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The year 2024 is the 20th anniversary of the discovery of activating epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC). Since then, tremendous advances have been made in the treatment of NSCLC based on this discovery. Some of these studies have led to seismic changes in the concept of oncology research and spurred treatment advances beyond NSCLC, leading to a current true era of precision oncology for all solid tumors. We now routinely molecularly profile all tumor types and even plasma samples of patients with NSCLC for multiple actionable driver mutations, independent of patient clinical characteristics nor is profiling limited to the advanced incurable stage. We are increasingly monitoring treatment responses and detecting resistance to targeted therapy by using plasma genotyping. Furthermore, we are now profiling early-stage NSCLC for appropriate adjuvant targeted treatment leading to an eventual potential "cure" in early-stage EGFR+ NSCLC which have societal implication on implementing lung cancer screening in never-smokers as most EGFR+ NSCLC patients are never-smokers. All these advances were unfathomable in 2004 when the five papers that described "discoveries" of activating EGFR mutations (del19, L858R, exon 20 insertions, and "uncommon" mutations) were published. To commemorate this 20th anniversary, we assembled a global panel of thoracic medical oncology experts to select the top 20 papers (publications or congress presentation) from the 20 years since this seminal discovery with December 31, 2023 as the cutoff date for inclusion of papers to be voted on. Papers ranked 21 to 30 were considered "honorable mention" and also annotated. Our objective is that these 30 papers with their annotations about their impact and even all the ranked papers will serve as "syllabus" for the education of future thoracic oncology trainees. Finally, we mentioned potential practice-changing clinical trials to be reported. One of them, LAURA was published online on June 2, 2024 was not included in the list of papers to be voted on but will surely be highly ranked if this consensus survery is performed again on the 25th anniversay of the discovery EGFR mutations (i.e. top 25 papers on the 25 years since the discovery of activating EGFR mutations).
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Introduction: NSCLC with MET exon 14 skipping mutation (METex14) is associated with poor outcomes. Integration of novel targeted therapies is challenging because of barriers in testing and drug access. We, therefore, sought to characterize the treatment patterns, outcomes, and emerging issues of treatment sequencing in patients with METex14-mutant NSCLC. Methods: We reviewed all NSCLC cases with METex14 alterations between 2014 and 2020 across four Canadian cancer centers. Demographics, disease characteristics, systemic therapy, overall response rates (ORRs), survival, and toxicity were summarized. Results: Among 64 patients with METex14-mutant NSCLC, the median overall survival was 23.1 months: 127.0 months in stage 1, 27.3 months in resected stage 2 and 3, and 16.6 months in unresectable stage 3 or 4 disease, respectively. In patients with advanced disease, 22% were too unwell for systemic treatment. MET tyrosine kinase inhibitors (TKIs) were administered to 28 patients with an ORR of 33%, median progression-free survival of 2.7 months, and 3.8 months for selective TKIs. Programmed cell death protein-1 (PD-1) inhibitors were given to 25 patients-the ORR was 44% and progression-free survival was 10.6 months. No responses were seen with subsequent MET TKIs after initial TKI treatment. Grade 3 or higher toxicities occurred in 64% of patients who received MET TKI after PD-1 inhibitors versus 8% in those who did not receive PD-1 inhibitors. Conclusions: Many patients with advanced METex14 NSCLC were too unwell to receive treatment. PD-1 inhibitors seem effective as an initial treatment, although greater toxicity was seen with subsequent MET TKIs. Thus, timely testing for METex14 skipping and initial therapy are imperative to improving patient survival.
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LKB1/STK11 is a serine/threonine kinase that plays a major role in controlling cell metabolism, resulting in potential therapeutic vulnerabilities in LKB1-mutant cancers. Here, we identify the NAD + degrading ectoenzyme, CD38, as a new target in LKB1-mutant NSCLC. Metabolic profiling of genetically engineered mouse models (GEMMs) revealed that LKB1 mutant lung cancers have a striking increase in ADP-ribose, a breakdown product of the critical redox co-factor, NAD + . Surprisingly, compared with other genetic subsets, murine and human LKB1-mutant NSCLC show marked overexpression of the NAD+-catabolizing ectoenzyme, CD38 on the surface of tumor cells. Loss of LKB1 or inactivation of Salt-Inducible Kinases (SIKs)-key downstream effectors of LKB1- induces CD38 transcription induction via a CREB binding site in the CD38 promoter. Treatment with the FDA-approved anti-CD38 antibody, daratumumab, inhibited growth of LKB1-mutant NSCLC xenografts. Together, these results reveal CD38 as a promising therapeutic target in patients with LKB1 mutant lung cancer. SIGNIFICANCE: Loss-of-function mutations in the LKB1 tumor suppressor of lung adenocarcinoma patients and are associated with resistance to current treatments. Our study identified CD38 as a potential therapeutic target that is highly overexpressed in this specific subtype of cancer, associated with a shift in NAD homeostasis.
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Lung neuroendocrine neoplasms (NENs) encompass a spectrum of neoplasms that are subdivided into the well-differentiated neuroendocrine tumors comprising the low- and intermediate-grade typical and atypical carcinoids, respectively, and the poorly differentiated, high-grade neuroendocrine carcinomas including large-cell neuroendocrine carcinomas and small-cell lung carcinoma (SCLC). Here, we review the current morphological and molecular classifications of the NENs on the basis of the updated WHO Classification of Thoracic Tumors and discuss the emerging subclassifications on the basis of molecular profiling and the potential therapeutic implications. We focus on the efforts in subtyping SCLC, a particularly aggressive tumor with few treatment options, and the recent advances in therapy with the adoption of immune checkpoint inhibitors in the frontline setting for patients with extensive-stage SCLC. We further highlight the promising immunotherapy strategies in SCLC that are currently under investigation.
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Carcinoma Neuroendócrino , Neoplasias Pulmonares , Tumores Neuroendócrinos , Carcinoma de Pequenas Células do Pulmão , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/terapia , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/terapia , Carcinoma Neuroendócrino/patologia , PulmãoRESUMO
Lung squamous cell carcinoma (LUSC) represents a major subtype of lung cancer with limited treatment options. KMT2D is one of the most frequently mutated genes in LUSC (>20%), and yet its role in LUSC oncogenesis remains unknown. Here, we identify KMT2D as a key regulator of LUSC tumorigenesis wherein Kmt2d deletion transforms lung basal cell organoids to LUSC. Kmt2d loss increases activation of receptor tyrosine kinases (RTKs), EGFR and ERBB2, partly through reprogramming the chromatin landscape to repress the expression of protein tyrosine phosphatases. These events provoke a robust elevation in the oncogenic RTK-RAS signaling. Combining SHP2 inhibitor SHP099 and pan-ERBB inhibitor afatinib inhibits lung tumor growth in Kmt2d-deficient LUSC murine models and in patient-derived xenografts (PDXs) harboring KMT2D mutations. Our study identifies KMT2D as a pivotal epigenetic modulator for LUSC oncogenesis and suggests that KMT2D loss renders LUSC therapeutically vulnerable to RTK-RAS inhibition.
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Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Animais , Humanos , Camundongos , Carcinogênese/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/genética , Transformação Celular Neoplásica , Pulmão/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Proteínas ras/antagonistas & inibidores , Proteínas ras/metabolismoRESUMO
Squamous cell lung cancers (lung squamous cell carcinomas [LUSCs]) are associated with high mortality and a lack of therapies specific to this disease. Although recurrent molecular aberrations are present in LUSCs, efforts to develop targeted therapies against receptor tyrosine kinases, signaling transduction, and cell cycle checkpoints in LUSCs were met with significant challenges. The present therapeutic landscape focuses on epigenetic therapies to modulate the expression of lineage-dependent survival pathways and undruggable oncogenes. Another important therapeutic approach is to exploit metabolic vulnerabilities unique to LUSCs. These novel therapies may synergize with immune checkpoint inhibitors in the right therapeutic context. For example, the recognition that alterations in KEAP1-NFE2L2 in LUSCs affected antitumor immune responses created unique opportunities for targeted, metabolic, and immune combinations. This article provides a perspective on how lessons learned from the past influence the current therapeutic landscape and opportunities for future drug development for LUSCs.
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Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Fator 2 Relacionado a NF-E2/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Células Epiteliais/patologiaAssuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Acrilamidas , Ásia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Humanos , Indóis , Neoplasias Pulmonares/tratamento farmacológico , Morfolinas , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis , PirimidinasRESUMO
Type I interferons (IFN-Is) are central regulators of anti-tumor immunity and responses to immunotherapy, but they also drive the feedback inhibition underlying therapeutic resistance. In the present study, we developed a mass cytometry approach to quantify IFN-I-stimulated protein expression across immune cells and used multi-omics to uncover pre-therapy cellular states encoding responsiveness to inflammation. Analyzing peripheral blood cells from multiple cancer types revealed that differential responsiveness to IFN-Is before anti-programmed cell death protein 1 (PD1) treatment was highly predictive of long-term survival after therapy. Unexpectedly, IFN-I hyporesponsiveness efficiently predicted long-term survival, whereas high responsiveness to IFN-I was strongly associated with treatment failure and diminished survival time. Peripheral IFN-I responsive states were not associated with tumor inflammation, identifying a disconnect between systemic immune potential and 'cold' or 'hot' tumor states. Mechanistically, IFN-I responsiveness was epigenetically imprinted before therapy, poising cells for differential inflammatory responses and dysfunctional T cell effector programs. Thus, we identify physiological cell states with clinical importance that can predict success and long-term survival of PD1-blocking immunotherapy.
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Interferon Tipo I , Humanos , Imunoterapia , Inflamação , Linfócitos TRESUMO
BACKGROUND: Testing for tumor programmed death ligand-1 (PD-L1) expression was initially developed with histology specimens in non-small cell lung cancer (NSCLC). However, cytology specimens are widely used for primary diagnosis and biomarker studies in clinical practice. Limited clinical data exist on the predictiveness of cytology-derived PD-L1 scores for response to immune checkpoint inhibitor (ICI) therapy. METHODS: We reviewed all NSCLC specimens clinically tested at the University Health Network (UHN) for PD-L1 with 22C3pharmDx, from 01/2013 to 04/2021. Treatment outcomes in patients treated with single agent ICI therapy were reviewed and compared according to cytology- and histology-derived PD-L1 scores. RESULTS: We identified 494 and 1942 unique patients with cytology- and histology-derived tumor proportion scores, respectively, during the study period. Informative testing rates were 95 % vs 98 % for cytology and histology, respectively. Clinical data were available for 152 patients treated with single agent ICI: 61 cytology and 91 histology. Overall response rates (ORR) were similar for cytology and histology (36 % vs 34 %; p = 0.23), as well as median progression free survival (PFS) (4.9 vs 4.2 months; p = 0.99) and overall survival (23.4 vs 19.7 months; p = 0.99). The results remained similar even after adjusting for PD-L1 expression levels and line of ICI treatment (PFS HR 1.15; 95 %CI 0.78-1.70; p = 0.47). CONCLUSIONS: Treatment outcomes to single agent ICI based on cytology-derived PD-L1 scores were comparable to histology controls. Our results support PD-L1 biomarker testing on both cytology and histology specimens.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/patologiaRESUMO
INTRODUCTION: The addition of durvalumab after chemoradiation therapy (CRT) in unresectable stage III NSCLC significantly improves survival. The benefit of this approach in elderly patients is controversial given the toxicity associated with CRT and, thus, may be underutilized. We sought to investigate the outcomes of elderly patients treated with CRT without or without durvalumab at our center. METHODS: We reviewed all stage III patients with NSCLC treated with CRT between 2018 and 2020. Patients were analyzed on the basis of age: less than 70 years and 70 years and older. The end points evaluated were treatment patterns, toxicity, progression-free survival, and overall survival. RESULTS: The baseline characteristics including Eastern Cooperative Oncology Group performance status and comorbidities were similar among the 115 patients (44 elderly, 71 young). Completion rates of CRT (100%, 97%) and chemotherapy dose intensity (97%, 97%) were high in elderly and young patients, respectively. There was a trend toward increased hospitalizations in elderly patients because of infections (27% versus 13%, p = 0.08). Of those who did not have primary progression after CRT, 78% of eldery and 81% of young patients received durvalumab. The incidence of grade 3 or higher immune-related adverse events was 9% in elderly and 6% in young patients (p = 0.67). The median progression-free survival was similar (15.6 versus 10.5 mo, p = 0.10), even after adjusting for comorbidities (hazard ratio = 0.6, p = 0.09). The 12-month overall survival rates were 78% in the elderly and 76% in young patients (p = 0.98). CONCLUSIONS: Well-selected elderly patients can be treated safely with CRT followed by durvalumab with similar survival benefits compared with their younger counterparts. We would advocate for the referral of all elderly patients for oncologic assessment to avoid undertreatment.
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BACKGROUND: Immune checkpoint inhibitors (ICIs) have excellent systemic activity and are standard first line treatment in EGFR/ALK wild type metastatic non-small cell lung cancer (NSCLC). However, their role in patients with brain metastases, which affects over 20% of patients and cause significant morbidity, is less clear. METHODS: We reviewed patients with EGFR/ALK wild-type mNSCLC with CNS metastases. Serial MRIs were reviewed to determine the time to intracranial progression (iPFS). Multivariate regression was performed to adjust for the disease-specific graded prognostic score (ds-GPA). RESULTS: We identified 36 ICI- and 33 chemotherapy-treated patients with baseline CNS metastases and available serial MRIs (average frequency:3.5 months). Baseline radiation was given except for 2 chemotherapy-treated patients with asymptomatic solitary metastasis. The CNS burden of disease was higher in the ICI-treated group (ICI:22% vs. chemotherapy:0% had >10 lesions; p = 0.02), but the utilization of WBRT was not (ICI:31% vs. chemotherapy:45%; p = 0.09). At the time of progression, CNS involvement was identified in 30 % of ICI-treated patients compared to 64 % of chemotherapy controls (p = 0.02). ICI-treated patients had superior iPFS (13.5 vs 8.4 months) that remained significant in multivariate analysis (HR 1.9; 95%CI 1.1--3.4). Superior CNS outcomes in ICI-treated patients were driven by the PD-L1 high subgroup where the 12-month cumulative incidence rate of CNS progression was 19% in ICI-treated PD-L1 ≥ 50%, 50% in ICI-treated PD-L1 < 50% and 58% in chemotherapy-treated patients (p = 0.03). CONCLUSIONS: Remarkable CNS disease control is seen with baseline RT plus ICIs in patients with PD-L1 ≥ 50%. Strategies for delaying WBRT should be investigated in this subgroup of patients.
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Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Neoplasias Encefálicas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Irradiação Craniana , Humanos , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
INTRODUCTION: Programmed death-ligand 1 (PD-L1) is used as a biomarker for anti-programmed cell death protein-1 (PD-1) or anti-PD-L1 immunotherapies in NSCLC. We report here the results of population-based PD-L1 testing using the 22C3 IHC pharmDx Assay (Agilent Technologies) in a large Canadian regional reference pathology laboratory. METHODS: Testing was conducted reflexively on biopsies and resections for NSCLC during an 8-month period. Tumor proportion score (TPS) cutoffs for low and high expression were 1% and 50%, respectively. RESULTS: Altogether, 2031 PD-L1 tests were performed on specimens from 1795 patients, with 107 inconclusive results (5.3%). Excluding cases with inconclusive/missing data, proportions for the remaining 1713 patients were 41.6% for TPS less than 1%, 28.6% for TPS 1% to 49%, and 29.8% for TPS greater than or equal to 50%. Higher PD-L1 expression rates were noted in EGFR wild-type versus mutant tumors (p < 0.001), squamous versus adenocarcinoma (p < 0.001), and metastatic versus primary tumors (p < 0.001). PD-L1 among 103 patients with paired biopsy and resection specimens revealed moderate concordance (κ = 0.67). A total of 52% (25 of 48) of biopsies with TPS less than 1% had TPS greater than 1% in resection, whereas 84.6% (22 of 26) of biopsies with TPS greater than or equal to 50% were concordant in resected tumors. Discordance rates between biopsy and resection were 71.4% for biopsies with less than 8 mm2 total area, compared with 33.3% for biopsies with greater than or equal to 8 mm2 area (p < 0.026). Concordance among 27 patients with paired primary lung and metastatic tumor biopsies revealed only weak concordance (κ = 0.48). CONCLUSIONS: Intratumoral heterogeneity of PD-L1 expression may result in misclassification of PD-L1 status in a substantial proportion of PD-L1-negative small biopsy samples. Biopsy of metastatic site may increase proportion of patients with high PD-L1 expression.
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Antígeno B7-H1 , Neoplasias Pulmonares , Biomarcadores Tumorais/genética , Canadá , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/genética , PrevalênciaRESUMO
INTRODUCTION: The efficacy of immune checkpoint inhibitors (ICIs) is low among EGFR-mutated non-small-cell lung cancer (NSCLC), although prolonged responses have occasionally been reported. We investigated the association between mutation subtypes and ICI outcomes among HER2- and EGFR-mutated NSCLC. PATIENTS AND METHODS: This retrospective single-center study analyzed patients with EGFR- and HER2-mutated advanced NSCLC who received at least 1 cycle of ICI between 2013 and 2019. Patient characteristics, mutation subtype, and ICI outcomes. RESULTS: Among 48 patients with advanced NSCLC, 14 (29%) had HER2 mutations and 34 (71%) had EGFR mutations. EGFR mutations included 16 (47%) exon 19 deletion, 7 (21%) L858R, 5 (15%) uncommon, and 6 (18%) exon 20 insertion. Compared to EGFR-sensitizing mutations (ESMs), HER2 and EGFR exon 20 mutations were associated with a trend toward better response (respectively, ESM, HER2, and EGFR exon 20: 11%, 29%, and 50%; P = .07) and significantly better disease control rates (respectively, 18%, 57%, and 67%; P = .008). Compared to ESM, HER2 mutations (adjusted hazard ratio, 0.35; P = .02) and EGFR exon 20 mutations (adjusted hazard ratio, 0.37; P = .10 trend) were also associated with improved PFS. Programmed death ligand 1 (PD-L1) expression remained an independent predictor of PFS (adjusted hazard ratio, 0.42; 95% confidence interval, 0.23-0.76; P = .004). The 6-month PFS rates were 29% (HER2), 33% (EGFR exon 20), and 4% (ESM). ICIs were generally well tolerated in this population. Importantly, no immune-related toxicity was observed in 10 patients who received a tyrosine kinase inhibitor (TKI) as the immediate next line treatment after ICI. CONCLUSION: HER2 and EGFR exon 20 mutations derive greater benefit from ICIs with comparable PFS to wild-type historical second/third-line unselected cohorts. ICIs remain a treatment option for this genomic subgroup, given the absence of approved targeted therapies for these rare mutations.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos de Coortes , Receptores ErbB/genética , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Receptor ErbB-2/genética , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Tobacco exposure contributes to over 80 % of lung cancer cases. Smoking is associated with programmed death-ligand 1 (PD-L1) tumor expression and better outcomes from anti-programmed cell death protein 1 (anti-PD-1) therapy in patients with advanced non-small cell lung cancer (NSCLC). PD-L1 tumor expression is now routinely used to predict benefit from anti-PD-1 therapy in patients with advanced NSCLC. In this study, we explored the impact of smoking status on patient outcomes with anti-PD-1 therapy in addition to PD-L1 tumor expression. METHODS: A prospective real-world cohort of 268 patients with advanced NSCLC treated with anti-PD-1 monotherapy at the Princess Margaret Cancer Centre (PMCC) was used for this analysis. Logistic regression was performed to test factors associated with treatment response (RECIST v1.1), including PD-L1 tumour proportion score (TPS) and smoking status. RESULTS: Overall response rates (ORR) to immunotherapy were significantly higher in current and former smokers than never smokers (36 % vs 26 % vs 14 %; pâ¯=â¯0.02). In patients with PD-L1 tumour proportion score (TPS) ≥50 %, current smokers continued to experience better ORR to anti-PD-1 therapy than never smokers (58 % vs 19 %; pâ¯=â¯0.03). Current smoking was associated with higher response even after adjusting for level of PD-L1 TPS expression (adjusted odds ratio 5.9, 95 % CI 1.6-25.0, pâ¯=â¯0.03). Exploratory analysis demonstrated higher 1-year survival rates in smokers compared to never smokers (pâ¯=â¯0.003). CONCLUSIONS: Smoking remains an important factor associated with response to anti-PD-1 monotherapy. Advanced NSCLC patients with positive PD-L1 expression are more likely to respond to anti-PD-1 monotherapy if they are current smokers compared to never smokers.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Imunoterapia , Neoplasias Pulmonares/terapia , Estudos Prospectivos , NicotianaAssuntos
Adenocarcinoma de Pulmão , Carcinoma Neuroendócrino , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/genética , Quinase do Linfoma Anaplásico/genética , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/genética , Rearranjo Gênico , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genéticaRESUMO
The use of targeted therapy in the management of epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer is an important milestone in the management of advanced lung cancer. There are several generations of EGFR tyrosine kinase inhibitors available for clinical use. Dacomitinib is a second-generation irreversible EGFR tyrosine kinase inhibitor with early-phase clinical studies showing efficacy in non-small-cell lung cancer. In the recently published ARCHER 1050 phase III study, dacomitinib given at 45 mg/day orally was superior to gefitinib, a first-generation reversible EGFR tyrosine kinase inhibitor, in improving both progression-free survival and overall survival when given as first-line therapy. There is no prospective evidence to support the use of dacomitinib as subsequent therapy in patients previously treated with chemotherapy or a first-generation EGFR tyrosine kinase inhibitor such as gefitinib and erlotinib. Dacomitinib has not demonstrated any benefit in unselected patients with non-small-cell lung cancer, and its use should be limited to those with known EGFR-sensitizing mutations. Dacomitinib is associated with increased toxicities of diarrhea, rash, stomatitis, and paronychia compared with first-generation EGFR inhibitors. Global quality of life was maintained when assessed in phase III studies. Overall, dacomitinib is an important first- line agent in EGFR-mutated non-small-cell lung cancer in otherwise fit patients whose toxicities can be well managed.