- |||||||||| imatinib / Generic mfg.
Journal: Lentiviral-driven discovery of cancer drug resistance mutations. (Pubmed Central) - Jan 4, 2022
In KRAS-G12C or wild-type KRAS, point mutations in the AMG 510 binding pocket or oncogenic non-G12C mutations conferred resistance to AMG 510. LentiMutate should prove highly valuable for clinical and preclinical cancer drug development.
- |||||||||| Lumakras (sotorasib) / Amgen
Journal: The promise and peril of KRAS G12C inhibitors. (Pubmed Central) - Dec 28, 2021
RAS mutant tumors have been largely refractory to therapies until now. Recent findings published in the New England Journal of Medicine show that sotorasib provides clinical benefit for KRAS p.G12C-mutated non-small-cell lung cancer (NSCLC) and provide mechanistic insights into acquired resistance to KRAS-specific inhibition.
- |||||||||| Lumakras (sotorasib) / Amgen
Journal: Dose Optimization of Sotorasib: Is the US Food and Drug Administration Sending a Message? (Pubmed Central) - Dec 23, 2021
Recent findings published in the New England Journal of Medicine show that sotorasib provides clinical benefit for KRAS p.G12C-mutated non-small-cell lung cancer (NSCLC) and provide mechanistic insights into acquired resistance to KRAS-specific inhibition. No abstract available
- |||||||||| JNJ-74699157 / J&J, adagrasib (MRTX849) / Mirati, Lumakras (sotorasib) / Amgen
Review, Journal, PD(L)-1 Biomarker, IO biomarker: KRAS G12C-mutant non-small-cell lung cancer: biology, developmental therapeutics, and molecular testing. (Pubmed Central) - Dec 16, 2021
These agents include sotorasib (AMG 510), adagrasib (MRTX 849), and JNJ-74699157. In addition to testing for known actionable oncogenic driver alterations in EGFR, ALK, ROS1, BRAF, MET exon 14 skipping, RET, and NTRK and for expression of PD-L1, pathologists, medical oncologists, and community practitioners will need to incorporate routine testing for emerging biomarkers such as MET amplification, ERBB2 (HER2), and KRAS mutations, particularly KRAS G12C, considering the promising development of direct inhibitors of KRAS protein.
- |||||||||| Lumakras (sotorasib) / Amgen
Review, Journal: Stopping the beating heart of cancer: KRAS reviewed. (Pubmed Central) - Dec 16, 2021
In particular, the last decade has seen a paradigm shift with the discovery of druggable pockets on KRAS and clinical efficacy with covalent KRAS inhibitors, culminating in the first approval of sotorasib monotherapy as second-line treatment in KRAS-driven non-small-cell lung cancer...The range of molecular modalities being explored, including PROTACs and glues, will also be described. Finally, an outlook toward the next wave of KRAS drugs and the challenges of resistance will be given.
- |||||||||| Lumakras (sotorasib) / Amgen
Review, Journal: KRAS-G12C Covalent Inhibitors: A game changer in the scene of cancer therapies. (Pubmed Central) - Dec 16, 2021
In 2021, the Food and Drug Administration (FDA) approved the use of Sotorasib (Lumakras) for the treatment of adult patients with KRAS-G12C mutated locally advanced or metastatic NSCLC, following at least one prior systemic therapy...In order to overcome these resistances, researchers are now working on combination strategies. Furthermore, studies are currently ongoing to better elucidate the status of KRAS-G12C as a predictive and prognostic tool and to strengthen its role in the field of personalized medicine.
- |||||||||| Lumakras (sotorasib) / Amgen
Trial completion date, Trial primary completion date, Metastases: AMG 510 Ethnic Sensitivity Study (CodeBreaK 105). (clinicaltrials.gov) - Dec 15, 2021
P1, N=12, Active, not recruiting,
Furthermore, studies are currently ongoing to better elucidate the status of KRAS-G12C as a predictive and prognostic tool and to strengthen its role in the field of personalized medicine. Trial completion date: May 2022 --> Nov 2022 | Trial primary completion date: Dec 2021 --> Apr 2022
- |||||||||| adagrasib (MRTX849) / Mirati, Lumakras (sotorasib) / Amgen
KRAS G12C – STK11 Co-Mutated Lung Adenocarcinomas. Are There New Hopes for Targeted Immunotherapy? (Poster Board Number: 141; LACC West Exhibit Hall A) - Dec 13, 2021 - Abstract #USCAP2022USCAP_953;
We realized a complex characterization of a specific subgroup of KRAS G12C - STK11 co-mutated LAUDs that could have an improved response to KRAS G12C inhibitors. This result is of high interest as previously STK11 mutated LUADs were associated with a poor prognosis, reduced PD-L1 positivity, and resistance to anti-PD1 / anti-PD-L1 blockade.
- |||||||||| Erbitux (cetuximab) / Eli Lilly, EMD Serono, VS-6766 / Verastem
A phase 1b/2 study of VS-6766 in combination cetuximab in patients (pts) with advanced KRAS mt colorectal cancer (CRC). (In-Person Only | Level 1, West Hall; Online Only) - Dec 4, 2021 - Abstract #ASCOGI2022ASCO_GI_610;
Regorafenib or TAS-102 is commonly used however, the modest clinical benefit, and toxicity limit their use...Adagrasib (a KRAS G12C inhibitor) was used with/without cetuximab in heavily pretreated CRC pts harboring KRAS G12C mts...Phase 1b CodeBreaK101 study evaluating sotorasib (KRAS G12C inhibitor) and panitumumab (anti-EGFR) combination in KRAS G12C mt CRC showed 15.4% confirmed ORR and 26.9% unconfirmed ORR...Eligible pts include those with metastatic CRC and progression after 5-FU, oxaliplatin, irinotecan and VEGFi therapy...The study is funded by research grants from Verastem Oncology. Cetuximab will be supplied by Eli Lilly.
- |||||||||| adagrasib (MRTX849) / Mirati, Lumakras (sotorasib) / Amgen
Clinical, Clinical data, Review, Journal: Selective KRAS G12C inhibitors in non-small cell lung cancer: chemistry, concurrent pathway alterations, and clinical outcomes. (Pubmed Central) - Dec 1, 2021
Here, we present perspectives on the initial progress in targeting KRAS G12C, examine co-mutations evident in KRAS G12C NSCLC, and comment on potential future combinatorial approaches including SHP2, SOS1, MEK, EGFR, mTOR, CDK, and checkpoint blockade which are currently being evaluated in clinical trials. As of May 28, 2021, sotorasib has achieved US FDA approval for patients with KRAS G12C mutant lung cancer after one line of a prior therapy.
- |||||||||| Lumakras (sotorasib) / Amgen
Journal: EGFR blockade reverts resistance to KRAS G12C inhibition in colorectal cancer. (Pubmed Central) - Dec 1, 2021
To investigate the cause of the limited efficacy of KRAS inhibitors in colorectal cancer, we examined the effects of AMG510 in KRAS colorectal cancer cell lines...Although upstream activation of several RTKs interferes with KRAS G12C blockade, we identify EGFR signaling as the dominant mechanism of CRC resistance to KRAS G12C inhibitors. The combinatorial targeting of EGFR and KRAS G12C is highly effective in CRC cells, patient-derived organoids and xenografts, suggesting a novel therapeutic strategy to treat KRAS G12C CRC patients.
- |||||||||| adagrasib (MRTX849) / Mirati, Lumakras (sotorasib) / Amgen
Review, Journal: KRAS Inhibitors- yes but what next? Direct targeting of KRAS- vaccines, adoptive T cell therapy and beyond. (Pubmed Central) - Nov 24, 2021
While the conditional approval of sotorasib was a major breakthrough for those patients harboring KRAS G12C mutations, G12C only accounts for a fraction of those with KRAS mutations and eventual resistance to G12C inhibitors are unavoidable. This comprehensive review on KRAS inhibitors covers accumulating evidence on not only the G12C inhibitors but also other therapeutic attempts to tackle KRAS including combination therapy as well as direct inhibition with vaccines, adoptive T cell therapy, proteolysis-targeted chimeras (PROTACs) and CRISPR/Cas9.
- |||||||||| Lumakras (sotorasib) / Amgen
Trial primary completion date, Metastases: Study to Compare AMG 510 "Proposed INN Sotorasib" With Docetaxel in Non Small Cell Lung Cancer (NSCLC) (CodeBreak 200). (clinicaltrials.gov) - Nov 18, 2021
P3, N=345, Active, not recruiting,
This comprehensive review on KRAS inhibitors covers accumulating evidence on not only the G12C inhibitors but also other therapeutic attempts to tackle KRAS including combination therapy as well as direct inhibition with vaccines, adoptive T cell therapy, proteolysis-targeted chimeras (PROTACs) and CRISPR/Cas9. Trial primary completion date: Nov 2021 --> Jul 2022
- |||||||||| 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) - Nov 15, 2021
P1/2, N=733, Recruiting,
Organized data in an accessible database that allows searching by gene name or variant facilitates gathering this information. Trial completion date: Jul 2026 --> Nov 2024 | Trial primary completion date: Jul 2026 --> Nov 2024
- |||||||||| Lumakras (sotorasib) / Amgen
Review, Journal: Emerging strategies to target RAS signaling in human cancer therapy. (Pubmed Central) - Nov 4, 2021
However, recent studies on the structure, signaling, and function of RAS have shed light on the development of RAS-targeting drugs, especially with the approval of Lumakras (sotorasib, AMG510) in treatment of KRAS-mutant NSCLC patients. Therefore, here we fully review RAS mutations in human cancer and especially focus on emerging strategies that have been recently developed for RAS-targeting therapy.
- |||||||||| [VIRTUAL] Lung () - Nov 1, 2021 - Abstract #SWOGFall2021SWOG_Fall_234;
This study is evaluating the recently approved KRAS G12C inhibitor sotorasib in distinct cohorts based on co-mutation status...A concept we’re working on that we’re excited about: Just in time for the fall meeting, S1934 “NASSIST: A randomized phase II trial of trimodality therapy +/- atezolizumab in resectable superior sulcus non-small cell lung cancer” will be activated...Given the overall survival benefit of durvalumab in stage III NSCLC, the addition of an immune checkpoint inhibitor warrants evaluation...This SWOG CTP randomized trial will evaluate whether a combination regimen for patients with EGFR mutation positive tumors with persistent ctDNA at 3 weeks could be beneficial versus continuing osimertinib. The rationale for this study is based on data from FLAURA and S1403 demonstrating that patients who remain ctDNA positive after starting a TKI have poorer outcomes.
- |||||||||| adagrasib (MRTX849) / Mirati, Lumakras (sotorasib) / Amgen
Journal: Therapeutics Targeting Mutant KRAS. (Pubmed Central) - Oct 31, 2021
Expected final online publication date for the Annual Review of Medicine, Volume 72 is January 27, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
- |||||||||| adagrasib (MRTX849) / Mirati, Lumakras (sotorasib) / Amgen
Review, Journal, IO biomarker: Strategies to tackle RAS-mutated metastatic colorectal cancer. (Pubmed Central) - Oct 31, 2021
Besides, concomitant therapies increasing metabolic stress are currently under evaluation and expected to also provide remarkable results in RAS codon mutations apart from KRAS. In conclusion, based on hereby reported efforts of translational research, RAS mutations should no longer be regarded as 'undruggable' and future avenues are now opening for translation in the clinic in mCRC.
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