- |||||||||| adagrasib (MRTX849) / Mirati, Lumakras (sotorasib) / Amgen
Journal: KRAS G12C fragment screening renders new binding pockets. (Pubmed Central) - Feb 12, 2022
MRTX849 and recently approved Sotorasib are covalent binders targeting the mutated cysteine 12, occupying Switch II pocket.Herein, we describe two fragment screening drug discovery campaigns that led to the identification of binding pockets on the KRAS G12C surface that have not previously been described. One screen focused on non-covalent binders to KRAS G12C, the other on covalent binders.
- |||||||||| Lumakras (sotorasib) / Amgen
Use of sotorasib in KRAS p.G12C mutated NSCLC: a case report ([VIRTUAL]) - Feb 9, 2022 - Abstract #BTOG2022BTOG_303;
Sotorasib has now been approved for use in the UK and can be accessed via the Early Access scheme. In this case report, we discuss the details of the clinical course of a 56-year-old female, has been started on Sotorasib as third line therapy for Recurrent Metastatic Non-Small Cell Lung cancer, with KRAS G12C mutation, after having progressed on triplet therapy (Pembrolizumab/Pemetrexed/Carboplatin) and second line docetaxel chemotherapy and describe our real-life experience with the use of Sotorasib.
- |||||||||| Remicade (infliximab) / Merck (MSD), Mitsubishi Tanabe, J&J, Lumakras (sotorasib) / Amgen
A case of multiple recurrent immune-related adverse events (irAEs) with sequential sotorasib after chemoimmunotherapy for KRAS G12C-mutant non-small cell lung cancer (NSCLC) ([VIRTUAL]) - Feb 9, 2022 - Abstract #BTOG2022BTOG_295;
Synergistic irAEs have been reported with sequential osimertinib post-immunotherapy [2], and one case of ir-hepatitis with sotorasib [3]...Case presentation: A 68-year-old man with T4N2M1a KRAS G12Cmutant NSCLC received second-line sotorasib 960mg once daily, after disease progression on carboplatin-pemetrexed-pembrolizumab...Sotorasib was inter rupted and infliximab commenced with slow symptomatic improve ment. This case highlights the possibility of synergistic irAEs with sequential chemoimmunotherapy and sotorasib and is pertinent for clinical practice as sotorasib becomes the new standard second-line treatment in KRAS G12C-mutant NSCLC.
- |||||||||| Lumakras (sotorasib) / Amgen
Clinical, Journal: Virtual Clinical Trial Simulations for a Novel KRAS Inhibitor (ASP2453) in Non-Small Cell Lung Cancer. (Pubmed Central) - Feb 1, 2022
Publicly disclosed clinical data for AMG 510 were used to generate a virtual population, and tumor size changes in response to ASP2453 and AMG 510 were simulated. The QSP model predicted ASP2453 exhibits greater clinical response than AMG 510, supporting potential differentiation and critical thinking for clinical trials.
- |||||||||| Lumakras (sotorasib) / Amgen
SY20. KRAS Anniversary Session: Novel Mechanisms for Targeting KRAS (Hall B-C, Convention Center) - Jan 28, 2022 - Abstract #AACR2022AACR_795;
It will cover mechanisms of resistance to KRAS inhibitors and the comparative merits of KRAS inhibition using sotorasib, as an example, versus KRAS degradation using a genetic model of KRAS ablation...Ongoing investigations focusing on drugging other oncogenic mutants of KRAS, including both reversible ligands for the most frequent KRAS G12D allele as well as covalent drugs targeting less common variants, will also be discussed. Finally, the session will conclude with clinical development strategies that have been investigated for targeting KRAS and the challenges that remain.
- |||||||||| adagrasib (MRTX849) / Mirati, Lumakras (sotorasib) / Amgen
Review, Journal, IO biomarker: Targeting KRAS in Non-Small Cell Lung Cancer. (Pubmed Central) - Jan 28, 2022
Another area of interest is the potential role of co-mutations in treatment selection, particularly immunotherapy. The best first-line strategy remains to be determined and, due to the heterogeneity of KRAS, is likely to be based on combination therapies.
- |||||||||| C–H radioiodination of small molecule drugs (Room 2 (San Diego Convention Center)) - Jan 28, 2022 - Abstract #ACSSp2022ACS_Sp_10870;
Radiochemical conversions of all small molecule drugs ranged from 70-90%, with the exception of sotorasib, which gave a lower yield of 40% and a mixture of ortho- para- substituents on the phenol moiety. In summary, we identified a new method for C–H radioiodination of small molecule drugs under mild conditions that enables access to new radiopharmaceuticals.
- |||||||||| Lumakras (sotorasib) / Amgen
Clinical, Journal: Nonclinical Safety Profile of Sotorasib, a KRAS-Specific Covalent Inhibitor for the Treatment of KRAS p.G12C-Mutated Cancer. (Pubmed Central) - Jan 27, 2022
Human, dog, and rat circulating metabolites, M24, M10, and M18, raised no clinically relevant safety concerns based on the general toxicology studies, primary/secondary pharmacology screening, an in vitro human ether-à-go-go-related gene assay, or mutagenicity assessment. Overall, the results of the nonclinical safety program support a high benefit/risk ratio of sotorasib for the treatment of patients with KRAS p.G12C-mutated tumors.
- |||||||||| Lumakras (sotorasib) / Amgen
Review, Journal: Targeting mutated GTPase KRAS in tumor therapies. (Pubmed Central) - Jan 27, 2022
To better understand the current state of KRAS inhibitors, this review summarizes the biological functions of KRAS, the structure-activity relationship studies of the small-molecule inhibitors that directly target KRAS, and highlights the therapeutic agents with improved selectivity, bioavailability and physicochemical properties. Furthermore, the combined medication that can enhance efficacy and overcome drug resistance of KRAS covalent inhibitors is also reviewed.
- |||||||||| zotatifin (eFT226) / eFFECTOR Therap
Trial completion date, Trial primary completion date: Study of eFT226 in Subjects With Selected Advanced Solid Tumor Malignancies (clinicaltrials.gov) - Jan 27, 2022
P1/2, N=45, Recruiting,
Furthermore, the combined medication that can enhance efficacy and overcome drug resistance of KRAS covalent inhibitors is also reviewed. Trial completion date: Dec 2021 --> Jul 2023 | Trial primary completion date: Oct 2021 --> Dec 2022
- |||||||||| adagrasib (MRTX849) / Mirati, Lumakras (sotorasib) / Amgen
Review, Journal: A Breakthrough Brought about by Targeting KRAS: Nonconformity Is Punished. (Pubmed Central) - Jan 26, 2022
A promising strategy to optimize G12C inhibitor therapy is combination treatments with other therapeutic agents, the identification of which is empowered by the insightful appreciation of compensatory signaling pathways or evasive mechanisms, such as those that attenuate immune responses. Here, we review recent advances in targeting KRAS and discuss the challenges of KRAS inhibitor therapy, as well as future directions.
- |||||||||| Lumakras (sotorasib) / Amgen
Review, Journal: Targeting KRAS G12C mutation in lung adenocarcinoma. (Pubmed Central) - Jan 26, 2022
We will discuss the efficacy and toxicities of the novel KRAS G12C inhibitors as well as other indirect strategies for targeting oncogenic KRAS mutations. We will review the limited literature on acquired resistance to these inhibitors and the novel combinatorial treatment strategies that are being tested currently in clinical trials.
- |||||||||| Journal, PD(L)-1 Biomarker, IO biomarker: Advances in Lung Cancer Treatment (Pubmed Central) - Jan 21, 2022
Sotorasib with efficacy in kRAS-G12C mutation of NSCLC. The nationwide network nNGM provides NSCLC patients with access to state-of-the-art molecular diagnostics and the latest treatment options.
- |||||||||| Lumakras (sotorasib) / Amgen
Trial completion date, Trial primary completion date, Combination therapy, Monotherapy, Metastases: A Phase 1/2, Study Evaluating the Safety, Tolerability, PK, and Efficacy of Sotorasib (AMG 510) in Subjects With Solid Tumors With a Specific KRAS Mutation (CodeBreaK 100) (clinicaltrials.gov) - Jan 20, 2022
P1/2, N=733, Recruiting,
The nationwide network nNGM provides NSCLC patients with access to state-of-the-art molecular diagnostics and the latest treatment options. Trial completion date: Nov 2024 --> Dec 2025 | Trial primary completion date: Nov 2024 --> Dec 2025
- |||||||||| Lumakras (sotorasib) / Amgen
Trial completion date, Trial primary completion date, Metastases: AMG 510 Ethnic Sensitivity Study (CodeBreaK 105). (clinicaltrials.gov) - Jan 20, 2022
P1, N=12, Active, not recruiting,
Trial completion date: Nov 2024 --> Dec 2025 | Trial primary completion date: Nov 2024 --> Dec 2025 Trial completion date: Nov 2022 --> Jul 2022 | Trial primary completion date: Apr 2022 --> Dec 2021
- |||||||||| JAB-3312 / Jacobio Pharma
Enrollment change, Trial completion date, Trial primary completion date, Metastases: JAB-3312 Based Combination Therapy in Adult Patients With Advanced Solid Tumors (clinicaltrials.gov) - Jan 19, 2022
P1/2, N=200, Recruiting,
Trial completion date: Nov 2022 --> Jul 2022 | Trial primary completion date: Apr 2022 --> Dec 2021 N=136 --> 200 | Trial completion date: Dec 2022 --> Jun 2023 | Trial primary completion date: Sep 2022 --> Mar 2023
- |||||||||| Lumakras (sotorasib) / Amgen
Review, Journal: Sotorasib: First Approval. (Pubmed Central) - Jan 15, 2022
In May 2021, sotorasib was granted accelerated approval by the US FDA for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic NSCLC, as determined by an FDA-approved test, who have received at least one prior systemic therapy. This article summarizes the milestones in the development of sotorasib leading to this first approval for KRAS G12C-mutated NSCLC.
- |||||||||| adagrasib (MRTX849) / Mirati, Lumakras (sotorasib) / Amgen
Review, Journal: Resistance to KRAS Inhibitors in Non-Small Cell Lung Cancer. (Pubmed Central) - Jan 11, 2022
Acquired resistance to KRAS inhibitors include novel KRAS mutations such as Y96D/C and other RAS-MAPK effector protein mutations. This review focuses on the intrinsic and acquired mechanisms of resistance to KRAS inhibitors in KRAS mutant non-small cell lung cancer and the potential clinical strategies to overcome or prevent it.
- |||||||||| Lumakras (sotorasib) / Amgen, Mvasi (bevacizumab-awwb) / Daiichi Sankyo, Amgen, AbbVie
New P1/2 trial, Combination therapy, Metastases: A Phase I/II Study of AMG 510 in Combination With MVASI in Patients With Advanced, Unresectable or Metastatic KRAS G12C Mutant NSCLC With Asymptomatic Brain Metastasis (clinicaltrials.gov) - Jan 6, 2022
P1/2, N=43, Not yet recruiting,
- |||||||||| adagrasib (MRTX849) / Mirati, Lumakras (sotorasib) / Amgen
Review, Journal: Targeting KRAS in Colorectal Cancer. (Pubmed Central) - Jan 5, 2022
For the first time, the preclinical success of targeting KRAS has translated into clinical benefits, which holds the potential of transforming clinical management of KRAS mutated solid tumors. Additional efforts are needed to identify biomarkers that predict response to KRAS inhibition in patients with KRAS as well as to develop strategies to overcome resistance.
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