Background: Several EGFR tyrosine kinase inhibitors (TKIs) are used for the treatment of EGFR-mutant non-small cell lung cancer (NSCLC), however resistance inevitably develops. The combination of the irreversible ErbB family TKI afatinib and the EGFR monoclonal antibody cetuximab was previously shown to overcome resistance to first-line EGFR TKIs. To attempt to delay resistance, we conducted a randomized trial of afatinib plus cetuximab versus afatinib alone in treatment-naïve patients with advanced EGFR-mutant NSCLC (NCT02438722). Method: Patients with previously-untreated EGFR-mutant NSCLC were randomized to afatinib 40mg PO daily plus cetuximab 500mg/m2 IV every 2 weeks or afatinib 40mg PO daily. The study was designed to accrue a total of 212 patients, comparing progression-free survival (PFS) between the arms at the 1-sided 0.025 level when 134 PFS events had been observed. Secondary objectives included comparison of overall survival (OS), time to treatment discontinuation (TTD), and toxicity. An interim analysis evaluating early stopping for futility occurred when at least 64 PFS events were reported. Result: Between March 26, 2015 and April 23, 2018, 170 eligible patients were accrued: 86 to afatinib/ cetuximab and 84 to afatinib. Median age was 66.4 years, 66% were female, 64% had an EGFR exon 19 deletion mutation and 36% had an L858R point mutation. With 109 events observed, there was no improvement in PFS with the combination compared to single-agent (HR 1.17, 95% CI 0.80-1.73, P ¼ 0.42, median 10.6 months vs 13.1 months). OS was also not improved with the addition of cetuximab (HR 1.23, 95% CI 0.62-2.44, P ¼ 0.55, median 26.9 months vs not reached). TTD was similar between the two groups (HR 0.95, 95% CI 0.64-1.39, P ¼ 0.79, median 12.5 months vs 12.2 months). Grade > 3 treatmentrelated adverse events (AEs) were more common among patients treated with afatinib/cetuximab, and more patients in the combination arm required at least 1 dose reduction of afatinib (57% vs 26%). However, treatment discontinuations due to AEs were similar between the two groups (11.6% vs 10.7%). Conclusion: There was no difference in PFS, OS or TTD with the addition of cetuximab to afatinib for treatment-naïve patients with EGFR-mutant NSCLC. The trial was closed to accrual at the interim analysis having met the criteria for futility. Correlative analysis of tumor tissue and blood from patients is ongoing.Background: Approximately 10% of EGFR mutants harbor uncommon mutations, which represent a heterogeneous group of rare molecular alterations within exons 18-21 and the sensitivity to EGFR TKIs is variable. Osimertinib is a potent irreversible inhibitor of both S344Journal of Thoracic Oncology Vol. 13 No. 10S12%. Infusion-related reactions were grade 2 severity, observed primarily with the first dose. The worst severity of rash/acneiform dermatitis was grade 2 (16%). One treatment-related AE of grade 3 severity was reported (neutropenia grade 3, possibly related). JNJ-372 demonstrated linear PK at dose levels 350 mg and above w...

No abstract

Methods: Diagnostic biopsy at baseline and subsequent tumorrebiopsies at progressions were examined by targeted next-generation sequencing of genomic DNA (Oncomine TM Focus; ThermoFisher Scientific) and total RNA (Archer® FusionPlex Solid Tumor panel; Arch-erDx). Circulating free DNA (cfDNA) from plasma was analyzed for relevant mutations by Oncomine Lung cfDNA NGS-assay (ThermoFisher Scientific). Results: At diagnosis, the patient had multiple brain and bone metastases and was treated with Erlotinib, whole-brain-radiotherapy (WBRT) and palliative bone radiation. Despite radiological SD, a liquid biopsy (LB) six months later revealed persistent EGFR-L858R mutation in the cfDNA. After 9 months of Erlotinib treatment the tumor progressed with liver metastasis. The 1 st rebiopsy revealed T790M mutation and the patient started Osimertinib. After 8 months, isolated metastatic adrenal progression was observed and 2 nd rebiopsy revealed persistent EGFR-L858R, -T790M, and a new -C797S mutation in cis-position. The patient received stereotactic radiotherapy, continued Osimertinib, and after 11 months a new LB still showed EGFR-L858R, while after 14 months, progression emerged with new thoracic, hepatic and adrenal metastases. Rebiopsy of a thoracic lesion revealed phenotypic transformation to small-cell carcinoma (SCLC), while concomitant LB showed EGFR-L858R, -T790M, TP53 (Y220C), and KRAS (G12V) mutations. Carboplatin/Etoposide was initiated while continuing Osimertinib. After 3 cycles, a CT-scan showed PR in the thorax, but mixed response of liver metastases. The 4 th hepatic rebiopsy only displayed NSCLC with EGFR-L858R. Osimertinib was continued and chemotherapy modified to Carboplatin/Pemetrexed. However, contemporaneous cfDNA contained persistent co-existing EGFR-L858R, EGFR-T790M, EGFR-C797S, KRAS-G12V, and TP53-Y220C, indicating multiclonal disease. The patient's condition deteriorated with additional pulmonary embolism. Osimertinib was continued together with Gefitinib. The following CT scan showed thoracic SD, but new hepatic progression. The patient s PS terminally worsened to 4. The last LB showed persistent EGFR-L858R, EGFR-T790M, KRAS-G12V, and TP53-Y220C clones, as well as newly appeared BRAF-V600E mutation. Conclusion: 1. EGFR-L858R NSCLC is biologically unstable disease and may display variable EGFR-dependent/-independent mechanisms of acquired TKI-resistance detectable both in tumor-rebiopsies and LBs, with the latter ones being more suitable for identifying multiple resistant clones and the former ones necessary for recognition of SCLCtransformation. 2. In our patient, persistent EGFR-L858R mutation in the cfDNA 6 months after Erlotinib-start and 11 months after Osimertinib-start correlated with aggressive disease course. 3. The TKI-resistance mechanisms observed in the terminal phase (KRAS-and BRAF-mutations) represent targets for emerging combination-treatment options that are appearing in the repertoire of targeted therapies for NSCLC and may lead extended control of this complex disease in the futu...

No abstract

No abstract