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.

No new osimertinib safety findings were observed. The increase in fexofenadine exposure following osimertinib coadministration shows osimertinib as a weak P-glycoprotein inhibitor.

Patients with exon 19 deletion are likely to acquire T790M mutation. This would prove useful for clinicians to prognosticate and plan subsequent treatments for patients with advanced NSCLC harbouring EGFR mutations.

Lung cancer and genetically engineered cell lines, as well as murine xenograft models were used to evaluate the efficacy of TAS6417 and other approved/in-development EGFR TKIs (erlotinib, afatinib, osimertinib, and poziotinib). Taken together, we demonstrate that TAS6417 is a potent EGFR TKI with a broad spectrum of activity and a wider therapeutic window than most approved/in-development generations of EGFR inhibitors. Implications: TAS6417/CLN-081 is a potent EGFR TKI with a wide therapeutic window and may be effective in lung cancer patients with clinically relevant EGFR mutations.

While heart failure induced by EGFR-TKIs has been rarely reported, osimertinib may cause cardiomyopathy due to human epidermal growth factor receptor type 2(HER2)inhibitory activity.

This report provides the first comprehensive actionable alteration portrait of LA in Brazil. The high rate of actionable alterations in EGFR and other driver genes in LA reinforces the need to incorporate TKI guided by molecular diagnostics into clinical routines for patients in both public and private healthcare systems.

Funding: AstraZeneca. Clinical trial identification: D5161R00007; NCT03761901.

1L TKI: 45.4% afatinib, 27.3% erlotinib, 27.2% gefitinib...2L median duration was 2.3 (2.0,2.8) m for chemotherapy and 10.9 (9.4,12.4) m for osimertinib...Funding: AstraZeneca. Clinical trial identification: NCT04031898.

Background In the phase III FLAURA study (NCT02296125), osimertinib significantly improved OS vs comparator EGFR-TKI (gefitinib/erlotinib) in treatment-naïve patients (pts) with EGFRm advanced NSCLC; OS hazard ratio (HR) 0.799, p=0.0462. Funding: AstraZeneca. Clinical trial identification: NCT02296125.

Funding: Nippon Boehringer Ingelheim, TORG, NBI. Clinical trial identification: UMIN000027338.

Our findings indicate that the EGFR 19Del subtypes affect the clinical outcomes and resistance mechanisms to osimertinib in T790M-positive patients. Identifying patients with relatively worse treatment outcomes may be informative for establishing new therapies for these patients.

This study shows that BAL samples are superior to plasma samples and almost equal to FFPET samples in detecting EGFR mutations, therefore BAL samples should be preferred before blood samples when possible.

Resistance mechanisms to osimertinib are diverse, therefore re-biopsy and Next Generation Sequencing are important to decide the subsequent strategy.

Molecular targeted therapy is now the standard first-line treatment for patients with advanced non-small cell lung cancer (NSCLC). Samples of 1,200 Chinese patients with NSCLC were analyzed through next-generation sequencing to characterize the unique feature of uncommon EGFR mutations and ALK fusion. The results showed that 7.4% of EGFR-mutant patients harbored both sensitizing and uncommon mutations and 11.6% harbored only uncommon mutations. Uncommon EGFR mutations more frequently combined with the genomic alterations of ALK, CDKN2A, NTRK3, TSC2, and KRAS. ALK fusion was more common in younger patients, and the frequency decreased monotonically with age. 3.2% of ALK-positive patients harbored multi ALK rearrangement, and seven new partner genes were identified.

In addition, patient care would have been changed in four of these cases: targeted therapies were identified in two cases, and repeated biopsies would have been avoided in two cases. The Idylla molecular testing system is an accessible, rapid, robust, and reliable testing option for both routine and challenging formalin-fixed, paraffin-embedded specimens.

A man with recurrent lung adenocarcinoma harboring an EGFR exon 19 deletion received erlotinib for 10 months following curative surgery and adjuvant chemotherapy...The tumor was reduced after four cycles of etoposide and cisplatin and his respiratory symptoms improved...The patient received paclitaxel plus cisplatin for two cycles with partial response. Because heterogeneous genetic and phenotypic mechanisms of TKI-resistance may occur at different times and locations, histopathological and molecular testing both provide evidence to support appropriate treatment.

In Chinese NSCLC patients, EGFR mutation was significantly associated with female, younger age (< 65 years), and adenocarcinoma. Genomic profiles of NSCLC were associated with the treatment history; TP53 mutation was significantly more frequent in the patients with history of radiochemotherapy/chemotherapy therapy. Various multiple genes co-mutation panels, especially EGFR and KRAS co-mutation, were observed in the ctDNA of Chinese NSCLC patients.

This is the first reported survival analysis of osimertinib-treated Chinese patients, which indicates a median OS of 47.86 months. The EGFR T790M mutation is likely to coexist with 19del and indicate longer PFS and OS1 than EGFR 21 L858R/T790M. Additionally, the extrathoracic metastasis status and biopsy specimen type might also affect the survival of patients treated with osimertinib.

We conclude that eLB is an assay platform that interrogates a biomarker not targeted by any other extant platform, namely, circulating single stranded DNA molecules. The assay has acceptable performance characteristics in both quantitative and qualitative assays on both saliva and plasma.

Treatment with afatinib in the first line is dominant with respect to the strategy with gefitinib. The ICER of osimertinib exceeds the threshold when compared with afatinib.

The ddPCR test for EGFR T790M mutations effectively triaged 24% of patients for treatment with osimertinib, avoiding the need for invasive tissue biopsy in these patients. Our findings suggest that initial and repeat ctDNA testing can be used to monitor for acquired EGFR T790M resistance for NSCLC.

Deletion location and type variants (with or without an insertion and/or a substitution) might affect first-generation TKI efficacy, and different EGFR exon 19dels should be considered when making decisions on which EGFR TKI should be used.

The cobas test is a sensitive, robust, and accurate assay that delivers reproducible results.

ctDNA clearance was comparable at C3D1/C4D1 for cohort B2 and Part D. ctDNA clearance was similar between the two doses of savolitinib, suggesting efficacy is maintained at the lower dose (300 mg). These data also indicate that ctDNA clearance may be predictive of PFS in EGFRm MET-amplified NSCLC.

This study’s findings reveal that different EGFR mutation subtypes display heterogeneous immunotherapeutic features, and EGFR G719X was associated with an increased TMB, a higher proportion of TMB-H/PD-L1 positive patients, and fewer concurrent copy number amplification GAs. This suggests that GAs of G719X may have implications as a biomarker for guiding ICI treatment in EGFR-mutated NSCLC.

94% of patients were treated with first-line erlotinib (253/270), and 30% received second-line osimertinib (82/270). While TP53 mutations associate with shorter PFS, there is no association with baseline TP53 mutation status and small cell transformation, and TP53+ patients also develop the T790M resistance mutation earlier than TP53- patients. Higher mutation and copy number burden in TP53+ patients suggests greater genomic instability and may act as a mechanism of earlier resistance development.

NCI-H1975-C797S derived-xenografts were treated with APG-1252, cisplatin/docetaxel or their combinations.Combination therapy with APG-1252 and cisplatin or docetaxel exhibited synergistic antitumor activity. Similar results were demonstrated in a patient-derived xenograft (PDX) tumor model derived from an osimertinib-resistant NSCLC patient harboring 19del-T790M-C797S mutations. Furthermore, the combinations also exhibited enhanced antitumor activity in an osimertinib-resistant PDX model that the resistant mechanism remained unknown.In summary, our results suggest that the combination treatment with APG-1252 and chemotherapeutics can overcome acquired resistance to osimertinib and the combination deserves further clinical evaluations.

In vivo efficacy results show that this triple mutant NSCLC PDX model was resistant to Erlotinib and AZD9291 and sensitive to the combination of Cetuximab and Brigatinib. We also established CD74-ROS1 fusion and G2032R mutant NSCLC PDX model; EML4-ALK fusion and L1196M mutant NSCLC PDX model; Olaparib resistant Ovarian cancer PDX model; Heceptin resistant gastric PDX model; Rituximab and ABT-199 resistant DLBCL PDX model, and so on. In conclusion, these precious PDX models provide insight into resistance mechanisms as well as serve as models to develop new therapeutics drug candidates that overcome the drug resistant.

All of patients received at least one prior EGFR-TKI therapy, among which 46% (36/78) had gefitinib, 49% (38/78) had erlotinib, 19% (15/78) had icotinib. The efficacy of osimertinib was associated with EGFR genotypes in pre-TKI treated NSCLC patients with BrMs, and L858R maybe an independent bad factor for long-term outcomes of osimertinib. Research Funding: None