehensive understanding of the efficacy and safety of KRASG12C inhibitors in treating solid tumors and identified KEAP1 mutation as a potential predictive biomarker of inferior response in patients treated with KRASG12C inhibitors. These findings may assist in the design of future clinical trials for identifying populations that may benefit from KRASG12C inhibitor treatment.
- |||||||||| Lumakras (sotorasib) / Amgen
Journal: Mass spectrometry analysis of intact protein N-glycosylation signatures of cells and sera in pancreatic adenocarcinomas. (Pubmed Central) - Jan 6, 2024
These results indicated the potential role for tumor-specific glycosylation as disease biomarkers. We also found that AMG-510, a small molecule inhibitor against Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C mutation, profoundly reduced the glycosylation level in MIA PaCa-2 cells, suggesting that KRAS plays a role in the cellular glycosylation process, and thus glycosylation inhibition contributes to the anti-tumor effect of AMG-510.
- |||||||||| MODULE 5: HER2 and Other Emerging Biomarkers for Targeted Therapy in mCRC (Golden Gate Ballroom ) - Jan 2, 2024 - Abstract #ASCOGI2024ASCO_GI_914;
This activity is supported by educational grants from Natera Inc and Pfizer Inc. Frequency and clinical relevance of HER2 aberrations among patients with mCRC Published data from the pivotal Phase II MOUNTAINEER trial evaluating tucatinib/trastuzumab for previously treated HER2-positive mCRC; recent FDA approval and optimal incorporation into practice Available efficacy and safety findings with trastuzumab deruxtecan (T-DXd) for patients with HER2-expressing mCRC (eg, from the DESTINY-CRC01 and DESTINY-CRC02 trials); current and potential nonresearch role Incidence of KRAS G12C mutations in patients with mCRC; early data with sotorasib and adagrasib monotherapy Biological rationale for combining KRAS G12C inhibitors with EGFR antibodies Recently presented results from the Phase III CodeBreaK 300 study evaluating sotorasib with panitumumab versus standard therapy for chemorefractory mCRC with KRAS G12C mutations; implications for clinical practice Early data with and ongoing evaluations of other targeted strategies for mCRC
- |||||||||| Lumakras (sotorasib) / Amgen
Journal: Modifying Trial Design May Be Key to Full Sotorasib Approval. (Pubmed Central) - Dec 17, 2023
It represents a valuable resource informing progress towards contextualised precision medicine. Due to design flaws and disappointing progression-free survival data in CodeBreaK 200, a confirmatory phase III trial for the KRASG12C inhibitor sotorasib, the drug's full approval as a second-line option for metastatic KRASG12C non-small cell lung cancer may be delayed and will likely hinge on further studies.
- |||||||||| Krazati (adagrasib) / Mirati, Lumakras (sotorasib) / Amgen
Preclinical, Review, Journal, IO biomarker, Metastases: Targeted Therapies for Kirsten Rat Sarcoma (KRAS) G12C Mutant Metastatic Non-Small-Cell Lung Cancers. (Pubmed Central) - Dec 9, 2023
Though classically difficult to target, recently developed KRAS G12C inhibitors (sotorasib and adagrasib) have now overcome this therapeutic hurdle...Though these medications demonstrate substantial response rates in a heavily pre-treated advanced NSCLC cohort, as phase-3 evidence does not yet demonstrate an overall survival benefit versus standard-of-care chemotherapy, docetaxel...Despite this, it is undeniable that these medications represent an important advancement in targeted and personalised oncological treatment. Current and future trials assessing these medications in combination and through sequencing strategies will likely yield further clinically meaningful outcomes to guide treatment in this patient cohort.
- |||||||||| Vectibix (panitumumab) / Amgen, Takeda, Lumakras (sotorasib) / Amgen
A phase 1b study of sotorasib combined with panitumumab as second-line treatment of KRAS G12C-mutated colorectal cancer. (Level 1, West Hall; Poster Bd # H13) - Dec 6, 2023 - Abstract #ASCOGI2024ASCO_GI_774;
P1/2
The toxicities of sotorasib plus panitumumab were consistent with the expected safety profile of the individual agents and with that reported previously for this combination; the ORR was similar to that previously observed for this combination in a more chemorefractory population. The ORR and PFS of sotorasib plus panitumumab compare favorably to current standard approaches in the 2L treatment of metastatic colorectal cancer.
- |||||||||| Lumakras (sotorasib) / Amgen
P1 data, Journal: First-in-Humans PET Imaging of KRAS Mutation Status in Non-Small Cell Lung and Colorectal Cancer Patients Using [F]PFPMD. (Pubmed Central) - Dec 4, 2023
The ORR and PFS of sotorasib plus panitumumab compare favorably to current standard approaches in the 2L treatment of metastatic colorectal cancer. [F]PFPMD was synthesized on the basis of AMG510 (sotorasib) by attaching a polyethylene glycol chain to the quinazolinone structure...The accumulation of [F]PFPMD in KRAS mutation tumors was significantly higher than that in non-KRAS mutation tumors (SUV: 3.73?
- |||||||||| Lumakras (sotorasib) / Amgen
Trial primary completion date, Monotherapy: CodeBreak101: Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101) (clinicaltrials.gov) - Nov 30, 2023
P1/2, N=1143, Recruiting,
In conclusion, this is the first study to demonstrate that KRASG12C inhibitors can synergize with the PAK4 inhibitor KPT9274 and combining KRASG12C inhibitors with KPT9274 can lead to remarkably enhanced antitumor activity and survival benefits, providing a novel combination therapy for cancer patients who do not respond or develop resistance to KRASG12C inhibitor treatment. Trial primary completion date: Jun 2026 --> Sep 2026
- |||||||||| Krazati (adagrasib) / Mirati, Lumakras (sotorasib) / Amgen
Journal: A Nexus between Genetic and Non-Genetic Mechanisms Guides KRAS Inhibitor Resistance in Lung Cancer. (Pubmed Central) - Nov 29, 2023
Thus, in response to drug treatment, reversible drug-tolerant phenotypes emerge via non-genetic mechanisms that eventually enable the emergence of irreversible resistant clones via genetic mutations. Furthermore, we also discuss the recent data demonstrating how combination therapy can help alleviate KRAS drug resistance in lung cancer, and how new treatment strategies based on evolutionary principles may help minimize or even preclude the emergence of drug resistance.
- |||||||||| Review, Journal: Management of Brain Metastases: A Review of Novel Therapies. (Pubmed Central) - Nov 28, 2023
Novel systemic therapies with intracranial utility include new anaplastic lymphoma kinase inhibitors like brigatinib and ensartinib; selective "rearranged during transfection" inhibitors like selpercatinib and pralsetinib; B-raf proto-oncogene inhibitors like encorafenib and vemurafenib; Kirsten rat sarcoma viral oncogene inhibitors like sotorasib and adagrasib; ROS1 gene rearrangement (ROS1) inhibitors, anti-neurotrophic tyrosine receptor kinase agents like larotrectinib and entrectinib; anti-human epidermal growth factor receptor 2/epidermal growth factor receptor exon 20 agent like poziotinib; and antibody-drug conjugates like trastuzumab-emtansine and trastuzumab-deruxtecan. This review highlights the modern multidisciplinary management of BM, emphasizing the integration of systemic and local therapies.
- |||||||||| Lumakras (sotorasib) / Amgen
Trial completion date, Trial initiation date, Trial primary completion date: A Clinical Trial to Evaluate Bioavailability and Effect of Food for Sotorasib in Healthy Participants (clinicaltrials.gov) - Nov 18, 2023
P1, N=140, Not yet recruiting,
Taken together, our study highlights the potential of FBXL16 as a therapeutic target for treating LUAD with KRAS activating mutations. Trial completion date: Jan 2024 --> Jun 2024 | Initiation date: Nov 2023 --> Apr 2024 | Trial primary completion date: Jan 2024 --> Jun 2024
- |||||||||| NB004 / Ningbo Tai Kang
Enrollment change, Trial completion date, Trial primary completion date, Combination therapy, Monotherapy, Metastases: A Study of NB004 as Monotherapy or Combination Therapy in Patients With Advanced Solid Tumors (clinicaltrials.gov) - Nov 18, 2023
P1, N=120, Recruiting,
Trial completion date: Jan 2024 --> Jun 2024 | Initiation date: Nov 2023 --> Apr 2024 | Trial primary completion date: Jan 2024 --> Jun 2024 N=36 --> 120 | Trial completion date: Sep 2023 --> Jun 2025 | Trial primary completion date: May 2023 --> Feb 2025
- |||||||||| Lumakras (sotorasib) / Amgen
Journal: KRAS-Degrading Compounds: A Novel Approach to Treat Cancer by Targeting Both Wild-Type and Mutated KRAS Forms. (Pubmed Central) - Nov 17, 2023
Notably, covalent inhibitors such as sotorasib show success in binding to specific KRAS mutations...This Patent Highlight reveals exemplary KRAS-degrading compounds with anti-tumor activity, effective against both wild-type and mutated KRAS. They present desirable pharmacological properties, promising a revolution in cancer treatment upon further clinical investigation.
- |||||||||| Krazati (adagrasib) / Mirati, Lumakras (sotorasib) / Amgen, garsorasib (D-1553) / InventisBio
Retrospective data, Review, Journal: Efficacy and toxicity of drugs targeting KRAS mutation in non-small cell lung cancer: a meta-analysis. (Pubmed Central) - Nov 11, 2023
The most common grade???3 AEs were Alaninetransaminase (ALT) or Aspartatetransaminase (AST) increased and diarrhea. Sotorasib, Adagrasib, and Garsorasib as the drugs of choice for patients with KRAS mutation NSCLC, have definite efficacy and acceptable safety, especially for patients with advanced or metastatic disease and within posterior line therapy.
- |||||||||| Krazati (adagrasib) / Mirati, Lumakras (sotorasib) / Amgen
Journal: A New Dawn for Targeted Cancer Therapy: Small Molecule Covalent Binding Inhibitor Targeting K-Ras (G12C). (Pubmed Central) - Nov 8, 2023
In recent years, with the popularization of highly sensitive surface plasmon resonance (SPR) technology, fragment-based drug design strategies have shown great potential in the development of small molecule inhibitors targeting K-Ras(G12C), but with the increasing number of clinically reported acquired drug resistance, addressing inhibitor resistance has gradually become the focus of this field, indirectly indicating that such small molecule inhibitors still the potential for the development of these small molecule inhibitors are also indirectly indicated. This paper traces the development of small molecule covalent inhibitors targeting K-Ras(G12C), highlighting and analyzing the structural evolution and optimization process of each series of inhibitors and the previous inhibitor design methods and strategies, as well as their common problems and general solutions, in order to provide inspiration and help to the subsequent researchers.
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