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Lung cancer, the leading cause of cancer-related deaths globally, remains a pressing health issue despite significant medical advances. The New York Lung Cancer Foundation brought together experts from academia, the pharmaceutical and biotech industries as well as organizational leaders and patient advocates, to thoroughly examine the current state of lung cancer diagnosis, treatment, and research. The goal was to identify areas where our understanding is incomplete and to develop collaborative public health and scientific strategies to generate better patient outcomes, as highlighted in our "Calls to Action." The consortium prioritized 8 different calls to action. These include (1) develop strategies to cure more patients with early-stage lung cancer, (2) investigate carcinogenesis leading to lung cancers in patients without a history of smoking, (3) harness precision medicine for disease interception and prevention, (4) implement solutions to deliver prevention measures and effective therapies to individuals in under-resourced countries, (5) facilitate collaborations with industry to collect and share data and samples, (6) create and maintain open access to big data repositories, (7) develop new immunotherapeutic agents for lung cancer treatment and prevention, and (8) invest in research in both the academic and community settings. These calls to action provide guidance to representatives from academia, the pharmaceutical and biotech industries, organizational and regulatory leaders, and patient advocates to guide ongoing and planned initiatives.
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After disease progression on EGFR tyrosine kinase inhibitor (TKI) therapy, patients with EGFR-mutated NSCLC who are then treated with platinum-based chemotherapy (PBC) obtain only limited clinical benefit with transient responses. Therapies with greater efficacy and tolerable safety profiles are needed in this setting. The receptor tyrosine kinase HER3 is widely expressed in NSCLC, and increased expression is associated with poor treatment outcomes. In the U31402-A-U102 phase I trial, HER3-DXd showed promising antitumor activity with manageable safety in heavily pre-treated patients with EGFR-mutated NSCLC across a range of tumor HER3 expression levels and EGFR TKI resistance mechanisms. HERTHENA-Lung02 is the first phase III trial to evaluate the safety and efficacy of HER3-DXd versus PBC in patients with progression on a third-generation EGFR TKI. Clinical Trial Registration: NCT05338970 (clinicaltrials.gov); 2021-005879-40 (EudraCT Number).
In some patients with non-small-cell lung cancer, changes (or mutations) in the DNA sequence can alter a protein called EGFR and allow tumors to grow and survive. Drugs called EGFR tyrosine kinase inhibitors (EGFR TKIs for short) are used to treat these tumors by interfering with the abnormal EGFR protein. Treatment with these drugs can work well at first, but some tumors never respond, and for tumors that do respond, the cancer eventually becomes resistant to the EGFR TKI and the drug stops working. Platinum-based chemotherapy is often prescribed after an EGFR TKI stops working; however, platinum-based chemotherapy can provide only temporary control of the tumor growth. Most patients with non-small-cell lung cancer have a protein called HER3 on the surface of their tumor cells. A new drug candidate called patritumab deruxtecan (HER3-DXd) finds tumor cells and attaches to the HER3 protein on their surface. HER3-DXd then moves inside the cancer cells, where a novel antitumor payload is released and kills the tumor cells. This article describes the phase III clinical trial HERTHENA-Lung02 (NCT05338970) that compares the benefit of HER3-DXd to platinum-based chemotherapy for patients who have non-small-cell lung cancer with the abnormal EGFR protein and whose disease stopped responding or never responded to EGFR TKI therapy.
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Anticuerpos Monoclonales Humanizados , Camptotecina , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Camptotecina/análogos & derivados , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Ensayos Clínicos Fase III como Asunto , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mutación , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
BACKGROUND: Lorlatinib, a third-generation inhibitor of anaplastic lymphoma kinase (ALK), has antitumor activity in previously treated patients with ALK-positive non-small-cell lung cancer (NSCLC). The efficacy of lorlatinib, as compared with that of crizotinib, as first-line treatment for advanced ALK-positive NSCLC is unclear. METHODS: We conducted a global, randomized, phase 3 trial comparing lorlatinib with crizotinib in 296 patients with advanced ALK-positive NSCLC who had received no previous systemic treatment for metastatic disease. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included independently assessed objective response and intracranial response. An interim analysis of efficacy was planned after approximately 133 of 177 (75%) expected events of disease progression or death had occurred. RESULTS: The percentage of patients who were alive without disease progression at 12 months was 78% (95% confidence interval [CI], 70 to 84) in the lorlatinib group and 39% (95% CI, 30 to 48) in the crizotinib group (hazard ratio for disease progression or death, 0.28; 95% CI, 0.19 to 0.41; P<0.001). An objective response occurred in 76% (95% CI, 68 to 83) of the patients in the lorlatinib group and 58% (95% CI, 49 to 66) of those in the crizotinib group; among those with measurable brain metastases, 82% (95% CI, 57 to 96) and 23% (95% CI, 5 to 54), respectively, had an intracranial response, and 71% of the patients who received lorlatinib had an intracranial complete response. The most common adverse events with lorlatinib were hyperlipidemia, edema, increased weight, peripheral neuropathy, and cognitive effects. Lorlatinib was associated with more grade 3 or 4 adverse events (mainly altered lipid levels) than crizotinib (in 72% vs. 56%). Discontinuation of treatment because of adverse events occurred in 7% and 9% of the patients, respectively. CONCLUSIONS: In an interim analysis of results among patients with previously untreated advanced ALK-positive NSCLC, those who received lorlatinib had significantly longer progression-free survival and a higher frequency of intracranial response than those who received crizotinib. The incidence of grade 3 or 4 adverse events was higher with lorlatinib than with crizotinib because of the frequent occurrence of altered lipid levels. (Funded by Pfizer; CROWN ClinicalTrials.gov number, NCT03052608.).
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Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Crizotinib/uso terapéutico , Lactamas Macrocíclicas/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Aminopiridinas , Quinasa de Linfoma Anaplásico/genética , Antineoplásicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Crizotinib/efectos adversos , Femenino , Humanos , Hiperlipidemias/inducido químicamente , Análisis de Intención de Tratar , Lactamas , Lactamas Macrocíclicas/efectos adversos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Mutación , Pirazoles , Análisis de SupervivenciaRESUMEN
BACKGROUND: Baveno VII criteria for predicting varices needing treatment (VNT) have not been tested in hepatocellular carcinoma (HCC) population. We evaluated Baveno VII consensus for VNT in HCC patients of different stages according to Barcelona Clinic Liver Cancer (BCLC) stages undergoing curative hepatectomy. METHODS: This was a prospective cohort study of patients with HCC. Patients underwent transient elastography examination before HCC treatment and received at least one upper endoscopic examination afterwards. Patients were prospectively followed for clinical events including VNT. RESULTS: Six hundred and seventy-three patients (83.1% male, median age 62 years) with HCC of BCLC stage 0 (10%), A (57%), B (17%) and C (15%) were recruited and followed for 47 months. The median (range) LSM was 10.5 (6.9-20.4) kPa; 74% had LSM ≤ 20 kPa and 58% had platelet count ≥150 × 10/L, respectively. VNT occurred in 51 (7.6%) patients. In patients who fulfilled Baveno VII criteria, that is, LSM ≤ 20 kPa and platelet count above 150 × 10/L, only 11 (1.6%) patients had VNT. In all BCLC stages of HCC, the proportion of patients with VNT was below 5%, which support the validity and applicability of Baveno VII criteria in all BCLC stages of HCC. CONCLUSIONS: The Baveno VII criteria are valid and applicable in HCC patients undergoing curative hepatectomy for selecting patients to undergo screening endoscopy for VNT. The validity was consistent across different BCLC stages of HCC.
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Carcinoma Hepatocelular , Diagnóstico por Imagen de Elasticidad , Várices Esofágicas y Gástricas , Neoplasias Hepáticas , Várices , Humanos , Masculino , Persona de Mediana Edad , Femenino , Cirrosis Hepática/diagnóstico , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/terapia , Várices Esofágicas y Gástricas/diagnóstico , Várices Esofágicas y Gástricas/etiología , Várices Esofágicas y Gástricas/terapia , Estudios Prospectivos , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/cirugía , Estudios RetrospectivosRESUMEN
WHAT IS THIS SUMMARY ABOUT?: This summary shows the updated results of an ongoing research study called CROWN that was published in The Lancet Respiratory Medicine in December 2022. In the CROWN study, researchers looked at the effects of two study medicines called lorlatinib and crizotinib. The study included people with advanced non-small-cell lung cancer (NSCLC) that had not been treated previously. All people in the study had cancer cells with changes (known as alterations) in a gene called anaplastic lymphoma kinase, or ALK. This ALK gene is involved in cancer growth. In this updated study, researchers looked at the continued benefit in people who took lorlatinib compared with people who took crizotinib after 3 years. WHAT DID THIS STUDY FIND?: After 3 years of being observed, people who took lorlatinib were more likely to be alive without their cancer getting worse than people who took crizotinib. At 3 years, 64% of people who took lorlatinib were alive without their cancer getting worse compared with 19% of people who took crizotinib. The cancer was less likely to have spread within or to the brain in people who took lorlatinib than in people who took crizotinib. After 3 years of being observed, 61% of people were still taking lorlatinib and 8% of people were still taking crizotinib. People who took lorlatinib had more severe side effects than people who took crizotinib. However, these side effects were manageable. The most common side effects with lorlatinib were high levels of cholesterol or high levels of triglycerides (a type of fat) in the blood. Life-threatening side effects were seen in 13% of people who took lorlatinib and 8% in crizotinib. Two people who took lorlatinib died because of side effects from lorlatinib. WHAT DO THE RESULTS OF THE STUDY MEAN?: The updated results from the CROWN study showed that a larger percentage of people who took lorlatinib continued to benefit from their treatment after being observed for 3 years compared with those who took crizotinib.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Crizotinib/efectos adversos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Antineoplásicos/uso terapéutico , Aminopiridinas/efectos adversos , Lactamas Macrocíclicas/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
Introduction: This paper presents results from Cohort B (rearranged during transfection [RET], fusion-positive) of the Blood First Assay Screening Trial in patients with advanced non-small cell lung cancer (NSCLC) screened for genetic alterations using blood-based next-generation sequencing. Material and methods: Adults with advanced RET fusion-positive NSCLC received alectinib 900 mg twice daily (BID) in Phase I. Enrolment closed prematurely with Phase II uninitiated. Results: Among eight treated patients, confirmed best overall responses in evaluable patients were stable disease (4/5) and progressive disease (1/5). One dose-limiting toxicity (death, unknown cause) was considered by the investigator to be related to treatment and underlying disease. Serious adverse events (SAEs) occurred in five patients, and SAEs that may be related to treatment occurred in two patients. Conclusions: Alectinib showed limited activity in advanced RET fusion-positive NSCLC, and further investigation was not conducted due to the development of selective RET inhibitors pralsetinib and selpercatinib. No new safety signals were observed, and the safety profile of alectinib was in line with previous reports at the 600 mg BID dose.
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Cell-free DNA (cfDNA) in human plasma is a class of biomarkers with many current and potential future diagnostic applications. Recent studies have shown that cfDNA molecules are not randomly fragmented and possess information related to their tissues of origin. Pathologies causing death of cells from particular tissues result in perturbations in the relative distribution of DNA from the affected tissues. Such tissue-of-origin analysis is particularly useful in the development of liquid biopsies for cancer. It is therefore of value to accurately determine the relative contributions of the tissues to the plasma DNA pool in a simultaneous manner. In this work, we report that in open chromatin regions, cfDNA molecules show characteristic fragmentation patterns reflected by sequencing coverage imbalance and differentially phased fragment end signals. The latter refers to differences in the read densities of sequences corresponding to the orientation of the upstream and downstream ends of cfDNA molecules in relation to the reference genome. Such cfDNA fragmentation patterns preferentially occur in tissue-specific open chromatin regions where the corresponding tissues contributed DNA into the plasma. Quantitative analyses of such signals allow measurement of the relative contributions of various tissues toward the plasma DNA pool. These findings were validated by plasma DNA sequencing data obtained from pregnant women, organ transplantation recipients, and cancer patients. Orientation-aware plasma DNA fragmentation analysis therefore has potential diagnostic applications in noninvasive prenatal testing, organ transplantation monitoring, and cancer liquid biopsy.
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Biomarcadores de Tumor/sangre , Ácidos Nucleicos Libres de Células/genética , Cromatina/genética , Fragmentación del ADN , Biomarcadores de Tumor/normas , Ácidos Nucleicos Libres de Células/sangre , Ácidos Nucleicos Libres de Células/química , Cromatina/química , Humanos , Especificidad de Órganos , Estándares de ReferenciaRESUMEN
Inflammation in the tumor microenvironment is a complicit and known carcinogenesis driver. Inhibition of IL-1ß, one of the most abundant and influential cytokines in the tumor microenvironment, may enhance the efficacy of PD-1. In a post-hoc analysis of phase III cardiovascular CANTOS trial, canakinumab, a monoclonal anti-IL-1ß antibody, significantly reduced lung cancer incidence. Immune checkpoint inhibition (ICI) is the standard of care in non-small-cell lung cancer. However, ICI efficacy is heavily impacted by programmed death ligand-1 (PD-L1) status. Most patients with non-small-cell lung cancer have low PD-L1 expression levels. Thus, combinational strategies are needed to improve ICI efficacy and expand its use. Here, we describe the preclinical and clinical evidence to support the combination of IL-1ß and PD-1 under investigation in the CANOPY program. The perioperative use of canakinumab with or without PD-1 inhibition in the CANOPY-N trial is described as a potential chemotherapy-free immunotherapy strategy.
IL-1ß is a small molecule involved in the spreading of cancer cells and scouting for cells that work against the body's protective inflammatory response. In a follow-up analysis of the CANTOS study, people with atherosclerosis who received canakinumab, a drug which limits the activity of IL-1ß in the body, were diagnosed with lung cancer less often than people who received an inactive substance. Immunotherapy is a treatment that can boost the natural defenses of the immune system, but how well it works varies from patient to patient. Recent efforts aim to understand whether blocking unhealthy inflammation with canakinumab and stimulating the body's protective system with immunotherapy at the same time could be an efficacious treatment for patients with lung cancer. Currently there are limited data from experiments in cell and animal models; however, data from the ongoing CANOPY-N clinical trial, which is investigating this treatment combination prior to surgery for patients with lung cancer, are expected by the first half of this year.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Antígeno B7-H1 , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Ensayos Clínicos Fase III como Asunto , Humanos , Inhibidores de Puntos de Control Inmunológico , Terapia de Inmunosupresión , Inmunoterapia , Inflamación/tratamiento farmacológico , Neoplasias Pulmonares/epidemiología , Receptor de Muerte Celular Programada 1 , Microambiente TumoralRESUMEN
In the global KEYNOTE-042 study (Clinicaltrials.gov, NCT02220894), pembrolizumab significantly improved overall survival (OS) vs chemotherapy in patients with previously untreated programmed death ligand 1 (PD-L1)-positive locally advanced/metastatic non-small-cell lung cancer (NSCLC) without EGFR/ALK alterations. We present results from patients in KEYNOTE-042 enrolled from China in the global or extension study (NCT03850444; protocol identical to global study). Patients were randomized 1:1 (stratified by ECOG performance status 0 vs 1, squamous vs nonsquamous histology and PD-L1 tumor proportion score [TPS] ≥50% vs 1%-49%) to 35 cycles of pembrolizumab 200 mg every 3 weeks (Q3W) or investigator's choice of 4 to 6 cycles of carboplatin plus paclitaxel or pemetrexed Q3W with optional pemetrexed maintenance for nonsquamous tumors. Primary endpoints were OS in patients with PD-L1 TPS ≥50%, ≥20% or ≥1%. Two hundred sixty-two patients (pembrolizumab, n = 128; chemotherapy, n = 134) were enrolled from China. At data cutoff (February 21, 2020; median follow-up, 33.0 [range, 25.6-41.9] months), pembrolizumab was shown to improve OS vs chemotherapy in patients with PD-L1 TPS ≥50% (hazard ratio [95% CI], 0.63 [0.43-0.94]), TPS ≥20% (0.66 [0.47-0.92]) and TPS ≥1% (0.67 [0.50-0.89]). Grade 3 to 5 treatment-related adverse events occurred less frequently with pembrolizumab vs chemotherapy (19.5% vs 68.8%). In 22 patients who completed 35 cycles of pembrolizumab, objective response rate was 77.3% and median duration of response was 27.6 months. Consistent with the global KEYNOTE-042 study, pembrolizumab improved OS vs chemotherapy in this study of Chinese patients with locally advanced/metastatic NSCLC and PD-L1 TPS ≥1%, supporting first-line pembrolizumab monotherapy for PD-L1-positive advanced/metastatic NSCLC in China.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma de Pulmón de Células no Pequeñas/patología , China , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Enhancing tumor-specific T-cell immunity by inhibiting programmed death ligand 1 (PD-L1)-programmed death 1 (PD-1) signaling has shown promise in the treatment of extensive-stage small-cell lung cancer. Combining checkpoint inhibition with cytotoxic chemotherapy may have a synergistic effect and improve efficacy. METHODS: We conducted this double-blind, placebo-controlled, phase 3 trial to evaluate atezolizumab plus carboplatin and etoposide in patients with extensive-stage small-cell lung cancer who had not previously received treatment. Patients were randomly assigned in a 1:1 ratio to receive carboplatin and etoposide with either atezolizumab or placebo for four 21-day cycles (induction phase), followed by a maintenance phase during which they received either atezolizumab or placebo (according to the previous random assignment) until they had unacceptable toxic effects, disease progression according to Response Evaluation Criteria in Solid Tumors, version 1.1, or no additional clinical benefit. The two primary end points were investigator-assessed progression-free survival and overall survival in the intention-to-treat population. RESULTS: A total of 201 patients were randomly assigned to the atezolizumab group, and 202 patients to the placebo group. At a median follow-up of 13.9 months, the median overall survival was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (hazard ratio for death, 0.70; 95% confidence interval [CI], 0.54 to 0.91; P=0.007). The median progression-free survival was 5.2 months and 4.3 months, respectively (hazard ratio for disease progression or death, 0.77; 95% CI, 0.62 to 0.96; P=0.02). The safety profile of atezolizumab plus carboplatin and etoposide was consistent with the previously reported safety profile of the individual agents, with no new findings observed. CONCLUSIONS: The addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by F. Hoffmann-La Roche/Genentech; IMpower133 ClinicalTrials.gov number, NCT02763579 .).
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Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Método Doble Ciego , Etopósido/administración & dosificación , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Supervivencia sin Progresión , Carcinoma Pulmonar de Células Pequeñas/mortalidadRESUMEN
INTRODUCTION: Immunotherapy has dramatically improved the survival of patients with advanced or metastatic malignancies. Recent studies suggest that immunotherapy may increase the risk of hepatitis, whereas it may also induce functional cure of chronic hepatitis B virus (HBV) infection. We evaluated the incidence of hepatitis flare, HBV reactivation, hepatitis B surface antigen (HBsAg) seroclearance or seroreversion in patients with current or past HBV infection who had received immunotherapy. METHODS: This was a territory-wide observational cohort study in Hong Kong. We identified patients through electronic medical records based on the prescriptions of immune checkpoint inhibitors from July 1, 2014, to December 31, 2019. Patients who were HBsAg positive or HBsAg negative with results for antibody to hepatitis B surface or core antigen (anti-HBs or anti-HBc) were included. RESULTS: A total of 990 patients (397 HBsAg-positive, 593 HBsAg-negative with 482 anti-HBc and/or anti-HBs positive, and 111 both anti-HBc and anti-HBs negative) were identified. All of HBsAg-positive and 15.9% HBsAg-negative patients were put on oral antiviral treatment. Hepatitis flare (alanine aminotransferase >2 times of the upper limit of normal) occurred in 39.3% HBsAg-positive and 30.4% HBsAg-negative patients. High baseline alanine aminotransferase and combination of immunotherapy increased the risk of hepatitis. HBV reactivation (≥2 log increase in HBV DNA from baseline) occurred in 2 HBsAg-positive patients; HBsAg seroclearance and seroreversion was observed in 1 HBsAg-positive and 1 HBsAg-negative patient, respectively (<1%). DISCUSSION: Hepatitis flare occurs in approximately 40% of HBsAg-positive patients and 30% of HBsAg-negative patients during immunotherapy. HBV reactivation, HBsAg seroclearance, and HBsAg seroreversion are rare. Current or past HBV infection has no impact on the emergence of hepatic flare associated with immunotherapy.
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Hepatitis B/inmunología , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Brote de los Síntomas , Administración Oral , Anciano , Alanina Transaminasa/sangre , Antivirales/administración & dosificación , Biomarcadores/sangre , Femenino , Hepatitis B/tratamiento farmacológico , Antígenos de Superficie de la Hepatitis B/inmunología , Hong Kong , Humanos , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Activación Viral/efectos de los fármacos , Activación Viral/inmunologíaRESUMEN
BACKGROUND: Pegylated recombinant human arginase (PEG-BCT-100) is an arginine depleting drug. Preclinical studies showed that HCC is reliant on exogenous arginine for growth due to the under-expression of the arginine regenerating enzymes argininosuccinate synthetase (ASS) and ornithine transcarbamylase (OTC). METHODS: This is a single arm open-label Phase II trial to assess the potential clinical efficacy of PEG-BCT-100 in chemo naïve sorafenib-failure HCC patients. Pre-treatment tumour biopsy was mandated for ASS and OTC expression by immunohistochemistry (IHC). Weekly intravenous PEG-BCT-100 at 2.7 mg/kg was given. Primary endpoint was time to progression (TTP); secondary endpoints included radiological response as per RECIST1.1, progression free survival (PFS) and overall survival (OS). Treatment outcomes were correlated with tumour immunohistochemical expressions of ASS and OTC. RESULTS: In total 27 patients were recruited. The median TTP and PFS were both 6 weeks (95% CI, 5.9-6.0 weeks). The disease control rate (DCR) was 21.7% (5 stable disease). The drug was well tolerated. Post hoc analysis showed that duration of arginine depletion correlated with OS. For patients with available IHC results, 10 patients with ASS-negative tumour had OS of 35 weeks (95% CI: 8.3-78.0 weeks) vs. 15.14 weeks (95% CI: 13.4-15.1 weeks) in 3 with ASS-positive tumour; expression of OTC did not correlate with treatment outcomes. CONCLUSIONS: PEG-BCT-100 in chemo naïve post-sorafenib HCC is well tolerated with moderate DCR. ASS-negative confers OS advantage over ASS-positive HCC. ASS-negativity is a potential biomarker for OS in HCC and possibly for other ASS-negative arginine auxotrophic cancers. TRIAL REGISTRATION NUMBER: NCT01092091. Date of registration: March 23, 2010.
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Arginasa/uso terapéutico , Argininosuccinato Sintasa/efectos de los fármacos , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Ornitina Carbamoiltransferasa/efectos de los fármacos , Proteínas Recombinantes/uso terapéutico , Anciano , Anciano de 80 o más Años , Arginasa/efectos adversos , Argininosuccinato Sintasa/biosíntesis , Biomarcadores , Carcinoma Hepatocelular/patología , Femenino , Humanos , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Ornitina Carbamoiltransferasa/biosíntesis , Supervivencia sin Progresión , Calidad de Vida , Proteínas Recombinantes/efectos adversosRESUMEN
Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have improved outcomes in ALK-rearranged (ALK+) non-small-cell lung cancer (NSCLC). However, almost all patients eventually develop progressive disease on first-line ALK TKIs (e.g., crizotinib, alectinib and ceritinib). Brigatinib, a second-generation ALK TKI, may show efficacy in alectinib- and ceritinib-refractory ALK+ NSCLC. We describe the rationale and design of ALTA-2, a Phase II study of brigatinib in patients with locally advanced/metastatic ALK+ NSCLC and documented progressive disease on alectinib or ceritinib. The primary end point is confirmed objective response rate per independent review committee using response evaluation criteria in solid tumors version 1.1. Secondary end points include duration of response, progression-free survival, overall survival, safety and health-related quality of life.
Lay abstract Tyrosine kinase inhibitor medications (like crizotinib, alectinib or ceritinib) may work as the first treatment for people with non-small-cell lung cancer (NSCLC) that has spread to other parts of the body and has the ALK+ mutation (ALK+ NSCLC) in tumor testing. However, after a while, many people stop responding to treatment with one of these medicines. Brigatinib is a tyrosine kinase inhibitor medicine that may be effective in people with ALK+ NSCLC who have stopped responding to alectinib or ceritinib treatment. We describe the need for and design of a study of brigatinib in people with ALK+ NSCLC whose disease got worse on alectinib or ceritinib. Clinical trial registration: NCT03535740 (ClinicalTrials.gov).
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Compuestos Organofosforados/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas/administración & dosificación , Adulto , Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Carbazoles/administración & dosificación , Carbazoles/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Ensayos Clínicos Fase II como Asunto , Progresión de la Enfermedad , Esquema de Medicación , Resistencia a Antineoplásicos , Femenino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Compuestos Organofosforados/efectos adversos , Piperidinas/administración & dosificación , Piperidinas/efectos adversos , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/efectos adversos , Pirimidinas/efectos adversos , Calidad de Vida , Criterios de Evaluación de Respuesta en Tumores Sólidos , Sulfonas/administración & dosificación , Sulfonas/efectos adversosRESUMEN
This is a summary of a research study (known as a clinical trial) called CROWN. The study tested two medicines called lorlatinib and crizotinib in participants with untreated non-small cell lung cancer that had spread to other parts of their body. All those who took part had changes in a gene called ALK, which is involved in cell growth. In total, 296 participants from 23 countries took part. Half the participants took lorlatinib and half took crizotinib. After participants started taking lorlatinib or crizotinib, they were checked regularly to see if their tumors had grown or spread to other parts of their body (known as tumor progression) and to monitor any side effects. After 1 year of treatment, the participants who took lorlatinib were twice as likely to be alive with no tumor growth as the participants who took crizotinib. More participants who took lorlatinib had cancer that shrank (76%) compared with the participants who took crizotinib (58%). This was also true of the participants whose cancer had spread to their brain. The most common side effects in participants who took lorlatinib were increases in the amount of cholesterol and triglycerides (a type of fat) in their blood, swelling, weight gain, nerve damage, unclear thoughts, and diarrhea. Among the participants who took crizotinib, the most common side effects were diarrhea, feeling like you want to throw up, sight problems, swelling, vomiting, changes in liver function, and feeling tired. Overall, the CROWN study showed that fewer participants with advanced ALK+ non-small cell lung cancer died or had tumor growth with lorlatinib compared with crizotinib treatment. ClinicalTrials.gov NCT number: NCT03052608.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Aminopiridinas , Quinasa de Linfoma Anaplásico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Crizotinib , Humanos , Lactamas , Lenguaje , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , PirazolesRESUMEN
Canakinumab is a human IgGκ monoclonal antibody, with high affinity and specificity for IL-1ß. The Canakinumab Anti-Inflammatory Thrombosis Outcome Study (CANTOS) trial, evaluating canakinumab for cardiovascular disease, provided the first signal of the potential of IL-1ß inhibition on lung cancer incidence reduction. Here, we describe the rationale and design for CANOPY-N, a randomized Phase II trial evaluating IL-1ß inhibition with or without immune checkpoint inhibition as neoadjuvant treatment in patients with non-small-cell lung cancer. Patients with stage IB to IIIA non-small-cell lung cancer eligible for complete resection will receive canakinumab or pembrolizumab as monotherapy, or in combination. The primary end point is major pathological response by central review; secondary end points include overall response rate, major pathological response (local review), surgical feasibility rate and pharmacokinetics. Clinical trial registration: NCT03968419 (ClinicalTrials.gov).
Lay abstract A previous study showed that canakinumab reduced the risk of lung cancer in patients with heart disease. Canakinumab blocks an inflammatory protein called IL-1ß that is involved in cancer. Anti-cancer drugs used before surgery ('neo-adjuvant') can improve the success rate of surgery and may help prevent the cancer from returning. Neo-adjuvant trials help us understand how the drugs work and how they affect cancer. CANOPY-N (NCT03968419) is an ongoing randomized, exploratory, Phase II clinical trial testing canakinumab and pembrolizumab (a different cancer immunotherapy), alone or combined, for patients with early non-small-cell lung cancer. The study will test whether treatment can kill most cancer cells in the surgery sample ('major pathological response'). It will also investigate other effects on cancer biology, levels of molecules that measure possible clinical benefit ('biomarkers') and side effects.
Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/terapia , Adolescente , Adulto , Anticuerpos Monoclonales Humanizados/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Ensayos Clínicos Fase II como Asunto , Femenino , Humanos , Interleucina-1beta/antagonistas & inhibidores , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/cirugía , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/inmunología , Masculino , Terapia Neoadyuvante/métodos , Estadificación de Neoplasias , Neumonectomía , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Ensayos Clínicos Controlados Aleatorios como Asunto , Adulto JovenRESUMEN
Aim: Patient-reported symptoms, functioning and overall quality of life (QoL) were compared between dacomitinib and gefitinib in ARCHER 1050. Patients & methods: Patients (n = 448) with advanced EGFR mutation-positive non-small-cell lung cancer completed the EORTC-QLQ-C30 questionnaire and its lung-specific module, LC-13. Mean scores over time were analyzed using a mixed model for repeated measures. Results: Both treatments showed early improvement in disease-related symptoms that was maintained during treatment. Treatment-related diarrhea and sore mouth decreased following dose reduction with dacomitinib. There were no clinically meaningful changes in functioning and overall QoL in either treatment group. Conclusion: Longer treatment duration, enabled by dose reduction, allowed patients on dacomitinib to improve treatment-related symptoms and maintain functioning and overall QoL for longer than gefitinib.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Medición de Resultados Informados por el Paciente , Inhibidores de Proteínas Quinasas/administración & dosificación , Quinazolinonas/administración & dosificación , Actividades Cotidianas , Administración Oral , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Receptores ErbB/genética , Femenino , Mutación con Ganancia de Función , Gefitinib/administración & dosificación , Gefitinib/efectos adversos , Humanos , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/efectos adversos , Calidad de Vida , Quinazolinonas/efectos adversos , Criterios de Evaluación de Respuesta en Tumores SólidosRESUMEN
BACKGROUND: This study assesses different technologies for detecting epidermal growth factor receptor (EGFR) mutations from circulating tumor DNA in patients with EGFR T790M-positive advanced non-small cell lung cancer (NSCLC) from the AURA3 study (NCT02151981), and it evaluates clinical responses to osimertinib and platinum-pemetrexed according to the plasma T790M status. METHODS: Tumor tissue biopsy samples were tested for T790M during screening with the cobas EGFR Mutation Test (cobas tissue). Plasma samples were collected at screening and at the baseline and were retrospectively analyzed for EGFR mutations with the cobas EGFR Mutation Test v2 (cobas plasma), droplet digital polymerase chain reaction (ddPCR; Biodesix), and next-generation sequencing (NGS; Guardant360, Guardant Health). RESULTS: With cobas tissue test results as a reference, the plasma T790M positive percent agreement (PPA) was 51% (110 of 215 samples) by cobas plasma, 58% (110 of 189) by ddPCR, and 66% (136 of 207) by NGS. Plasma T790M detection was associated with a larger median baseline tumor size (56 mm for T790M-positive vs 39 mm for T790M-negative; P < .0001) and the presence of extrathoracic disease (58% for M1b-positive vs 39% for M0-1a-positive; P = .002). Progression-free survival (PFS) was prolonged in randomized patients (tissue T790M-positive) with a T790M-negative cobas plasma result in comparison with those with a T790M-positive plasma result in both osimertinib (median, 12.5 vs 8.3 months) and platinum-pemetrexed groups (median, 5.6 vs 4.2 months). CONCLUSIONS: PPA was similar between ddPCR and NGS assays; both were more sensitive than cobas plasma. All 3 test platforms are suitable for routine clinical practice. In patients with tissue T790M-positive NSCLC, an absence of detectable plasma T790M at the baseline is associated with longer PFS, which may be attributed to a lower disease burden.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Análisis Mutacional de ADN/métodos , Neoplasias Pulmonares/tratamiento farmacológico , Acrilamidas/farmacología , Acrilamidas/uso terapéutico , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carboplatino/farmacología , Carboplatino/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Cisplatino/farmacología , Cisplatino/uso terapéutico , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Femenino , Humanos , Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación , Pemetrexed/farmacología , Pemetrexed/uso terapéutico , Supervivencia sin Progresión , Estudios Retrospectivos , Carga Tumoral/genéticaRESUMEN
BACKGROUND: First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater. METHODS: This randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries. Eligible patients were adults (≥18 years) with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation was computer generated, accessed via an interactive voice-response and integrated web-response system, and stratified by region of enrolment (east Asia vs rest of world), ECOG performance status score (0 vs 1), histology (squamous vs non-squamous), and PD-L1 TPS (≥50% vs 1-49%). Enrolled patients were randomly assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles or the investigator's choice of platinum-based chemotherapy for four to six cycles. Primary endpoints were overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater (one-sided significance thresholds, p=0·0122, p=0·0120, and p=0·0124, respectively) in the intention-to-treat population, assessed sequentially if the previous findings were significant. This study is registered at ClinicalTrials.gov, number NCT02220894. FINDINGS: From Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women, median age 63 years [IQR 57-69]) with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n=637) or chemotherapy (n=637) and included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up was 12·8 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (≥50% hazard ratio 0·69, 95% CI 0·56-0·85, p=0·0003; ≥20% 0·77, 0·64-0·92, p=0·0020, and ≥1% 0·81, 0·71-0·93, p=0·0018). The median surival values by TPS population were 20·0 months (95% CI 15·4-24·9) for pembrolizumab versus 12·2 months (10·4-14·2) for chemotherapy, 17·7 months (15·3-22·1) versus 13·0 months (11·6-15·3), and 16·7 months (13·9-19·7) versus 12·1 months (11·3-13·3), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively. INTERPRETATION: The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS. FUNDING: Merck Sharp & Dohme.
Asunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/secundario , Neoplasias Pulmonares/tratamiento farmacológico , Anciano , Quinasa de Linfoma Anaplásico/efectos de los fármacos , Quinasa de Linfoma Anaplásico/genética , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Supervivencia sin Enfermedad , Esquema de Medicación , Asia Oriental/epidemiología , Femenino , Genes erbB-1/efectos de los fármacos , Genes erbB-1/genética , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Masculino , Persona de Mediana Edad , Mutación , Metástasis de la Neoplasia/patología , Translocación GenéticaRESUMEN
BACKGROUND: Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in patients with non-small-cell lung cancer. The efficacy of osimertinib as compared with platinum-based therapy plus pemetrexed in such patients is unknown. METHODS: In this randomized, international, open-label, phase 3 trial, we assigned 419 patients with T790M-positive advanced non-small-cell lung cancer, who had disease progression after first-line EGFR-TKI therapy, in a 2:1 ratio to receive either oral osimertinib (at a dose of 80 mg once daily) or intravenous pemetrexed (500 mg per square meter of body-surface area) plus either carboplatin (target area under the curve, 5 [AUC5]) or cisplatin (75 mg per square meter) every 3 weeks for up to six cycles; maintenance pemetrexed was allowed. In all the patients, disease had progressed during receipt of first-line EGFR-TKI therapy. The primary end point was investigator-assessed progression-free survival. RESULTS: The median duration of progression-free survival was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; hazard ratio; 0.30; 95% confidence interval [CI], 0.23 to 0.41; P<0.001). The objective response rate was significantly better with osimertinib (71%; 95% CI, 65 to 76) than with platinum therapy plus pemetrexed (31%; 95% CI, 24 to 40) (odds ratio for objective response, 5.39; 95% CI, 3.47 to 8.48; P<0.001). Among 144 patients with metastases to the central nervous system (CNS), the median duration of progression-free survival was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; hazard ratio, 0.32; 95% CI, 0.21 to 0.49). The proportion of patients with adverse events of grade 3 or higher was lower with osimertinib (23%) than with platinum therapy plus pemetrexed (47%). CONCLUSIONS: Osimertinib had significantly greater efficacy than platinum therapy plus pemetrexed in patients with T790M-positive advanced non-small-cell lung cancer (including those with CNS metastases) in whom disease had progressed during first-line EGFR-TKI therapy. (Funded by AstraZeneca; AURA3 ClinicalTrials.gov number, NCT02151981 .).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Pemetrexed/administración & dosificación , Piperazinas/administración & dosificación , Acrilamidas , Adulto , Anciano , Anciano de 80 o más Años , Compuestos de Anilina , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Pemetrexed/efectos adversos , Piperazinas/efectos adversos , Platino (Metal)/administración & dosificación , Adulto JovenRESUMEN
BACKGROUND: Alectinib, a highly selective inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system (CNS) efficacy in the treatment of ALK-positive non-small-cell lung cancer (NSCLC). We investigated alectinib as compared with crizotinib in patients with previously untreated, advanced ALK-positive NSCLC, including those with asymptomatic CNS disease. METHODS: In a randomized, open-label, phase 3 trial, we randomly assigned 303 patients with previously untreated, advanced ALK-positive NSCLC to receive either alectinib (600 mg twice daily) or crizotinib (250 mg twice daily). The primary end point was investigator-assessed progression-free survival. Secondary end points were independent review committee-assessed progression-free survival, time to CNS progression, objective response rate, and overall survival. RESULTS: During a median follow-up of 17.6 months (crizotinib) and 18.6 months (alectinib), an event of disease progression or death occurred in 62 of 152 patients (41%) in the alectinib group and 102 of 151 patients (68%) in the crizotinib group. The rate of investigator-assessed progression-free survival was significantly higher with alectinib than with crizotinib (12-month event-free survival rate, 68.4% [95% confidence interval (CI), 61.0 to 75.9] with alectinib vs. 48.7% [95% CI, 40.4 to 56.9] with crizotinib; hazard ratio for disease progression or death, 0.47 [95% CI, 0.34 to 0.65]; P<0.001); the median progression-free survival with alectinib was not reached. The results for independent review committee-assessed progression-free survival were consistent with those for the primary end point. A total of 18 patients (12%) in the alectinib group had an event of CNS progression, as compared with 68 patients (45%) in the crizotinib group (cause-specific hazard ratio, 0.16; 95% CI, 0.10 to 0.28; P<0.001). A response occurred in 126 patients in the alectinib group (response rate, 82.9%; 95% CI, 76.0 to 88.5) and in 114 patients in the crizotinib group (response rate, 75.5%; 95% CI, 67.8 to 82.1) (P=0.09). Grade 3 to 5 adverse events were less frequent with alectinib (41% vs. 50% with crizotinib). CONCLUSIONS: As compared with crizotinib, alectinib showed superior efficacy and lower toxicity in primary treatment of ALK-positive NSCLC. (Funded by F. Hoffmann-La Roche; ALEX ClinicalTrials.gov number, NCT02075840 .).