- |||||||||| adagrasib (MRTX849) / Mirati, Lumakras (sotorasib) / Amgen
Review, Journal: Targeting Mutated KRAS Genes to Treat Solid Tumours. (Pubmed Central) - Apr 23, 2022
Mutant-specific KRAS G12C inhibitors are the most advanced, with two inhibitors, adagrasib and sotorasib, achieving approval in 2021 for the second-line treatment of patients with KRAS G12C mutant lung cancer. In this review, we summarise the importance of mutant KRAS in solid tumours, prior attempts at inhibiting mutant KRAS, and the current promising targeted agents being investigated in clinical trials, along with future challenges.
- |||||||||| Lumakras (sotorasib) / Amgen
PK/PD data, Preclinical, Journal, IO biomarker: Integrative Analysis of Pharmacokinetic and Metabolomic Profiles for Predicting Metabolic Phenotype and Drug Exposure Caused by Sotorasib in Rats. (Pubmed Central) - Apr 23, 2022
With multivariate statistical analysis, the selected six (AUC model) and nine (C model) metabolites completely distinguished the high- and low-exposure groups after sotorasib treatment, which indicates that these potential biomarkers can predict drug exposure or toxicity. The results of this study will not only shed light on how sotorasib disturbs the metabolic profiles and the relationship between PK and PM but also offer meaningful references for precision therapy in patients with the KRAS (G12C) mutation.
- |||||||||| Lumakras (sotorasib) / Amgen
FDA event, Review, Journal: FDA Approval Summary: Sotorasib for KRAS G12C Mutated Metastatic NSCLC. (Pubmed Central) - Apr 19, 2022
This is the first approval of a targeted therapy for KRAS G12C-mutated NSCLC. Due to pharmacokinetic data and ORRs of patient cohorts who took sotorasib at lower doses in the dose escalation portion of CodeBreaK 100, a dose comparison study is being conducted as a post-marketing requirement (PMR).
- |||||||||| Lumakras (sotorasib) / Amgen
Journal: Sotorasib's Benefits in Colorectal Cancer Modest. (Pubmed Central) - Apr 19, 2022
The KRAS inhibitor sotorasib provides some clinical benefit in patients with advanced or metastatic KRASG12C-mutant colorectal cancer, according to results of a phase II clinical trial. The objective response rate was 9.7%, the disease control rate was 82.3%, and the progression-free survival was 4 months.
- |||||||||| Lumakras (sotorasib) / Amgen
Journal: Sotorasib: a treatment for non-small cell lung cancer with the KRAS G12C mutation. (Pubmed Central) - Apr 19, 2022
Currently, clinical data suggests that sotorasib monotherapy has significant efficacy in NSCLC patients with the KRAS G12C mutation and tolerable toxicity, and it could represent a novel targeted therapy. Additional research will be required to delineate the mechanisms of resistance to sotorasib and determine the efficacy and safety of combination therapy for the treatment of NSCLC containing the KRAS G12C mutation.
- |||||||||| DT2216 / Dialectic Therap, Lumakras (sotorasib) / Amgen
Preclinical, Journal: BCL-X PROTAC degrader DT2216 synergizes with sotorasib in preclinical models of KRAS-mutated cancers. (Pubmed Central) - Apr 13, 2022
Furthermore, DT2216 co-treatment significantly improved the antitumor efficacy of sotorasib in vivo. Collectively, our findings suggest that due to cytostatic activity, the efficacy of sotorasib is limited, and therefore, its combination with a pro-apoptotic agent, i.e., DT2216, shows synergistic responses and can potentially overcome resistance.
- |||||||||| zotatifin (eFT226) / eFFECTOR Therap
Enrollment change, Trial primary completion date: Study of eFT226 in Subjects With Selected Advanced Solid Tumor Malignancies (clinicaltrials.gov) - Apr 8, 2022
P1/2, N=198, Recruiting,
Collectively, our findings suggest that due to cytostatic activity, the efficacy of sotorasib is limited, and therefore, its combination with a pro-apoptotic agent, i.e., DT2216, shows synergistic responses and can potentially overcome resistance. N=45 --> 198 | Trial primary completion date: Dec 2022 --> Jul 2023
- |||||||||| Lumakras (sotorasib) / Amgen
Journal: Novel approaches for the development of direct KRAS inhibitors: structural insights and drug design. (Pubmed Central) - Apr 6, 2022
Despite the efforts of more than four decades, not many KRAS inhibitors have been successful in obtaining clinical approval, except the very recent FDA approval for sotorasib...In view of this aspect, specific attention is required to target all other mutations as well. Accordingly, for the development of KRAS targeted therapies, the design of small molecule inhibitors that can inhibit KRAS signaling and as well as target inhibition of other signaling pathways like RAS-SOS and RAS-PI3K has to be explored extensively.
- |||||||||| Lumakras (sotorasib) / Amgen
Journal: Sotorasib Tackles KRASG12C-Mutated Pancreatic Cancer. (Pubmed Central) - Apr 5, 2022
The KRASG12C inhibitor sotorasib was associated with a 21.1% objective response rate and an 84.2% disease control rate among patients who had already received at least one therapy for pancreatic ductal adenocarcinoma. These data come from the phase I/II CodeBreaK100 trial.
- |||||||||| Lumakras (sotorasib) / Amgen
Review, Journal: The Influence of Oncogenic RAS on Chemotherapy and Radiotherapy Resistance Through DNA Repair Pathways. (Pubmed Central) - Apr 2, 2022
In fact, the first mutant RAS inhibitor, Sotorasib, was only approved by the FDA until 2021...Here, we discuss key aspects of RAS biology and detail some of the mechanisms that mediate chemo- and radiotherapy resistance of mutant RAS cancers through the DNA repair pathways. We also discuss recent progress in therapeutic RAS targeting and propose future directions for the field.
- |||||||||| Lumakras (sotorasib) / Amgen
Journal: Pan-RAS inhibitors: Hitting multiple RAS isozymes with one stone. (Pubmed Central) - Mar 31, 2022
Despite the well-established role of RAS in tumorigenesis, past efforts to develop small molecule inhibitors have failed for various reasons leading many to consider RAS as "undruggable." Advances over the past decade with KRAS(G12C) mutation-specific inhibitors have culminated in the first FDA-approved RAS drug, sotorasib...One such approach is pan-RAS inhibition, whereby all RAS isozymes co-expressed in the tumor cell population are targeted by a single inhibitor to block constitutively activated RAS regardless of the underlying mutation. This chapter provides a review of past and ongoing strategies to develop pan-RAS inhibitors in detail and seeks to outline the trajectory of this promising strategy of RAS inhibition.
- |||||||||| adagrasib (MRTX849) / Mirati, Lumakras (sotorasib) / Amgen
Review, Journal: KRAS mutation: from undruggable to druggable in cancer. (Pubmed Central) - Mar 23, 2022
This review summarises the most recent understanding of fundamental aspects of KRAS, the relationship between the KRAS mutations and tumour immune evasion, and new progress in targeting KRAS, particularly KRAS (G12C). Moreover, the possible mechanisms of resistance to KRAS (G12C) inhibitors and possible combination therapies are summarised, with a view to providing the best regimen for individualised treatment with KRAS (G12C) inhibitors and achieving truly precise treatment.
- |||||||||| adagrasib (MRTX849) / Mirati, Lumakras (sotorasib) / Amgen
Review, Journal: The path to the clinic: a comprehensive review on direct KRAS inhibitors. (Pubmed Central) - Mar 23, 2022
Adagrasib (MRTX849) and other direct KRAS inhibitors are currently being investigated in multiple clinical trials...We then examine the clinical relevance of KRAS, especially the KRAS mutation in human cancer, by providing an in-depth analysis of its cancer epidemiology. Finally, we review the preclinical evidence that supported the initial development of the direct KRAS inhibitors and summarize the ongoing clinical trials of all direct KRAS inhibitors.
- |||||||||| adagrasib (MRTX849) / Mirati, Lumakras (sotorasib) / Amgen
MRTX0902: A SOS1 inhibitor for therapeutic intervention of KRAS-driven cancers (La Nouvelle Orleans A-B, Convention Center) - Mar 23, 2022 - Abstract #AACR2022AACR_7974;
In summary, we have used a structure-based approach to discover a SOS1 inhibitor that augments the anti-tumor activity of MRTX849 and additional targeted MAPK pathway inhibitors. We anticipate our findings to translate into the clinic and make an impact in patients with RAS-addicted tumors.
- |||||||||| Lumakras (sotorasib) / Amgen
Review, Journal: Resistance looms for KRAS G12C inhibitors and rational tackling strategies. (Pubmed Central) - Mar 19, 2022
Recent efforts have witnessed a revolutionary strategy for KRAS G12C inhibitors with exhibiting conspicuous clinical responses across multiple tumor types, providing new impetus for renewed drug development and culminating in sotorasib with approximately 6-month median progression-free survival in KRAS G12C-driven lung cancer...We then comprehensively interrogate and underscore our current understanding of resistance mechanisms and the necessity of incorporating genomic analyses into the clinical investigation to further decipher resistance mechanisms. Finally, we highlight the future role of novel treatment strategies especially rational identification of targeted combinatorial approaches in tackling drug resistance, and propose our views on including the application of robust biomarkers to precisely guide combination medication regimens.
- |||||||||| Lumakras (sotorasib) / Amgen
Journal: Understanding the influence of AMG 510 on the structure of KRAS empowered by molecular dynamics simulation. (Pubmed Central) - Mar 15, 2022
By further combining MD simulations and the PCA model, we not only recapitulated the currently known resistance mutations of AMG 510 successfully but also proposed some novel potential resistant mutations. Taken together, these results broaden our insight into the influence of AMG 510 on the conformational change of the KRAS mutant at the atomic level, thereby providing crucial hints for the improvement and optimization of drug candidates.
- |||||||||| Herceptin (trastuzumab) / Roche
Journal, Companion diagnostic: Oncology drug-companion diagnostic combinations. (Pubmed Central) - Mar 11, 2022
With the development of trastuzumab for metastatic breast cancer a new era began in cancer drug development...For these drugs, the CDx assays play an important role in defining the patient population likely to respond and without the assay they will often lose their value. This short article is based on an analysis of the FDA List of Cleared or Approved Companion Diagnostic Devices and relevant information in the Drugs@FDA, and will focus on the drug-CDx combinations, drug classes, clinical development, and the regulatory path and status.
- |||||||||| Lumakras (sotorasib) / Amgen
Review, Journal, IO biomarker: Direct Targeting KRAS Mutation in Non-Small Cell Lung Cancer: Focus on Resistance. (Pubmed Central) - Mar 11, 2022
Little is known about primary or acquired resistance. Acquired resistance does occur and may be due to genetic alterations in the nucleotide exchange function or adaptative mechanisms in either downstream pathways or in newly expressed KRAS G12C mutation.
- |||||||||| Developing drug-induced resistant tumor models for efficacy evaluation of next-generation anticancer therapies (E-Poster Website) - Mar 9, 2022 - Abstract #AACR2022AACR_7557;
Uncovering the underlying mechanism would help develop novel therapies that overcome the drug resistance.To mimic the clinical resistance after long-term drug treatment, we established a panel of drug-induced resistant tumor models by continuous dosing of targeted drugs to tumor-bearing mice or cancer cell lines, covering a series of first-line targeted drugs including Sotorasib, Palbociclib, Ibrutinib, Capmatinib, Fulvestrant, Tamoxifen and TDM-1...Given that target gene mutation, alternative pathway activation or tumor microenvironment evolution could promote therapy resistance and cancer progression, we performed transcript and protein analysis to explore the molecular mechanism, and evaluated the potential therapeutic strategies overcoming drug resistance in the established models. Taken together, drug-induced resistant tumor models provide a promising opportunity to the better understanding of drug resistance mechanisms and to the accelerated development of next-generation anticancer agents.
- |||||||||| adagrasib (MRTX849) / Mirati, Lumakras (sotorasib) / Amgen
Preclinical characterization of EB160, a novel, highly potent and brain-penetrant KRASG12C inhibitor (E-Poster Website) - Mar 9, 2022 - Abstract #AACR2022AACR_6898;
And in the 30 mg/kg treatment group, whole 6 mice showed near complete tumor regression. In the H1373Luc KRASG12C brain metastases model, 30 mg/kg QD EB160 oral dose in mice for 28 days results in tumor regression 92%, while in the same dosage of MRTX849 treatment group, the tumor regression was 50%.
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