RESUMO
BACKGROUND: We explored potential predictive biomarkers of immunotherapy response in patients with extensive-stage small-cell lung cancer (ES-SCLC) treated with durvalumab (D) + tremelimumab (T) + etoposide-platinum (EP), D + EP, or EP in the randomized phase 3 CASPIAN trial. METHODS: 805 treatment-naïve patients with ES-SCLC were randomized (1:1:1) to receive D + T + EP, D + EP, or EP. The primary endpoint was overall survival (OS). Patients were required to provide an archived tumor tissue block (or ≥ 15 newly cut unstained slides) at screening, if these samples existed. After assessment for programmed cell death ligand-1 expression and tissue tumor mutational burden, residual tissue was used for additional molecular profiling including by RNA sequencing and immunohistochemistry. RESULTS: In 182 patients with transcriptional molecular subtyping, OS with D ± T + EP was numerically highest in the SCLC-inflamed subtype (n = 10, median 24.0 months). Patients derived benefit from immunotherapy across subtypes; thus, additional biomarkers were investigated. OS benefit with D ± T + EP versus EP was greater with high versus low CD8A expression/CD8 cell density by immunohistochemistry, but with no additional benefit with D + T + EP versus D + EP. OS benefit with D + T + EP versus D + EP was associated with high expression of CD4 (median 25.9 vs. 11.4 months) and antigen-presenting and processing machinery (25.9 vs. 14.6 months) and MHC I and II (23.6 vs. 17.3 months) gene signatures, and with higher MHC I expression by immunohistochemistry. CONCLUSIONS: These findings demonstrate the tumor microenvironment is important in mediating better outcomes with D ± T + EP in ES-SCLC, with canonical immune markers associated with hypothesized immunotherapy mechanisms of action defining patient subsets that respond to D ± T. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03043872.
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Biomarcadores Tumorais , Imunoterapia , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/terapia , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/mortalidade , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/metabolismo , Feminino , Masculino , Imunoterapia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pessoa de Meia-Idade , Idoso , Anticorpos Monoclonais/uso terapêutico , Resultado do Tratamento , Estadiamento de Neoplasias , Anticorpos Monoclonais Humanizados/uso terapêutico , Prognóstico , AdultoRESUMO
BACKGROUND: The Phase 1 CLOVER study (NCT03509012) assessed durvalumab in combination with concurrent chemoradiotherapy (cCRT) in patients with advanced solid tumors; we report results from the head and neck squamous cell carcinoma (HNSCC) cohort. METHODS: Patients with histologically/cytologically confirmed locally advanced HNSCC, eligible for definitive cCRT and not considered for primary surgery, received durvalumab plus cisplatin and concurrent external beam radiation. Objectives were to assess safety/tolerability and preliminary efficacy. RESULTS: Eight patients were enrolled. The most frequent any-cause adverse events (AEs) were nausea and radiation skin injury (each n = 5); most frequent grade 3/4 AEs were lymphopenia and stomatitis (each n = 3). No patients had dose-limiting toxicities. Objective response rate was 71.4% (5/7 patients; four complete responses, one partial response); disease control rate was 85.7% at 18 weeks and 83.3% at 48 weeks. CONCLUSIONS: Durvalumab plus cCRT was tolerable and active in patients with unresected, locally advanced HNSCC.
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Anticorpos Monoclonais , Neoplasias de Cabeça e Pescoço , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Neoplasias de Cabeça e Pescoço/terapia , Neoplasias de Cabeça e Pescoço/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodosRESUMO
INTRODUCTION: For patients with unresectable, stage III non-small-cell lung cancer (NSCLC), current standard of care is concurrent chemoradiotherapy (cCRT) followed by consolidation durvalumab. However, earlier initiation of durvalumab simultaneously with cCRT may increase antitumor activity relative to initiation after cCRT. The phase 1 CLOVER study (NCT03509012) evaluated durvalumab combined with cCRT in patients with advanced solid tumors; we report findings from the NSCLC cohort. METHODS: CLOVER comprised a dose-limiting toxicity (DLT) assessment part, followed by an expansion part. In the NSCLC cohort, patients with previously untreated, unresectable, stage III NSCLC were enrolled in three treatment arms: durvalumab every 4 weeks (Q4W) + cisplatin + etoposide + radiotherapy (Arm 1); durvalumab Q4W + carboplatin + paclitaxel + radiotherapy (Arm 2); or durvalumab Q4W + carboplatin or cisplatin + pemetrexed + radiotherapy (non-squamous histology only; Arm 3). Patients received durvalumab until disease progression or unacceptable toxicity. The primary endpoint was safety and tolerability. RESULTS: Sixty-four patients were enrolled: 21, 22, and 21 in Arms 1, 2, and 3, respectively. One patient in Arm 1 had DLT (grade 3 aspartate aminotransferase increase and grade 4 alanine aminotransferase increase); no DLTs were observed in Arms 2 or 3. Grade 3/4 adverse events occurred in 76.6 % of patients overall; the most common were neutropenia (51.6 %), leukopenia (20.3 %), and anemia (17.2 %). In a post-hoc analysis, 7.8 % of patients had grade 3 pneumonitis/radiation pneumonitis (grouped term) events. Overall, the objective response rate was 60.9 % (95 % confidence interval [CI], 47.9-72.9); median duration of response was 15.8 months (95 % CI, 9.0-not estimable [NE]). Median progression-free survival was 13.4 months (95 % CI, 8.8-20.1) and median overall survival was not reached (95 % CI, 21.9-NE). CONCLUSION: Durvalumab in combination with cCRT was well tolerated, with a manageable safety profile and showed encouraging antitumor activity in patients with unresectable, stage III NSCLC.
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Anticorpos Monoclonais , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Cisplatino/uso terapêutico , Carboplatina , Paclitaxel , Quimiorradioterapia/métodos , Estadiamento de NeoplasiasRESUMO
Aim: We retrospectively investigated the impact of tumor PD-L1 expression and prior chemoradiotherapy (CRT)-related variables on patient-reported outcomes (PROs) from PACIFIC. Patients & methods: PACIFIC was a Phase III study of durvalumab versus placebo after CRT in patients with unresectable, stage III non-small-cell lung cancer. If available, pre-CRT tumor tissue was tested for PD-L1 tumor-cell expression, scored at prespecified (25%) and post-hoc (1%) cut-offs. PROs were assessed using EORTC QLQ C30/-LC13. Results: Similar to the intent-to-treat (ITT) population, most PROs remained stable over time across PD-L1 and CRT subgroups, with few clinically relevant differences between treatment arms. Time to deterioration was generally similar to the ITT population. Conclusion: Neither PD-L1 expression nor prior CRT-related variables influenced PROs with durvalumab therapy. Clinical trial registration: NCT02125461 (ClinicalTrials.gov).
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Anticorpos Monoclonais/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Carcinoma Pulmonar de Células não Pequenas/etiologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/mortalidade , Masculino , Terapia de Alvo Molecular , Estadiamento de Neoplasias , Medidas de Resultados Relatados pelo Paciente , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: The risk of serious infectious events (SIEs) is increased in patients with rheumatoid arthritis (RA). The aim of this study was to develop an age-adjusted comorbidity index (AACI) to predict, using baseline characteristics, the SIE risk in patients with RA treated with certolizumab pegol (CZP). METHODS: Data of CZP-treated patients with RA were pooled from the RAPID1/RAPID2 randomized controlled trials (RCT CZP) and their open-label extensions (All CZP). Predictors of the first SIE were examined using multivariate Cox models. The AACI was developed by assigning specific weights to patient age and comorbidities on the basis of relative SIE risk. SIE rates were predicted using AACI score and baseline glucocorticoid use, and they were compared with observed rates. The percentage of patients in each SIE risk group achieving low disease activity (LDA)/remission was examined at 1 year of treatment. RESULTS: Among 1224 RCT CZP patients, 40 reported ≥ 1 SIE (incidence rate [IR] 5.09/100 patient-years [PY]), and 201 of 1506 All CZP patients reported ≥ 1 SIE (IR 3.66/100 PY). Age ≥ 70 years, diabetes mellitus, and chronic obstructive pulmonary disease/asthma made the greatest contributions to AACI score. SIE rates predicted using AACI and glucocorticoid use at baseline showed good agreement with observed SIE rates across low-risk and high-risk groups. At 1 year, more high-risk All CZP patients than low-risk All CZP patients reported SIEs (IR 8.4/100 PY vs. IR 3.4/100 PY). Rates of LDA/remission were similar between groups. CONCLUSIONS: AACI and glucocorticoid use were strong baseline predictors of SIE risk in CZP-treated patients with RA. Predicted SIE risk was not associated with patients' likelihood of clinical response. This SIE risk score may provide a valuable tool for clinicians when considering the risk of infection in individual patients with RA. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00152386 (registered 7 September 2005); NCT00160602 (registered 8 September 2005); NCT00175877 (registered 9 September 2005); and NCT00160641 (registered 8 September 2005).
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Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Certolizumab Pegol/efeitos adversos , Infecções/epidemiologia , Infecções/etiologia , Adulto , Artrite Reumatoide/complicações , Comorbidade , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores de RiscoRESUMO
BACKGROUND: Comorbidities may contribute to disease activity and treatment response in rheumatoid arthritis (RA) patients. We defined a somatization comorbidity phenotype (SCP) and examined its influence on response to certolizumab pegol (CZP) using data from the PREDICT trial. METHODS: Patients in PREDICT were randomized to the patient-reported Routine Assessment of Patient Index Data 3 (RAPID3) or physician-based Clinical Disease Activity Index (CDAI) for treatment response assessment. Post-hoc analyses identified patients with the SCP, which included diagnosis of depression, fibromyalgia/myalgias, and/or use of medications indicated for treatment of depression, anxiety, or neuropathic pain. The effect of the SCP on RAPID3 or CDAI response at week 12 and low disease activity (LDA; Disease Activity Score in 28 joints based on erythrocyte sedimentation rate ≤ 3.2) at week 52, in week-12 responders, was analyzed using non-parametric analysis of covariance (ANCOVA). RESULTS: At baseline, 43% (313/733) of patients met the SCP classification. Patients with the SCP were 9% more likely to withdraw from the trial. American College of Rheumatology 20% (ACR20), ACR50, and ACR70 responses were 5-14% lower among those with the SCP, and 11% more patients reported adverse events (AEs). Patients without SCP in the CDAI arm were twice as likely to achieve LDA at week 52 compared with those with SCP (32% versus 16%). No differentiation by SCP was observed in the RAPID3 arm (pooled result 21.5%). CONCLUSIONS: We operationalized a potentially important somatization comorbidity phenotype in a trial setting that was associated with a substantially lower likelihood of treatment response and a higher frequency of AEs. Including large numbers of patients with this phenotype in RA trials may reduce the measured clinical effectiveness of a new molecule. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01255761 . Registered on 6 December 2010.
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Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Certolizumab Pegol/uso terapêutico , Adulto , Idoso , Artrite Reumatoide/epidemiologia , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Resultado do TratamentoRESUMO
Soliciting a patient's agenda (the reason for their visit, concerns and expectations) is fundamental to health care but if not done effectively outcomes can be adversely affected. Forms to help patients consider important issues prior to a consultation have been tested with mixed results. We hypothesized that using an agenda form would impact the extent to which patients felt their doctor discussed the issues that were important to them. Patients were randomized to receive an agenda form to complete whilst waiting or usual care. The primary outcome measure was the proportion of patients agreeing with the statement 'My doctor discussed the issues that were important to me' rated on a four-point scale. Secondary outcomes included other experience and satisfaction measures, consultation duration and patient confidence. There was no significant effect of agenda form use on primary or secondary outcomes. Post hoc exploratory analyses suggested possible differential effects for new compared to follow-up patients. There was no overall benefit from the form and a risk of detrimental impact on patient experience for some patients. There is a need for greater understanding of what works for whom in supporting patients to get the most from their consultation.
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Assistência Ambulatorial/métodos , Asma/terapia , Doenças Pulmonares Intersticiais/terapia , Planejamento de Assistência ao Paciente , Participação do Paciente/métodos , Satisfação do Paciente , Doença Pulmonar Obstrutiva Crônica/terapia , Infecções Respiratórias/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Agendamento de Consultas , Atitude do Pessoal de Saúde , Humanos , Pessoa de Meia-Idade , Pneumologia/métodosRESUMO
BACKGROUND: Neuropathic pain remains one of the most challenging pain syndromes; under-diagnosed, poorly managed and associated with significant co-morbidity. With standard therapeutic treatments, responders rarely exceed 50% pain relief and the majority suffer from residual pain. Titration to optimum dose is often limited by dose-related adverse events. AIMS: This randomized, double-blind, placebo-controlled study assessed the potential benefit of adding oxycodone (OxyContin tablets) to gabapentin. The primary endpoint was to evaluate the analgesic efficacy of co-administration of gabapentin and prolonged-release oxycodone, whilst also evaluating the use of escape medication, sleep quality and global assessment of pain. METHODS: Three hundred and thirty eight patients with moderate to severe painful diabetic neuropathy despite receiving their maximum tolerated dose of gabapentin, had oral prolonged-release oxycodone or placebo tablets added to their therapy for up to 12 weeks. RESULTS: Oxycodone-gabapentin reduced pain score by 33% from baseline to end of treatment. The overall treatment effect was greater with oxycodone-gabapentin than with placebo-gabapentin (P = 0.007). Oxycodone-gabapentin also significantly improved pain relief vs gabapentin alone (P = 0.003). Oxycodone-gabapentin co-administration was associated with less escape medication use (P = 0.03) and fewer nights of disturbed sleep (P < 0.05). Discontinuations due to lack of therapeutic effect were much lower (14% vs 54%) with oxycodone-gabapentin. The commonly seen opiate-induced adverse events were not exacerbated by the combination of oxycodone and gabapentin. CONCLUSIONS: This study provides the first evidence that co-administration of prolonged-release oxycodone and existing gabapentin therapy has a clinically meaningful effect in painful diabetic neuropathy.