EGFR T790M + exon 19 deletion

Brigatinib-based therapy and chemotherapy plus anti-angiogenics could be considered beyond progression from osimertinib therapy. For patients harboring EGFR exon 19 deletion/T790M/cis-C797S mutation, the clinical efficacy was superior to patients harboring EGFR exon 21 p.L858R/T790M/cis-C797S mutation.

The epidermal growth factor receptor (EGFR) harboring activating mutations is a clinically validated target in non-small-cell lung cancer, and a number of inhibitors of the EGFR tyrosine kinase domain, including osimertinib, have been approved for clinical use...We describe the medicinal chemistry optimization of a biochemically potent but modestly cell-active, reversible EGFR inhibitor starting point with sub-optimal physicochemical properties. These studies culminated in the identification of compound 12 that showed improved cell potency, oral exposure, and in vivo activity in clinically relevant EGFR-mutant-driven disease models, including an Exon19 deletion/T790M/C797S triple-mutant mouse xenograft model.

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

Among patients with positive factors associated with the T790M mutation, repeated tissue or liquid biopsies are useful to maximize the detection rate of the T790M substitution. Furthermore, these biopsies need to be repeated numerous times in order to reduce "detection overlook" among such patients.

We generated OR cell lines in-vitro as evidenced by increased drug resistance potential, increased mesenchymal features and enhanced autophagy activity. Development of Osimertinib resistance cells may serve as in-vitro model facilitating discovery of molecular aberration present during acquired mechanism of resistance.

One patient discontinued the drug because of drug-related interstitial pneumonitis. Osimertinib had favorable efficacy in the first-line treatment of metastatic NSCLC harboring activating EGFR mutations in ctDNA as well as tumor DNA.

Afatinib treatment at 40 mg daily is associated with high rates of adverse events and dose reductions; alternative strategies including pulse intermittent dosing should be evaluated prospectively. Osimertinib (with favorable safety profile and intracranial penetration) has shown promising results in this population in a phase II trial from South Korea; additional trials are ongoing.

Approximately one fifth of EGFR-mutant patients harbor uncommon and compound mutations. Unlike those with exon19del/L858R, these patients-particularly those with baseline T790M mutations-show significantly inferior response rates to treatment (EGFR TKI or chemotherapy) and early disease progression.

Different 19del subtypes with T790M mutation had similar PFS when treated with osimertinib (P=0.102). Patients with EGFR 19del subtypes had different clinicopathological features, and resistant pattern when treated with first-line TKIs. Patients harboring deletions starting from L747 with insertions had inferior outcomes than other subtypes.

PD-L1 TPS ≥ 50% was an independent predictor of a lower frequency of this mutation (HR = 0.63, p = 0.043). High PD-L1 expression was associated with unfavorable clinical outcome and less development of secondary T790M mutation, suggesting a distinct subgroup warranting active surveillance and tailored therapeutic approach.

Osimertinib demonstrated favorable activity with manageable toxicity in patients with NSCLC harboring uncommon EGFR mutations.