Successful treatment after toxic epidermal necrolysis induced by AZD-9291 in a patient with non-small cell lung cancer: A case report

BACKGROUNDToxic epidermal necrolysis and Stevens-Johnson syndrome are acute life-threatening skin reactions. AZD9291 has been developed as a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) with activity against T790M mutation.CASE SUMMARYHerein we report a 68-year-old woman who developed a large area of skin necrosis and was diagnosed with toxic epidermal necrolysis after AZD-9291 ingestion. To the best of our knowledge, this is the first case reported in patients with EGFR T790M mutation in non-small cell lung cancer (NSCLC). Cabozantinib combined with erlotinib had clinically meaningful effectiveness, with additional toxicity that was generally manageable.CONCLUSIONTreatment with AZD-9261 is effective in regressing the growth of the NSCLC and can bring some hope to despairing patients. We hope that more research will be carried out on the association between severe rashes and EGFR-TKIs, and more safe and effective drugs can be developed.     

Tyrosine Kinase Inhibitors for the Treatment of EGFR Mutation-Positive Non–Small-Cell Lung Cancer: A Clash of the Generations

The availability of 3 generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with different pharmacologic characteristics and clinical profiles has provided oncologists with a potentially confusing choice for the treatment of EGFR mutation-positive non–small-cell lung cancer. Although recent head-to-head clinical trials have demonstrated improved efficacy with second-generation (ie, afatinib, dacomitinib) and third-generation (ie, osimertinib) TKIs compared with the first-generation TKIs (eg, erlotinib, gefitinib), acquired resistance has been inevitable, regardless of which agent has been chosen as first-line therapy. Thus, the potential availability of subsequent treatment options is an important consideration. Recent data have demonstrated that osimertinib confers an overall survival benefit compared with first-generation EGFR TKIs, and dacomitinib has shown an overall survival benefit compared with gefitinib in an exploratory analysis. However, the relative benefits of different sequential EGFR-TKI regimens, especially those involving second- and third-generation agents, have remained uncertain and require prospective evaluation. Few such data currently exist to inform treatment choices. In the present review, we examined the pharmacologic characteristics and current clinical data for EGFR TKIs, including emerging information on the molecular mechanisms of resistance across the different generations of TKIs. Given the uncertainties regarding the optimal treatment choice, we have focused on the factors that might help determine the treatment decisions, such as efficacy and safety in patient subgroups. We also discussed the emerging real-world data, which have provided some insights into the benefits of sequential regimens in everyday clinical practice.     

新型双胍衍生物1-正戊基-5-(4-三氟甲氧基苯基)双胍联合奥希替尼抑制膀胱癌细胞增殖

目的 探讨新型双胍衍生物1-正戊基-5-（4-三氟甲氧基苯基）双胍（5C）、奥希替尼单用及联用对膀胱癌的抑制作用及机制。方法 采用MTT实验、细胞克隆实验检测5C、奥希替尼单用及联用对膀胱癌细胞增殖、集落形成的影响。采用Western blotting检测5C联合奥希替尼对表皮生长因子受体（EGFR）及其下游信号通路的影响。结果 5C、奥希替尼单用均可显著抑制膀胱癌细胞增殖和集落形成,且二者联用能更好地抑制膀胱癌细胞的增殖与集落形成能力。机制研究表明,5C与奥希替尼联用能显著抑制EGFR及其下游信号通路Akt/Erk的磷酸化。结论 5C联合奥希替尼可通过下调EGFR及其下游信号通路抑制膀胱癌细胞生长。     

Effective Treatment of Lung Adenocarcinoma Harboring EGFR-Activating Mutation,T790M,and cis-C797S Triple Mutations by Brigatinib and Cetuximab Combination Therapy

IntroductionAcquired resistance to osimertinib mediated by EGFR cis-C797S is now a growing challenge. No effective treatment strategy is currently available to overcome cis-C797S–mediated resistance.MethodsIn this retrospective cohort study, 15 patients with advanced lung adenocarcinoma and EGFR-activating mutation, T790M, and cis-C797S after osimertinib progression were identified by targeted next-generation sequencing. Five of these patients received a combined therapy of brigatinib and cetuximab, and 10 patients received cisplatin-based doublet chemotherapy.ResultsAmong the five patients who were positive for EGFR 19del-T790M-cis-C797S mutations, and who received brigatinib and cetuximab combination therapy, three patients achieved partial response, and two had stable disease, resulting in an overall objective response rate of 60% and disease control rate of 100%. Among the 10 patients who were positive for EGFR 19del or L858R-T790M-cis-C797S mutations and received chemotherapy, only one patient achieved partial response, five had stable disease, and the other four did not benefit from chemotherapy, resulting in an overall objective response rate and disease control rate of 10% and 60%, respectively. The median progression-free survival of patients who received combined targeted therapy was 14 months, and 3 months for those treated with chemotherapy. No grade III to IV adverse events were observed in any patient.ConclusionsOur retrospective study provides clinical evidence that a combined targeted therapy of brigatinib and cetuximab could be of benefit and may potentially be an effective treatment strategy to improve survival outcomes in patients who acquire EGFR T790M-cis-C797S–mediated resistance to osimertinib.     

Exon 16–Skipping HER2 as a Novel Mechanism of Osimertinib Resistance in EGFR L858R/T790M–Positive Non–Small Cell Lung Cancer

IntroductionOsimertinib is the current recommended treatment for EGFR T790M–positive NSCLC after EGFR tyrosine kinase inhibitor therapy. However, resistance to osimertinib therapy is inevitably acquired after a period of effective treatment. We had a patient with EGFR L858R/T790M–positive NSCLC who initially responded to osimertinib therapy but eventually experienced development of resistance. Plasma cell–free DNA analysis revealed the occurrence of exon 16–skipping HER2, which may have resulted in the erb-b2 receptor tyrosine kinase 2 gene (HER2) splice variant HER2D16. HER2D16 has never been reported in lung cancer, and HER2D16-driven signaling is known to be regulated by Src kinase in breast cancer. We investigated the role of HER2D16 as an osimertinib-resistant mechanism.MethodsWe constructed and established H1975 cells stably expressing HER2D16. The dimeric formation of HER2D16 was tested by using nonreducing polyacrylamide gel electrophoresis. The effects of the study drugs on signaling transduction were examined by using Western blot. Synergistic effect was assessed by using the Chou-Talalay method.ResultsWe found that HER2D16 can form a homodimer in NSCLC cells. HER2D16-expressing H1975 cells were resistant to osimertinib treatment. We also found that mutant EGFR and HER2D16 cooperated to activate downstream signaling for osimertinib resistance. In addition, cotreatment with osimertinib and an Src kinase inhibitor failed to reverse resistance, indicating that HER2D16-driven signaling in NSCLC did not occur through a canonical pathway. Finally, we revealed that the combination of osimertinib with the pan-HER small-molecule inhibitor afatinib could synergistically repress cell growth and signaling in H1975-HER2D16 cells.ConclusionHER2D16 can contribute to osimertinib resistance through an Src-independent pathway. HER2D16 should be included in the molecular diagnosis panel for lung cancer.     

Triple administration of osimertinib followed by chemotherapy for advanced lung adenocarcinoma: A case report

BACKGROUNDOsimertinib is the recommended first-line treatment for adult patients with epidermal growth factor receptor (EGFR) mutation positive advanced or metastatic non-small cell lung cancer (NSCLC). However, primary or acquired resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) seems inevitable, and when drug-resistance occurs during treatment with osimertinib, the standard of care is to discontinue the TKI. CASE SUMMARYA 57-year-old female patient with lung adenocarcinoma presented with an irritating cough accompanied by chest distress of one month duration. An enhanced head magnetic resonance imaging scan showed brain metastases. An EGFR mutation (exon 21 L858R) was detected in pleural fluid. The patient was treated with oral osimertinib (80 mg once daily) from January 2018 but developed progressive disease on December 2018. She was then successfully treated with re-challenge and tri-challenge with osimertinib (80 mg once daily) by resensitization chemotherapy twice after the occurrence of drug-resistance to osimertinib, and to date has survived for 31 mo.CONCLUSIONThis case may provide some selective therapeutic options for NSCLC patients with acquired drug-resistance who were previously controlled on osimertinib treatment.     

Modulation of Biomarker Expression by Osimertinib: Results of the Paired Tumor Biopsy Cohorts of the AURA Phase I Trial

IntroductionOsimertinib is an oral, potent, irreversible EGFR tyrosine kinase inhibitor (TKI) selective for EGFR TKI and T790M resistance mutations. To enhance understanding of osimertinib’s mechanism of action, we aimed to evaluate the modulation of key molecular biomarkers after osimertinib treatment in paired clinical samples from the phase I AURA trial.MethodsPaired tumor biopsy samples were collected before the study and after 15 plus or minus 7 days of osimertinib treatment (80 or 160 mg daily). Clinical efficacy outcomes were assessed according to whether viable paired biopsy samples could be collected; safety was also assessed. Immunohistochemical analyses assessed key pathway and tumor/immune-relevant markers (phospho-EGFR, phospho-S6, phospho-AKT, programmed death ligand 1, and CD8), with samples scored by image analysis or a pathologist blinded to treatment allocation.ResultsPredose tumor biopsy samples were collected from 61 patients with EGFR T790M tumors; 29 patients had no viable postdose biopsy sample because of tumor regression or insufficient tumor sample. Evaluable predose and postdose tumor biopsy samples were collected from 24 patients. Objective response rate (ORR) and median progression-free survival (mPFS) were improved in patients from whom a postdose biopsy sample could not be collected (ORR 62% and mPFS 9.7 months [p = 0.027]) compared with those from whom paired samples were collected (ORR 29% and mPFS 6.6 months). Osimertinib modulated key EGFR signaling pathways and led to increased immune cell infiltration.ConclusionsCollection of paired biopsy samples was challenging because of rapid tumor regression after osimertinib treatment, highlighting the difficulties of performing on-study biopsies in patients treated with highly active drugs.