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Importance: Immune-related adverse events (irAEs) arising from immune checkpoint inhibitor (ICI) cancer therapy may potentially predict improved outcomes. Objective: To evaluate the association between irAEs and atezolizumab efficacy in patients with advanced non-small cell lung cancer (NSCLC) using pooled data from 3 phase 3 ICI studies. Design, Setting, and Participants: IMpower130, IMpower132, and IMpower150 were phase 3, multicenter, open-label, randomized clinical trials to evaluate the efficacy and safety of chemoimmunotherapy combinations involving atezolizumab. Participants were chemotherapy-naive adults with stage IV nonsquamous NSCLC. These post hoc analyses were conducted during February 2022. Interventions: Eligible patients were randomly assigned 2:1 to receive atezolizumab with carboplatin plus nab-paclitaxel, or chemotherapy alone (IMpower130); 1:1 to receive atezolizumab with carboplatin or cisplatin plus pemetrexed, or chemotherapy alone (IMpower132); and 1:1:1 to receive atezolizumab plus bevacizumab plus carboplatin and paclitaxel, atezolizumab plus carboplatin and paclitaxel, or bevacizumab plus carboplatin and paclitaxel (IMpower150). Main Outcomes and Measures: Pooled data from IMpower130 (cutoff: March 15, 2018), IMpower132 (cutoff: May 22, 2018), and IMpower150 (cutoff: September 13, 2019) were analyzed by treatment (atezolizumab-containing vs control), irAE status (with vs without), and highest irAE grade (1-2 vs 3-5). To account for immortal bias, a time-dependent Cox model and landmark analyses of irAE occurrence at 1, 3, 6, and 12 months from baseline were used to estimate the hazard ratio (HR) of overall survival (OS). Results: Of 2503 randomized patients, 1577 were in the atezolizumab-containing arm and 926 were in the control arm. The mean (SD) age of patients was 63.1 (9.4) years and 63.0 (9.3) years, and 950 (60.2%) and 569 (61.4%) were male, respectively, in the atezolizumab arm and the control arm. Baseline characteristics were generally balanced between patients with irAEs (atezolizumab, n = 753; control, n = 289) and without (atezolizumab, n = 824; control, n = 637). In the atezolizumab arm, OS HRs (95% CI) in patients with grade 1 to 2 irAEs and grade 3 to 5 irAEs (each vs those without irAEs) in the 1-, 3-, 6-, and 12-month subgroups were 0.78 (0.65-0.94) and 1.25 (0.90-1.72), 0.74 (0.63-0.87) and 1.23 (0.93-1.64), 0.77 (0.65-0.90) and 1.1 (0.81-1.42), and 0.72 (0.59-0.89) and 0.87 (0.61-1.25), respectively. Conclusions and Relevance: In this pooled analysis of 3 randomized clinical trials, longer OS was observed in patients with vs without mild to moderate irAEs in both arms and across landmarks. These findings further support the use of first-line atezolizumab-containing regimens for advanced nonsquamous NSCLC. Trial Registration: ClinicalTrials.gov Identifiers: NCT02367781, NCT02657434, and NCT02366143.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Bevacizumab/uso terapêutico , Carboplatina/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Paclitaxel/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
INTRODUCTION: Sitravatinib, a receptor tyrosine kinase inhibitor targeting TYRO3, AXL, MERTK receptors, and vascular epithelial growth factor receptor 2, can shift the tumor microenvironment toward an immunostimulatory state. Combining sitravatinib with checkpoint inhibitors (CPIs) may augment antitumor activity. METHODS: The phase 2 MRTX-500 study evaluated sitravatinib (120 mg daily) with nivolumab (every 2 or 4 wk) in patients with advanced nonsquamous NSCLC who progressed on or after previous CPI (CPI-experienced) or chemotherapy (CPI-naive). CPI-experienced patients had a previous clinical benefit (PCB) (complete response, partial response, or stable disease for at least 12 weeks then disease progression) or no PCB (NPCB) from CPI. The primary end point was objective response rate (ORR); secondary objectives included safety and secondary efficacy end points. RESULTS: Overall, 124 CPI-experienced (NPCB, n = 35; PCB, n = 89) and 32 CPI-naive patients were treated. Investigator-assessed ORR was 11.4% in patients with NPCB, 16.9% with PCB, and 25.0% in CPI-naive. The median progression-free survival was 3.7, 5.6, and 7.1 months with NPCB, PCB, and CPI-naive, respectively; the median overall survival was 7.9 and 13.6 months with NPCB and PCB, respectively (not reached in CPI-naive patients; median follow-up 20.4 mo). Overall, (N = 156), any grade treatment-related adverse events (TRAEs) occurred in 93.6%; grade 3/4 in 58.3%. One grade 5 TRAE occurred in a CPI-naive patient. TRAEs led to treatment discontinuation in 14.1% and dose reduction or interruption in 42.9%. Biomarker analyses supported an immunostimulatory mechanism of action. CONCLUSIONS: Sitravatinib with nivolumab had a manageable safety profile. Although ORR was not met, this combination exhibited antitumor activity and encouraged survival in CPI-experienced patients with nonsquamous NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Anilidas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Microambiente TumoralRESUMO
BACKGROUND: The efficacy of atezolizumab (A) and/or bevacizumab (B) with carboplatin/paclitaxel (CP) chemotherapy was explored in the phase III, randomized IMpower150 study in patients with non-squamous non-small cell lung cancer (NSCLC) according to KRAS mutations (mKRAS) and co-occurring STK11, KEAP1, or TP53 mutations. METHODS: Mutation status was determined by circulating tumor DNA next-generation sequencing. Overall survival (OS) and progression-free survival (PFS) were analyzed in a mutation-evaluable intention-to-treat population (MEP; n=920) and SP263 (programmed cell death ligand 1 (PD-L1)) biomarker-evaluable population (n=774). RESULTS: Within the mKRAS population (24.5% of MEP), ABCP showed numerical improvements vs BCP in median OS (19.8 vs 9.9 months; HR 0.50; 95% CI 0.34 to 0.72) and PFS (8.1 vs 5.8 months; HR 0.42; 95% CI 0.29 to 0.61)-greater than with ACP (OS: 11.7 vs 9.9 months; HR 0.63; 95% CI 0.43 to 0.91; PFS: 4.8 vs 5.8 months; HR 0.80; 95% CI 0.56 to 1.13) vs BCP. Across PD-L1 subgroups in mKRAS patients, OS and PFS were longer with ABCP vs BCP, but OS with ACP was similar to BCP in PD-L1-low and PD-L1-negative subgroups. Conversely, in KRAS-WT patients, OS was longer with ACP than with ABCP or BCP across PD-L1 subgroups. KRAS was frequently comutated with STK11, KEAP1, and TP53; these subgroups conferred different prognostic outcomes. Within the mKRAS population, STK11 and/or KEAP1 mutations were associated with inferior OS and PFS across treatments compared with STK11-WT and/or KEAP1-WT. In mKRAS patients with co-occurring mSTK11 and/or mKEAP1 (44.9%) or mTP53 (49.3%), survival was longer with ABCP than with ACP or BCP. CONCLUSIONS: These analyses support previous findings of mutation of STK11 and/or KEAP1 as poor prognostic indicators. While clinical efficacy favored ABCP and ACP vs BCP in these mutational subgroups, survival benefits were greater in the mKRAS and KEAP1-WT and STK11-WT population vs mKRAS and mKEAP1 and mSTK11 population, suggesting both prognostic and predictive effects. Overall, these results suggest that atezolizumab combined with bevacizumab and chemotherapy is an efficacious first-line treatment in metastatic NSCLC subgroups with mKRAS and co-occurring STK11 and/or KEAP1 or TP53 mutations and/or high PD-L1 expression.
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Quinases Proteína-Quinases Ativadas por AMP/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Proteína Supressora de Tumor p53/metabolismo , Adulto , Anticorpos Monoclonais Humanizados/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Bevacizumab/farmacologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Mutação , Prognóstico , Intervalo Livre de Progressão , Estudos RetrospectivosRESUMO
INTRODUCTION: Final overall survival (OS) analyses are presented for EGFR mutations and liver or brain metastases subgroups in the phase 3 IMpower150 study (NCT02366143) evaluating atezolizumab plus bevacizumab plus carboplatin and paclitaxel (ABCP) or atezolizumab plus carboplatin and paclitaxel (ACP) versus bevacizumab plus carboplatin and paclitaxel (BCP). METHODS: Overall, 1202 patients (intention-to-treat population) with chemotherapy-naive, metastatic, nonsquamous NSCLC were randomized to ABCP, ACP, or BCP. Patients with treated, stable brain metastases were permitted. OS was evaluated in EGFR mutations and baseline liver metastases subgroups; rate and time to development of new brain metastases were evaluated in the intention-to-treat patients. RESULTS: At data cutoff (September 13, 2019; median follow-up, 39.3 mo), OS improvements were sustained with ABCP versus BCP in sensitizing EGFR mutations (all: hazard ratio [HR] = 0.60; 95% confidence interval [CI]: 0.31-1.14; previous tyrosine kinase inhibitor [TKI]: HR = 0.74; 95% CI: 0.38-1.46) and baseline liver metastases (HR = 0.68; 95% CI: 0.45-1.02) subgroups. ACP did not have survival benefit versus BCP in sensitizing EGFR mutations (all: HR = 1.0; 95% CI: 0.57-1.74; previous TKI: HR = 1.22; 95% CI: 0.68-2.22) or liver metastases (HR = 1.01; 95% CI: 0.68-1.51) subgroups. Overall, 100 patients (8.3%) developed new brain metastases. Although not formally evaluated, an improvement toward delayed time to development was found with ABCP versus BCP (HR = 0.68; 95% CI: 0.39-1.19). CONCLUSIONS: This final exploratory analysis revealed OS benefits for ABCP versus BCP in patients with sensitizing EGFR mutations, including those with previous TKI failures, and with liver metastases, although these results should be interpreted with caution. The impact of ABCP on delaying the development of new brain lesions requires further investigation.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Bevacizumab/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Encéfalo/patologia , Neoplasias Encefálicas/secundário , Carboplatina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Humanos , Fígado/patologia , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , MutaçãoRESUMO
INTRODUCTION: We report the final overall survival (OS) analyses of atezolizumab-carboplatin-paclitaxel (ACP [experimental arm]) and OS data with approximately 39.8 months of median follow-up with atezolizumab-bevacizumab-carboplatin-paclitaxel (ABCP) versus bevacizumab-carboplatin-paclitaxel (BCP) in chemotherapy-naive patients with metastatic nonsquamous NSCLC in the phase 3 IMpower150 study (NCT02366143). METHODS: In this randomized, open-label study (N = 1202), coprimary end points included investigator-assessed progression-free survival and OS in intention-to-treat (ITT) wild-type (WT; no EGFR or ALK alterations) patients. Secondary and exploratory end points included OS in ITT and programmed death-ligand 1 (PD-L1) subgroups defined by the VENTANA SP142 and SP263 immunohistochemistry assays. RESULTS: At the final analysis with ACP versus BCP (data cutoff: September 13, 2019; minimum follow-up: 32.4 mo), ACP had numerical, but not statistically significant, improvements in OS (ITT-WT: median OS = 19.0 versus 14.7 mo; hazard ratio = 0.84; 95% confidence interval: 0.71-1.00). OS benefit was sustained with ABCP versus BCP (ITT-WT: 19.5 versus 14.7 mo; hazard ratio = 0.80; 95% confidence interval: 0.67-0.95). Exploratory analyses in the SP142-defined PD-L1 subgroups revealed longer median OS with ABCP and ACP versus BCP in PD-L1-high and PD-L1-positive subgroups; in the PD-L1-negative subgroups, median OS was similar with ACP and ABCP versus BCP. Safety was consistent with that in earlier analyses (data cutoff: January 22, 2018). CONCLUSIONS: At the final IMpower150 OS analysis, ACP had numerical, but not statistically significant, OS improvement versus BCP. Updated data with an additional 20 months of follow-up revealed continued OS improvement with ABCP versus BCP in all patients.
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Neoplasias Pulmonares , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Carboplatina/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/uso terapêutico , Análise de SobrevidaRESUMO
PURPOSE: Trilaciclib is a first-in-class CDK4/6 inhibitor that transiently arrests hematopoietic stem and progenitor cells (HSPCs) in the G1 phase of the cell cycle to preserve them from chemotherapy-induced damage (myelopreservation). We report integrated analyses of preclinical and clinical data that informed selection of the recommended Phase II dose (RP2D) used in trilaciclib trials in extensive-stage small cell lung cancer (ES-SCLC). METHODS: A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model developed from preclinical data guided selection of an optimal dose for G1 bone marrow arrest in a first-in-human Phase I study (G1T28-1-01). PK, PD, safety, and efficacy data from G1T28-1-01 and two Phase Ib/IIa studies (G1T28-02/-03) in ES-SCLC were analyzed to support RP2D selection. RESULTS: Model simulation of bone marrow arrest based on preclinical data predicted that a ≥ 192 mg/m2 dose would induce a 40-50% decrease in total bone marrow proliferation in humans and almost 100% cell cycle arrest of cycling HSPCs. Consistent with this model, analysis of bone marrow aspirates in healthy volunteers after trilaciclib 192 mg/m2 administration demonstrated almost 100% G1 arrest in HSPCs and 40% decrease in total bone marrow proliferation, with minimal toxicity. G1T28-02/-03 reported similar PK parameters with trilaciclib 200 mg/m2 but slightly lower exposures than expected compared with healthy volunteers; consequently, 240 and 280 mg/m2 doses were also tested to match healthy volunteer exposures. Based on PK and relevant safety data, 240 mg/m2 was selected as the RP2D, which was also favored by myelopreservation endpoints in G1T28-02/-03. CONCLUSION: Integrated PK/PD, safety, and efficacy data support 240 mg/m2 as the RP2D for trilaciclib. CLINICALTRIALS. GOV IDENTIFIERS: NCT02243150; NCT02499770; NCT02514447.
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Neoplasias Pulmonares/tratamento farmacológico , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Adolescente , Adulto , Ensaios Clínicos como Assunto , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Pirróis/farmacocinética , Pirróis/farmacologia , Carcinoma de Pequenas Células do Pulmão/patologia , Adulto JovemRESUMO
BACKGROUND: We evaluated maintenance nanoparticle albumin-bound (nab) paclitaxel in the treatment of advanced squamous non-small-cell lung cancer. PATIENTS AND METHODS: Patients with treatment-naive squamous non-small-cell lung cancer received four 21-day cycles of nab-paclitaxel 100 mg/m2 on days 1, 8, 15 plus carboplatin area under the curve 6 on day 1 as induction therapy. Patients without disease progression after induction were randomized 2:1 to maintenance nab-paclitaxel 100 mg/m2 (days 1 and 8 every 21 days) plus best supportive care (BSC) or BSC alone. The primary endpoint was progression-free survival (PFS). Secondary endpoints included safety and overall survival (OS). RESULTS: Overall, 420 patients had received induction therapy; 202 (nab-paclitaxel plus BSC, 136; BSC, 66) had received maintenance therapy. Enrollment was discontinued after a preplanned interim futility analysis (patients could remain in the study at the investigator's discretion). The median PFS was 3.12 months for nab-paclitaxel plus BSC and 2.60 months for BSC; the difference was not statistically significant (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.61-1.19; P = .36). The median OS (median follow-up, 24.2 months) was 17.18 months for nab-paclitaxel plus BSC and 12.16 months for BSC (HR, 0.70; 95% CI, 0.48-1.02; nominal P = .07). An updated analysis (median follow-up, 28.4 months) revealed a median OS of 17.61 months for nab-paclitaxel plus BSC and 12.16 months for BSC (HR, 0.68; 95% CI, 0.47-0.98; nominal P = .037). The most frequent grade 3 and 4 treatment-emergent adverse events for the entire study were neutropenia (53.1% [nab-paclitaxel plus BSC] vs. 50.0% [BSC]) and anemia (33.1% [nab-paclitaxel plus BSC] vs. 32.3% [BSC]). Only peripheral neuropathy had occurred in ≥ 5% of patients during maintenance therapy (13.1%; nab-paclitaxel plus BSC). CONCLUSIONS: The results of the ABOUND.sqm did not meet the primary endpoint of PFS. An updated OS analysis revealed a trend favoring nab-paclitaxel plus BSC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/administração & dosagem , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Nanopartículas/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Paclitaxel/administração & dosagem , Prognóstico , Taxa de SobrevidaRESUMO
INTRODUCTION: Checkpoint inhibitors (CPIs) have been approved to treat metastatic NSCLC. Pegilodecakin + CPI suggested promising efficacy in phase 1 IVY, providing rationale for randomized phase 2 trials CYPRESS 1 and CYPRESS 2. METHODS: CYPRESS 1 (N = 101) and CYPRESS 2 (N = 52) included Eastern Cooperative Oncology Group performance status of 0 to 1 and first-line/second-line metastatic NSCLC, respectively, without known EGFR/ALK mutations. Patients were randomized 1:1; control arms received pembrolizumab (CYPRESS 1) or nivolumab (CYPRESS 2); experimental arms received pegilodecakin + CPI. Patients had programmed death-ligand 1 tumor proportion score of greater than or equal to 50% (CYPRESS 1) or 0% to 49% (CYPRESS 2). Primary end point was objective response rate (ORR) per investigator. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. Exploratory end points included immune activation biomarkers. RESULTS: Median follow-up for CYPRESS 1 and CYPRESS 2 was 10.0 and 11.6 months, respectively. Results for pegilodecakin + pembrolizumab versus pembrolizumab were as follows: ORR per investigator 47% versus 44% (OR = 1.1, 95% confidence interval [CI]: 0.5-2.5); median PFS 6.3 versus 6.1 months (hazard ratio [HR] = 0.937, 95% CI: 0.54-1.625); and median OS 16.3 months versus not reached (HR = 1.507, 95% CI: 0.708-3.209). Results per blinded independent central review were consistent. Treatment discontinuation rate owing to adverse events (AEs) doubled in the experimental arm (32% versus 15%). AEs with grade greater than or equal to 3 treatment-related AEs (62% versus 19%) included anemia (20% versus 0%) and thrombocytopenia (12% versus 2%). Results for pegilodecakin + nivolumab versus nivolumab were as follows: ORR per investigator 15% versus 12% (OR = 1.2, 95% CI: 0.3-5.9); median PFS 1.9 versus 1.9 months (HR = 1.006, 95% CI: 0.519-1.951); and median OS 6.7 versus 10.7 months (HR = 1.871, 95% CI: 0.772-4.532). AEs with grade greater than or equal to 3 treatment-related AEs (70.4% versus 16.7%) included anemia (40.7% versus 0%), fatigue (18% versus 0%), and thrombocytopenia (14.8% versus 0%). Biomarker data suggested activation of immunostimulatory signals of interleukin-10R pathway in pegilodecakin-containing arms. CONCLUSIONS: Despite evidence of biological effect in peripheral blood, adding pegilodecakin to CPI did not improve ORR, PFS, or OS, in first-line/second-line NSCLC. Pegilodecakin + CPI has been found to have overall higher toxicity compared with CPI alone, leading to doubling of treatment discontinuation rate owing to AEs.
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Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica , Humanos , Interleucina-10 , Neoplasias Pulmonares/tratamento farmacológico , Polietilenoglicóis/uso terapêuticoRESUMO
PURPOSE: Polyamines are absolutely essential for maintaining tumor cell proliferation. PG-11047, a polyamine analogue, is a nonfunctional competitor of the natural polyamine spermine that has demonstrated anticancer activity in cells and animal models of multiple cancer types. Preclinical investigations into the effects of common chemotherapeutic agents have revealed overlap with components of the polyamine metabolic pathway also affected by PG-11047. This report describes a Phase Ib clinical trial investigating PG-11047 in combination with cytotoxic and anti-angiogenic chemotherapeutic agents in patients with advanced refractory metastatic solid tumors or lymphoma. METHODS: A total of 172 patients were assigned to treatment arms based on cancer type to receive the appropriate standard-of-care therapy (gemcitabine, docetaxel, bevacizumab, erlotinib, cisplatin, 5-fluorouracil (5-FU), or sunitinib as directed) along with once weekly intravenous infusions of PG-11047. PG-11047 dose escalation ranged from 50 to 590 mg. RESULTS: The maximum tolerated dose (MTD) of PG-11047 in combination with bevacizumab, erlotinib, cisplatin, and 5-FU was 590 mg. Dose-limiting toxicities (DLTs) in these groups were rare (5 of 148 patients). Overall partial responses (PR) were observed in 12% of patients treated with PG-11047 and bevacizumab, with stable disease documented in an additional 40%. Stable disease occurred in 71.4% of patients in the 5-FU arm, 54.1% in the cisplatin arm, and 33.3% in the erlotinib arm. Four of the patients receiving cisplatin + PG-11047 (20%) had unconfirmed PRs. MTDs for gemcitabine, docetaxel, and sunitinib could not be determined due to DLTs at low doses of PG-11047 and small sample size. CONCLUSIONS: Results of this Phase Ib trial indicate that PG-11047 can be safely administered to patients in combination with bevacizumab, erlotinib, cisplatin, and 5-FU on the once weekly dosing schedule described and may provide therapeutic benefit. The manageable toxicity profile and high MTD determination provide a safety profile for further clinical studies.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma/tratamento farmacológico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Docetaxel/administração & dosagem , Relação Dose-Resposta a Droga , Cloridrato de Erlotinib/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Linfoma/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia , Espermina/administração & dosagem , Espermina/análogos & derivados , Sunitinibe/administração & dosagem , GencitabinaRESUMO
PURPOSE: Limited data exist on the optimal duration of immunotherapy, including for non-small-cell lung cancer (NSCLC). We present an exploratory analysis of CheckMate 153, a largely community-based phase IIIb/IV study, to evaluate the impact of 1-year fixed-duration versus continuous therapy on the efficacy and safety of nivolumab. METHODS: Patients with previously treated advanced NSCLC received nivolumab monotherapy (3 mg/kg every 2 weeks). Those still receiving treatment at 1 year, including patients perceived to be deriving benefit despite radiographic progression, were randomly assigned to continue nivolumab until disease progression or unacceptable toxicity or to stop nivolumab with the option of on-study retreatment after disease progression (1-year fixed duration). RESULTS: Of 1,428 patients treated, 252 were randomly assigned to continuous (n = 127) or 1-year fixed-duration (n = 125) treatment (intent-to-treat [ITT] population). Of these, 89 and 85 patients in the continuous and 1-year fixed-duration arms, respectively, had not progressed (progression-free survival [PFS] population). With minimum post-random assignment follow-up of 13.5 months, median PFS was longer with continuous versus 1-year fixed-duration treatment (PFS population: 24.7 months v 9.4 months; hazard ratio [HR], 0.56 [95% CI, 0.37 to 0.84]). Median overall survival from random assignment was longer with continuous versus 1-year fixed-duration treatment in the PFS (not reached v 32.5 months; HR, 0.61 [95% CI, 0.37 to 0.99]) and ITT (not reached v 28.8 months; HR, 0.62 [95% CI, 0.42 to 0.92]) populations. Few new-onset treatment-related adverse events occurred. No new safety signals were identified. CONCLUSION: To our knowledge, these findings from an exploratory analysis represent the first randomized data on continuous versus fixed-duration immunotherapy in previously treated advanced NSCLC and suggest that continuing nivolumab beyond 1 year improves outcomes.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Esquema de Medicação , Feminino , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversosRESUMO
INTRODUCTION: Cytotoxic agents have immunomodulatory effects, providing a rationale for combining atezolizumab (anti-programmed death-ligand 1 [anti-PD-L1]) with chemotherapy. The randomized phase III IMpower131 study (NCT02367794) evaluated atezolizumab with platinum-based chemotherapy in stage IV squamous NSCLC. METHODS: A total of 1021 patients were randomized 1:1:1 to receive atezolizumab+carboplatin+paclitaxel (A+CP) (n = 338), atezolizumab+carboplatin+nab-paclitaxel (A+CnP) (n = 343), or carboplatin+nab-paclitaxel (CnP) (n = 340) for four or six 21-day cycles; patients randomized to the A+CP or A+CnP arms received atezolizumab maintenance therapy until progressive disease or loss of clinical benefit. The coprimary end points were investigator-assessed progression-free survival (PFS) and overall survival (OS) in the intention-to-treat (ITT) population. The secondary end points included PFS and OS in PD-L1 subgroups and safety. The primary PFS (January 22, 2018) and final OS (October 3, 2018) for A+CnP versus CnP are reported. RESULTS: PFS improvement with A+CnP versus CnP was seen in the ITT population (median, 6.3 versus 5.6 mo; hazard ratio [HR] = 0.71, 95% confidence interval [CI]: 0.60-0.85; p = 0.0001). Median OS in the ITT population was 14.2 and 13.5 months in the A+CnP and CnP arms (HR = 0.88, 95% CI: 0.73-1.05; p = 0.16), not reaching statistical significance. OS improvement with A+CnP versus CnP was observed in the PD-L1-high subgroup (HR = 0.48, 95% CI: 0.29-0.81), despite not being formally tested. Treatment-related grade 3 and 4 adverse events and serious adverse events occurred in 68.0% and 47.9% (A+CnP) and 57.5% and 28.7% (CnP) of patients, respectively. CONCLUSIONS: Adding atezolizumab to platinum-based chemotherapy significantly improved PFS in patients with first-line squamous NSCLC; OS was similar between the arms.
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Carcinoma de Células Escamosas , Neoplasias Pulmonares , Albuminas , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina , Carcinoma de Células Escamosas/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/uso terapêuticoRESUMO
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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Nivolumabe/uso terapêutico , Qualidade de Vida/psicologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nivolumabe/farmacologia , Adulto JovemRESUMO
BACKGROUND: The IMpower150 trial showed significant improvements in progression-free and overall survival with atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP) versus the standard-of-care bevacizumab plus carboplatin plus paclitaxel (BCP) in chemotherapy-naive patients with non-squamous non-small-cell lung cancer. Here, we report the efficacy of ABCP or atezolizumab plus carboplatin plus paclitaxel (ACP) versus BCP in key patient subgroups. METHODS: IMpower150 was a randomised, open-label, phase 3 study done at 240 academic medical centres and community oncology practices across 26 countries worldwide. Patients with chemotherapy-naive metastatic non-small-cell lung cancer were randomly assigned (1:1:1) to receive ABCP, ACP, or BCP every three weeks. The co-primary endpoints were overall survival and investigator-assessed progression-free survival in intention-to-treat wild-type patients (patients with epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK] genetic alterations were excluded). Efficacy was assessed in key subgroups within the intention-to-treat population, including patients with EGFR mutations (both sensitising and non-sensitising; EGFR-positive) previously treated with one or more tyrosine kinase inhibitors and patients with baseline liver metastases. Overall survival in the intention-to-treat population was included among secondary efficacy endpoints. Exploratory endpoints included the proportion of patients achieving an objective response in the intention-to-treat population, including EGFR-positive patients and patients with baseline liver metastases. Data are reported as per the Jan 22, 2018, data cutoff date, at which the number of coprimary prespecified overall survival events was met in the ABCP versus BCP groups. This trial is registered with ClinicalTrials.gov, number NCT02366143, and is ongoing. FINDINGS: Between March 31, 2015, and Dec 30, 2016, 1202 patients were enrolled. 400 patients were randomly assigned to ABCP, 402 to ACP, and 400 to BCP. In EGFR-positive patients (124 of 1202), median overall survival was not estimable (NE; 95% CI 17·0-NE) with ABCP (34 of 400) and 18·7 months (95% CI 13·4-NE) with BCP (45 of 400; hazard ratio [HR] 0·61 [95% CI 0·29-1·28]). Improved overall survival with ABCP versus BCP was observed in patients with sensitising EGFR mutations (median overall survival NE [95% CI NE-NE] with ABCP [26 of 400] vs 17·5 months [95% CI 11·7-NE] with BCP [32 of 400]; HR 0·31 [95% CI 0·11-0·83]) and in the intention-to-treat population (19·8 months [17·4-24·2] vs 14·9 months [13·4-17·1]; HR 0·76 [0·63-0·93]). Improved median overall survival with ABCP versus BCP was seen in patients with baseline liver metastases (13·3 months [11·6-NE] with ABCP [52 of 400] vs 9·4 months [7·9-11·7] with BCP [57 of 400]; HR 0·52 [0·33-0·82]). Median overall survival was 21·4 months (95% CI 13·8-NE) with ACP versus 18·7 months (95% CI 13·4-NE) with BCP in EGFR-positive patients (HR 0·93 [95% CI 0·51-1·68]). No overall survival benefit was seen with ACP versus BCP in patients with sensitising EGFR mutations (HR 0·90 [95% CI 0·47-1·74]), in the intention-to-treat population (HR 0·85 [0·71-1·03]), or in patients with baseline liver metastases (HR 0·87 [0·57-1·32]). In the intention-to-treat safety-evaluable population, grade 3-4 treatment-related events occurred in 223 (57%) patients in the ABCP group, in 172 (43%) in the ACP group, and in 191 (49%) in the BCP group; 11 (3%) grade 5 adverse events occurred in the ABCP group, as did four (1%) in the ACP group, and nine (2%) in the BCP group. INTERPRETATION: Improved survival was noted for patients treated with ABCP compared with those given BCP in the intention-to-treat population, and in patients with baseline liver metastases. The overall survival signal in the subgroup of patients with EGFR sensitising mutations warrants further study. FUNDING: F. Hoffmann-La Roche, Genentech.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carboplatina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Receptores ErbB , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Mutação , Paclitaxel/uso terapêutico , Resultado do TratamentoRESUMO
The phase 4 ABOUND.70+ trial assessed the safety and efficacy of nab-paclitaxel/carboplatin continuously or with a 1-week break between cycles in elderly patients with advanced non-small cell lung cancer (NSCLC). Patients ≥70 years with locally advanced/metastatic NSCLC were randomized 1:1 to first-line nab-paclitaxel days 1, 8, 15 plus carboplatin day 1 of a 21-day cycle (21d) or the same nab-paclitaxel/carboplatin regimen with a 1-week break between cycles (21d + break; 28d). The primary endpoint was the percentage of patients with grade ≥ 2 peripheral neuropathy (PN) or grade ≥ 3 myelosuppression. Other key endpoints included progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). A total of 143 patients were randomized (71 to 21d, 72 to 21d + break). The percentage of patients with grade ≥ 2 PN or grade ≥ 3 myelosuppression was similar between the 21d and 21d + break arms (76.5 and 77.1%; P = 0.9258). Treatment exposure was lower in the 21d arm compared with the 21d + break arm. Median OS was 15.2 and 16.2 months [hazard ratio (HR) 0.72, 95% CI 0.44-1.19; P = 0.1966], median PFS was 3.6 and 7.0 months (HR 0.48, 95% CI 0.30-0.76; P < 0.0019), and ORR was 23.9 and 40.3% (risk ratio 1.68, 95% CI 1.02-2.78; P = 0.0376) in the 21d and 21d + break arms, respectively. In summary, the 1-week break between treatment cycles significantly improved PFS and ORR but did not significantly reduce the percentage of grade ≥ 2 PN or grade ≥ 3 myelosuppression. Overall, the findings support the results of prior subset analyses on the safety and efficacy of first-line nab-paclitaxel/carboplatin in elderly patients with advanced NSCLC.
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BACKGROUND: The cancer-cell-killing property of atezolizumab may be enhanced by the blockade of vascular endothelial growth factor-mediated immunosuppression with bevacizumab. This open-label, phase 3 study evaluated atezolizumab plus bevacizumab plus chemotherapy in patients with metastatic nonsquamous non-small-cell lung cancer (NSCLC) who had not previously received chemotherapy. METHODS: We randomly assigned patients to receive atezolizumab plus carboplatin plus paclitaxel (ACP), bevacizumab plus carboplatin plus paclitaxel (BCP), or atezolizumab plus BCP (ABCP) every 3 weeks for four or six cycles, followed by maintenance therapy with atezolizumab, bevacizumab, or both. The two primary end points were investigator-assessed progression-free survival both among patients in the intention-to-treat population who had a wild-type genotype (WT population; patients with EGFR or ALK genetic alterations were excluded) and among patients in the WT population who had high expression of an effector T-cell (Teff) gene signature in the tumor (Teff-high WT population) and overall survival in the WT population. The ABCP group was compared with the BCP group before the ACP group was compared with the BCP group. RESULTS: In the WT population, 356 patients were assigned to the ABCP group, and 336 to the BCP group. The median progression-free survival was longer in the ABCP group than in the BCP group (8.3 months vs. 6.8 months; hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.52 to 0.74; P<0.001); the corresponding values in the Teff-high WT population were 11.3 months and 6.8 months (hazard ratio, 0.51 [95% CI, 0.38 to 0.68]; P<0.001). Progression-free survival was also longer in the ABCP group than in the BCP group in the entire intention-to-treat population (including those with EGFR or ALK genetic alterations) and among patients with low or negative programmed death ligand 1 (PD-L1) expression, those with low Teff gene-signature expression, and those with liver metastases. Median overall survival among the patients in the WT population was longer in the ABCP group than in the BCP group (19.2 months vs. 14.7 months; hazard ratio for death, 0.78; 95% CI, 0.64 to 0.96; P=0.02). The safety profile of ABCP was consistent with previously reported safety risks of the individual medicines. CONCLUSIONS: The addition of atezolizumab to bevacizumab plus chemotherapy significantly improved progression-free survival and overall survival among patients with metastatic nonsquamous NSCLC, regardless of PD-L1 expression and EGFR or ALK genetic alteration status. (Funded by F. Hoffmann-La Roche/Genentech; IMpower150 ClinicalTrials.gov number, NCT02366143 .).
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Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Quinase do Linfoma Anaplásico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Feminino , Genes erbB-1 , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica/tratamento farmacológico , Paclitaxel/administração & dosagem , Receptores Proteína Tirosina Quinases/genética , Análise de Sobrevida , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
INTRODUCTION: Crizotinib, an anaplastic lymphoma kinase (ALK) inhibitor, is a first-line treatment for ALK translocation-positive advanced non-small cell lung cancer (NSCLC); however, patients eventually progress. Immunotherapies, including the programmed death-1 inhibitor nivolumab, have resulted in durable responses and long-term overall survival in patients with NSCLC. We hypothesized that combining targeted therapy with immunotherapy could result in more patients with responses and/or more durable responses. Herein we report data from a study assessing nivolumab plus crizotinib in patients with previously untreated advanced ALK translocation-positive NSCLC. METHODS: Group E in CheckMate 370 was a single-arm cohort designed to evaluate the safety of first-line nivolumab (240 mg every 2 weeks) plus crizotinib (250 mg twice daily) in patients with ALK translocation-positive NSCLC. The primary endpoint of safety would be met if ≤20% of patients discontinued treatment due to treatment-related adverse events by week 17. Objective response rate was a secondary endpoint. A planned safety review occurred in November 2016; the data cutoff was May 26, 2017. RESULTS: Of the first 13 patients treated with nivolumab plus crizotinib, 5 (38%) developed severe hepatic toxicities leading to the discontinuation of the combination. Of these, two patients died and the presence of severe hepatic toxicities may have contributed to death. Enrollment was closed and combination treatment discontinued due to observed grade ≥3 hepatic toxicities. Five patients (38%) had a partial response. CONCLUSIONS: These findings do not support further evaluation of nivolumab 240 mg every 2 weeks plus crizotinib 250 mg twice daily.
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Quinase do Linfoma Anaplásico/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico/genética , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Crizotinibe/administração & dosagem , Crizotinibe/efeitos adversos , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Translocação GenéticaRESUMO
OBJECTIVES: The REVEL study demonstrated improved efficacy for patients with advanced non-small cell lung cancer treated with ramucirumab plus docetaxel, independent of histology. This exploratory analysis characterized the treatment effect in REVEL patients who were refractory to prior first-line treatment. MATERIALS AND METHODS: Refractory patients had a best response of progressive disease to first-line treatment. Endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), quality of life (QoL), and safety. Kaplan-Meier and Cox proportional hazards regression were performed for OS and PFS, and Cochran-Mantel-Haenszel test was used for response. QoL was assessed with the Lung Cancer Symptom Scale. Sensitivity analyses were performed on subgroups of the intent-to-treat population with limited time on first-line therapy. RESULTS: Of 1253 randomized patients in REVEL, 360 (29%) were refractory to first-line treatment. Baseline characteristics were largely balanced between treatment arms. In the control arm, median OS for refractory patients was 6.3 versus 10.3 months for patients not meeting this criterion, demonstrating the poor prognosis of refractory patients. Median OS (8.3 vs. 6.3 months; HR, 0.86; 95% CI, 0.68-1.08), median PFS (4.0 vs. 2.5 months; HR, 0.71; 95% CI, 0.57-0.88), and ORR (22.5% vs. 12.6%) were improved in refractory patients treated with ramucirumab compared to placebo, without new safety concerns or further deteriorating patient QoL. CONCLUSIONS: The effect of ramucirumab in refractory patients is similar to that in the intent-to-treat population. The benefit/risk profile for refractory patients suggests that ramucirumab plus docetaxel is an appropriate treatment option even in this difficult-to-treat population.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Progressão da Doença , Docetaxel , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Qualidade de Vida , Retratamento , Taxoides/administração & dosagem , Resultado do Tratamento , Adulto Jovem , RamucirumabRESUMO
BACKGROUND: Longitudinal data on the impact of treatment on quality of life (QoL) in advanced non-small cell lung cancer (NSCLC) are limited. In this palliative setting, treatment that does not deteriorate QoL is key. Here we report longitudinal QoL in patients with squamous NSCLC, receiving ≤4 cycles of nab-paclitaxel/carboplatin combination chemotherapy. METHODS: Patients received nab-paclitaxel 100 mg/m2 days 1, 8, 15 + carboplatin area under the curve 6 mgâ¢min/mL day 1 (q3w) for four cycles. QoL was assessed by the Lung Cancer Symptom Scale (LCSS) and Euro-QoL-5 Dimensions-5 Levels (EQ-5D-5L) at baseline and each cycle (day 1). RESULTS: Two-hundred and six lesion-response-evaluable patients completed baseline + ≥1 postbaseline QoL assessment and were QoL evaluable. LCSS average total score and symptom burden index improved from baseline throughout four cycles. In the LCSS pulmonary symptoms score, 46% of patients reported clinically meaningful improvement (≥10 mm visual analog scale) from baseline. Individual EQ-5D-5L dimensions remained stable/improved in ≥83% of patients; ≈33% reported complete resolution of baseline problems at least once during four cycles. Generally, responders (unconfirmed complete/partial response) had higher scores vs nonresponders. CONCLUSION: In patients with squamous NSCLC, four cycles of nab-paclitaxel/carboplatin demonstrated clinically meaningful QoL improvements, with greater benefits in responders vs nonresponders.
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Molecularly targeted therapies, directed against the features of a given tumor, have allowed for a personalized approach to the treatment of advanced non-small-cell lung cancer (NSCLC). The reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib had undergone turbulent clinical development until it was discovered that these agents have preferential activity in patients with NSCLC harboring activating EGFR mutations. Since then, a number of phase 3 clinical trials have collectively shown that EGFR-TKI monotherapy is more effective than combination chemotherapy as first-line therapy for EGFR mutation-positive advanced NSCLC. The next generation of EGFR-directed agents for EGFR mutation-positive advanced NSCLC is irreversible TKIs against EGFR and other ErbB family members, including afatinib, which was recently approved, and dacomitinib, which is currently being tested in phase 3 trials. As research efforts continue to explore the various proposed mechanisms of acquired resistance to EGFR-TKI therapy, agents that target signaling pathways downstream of EGFR are being studied in combination with EGFR TKIs in molecularly selected advanced NSCLC. Overall, the results of numerous ongoing phase 3 trials involving the EGFR TKIs will be instrumental in determining whether further gains in personalized therapy for advanced NSCLC are attainable with newer agents and combinations. This article reviews key clinical trial data for personalized NSCLC therapy with agents that target the EGFR and related pathways, specifically based on molecular characteristics of individual tumors, and mechanisms of resistance.