Current knowledge of small cell lung cancer transformation from non-small cell lung cancer.

Lung cancer is the leading cause of cancer related death, and is divided into two major histological subtypes, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Histological transformation from NSCLC to SCLC has been reported as a mechanism of treatment resistance in patients who received tyrosine kinase inhibitors (TKIs) targeting EGFR, ALK and ROS1 or immunotherapies. The transformed histology could be due to therapy-induced lineage plasticity or clonal selection of pre-existing SCLC cells. Evidence supporting either mechanism exist in the literature. Here, we discuss potential mechanisms of transformation and review the current knowledge about cell of origin of NSCLC and SCLC. In addition, we summarize genomic alterations that are frequently observed in both "de novo" and transformed SCLC, such as TP53, RB1 and PIK3CA. We also discuss treatment options for transformed SCLC, including chemotherapy, radiotherapy, TKIs, immunotherapy and anti-angiogenic agents.

Advancements in small cell lung cancer.

Small cell lung cancer (SCLC) is a recalcitrant cancer with an urgent need for novel therapeutics, preclinical models, and elucidation of the molecular pathways responsible for its rapid resistance. Recently, there have been many significant advancements in our knowledge of SCLC that led to the development of novel treatments. This review will go over the recent attempts to provide new molecular subcategorization of SCLC, recent breakthroughs in various systemic treatments including immunotherapy, targeted therapy, cellular therapy, as well as advancements in radiation therapy.

Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC.

BACKGROUND: The efficacy and safety of the anti-programmed death ligand 1 (PD-L1) monoclonal antibody atezolizumab, as compared with those of platinum-based chemotherapy, as first-line treatment for patients with metastatic non-small-cell lung cancer (NSCLC) with PD-L1 expression are not known. METHODS: We conducted a randomized, open-label, phase 3 trial involving patients with metastatic nonsquamous or squamous NSCLC who had not previously received chemotherapy and who had PD-L1 expression on at least 1% of tumor cells or at least 1% of tumor-infiltrating immune cells as assessed by the SP142 immunohistochemical assay. Patients were assigned in a 1:1 ratio to receive atezolizumab or chemotherapy. Overall survival (primary end point) was tested hierarchically according to PD-L1 expression status among patients in the intention-to-treat population whose tumors were wild-type with respect to EGFR mutations or ALK translocations. Within the population with EGFR and ALK wild-type tumors, overall survival and progression-free survival were also prospectively assessed in subgroups defined according to findings on two PD-L1 assays as well as by blood-based tumor mutational burden. RESULTS: Overall, 572 patients were enrolled. In the subgroup of patients with EGFR and ALK wild-type tumors who had the highest expression of PD-L1 (205 patients), the median overall survival was longer by 7.1 months in the atezolizumab group than in the chemotherapy group (20.2 months vs. 13.1 months; hazard ratio for death, 0.59; P = 0.01). Among all the patients who could be evaluated for safety, adverse events occurred in 90.2% of the patients in the atezolizumab group and in 94.7% of those in the chemotherapy group; grade 3 or 4 adverse events occurred in 30.1% and 52.5% of the patients in the respective groups. Overall and progression-free survival favored atezolizumab in the subgroups with a high blood-based tumor mutational burden. CONCLUSIONS: Atezolizumab treatment resulted in significantly longer overall survival than platinum-based chemotherapy among patients with NSCLC with high PD-L1 expression, regardless of histologic type. (Funded by F. Hoffmann-La Roche/Genentech; IMpower110 ClinicalTrials.gov number, NCT02409342.).

Avelumab plus axitinib in unresectable or metastatic type B3 thymomas and thymic carcinomas (CAVEATT): a single-arm, multicentre, phase 2 trial.

BACKGROUND: Patients with advanced type B3 thymoma and thymic carcinoma resistant to chemotherapy have few treatment options. We report the efficacy and safety results of the combination of the anti-PD-L1 inhibitor avelumab with the anti-angiogenesis drug axitinib in patients with advanced type B3 thymoma and thymic carcinoma. METHODS: CAVEATT was a single-arm, multicentre, phase 2 trial, conducted in two Italian centres (the European Instituteof Oncology and the Humanitas Institute, Milan) in patients with histologically confirmed type B3 thymoma or thymic carcinoma, with advanced stage of disease who had progressed after at least one line of platinum-based chemotherapy. Previous treatment with an anti-angiogenesis drug was allowed but not with immune checkpoint inhibitors. Other inclusion criteria were age 18 years or older, an Eastern Cooperative Oncology Group performance status of 0-2, progressive disease, and presence of measurable disease according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1. Patients received avelumab 10 mg/kg intravenously every 2 weeks and axitinib 5 mg orally twice daily until disease progression or unacceptable toxicity. The primary endpoint was the centrally assessed overall response rate according to RECIST version 1.1. Patients who received at least one cycle of treatment and had at least one CT scan after treatment start at scheduled time point by protocol were judged assessable for response and were included in efficacy and safety analyses. This study is registered with EUDRACT, 2017-004048-38; enrolment is completed and follow-up is ongoing. FINDINGS: Between April 22, 2019, and June 30, 2021, 32 patients were enrolled. 27 patients had a thymic carcinoma, three a type B3 thymoma, and two a mixed type B3 thymoma and thymic carcinoma. 29 (91%) of 32 patients had stage IVB disease and 13 (41%) of 32 had been pretreated with an anti-angiogenesis drug. 11 of 32 patients had an overall response; thus the overall response rate was 34% (90% CI 21-50); no patients had a complete response, 11 (34%) had a partial response, 18 (56%) had stable disease, and in two patients (6%) progressive disease was the best response. The most common grade 3 or 4 adverse event was hypertension (grade 3 in six [19%] of 32 patients). Four (12%) of 32 patients developed serious adverse events that were new-onset immune-related adverse events, including one grade 3 interstitial pneumonitis, one grade 4 polymyositis, and two grade 3 polymyositis. There were no treatment-related deaths. INTERPRETATION: Avelumab combined with axitinib has promising anti-tumour activity and acceptable toxicity in patients with advanced type B3 thymoma and thymic carcinoma progressing after chemotherapy, and could emerge as a new standard treatment option in this setting. FUNDING: Pfizer.

Exploiting mesothelin in thymic carcinoma as a drug delivery target for anetumab ravtansine.

BACKGROUND: Thymic epithelial tumours (TETs) are rare tumours comprised of thymomas and thymic carcinoma. Novel therapies are needed, especially in thymic carcinoma where the 5-year survival rate hovers at 30%. Mesothelin (MSLN), a surface glycoprotein that is cleaved to produce mature MSLN (mMSLN) and megakaryocyte potentiating factor (MPF), is expressed in limited tissues. However, its expression is present in various cancers, including thymic carcinoma, where it is expressed in 79% of cases. METHODS: We utilised flow cytometry, in vitro cytotoxicity assays, and an in vivo xenograft model in order to demonstrate the ability of the MSLN targeting antibody-drug conjugate (ADC) anetumab ravtansine (ARav) in inhibiting the growth of thymic carcinoma. RESULTS: Thymoma and thymic carcinoma cell lines express MSLN, and anetumab, the antibody moiety of ARav, was capable of binding MSLN expressing thymic carcinoma cells and internalising. ARav was effective at inhibiting the growth of thymic carcinoma cells stably transfected with mMSLN in vitro. In vivo, 15 mg/kg ARav inhibited T1889 xenograft tumour growth, while combining 7.5 mg/kg ARav with 4 mg/kg cisplatin yielded an additive effect on inhibiting tumour growth. CONCLUSIONS: These data demonstrate that anetumab ravtansine inhibits the growth of MSLN positive thymic carcinoma cells in vitro and in vivo.

Metastatic intracranial solitary fibrous tumors/hemangiopericytomas: description of two cases with radically different behaviors and review of the literature.

Solitary fibrous tumor/hemangiopericytoma with primary tumor location in the central nervous system accounts for less than 1% of all central nervous system tumors. Despite the relatively indolent clinical course, extracranial metastases are reported in 28% of cases. In recent years, NAB2-STAT6 gene fusion has been recognized as the pathognomonic molecular feature of solitary fibrous tumor/hemangiopericytoma and STAT6 immunohistochemistry has been shown to be a sensitive and specific surrogate for the identification of the gene fusion in these patients. Here we report two cases of patients who experienced occurrence of diffuse extracranial metastases several years after successful surgery for an intracranial solitary fibrous tumor/hemangiopericytoma. In the first patient, the metastases had maintained similar histological features to the primary tumor; in contrast, in the second case, a dedifferentiation occurred with loss of expression of CD34 and Bcl-2. These different histological features were associated with radically different behaviors. Whereas the first case experienced an indolent course of the disease, the second patient had a rapid disease progression and deterioration of clinical conditions. The molecular imaging findings in these two cases and the role of functional imaging for tumor detection, disease staging and monitoring in this rare cancer are also discussed. Recurrences and metastases maintained high expression of somatostatin receptors confirmed by somatostatin receptor imaging in the first case. In contrast, in the second patient, the abrupt transition into a highly aggressive form was associated with the absence of somatostatin receptors at 111In Pentetreotide scan and intense hypermetabolism at 18F-FDG PET.

Comparison of Eight Technologies to Determine Genotype at the UGT1A1 (TA)n Repeat Polymorphism: Potential Clinical Consequences of Genotyping Errors?

To ensure accuracy of UGT1A1 (TA)n (rs3064744) genotyping for use in pharmacogenomics-based irinotecan dosing, we tested the concordance of several commonly used genotyping technologies. Heuristic genotype groupings and principal component analysis demonstrated concordance for Illumina sequencing, fragment analysis, and fluorescent PCR. However, Illumina sequencing and fragment analysis returned a range of fragment sizes, likely arising due to PCR "slippage". Direct sequencing was accurate, but this method led to ambiguous electrophoregrams, hampering interpretation of heterozygotes. Gel sizing, pyrosequencing, and array-based technologies were less concordant. Pharmacoscan genotyping was concordant, but it does not ascertain (TA)8 genotypes that are common in African populations. Method-based genotyping differences were also observed in the publication record (p < 0.0046), although fragment analysis and direct sequencing were concordant (p = 0.11). Genotyping errors can have significant consequences in a clinical setting. At the present time, we recommend that all genotyping for this allele be conducted with fluorescent PCR (fPCR).

An endogenous DNA adduct as a prognostic biomarker for hepatocarcinogenesis and its prevention by Theaphenon E in mice.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, mainly because of its poor prognosis. A valid mechanism-based prognostic biomarker is urgently needed. γ-hydroxy-1,N2 -propanodeoxyguanosine (γ-OHPdG) is an endogenously formed mutagenic DNA adduct derived from lipid peroxidation. We examined the relationship of γ-OHPdG with hepatocarcinogenesis in two animal models and its potential role as a prognostic biomarker for recurrence in HCC patients. Bioassays were conducted in xeroderma pigmentosum group A knockout mice and diethylnitrosamine-injected mice, both prone to HCC development. γ-OHPdG levels in the livers of these animals were determined. The effects of antioxidant treatments on γ-OHPdG and hepatocarcinogenesis were examined. Using two independent sets of HCC specimens from patients, we examined the relationship between γ-OHPdG and survival or recurrence-free survival. γ-OHPdG levels in liver DNA showed an age-dependent increase and consistently correlated with HCC development in all three animal models. Theaphenon E treatment significantly decreased γ-OHPdG levels in the liver DNA of xeroderma pigmentosum group A knockout mice and remarkably reduced HCC incidence in these mice to 14% from 100% in the controls. It also effectively inhibited HCC development in the diethylnitrosamine-injected mice. Using clinical samples from two groups of patients, our study revealed that higher levels of γ-OHPdG are strongly associated with low survival (P < 0.0001) and low recurrence-free survival (P = 0.007). CONCLUSION: These results support γ-OHPdG as a mechanism-based, biologically relevant biomarker for predicting the risk of HCC and its recurrence. (Hepatology 2018;67:159-170).

Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study.

BACKGROUND: Treatment options are limited for patients with thymic carcinoma. These aggressive tumours are not typically associated with paraneoplastic autoimmune disorders, and strong PD-L1 expression has been reported in thymic epithelial tumours. We aimed to assess the activity of pembrolizumab, a monoclonal antibody that targets PD-1, in patients with advanced thymic carcinoma. METHODS: We completed a single-arm phase 2 study of pembrolizumab in patients with recurrent thymic carcinoma who had progressed after at least one line of chemotherapy. This was a single-centre study performed at Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA. Key inclusion criteria were an Eastern Cooperative Oncology Group performance status of 0-2, no history of autoimmune disease or other malignancy requiring treatment or laboratory abnormality, and adequate organ function. Patients received 200 mg of pembrolizumab every 3 weeks for up to 2 years. The primary objective of the study was the proportion of patients who had achieved a response assessed with Response Evaluation Criteria in Solid Tumors version 1.1. Analysis was per protocol, in all eligible patients. The study is registered with ClinicalTrials.gov, number NCT02364076, and is closed to accrual; we report the final analysis. FINDINGS: 41 patients were enrolled from March 12, 2015, to Dec 16, 2016, of whom 40 were eligible and evaluable and one was excluded because of elevated liver enzymes at screening. The median follow-up was 20 months (IQR 14-26). The proportion of patients who achieved a response was 22·5% (95% CI 10·8-38·5); one (3%) patient achieved a complete response, eight (20%) patients achieved partial responses, and 21 (53%) patients achieved stable disease. The most common grade 3 or 4 adverse events were increased aspartate aminotransferase and alanine aminotransferase (five [13%] patients each). Six (15%) patients developed severe autoimmune toxicity, including two (5%) patients with myocarditis. There were 17 deaths at the time of analysis, but no deaths due to toxicity. INTERPRETATION: Pembrolizumab is a promising treatment option in patients with thymic carcinoma. Because severe autoimmune disorders are more frequent in thymic carcinoma than in other tumour types, careful monitoring is essential. FUNDING: Merck & Co.

Phase I trial of belinostat with cisplatin and etoposide in advanced solid tumors, with a focus on neuroendocrine and small cell cancers of the lung.

The standard-of-care for advanced small cell lung cancer (SCLC) is chemotherapy with cisplatin+etoposide (C+E). Most patients have chemosensitive disease at the outset, but disease frequently relapses and limits survival. Efforts to improve therapeutic outcomes in SCLC and other neuroendocrine cancers have focused on epigenetic agents, including the histone deacetylase inhibitor belinostat. The primary objective was to determine the maximum tolerated dose of the combination of belinostat (B) with C+E. Belinostat was administered as a 48-h continuous intravenous infusion on days 1-2; cisplatin was administered as a 1-h intravenous infusion on day 2; and etoposide was administered as a 1-h intravenous infusion on days 2, 3, and 4. Twenty-eight patients were recruited in this single-center study. The maximum tolerated dose was belinostat 500 mg/m/24 h, cisplatin 60 mg/m, and etoposide 80 mg/m. The combination was safe, although some patients were more susceptible to adverse events. Hematologic toxicities were most commonly observed. Objective responses were observed in 11 (39%) of 28 patients and seven (47%) of 15 patients with neuroendocrine tumors (including SCLC). Patients carrying more than three copies of variant UGT1A1 (*28 and *60) had higher serum levels of belinostat because of slower clearance. DNA damage peaked at 36 h after the initiation of belinostat, as did global lysine acetylation, but returned to baseline 12 h after the end of infusion. The combination of B+C+E is safe and active in SCLC and other neuroendocrine cancers. Future phase II studies should consider genotyping patients for UGT1A1*28 and UGT1A1*60 and to identify patients at an increased risk of adverse events.

Sunitinib in patients with chemotherapy-refractory thymoma and thymic carcinoma: an open-label phase 2 trial.

BACKGROUND: No standard treatments are available for advanced thymic epithelial tumours after failure of platinum-based chemotherapy. We investigated the activity of sunitinib, an orally administered tyrosine kinase inhibitor. METHODS: Between May 15, 2012, and Oct 2, 2013, we did an open-label phase 2 trial in patients with histologically confirmed chemotherapy-refractory thymic epithelial tumours. Patients were eligible if they had disease progression after at least one previous regimen of platinum-containing chemotherapy, an Eastern Cooperative Oncology Group performance status of two or lower, measurable disease, and adequate organ function. Patients received 50 mg of sunitinib orally once a day, in 6-week cycles (ie, 4 weeks of treatment followed by 2 weeks without treatment), until tumour progression or unacceptable toxic effects arose. The primary endpoint was investigator-assessed best tumour response at any point, which we analysed separately in thymoma and thymic carcinoma cohorts. Patients who had received at least one cycle of treatment and had their disease reassessed were included in the analyses of response. The trial was registered with ClinicalTrials.gov, number NCT01621568. FINDINGS: 41 patients were enrolled, 25 with thymic carcinoma and 16 with thymoma. One patient with thymic carcinoma was deemed ineligible after enrolment and did not receive protocol treatment. Of patients who received treatment, one individual with thymic carcinoma was not assessable because she died. Median follow-up on trial was 17 months (IQR 14.0-18.4). Of 23 assessable patients with thymic carcinoma, six (26%, 90% CI 12.1-45.3, 95% CI 10.2-48.4) had partial responses, 15 (65%, 95% CI 42.7-83.6) achieved stable disease, and two (9%, 1.1-28.0) had progressive disease. Of 16 patients with thymoma, one (6%, 95% CI 0.2-30.2) had a partial response, 12 (75%, 47.6-92.7) had stable disease, and three (19%, 4.1-45.7) had progressive disease. The most common grade 3 and 4 treatment-related adverse events were lymphocytopenia (eight [20%] of 40 patients), fatigue (eight [20%]), and oral mucositis (eight [20%]). Five (13%) patients had decreases in left-ventricular ejection fraction, of which three (8%) were grade 3 events. Three (8%) patients died during treatment, including one individual who died of cardiac arrest that was possibly treatment-related. INTERPRETATION: Sunitinib is active in previously treated patients with thymic carcinoma. Further studies are needed to identify potential biomarkers of activity. FUNDING: National Cancer Institute (Cancer Therapy Evaluation Program).

Evolutionarily conserved protein ERH controls CENP-E mRNA splicing and is required for the survival of KRAS mutant cancer cells.

Cancers with Ras mutations represent a major therapeutic problem. Recent RNAi screens have uncovered multiple nononcogene addiction pathways that are necessary for the survival of Ras mutant cells. Here, we identify the evolutionarily conserved gene enhancer of rudimentary homolog (ERH), in which depletion causes greater toxicity in cancer cells with mutations in the small GTPase KRAS compared with KRAS WT cells. ERH interacts with the spliceosome protein SNRPD3 and is required for the mRNA splicing of the mitotic motor protein CENP-E. Loss of ERH leads to loss of CENP-E and consequently, chromosome congression defects. Gene expression profiling indicates that ERH is required for the expression of multiple cell cycle genes, and the gene expression signature resulting from ERH down-regulation inversely correlates with KRAS signatures. Clinically, tumor ERH expression is inversely associated with survival of colorectal cancer patients whose tumors harbor KRAS mutations. Together, these findings identify a role of ERH in mRNA splicing and mitosis, and they provide evidence that KRAS mutant cancer cells are dependent on ERH for their survival.

Loss of p63 and its microRNA-205 target results in enhanced cell migration and metastasis in prostate cancer.

p63 inhibits metastasis. Here, we show that p63 (both TAp63 and ΔNp63 isoforms) regulates expression of miR-205 in prostate cancer (PCa) cells, and miR-205 is essential for the inhibitory effects of p63 on markers of epithelial-mesenchymal transition (EMT), such as ZEB1 and vimentin. Correspondingly, the inhibitory effect of p63 on EMT markers and cell migration is reverted by anti-miR-205. p53 mutants inhibit expression of both p63 and miR-205, and the cell migration, in a cell line expressing endogenous mutated p53, can be abrogated by pre-miR-205 or silencing of mutated p53. In accordance with this in vitro data, ΔNp63 or miR-205 significantly inhibits the incidence of lung metastasis in vivo in a mouse tail vein model. Similarly, one or both components of the p63/miR-205 axis were absent in metastases or colonized lymph nodes in a set of 218 human prostate cancer samples. This was confirmed in an independent clinical data set of 281 patients. Loss of this axis was associated with higher Gleason scores, an increased likelihood of metastatic and infiltration events, and worse prognosis. These data suggest that p63/miR-205 may be a useful clinical predictor of metastatic behavior in prostate cancer.

Cixutumumab for patients with recurrent or refractory advanced thymic epithelial tumours: a multicentre, open-label, phase 2 trial.

BACKGROUND: No standard treatment exists for refractory or relapsed advanced thymic epithelial tumours. We investigated the efficacy of cixutumumab, a fully human IgG1 monoclonal antibody targeting the insulin-like growth factor 1 receptor in thymic epithelial tumours after failure of previous chemotherapy. METHODS: Between Aug 25, 2009, and March 27, 2012, we did a multicentre, open-label, phase 2 trial in patients aged 18 years or older with histologically confirmed recurrent or refractory thymic epithelial tumours. We enrolled individuals who had progressed after at least one previous regimen of platinum-containing chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had measurable disease and adequate organ function. Eligible patients received intravenous cixutumumab (20 mg/kg) every 3 weeks until disease progression or development of intolerable toxic effects. The primary endpoint was the frequency of response, analysed on an intention-to-treat basis. We also did pharmacodynamic studies. This trial is registered with ClinicalTrials.gov, number NCT00965250. FINDINGS: 49 patients were enrolled (37 with thymomas and 12 with thymic carcinomas) who received a median of eight cycles of cixutumumab (range 1-46). At the final actuarial analysis when follow-up data were updated (Nov 30, 2012), median potential follow-up (from on-study date to most current follow-up date) was 24·0 months (IQR 17·3-36·9). In the thymoma cohort, five (14%) of 37 patients (95% CI 5-29) achieved a partial response, 28 had stable disease, and four had progressive disease. In the thymic carcinoma cohort, none of 12 patients (95% CI 0-26) had a partial response, five had stable disease, and seven had progressive disease. The most common grade 3-4 adverse events in both cohorts combined were hyperglycaemia (five [10%]), lipase elevation (three [6%]), and weight loss, tumour pain, and hyperuricaemia (two each [4%]). Nine (24%) of 37 patients with thymoma developed autoimmune conditions during treatment (five were new-onset disorders), the most common of which was pure red-cell aplasia. Two (4%) patients died; one was attributed to disease progression and the other to disease-related complications (respiratory failure, myositis, and an acute coronary event), which could have been precipitated by treatment with cixutumumab. INTERPRETATION: Cixutumumab monotherapy is well-tolerated and active in relapsed thymoma. Development of autoimmunity during treatment needs further investigation. FUNDING: Division of Cancer Treatment and Diagnosis at the National Cancer Institute (National Institutes of Health), ImClone Systems.

A phase 2 trial of dacomitinib (PF-00299804), an oral, irreversible pan-HER (human epidermal growth factor receptor) inhibitor, in patients with advanced non-small cell lung cancer after failure of prior chemotherapy and erlotinib.

BACKGROUND: This phase 2 trial (ClinicalTrials.gov identifier NCT00548093) assessed the efficacy, safety, and impact on health-related quality of life of dacomitinib (PF-00299804), an irreversible tyrosine kinase inhibitor (TKI) of human epidermal growth factor receptors (EGFR)/HER1, HER2, and HER4, in patients with KRAS wild-type non-small cell lung cancer (NSCLC). METHODS: Patients with advanced NSCLC, progression on 1 or 2 regimens of chemotherapy and erlotinib, KRAS wild-type or known EGFR-sensitizing mutant tumor, and Eastern Cooperative Oncology Group performance status of 0 to 2 received 45 mg of dacomitinib once daily continuously in 21-day cycles. RESULTS: A total of 66 patients enrolled (adenocarcinoma, n = 50; those without adenocarcinoma [nonadenocarcinoma], n = 16). The objective response rate (ORR) for patients with adenocarcinoma (primary endpoint) was 5% (2 partial responses; 1-sided P = .372 for null hypothesis [H0 ]: ORR ≤ 5%) and 6% (1 partial response) for patients with nonadenocarcinoma. Responders included: 2 of 25 EGFR mutation-positive tumors; 1 of 3 EGFR wild-type with HER2 amplification. Median progression-free survival was 12 weeks overall (n = 66) and 18 weeks (n = 26) for patients with EGFR mutation-positive tumors. Common treatment-related adverse events were of grade 1 or 2 severity, manageable with standard supportive care, and included diarrhea (grade 3 [G3], 12%), acneiform dermatitis (G3, 6%), exfoliative rash (G3, 3%), dry skin (G3, 0%), fatigue (G3, 3%), and stomatitis (G3, 2%). Six patients (9%) discontinued due to treatment-related adverse events. By patient report, NSCLC symptoms of dyspnea, cough, and pain (chest, arm/shoulder) showed improvement first observed after 3 weeks on therapy. CONCLUSIONS: Dacomitinib demonstrated preliminary activity and acceptable tolerability in heavily pretreated patients, and may offer benefit in molecularly defined patient subsets.

Emerging protein kinase inhibitors for non-small cell lung cancer.

INTRODUCTION: In the current paradigm of precision medicine in non-small cell lung cancer (NSCLC), the therapeutic strategy is determined by the molecular characteristics. The best examples of this approach are the kinase inhibitors that selectively target tumors bearing an epidermal growth factor receptor (EGFR) mutation or an anaplastic lymphoma kinase (ALK) rearrangement. Emerging protein kinase inhibitors may enhance our ability to effectively treat these and other genomic subtypes of NSCLC. AREAS COVERED: This article reviews the next-generation kinase inhibitors targeting EGFR and ALK-positive NSCLC. In addition, targeted kinase inhibitors in clinical development for other specific molecular subtypes of NSCLC are covered, including ROS1, BRAF, RET, HER2, KRAS (upstream of the MEK kinase), MET, PIK3CA, FGFR1, DDR2, VEGFR and AAK. EXPERT OPINION: In EGFR-mutant NSCLC, there are several kinase inhibitors with promising activity, most notably dacomitinib and CO-1686 in tumors with acquired resistance to EGFR-targeted therapy. Next-generation ALK inhibitors appear to have greater potency than crizotinib and several ongoing trials may shed light on their role in both ALK- and ROS1-positive NSCLC. While there is optimism regarding the role of kinase inhibitors in other molecular subtypes, the available evidence is too immature to make recommendations and results from prospective trials are needed.

Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs.

IMPORTANCE: Targeting oncogenic drivers (genomic alterations critical to cancer development and maintenance) has transformed the care of patients with lung adenocarcinomas. The Lung Cancer Mutation Consortium was formed to perform multiplexed assays testing adenocarcinomas of the lung for drivers in 10 genes to enable clinicians to select targeted treatments and enroll patients into clinical trials. OBJECTIVES: To determine the frequency of oncogenic drivers in patients with lung adenocarcinomas and to use the data to select treatments targeting the identified driver(s) and measure survival. DESIGN, SETTING, AND PARTICIPANTS: From 2009 through 2012, 14 sites in the United States enrolled patients with metastatic lung adenocarcinomas and a performance status of 0 through 2 and tested their tumors for 10 drivers. Information was collected on patients, therapies, and survival. INTERVENTIONS: Tumors were tested for 10 oncogenic drivers, and results were used to select matched targeted therapies. MAIN OUTCOMES AND MEASURES: Determination of the frequency of oncogenic drivers, the proportion of patients treated with genotype-directed therapy, and survival. RESULTS: From 2009 through 2012, tumors from 1007 patients were tested for at least 1 gene and 733 for 10 genes (patients with full genotyping). An oncogenic driver was found in 466 of 733 patients (64%). Among these 733 tumors, 182 tumors (25%) had the KRAS driver; sensitizing EGFR, 122 (17%); ALK rearrangements, 57 (8%); other EGFR, 29 (4%); 2 or more genes, 24 (3%); ERBB2 (formerly HER2), 19 (3%); BRAF, 16 (2%); PIK3CA, 6 (<1%); MET amplification, 5 (<1%); NRAS, 5 (<1%); MEK1, 1 (<1%); AKT1, 0. Results were used to select a targeted therapy or trial in 275 of 1007 patients (28%). The median survival was 3.5 years (interquartile range [IQR], 1.96-7.70) for the 260 patients with an oncogenic driver and genotype-directed therapy compared with 2.4 years (IQR, 0.88-6.20) for the 318 patients with any oncogenic driver(s) who did not receive genotype-directed therapy (propensity score-adjusted hazard ratio, 0.69 [95% CI, 0.53-0.9], P = .006). CONCLUSIONS AND RELEVANCE: Actionable drivers were detected in 64% of lung adenocarcinomas. Multiplexed testing aided physicians in selecting therapies. Although individuals with drivers receiving a matched targeted agent lived longer, randomized trials are required to determine if targeting therapy based on oncogenic drivers improves survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01014286.

Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial.

BACKGROUND: Erlotinib is registered for treatment of all patients with advanced non-small-cell lung cancer (NSCLC). However, its efficacy for treatment of patients whose tumours are EGFR wild-type-which includes most patients-is still contentious. We assessed the efficacy of erlotinib compared with a standard second-line chemotherapy in such patients. METHODS: We did this randomised controlled trial in 52 Italian hospitals. We enrolled patients who had metastatic NSCLC, had had platinum-based chemotherapy, and had wild-type EGFR as assessed by direct sequencing. Patients were randomly assigned centrally (1:1) to receive either erlotinib orally 150 mg/day or docetaxel intravenously 75 mg/m(2) every 21 days or 35 mg/m(2) on days 1, 8, and 15, every 28 days. Randomisation was stratified by centre, stage, type of first-line chemotherapy, and performance status. Patients and investigators who gave treatments or assessed outcomes were not masked to treatment allocation, investigators who analysed results were. The primary endpoint was overall survival in the intention-to-treat population. The study is registered at ClinicalTrials.gov, number NCT00637910. FINDINGS: We screened 702 patients, of whom we genotyped 540. 222 patients were enrolled (110 assigned to docetaxel vs 112 assigned to erlotinib). Median overall survival was 8·2 months (95% CI 5·8-10·9) with docetaxel versus 5·4 months (4·5-6·8) with erlotinib (adjusted hazard ratio [HR] 0·73, 95% CI 0·53-1·00; p=0·05). Progression-free survival was significantly better with docetaxel than with erlotinib: median progression-free survival was 2·9 months (95% CI 2·4-3·8) with docetaxel versus 2·4 months (2·1-2·6) with erlotinib (adjusted HR 0·71, 95% CI 0·53-0·95; p=0·02). The most common grade 3-4 toxic effects were: low absolute neutrophil count (21 [20%] of 104 in the docetaxel group vs none of 107 in the erlotinib group), skin toxic effects (none vs 15 [14%]), and asthenia (ten [10%] vs six [6%]). INTERPRETATION: Our results show that chemotherapy is more effective than erlotinib for second-line treatment for previously treated patients with NSCLC who have wild-type EGFR tumours.