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1.
Am J Hematol ; 95(4): 362-371, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31868245

RESUMO

Safety profiles of oral PI3K inhibitors have resulted in US FDA black box warnings regarding fatal/serious toxicities. The approved intravenous PI3K inhibitor copanlisib has low incidence of severe toxicities and no black box warnings, but chronic treatment effects were unknown. We provide an update on safety and efficacy of copanlisib with a minimum 2-year follow-up of the CHRONOS-1 study. A total of 142 patients with histologically confirmed indolent B-cell lymphoma who had relapsed after or were refractory to ≥2 prior treatments received intravenous copanlisib 60 mg on days 1, 8, and 15 (28-day cycle). The primary efficacy endpoint was objective response rate (ORR) after ≥4 cycles (independent assessment). The predominant histology was follicular lymphoma (n = 104). The ORR was 60.6% (seven additional complete responses since primary analysis). Secondary endpoints of median duration of response, progression-free survival, and overall survival were 14.1 months (median follow-up, 16.1 months), 12.5 months (median follow-up, 14.0 months), and 42.6 months (median follow-up, 31.5 months), respectively. Median safety follow-up was 6.7 months; 26% of patients received treatment for >1 year. Common treatment-emergent adverse events (TEAEs) (all grade/grade 3/grade 4) were transient hyperglycemia (50.0%/33.1%/7.0%), diarrhea (35.2%/8.5%/0%), transient hypertension (29.6%/23.9%/0%), and neutropenia (28.9%/9.2%/14.8%). Serious AEs were largely unchanged, with no new cases of pneumonitis (4.2%), diarrhea (2.8%), or grade 5 events. Note, TEAEs showed no evidence for increased incidence or worsening following longer exposure in patients treated >1 year. Long-term follow-up of patients with relapsed/refractory indolent B-cell lymphoma treated with intravenous copanlisib demonstrated durable, enhanced responses without evidence of worsening TEAEs, as reported for orally administered PI3K inhibitors.


Assuntos
Linfoma de Células B/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Pirimidinas/uso terapêutico , Quinazolinas/uso terapêutico , Terapia de Salvação , Adulto , Idoso , Idoso de 80 Anos ou mais , Aloenxertos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos Fase II como Assunto/estatística & dados numéricos , Terapia Combinada , Diarreia/induzido quimicamente , Esquema de Medicação , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Humanos , Hiperglicemia/induzido quimicamente , Hipertensão/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Neutropenia/induzido quimicamente , Inibidores de Fosfoinositídeo-3 Quinase/efeitos adversos , Intervalo Livre de Progressão , Pirimidinas/efeitos adversos , Quinazolinas/efeitos adversos , Terapia de Salvação/efeitos adversos , Análise de Sobrevida , Transplante Autólogo , Resultado do Tratamento
2.
Blood Adv ; 5(3): 823-828, 2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33560394

RESUMO

Marginal zone lymphoma (MZL) is challenging to treat, with many patients relapsing following initial treatment. We report the long-term efficacy and safety of copanlisib, a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, in the subset of 23 patients with relapsed/refractory MZL treated in the phase 2 CHRONOS-1 study (#NCT01660451, Part B; www.clinicaltrials.gov). Patients had a median of 3 prior lines of therapy, including rituximab and alkylating agents, and received IV copanlisib 60 mg on days 1, 8, and 15 of 28-day cycles for a median of 23 weeks. The objective response rate was 78.3% (18/23; 3 complete responses and 15 partial responses). The median duration of response was 17.4 months (median follow-up, 9.4 months), and median time to response was 2.1 months. Median progression-free survival was 24.1 months (median follow-up, 10.3 months), and median overall survival was not reached (median follow-up, 28.4 months). The most common all-grade treatment-emergent adverse events (TEAEs) included fatigue (52.2%, 12/23), diarrhea, and transient, infusion-related hyperglycemia (each 47.8%, 11/23). Nineteen patients (82.6%) had grade 3/4 TEAEs, most commonly transient, infusion-related hyperglycemia and hypertension (each 39.1%, 9/23). TEAEs led to dose reduction or dose interruptions /delays in 9 patients (39.1%) and 18 patients (78.3%), respectively. Patients with activated PI3K/B-cell antigen receptor signaling had improved response rates. Overall, copanlisib demonstrated strong efficacy, with a short time to objective response, improved objective response rate with longer treatment duration, durable responses, and manageable safety, in line with previous reports. These data provide rationale for long-term treatment with copanlisib in patients with relapsed/refractory MZL.


Assuntos
Linfoma de Zona Marginal Tipo Células B , Humanos , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Recidiva Local de Neoplasia , Fosfatidilinositol 3-Quinases , Pirimidinas , Quinazolinas
3.
Clin Cancer Res ; 25(19): 5832-5842, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31300450

RESUMO

PURPOSE: RET is an emerging oncogenic target showing promise in phase I/II clinical trials. An understudied aspect of RET-driven cancers is the extent to which co-occurring genomic alterations exist and how they may impact prognosis or therapeutic response. EXPERIMENTAL DESIGN: Somatic activating RET alterations were identified among 32,989 consecutive patients with metastatic solid tumors tested with a clinical cell-free circulating tumor DNA (cfDNA) assay. This comprehensive next-generation sequencing (NGS) assay evaluates single-nucleotide variants, and select indels, fusions, and copy number gains in 68-73 clinically relevant cancer genes. RESULTS: A total of 176 somatic activating RET alterations were detected in 170 patients (143 fusions and 33 missense mutations). Patients had non-small cell lung (NSCLC, n = 125), colorectal (n = 15), breast (n = 8), thyroid (n = 8), or other (n = 14) cancers. Alterations in other oncogenic signaling pathway genes were frequently identified in RET-positive samples and varied by specific RET fusion gene partner. RET fusions involving partners other than KIF5B were enriched for alterations in MAPK pathway genes and other bona fide oncogenic drivers of NSCLC, particularly EGFR. Molecular and clinical data revealed that these variants emerged later in the genomic evolution of the tumor as mechanisms of resistance to EGFR tyrosine kinase inhibitors. CONCLUSIONS: In the largest cancer cohort with somatic activating RET alterations, we describe novel co-occurrences of oncogenic signaling pathway aberrations. We find that KIF5B-RET fusions are highly specific for NSCLC. In our study, only non-KIF5B-RET fusions contributed to anti-EGFR therapy resistance. Knowledge of specific RET fusion gene partner may have clinical significance.


Assuntos
DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , Mutação , Neoplasias/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-ret/genética , Estudos de Coortes , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Estadiamento de Neoplasias , Neoplasias/sangue , Neoplasias/patologia , Oncogenes , Prognóstico , Proteínas Proto-Oncogênicas c-ret/metabolismo , Transdução de Sinais
4.
J Clin Oncol ; 35(5): 490-497, 2017 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-28029303

RESUMO

Purpose Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is treatment-responsive. Definitive chemoradiation results in high cure rates but causes long-term toxicity and may represent overtreatment of some patients. This phase II trial evaluated whether complete clinical response (cCR) to induction chemotherapy (IC) could select patients with HPV-associated OPSCC for reduced radiation dose as a means of sparing late sequelae. Methods Patients with HPV16 and/or p16-positive, stage III-IV OPSCC received three cycles of IC with cisplatin, paclitaxel, and cetuximab. Patients with primary-site cCR to IC received intensity-modulated radiation therapy (IMRT) 54 Gy with weekly cetuximab; those with less than cCR to IC at the primary site or nodes received 69.3 Gy and cetuximab to those regions. The primary end point was 2-year progression-free survival. Results Of the 90 patients enrolled, 80 were evaluable. Their median age was 57 years (range, 35 to 73 years), with the majority having stage T1-3N0-N2b OPSCC and a history of ≤ 10 pack-years of cigarette smoking. Three cycles of IC were delivered to 77 of the 80 patients. Fifty-six patients (70%) achieved a primary-site cCR to IC and 51 patients continued to cetuximab with IMRT 54 Gy. After median follow-up of 35.4 months, 2-year progression-free survival and overall survival rates were 80% and 94%, respectively, for patients with primary-site cCR treated with 54 Gy of radiation (n = 51); 96% and 96%, respectively, for patients with < T4, < N2c, and ≤ 10 pack-year smoking history who were treated with ≤ 54 Gy of radiation (n = 27). At 12 months, significantly fewer patients treated with a radiation dose ≤ 54 Gy had difficulty swallowing solids (40% v 89%; P = .011) or had impaired nutrition (10% v 44%; P = .025). Conclusion For IC responders, reduced-dose IMRT with concurrent cetuximab is worthy of further study in favorable-risk patients with HPV-associated OPSCC. Radiation dose reduction resulted in significantly improved swallowing and nutritional status.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/terapia , Neoplasias Orofaríngeas/terapia , Dosagem Radioterapêutica , Adulto , Idoso , Carcinoma de Células Escamosas/complicações , Cetuximab/administração & dosagem , Quimiorradioterapia/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Exantema/etiologia , Feminino , Papillomavirus Humano 16/fisiologia , Humanos , Quimioterapia de Indução/métodos , Masculino , Pessoa de Meia-Idade , Neutropenia/etiologia , Neoplasias Orofaríngeas/complicações , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Indução de Remissão
5.
J Clin Oncol ; 35(35): 3898-3905, 2017 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-28976790

RESUMO

Purpose Phosphatidylinositol 3-kinase (PI3K) signaling is critical for the proliferation and survival of malignant B cells. Copanlisib, a pan-class I PI3K inhibitor with predominant activity against PI3K-α and -δ isoforms, has demonstrated efficacy and a manageable safety profile in patients with indolent lymphoma. Patients and Methods In this phase II study, 142 patients with relapsed or refractory indolent lymphoma after two or more lines of therapy were enrolled to receive copanlisib 60 mg intravenously on days 1, 8, and 15 of a 28-day cycle. The primary end point was objective response rate; secondary end points included duration of response, progression-free survival, and overall survival. In addition, safety and gene expression were evaluated. Results Median age was 63 years (range, 25 to 82 years), and patients had received a median of three (range, two to nine) prior regimens. The objective response rate was 59% (84 of 142 patients); 12% of patients achieved a complete response. Median time to response was 53 days. Median duration of response was 22.6 months, median progression-free survival was 11.2 months, and median overall survival had not yet been reached. The most frequent treatment-emergent adverse events were transient hyperglycemia (all grades, 50%; grade 3 or 4, 41%) and transient hypertension (all grades, 30%; grade 3, 24%). Other grade ≥3 events included decreased neutrophil count (24%) and lung infection (15%). High response rates to copanlisib were associated with high expression of PI3K/B-cell receptor signaling pathway genes. Conclusion PI3K-α and -δ inhibition by copanlisib demonstrated significant efficacy and a manageable safety profile in heavily pretreated patients with relapsed or refractory indolent lymphoma.


Assuntos
Linfoma de Células B/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Quinazolinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Isoenzimas , Linfoma de Células B/enzimologia , Linfoma de Células B/genética , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Quinazolinas/efeitos adversos , Transcriptoma
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