EGFR T790M + EGFR C797S

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

"While T790M and C797S mutations are well described, we document L718V mutations in osimertinib-treated pts with an original L858R. We need to increase NGS in pts who develop resistance because it is very heterogeneous and will help to develop new TKIs."

"This study shows the wide spectrum of primary and secondary EGFR resistance mechanisms to first, second and third generation of TKIs and helps us to identify newer therapeutic targets that could carry forward the initial advantage offered by EGFR TKIs."

Preclinically it has shown activity as monotherapy in osimertinib-resistant patient-derived xenograft (PDX) models. Patients may receive treatment until disease progression or unacceptable toxicity. Recruitment is ongoing and approximately 30 sites will be open for enrollment across North America, Europe, and Asia.

This analysis provides the first description of NGS genotyping on liquid biopsy of a cohort of patients with advanced NSCLC in Argentina.

Acquired resistance in EGFR mutant NSCLC remains very heterogeneous; the frequency of individual mutations is low, one of the reasons might be lack of testing at resistance. While T790M and C797S mutations are well described, this report also documents a significant number of L718V mutations, primarily in osimertinib-treated pts with an original L858R. These data support the need to increase NGS evaluation of patients with EGFR mutant lung cancers who have developed clinical resistance.

Additionally, molecular docking analyses were performed to explain the action modes between the compounds and the corresponding EGFR kinases. In conclusion, compounds 9h and 22a have been demonstrated as promising candidates and worth further study.

We further uncover that EGFR homo- or heterodimerization with other ERBB family members, as well as the EGFR L747S mutation, confers resistance to JBJ-09-063, but not to ATP-competitive EGFR TKIs. Overall, our studies highlight the potential clinical utility of JBJ-09-063 as a single agent or in combination with EGFR TKIs to define more effective strategies to treat EGFR-mutant lung cancer.

Personalized group：22 patients with MET amplification received the combination therapy of EGFR-TKIs and MET inhibitors; 6 patients with SCLC transformation received EP/EC chemotherapy; 2 patients with BRAF mutation were treated with the combination of EGFR-TKIs, dabrafenib and trametinib; 3 patients with ERBB2 amplification were added Trastuzumab in the therapy; 2 patients with RET fusion were accepted LOXO-292 therapy; 1 patient had the combination therapy of the 1st and 3rd EGFR-TKIs because of T790m and C797S mutations in trans allelic context.Chemotherapy group: 79 patients received pemetrexed plus platinum therapy, 14 patients received paclitaxel plus platinum therapy. Chemotherapy maybe is the optimal choice to patients with advanced EGFR-mutant lung adenocarcinoma and disease progression on the prior EGFR-TKI in current medical conditions.

Preclinically it has shown activity as monotherapy in osimertinib-resistant patient-derived xenograft (PDX) models. Patients may receive treatment until disease progression or unacceptable toxicity. Recruitment has started and approximately 30 sites will be open for enrollment across North America, Europe, and Asia.

Acquired resistance in EGFR mutant NSCLC is very heterogeneous and their frequency is still low most likely due to lack of enough sequencing of EGFR resistant tumors. While T790M and C797S mutations are well described, this report also notes a significant number of L718V mutations, primarily in osimertinib-treated pts with an original L858R. These data support the NGS evaluation of patients with resistant EGFR mutant lung cancers.

Background: Despite recent advances in the treatment of EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC), most patients treated with third-generation (3G) EGFR tyrosine kinase inhibitors (TKIs), such as osimertinib, experience disease progression. As of the data cut, BLU-945 was generally well tolerated in heavily pre-treated patients with EGFRm NSCLC. There was also early evidence of a reduction in EGFR mutation allele fractions by ctDNA.

P1/2, N=190, Recruiting, Blueprint Medicines Corporation | N=120 --> 190

This study assessed the efficacy of osimertinib against radiotherapy-naïve CNS metastasis from T790M-positive NSCLC. The primary endpoint was met, and the results demonstrated the efficacy of osimertinib in patients with CNS metastasis harboring EGFR T790M mutations especially for EGFR-sensitizing mutation of exon 19 deletion.

P1/2, N=120, Recruiting, Blueprint Medicines Corporation

The method was successfully applied to the pharmacokinetic study of XHL-31 in rats. Results indicated that there were significant gender differences in oral absorption and the absolute bioavailability of XHL-31 in female rats were extremely low (less than 10%).

Ramucirumab plus osimertinib demonstrated encouraging safety and antitumor activity in T790M-positive EGFR-mutant NSCLC.

Compound 27 also exhibited good microsomes stabilities in human, rat and mouse liver species, but low bioavailability. This work would be very useful for discovering new quinazoline derivatives as tyrosine kinase inhibitors targeting triple mutant L858R/T790M/C797S.

Selective N-methylation of the H-bond accepting nitrogen ablates inhibitor potency, confirming the role of the K745 H-bond in potent, non-covalent inhibition of C797S variant. Insights from these studies offer new strategies for developing next generation inhibitors targeting EGFR in non-small cell lung cancer.

Furthermore, crystal structure analysis suggested that CH7233163 is a non-covalent ATP competitive inhibitor for EGFR-Del19/T790M/C797S that utilizes multiple interactions with the EGFR's αC-helix-in conformation to achieve potent inhibitory activity and mutant selectivity. Therefore, we conclude that CH7233163 is a potentially effective therapy for osimertinib resistant patients, especially in cases of EGFR-Del19/T790M/C797S.

Legal entity responsible for the study: The authors. Funding: Guardant Health.

Table: 1195P * ALK fusion+ pts received prior alectinib (median 3 prior TKI); EGFR T790M+ pts received prior osimertinib (median 2 prior TKI).**concurrent aberrations (G1202R+C1156Y; MET amp+ T790M; FGFR1 amp + CDK4 amp; C797S + BRAF; EGFR amp+CCND2 amp) Legal entity responsible for the study: The authors. Funding: Princess Margaret Cancer Foundation; Guardant Health. Clinical trial identification: NCT03576937.