ABSTRACT
BACKGROUND: The efficacy of ceritinib in patients with untreated anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is not known. We assessed the efficacy and safety of ceritinib versus platinum-based chemotherapy in these patients. METHODS: This randomised, open-label, phase 3 study in untreated patients with stage IIIB/IV ALK-rearranged non-squamous NSCLC was done in 134 centres across 28 countries. Eligible patients were assigned via interactive response technology to oral ceritinib 750 mg/day or platinum-based chemotherapy ([cisplatin 75 mg/m2 or carboplatin AUC 5-6 plus pemetrexed 500 mg/m2] every 3 weeks for four cycles followed by maintenance pemetrexed); randomisation was stratified by World Health Organization performance status (0 vs 1-2), previous neoadjuvant or adjuvant chemotherapy, and presence of brain metastases as per investigator's assessment at screening. Investigators and patients were not masked to treatment assignment. The primary endpoint was blinded independent review committee assessed progression-free survival, based on all randomly assigned patients (the full analysis set). Efficacy analyses were done based on the full analysis set. All safety analyses were done based on the safety set, which included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01828099. FINDINGS: Between Aug 19, 2013, and May 11, 2015, 376 patients were randomly assigned to ceritinib (n=189) or chemotherapy (n=187). Median progression-free survival (as assessed by blinded independent review committee) was 16·6 months (95% CI 12·6-27·2) in the ceritinib group and 8·1 months (5·8-11·1) in the chemotherapy group (hazard ratio 0·55 [95% CI 0·42-0·73]; p<0·00001). The most common adverse events were diarrhoea (in 160 [85%] of 189 patients), nausea (130 [69%]), vomiting (125 [66%]), and an increase in alanine aminotransferase (114 [60%]) in the ceritinib group and nausea (in 97 [55%] of 175 patients), vomiting (63 [36%]), and anaemia (62 [35%]) in the chemotherapy group. INTERPRETATION: First-line ceritinib showed a statistically significant and clinically meaningful improvement in progression-free survival versus chemotherapy in patients with advanced ALK-rearranged NSCLC. FUNDING: Novartis Pharmaceuticals Corporation.
Subject(s)
Antineoplastic Agents/administration & dosage , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Pyrimidines/administration & dosage , Sulfones/administration & dosage , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carboplatin/administration & dosage , Carboplatin/adverse effects , Carcinoma, Non-Small-Cell Lung/mortality , Cisplatin/administration & dosage , Cisplatin/adverse effects , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Lung Neoplasms/mortality , Male , Middle Aged , Pemetrexed/administration & dosage , Pemetrexed/adverse effects , Pyrimidines/adverse effects , Sulfones/adverse effects , Treatment Outcome , Young AdultABSTRACT
PURPOSE: To evaluate efficacy and toxicity of stereotactic body radiation therapy (SBRT) with CyberKnife® (Accuray, Sunnyvale, CA, USA) in a selected cohort of primary, medically inoperable early-stage non-small cell lung cancer (NSCLC) patients. METHODS: From 2012 to 2016, 106 patients (median age 74 years, range 50-94 years) with primary NSCLC were treated with SBRT using CyberKnife®. Histologic confirmation was available in 87 patients (82%). For mediastinal staging, 92 patients (87%) underwent 18F-fluorodeoxyglucose positron-emission tomography (18-FDG-PET) and/or endobronchial ultrasound (EBUS)-guided lymph node biopsy or mediastinoscopy. Tumor stage (UICC8, 2017) was IA/B (T1a-c, 1-3 cm) in 86 patients (81%) and IIA (T2a/b, 3-5 cm) in 20 patients (19%). Depending on tumor localization, three different fractionation schedules were used: 3 fractions of 17Gy, 5 fractions of 11Gy, or 8 fractions of 7.5 Gy. Tracking was based on fiducial implants in 13 patients (12%) and on image guidance without markers in 88%. RESULTS: Median follow-up was 15 months (range 0.5-46 months). Acute side effects were mild (fatigue grade 1-2 in 20% and dyspnea grade 1-2 in 17%). Late effects were observed in 4 patients (4%): 3 patients developed pneumonitis requiring therapy (grade 2) and 1 patient suffered a rib fracture (grade 3). In total, 9/106 patients (8%) experienced a local recurrence, actuarial local control rates were 88% (95% confidence interval, CI, 80-96%) at 2 years and 77% (95%CI 56-98%) at 3 years. The median disease-free survival time was 27 months (95%CI 23-31 months). Overall survival was 77% (95%CI 65-85%) at 2 years and 56% (95%CI 39-73%) at 3 years. CONCLUSION: CyberKnife® lung SBRT which allows for real-time tumor tracking and risk-adapted fractionation achieves satisfactory local control and low toxicity rates in inoperable early-stage primary lung cancer patients.
Subject(s)
Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/surgery , Lung Neoplasms/pathology , Lung Neoplasms/surgery , Radiosurgery/methods , Risk Adjustment , Robotic Surgical Procedures/methods , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/mortality , Cohort Studies , Dose Fractionation, Radiation , Female , Follow-Up Studies , Humans , Kaplan-Meier Estimate , Lung Neoplasms/mortality , Male , Middle Aged , Neoplasm Staging , Radiosurgery/adverse effects , Robotic Surgical Procedures/adverse effects , Treatment OutcomeABSTRACT
BACKGROUND: Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies. METHODS: In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib. RESULTS: A total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5). CONCLUSIONS: Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT01283516.).
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Drug Resistance, Neoplasm/genetics , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/administration & dosage , Pyrimidines/administration & dosage , Receptor Protein-Tyrosine Kinases/genetics , Sulfones/administration & dosage , Adult , Aged , Aged, 80 and over , Anaplastic Lymphoma Kinase , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/mortality , Female , Humans , Lung Neoplasms/genetics , Lung Neoplasms/mortality , Male , Maximum Tolerated Dose , Middle Aged , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Pyrimidines/adverse effects , Pyrimidines/pharmacokinetics , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Recombination, Genetic , Sulfones/adverse effects , Sulfones/pharmacokinetics , Treatment Outcome , Young AdultABSTRACT
Importance: There are no specifically approved targeted therapies for the most common genomically defined subset of non-small cell lung cancer (NSCLC), KRAS-mutant lung cancer. Objective: To compare efficacy of the mitogen-activated protein kinase kinase (MEK) inhibitor selumetinib + docetaxel with docetaxel alone as a second-line therapy for advanced KRAS-mutant NSCLC. Design, Setting, and Participants: Multinational, randomized clinical trial conducted at 202 sites across 25 countries from October 2013 through January 2016. Of 3323 patients with advanced NSCLC and disease progression following first-line anticancer therapy tested for a KRAS mutation, 866 were enrolled and 510 randomized. Primary reason for exclusion was ineligibility. The data cutoff date for analysis was June 7, 2016. Interventions: Patients were randomized 1:1; 254 to receive selumetinib + docetaxel and 256 to receive placebo + docetaxel. Main Outcomes and Measures: Primary end point was investigator assessed progression-free survival. Secondary end points included overall survival, objective response rate, duration of response, effects on disease-related symptoms, safety, and tolerability. Results: Of 510 randomized patients (mean age, 61.4 years [SD, 8.3]; women, 207 [41%]), 505 patients (99%) received treatment and completed the study (251 received selumetinib + docetaxel; 254 received placebo + docetaxel). At the time of data cutoff, 447 patients (88%) had experienced a progression event and 346 deaths (68%) had occurred. Median progression-free survival was 3.9 months (interquartile range [IQR], 1.5-5.9) with selumetinib + docetaxel and 2.8 months (IQR, 1.4-5.5) with placebo + docetaxel (difference, 1.1 months; hazard ratio [HR], 0.93 [95% CI, 0.77-1.12]; P = .44). Median overall survival was 8.7 months (IQR, 3.6-16.8) with selumetinib + docetaxel and 7.9 months (IQR, 3.8-20.1) with placebo + docetaxel (difference, 0.9 months; HR, 1.05 [95% CI, 0.85-1.30]; P = .64). Objective response rate was 20.1% with selumetinib + docetaxel and 13.7% with placebo + docetaxel (difference, 6.4%; odds ratio, 1.61 [95% CI, 1.00-2.62]; P = .05). Median duration of response was 2.9 months (IQR, 1.7-4.8; 95% CI, 2.7-4.1) with selumetinib + docetaxel and 4.5 months (IQR, 2.3-7.3; 95% CI, 2.8-5.6) with placebo + docetaxel. Adverse events of grade 3 or higher were more frequent with selumetinib + docetaxel (169 adverse events [67%] for selumetinib + docetaxel vs 115 adverse events [45%] for placebo + docetaxel; difference, 22%). Conclusions and Relevance: Among patients with previously treated advanced KRAS-mutant non-small cell lung cancer, addition of selumetinib to docetaxel did not improve progression-free survival compared with docetaxel alone. Trial Registration: clinicaltrials.gov: NCT01933932.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Benzimidazoles/administration & dosage , Proto-Oncogene Proteins p21(ras)/genetics , Taxoids/administration & dosage , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Benzimidazoles/adverse effects , Carcinoma, Non-Small-Cell Lung/drug therapy , Disease Progression , Disease-Free Survival , Docetaxel , Female , Humans , Male , Middle Aged , Mutation , Taxoids/adverse effects , Treatment OutcomeABSTRACT
BACKGROUND: This study provides comparative evidence of the selective MET inhibitor capmatinib versus standard of care (SOC) in first-line (1 L) and second-line (2 L) non-small cell lung cancer (NSCLC) patients with METex14 mutations in German routine care. METHODS: SOC data were collected from German routine care via retrospective chart review. Analyses were conducted as naive and propensity score adjusted (PSA) comparisons to capmatinib-treated patients within the GEOMETRY mono-1 trial. Effectiveness endpoints included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), time to CNS progression (CNSprog), and exploratory safety endpoints. RESULTS: The SOC arm included 119 patients in 1 L and 46 in 2 L versus 60 patients in 1 L and 81 in 2 L treated with capmatinib, with balanced baseline characteristics after PSA. In 1 L, the naive comparison showed a significant benefit of capmatinib versus SOC for OS (median: 25.49 vs 14.59 months; HR 0.58; 95 % CI 0.39-0.87; P = 0.011), PFS (median: 12.45 vs 5.03 months; HR: 0.44; 95 % CI: 0.31-0.63; P < 0.001), and ORR (event rate: 68.3 vs 26.9 %; RR 2.54; 95 % CI 1.80-3.58; P < 0.001). In 2 L, OS, PFS, and ORR showed positive trends favoring capmatinib over SOC. Capmatinib treatment in the 1 L and 2 L led to significant benefit in CNSprog. PSA analyses showed consistent results to naive analysis. Exploratory safety endpoints indicated a manageable safety profile for capmatinib. CONCLUSIONS: The present study demonstrates the important role of capmatinib in providing robust clinically meaningful benefit to patients with NSCLC harboring METex14 mutations and its significant role in preventing the development of brain metastases.
Subject(s)
Benzamides , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Mutation , Proto-Oncogene Proteins c-met , Triazines , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Male , Female , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Middle Aged , Aged , Benzamides/therapeutic use , Germany , Proto-Oncogene Proteins c-met/genetics , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Triazines/therapeutic use , Triazines/adverse effects , Retrospective Studies , Adult , Aged, 80 and over , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/adverse effects , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/adverse effects , ImidazolesABSTRACT
INTRODUCTION: Dysregulated MET is an established oncogenic driver in non-small cell lung cancer (NSCLC). MET signaling may also suppress anticancer immune responses. Concomitant MET inhibition with capmatinib (a MET inhibitor) synergistically enhanced the efficacy of immunotherapies in murine cancer models, regardless of tumor dependency to MET signaling. Here, we report results of a multicenter, open-label, phase 2 study of capmatinib plus nivolumab (a PD-1 inhibitor) in patients with EGFR wild-type advanced NSCLC, previously treated with platinum-based chemotherapy. METHODS: Patients were allocated into high-MET or low-MET groups according to MET expression determined by immunohistochemistry, MET gene copy number as assessed by fluorescence in-situ hybridization, and presence of MET exon 14 skipping mutation, then received capmatinib 400 mg, oral, twice daily in combination with nivolumab 3 mg/kg intravenously every 2 weeks. The primary endpoint was investigator-assessed 6-month progression-free survival (PFS) rate per RECIST v1.1. RESULTS: The primary endpoint was met in both the high-MET (N = 16) and low-MET (N = 30) groups. In the high-MET and low-MET groups, respectively, the estimated mean 6-month PFS rate (95 % credible interval) by Bayesian analysis was 68.9 % (48.5-85.7) and 50.9 % (35.6-66.4). The Kaplan-Meier median PFS (95 % CI) was 6.2 months (3.5-19.2) and 4.2 months (1.8-7.4). The overall response rate (95 % CI) was 25.0 % (7.3-52.4) and 16.7 % (5.6-34.7). Most frequent treatment-related adverse events (≥30 % any grade, N = 46) were nausea (52.2 %), peripheral edema (34.8 %), and increased blood creatinine (30.4 %). CONCLUSIONS: Capmatinib plus nivolumab showed clinical activity and manageable safety in pretreated patients with advanced EGFR wild-type NSCLC, independent of MET status. TRIAL REGISTRATION: ClinicalTrials.gov NCT02323126.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Carcinoma, Non-Small-Cell Lung , ErbB Receptors , Lung Neoplasms , Nivolumab , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/mortality , Nivolumab/administration & dosage , Nivolumab/therapeutic use , Female , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Middle Aged , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , ErbB Receptors/genetics , ErbB Receptors/antagonists & inhibitors , Benzamides/therapeutic use , Benzamides/administration & dosage , Adult , Proto-Oncogene Proteins c-met/genetics , Proto-Oncogene Proteins c-met/metabolism , Aged, 80 and over , Acrylamides/therapeutic use , Acrylamides/administration & dosage , Imidazoles , TriazinesABSTRACT
INTRODUCTION: Activation of the antioxidant KEAP1/NFE2L2 (NRF2) pathway leads to increased glutamine dependence and an aggressive phenotype in NSCLC. Because this pathway has been explored as a clinical target, we developed a transcriptomic signature for identifying KEAP1/NFE2L2-activated tumors. METHODS: A total of 971 NSCLC samples were used to train an expression signature (K1N2-score) to predict KEAP1/NFE2L2 mutations. There were 348 in-house NSCLCs that were analyzed using a NanoString expression panel for validation. RESULTS: The 46-gene K1N2 score robustly predicted KEAP1/NFE2L2 mutations in the validation set irrespective of histology and mutation (area under the curve: 89.5, sensitivity: 90.2%), suggesting that approximately 90% of KEAP1/NFE2L2 mutations are pathway-activating. The K1N2-score outperformed KEAP1/NFE2L2 mutational status when predicting patient survival (score p = 0.047; mutation p = 0.215). In K1N2 score-positive but KEAP1/NFE2L2 wild-type samples, enrichment testing identified SMARCA4/BRG1 and CUL3 mutations as mimics of KEAP1/NFE2L2 mutations. CONCLUSIONS: The K1N2-score identified KEAP1/NFE2L2-activated NSCLC by robustly detecting KEAP1/NFE2L2mut cases and discovering alternative genomic activators. It is a potential means for selecting patients with a constitutively active KEAP1/NFE2L2 pathway.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Lung Neoplasms/pathology , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Kelch-Like ECH-Associated Protein 1/genetics , Kelch-Like ECH-Associated Protein 1/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Mutation , DNA Helicases/genetics , Nuclear Proteins/genetics , Transcription Factors/geneticsABSTRACT
BACKGROUND: In 2006, our comprehensive cancer center decided to implement early integration (EI) of palliative care (PC) by (a) literally adopting the WHO definition of PC into cancer care guidelines and (b) providing a PC consulting team (PCST) to provide EI on in- and outpatient wards. The experience with this approach was assessed to identify shortcomings. METHODS: A retrospective systematic chart analysis of a 2-year period was performed. RESULTS: A total of 862 patients were treated (May 2006-April 2008). Many patients consulted by the PCST for the first time were already in a reduced performance status (ECOG 3 & 4: 40%) or experiencing burdening symptoms (i.e., dyspnoea 27%). After the first year (period A; "getting started"), the overall prevalence of symptoms identified on first PC contact decreased from seven to three, (p < 0.001) as well as surrogate measures for advanced disease (i.e., frailty: from 63% to 33%; CI: [-36%; -23%], p < 0.001). CONCLUSION: Surrogate measures (symptom burden, performance status) indicate that PC was integrated earlier in the course of the disease after a 1-year phase of "getting started" with EI. Yet, the WHO recommendation alone was too vague to successfully trigger EI of PC. Therefore, the authors advocate the provision of disease specific guidelines to institutionalize EI of PC. Such guidelines have been developed for 19 different malignancies and are presented separately.
Subject(s)
Delivery of Health Care, Integrated/methods , Delivery of Health Care, Integrated/organization & administration , Neoplasms/therapy , Palliative Care/methods , Palliative Care/organization & administration , Adolescent , Adult , Aged , Aged, 80 and over , Anxiety/epidemiology , Child , Child, Preschool , Comorbidity , Constipation/epidemiology , Depression/epidemiology , Dyspnea/epidemiology , Fatigue/epidemiology , Feeding and Eating Disorders/epidemiology , Germany , Humans , Infant , Infant, Newborn , Middle Aged , Neoplasms/epidemiology , Pain/epidemiology , Palliative Care/statistics & numerical data , Retrospective Studies , Secondary Prevention , Young AdultABSTRACT
INTRODUCTION: Nazartinib, a novel third-generation EGFR-tyrosine kinase inhibitor, previously demonstrated antitumor activity and manageable safety in patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC) who received ≤ 3 prior lines of systemic therapy. Herein, we report phase 2 efficacy and safety of first-line nazartinib. METHODS: This single-arm, open-label, global study enrolled treatment-naive adult patients with stage IIIB/IV NSCLC harboring EGFR-activating mutations (eg, L858R and/or ex19del). Patients with neurologically stable and controlled brain metastases were also eligible. Patients received oral nazartinib 150 mg once daily. The primary endpoint was Blinded Independent Review Committee (BIRC)-assessed overall response rate (ORR) per RECIST v1.1. RESULTS: Forty-five patients received ≥ 1 dose of nazartinib. The median follow-up time from enrollment to data cutoff (November 1, 2019) was 30 months (range: 25-34). The BIRC-assessed ORR was 69% (95% CI, 53-82). The median progression-free survival (PFS) was 18 months (95% CI, 15-not estimable [NE]). The median overall survival was NE. In patients with baseline brain metastases (n = 18), the ORR and median PFS (95% CIs) were 67% (41-87) and 17 months (11-21). Seventeen of 18 patients had brain metastases as non-target lesions; the CNS lesions were absent/normalized in 9 of 17 (53%). Only 2 of 27 patients without baseline brain metastases developed new brain metastases postbaseline. Most frequent adverse events (≥ 25%, any grade, all-causality) were diarrhea (47%), maculopapular rash (38%), pyrexia (29%), cough, and stomatitis (27% each). CONCLUSIONS: First-line nazartinib demonstrated promising efficacy, including clinically meaningful antitumor activity in the brain, and manageable safety in patients with EGFR-mutant NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02108964.
Subject(s)
Brain Neoplasms , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Adult , Benzimidazoles , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , ErbB Receptors/genetics , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mutation , Nicotine/analogs & derivatives , Protein Kinase Inhibitors/adverse effectsABSTRACT
BACKGROUND: Our comprehensive cancer centre adopted the WHO recommendation literally in the cancer care guidelines to implement the early integration (EI) of palliative care (PC). Evaluation of the first 2 years of this approach revealed that this guideline was too vague to trigger EI. OBJECTIVE: As a consequence, an interdisciplinary working group was set up to propose and implement a more effective concept. METHODS: An interdisciplinary (PC, oncology, radiotherapy, etc.) working group identified the need to (a) specify the timing of EI and (b) specify PC assignments by (c) providing more clear cut semantic and clinical definitions. As a result of repeated discussion in the different interdisciplinary working groups in charge of developing and consenting a once-yearly update of treatment guidelines [standard operating procedure (SOP)] for each malignancy, the need for disease-specific EI SOPs was identified. RESULTS: SOPs were developed for 19 malignancies (a) to identify a disease-specific point in each disease trajectory to initiate EI ("green flags") and to provide (b) a clear delineation and semantic differentiation of PC assignments ["palliative care" vs. "supportive" or "palliative therapies" ("green" vs. "red flags")]. DISCUSSION: To date, ASCO and WHO recommendations for EI lack detailed information about timing and infrastructure. The guidelines presented here aim to provide the missing information by reporting our developed and consented interdisciplinary guidelines for EI. CONCLUSION: With this concept, the authors provide a framework for realizing EI and hope to initiate a discussion about specific recommendations for EI.
Subject(s)
Bereavement , Delivery of Health Care, Integrated/organization & administration , Health Policy , Neoplasms/psychology , Palliative Care/organization & administration , Humans , Palliative Care/methods , Palliative Care/psychology , Patient Care Team , Prognosis , Program Evaluation , Time Factors , World Health OrganizationABSTRACT
Lung cancer is the leading cause of cancer-related mortality worldwide due to difficulties in early detection and high postsurgical recurrence rate. Current European Guidelines recommend follow-up via computerized tomography (CT) scans on regular basis within the first 2 years after radical surgical resection. Despite these efforts, recurrence rates remain high with 30-70 %. Therefore, it is imperative to develop predictive markers for metastases and postsurgical recurrence using minimally invasive methods. This prospective study aims at defining the feasibility of detecting circulating tumor DNA (ctDNA) in presurgical plasma samples of patients with lung cancer by digital droplet PCR. Resected tumor tissue and simultaneous blood samples were collected from 24 patients with lung cancer in stage I-IIIA (12 stage I, 8 stage II, 4 stage III). Genomic DNA from the tumor tissue samples were analyzed for hotspot mutations using a 17 gene panel next-generation sequencing (NGS) assay. CtDNA from corresponding plasma samples were analyzed using digital droplet PCR (ddPCR). Additionally, DNA sequencing results were correlated with patients' outcome. At least one somatic mutation was detected by NGS (96 %) in 23 of the tested tissue samples. DdPCR detected mutations in circulating cell-free DNA (ccfDNA) of nine patients' samples (9/23, 39 %). Postsurgical outcome analysis was performed for those patients who had received complete tumor resection (nâ¯=â¯21). Four of them suffered from an early relapse within the first two years after surgery, including two with detectable somatic mutations in ccfDNA during primary staging. Taken together, we showed that the 17 gene panel assay revealed in 23 of 24 patients at least one somatic mutation in the primary tumor by NGS. Tumor-specific mutation was detectable in 39 % from the blood of early stage lung cancer patients by ddPCR.
Subject(s)
Circulating Tumor DNA , Lung Neoplasms , Neoplasm Recurrence, Local , Biomarkers, Tumor/genetics , Circulating Tumor DNA/genetics , High-Throughput Nucleotide Sequencing , Humans , Lung Neoplasms/diagnosis , Lung Neoplasms/genetics , Mutation , Neoplasm Recurrence, Local/genetics , Polymerase Chain Reaction , Prospective StudiesABSTRACT
OBJECTIVE: The use of atypical antipsychotics (AAPs) for the treatment of unipolar and bipolar depression has been more and more frequently evaluated, and aripiprazole showed positive effects in the treatment of unipolar depression. However, no placebo-controlled studies of adjunctive aripiprazole for the treatment of bipolar depression have been performed yet. METHODS: In this prospective, double-blind, placebo-controlled, randomized trial, 23 inpatients with bipolar depression according to DSM-IV criteria were included. Before randomization, patients had to be on a constant mood stabilizer treatment with lithium or valproate for at least 1 week. After inclusion, all patients were openly treated with additional citalopram and with additional aripiprazole or placebo for 6 weeks. The primary outcome parameter was the reduction in depressive symptoms according to the Hamilton Depression Rating Scale (HDRS) within 6 weeks. RESULTS: After 6 weeks of treatment, the HDRS score decreased in both groups. There was no significant difference between both the groups at any point of time with respect to the HDRS. CONCLUSIONS: Derived from this small pilot study, adjunctive aripiprazole does not seem to be a promising strategy for the acute treatment of bipolar depression. However, this lack of additional benefit seems to stem from the already good effectiveness of the control group, namely the treatment with citalopram.
Subject(s)
Antidepressive Agents, Second-Generation/therapeutic use , Antimanic Agents/therapeutic use , Bipolar Disorder/drug therapy , Citalopram/therapeutic use , Piperazines/therapeutic use , Quinolones/therapeutic use , Selective Serotonin Reuptake Inhibitors/therapeutic use , Adult , Aged , Antidepressive Agents, Second-Generation/adverse effects , Aripiprazole , Diagnostic and Statistical Manual of Mental Disorders , Double-Blind Method , Drug Therapy, Combination/adverse effects , Female , Humans , Male , Middle Aged , Pilot Projects , Piperazines/adverse effects , Quality of Life , Quinolones/adverse effects , Severity of Illness Index , Surveys and QuestionnairesABSTRACT
BRAF V600 mutations occur in a wide range of tumor types, and RAF inhibition has become standard in several of these cancers. Despite this progress, BRAF V600 mutations have historically been considered a clear demonstration of tumor lineage context-dependent oncogene addiction, based predominantly on the insensitivity to RAF inhibition in colorectal cancer. However, the true broader activity of RAF inhibition pan-cancer remains incompletely understood. To address this, we conducted a multicohort "basket" study of the BRAF inhibitor vemurafenib in non-melanoma BRAF V600 mutation-positive solid tumors. In total, 172 patients with 26 unique cancer types were treated, achieving an overall response rate of 33% and median duration of response of 13 months. Responses were observed in 13 unique cancer types, including historically treatment-refractory tumor types such as cholangiocarcinoma, sarcoma, glioma, neuroendocrine carcinoma, and salivary gland carcinomas. Collectively, these data demonstrate that single-agent BRAF inhibition has broader clinical activity than previously recognized. SIGNIFICANCE: These data suggest that BRAF V600 mutations lead to oncogene addiction and are clinically actionable in a broad range of non-melanoma cancers, including tumor types in which RAF inhibition is not currently considered standard of care.See related commentary by Ribas and Lo, p. 640.This article is highlighted in the In This Issue feature, p. 627.
Subject(s)
Neoplasms/drug therapy , Proto-Oncogene Proteins B-raf/metabolism , Vemurafenib/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Humans , Middle Aged , Treatment Outcome , Vemurafenib/pharmacology , Young AdultABSTRACT
BACKGROUND: Resistance to first-generation and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is mediated by the emergence of the Thr790Met mutation in 50-60% of treated patients with non-small-cell lung cancer (NSCLC). We aimed to assess the safety and activity of nazartinib (EGF816), a third-generation EGFR TKI that selectively inhibits EGFR with Thr790Met or activating mutations (or both), while sparing wild-type EGFR, in patients with advanced EGFR-mutant NSCLC. METHODS: This phase 1 dose-escalation part of an open-label, multicentre, phase 1/2 study was conducted at nine academic medical centres located in Europe, Asia, and North America. Patients were included if they were aged 18 years or older and had stage IIIB-IV EGFR-mutant NSCLC (with varying statuses of EGFR mutation and previous therapy allowed), at least one measurable lesion, and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. Nazartinib (at seven dose levels between 75 mg and 350 mg, in capsule or tablet form) was administered orally, once daily, on a continuous 28-day dosing schedule. A two-parameter Bayesian logistic regression model, guided by the escalation with overdose control principle, was implemented to make dose recommendations and estimate the maximum tolerated dose or recommended phase 2 dose of nazartinib (the primary outcome). This study is registered with ClinicalTrials.gov (NCT02108964); enrolment to phase 1 is complete and the study is ongoing. FINDINGS: By Aug 31, 2017, 180 patients (116 [64%] women; median age 60 years (52-69); 116 [64%] with ECOG performance status 1) received nazartinib across seven dose levels: 75 mg (n=17), 100 mg (n=38), 150 mg (n=73), 200 mg (n=8), 225 mg (n=28), 300 mg (n=5), and 350 mg (n=11). Seven dose-limiting toxicities were observed in six (3%) patients who received 150 mg, 225 mg, or 350 mg nazartinib once daily. Although the maximum tolerated dose was not met, the recommended phase 2 dose was declared as 150 mg once daily (tablet). The most common adverse events, regardless of cause, were rash (all subcategories 111 [62%] patients, maculopapular rash 72 [40%], dermatitis acneiform 22 [12%]), diarrhoea (81 [45%]), pruritus (70 [39%]), fatigue (54 [30%]), and stomatitis (54 [30%]), and were mostly grades 1-2. Any-cause grade 3-4 adverse events were reported in 99 (55%) patients across all doses, the most common being rash (all subcategories grouped 27 [15%]), pneumonia (12 [7%]), anaemia (ten [6%]), and dyspnoea (nine [5%]). Serious adverse events suspected to be drug-related occurred in 16 (9%) patients. INTERPRETATION: Nazartinib has a favourable safety profile, with low-grade skin toxicity characterised by a predominantly maculopapular rash that required minimal dose reductions. FUNDING: Novartis Pharmaceuticals Corporation.
Subject(s)
Antineoplastic Agents/therapeutic use , Benzimidazoles/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Nicotine/analogs & derivatives , Aged , Antineoplastic Agents/adverse effects , Benzimidazoles/adverse effects , Carcinoma, Non-Small-Cell Lung/genetics , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Female , Humans , Lung Neoplasms/genetics , Male , Middle Aged , Nicotine/adverse effects , Nicotine/therapeutic use , Treatment OutcomeABSTRACT
BACKGROUND: CheckMate 171 (NCT02409368) is an open-label, multicentre, phase 2 trial of nivolumab in previously treated advanced squamous non-small cell lung cancer (NSCLC), conducted as part of a post-approval commitment to the European Medicines Agency (EMA). We report outcomes from this trial. METHODS: Patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2 and disease progression during/after ≥1 systemic treatment (≥1 being platinum-based chemotherapy) for advanced or metastatic disease were treated with nivolumab 3 mg/kg every 2 weeks until progression or unacceptable toxicity. The primary end-point was incidence of grade 3-4 treatment-related select adverse events (AEs). Other end-points included overall survival (OS) and safety. RESULTS: Of 811 patients treated, 103 had ECOG PS 2; 278 were aged ≥70 years and 125 were ≥75 years of age. Minimum follow-up was ~18 months. Safety was similar across populations; the most frequent grade 3-4 treatment-related select AEs in all treated patients were diarrhoea (1%), increased alanine aminotransferase (ALT, 1%), pneumonitis (0.7%), colitis (0.6%) and increased aspartate aminotransferase (AST, 0.5%). Median OS was similar in all treated patients and those aged ≥70 and ≥75: 10.0 months, 10.0 months and 11.2 months, respectively. Median OS was 5.2 months in patients with ECOG PS 2. CONCLUSION: These results suggest that nivolumab is well tolerated and active in patients with advanced, relapsed squamous NSCLC, including the elderly, with OS outcomes consistent with phase 3 data. In patients with ECOG PS 2, nivolumab had similar tolerability, but outcomes were worse, as expected in this difficult-to-treat, poor prognosis population. CLINICAL TRIAL REGISTRATION: NCT02409368.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Squamous Cell/drug therapy , Lung Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Carboplatin/administration & dosage , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Squamous Cell/pathology , Female , Follow-Up Studies , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Nivolumab/administration & dosage , Prognosis , Retrospective Studies , Survival RateABSTRACT
SCLC remains an aggressive, deadly cancer with only modest effect on survival from standard chemotherapy. However, with the advent of immunotherapy and comprehensive genomic and transcriptomic profiling, multiple new targets are showing promise in the clinical arena, and just recently programmed death ligand 1 inhibition has been shown to improve the efficacy of standard chemotherapy in extended-disease SCLC. Our increasing understanding of the interactions between different pathways will enable more tailored immunotherapy and targeted therapies based on specific biomarkers and rational combinations. Here we discuss the preclinical and clinical strides in 2017 and 2018 that put us on the threshold of a new era in therapeutics and will, it is hoped, translate into significant improvements in survival.
Subject(s)
Lung Neoplasms/epidemiology , Medical Oncology/standards , Small Cell Lung Carcinoma/epidemiology , Thoracic Neoplasms/epidemiology , History, 21st Century , HumansABSTRACT
BACKGROUND: By definition, palliative care (PC) is applicable already in early stages of incurable and life-threatening diseases, in conjunction with therapies that are intended to prolong life, such as for example chemo- or radiotherapy. Many patients suffer from distressing symptoms or problems in early phases of such illness. Therefore, it is not a question of "if" PC should be integrated early into oncology, but "how." General PC is defined as an approach that should be delivered by healthcare professionals regardless of their discipline. This is often referred to as "general" or "primary" PC. For this, routine symptom assessment, expertise concerning basic symptom management, and communication skills are basic requirements. Communication skills include the willingness to engage in discussions concerning patients' fears, worries and end-of-life issues without the fear of destroying hope. Specialist PC is provided by specialist teams regardless of the patients' disease, be it cancer or non-cancer. Such teams should be integrated in the care of PC patients depending on the availability of these services and the patients' needs. Key messages: "Early PC" must not be used synonymously with "early specialist PC" because much of the PC is delivered as basic oncology PC. For the integration of specialist PC, the identification of triggers is warranted in different institutions to facilitate a meaningful and effective cooperation. Such cooperations should be based on patients' needs, but must also account for questions of availability and resources.
Subject(s)
Neoplasms/therapy , Palliative Care , Advance Care Planning , Communication , Fear , Humans , Practice Guidelines as TopicABSTRACT
One distinct molecular subtype of non-small cell lung cancer (NSCLC) is defined by rearrangement of the anaplastic lymphoma kinase (ALK). The increasing knowledge over the last years has enabled the continuous improvement of ALK inhibitors; however, resistance in these patients remains a major concern. In this review, we summarize recent findings in ALK+-adenocarcinoma of the lung, highlighting the role of TP53 mutations in this specific cancer type and suggest new diagnostic strategies for the future, in order to improve patient's outcome.
ABSTRACT
Clinical data confirmed that patients with ROS1 rearrangement are sensitive to specific inhibitors. Therefore, reliable detection of ROS1 rearrangements is essential. Several diagnostic techniques are currently available. However, previous studies were hampered by the low number of ROS1-positive samples. Thirty-five samples, including 32 ROS1 fluorescent in situ hybridization (FISH)-positive and three ROS1 FISH-negative samples were evaluated by ROS1 chromogenic in situ hybridization, ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) immunohistochemistry (IHC), an Agilent SureSelectXT HS custom panel, the Archer FusionPlex Comprehensive Thyroid and Lung panel, and a custom NanoString fusion panel. Some samples were additionally analyzed with the Illumina TruSight Tumor 170 assay. Eleven samples were ROS1 FISH positive by a break-apart signal pattern. In all 11 samples, a ROS1 fusion was confirmed by at least one other method. The other 21 samples tested ROS1 FISH positive by an isolated 3' green signal pattern. Ten of 21 samples could be confirmed by at least two other methods. The other 11 samples tested negative by ROS1 IHC and at least one other method, indicating a false-positive ROS1 FISH result. Our study found that all ROS1 FISH-positive samples with isolated 3' green signals should be confirmed by another method. When sufficient material is available, extraction-based parallel sequencing approaches for the verification of these cases might be preferable.
Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Gene Rearrangement/genetics , In Situ Hybridization/methods , Lung Neoplasms/genetics , Protein-Tyrosine Kinases/genetics , Proto-Oncogene Proteins/genetics , Antigens, Differentiation, B-Lymphocyte/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Chemical Fractionation/methods , Gene Fusion , Histocompatibility Antigens Class II/genetics , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence/methods , Lung Neoplasms/pathology , Proto-Oncogene MasABSTRACT
INTRODUCTION: Mutations in erb-b2 receptor tyrosine kinase 2 (HER2) oncogene are observed in approximately 3% of lung adenocarcinomas or mixed tumors with adenocarcinoma component. Activity of various biologically distinct HER2 inhibitors, including the pan-HER inhibitor afatinib, has been reported in several retrospective trials or small series in advanced pretreated NSCLC with HER2 mutations. We report the first prospective evaluation of afatinib for the treatment of this molecularly defined entity. METHODS: NICHE, a single-arm phase II trial using a two-stage Simon's design, explored the potential of afatinib to control disease in pretreated patients with advanced NSCLC harboring HER2 exon 20 mutations. A total of 13 patients entered the trial and were treated with afatinib 40 mg/day until tumor progression or lack of tolerability. RESULTS: The first-stage stopping boundary was crossed when five of nine patients did not achieve disease control at 12 weeks. The accrual into the trial was stopped with total 13 patients enrolled, with 7 (53.8%) achieving disease control at 12 weeks. Except for 1 patient with early death, progression was documented for all patients, with median progression-free survival of 15.9 weeks (95% confidence interval: 6.0-35.4), and median overall survival of 56.0 weeks (95% confidence interval: 16.3- upper limit not estimable). The toxicity profile was in the expected range. CONCLUSIONS: Afatinib did not show the expected potential for disease control in NSCLC. However, more than half of the patients in the full cohort achieved disease control at 12 weeks.