EGFR C797S

Osimertinib has become the first globally accessible third-generation EGFR inhibitor, representing one of the most advanced developments in non-small-cell lung cancer (NSCLC) therapy...These degraders compared with EGFR inhibitors showed better efficiency in their cellular potency, inhibition, and toxicity profiles. In this review, we first introduce the structural properties of EGFR, the resistance, and mutations of EGFR, and then mainly focus on the recent advances of EGFR-targeting degraders along with its advantages and outstanding challenges.

Mechanism studies revealed that 14o was a potent EGFR L858R/T790M/C797S and EGFR Del19/T790M/C797S kinase inhibitor, which could downregulate the protein phosphorylation of EGFR and m-TOR signaling pathways, arrest cell cycle at G2/M phase by affecting the expression of CDC25C, and promote cell apoptosis by regulating the expression of cleaved caspase-3. In summary, 14o could serve as a promising deuterated compound for the development of highly efficient anticancer agents.

P1, N=751, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Dec 2024 --> Jun 2025

Here, we reported two cases with NSCLC who initially harbored an EGFR-sensitive mutation and were both treated with osimertinib, a third-generation TKI. Our findings suggested that a combined regimen of brigatinib and cetuximab could serve as a potentially life-saving therapeutic strategy for critically ill patients with NSCLC, particularly those demonstrating EGFR p.C797S-mediated resistance. Further studies, however, are required to validate and expand upon these promising findings.

Structures show that BI-4020 is likely rendered selective due to interactions with the kinase domain hinge region as well as T790M, akin to Osimertinib. Additionally, BI-4020 is also rendered more potent due to its constrained macrocycle geometry as well as additional H-bonds to conserved K745 and T845 residues in both active and inactive conformations. These findings taken together show how this novel macrocyclic inhibitor is both highly potent and selective for mutant EGFR in a reversible mechanism and motivate structure- inspired approaches to developing targeted therapies in medicinal oncology.

Regrettably, the patient eventually died from heart disease. This report provides the first reported evidence for the use of furmonertinib and intrathecal pemetrexed chemotherapy in NSCLC patients harboring EGFR R776S/C797S/L858R mutations who progressed on previous EGFR-TKIs.

In 73% of participants, loss of T790M ctDNA is observed at progression and no participants have evidence of the EGFR C797S resistance mutation following the alternating regimen. These findings highlight the challenges of treatment strategies designed to modulate clonal evolution and the clinical importance of resistance mechanisms beyond suppression of selected genetic mutations in driving therapeutic escape to highly potent targeted therapies.

Brigatinib-based therapy was effective against osimertinib-resistant EGFR C797S mutants and is undergoing clinical studies. Molecular dynamics simulation revealed the binding mode and affinity between BI-4020 and EGFR mutants. This study identified potential therapeutic strategies using the new-generation macrocyclic EGFR inhibitor to overcome the emerging ultimate resistance mutants.

At concentration of 10 μM, A9 can be employed as the fourth-generation of EGFR inhibitors with the ability to overcome the C797S drug resistance since it can suppress EGFRDel19/T790M/C797S cells and kinase by 98.90% and 85.88%, respectively. Moreover, the tumor-bearing nude mice experiment further shows that A9 can significantly inhibit the growth of tumor in vivo, with the tumor inhibition rate (TIR) of 55.92%, which was equivalent to the positive group. After that, from the result of HE staining experiment and blood biochemical analysis experiment, A9 show low toxicity and good safety, which is worthy of further research and development.

Compound mutations responded better than single mutations for each PACC mutation. Table: 24P PACC mutations Guardant360 Retrospective clinical response data Case # Percent First-gen TKI Second-gen TKI Third-gen TKI ORR N ORR N ORR N G719 Single 191 26.8% 39% 310 56% 248 33% 36 Compound 521 73.2% 42% 52 77% 77 59% 27 S768 Single 44 13.1% 31% 29 48% 46 33% 9 Compound 291 86.9% 54% 11 63% 52 59% 17 G709 Single 6 2.9% 0% 5 50% 6 50% 4 Compound 201 97.1% 43% 7 62% 16 83% 6 Conclusions Compared to classical EGFR mutations, PACC mutations frequently occur as compound mutations, and tend to have improved response to EGFR TKIs than single PACC mutations.

EGFR-C797S in cis to all EGFR mutations evaluated generated dependent cells that were resistant to the covalent EGFR tyrosine kinase inhibitors mobocertinib, zipalertinib, furmonertinib, sunvozertinib, poziotinib, and osimertinib. This report highlights that poziotinib and mobocertinib are susceptible to on-target resistance mediated by EGFR-T790M or -C797S in the background of the most prevalent EGFR exon 20 insertion mutations. Furmonertinib, sunvozertinib, and to a less extent zipalertinib can overcome EGFR-T790M compound mutants, whereas EGFR-C797S leads to covalent inhibitor cross-resistance-robust data that support the limitations of mobocertinib and should further spawn the development of next-generation covalent and reversible EGFR exon 20 insertion mutation active inhibitors with favorable therapeutic windows that are less vulnerable to on-target resistance.

P1/2, N=190, Active, not recruiting, Blueprint Medicines Corporation | Recruiting --> Active, not recruiting

P1/2, N=200, Recruiting, Black Diamond Therapeutics, Inc. | Phase classification: P1 --> P1/2 | N=120 --> 200

These results suggest that T6496 may mitigate EGFR resistance caused by T790M or C797S mutations. Moreover, the AO staining assay, JC-1 staining, ROS experiment and hemolytic toxicity evaluation revealed that T6496 could induce apoptosis in H1975 cell lines in a time-dependent and concentration-dependent manner, and is a potential compound for further structural optimization.Communicated by Ramaswamy H. Sarma.

P1/2, N=200, Recruiting, Taiho Oncology, Inc.

The case showed that individualized treatment aided by D ~ Sense ex-vivo viability assay can be a viable option for patients with advanced lung adenocarcinoma with pleural effusions.

The first-generation of drugs such as gefitinib bind reversibly and were followed by a second-generation such as dacomitinib that harbor an acrylamide moiety that forms a covalent bond with C797 in the ATP binding pocket...A third generation of drugs, such as osimertinib were developed which were effective against T790M EGFR in which an acrylamide moiety forms a covalent bond with C797, although resistance has emerged by mutation to S797...A number of acrylamide containing fragments were identified that selectively reacted with C775. One of these acrylamides was optimized to a highly selective inhibitor with sub-1 μM activity, that is active against T790M, C797S mutant EGFR independent of ATP concentration, providing a potential new strategy for pan-EGFR mutant inhibition.

Importantly, JC-010a abolished acquired resistance induced by targeted therapies: in KRAS-mutant cancers, JC-010a abrogated selumetinib-induced adaptive resistance mediated by RTK/SHP2; in BCR-ABL-driven leukemia cells, we demonstrated JC-010a inhibited BCR-ABL T315I mutation-mediated imatinib resistance and proposed a novel mechanism of JC-010a involving the disrupted co-interaction of SHP2, BCR-ABL, and Hsp90; in non-small cell lung cancer (NSCLC) cells, JC-010a inhibited both EGFR T790M/C797S mutation and alternate RTK-driven resistance to gefitinib or osimertinib; importantly, we first proposed a novel potential therapeutic strategy for RET-rearranged cancer, we confirmed that JC-010a monotherapy inhibited cell resistance to BLU-667, and JC-010a/BLU-667 combination prolonged anticancer response both in vivo and in vitro cancer models by inhibiting the alternate MET activation-induced RAS/MAPK reactivation, thereby promoting cancer cell apoptosis. These findings suggested that JC-010a was a novel selective SHP2 allosteric inhibitor, and combing JC-010a with current targeted therapy agents provided a promising therapeutic approach for clinical resistant cancers.

The third-generation kinase inhibitor Osimertinib is currently playing a very vital role in the treatment of NSCLC...Finally, the binding mechanism and important hydrogen-bonding residues during unbinding of the inhibitors were fully elucidated. This study provides insight into the binding of the receptor-orthosteric inhibitor-allosteric inhibitor, which can be helpful for further design of novel inhibitors that have a better inhibitory action.

P1, N=751, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Jan 2024 --> Dec 2024

The detection of T790M at PD after osimertinib initiation was a significant independent prognostic factor for predicting shorter prognosis, and the presence of major EGFR mutations at pretreatment and PD was closely linked to worse survival after osimertinib initiation. Molecular testing based on ctDNA is helpful for predicting outcomes of osimertinib treatment in T790M-positive NSCLC after previous EGFR-TKI treatment.

Allelic context could define four EGFR C797X-mutant NSCLC subtypes with heterogeneous genetic landscape and distinct clinical outcomes. Subsequent treatments further complicate the scenario through subtype switching.

P1, N=751, Active, not recruiting, Janssen Research & Development, LLC | Recruiting --> Active, not recruiting

Resistance to osimertinib demonstrated to be highly heterogeneous, with MET amplification the main mechanism. Plasma genotyping is a relevant complementary tool which might integrate tissue analysis for the study of resistance mechanisms.

Our findings demonstrate that MUC1-C is a common effector of osimertinib resistance and is a potential target for the treatment of osimertinib resistant NSCLCs.

The computed binding energies of selected leads and their molecular dynamics simulations exhibited enhanced conformational stability of QU648 and QU351 when compared to standard drugs Erlotinib and Afatinib. Notably, the lead compounds also demonstrated promising pharmacokinetic properties, metabolic reactivity, and cardiotoxicity profiles. Collectively, the outcomes of our study provide compelling evidence supporting the potential of QU648 and QU351 as prominent anti-angiogenic agents, effectively inhibiting EGFR activity across various cancer types harboring diverse EGFR mutations.Communicated by Ramaswamy H. Sarma.

P2, N=47, Not yet recruiting, Samsung Medical Center

The osimertinib resistance landscape is diverse with on-target ssEGFRm and off-target resistance detected in tissue and liquid biopsy. Post-osimertinib, patients are receiving primarily chemotherapy-based regimens with poor outcomes and CGP at resistance may offer an opportunity to inform therapeutic development and improve treatment selection.

Furthermore, additional EGFR resistance mutations, such as C797S, were 1 case. Expected Conclusions MET amp and PIK3CA mutation are the common resistance mechanisms of osimertinib PD, and the rate of additional EGFR resistance mutations is lower compared with prior studies.

Methods Pts with treatment-naïve, EGFRm advanced NSCLC received osi + CT (osi 80 mg once daily [QD] + pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 or carboplatin AUC5 every 3 weeks [Q3W] for 4 cycles, followed by osi 80 mg QD + pemetrexed 500 mg/m2 Q3W) or osi monotherapy (80 mg QD) until PD/discontinuation criterion. Osi + CT resulted in similar resistance mechanisms to osi monotherapy, and should not impact subsequent targeted second-line tx options. This analysis was enriched with pts who had early progression; further follow-up is required.

Plasma EGFR mutation analysis was effective in predicting the effect of osimertinib treatment.

T790M or C797S, depending on the original X20ins mutations, conferred acquired resistance to mobocertinib. Sunvozertinib may be the treatment of choice for patients with tumors resistant to mobocertinib because of T790M.

Patients with NSCLC with both MET amplification and EGFR mutation who have received crizotinib, capmatinib, savolitinib, or tepotinib plus osimertinib (OSI) after progression on OSI at MD Anderson Cancer Center were included in this study. Dual EGFR and MET inhibition yielded high clinical response rate after progression on OSI. Resistance mechanisms to EGFR-MET double TKI inhibition include MET secondary mutation, EGFR secondary mutation, or loss of MET amplification.

BBT-176 is a fourth-generation EGFR inhibitor showing promising preclinical activity against NSCLC resistant to current EGFR TKIs.

No abstract available

JIN-A02, a 4th generation EGFR TKI, selectively and reversibly binds to EGFR mutations, including C797S mutation that causes resistance to Osimertinib. Primary end points include dose limiting toxicity and AE/SAE for part A, RP2D for part B, and objective response rate for part C. Part A of JIN-A02 study has begun site activation in January 2023 in US, approved in Korea and is awaiting regulatory approval in Thailand. Clinical trial information: NCT05394831

The combination of anlotinib and osimertinib might be an efficacy and safety treatment option for patients with EGFR T790M mutation who have failed prior EGFR-TKI. Dynamic changes of ctDNA could be used to monitor treatment response and to explore mechanisms of acquired resistance to therapy.

However, a novel EGFR-TKI, mobocertinib, was approved by the US FDA for NSCLC patients with EGFR exon20 insertion. We examined efficacy of mobocertinib and other EGFR-TKIs (erlotinib, afatinib, poziotinib, CLN-081, sunvozertinib , osimertinib, and brigatinib) using murine pro-B-cell line (Ba/F3) models harboring one of five most common EGFR exon 20 insertions (A763_Y764insFQEA, V769_D770insASV, D770_N771insSVD, H773_V774insNPH and H773_V774insH). These findings indicate that T790M or C797S, depending on the original activating mutations, will cause acquired resistance to mobocertinib in NSCLCs with EGFR exon 20 mutations. Further analyses suggest that sunvozertinib will be effective against acquired resistant cells with T790M mutation. However, except for A763_Y764insFQEA plus C797S mutation that is sensitive to erlotinib, other treatment strategy, such as cytotoxic chemotherapy, should be considered for patients who develop C797S secondary mutation.

Osimertinib is an effective first-line treatment in Asian patients with advanced EGFRm+ NSCLC with durable OS, PFS and TTF, comparable with reported data. Positive smoking history, poor ECOG and EGFR exon 21+ are negative prognostic factors. Common post-osimertinib resistance mechanisms in this cohort were cMET amplification, C797S mutation and histologic transformation.