osimertinib and Small-Cell-Lung-Carcinoma

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Around 30% of patients are diagnosed with early disease and 60% after the tumour has spread to a different part of the body. The earlier NSCLC is diagnosed, the better the chances of prolonging survival. Recent years have seen striking improvements in cancer treatment outcomes through increased use of molecular diagnostics. Therapy decisions are now based on a combination of genetic testing and genetically matched targeted therapies. The positive results obtained with the use of tyrosine kinase inhibitors (TKIs), including osimertinib, in the metastatic disease, coupled with recent data in early stage disease support the importance of molecular testing in this setting. In this overview we discuss factors paramount in pathological pathways to ensure optimal management of early stage NSCLC and also provide an overview of requirements/recommendations. Critical issues in the pre-analytical phases regarding both cytology/biopsy samples and surgically resected tissues are highlighted and solutions are proposed to guarantee accuracy, adequacy and sustainability in the innovative approach to be introduced in clinical practice for NSCLC patients.

Topics: Acrylamides; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Chemotherapy, Adjuvant; Humans; Indoles; Lung Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Small Cell Lung Carcinoma

Topics: Acrylamides; Adenocarcinoma; Aniline Compounds; Cell Transformation, Neoplastic; ErbB Receptors; Female; Humans; Lung Neoplasms; Middle Aged; Mutation; Prognosis; Small Cell Lung Carcinoma

This Delphi panel study assessed the level of consensus between medical oncologists on the clinical management of patients with early-stage EGFR-mutated non-small cell lung cancer (NSCLC).. A modified two-round Delphi approach was used. A scientific committee comprised of medical oncologists developed an online questionnaire. Delphi panel experts rated their level of agreement with each questionnaire statement on a 9-point Likert scale. The questionnaire included 36 statements from 3 domains (clinical management of early-stage NSCLC: 15 statements; role of adjuvant therapy in early-stage NSCLC: 9 statements; and role of adjuvant therapy in early-stage NSCLC with sensitizing EGFR mutation: 12 statements).. In round 1, consensus was reached for 24/36 statements (66.7%). Nine statements that did not achieve consensus after the first round were evaluated in round 2, and none of them reached consensus. Overall, 84.4% of the panelists agreed that EGFR mutation testing should be done after surgery. Consensus was not achieved on whether the implementation of EGFR mutation testing in resected early-stage NSCLC could limit the use of adjuvant osimertinib. The panelists recognized the rationale for the use of osimertinib in the adjuvant scenario (88%) and 72% agreed that it may change the treatment paradigm in stage IB-IIIA EGFR-mutated NSCLC. Consensus was not reached on the inconvenience of prolonged duration of osimertinib.. This Delphi study provides valuable insights into relevant questions in the management of early-stage EGFR-mutated NSCLC. However, specific issues remain unresolved. The expert consensus emphasizes the role of adjuvant treatment with osimertinib in this scenario.

Topics: Carcinoma, Non-Small-Cell Lung; Delphi Technique; ErbB Receptors; Humans; Lung Neoplasms; Small Cell Lung Carcinoma; Spain

Osimertinib is a third-generation tyrosine kinase inhibitor for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)-sensitizing mutations and acquired drug-resistant mutation T790M. Despite promising treatment benefits of osimertinib in first- and second-line settings, drug resistance has been an inevitable clinical issue. The resistance to osimertinib is heterogeneous, which may involve EGFR-dependent and independent mechanisms as well as histological transformation from NSCLC to small cell lung cancer (SCLC). Current clinical studies of NSCLC were mainly focused on patients with EGFR-sensitizing mutations or acquired T790M mutation or both. The treatments and drug-resistant mechanisms in patients with de-novo T790M mutation remain undefined. Herein, we reported the presence of the less common de-novo EGFR T790M mutation in a stage IV NSCLC patient. The patient received osimertinib as first-line treatment and achieved durable progression-free survival (PFS) for 24 months. After osimertinib resistance, tumor biopsy indicated histologic transformation from NSCLC to SCLC. Given persistent presence of de-novo T790M mutation, osimertinib was used in combination with etoposide and cisplatin as second-line treatment and the patient achieved partial response with PFS of 7 months. Our study suggested that NSCLC patients with de-novo T790M mutation could also benefit from osimertinib and the SCLC transformation may be a potential resistance mechanism that could be targeted through the combination of targeted therapy and chemotherapy.

Topics: Adenocarcinoma of Lung; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Small Cell Lung Carcinoma

In the phase III ADAURA trial, adjuvant treatment with osimertinib versus placebo, with/without prior adjuvant chemotherapy, resulted in a statistically significant and clinically meaningful disease-free survival benefit in completely resected stage IB-IIIA EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). We report health-related quality of life (HRQoL) outcomes from ADAURA.. Patients randomized 1:1 received oral osimertinib 80 mg or placebo for 3 years or until recurrence/discontinuation. HRQoL (secondary endpoint) was measured using the Short Form-36 (SF-36) health survey at baseline, 12, and 24 weeks, then every 24 weeks until recurrence or treatment completion/discontinuation. Exploratory analyses of SF-36 score changes from baseline until week 96 and time to deterioration (TTD) were performed in the overall population (stage IB-IIIA; N = 682). Clinically meaningful changes were defined using the SF-36 manual.. Baseline physical/mental component summary (PCS/MCS) scores were comparable between osimertinib and placebo (range, 46-47) and maintained to Week 96, with no clinically meaningful differences between arms; difference in adjusted least squares (LS) mean [95% confidence intervals (CI), -1.18 (-2.02 to -0.34) and -1.34 (-2.40 to -0.28), for PCS and MCS, respectively. There were no differences between arms for TTD of PCS and MCS; HR, 1.17 (95% CI, 0.82-1.67) and HR, 0.98 (95% CI, 0.70-1.39), respectively.. HRQoL was maintained with adjuvant osimertinib in patients with stage IB-IIIA EGFRm NSCLC, who were disease-free after complete resection, with no clinically meaningful differences versus placebo, further supporting adjuvant osimertinib as a new treatment in this setting. See related commentary by Patil and Bunn, p. 2204.

Topics: Acrylamides; Adjuvants, Immunologic; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Quality of Life; Small Cell Lung Carcinoma

The ADAURA trial demonstrated the benefit of adjuvant osimertinib among patients with resected, early-stage, epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC). To understand the potential population impact, it is critical to deduce the prevalence, management, and outcomes of this patient population in the real-world setting before use of adjuvant osimertinib.. Using PALEOS (Pan-cAnadian Lung cancEr Observational Study) data (2012-2019), a retrospective, multi-center, observational cohort study was conducted among patients with early-stage (IB-IIIA) resected NSCLC who had not received neoadjuvant therapy. Study outcomes included EGFRm prevalence, treatment patterns, recurrence outcomes, and overall and disease-free survival (OS/DFS).. Among patients undergoing reflexive EGFRm testing by a pathologist at time of diagnosis irrespective of disease stage (N = 535), 23 % were EGFRm-positive; 15.9 % had common mutations and 5.6 % had uncommon mutations. Within the EGFRm-positive cohort (N = 156), mean age at diagnosis was 68 years, 65 % of patients were female, and 35 % were of Asian descent. At diagnosis, 48 %, 31 %, and 21 % had stage IB, II, or IIIA disease, respectively; 46 % received adjuvant therapy after resection. Half of patients experienced disease recurrence, typically involving distant sites; central nervous system metastasis varied from 12 % to 15.0 % across disease stages. EGFR tyrosine kinase inhibitors were the most commonly received therapy after first metastatic recurrence. Median OS (DFS) was not reached, 71.2 (22.8) months, and 50.1 (18.0) months among stage IB, II, and IIIA patients. Patients with uncommon EGFRm had a lower probability of survival than those with common EGFRm (2 years: 87 % vs 91 %-94 %; 4 years: 56 % vs 73 %-82 %).. Approximately-one-quarter of patients with resected, early-stage NSCLC were EGFRm-positive in this study. These patients had high recurrence rates and suboptimal long-term survival after treatment with current therapies. New adjuvant treatments are warranted.

Topics: Canada; Carcinoma, Non-Small-Cell Lung; Chemotherapy, Adjuvant; ErbB Receptors; Female; Humans; Lung Neoplasms; Male; Mutation; Neoplasm Recurrence, Local; Neoplasm Staging; Prevalence; Protein Kinase Inhibitors; Retrospective Studies; Small Cell Lung Carcinoma

Genotypic and histological evolution of non-small-cell lung cancer (NSCLC) into small-cell lung cancer (SCLC) has been described as a mechanism of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy. However, the number of clinical cases is rare.. Two lung adenocarcinoma patients with EGFR mutations who recurred after radical resection transformed into SCLC under treatment with the sequential first- and third-generation EGFR-TKIs.. The 2 cases were both confirmed as SCLC by pathological rebiopsy after EGFR-TKIs resistance.. Case 1 was treated with etoposide plus cisplatin (EP) regimen and erlotinib, while case 2 was treated with erlotinib and EP followed by oral etoposide.. Case 1 treated with EP only achieved 3-month progression-free survival (PFS), which is the first case that reported T790 M/C797S cis-mutation for osimertinib resistance before the SCLC transformation. However, case 2 treated with erlotinib and EP followed by oral etoposide, PFS lasted for 8 months.. The cases highlighted the importance of rebiopsy that identified pathologically SCLC transformation after EGFR-TKI resistance, and suggested the treatment of erlotinib plus EP followed by etoposide, which could provide a reference for such phenotype.

Topics: Acrylamides; Adult; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Carcinoma, Non-Small-Cell Lung; Cisplatin; Drug Resistance, Neoplasm; Epirubicin; ErbB Receptors; Erlotinib Hydrochloride; Fatal Outcome; Female; Humans; Lung; Lung Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasm Recurrence, Local; Pneumonectomy; Protein Kinase Inhibitors; Small Cell Lung Carcinoma; Tomography, X-Ray Computed; Treatment Outcome

Epidermal growth factor receptor (EGFR) gene-mutated non-small cell lung cancer may initially respond to EGFR tyrosine kinase inhibitors (TKIs), but may subsequently become resistant; however, the resistance mechanisms remain unclear. We report a rare case of acquired resistance to osimertinib associated with transformation to small cell lung cancer (SCLC) with cis-C797S mutation. A man with recurrent lung adenocarcinoma harboring an

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Neoplasms; Male; Mutation; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Small Cell Lung Carcinoma

A large number of EGFR mutant non-small cell lung cancer patients primordially benefit from first-line treatment with first-generation EGFR-tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. However, multiple acquired resistance mechanisms have been described that limit the clinical efficacy of first-generation EGFR-TKIs. Herein, we report a rare case of lung adenocarcinoma harboring an EGFR exon 19-deletion mutation before the administration of target therapy. This patient acquired resistance to first-generation EGFR-TKIs through small cell lung cancer (SCLC) transformation accompanied by the T790M mutation. Unexpectedly, this SCLC patient maintained a sensitive response to the third-generation EGFR-TKI osimertinib. This special case may indicate that osimertinib represents an effective target drug for SCLC patients who harbor an EGFR T790M mutation.

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Lung Neoplasms; Middle Aged; Mutation; Prognosis; Protein Kinase Inhibitors; Small Cell Lung Carcinoma

Topics: Acrylamides; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Caveolin 1; Crizotinib; Female; Humans; Lung Neoplasms; Middle Aged; Small Cell Lung Carcinoma

AZD9291, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), benefits patients with T790M mutant non-small-cell lung cancer who fail treatment with first-generation EGFR TKIs. Acquisition of resistance to AZD9291 occurs inevitable and mechanisms need to be explored. We reported an advanced lung adenocarcinoma female with EGFR exon19 deletion treated on AZD9291 after failure of erlotinib and chemotherapy. Disease progressed again after 6 months' treatment of AZD9291 with hepatic metastasis. Re-biopsy of the hepatic lesion showed histopathology transformation to small cell lung cancer, which harbored EGFR exon19 deletion. Therefore, small cell carcinoma transformation is one of potential resistance mechanisms to AZD9291 and regimen for small cell carcinoma may be one of the treatment options.

Topics: Acrylamides; Aniline Compounds; Drug Resistance, Neoplasm; Female; Humans; Middle Aged; Protein Kinase Inhibitors; Small Cell Lung Carcinoma