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For patients with non-small-cell lung cancer (NSCLC) tumors without currently targetable molecular alterations, standard-of-care treatment is immunotherapy with anti-PD-(L)1 checkpoint inhibitors, alone or with platinum-doublet therapy. However, not all patients derive durable benefit and resistance to immune checkpoint blockade is common. Understanding mechanisms of resistance-which can include defects in DNA damage response and repair pathways, alterations or functional mutations in STK11/LKB1, alterations in antigen-presentation pathways, and immunosuppressive cellular subsets within the tumor microenvironment-and developing effective therapies to overcome them, remains an unmet need. Here the phase 2 umbrella HUDSON study evaluated rational combination regimens for advanced NSCLC following failure of anti-PD-(L)1-containing immunotherapy and platinum-doublet therapy. A total of 268 patients received durvalumab (anti-PD-L1 monoclonal antibody)-ceralasertib (ATR kinase inhibitor), durvalumab-olaparib (PARP inhibitor), durvalumab-danvatirsen (STAT3 antisense oligonucleotide) or durvalumab-oleclumab (anti-CD73 monoclonal antibody). Greatest clinical benefit was observed with durvalumab-ceralasertib; objective response rate (primary outcome) was 13.9% (11/79) versus 2.6% (5/189) with other regimens, pooled, median progression-free survival (secondary outcome) was 5.8 (80% confidence interval 4.6-7.4) versus 2.7 (1.8-2.8) months, and median overall survival (secondary outcome) was 17.4 (14.1-20.3) versus 9.4 (7.5-10.6) months. Benefit with durvalumab-ceralasertib was consistent across known immunotherapy-refractory subgroups. In ATM-altered patients hypothesized to harbor vulnerability to ATR inhibition, objective response rate was 26.1% (6/23) and median progression-free survival/median overall survival were 8.4/22.8 months. Durvalumab-ceralasertib safety/tolerability profile was manageable. Biomarker analyses suggested that anti-PD-L1/ATR inhibition induced immune changes that reinvigorated antitumor immunity. Durvalumab-ceralasertib is under further investigation in immunotherapy-refractory NSCLC.ClinicalTrials.gov identifier: NCT03334617.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Indoles , Neoplasias Pulmonares , Morfolinas , Pirimidinas , Sulfonamidas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Platino (Metal)/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anticuerpos Monoclonales , Antineoplásicos/uso terapéutico , Biomarcadores , Antígeno B7-H1 , Microambiente TumoralRESUMEN
Inuit are the Indigenous Arctic peoples and residents of the Canadian territory of Nunavut who have the highest global rate of lung cancer. Given lung cancer's mortality, histological and genomic characterization was undertaken to better understand the disease biology. We retrospectively studied all Inuit cases from Nunavut's Qikiqtani (Baffin) region, referred to the Ottawa Hospital Cancer Center between 2001 and 2011. Demographics were compiled from medical records and tumor samples underwent pathologic/histologic confirmation. Tumors were analyzed by next generation sequencing (NGS) with a cancer hotspot mutation panel. Of 98 patients, the median age was 66 years and 61% were male. Tobacco use was reported in 87%, and 69% had a history of lung disease (tuberculosis or other). Histological types were: non-small cell lung carcinoma (NSCLC), 81%; small cell lung carcinoma, 16%. Squamous cell carcinoma (SCC) represented 65% of NSCLC. NGS on 55 samples demonstrated mutation rates similar to public lung cancer datasets. In SCC, the STK11 F354L mutation was observed at higher frequency than previously reported. This is the first study to characterize the histologic/genomic profiles of lung cancer in this population. A high incidence of SCC, and an elevated rate of STK11 mutations distinguishes this group from the North American population.
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Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Anciano , Canadá , Carcinoma de Pulmón de Células no Pequeñas/genética , Femenino , Humanos , Inuk , Neoplasias Pulmonares/genética , Masculino , Estudios RetrospectivosRESUMEN
INTRODUCTION: First-line therapy for patients with metastatic NSCLC includes checkpoint inhibitor monotherapy, dual checkpoint inhibition, or combination with chemotherapy. We compared outcomes with combination chemoimmunotherapy versus dual checkpoint inhibition as first-line treatment for patients with metastatic NSCLC. METHODS: This open-label, randomized clinical trial was conducted at 44 sites in Canada and Australia. Patients with treatment-naive, metastatic NSCLC without sensitizing EGFR or ALK alterations were randomized (1:1) to receive treatment with durvalumab plus tremelimumab with or without platinum-doublet chemotherapy. The primary end point was overall survival (OS). Secondary end points were progression-free survival, overall response rate, and safety. RESULTS: A total of 301 patients were randomized. Median OS was 16.6 months (95% confidence interval [CI]: 12.6-19.1) with chemotherapy plus immunotherapy and 14.1 months (95% CI: 10.6-18.3) with immunotherapy (hazard ratio = 0.88, 90% CI: 0.67-1.16, p = 0.46). Median progression-free survival with chemotherapy plus immunotherapy was 7.7 months (95% CI: 5.5-8.5) and 3.2 months (95% CI: 2.7-5.1) with immunotherapy (hazard ratio = 0.67, 95% CI: 0.52-0.88). The overall response rate with chemoimmunotherapy was 42.4% and 29.3% with immunotherapy (adjusted OR = 1.69, 95% CI: 1.04-2.76). The percentage of patients with grade 3 or higher adverse events was 82% in the chemotherapy plus immunotherapy group and 70% in the immunotherapy group. Exploratory analyses of programmed death-ligand 1 expression and blood-based tumor mutation burden revealed no differential treatment effect on OS. CONCLUSIONS: The addition of chemotherapy to durvalumab plus tremelimumab in the first-line treatment of stage IV NSCLC did not improve survival compared with durvalumab plus tremelimumab alone. Further study is warranted to identify patients that benefit from initial immunotherapy alone versus combination chemotherapy plus immunotherapy as first-line treatment.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Anticuerpos Monoclonales , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Neoplasias Pulmonares/patología , Platino (Metal)/uso terapéuticoRESUMEN
Sarah Nanoparticles (SaNPs) are unique multicore iron oxide-based nanoparticles, developed for the treatment of advanced cancer, following standard care, through the selective delivery of thermal energy to malignant cells upon exposure to an alternating magnetic field. For their therapeutic effect, SaNPs need to accumulate in the tumor. Since the potential accumulation and associated toxicity in normal tissues are an important risk consideration, biodistribution and toxicity were assessed in naïve BALB/c mice. Therapeutic efficacy and the effect on survival were investigated in the 4T1 murine model of metastatic breast cancer. Toxicity evaluation at various timepoints did not reveal any abnormal clinical signs, evidence of alterations in organ function, nor histopathologic adverse target organ toxicity, even after a follow up period of 25 weeks, confirming the safety of SaNP use. The biodistribution evaluation, following SaNP administration, indicated that SaNPs accumulate mainly in the liver and spleen. A comprehensive pharmacokinetics evaluation, demonstrated that the total percentage of SaNPs that accumulated in the blood and vital organs was ~78%, 46%, and 36% after 4, 13, and 25 weeks, respectively, suggesting a time-dependent clearance from the body. Efficacy studies in mice bearing 4T1 metastatic tumors revealed a 49.6% and 70% reduction in the number of lung metastases and their relative size, respectively, in treated vs. control mice, accompanied by a decrease in tumor cell viability in response to treatment. Moreover, SaNP treatment followed by alternating magnetic field exposure significantly improved the survival rate of treated mice compared to the controls. The median survival time was 29 ± 3.8 days in the treated group vs. 21.6 ± 4.9 days in the control, p-value 0.029. These assessments open new avenues for generating SaNPs and alternating magnetic field application as a potential novel therapeutic modality for metastatic cancer patients.
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BACKGROUND: LUX-Lung 8 was a randomised, controlled, phase 3 study comparing afatinib and erlotinib as second-line treatment of patients with advanced squamous cell carcinoma (SCC) of the lung. We report the final overall survival (OS) and safety analyses of LUX-Lung 8 and investigate the characteristics of patients who achieved long-term benefit (≥12 months' treatment). METHODS: LUX-Lung 8 (NCT01523587) enroled patients between March 2012 and January 2014 in 183 cancer centres located in 23 countries worldwide and this final analysis had a data cut-off of March 2018. Eligible patients had stage IIIB or IV lung SCC and had progressed after at least four cycles of platinum-based chemotherapy. Patients were randomly assigned (1:1) to receive afatinib (40 mg per day) or erlotinib (150 mg per day) until disease progression. Endpoints included OS and safety; a post-hoc analysis of patients with long-term benefit (≥12 months on treatment) was also conducted. FINDINGS: 795 eligible patients were randomly assigned (398 to afatinib, 397 to erlotinib). OS was significantly prolonged with afatinib compared with erlotinib (median 7·8 months vs 6·8 months; hazard ratio 0·84; 95% CI 0·73-0·97; p = 0·0193). These findings were consistent with those of the primary analysis and were consistent across subgroups. Adverse events (AEs) were manageable with dose interruption and reduction, with similar AEs being experienced between both groups. Twenty-one (5·3%) patients receiving afatinib and 13 (3·3%) patients receiving erlotinib achieved long-term benefit; median OS was 34·6 months and 20·1 months, respectively. Amongst 132 afatinib-treated patients who underwent tumour genetic analysis, ERBB family mutations were more common in patients with long-term benefit than in the overall population (50% vs 21%). INTERPRETATION: Afatinib is a treatment option for patients with SCC of the lung progressing on chemotherapy who are ineligible for immunotherapy, particularly those with ERBB family genetic aberrations. Afatinib has a predictable and manageable tolerability profile, and long-term treatment may be well tolerated.
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BACKGROUND: In high grade serous ovarian cancer (HGSOC), there is a spectrum of sensitivity to first line platinum-based chemotherapy. This study molecularly characterizes HGSOC patients from two distinct groups of chemotherapy responders (good vs. poor). METHODS: Following primary debulking surgery and intravenous carboplatin/paclitaxel, women with stage III-IV HGSOC were grouped by response. Patients in the good response (GR) and poor response (PR) groups respectively had a progression-free intervals (PFI) of ≥12 and ≤6 months. Analysis of surgical specimens interrogated genomic and immunologic features using whole exome sequencing. RNA-sequencing detected gene expression outliers and inference of immune infiltrate, with validation by targeted NanoString arrays. PD-L1 expression was scored by immunohistochemistry (IHC). RESULTS: A total of 39 patient samples were analyzed (GR = 20; PR = 19). Median PFI for GR and PR patient cohorts was 32 and 3 months, respectively. GR tumors were enriched for loss-of-function BRCA2 mutations and had a significantly higher nonsynonymous mutation rate compared to PR tumors (p = 0.001). Samples from the PR cohort were characterized by mutations in MGA and RAD51B and trended towards a greater rate of amplification of PIK3CA, MECOM, and ATR in comparison to GR tumors. Gene expression analysis by NanoString correlated increased PARP4 with PR and increased PD-L1 and EMSY with GR. There was greater tumor immune cell infiltration and higher immune cell PD-L1 protein expression in the GR group. CONCLUSIONS: Our research demonstrates that tumors from HGSOC patients responding poorly to first line chemotherapy have a distinct molecular profile characterized by actionable drug targets including PARP4.
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Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/inmunología , Neoplasias Ováricas/genética , Neoplasias Ováricas/inmunología , Transcriptoma/genética , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteínas de la Ataxia Telangiectasia Mutada/genética , Antígeno B7-H1/metabolismo , Carboplatino/administración & dosificación , Fosfatidilinositol 3-Quinasa Clase I/genética , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/patología , Procedimientos Quirúrgicos de Citorreducción , Femenino , Amplificación de Genes , Perfilación de la Expresión Génica , Genes BRCA1 , Genes BRCA2 , Genes p53 , Humanos , Proteína del Locus del Complejo MDS1 y EV11/genética , Persona de Mediana Edad , Mutación , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Paclitaxel/administración & dosificación , Supervivencia sin Progresión , Proteínas Represoras/metabolismo , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Secuenciación del ExomaRESUMEN
This multicenter phase Ib study aimed to establish a recommended phase II dose for durvalumab (Du) ± tremelimumab (Tr) in combination with standard platinum-doublet chemotherapy. Eligible patients were enrolled into one of six dose levels (DL) of Du ± Tr which included concomitant treatment with standard platinum-doublet regimens; (pemetrexed, gemcitabine, etoposide, (each with cisplatin or carboplatin) or nab-paclitaxel (with carboplatin)). Dose escalation was according to a Rolling Six type design. Both weight-based and fixed dosing of Du and Tr were explored. Du was continued until progression. Tr dosing was finite (up to 6 doses) with increasing dose and/or frequency by DL. 136 patients were enrolled. The majority of drug-related adverse events (AEs) were ≤ grade 2 and attributable to chemotherapy. AEs considered related to immunotherapy were mainly ≤ grade 2; the most frequent (occurring ≥10 %) were colitis/diarrhea, skin, and thyroid dysfunction. Seven patients had DLTs including pneumonitis, myocarditis, diarrhea, encephalitis, motor neuropathy, and enterocolitis. There were 2 treatment-related deaths. Tr and Du exposures did not appear affected by chemotherapy. Among the 73 non-small cell lung cancer (NSCLC) patients treated, the objective response rate was 51 % (95 %CI = 38.7-62.6 %) with a median progression-free and overall survival of 6.5 months (95 % CI = 5.5-9.4 months) and 19.8 months (95 % CI = 14.8 months - not yet reached) respectively. Anti-tumour activity was observed across PD-L1 subtypes. Du 1500 mg q3w and Tr 75 mg q3wx5 can be safely combined with platinum-doublet chemotherapy. Efficacy among NSCLC patients appears comparable to results from other immunotherapy and chemotherapy combination trials. NCT02537418.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Carboplatino/administración & dosificación , Cisplatino/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/patología , Pronóstico , Tasa de SupervivenciaRESUMEN
Progression-free survival (PFS) hazard ratios and gain in median PFS are suggested predictors of overall survival (OS) gain (with gain defined as experimental arm minus control arm values). We assessed use of half-lives (time to progression/death of half remaining patients). We reviewed randomized trials from Journal of Clinical Oncology and New England Journal of Medicine, 01/2012-06/12/2017 (discovery series) and 01/01/2007-12/31/2011 (first validation series). If PFS or OS gains were significant, we used PFS/OS curve nonlinear regression analysis to estimate half-lives and defined "half-life gain" as experimental minus control arm half-life. With low crossover and significant PFS differences, PFS half-life gains ≥1.5 months had positive-predictive-values for OS gains ≥2 months of 79 % and 86 % and PFS half-life gains <1.5 months had negative-predictive-values for OS gains <2 months of 95 % and 75 %, in discovery and validation series, respectively. PFS half-life gains more reliably predicted OS gains than PFS hazard ratios or gains in median PFS. Findings were confirmed in a second validation series.
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Antineoplásicos/uso terapéutico , Supervivencia sin Enfermedad , Neoplasias/mortalidad , Supervivencia sin Progresión , Ensayos Clínicos Controlados Aleatorios como Asunto , Progresión de la Enfermedad , Humanos , Oncología Médica , Recurrencia Local de Neoplasia/mortalidad , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Modelos de Riesgos Proporcionales , Análisis de SupervivenciaRESUMEN
Mutations in the epidermal growth factor receptor (EGFR) gene are the most common targetable genomic drivers of non-small cell lung cancer (NSCLC), occurring in approximately 50% and 10-15% of adenocarcinomas of the lung in Asian and Western populations, respectively. The most common EGFR-activating mutations, the exon 19 deletion and the L858R point mutation occurring in the receptor tyrosine kinase domain, are susceptible to inhibition. The first EGFR tyrosine kinase inhibitors (TKIs) to be evaluated were the reversible first-generation EGFR TKIs, gefitinib and erlotinib, followed by the irreversible second-generation EGFR TKIs, afatinib and dacomitinib. The study of acquired resistance mechanisms to first- and second-generation EGFR TKIs in patients with activating EGFR-mutated NSCLC identified the gatekeeper T790M point mutation, present in over 50% of cases, as the most common mechanism of acquired resistance. The need to overcome this resistance mechanism led to the development of third-generation EGFR TKIs, of which osimertinib is the only one to date with regulatory approval. In this review, we present the clinical context leading to the development of third-generation EGFR TKIs, the mode of action of these inhibitors and the clinical data supporting their use. We review third-generation TKI agents that are approved, in development, and those that failed in clinical trials. Finally, we will touch upon ongoing studies and future directions, such as combination treatment strategies, currently being explored to improve the efficacy of treatment with third-generation EGFR TKIs.
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INTRODUCTION: Activation of the RAS/RAF/MEK/ERK pathway may confer resistance to chemotherapy in non-small cell lung cancer (NSCLC). Selumetinib (AZD6244, ARRY142886), a MEK1/2 inhibitor combined with chemotherapy in patients with NSCLC was evaluated in two schedules to evaluate efficacy and toxicity. METHODS: IND.219 was a three-arm study of first line pemetrexed/platinum chemotherapy with two schedules of selumetinib (Arm A: intermittent given on days 2-19; Arm B: continuous given on days 1-21) versus chemotherapy alone (Arm C). The primary endpoint was objective response rate (ORR); secondary objectives were tolerability, progression-free survival (PFS), overall survival (OS). The trial was stopped at the planned interim analysis. RESULTS: Arms A/B/C enrolled 20/21/21 patients, ORR was 35% (95% CI 15-59% median duration 3.8 months), 62% (95% CI 38-82%; median duration 6.3 months), 24% (95% CI 8-47%; median duration 11.6 months) respectively. The PFS (months Arm A, B, C) was 7.5, 6.7, 4.0 respectively (hazard ratio (HR) PFS Arm A over Arm C: 0.76 [95% CI, 0.38-1.51, 2-sided p = 0.42]; Arm B over Arm C 0.75 [95% CI 0.37-1.54, p = 0.43]. Skin and gastrointestinal adverse events were more common with the addition of selumetinib. A high incidence of venous thromboembolism was seen in all arms. CONCLUSIONS: Selumetinib combined with chemotherapy was associated with a higher response rate. Continuous selumetinib appeared to be superior to an intermittent schedule. PFS was prolonged with the addition of selumetinib, however this was not statistically significant.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencimidazoles/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Pemetrexed/uso terapéutico , Compuestos de Platino/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Canadá , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Proteínas Proto-Oncogénicas p21(ras)/genética , Análisis de SupervivenciaRESUMEN
INTRODUCTION: CheckMate 153 (NCT02066636) is a phase 3B/4 study assessing nivolumab in previously treated patients with advanced NSCLC. Eligibility criteria allowed enrollment of patients with poor prognostic features of advanced age or diminished Eastern Cooperative Oncology Group performance status (ECOG PS), which are typically underrepresented in or excluded from randomized controlled trials. METHODS: Patients with stage IIIB or IV NSCLC and an ECOG PS of 0 to 2 with disease progression after at least one systemic therapy received nivolumab (3 mg/kg every 2 weeks) until progression, unacceptable toxicity, or consent withdrawal. The primary end point was the incidence of grade 3 to 5 select treatment-related adverse events (TRAEs). RESULTS: Among 1426 treated patients, 556 (39%) were aged 70 years or older and 128 (9%) had an ECOG PS of 2. The median treatment duration was 3.2 months. Across subgroups and the overall population, the incidences of select grade 3 to 5 TRAEs (6%-9%) and grade 3 or 4 TRAEs (12%-14%) were similar. One grade 5 TRAE was documented. The median overall survival time was comparable in the overall population (9.1 months) and patients aged 70 years or older (10.3 months) but shorter in patients with an ECOG PS of 2 (4.0 months). Patient-reported outcomes generally improved. CONCLUSIONS: Data from this large predominantly community-based study, which included patients aged 70 years or older and with an ECOG PS of 2, are consistent with registrational studies. As expected, the median overall survival for patients with an ECOG PS of 2 was lower than for the overall population but comparable with historical data.
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Nivolumab/uso terapéutico , Calidad de Vida/psicología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nivolumab/farmacología , Adulto JovenRESUMEN
BACKGROUND: Most newly diagnosed advanced NSCLC patients have an initial medical oncology consult as an outpatient. Sometimes, the initial consult occurs as an inpatient. We explored differences among NSCLC patients presenting to medical oncology while hospitalized versus as outpatients. METHODS: With ethics approval, we performed a retrospective analysis of all stage IIIB and IV NSCLC patients at our institution consulted by medical oncology between 2009 and 2012. The primary analysis is descriptive, exploring differences in baseline characteristics, treatment choices, and overall survival (OS). RESULTS: In total, 637 patients were included: 123 inpatients and 514 outpatients. Among outpatients, 55% received systemic therapy compared to 21% of inpatients. Among treated patients, inpatients were likely to be younger (81% vs 70% <70 years, pâ¯=â¯0.04), have PS 3-4 (38% vs 5%, p<0.001), have ≥5% weight loss (54% vs 42%, pâ¯=â¯0.01), anemia (19% vs 4%, pâ¯=â¯0.001), leukocytosis (38% vs 32%, pâ¯=â¯0.001), thrombocytosis (27â¯vs 23%, pâ¯=â¯0.001), renal dysfunction (12% vs 5%, pâ¯=â¯0.01) and more rapid onset of symptoms (27% vs 6% for <2 weeks, 35% vs 11% for 2-6 weeks; p<0.001). Inpatients who received systemic therapy were more likely to have a complete or partial response (42% vs 26%, pâ¯=â¯0.007), however had a shorter median OS than treated outpatients (8.4â¯vs 10.5 months, pâ¯=â¯0.003). CONCLUSIONS: Patients initially consulted by medical oncologists while hospitalized were more unwell and fewer received systemic therapy. However, if treated, they had higher response rates than outpatients and reasonable OS. Systemic therapy can be considered in hospitalized advanced NSCLC patients. MICROABSTRACT: A minority of patients with lung cancer have an initial oncology consultation as an inpatient. We compared the characteristics and outcomes of inpatients with their outpatient counterparts. Inpatients were more unwell at diagnosis and fewer received systemic therapy, but among those who did, they were more likely to respond and their overall survival approached that of the outpatient cohort.
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Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Células Escamosas/mortalidad , Hospitalización/tendencias , Pacientes Internos/estadística & datos numéricos , Neoplasias Pulmonares/mortalidad , Pacientes Ambulatorios/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Pronóstico , Derivación y Consulta , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: Patients with active cancer have an increased risk of venous thromboembolism, which results in substantial morbidity, mortality, and health care expenditures. The Khorana score (range, 0 to 6, with higher scores indicating a higher risk of venous thromboembolism) has been validated to identify patients with cancer at elevated risk for this complication and may help select those who could benefit from thromboprophylaxis. METHODS: We conducted a randomized, placebo-controlled, double-blind clinical trial assessing the efficacy and safety of apixaban (2.5 mg twice daily) for thromboprophylaxis in ambulatory patients with cancer who were at intermediate-to-high risk for venous thromboembolism (Khorana score, ≥2) and were initiating chemotherapy. The primary efficacy outcome was objectively documented venous thromboembolism over a follow-up period of 180 days. The main safety outcome was a major bleeding episode. RESULTS: Of the 574 patients who underwent randomization, 563 were included in the modified intention-to-treat analysis. Venous thromboembolism occurred in 12 of 288 patients (4.2%) in the apixaban group and in 28 of 275 patients (10.2%) in the placebo group (hazard ratio, 0.41; 95% confidence interval [CI], 0.26 to 0.65; P<0.001). In the modified intention-to-treat analysis, major bleeding occurred in 10 patients (3.5%) in the apixaban group and in 5 patients (1.8%) in the placebo group (hazard ratio, 2.00; 95% CI, 1.01 to 3.95; P = 0.046). During the treatment period, major bleeding occurred in 6 patients (2.1%) in the apixaban group and in 3 patients (1.1%) in the placebo group (hazard ratio, 1.89; 95% CI, 0.39 to 9.24). CONCLUSIONS: Apixaban therapy resulted in a significantly lower rate of venous thromboembolism than did placebo among intermediate-to-high-risk ambulatory patients with cancer who were starting chemotherapy. The rate of major bleeding episodes was higher with apixaban than with placebo. (Funded by the Canadian Institutes of Health Research and Bristol-Myers Squibb-Pfizer Alliance; AVERT ClinicalTrials.gov number, NCT02048865.).
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Inhibidores del Factor Xa/uso terapéutico , Neoplasias/tratamiento farmacológico , Pirazoles/uso terapéutico , Piridonas/uso terapéutico , Tromboembolia Venosa/prevención & control , Administración Oral , Anciano , Antineoplásicos/uso terapéutico , Método Doble Ciego , Inhibidores del Factor Xa/efectos adversos , Femenino , Hemorragia/inducido químicamente , Humanos , Incidencia , Análisis de Intención de Tratar , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasias/complicaciones , Pirazoles/efectos adversos , Piridonas/efectos adversos , Factores de Riesgo , Tromboembolia Venosa/etiologíaRESUMEN
BACKGROUND: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that is selective for both EGFR-TKI-sensitizing and T790M (threonine-to-methionine substitution at codon 790)-resistance mutations. The authors present long-term follow-up data from a preplanned, pooled analysis of phase 2 studies, the AZD9291 First Time in Patients Ascending Dose Study (AURA) extension trial (clincialtrials.gov identifier NCT01802632) and the AURA2 trial (NCT02094261). METHODS: Patients with centrally confirmed, T790M mutation-positive, advanced non-small cell lung cancer received osimertinib 80 mg once daily until disease progression or study discontinuation. Response was assessed by a blinded, independent, central review using Response Evaluation Criteria in Solid Tumors, version 1.1. The primary endpoint was the objective response rate. RESULTS: In total, 411 patients received osimertinib (second line, 129 patients; third line or later, 282 patients). At the data cutoff date of November 1, 2016, the median treatment exposure was 16.4 months (range, 0-29.7 months), the objective response rate was 66% (95% confidence interval [CI], 61%-70%), the median response duration was 12.3 months (95% CI, 11.1-13.8 months), and the median progression-free survival was 9.9 months (95% CI, 9.5-12.3 months). At the data cutoff date of May 1, 2018, 271 patients (66%) had died, and 140 patients (34%) had discontinued before death. The median overall survival was 26.8 months (95% CI, 24.0-29.1 months); and the 12-month, 24-month, and 36-month survival rates were 80%, 55%, and 37%, respectively. Grade ≥3 possibly causally related (investigator assessed) adverse events were reported in 65 patients (16%), and the most common were rash (grouped terms; 42%; grade ≥3, 1%) and diarrhea (39%; <1%). CONCLUSIONS: This pooled analysis represents the most mature clinical trial data for osimertinib in patients with pretreated, T790M-positive, advanced non-small cell lung cancer, further establishing osimertinib as a standard of care for this patient population.
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Acrilamidas/administración & dosificación , Compuestos de Anilina/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Acrilamidas/uso terapéutico , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Compuestos de Anilina/uso terapéutico , Esquema de Medicación , Receptores ErbB/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Importance: Treatment choice for lung squamous cell carcinoma could be aided by identifying predictive biomarkers. Objective: To assess whether patient outcomes in the LUX-Lung 8 trial were associated with ERBB gene family member aberrations in tumor specimens. Design, Setting, and Participants: Ad hoc secondary analysis of the LUX-Lung 8 trial conducted at 183 centers in 23 countries from March 30, 2012, to January 30, 2014. Eligible patients had stage IIIB or IV lung squamous cell carcinoma with progressive disease after 4 or more cycles of platinum-based chemotherapy. Tumor genetic analysis (TGA) was performed using next-generation sequencing in a cohort enriched for patients with progression-free survival (PFS) of more than 2 months. Epidermal growth factor receptor (EGFR) expression levels were assessed by immunohistochemistry in a separate cohort of patients from the LUX-Lung 8 population. Associations of PFS and overall survival (OS) with ERBB gene alterations and EGFR expression levels were assessed. This analysis was conducted from February 26, 2015, to June 12, 2017. Interventions: Patients were randomized 1:1 to treatment with afatinib dimaleate (40 mg/d; n = 398) or erlotinib hydrochloride (150 mg/d; n = 397). Main Outcomes and Measures: Overall survival, PFS, pooled and individual ERBB gene mutations, ERBB copy number alterations, and EGFR expression. Results: Tumor specimens from 245 patients were eligible for next-generation sequencing (TGA subset: 132 patients treated with afatinib; 113 patients treated with erlotinib). In this population, outcomes were improved with afatinib vs erlotinib treatment (PFS: median, 3.5 vs 2.5 months; hazard ratio [HR], 0.69; 95% CI, 0.51-0.92; P = .01; OS: median, 8.4 vs 6.6 months; HR, 0.81; 95% CI, 0.62-1.05; P = .12). Of 245 patients in the TGA subset, 53 (21.6%) had tumors with 1 or more ERBB mutations. Among afatinib-treated patients, PFS (median, 4.9 vs 3.0 months; HR, 0.62; 95% CI, 0.37-1.02; P = .06) and OS (median, 10.6 vs 8.1 months; HR, 0.75; 95% CI, 0.47-1.17; P = .21) were longer among those with ERBB mutation-positive disease than among those without. The presence of HER2 mutations was associated with favorable PFS and OS following afatinib vs erlotinib treatment. There was no apparent association between copy number alteration or EGFR expression level and outcome. Conclusions and Relevance: Next-generation sequencing may help identify patients with lung squamous cell carcinoma who would derive additional benefit from treatment with afatinib. The role of ERBB mutations, particularly HER2 mutations, as predictive biomarkers for afatinib treatment in this setting warrants further evaluation. Trial Registration: ClinicalTrials.gov Identifier: NCT01523587.
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Afatinib/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Clorhidrato de Erlotinib/uso terapéutico , Genes erbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Anciano , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/uso terapéutico , Resultado del TratamientoRESUMEN
OBJECTIVES: Pelareorep (reolysin), a Dearing strain of reovirus serotype 3, has demonstrated oncolytic activity as single agent and synergy with chemotherapy. We evaluated pelareorep, combined with standard second-line chemotherapy in patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: This randomized phase II trial enrolled patients with advanced or metastatic NSCLC after first line chemotherapy. After a safety run-in, patients were randomized 1:1 to chemotherapy (pemetrexed [500â¯mg/m2, non-squamous], or docetaxel [75â¯mg/m2], day 1 every 21â¯days]) +/- pelareorep (4.5â¯×â¯1010 TCID50, days 1-3 every 21â¯days), stratified by EGFR mutation status. The primary outcome was progression free survival (PFS) of patients randomized to chemotherapyâ¯+â¯pelareorep vs. chemotherapy alone. Secondary outcomes included overall survival, objective response rate and exploratory translational analyses. RESULTS: Between October 2012 and August 2015, 166 patients were enrolled (14 to the safety run in). Pelareorep did not improve the PFS vs. single agent chemotherapy (median PFS 3.0 months, 95% confidence interval [CI] 2.6-4.1) vs. 2.8 months (95% CI 2.5-4.0), hazard ratio (HR) 0.90 (95% CI 0.65-1.25), Pâ¯=â¯0.53). Neither KRAS or EGFR mutation was associated with improved PFS, but STK11 mutations did appear to have an association with improved PFS (HR 0.29 [0.12-0.67); as did PIK3CA mutation (HR 0.45 [0.22-0.93]). The combination was tolerable, although associated with increased rates of neutropenic fever. CONCLUSION: The addition of pelareorep to second-line chemotherapy did not improve the PFS of patients with NSCLC. The three-day pelareorep schedule was tolerable. Further research is needed to evaluate the potential benefit in molecular subtypes of NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/terapia , Orthoreovirus Mamífero 3/inmunología , Viroterapia Oncolítica/métodos , Virus Oncolíticos , Infecciones por Reoviridae/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Canadá , Terapia Combinada , Docetaxel/uso terapéutico , Resistencia a Antineoplásicos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pemetrexed/uso terapéutico , Recurrencia , Terapia Recuperativa , Adulto JovenRESUMEN
Cancer cooperative groups have historically played a critical role in the advancement of non-small-cell lung cancer therapy. Representatives from cooperative groups worldwide convene at the International Lung Cancer Congress annually. The International Lung Cancer Congress had its 17th anniversary in the summer of 2016. The present review highlights the thoracic malignancy studies discussed by presenters. The included studies are merely a sample of the trials of thoracic malignancies ongoing globally.
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Ensayos Clínicos como Asunto , Inmunoterapia , Cooperación Internacional , Neoplasias Torácicas/terapia , Humanos , Pronóstico , Neoplasias Torácicas/inmunologíaRESUMEN
BACKGROUND: Epidermal growth factor receptor (EGFR) alterations are associated with multiple cancers. Current EGFR-directed therapies have led to increased efficacy but are associated with specific side effects. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) targets EGFR with a monoclonal antibody linked to a cytotoxin, and is highly tumor-specific. METHODS: This phase 1/2 study evaluated the safety, pharmacokinetics, and efficacy of depatux-m in patients who had advanced solid tumors with known wild-type EGFR overexpression, amplification, or mutated EGFR variant III. A 3 + 3 dose escalation was used, and 2 dosing schedules were evaluated. Depatux-m also was manufactured under an alternate process to reduce the drug load and improve the safety profile, and it was tested at the maximum tolerated dose (MTD). In another cohort, prolonged infusion time of depatux-m was evaluated; and a cohort with confirmed EGFR amplification also was evaluated at the MTD. RESULTS: Fifty-six patients were treated. The MTD and the recommended phase 2 dose for depatux-m was 3.0 mg/kg. Common adverse events (AEs) were blurred vision (48%) and fatigue (41%). A majority of patients (66%) experienced 1 or more ocular AEs. Grade 3 or 4 AEs were observed in 43% of patients. One patient with EGFR-amplified, triple-negative breast cancer had a partial response. Stable disease was observed in 23% of patients. Pharmacokinetics revealed that depatux-m exposures were approximately dose-proportional. CONCLUSIONS: Depatux-m resulted in infrequent nonocular AEs but increased ocular AEs. Patient follow-up confirmed that ocular AEs were reversible. Lowering the drug-antibody ratio did not decrease the number of ocular AEs. A partial response in 1 patient with EGFR-amplified disease provides the opportunity to study depatux-m in diseases with a high incidence of EGFR amplification. Cancer 2018;124:2174-83. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Fatiga/epidemiología , Inmunoconjugados/administración & dosificación , Neoplasias/tratamiento farmacológico , Trastornos de la Visión/epidemiología , Adulto , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Fatiga/inducido químicamente , Femenino , Estudios de Seguimiento , Amplificación de Genes , Humanos , Inmunoconjugados/efectos adversos , Inmunoconjugados/farmacocinética , Infusiones Intravenosas , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/genética , Neoplasias/patología , Resultado del Tratamiento , Trastornos de la Visión/inducido químicamenteRESUMEN
INTRODUCTION: In the phase III LUX-Lung 8 trial, afatinib significantly improved progression-free survival (PFS) and overall survival (OS) versus erlotinib in patients with squamous cell carcinoma (SCC) of the lung progressing during or after platinum-based chemotherapy. Patient-reported outcomes (PROs) and health-related quality of life (QoL) in these patients are presented. PATIENTS AND METHODS: Patients (n = 795) were randomized 1:1 to oral afatinib (40 mg/d) or erlotinib (150 mg/d). PROs were collected (baseline, every 28 days until progression, 28 days after discontinuation) using the European Organization for Research and Treatment of Cancer QoL questionnaire and lung cancer-specific module. The percentage of patients improved during therapy, time to deterioration (TTD), and changes over time were analyzed for prespecified lung cancer-related symptoms and global health status (GHS)/QoL. RESULTS: Questionnaire compliance was 77.3% to 99.0% and 68.7% to 99.0% with afatinib and erlotinib, respectively. Significantly more patients who received afatinib versus erlotinib experienced improved scores for GHS/QoL (36% vs. 28%; P = .041) and cough (43% vs. 35%; P = .029). Afatinib significantly delayed TTD in dyspnea (P = .008) versus erlotinib, but not cough (P = .256) or pain (P = .869). Changes in mean scores favored afatinib for cough (P = .0022), dyspnea (P = .0007), pain (P = .0224), GHS/QoL (P = .0320), and all functional scales. Differences in adverse events between afatinib and erlotinib, specifically diarrhea, did not affect GHS/QoL. CONCLUSION: In patients with SCC of the lung, second-line afatinib was associated with improved prespecified disease-related symptoms and GHS/QoL versus erlotinib, complementing PFS and OS benefits with afatinib.
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Afatinib/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Clorhidrato de Erlotinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma de Células Escamosas/mortalidad , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Medición de Resultados Informados por el Paciente , Compuestos de Platino/uso terapéutico , Calidad de Vida , Análisis de SupervivenciaRESUMEN
PURPOSE: MET and AXL mediate resistance to EGFR TKI in NSCLC. Foretinib, a MET/RON/AXL/TIE-2/VEGFR kinase inhibitor may overcome EGFR kinase resistance. This dose escalation study combined foretinib and erlotinib in advanced pretreated NSCLC patients. EXPERIMENTAL DESIGN: The primary endpoint was to define the RP2D of foretinib plus erlotinib as continuous oral daily dosing. Secondary objectives included safety, pharmacokinetics, response and potential biomarkers of response including EGFR, KRAS genotype, MET, AXL expression, and circulating HGF levels. Erlotinib (E100-150 mg) was commenced on day 1 cycle 1; if well tolerated, foretinib (F30-45 mg) was added on day 15 cycle 1, using standard 3+3 dose escalation. RESULTS: Of 31 patients enrolled in 3 dose levels, 6 were inevaluable for DLT and replaced. DLT occurred in 3/15 patients at DL2 (E150 mg, F30 mg): Gr3 pain, mucositis, fatigue and rash. Cycle 1 DLT was not seen at DL3 (E150 mg, F45 mg) but 27% experienced dose reduction/interruption. Adverse events in ≥20% included diarrhea, fatigue, anorexia, dry skin, rash and hypertension. No PK interaction was seen with the combination. RP2D was defined as erlotinib 150 mg daily x 14 days with foretinib 30 mg added on day 15 (continuous dosing in 28-day cycles). Responses were seen in 17.8% of response evaluable patients (5/28). In 18 samples, baseline MET expression uncontrolled for EGFR genotype appeared associated with response. AXL expression was associated with neither EGFR mutation nor response. CONCLUSION: Combining foretinib and erlotinib demonstrated response in unselected advanced NSCLC but also incremental toxicity. Future development will require molecular patient selection.