- |||||||||| adagrasib (MRTX849) / Mirati, Lumakras (sotorasib) / Amgen
Discovery and preclinical evaluation of VRTX126, a novel, highly selective and potent KRASG12Cinhibitor (Section 31) - Mar 9, 2022 - Abstract #AACR2022AACR_5879;
Additionally, early evaluation in acute (>1 g/kg (p.o.) and >0.2 g/kg (i.v.) was well tolerated, with no elevation in liver enzymes and repeat does studies indicated good safety margins, thus supporting further evaluation of VRTX126 in IND enabling studies. A first-in-human Phase 1 clinical study in KRASG12C mutated patients of NSCLC and mCRC will be planned upon completion of through safety evaluations.
- |||||||||| Lumakras (sotorasib) / Amgen
Proteomic and transcriptomic subtypes of KRASG12C mutant lung cancer (Section 21) - Mar 9, 2022 - Abstract #AACR2022AACR_5801;
Sotorasib (AMG510) is the first KRASG12C covalent inhibitor (KRASG12Ci) approved by the FDA in lung cancers harboring oncogenic KRASG12C mutation...Next, we plan to leverage existing gene expression microarray data and add exome sequencing proteomics, and phosphoproteomics for a comprehensive, protein-centric characterization on these tumors. Importantly, the inclusion of 8 PDXs being co-processed and co-analyzed along with the tumors will enable rapid follow-up experiments to validate the findings into preclinical therapy trials.
- |||||||||| Patient-derived organoid drug responses corroborate known target-drug interactions for selected anticancer agents (Section 9) - Mar 9, 2022 - Abstract #AACR2022AACR_5680;
The approved and investigational agents were selected to target specific genetic variants and pathways: KRAS G12C covalent inhibitors (sotorasib and MRTX-1257), RAS pathway inhibitors (BAY-293, BI-3406 and TNO-155), BRAF V600E/K inhibitors (dabrafenib and encorafenib), ABCB1 substrates (paclitaxel, doxorubicin, 5-FU, AZD-1775, and SN-38), and ABCB1 non-substrates (gemcitabine and trametinib)...This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261201500003I.
- |||||||||| Lumakras (sotorasib) / Amgen
Discovery of potent, orally bioavailable, SOS1 inhibitors for KRAS-driven tumors (E-Poster Website) - Mar 9, 2022 - Abstract #AACR2022AACR_5525;
The lead compounds show anti-proliferative activity across a panel of WT and mutant KRAS cell lines, and are synergistic with MAPK pathway inhibitors including KRASG12C inhibitor Sotorasib...PK-PD correlation is also established in a tumor bearing mice model, with dose-dependent reduction of both pERK and pAKT. The lead compound shows good ADME properties, and is orally bioavailable, making it amenable for further in vivo profiling.
- |||||||||| Lumakras (sotorasib) / Amgen
Profiling oncogenic Ras mutant drugs with homogeneous bioluminescent immunoassays (Section 4) - Mar 9, 2022 - Abstract #AACR2022AACR_5519;
Activating KRAS mutations present in many cancers are difficult to target with drugs until recently with the FDA approval of sotorasib (AMG-510), a KRAS G12C selective inhibitor...Unlike current assays that require lengthy sample preparation and multiple washing steps, the Lumit immunoassay provides an alternative platform because it is homogeneous and allows to decipher signaling pathways activities in a fast and simple manner. Our results demonstrate that this bioluminescent technology can be adapted to any signaling pathway node, allowing scientists to streamline the analysis of signaling pathways of interest such as Ras, and identify much needed inhibitors of its mutants.
- |||||||||| Probing and overcoming KRASG12C inhibitor resistance by combination with a pan-KRAS SOS1 inhibitor (Section 22) - Mar 9, 2022 - Abstract #AACR2022AACR_5354;
While more work is currently being undertaken to map the resistance mechanisms in both our in vitro and in vivo settings, all results highlight the benefit of combining a SOS1 inhibitor with a KRASG12C inhibitor to prevent and/or overcome acquired resistance. The pan-KRAS SOS1 inhibitor BI 1701963 is the first direct RAS signaling modifier in phase I clinical trials both as a monotherapy as well as in combination with KRASG12C inhibitors, MEK inhibitors and liposomal irinotecan.
- |||||||||| Transcriptomics-based stratification of response to MAPK inhibition in vitro better predicts sensitivity to single agent and combination treatment than MAPK genomic alteration status alone (Section 27) - Mar 9, 2022 - Abstract #AACR2022AACR_5199;
P1/2
Targeted MAPK pathway inhibitors have been approved as therapies in patient populations with genomic alterations to MAPK pathway genes (e.g. dabrafenib in BRAF-mutant melanoma), with multiple other MAPK-targeted therapies in development...However, MAPK oncogene status alone is not a universal indicator of sensitivity, nor is it clear that genomic markers of sensitivity to single agent inhibition represent the optimal approach to predicting response to MAPK targeted agents in the combination setting (e.g. sotorasib + trametinib)...The sensitivity was further increased when considering response to the combination of an ERK and SHP2 inhibitor compared to the ERK inhibitor as a single agent.This analysis demonstrates the potential use of MAPK pathway-related transcriptomics-based scores for the stratification of MAPK pathway inhibitor response. ASTX029 is currently undergoing clinical development in advanced solid tumours (NCT03520075) and transcriptomics-based methods may provide utility in refining patient selection in the clinic for single agent or combination approaches.
- |||||||||| Lumakras (sotorasib) / Amgen
Novel and selective inhibitors of KRASG12D (Section 25) - Mar 9, 2022 - Abstract #AACR2022AACR_4724;
Targeting the inactive, GDP bound KRASG12C has been a promising approach for generating novel anti RAS therapies, which is validated by the approval of AMG 510 (Lumakras) by the FDA...VRTX144 exhibited low propensity for metabolism in microsomes, and has high protein bound. VRTX144 was found to have no adverse effect in hERG upto 10 uM.
- |||||||||| BMF-219 / Biomea Fusion
Irreversible menin inhibitor, BMF-219, inhibits the growth of KRAS-mutated solid tumors (Section 25) - Mar 9, 2022 - Abstract #AACR2022AACR_4708;
High potency of BMF-219 was observed amongst various KRAS-mutant cell lines suggesting that BMF-219 broadly inhibits these tumors. As an irreversible menin inhibitor, BMF-219, manifests advantages over the KRAS-targeted inhibitor sotorasib in multiple cell lines tested, and displays unique potency compared with clinical reversible menin inhibitors in ex vivo preclinical models of CRC, NSCLC, and pancreatic cancer.
- |||||||||| VS-6766 / Verastem, Lumakras (sotorasib) / Amgen
A phase 1/2 study of VS-6766 in combination with sotorasib in patients with KRAS G12C mutant non-small cell lung cancer (NSCLC) (RAMP 203) (Section 34) - Mar 9, 2022 - Abstract #AACR2022AACR_4607;
P1, P1/2
In vivo, combination of VS-6766 with sotorasib induced strong tumor regressions in contrast to sotorasib monotherapy or sotorasib plus trametinib...Patients enrolled must have histologic or cytologic evidence of NSCLC, measurable disease according to RECIST V1.1 and known KRAS G12C mutation. The study will enroll up to 121 patients with a minimum of 6 and a maximum of 12 patients (dose levels 1 and -1 have >1 DLT in first 3 patients or dose levels 1 and 2 each enroll 6 patients) in Part A and an additional 109 patients in Part B (minimum of 41 patients RP2D stage 1 for cohort 1 and 2 or RP2D stages 1 and 2 in both cohorts).
- |||||||||| Targeted therapies prime lung cancer cells for macrophage-mediated destruction (Section 35) - Mar 9, 2022 - Abstract #AACR2022AACR_3429;
Overall, we have identified a novel therapeutic strategy to enhance the efficacy of RTK-MAPK pathway inhibitors by combining them with anti-CD47 therapies.Our findings suggest cross-sensitivity occurs such that lung cancer cells that become resistant to targeted therapies also become more sensitive to macrophage attack. Our findings provide rationale for testing this combination approach in patients with lung cancers bearing driver mutations.
- |||||||||| MET or SHP2 inhibition enhances targeted therapies and delays the emergence of resistance in oncogene-driven NSCLC (Section 23) - Mar 9, 2022 - Abstract #AACR2022AACR_3301;
Our data show that combining targeted therapies with a SHP2 inhibitor synergistically decreases the viability of oncogene-driven NSCLC cell lines, indicating that initial combination therapy may be an appealing approach to improve patient outcomes. The observed delay in the emergence of osimertinib resistance, from combining a MET inhibitor with osimertinib, provides preclinical evidence to support further investigating MET inhibition upfront to improve the long-term therapeutic efficacy of EGFR inhibitors.
- |||||||||| Lumakras (sotorasib) / Amgen
Effect of the combined therapy of sotorasib and metformin in non-small cell lung cancer cell lines (Section 24) - Mar 9, 2022 - Abstract #AACR2022AACR_3276;
Our results show a synergic effect in cytotoxicity by MTT assay, as well as increased inhibition of MAPK pathway inhibition at combinational treatment, compared to monotherapies in A549 cell lines; conversely, we did not find significant effects on cytotoxicity and signaling inhibition in H522 cell line. In conclusion, the combined treatment of metformin and sotorasib show synergistic effects in drug-induced cytotoxicity and inhibition of MAPK pathways in lung cancer cell lines.
- |||||||||| Anti-EGF antibodies significantly improve the activity of BRAF and KRAS inhibitors in preclinical models (Section 22) - Mar 9, 2022 - Abstract #AACR2022AACR_2723;
Our data provide a rationale for clinical trials testing the combination of anti-EGF VacAbs with targeted inhibitors in BRAF and KRAS mutant CRC and NSCLC patients. (1)“Anti-Epidermal Growth Factor Vaccine Antibodies Enhance the Efficacy of Tyrosine Kinase Inhibitors and Delay the Emergence of Resistance in EGFR Mutant Lung Cancer Cells” García-Roman S, Molina-Vila MA, et al.
- |||||||||| Characterization of KRas pathway inhibitors in 2D and 3D screening formats (Section 23) - Mar 9, 2022 - Abstract #AACR2022AACR_2691;
For selected conditions, we addressed this topic by analyzing the inhibitor impact on 3D spheroid growth after shorter incubation times. Our results show that 3D growth analysis either in the soft agar or spheroid setting clearly supports the development of KRas/Raf/MEK pathway inhibitors.
- |||||||||| VS-6766 / Verastem
Dual RAF/MEK inhibitor VS-6766 enhances antitumor efficacy of KRAS G12C inhibitors through vertical inhibition of RAS, RAF and MEK (Section 25) - Mar 9, 2022 - Abstract #AACR2022AACR_2671;
KRAS G12C inhibitors (G12Ci), sotorasib and adagrasib, have demonstrated antitumor activity in patients with KRAS G12C mutant (mt) non-small cell lung cancer (NSCLC), and sotorasib has recently received FDA approval...The combination of VS-6766 with the focal adhesion kinase (FAK) inhibitor defactinib with an intermittent schedule has shown clinical activity for patients with KRAS G12V and KRAS G12C mt NSCLC with a manageable safety profile relative to MEKi...Similarly, in the H2122 KRAS G12C mt NSCLC model, sotorasib + VS-6766 induced >20% tumor regression in 5/10 mice while sotorasib or sotorasib + trametinib were relatively ineffective. These results support the imminent clinical evaluation of VS-6766 in combination with a G12C inhibitor for treatment of KRAS G12C mt NSCLC in both G12Ci naïve patients and patients progressing on G12Ci treatment.
- |||||||||| Lumakras (sotorasib) / Amgen
Long-term outcomes with sotorasib in pretreated KRASp.G12C-mutated NSCLC: 2-year analysis of CodeBreaK100 (Great Hall AD, Convention Center) - Mar 9, 2022 - Abstract #AACR2022AACR_2129;
In the longest follow-up of any KRASG12C inhibitor, sotorasib continued to demonstrate a favorable safety profile and durable efficacy, including a 2-year OS observed in 30% of patients. Current analyses continue to support long-term clinical benefit across subgroups in patients with KRAS p.G12C-mutated NSCLC, and additional biomarker data will be presented.
- |||||||||| adagrasib (MRTX849) / Mirati, Lumakras (sotorasib) / Amgen
Review, Journal: Targeting KRAS Mutant in Non-Small Cell Lung Cancer: Novel Insights Into Therapeutic Strategies. (Pubmed Central) - Mar 8, 2022
In this setting, combined therapeutic strategies including inhibition of either SHP2, SOS1 or downstream effectors of KRAS G12C seem particularly interesting to overcome acquired resistance. In this review, we will discuss the novel therapeutic strategies targeting KRAS G12C and promising approaches of combined therapy to overcome acquired resistance to KRAS G12C inhibitors.
- |||||||||| Lumakras (sotorasib) / Amgen
Journal: Diverse alterations associated with resistance to KRAS(G12C) inhibition. (Pubmed Central) - Mar 5, 2022
Here we evaluated matched pre-treatment and post-treatment specimens from 43 patients treated with the KRAS(G12C) inhibitor sotorasib...A subset of patients in our cohort acquired oncogenic KRAS, NRAS or BRAF mutations, and resistance in this setting may be delayed by co-targeting of ERK signalling intermediates. These findings merit broader evaluation in prospective clinical trials.
- |||||||||| Lumakras (sotorasib) / Amgen
Journal: Strategies for targeting undruggable targets. (Pubmed Central) - Mar 4, 2022
Biomedical studies are capable of dissecting disease mechanisms, thus broadening the list of undruggable targets. Encouraged by the recent approval of the KRAS inhibitor Sotorasib, we believe that merging multiple discovery approaches and exploiting various novel therapeutic entities would pave the way for dealing with more 'undruggable' targets in the future.
- |||||||||| adagrasib (MRTX849) / Mirati, Lumakras (sotorasib) / Amgen
Review, Journal: Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges. (Pubmed Central) - Feb 25, 2022
In this review, we outline the mutations and functions of KRAS in human tumors and then analyze indirect and direct approaches to shut down the oncogenic KRAS network. Specifically, we discuss the mechanistic principles, clinical features, and strategies for overcoming primary or secondary resistance to KRAS-G12C blockade.
- |||||||||| adagrasib (MRTX849) / Mirati, Lumakras (sotorasib) / Amgen
Biomarker, Journal, Tumor microenvironment: Remodeling of the tumor/tumor microenvironment ecosystem during KRAS G12C inhibitor clinical resistance in lung cancer. (Pubmed Central) - Feb 22, 2022
This analysis of pre- and posttreatment tumors uncovered cancer cell-intrinsic and -extrinsic features of resistance, including reactivation of KRAS-mediated signaling, reprogramming of metabolism, epithelial-mesenchymal transition, and tumor microenvironment changes. This elegant study demonstrates the multifaceted nature of KRAS G12C inhibitor clinical resistance and potential avenues to overcome resistance.
- |||||||||| adagrasib (MRTX849) / Mirati, MRTX1133 / Mirati, Lumakras (sotorasib) / Amgen
The beginning of the end for KRAS cancers (Great Hall BC, Convention Center) - Feb 21, 2022 - Abstract #AACR2022AACR_1339;
These first inhibitors (sotorasib and adagrasib) are selective KRAS drugs which target the KRASG12C mutant and have clinically validated KRAS as a cancer drug for KRASG12C-mutant non-small cell lung cancer, colorectal cancer, and pancreatic cancer...Despite this higher hurdle the first clinical candidate (MRTX1133) and advanced lead compounds have been described.The complementary positioning of recently described therapeutic approaches selectively or broadly addressing KRAS mutants will be highlighted...In contrast to classical small molecule drugs, PROTAC-driven degradation not only removes the entire protein but also functions in a sub-stoichiometric nature. The talk will summarize our discovery of pan-KRAS(off) PROTACs, which potently degrade the majority of major KRAS mutants.Based on the recent progress the field has made in drugging KRAS and in starting to understand mechanisms of aquired resisistance, we can be optimistic that it will be possible in the long-term to complete this task and put an end to KRAS cancers.
- |||||||||| SAR442720 / Sanofi, Revolution Medicines, Lumakras (sotorasib) / Amgen
RMC-4630 and sotorasib for advanced KRASG12C NSCLC after failure of prior standard therapies: A phase II trial ([VIRTUAL]) - Feb 19, 2022 - Abstract #ELCC2022ELCC_349;
P2
Secondary endpoints include DOR, DCR, PFS, OS, safety/tolerability, and PK of RMC-4630 in combination with sotorasib. This trial is currently enrolling in the United States and will also be open at sites in Europe, UK, Australia, and Asia.
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