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1.
Lancet Reg Health Eur ; 43: 100970, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39040528

RESUMO

Background: The efficacy of front-line pembrolizumab has been established in studies that limit treatment duration to 2 years, but decision to stop pembrolizumab after 2 years is often at physician's discretion. ATHENA is a retrospective cohort study using a comprehensive administrative database aimed firstly at exploring the optimal duration of pembrolizumab and secondly real-life prognosis factors in patients with advanced non-small cell lung cancer (NSCLC). Methods: Using the French National Health Insurance database (SNDS), we identified patients with incident lung cancer in France from 2015 to 2022. Treatments and patients' characteristics were extracted or inferred from hospital, outpatient care, pharmacy delivery reports. The duration's hazard ratio (HR) was estimated with Cox model weighted by inverse of propensity score to account for confounding. Prognostics factors in first line population were identified with Cox model selected by a LASSO procedure. Findings: 391,106 patients with lung cancer were identified, of whom 43,359 received up-front pembrolizumab for an advanced disease. There were 67% (29,040/43,359) of male and the median age at diagnosis was 65 years old. After a median follow-up time of 25.9 months (min-max, [0-97.6]), the median overall survival (OS) after pembrolizumab initiation in first line was 15.7 [CI 95, 15.3-16.0] months. In multivariable analysis, several covariables were independently associated with worse OS, including male sex with chemo-immunotherapy, age, hospital category, high deprivation index, inpatient hospitalization for first pembrolizumab, and history of diabetes, diuretic, beta blocker, painkiller prescription. At landmark time of 29 months after pembrolizumab initiation, continuation beyond 2 years was not associated with better OS than a fixed 2-year treatment, HR = 0.97 [0.75-1.26] p = 0.95. Interpretation: This study supports the notion that stopping pembrolizumab after 2 years could be safe for patients with advanced NSCLC. However, because observational studies are prone to confounding and selection bias, causality cannot be affirmed. Funding: This study did not receive any specific grant.

3.
Cell ; 187(13): 3373-3389.e16, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38906102

RESUMO

The gut microbiota influences the clinical responses of cancer patients to immunecheckpoint inhibitors (ICIs). However, there is no consensus definition of detrimental dysbiosis. Based on metagenomics (MG) sequencing of 245 non-small cell lung cancer (NSCLC) patient feces, we constructed species-level co-abundance networks that were clustered into species-interacting groups (SIGs) correlating with overall survival. Thirty-seven and forty-five MG species (MGSs) were associated with resistance (SIG1) and response (SIG2) to ICIs, respectively. When combined with the quantification of Akkermansia species, this procedure allowed a person-based calculation of a topological score (TOPOSCORE) that was validated in an additional 254 NSCLC patients and in 216 genitourinary cancer patients. Finally, this TOPOSCORE was translated into a 21-bacterial probe set-based qPCR scoring that was validated in a prospective cohort of NSCLC patients as well as in colorectal and melanoma patients. This approach could represent a dynamic diagnosis tool for intestinal dysbiosis to guide personalized microbiota-centered interventions.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Microbioma Gastrointestinal , Imunoterapia , Neoplasias Pulmonares , Neoplasias , Feminino , Humanos , Masculino , Akkermansia , Carcinoma Pulmonar de Células não Pequenas/microbiologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Disbiose/microbiologia , Fezes/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia/métodos , Neoplasias Pulmonares/microbiologia , Neoplasias Pulmonares/tratamento farmacológico , Metagenômica/métodos , Neoplasias/microbiologia , Resultado do Tratamento
4.
J Clin Oncol ; : JCO2400720, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38843488

RESUMO

PURPOSE: Telisotuzumab vedotin (Teliso-V) is a c-Met-directed antibody-drug conjugate with a monomethyl auristatin E cytotoxic payload. The phase 2 LUMINOSITY trial (NCT03539536) aimed to identify the optimal c-Met protein-overexpressing non-small cell lung cancer (NSCLC) population for treatment with Teliso-V (stage 1) and expand the selected group for efficacy evaluation (stage 2). Stage 2 enrolled patients with non-squamous epidermal growth factor receptor (EGFR)-wildtype NSCLC. METHODS: Eligible patients had locally advanced/metastatic c-Met protein-overexpressing NSCLC and ≤2 prior lines of therapy (including ≤1 line of systemic chemotherapy). c-Met protein overexpression in non-squamous EGFR-wildtype NSCLC was defined as ≥25% tumor cells with 3+ staining (high [≥50% 3+]; intermediate [≥25%-<50%]). Teliso-V was administered at 1.9 mg/kg every 2 weeks. Primary endpoint was overall response rate (ORR) by independent central review. RESULTS: In total, 172 patients with non-squamous EGFR-wildtype NSCLC received Teliso-V in stages 1 and 2. ORR was 28.6% (95% CI, 21.7-36.2; c-Met high, 34.6% [24.2-46.2]; c-Met intermediate, 22.9% [14.4-33.4]). Median duration of response was 8.3 months (95% CI, 5.6-11.3; c-Met high, 9.0 [4.2-13.0]; c-Met intermediate: 7.2 [5.3-11.5]). Median overall survival was 14.5 months (95% CI, 9.9-16.6; c-Met high, 14.6 [9.2-25.6]; c-Met intermediate, 14.2 [9.6-16.6]). Median progression-free survival was 5.7 months (95% CI, 4.6-6.9; c-Met high, 5.5 [4.1-8.3]; c-Met intermediate: 6.0 [4.5-8.1]). Most common any-grade treatment-related adverse events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%); the most common grade ≥3 was peripheral sensory neuropathy (7%). CONCLUSION: Teliso-V was associated with durable responses in c-Met protein-overexpressing non-squamous EGFR-wildtype NSCLC, especially in those with high c-Met. AEs were generally manageable.

5.
Cancer Treat Rev ; 127: 102733, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38733648

RESUMO

Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are recurrent oncogenic drivers found in a variety of solid tumours, including lung cancer. Several tropomyosin receptor kinase (TRK) inhibitors have been developed to treat tumours with NTRK gene fusions. Larotrectinib and entrectinib are first-generation TRK inhibitors that have demonstrated efficacy in patients with TRK fusion lung cancers. Genomic testing is recommended for all patients with metastatic non-small cell lung cancer for optimal drug therapy selection. Multiple testing methods can be employed to identify NTRK gene fusions in the clinic and each has its own advantages and limitations. Among these assays, RNA-based next-generation sequencing (NGS) can be considered a gold standard for detecting NTRK gene fusions; however, several alternatives with minimally acceptable sensitivity and specificity are also available in areas where widespread access to NGS is unfeasible. This review highlights the importance of testing for NTRK gene fusions in lung cancer, ideally using the gold-standard method of RNA-based NGS, the various assays that are available, and treatment algorithms for patients.


Assuntos
Neoplasias Pulmonares , Receptor trkA , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Receptor trkA/genética , Fusão Gênica , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proteínas de Fusão Oncogênica/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Inibidores de Proteínas Quinases/uso terapêutico , Receptor trkB/genética
6.
NPJ Precis Oncol ; 8(1): 90, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38627602

RESUMO

In this review, we cover the current understanding of BRAF mutations and associated clinical characteristics in patients with metastatic NSCLC, approved and emerging treatment options, BRAF sequencing approaches, and unmet needs. The BRAFV600E mutation confers constitutive activity of the MAPK pathway, leading to enhanced growth, proliferation, and survival of tumor cells. Testing for BRAF mutations enables patients to be treated with therapies that directly target BRAFV600E and the MAPK pathway, but BRAF testing lags behind other oncogene testing in metastatic NSCLC. Additional therapies targeting BRAFV600E mutations provide options for patients with metastatic NSCLC. Emerging therapies and combinations under investigation could potentially overcome issues of resistance and target non-V600E mutations. Therefore, because targeted therapies with enhanced efficacy are on the horizon, being able to identify BRAF mutations in metastatic NSCLC may become even more important.

7.
J Clin Oncol ; 42(17): 2108-2110, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38569121
8.
Lancet Oncol ; 25(4): 439-454, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38547891

RESUMO

BACKGROUND: DESTINY-Lung01 is a multicentre, open-label, phase 2 study evaluating the antitumour activity and safety of trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate, in patients with HER2-overexpressing or HER2 (ERBB2)-mutant unresectable or metastatic non-small-cell lung cancer (NSCLC). The results of the HER2-mutant cohort (cohort 2) have been reported elsewhere. Herein, we report the primary analysis of cohorts 1 and 1A, which aimed to evaluate the activity and safety of trastuzumab deruxtecan 5·4 mg/kg and 6·4 mg/kg in patients with HER2-overexpressing NSCLC. METHODS: Patients aged 18 years or older with unresectable or metastatic (or both unresectable and metastatic) non-squamous NSCLC who had relapsed following or were refractory to standard treatment or for whom no standard treatment was available, with an HER2 immunohistochemistry score of 3+ or 2+ (without known HER2 mutations) and an Eastern Cooperative Oncology Group performance status score of 0 or 1, were enrolled at 20 specialist hospitals in France, Japan, the Netherlands, Spain, and the USA. Patients were assigned to cohorts sequentially, first to cohort 1, to receive trastuzumab deruxtecan 6·4 mg/kg (cohort 1), then to cohort 1A, to receive trastuzumab deruxtecan 5·4 mg/kg, both administered intravenously once every 3 weeks. The primary endpoint was confirmed objective response rate by independent central review and was assessed in the full analysis set, which included all patients who signed an informed consent form and were enrolled in the study. Safety was assessed in all enrolled patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT03505710, and is ongoing (closed to recruitment). FINDINGS: Between Aug 27, 2018, and Jan 28, 2020, 49 patients were enrolled in cohort 1 (median age 63·0 years [IQR 58·0-68·0], 30 [61%] male, 19 [39%] female, and 31 [63%] White), and from June 16 to Dec 9, 2020, 41 patients were enrolled in cohort 1A (median age 62·0 years [IQR 56·0-66·0], 22 [54%] male, 19 [46%] female, and 31 [76%] White). As of data cutoff (Dec 3, 2021), the median treatment duration was 4·1 months (IQR 1·4-7·1) in cohort 1 and 5·5 months (1·4-8·7) in cohort 1A, and median follow-up was 12·0 months (5·4-22·4) in cohort 1 and 10·6 months (4·5-13·5) in cohort 1A. Confirmed objective response rate by independent central review was 26·5% (95% CI 15·0-41·1; 13 of 49, all partial responses) in cohort 1 and 34·1% (20·1-50·6; 14 of 41; two complete responses and 12 partial responses) in cohort 1A. The most common treatment-emergent adverse events of grade 3 or worse were neutropenia (12 [24%] of 49 in cohort 1, none in cohort 1A), pneumonia (six [12%] and two [5%], respectively), fatigue (six [12%] and three [7%], respectively), and disease progression (six [12%] and four [10%], respectively). Drug-related treatment-emergent adverse events of grade 3 or worse occurred in 26 (53%) of 41 patients in cohort 1 and nine (22%) of 49 patients in cohort 1A. Drug-related serious adverse events were reported in ten (20%) patients and three (7%) patients, respectively. Deaths due to treatment-emergent adverse events occurred in ten (20%) patients in cohort 1 (disease progression in six (12%) patients and bronchospasm, hydrocephalus, respiratory failure, and pneumonitis in one [2%] patient each), and in seven (17%) patients in cohort 1A (due to disease progression in four (10%) patients and dyspnoea, malignant neoplasm, and sepsis in one (2%) patient each). One death due to a treatment-emergent adverse event was determined to be due to study treatment by the investigator, which was in cohort 1 (pneumonitis). Independent adjudication of interstitial lung disease or pneumonitis found that drug-related interstitial lung disease or pneumonitis occurred in ten (20%) patients in cohort 1 (two [4%] grade 1, five [10%] grade 2, and three [6%] grade 5) and two (5%) patients in cohort 1A (one [2%] grade 2 and one [2%] grade 5). An additional patient in cohort 1A had grade 4 pneumonitis after the data cutoff, which was subsequently adjudicated as drug-related grade 5 interstitial lung disease or pneumonitis. INTERPRETATION: Given the low antitumour activity of existing treatment options in this patient population, trastuzumab deruxtecan might have the potential to fill a large unmet need in HER2-overexpressing NSCLC. Our findings support further investigation of trastuzumab deruxtecan in patients with HER2-overexpressing NSCLC. FUNDING: Daiichi Sankyo and AstraZeneca.


Assuntos
Camptotecina , Carcinoma Pulmonar de Células não Pequenas , Imunoconjugados , Doenças Pulmonares Intersticiais , Neoplasias Pulmonares , Pneumonia , Trastuzumab , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Progressão da Doença , Imunoconjugados/efeitos adversos , Doenças Pulmonares Intersticiais/induzido quimicamente , Doenças Pulmonares Intersticiais/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Pneumonia/induzido quimicamente , Receptor ErbB-2/genética , Receptor ErbB-2/análise , Trastuzumab/efeitos adversos , Trastuzumab/uso terapêutico
10.
Br J Cancer ; 130(4): 682-693, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38177660

RESUMO

BACKGROUND: Resistance mechanisms to combination therapy with dabrafenib plus trametinib remain poorly understood in patients with BRAFV600E-mutant advanced non-small-cell lung cancer (NSCLC). We examined resistance to BRAF inhibition by single CTC sequencing in BRAFV600E-mutant NSCLC. METHODS: CTCs and cfDNA were examined in seven BRAFV600E-mutant NSCLC patients at failure to treatment. Matched tumour tissue was available for four patients. Single CTCs were isolated by fluorescence-activated cell sorting following enrichment and immunofluorescence (Hoechst 33342/CD45/pan-cytokeratins) and sequenced for mutation and copy number-alteration (CNA) analyses. RESULTS: BRAFV600E was found in 4/4 tumour biopsies and 5/7 cfDNA samples. CTC mutations were mostly found in MAPK-independent pathways and only 1/26 CTCs were BRAFV600E mutated. CTC profiles encompassed the majority of matched tumour biopsy CNAs but 72.5% to 84.5% of CTC CNAs were exclusive to CTCs. Extensive diversity, involving MAPK, MAPK-related, cell cycle, DNA repair and immune response pathways, was observed in CTCs and missed by analyses on tumour biopsies and cfDNA. Driver alterations in clinically relevant genes were recurrent in CTCs. CONCLUSIONS: Resistance was not driven by BRAFV600E-mutant CTCs. Extensive tumour genomic heterogeneity was found in CTCs compared to tumour biopsies and cfDNA at failure to BRAF inhibition, in BRAFV600E-mutant NSCLC, including relevant alterations that may represent potential treatment opportunities.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Ácidos Nucleicos Livres , Neoplasias Pulmonares , Células Neoplásicas Circulantes , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Células Neoplásicas Circulantes/patologia , Mutação
11.
J Thorac Oncol ; 19(1): 166-172, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37567387

RESUMO

INTRODUCTION: Dual immune checkpoint blockers regimen represents a standard first-line therapy in unresectable pleural mesothelioma (PM). Novel combination strategies, including immune checkpoint blockers and antiangiogenic drugs, are currently under investigation in this setting. We aimed to assess the efficacy of the chemoimmunotherapy combination by reference to literature evidence. METHODS: A systematic review and meta-analysis of trials with first-line platinum-based chemotherapy associated with programmed death-ligand 1 and programmed cell death protein 1 agent in unresectable PM. We estimated the weighted summary proportion of disease response, along with the landmark probability of survival outcomes. RESULTS: A total of 349 patients with unresectable PM from four trials (DREAM, PrE0505, JME-001, and IND.227) were included, 79% (n = 274) with epithelioid and 21% (n = 75) with nonepithelioid histologic type. In aggregate, the objective response rate was 59.2% (95% confidence interval [CI]: 50.3%-67.9%) and disease control rate was 92.2% (95% CI: 89.2%-94.8%). Comparing epithelioid versus nonepithelioid tumors, the objective response rate was 64.5% versus 46.4%, (p < 0.001) and the disease control rate was 92.3% versus 80.0%, (p = 0.043), with an OR of 2.56 (95% CI: 1.51-4.32) for disease response and of 3.37 (95% CI: 0.99-11.47) for disease control. The aggregated estimated probability of progression-free survival was 63% (95% CI: 53%-71%) at 6 months and 25% (95% CI: 21%-31%) at 12 months, whereas the 6-, 12- and 24-month overall survival rates were 88% (95% CI: 81%-93%), 71% (95% CI: 61%-79%) and 39% (95% CI: 34%-45%), respectively. CONCLUSIONS: According to our analysis, first-line chemoimmunotherapy holds promise as a new treatment approach for PM, exhibiting encouraging survival outcomes and an enhanced response rate, including for the epithelioid subtype. Ongoing studies are necessary to establish its precise placement within the treatment algorithm.


Assuntos
Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurais , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Ligantes , Neoplasias Pulmonares/patologia , Mesotelioma/patologia , Neoplasias Pleurais/patologia , Receptor de Morte Celular Programada 1/metabolismo
12.
J Clin Oncol ; 42(7): 808-820, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38042525

RESUMO

PURPOSE: We report CNS efficacy of first-line osimertinib plus chemotherapy versus osimertinib monotherapy in patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) from the phase III FLAURA2 study according to baseline CNS metastasis status. METHODS: Patients were randomly assigned to osimertinib plus platinum-pemetrexed (combination) or osimertinib monotherapy until disease progression or discontinuation. Brain scans were performed in all patients at baseline and progression and at scheduled assessments until progression for patients with baseline CNS metastases; scans were assessed by neuroradiologist CNS blinded independent central review (BICR). RESULTS: On the basis of baseline CNS BICR, 118 of 279 (combination) and 104 of 278 (monotherapy) randomly assigned patients had ≥one measurable and/or nonmeasurable CNS lesion and were included in the CNS full analysis set (cFAS); 40 of 118 and 38 of 104 had ≥one measurable target CNS lesion and were included in the post hoc CNS evaluable-for-response set (cEFR). In the cFAS, the hazard ratio (HR) for CNS progression or death was 0.58 (95% CI, 0.33 to 1.01). In patients without baseline CNS metastases, the HR for CNS progression or death was 0.67 (95% CI, 0.43 to 1.04). In the cFAS, CNS objective response rates (ORRs; 95% CI) were 73% (combination; 64 to 81) versus 69% (monotherapy; 59 to 78); 59% versus 43% had CNS complete response (CR). In the cEFR, CNS ORRs (95% CI) were 88% (73 to 96) versus 87% (72 to 96); 48% versus 16% had CNS CR. CONCLUSION: Osimertinib plus platinum-pemetrexed demonstrated improved CNS efficacy compared with osimertinib monotherapy, including delaying CNS progression, irrespective of baseline CNS metastasis status. These data support this combination as a new first-line treatment for patients with EGFR-mutated advanced NSCLC, including those with CNS metastases.


Assuntos
Acrilamidas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias do Sistema Nervoso Central , Indóis , Neoplasias Pulmonares , Pirimidinas , Humanos , Compostos de Anilina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Pemetrexede/uso terapêutico , Platina/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico
13.
Clin Lung Cancer ; 25(3): 233-243.e8, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38105153

RESUMO

INTRODUCTION: The LIPI, based on pretreatment derived neutrophils/[leukocytes-neutrophils] ratio (dNLR) and LDH, is associated with immune checkpoint inhibitors (ICI) outcomes in advanced non-small-cell lung cancer (NSCLC). We aimed to assess baseline LIPI correlation with durvalumab consolidation outcomes in the locally advanced setting. MATERIAL AND METHODS: Multicentre retrospective study (330 patients) with stage III unresectable NSCLC treated with durvalumab after chemo-radiotherapy between April 2015 and December 2020; 65 patients treated with chemo-radiotherapy only. Baseline LIPI characterized 3 groups: good (dNLR≤3+LDH≤ULN), intermediate (dNLR>3/LDH>ULN) and poor (dNLR>3+LDH>ULN). Primary endpoint was overall survival (OS). RESULTS: In the durvalumab cohort, median age was 67 years, 95% smokers, 98% with a performance status of 0-1; 60% had nonsquamous histology and 16% a PD-L1 expression <1%. Radiotherapy was delivered concurrently in 81%. LIPI was evaluable in 216 patients: 66% good, 31% intermediate, 3% poor. LIPI significantly correlated with median OS (median follow-up: 19 months): 18.1 months vs. 47.0 months vs. not reached in poor, intermediate and good LIPI groups, respectively (P = .03). A trend between objective response rate and LIPI groups was observed: 0% vs. 41% vs. 45%, respectively (P = .05). The pooled intermediate/poor LIPI group was associated with shorter OS (HR 1.97; P = .03) and higher risk of progressive disease (OR 2.68; P = .047). Survivals and response were not influenced in the control cohort. CONCLUSION: Baseline LIPI correlated with outcomes in patients with locally advanced NSCLC treated with durvalumab consolidation, but not in those who only received chemo-radiotherapy, providing further evidence of its prognostic and potential predictive role of ICI benefit in NSCLC.


Assuntos
Anticorpos Monoclonais , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Feminino , Masculino , Estudos Retrospectivos , Idoso , Prognóstico , Pessoa de Meia-Idade , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/administração & dosagem , Idoso de 80 Anos ou mais , Adulto , Antineoplásicos Imunológicos/uso terapêutico , Taxa de Sobrevida , Neutrófilos/patologia , Quimiorradioterapia/métodos
14.
Br J Cancer ; 130(3): 417-424, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38097741

RESUMO

BACKGROUND: Platinum-sensitivity is a phenotypic biomarker of Poly (ADP-ribose) polymerase inhibitors (PARPi) sensitivity in histotypes where PARPi are approved. Approximately one-third of non-small cell lung cancers (NSCLC) are platinum-sensitive. The double-blind, randomized phase II PIPSeN (NCT02679963) study evaluated olaparib, a PARPi, as maintenance therapy for patients with platinum-sensitive advanced NSCLC. METHODS: Chemonaïve patients with ECOG performance status of 0-1, platinum-sensitive, EGFR- and ALK-wild-type, stage IIIB-IV NSCLC were randomized (R) to receive either olaparib (O) maintenance or a placebo (P). The primary objective was progression-free survival (PFS) from R. Secondary objectives included overall survival (OS) and safety. With an anticipated hazard ratio of 0.65, 144 patients were required to be randomized, and approximately 500 patients enrolled. RESULTS: The trial was prematurely terminated because anti-PD(L)1 therapy was approved during the trial recruitment. A total of 182 patients were enrolled, with 60 patients randomized: 33 and 27 in the O and P arms, respectively. Patient and tumor characteristics were well-balanced between arms, except for alcohol intake (33% vs 11% in the O and P arms, respectively, p = 0.043). The median PFS was 2.9 and 2.0 months in the O and P arms, respectively (logrank p = 0.99). The median OS was 9.4 and 9.5 months in the O and P arms, respectively (p = 0.28). Grade ≥3 toxicities occurred in 15 and 8 patients in O and P arms, with no new safety concerns. CONCLUSION: PIPSeN was terminated early after enrollment of only 50% of the pre-planned population, thus being statistically underpowered. Olaparib maintenance did neither improve median PFS nor OS in this patient population.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Método Duplo-Cego , Neoplasias Pulmonares/patologia , Quimioterapia de Manutenção , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos
15.
N Engl J Med ; 389(21): 1935-1948, 2023 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-37937763

RESUMO

BACKGROUND: Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that is selective for EGFR-TKI-sensitizing and EGFR T790M resistance mutations. Evidence suggests that the addition of chemotherapy may extend the benefits of EGFR-TKI therapy. METHODS: In this phase 3, international, open-label trial, we randomly assigned in a 1:1 ratio patients with EGFR-mutated (exon 19 deletion or L858R mutation) advanced non-small-cell lung cancer (NSCLC) who had not previously received treatment for advanced disease to receive osimertinib (80 mg once daily) with chemotherapy (pemetrexed [500 mg per square meter of body-surface area] plus either cisplatin [75 mg per square meter] or carboplatin [pharmacologically guided dose]) or to receive osimertinib monotherapy (80 mg once daily). The primary end point was investigator-assessed progression-free survival. Response and safety were also assessed. RESULTS: A total of 557 patients underwent randomization. Investigator-assessed progression-free survival was significantly longer in the osimertinib-chemotherapy group than in the osimertinib group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; P<0.001). At 24 months, 57% (95% CI, 50 to 63) of the patients in the osimertinib-chemotherapy group and 41% (95% CI, 35 to 47) of those in the osimertinib group were alive and progression-free. Progression-free survival as assessed according to blinded independent central review was consistent with the primary analysis (hazard ratio, 0.62; 95% CI, 0.48 to 0.80). An objective (complete or partial) response was observed in 83% of the patients in the osimertinib-chemotherapy group and in 76% of those in the osimertinib group; the median response duration was 24.0 months (95% CI, 20.9 to 27.8) and 15.3 months (95% CI, 12.7 to 19.4), respectively. The incidence of grade 3 or higher adverse events from any cause was higher with the combination than with monotherapy - a finding driven by known chemotherapy-related adverse events. The safety profile of osimertinib plus pemetrexed and a platinum-based agent was consistent with the established profiles of the individual agents. CONCLUSIONS: First-line treatment with osimertinib-chemotherapy led to significantly longer progression-free survival than osimertinib monotherapy among patients with EGFR-mutated advanced NSCLC. (Funded by AstraZeneca; FLAURA2 ClinicalTrials.gov number, NCT04035486.).


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Humanos , Compostos de Anilina/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Pemetrexede/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Antineoplásicos/uso terapêutico
18.
Cancer Treat Rev ; 120: 102621, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37690180

RESUMO

Progresses of systemic treatments in advanced non-small cell lung cancer (NSCLC), such as immune checkpoint blockers (ICB) and targeted therapies, led to the increased incidence of oligoprogressive disease (OPD). The OPD is a subtype of oligometastatic disease (OMD) defined as a progression of a limited number of lesions during systemic treatment exposure. The hypothesis was formulated that local radical treatments (LRT) could eradicate progressive lesions resulting from resistant clones, ultimately leading to systemic treatment sensitivity restoration. Recently published international consensuses and guidelines aim to obtain a uniform definition of OMD NSCLC, to standardize the inclusion of these patients in future clinical trials, as well as their management in daily practice. Although there is no specific definition of OPD, LRT strategies in OPD are supported after reporting promising results. Both retrospective and preliminary prospective randomized data of LRT for patients with OPD NSCLC are encouraging. More clinical and translational data are needed for selecting best scenarios where LRT should be delivered. In this review, we analyze the current available literature on LRT for patients with OPD in advanced NSCLC and discuss about future trial design and challenges.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Radiocirurgia , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Estudos Prospectivos , Estudos Retrospectivos , Progressão da Doença , Radiocirurgia/métodos
20.
J Immunother Cancer ; 11(9)2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37678919

RESUMO

BACKGROUND: Our aim was to explore the prognostic value of anthropometric parameters in a large population of patients treated with immunotherapy. METHODS: We retrospectively included 623 patients with advanced non-small cell lung cancer (NSCLC) (n=318) or melanoma (n=305) treated by an immune-checkpoint-inhibitor having a pretreatment (thorax-)abdomen-pelvis CT scan. An external validation cohort of 55 patients with NSCLC was used. Anthropometric parameters were measured three-dimensionally (3D) by a deep learning software (Anthropometer3DNet) allowing an automatic multislice measurement of lean body mass, fat body mass (FBM), muscle body mass (MBM), visceral fat mass (VFM) and sub-cutaneous fat mass (SFM). Body mass index (BMI) and weight loss (WL) were also retrieved. Receiver operator characteristic (ROC) curve analysis was performed and overall survival was calculated using Kaplan-Meier (KM) curve and Cox regression analysis. RESULTS: In the overall cohort, 1-year mortality rate was 0.496 (95% CI: 0.457 to 0.537) for 309 events and 5-year mortality rate was 0.196 (95% CI: 0.165 to 0.233) for 477 events. In the univariate Kaplan-Meier analysis, prognosis was worse (p<0.001) for patients with low SFM (<3.95 kg/m2), low FBM (<3.26 kg/m2), low VFM (<0.91 kg/m2), low MBM (<5.85 kg/m2) and low BMI (<24.97 kg/m2). The same parameters were significant in the Cox univariate analysis (p<0.001) and, in the multivariate stepwise Cox analysis, the significant parameters were MBM (p<0.0001), SFM (0.013) and WL (0.0003). In subanalyses according to the type of cancer, all body composition parameters were statistically significant for NSCLC in ROC, KM and Cox univariate analysis while, for melanoma, none of them, except MBM, was statistically significant. In multivariate Cox analysis, the significant parameters for NSCLC were MBM (HR=0.81, p=0.0002), SFM (HR=0.94, p=0.02) and WL (HR=1.06, p=0.004). For NSCLC, a KM analysis combining SFM and MBM was able to separate the population in three categories with the worse prognostic for the patients with both low SFM (<5.22 kg/m2) and MBM (<6.86 kg/m2) (p<0001). On the external validation cohort, combination of low SFM and low MBM was pejorative with 63% of mortality at 1 year versus 25% (p=0.0029). CONCLUSIONS: 3D measured low SFM and MBM are significant prognosis factors of NSCLC treated by immune checkpoint inhibitors and can be combined to improve the prognostic value.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Melanoma , Animais , Humanos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Prognóstico , Estudos Retrospectivos , Melanoma/diagnóstico por imagem , Melanoma/tratamento farmacológico , Músculos , Inibidores de Checkpoint Imunológico , Imunoterapia
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