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1.
Clin Cancer Res ; 30(1): 74-81, 2024 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-37535056

RESUMO

PURPOSE: Disease progression during or after anti-PD-1-based treatment is common in advanced melanoma. Sotigalimab is a CD40 agonist antibody with a unique epitope specificity and Fc receptor binding profile optimized for activation of CD40-expressing antigen-presenting cells. Preclinical data indicated that CD40 agonists combined with anti-PD1 could overcome resistance to anti-PD-1. PATIENTS AND METHODS: We conducted a multicenter, open-label, phase II trial to evaluate the combination of sotigalimab 0.3 mg/kg and nivolumab 360 mg every 3 weeks in patients with advanced melanoma following confirmed disease progression on a PD-1 inhibitor. The primary objective was to determine the objective response rate (ORR). RESULTS: Thirty-eight subjects were enrolled and evaluable for safety. Thirty-three were evaluable for activity. Five confirmed partial responses (PR) were observed for an ORR of 15%. Two PRs are ongoing at 45.9+ and 26+ months, whereas the other three responders relapsed at 41.1, 18.7, and 18.4 months. The median duration of response was at least 26 months. Two additional patients had stable disease for >6 months. Thirty-four patients (89%) experienced at least one adverse event (AE), and 13% experienced a grade 3 AE related to sotigalimab. The most common AEs were pyrexia, chills, nausea, fatigue, pruritus, elevated liver function, rash, vomiting, headache, arthralgia, asthenia, myalgia, and diarrhea. There were no treatment-related SAEs, deaths, or discontinuation of sotigalimab due to AEs. CONCLUSIONS: Sotigalimab plus nivolumab had a favorable safety profile consistent with the toxicity profiles of each agent. The combination resulted in durable and prolonged responses in a subset of patients with anti-PD-1-resistant melanoma, warranting further evaluation in this setting. See related commentary by Wu and Luke, p. 9.


Assuntos
Melanoma , Nivolumabe , Humanos , Nivolumabe/efeitos adversos , Melanoma/patologia , Anticorpos Monoclonais/efeitos adversos , Progressão da Doença , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
2.
J Thorac Oncol ; 7(6): 1041-8, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22534814

RESUMO

INTRODUCTION: Pralatrexate, a folate analogue targeting dihydrofolate reductase, has antitumor activity in non-small-cell lung cancer (NSCLC). This randomized phase 2b trial was designed to further evaluate pralatrexate activity in NSCLC by estimating overall survival (OS) relative to erlotinib in patients with relapsed/refractory disease. METHODS: In 43 centers across 6 countries, patients were randomized 1:1 to receive intravenous pralatrexate 190 mg/m on days 1 and 15 of a 28-day cycle, or oral erlotinib 150 mg/day. The primary objective was to estimate OS in all patients and prespecified subgroups using relative comparisons of hazard ratios (HRs). Secondary endpoints included progression-free survival, response rate, and safety. Key eligibility criteria included: (1) ≥1 prior platinum-based therapy, (2) Eastern Cooperative Oncology Group performance status of 0 to 1, and 3) a smoking history of 100 cigarettes or more. RESULTS: A total of 201 patients were randomized. A trend toward improvement in OS favoring pralatrexate was observed with an HR of 0.84 (95% confidence interval: 0.61-1.14) in the intent-to-treat population. This favorable survival result was seen in most prespecified subgroups for pralatrexate. The largest reduction in the risk of death was observed in patients with nonsquamous cell carcinoma (n = 107; HR = 0.65; 95% confidence interval: 0.42-1.0). The most common grade 3 to 4 adverse event in the pralatrexate arm was mucositis (23%). Discontinuation of pralatrexate for any grade of mucositis was 21%. CONCLUSIONS: Pralatrexate demonstrated a trend toward improved survival relative to erlotinib in patients with advanced NSCLC. Future studies should include a mucositis management plan to improve tolerability and maximize treatment benefit.


Assuntos
Aminopterina/análogos & derivados , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Estadiamento de Neoplasias , Platina/uso terapêutico , Quinazolinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminopterina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib , Feminino , Antagonistas do Ácido Fólico , Seguimentos , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/administração & dosagem , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Falha de Tratamento , Estados Unidos/epidemiologia
3.
Clin Lung Cancer ; 13(1): 31-8, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21862415

RESUMO

INTRODUCTION: This open-label phase II study assessed the efficacy and tolerability of eribulin, a non-taxane microtubule dynamics inhibitor with novel mechanism of action, as monotherapy in patients who have advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Enrolled patients had progressed during or after platinum-based doublet chemotherapy. Initially, two patient cohorts (taxane-pre-treated and taxane-naïve) received eribulin mesylate (1.4 mg/m(2)) as a 2- to 5-minute intravenous infusion on days 1, 8, and 15 of a 28-day cycle. To assess tolerability of a second dosing schedule, a cohort of taxane-pre-treated patients received eribulin on days 1 and 8 of a 21-day cycle. The primary endpoint was objective response rate (ORR) evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) by independent radiographic review. RESULTS: One hundred three patients received eribulin. The ORR was 9.7% (all partial responses [PR]). Overall disease control rate (PR + stable disease) was 55.3%. Median duration of response, progression-free survival, and overall survival were 5.8, 3.4, and 9.4 months, respectively. The most common drug-related adverse events were neutropenia (54%; 49% grade 3/4); fatigue (49%; 11% grade 3, no grade 4); nausea (38%; 1% grade 3, no grade 4); alopecia (32%); anemia (29%, 4% grade 3/4) and neuropathy (23%; 2% grade 3, no grade 4). The 28-day schedule was associated with many dose delays, interruptions, or omissions due to neutropenia (day 15). The 21-day cycle was well-tolerated. CONCLUSIONS: Eribulin monotherapy administered on days 1 and 8 of a 21-day cycle is active and tolerated as second- or later-line chemotherapy for NSCLC.


Assuntos
Adenocarcinoma/tratamento farmacológico , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Furanos/uso terapêutico , Cetonas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Salvação , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Grandes/mortalidade , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma de Células Escamosas/mortalidade , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Taxa de Sobrevida , Resultado do Tratamento
4.
J Clin Oncol ; 28(6): 911-7, 2010 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-20100966

RESUMO

PURPOSE To evaluate the efficacy of cetuximab plus taxane/carboplatin (TC) as first-line treatment of advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS This multicenter, open-label, phase III study enrolled 676 chemotherapy-naïve patients with stage IIIB (pleural effusion) or IV NSCLC, without restrictions by histology or epidermal growth factor receptor expression. Patients were randomly assigned to cetuximab/TC or TC. TC consisted of paclitaxel (225 mg/m(2)) or docetaxel (75 mg/m(2)), at the investigator's discretion, and carboplatin (area under the curve = 6) on day 1 every 3 weeks for < or = six cycles; cetuximab (400 mg/m(2) on day 1, 250 mg/m(2) weekly) was administered until progression or unacceptable toxicity. The primary end point was progression-free survival assessed by independent radiologic review committee (PFS-IRRC); overall response rate (ORR), overall survival (OS), quality of life (QoL), and safety were key secondary end points. PFS and ORR assessed by investigators were also evaluated. Results Median PFS-IRRC was 4.40 months with cetuximab/TC versus 4.24 months with TC (hazard ratio [HR] = 0.902; 95% CI, 0.761 to 1.069; P = .236). Median OS was 9.69 months with cetuximab/TC versus 8.38 months with TC (HR = 0.890; 95% CI, 0.754 to 1.051; P = .169). ORR-IRRC was 25.7% with cetuximab/TC versus 17.2% with TC (P = .007). The safety profile of this combination was manageable and consistent with its individual components. CONCLUSION The addition of cetuximab to TC did not significantly improve the primary end point, PFS-IRRC. There was significant improvement in ORR by IRRC. The difference in OS favored cetuximab but did not reach statistical significance.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Cetuximab , Docetaxel , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Prognóstico , Taxa de Sobrevida , Taxoides/administração & dosagem , Resultado do Tratamento
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