RESUMEN
BACKGROUND: The long-term impact of tyrosine kinase inhibitor (TKI) discontinuation on resistance and survival in patients with advanced gastrointestinal stromal tumours (GIST) is unclear. We report the exploratory long-term outcomes of patients with advanced GIST stopping imatinib in the BFR14 trial. METHODS: BFR14, an open-label, randomised, phase 3 trial, was done in 17 comprehensive cancer centres or hospitals across France. Patients with advanced GIST aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-3, no previous treatment with imatinib, and no previous malignancy were eligible. Patients were treated with oral imatinib 400 mg daily. Patients with a complete or partial response, or stable disease, according to Response Evaluation Criteria in Solid Tumours (1.0) at 1 year, 3 years, and 5 years from the start of treatment were randomly assigned (1:1) to treatment discontinuation until progression (interruption group) or treatment continuation until progression (continuation group). Randomisation was done centrally with computer-generated permuted blocks of two and six patients stratified by participating centre and presence or absence of residual disease on CT scan. The primary endpoint was progression-free survival. Secondary endpoints included time to imatinib resistance and overall survival. Analyses were conducted on an intention-to-treat basis in all randomly assigned patients who were not lost to follow-up. This trial is registered with ClinicalTrial.gov, NCT00367861. FINDINGS: Between May 12, 2003, and March 16, 2004, after 1 year of imatinib, 32 patients were randomly assigned to the interruption group and 26 to the continuation group. Between June 13, 2005, and May 30, 2007, after 3 years of imatinib, 25 patients were randomly assigned to the interruption group and 25 to the continuation group. Between Nov 9, 2007, and July 12, 2010, after 5 years of imatinib, 14 patients were randomly assigned to the interruption group and 13 to the continuation group. Median follow-up was 235·2 months (IQR 128·8-236·6) after the 1-year randomisation, 200·9 months (190·2-208·4) after the 3-year randomisation, and 164·5 months (134·4-176·4) after the 5-year randomisation. Median progression-free survival in the interruption group versus the continuation group after 1 year of imatinib was 6·1 months (95% CI 2·5-10·1) versus 27·8 months (19·5-37·9; hazard ratio [HR] 0·36 [95% CI 0·20-0·64], log-rank p=0·0003), after 3 years of imatinib was 7·0 months (3·5-11·7) versus 67·0 months (48·8-85·6; 0·15 [0·07-0·32], log-rank p<0·0001), and after 5 years of imatinib was 12·0 months (9·0-16·6) versus not reached (NR; NR-NR; 0·13 [0·03-0·58], log-rank p=0·0016). The median time to imatinib resistance after 1 year of imatinib was 28·7 months (95% CI 18·1-39·1) versus 90·6 months (25·3-156·1; HR 0·93 [95% CI 0·51-1·71], log-rank p=0·82), after 3 years was 66·2 months (43·0-89·6) versus 127·3 months (15·0-239·7; 0·35 [0·17-0·72, log-rank p=0·0028), and after 5 years was 58·6 months (0·0-167·4) versus NR (NR-NR; 0·24 [0·05-1·12], log-rank p=0·049). Median overall survival after 1 year of imatinib was 56·0 months (95% CI 30·3-82·9) versus 105·0 months (20·6-189·6; HR 0·84 [95% CI 0·46-1·54], log-rank p=0·57), after 3 years was 104·0 months (90·7-118·7) versus 134·0 months (89·7-178·3; 0·40 [0·20-0·82], log-rank p=0·0096), and after 5 years was NR (NR-NR) versus 110·4 months (82·7-154·1; 1·28 [0·41-3·99]; log-rank p=0·67), INTERPRETATION: Imatinib interruption in patients with GIST without progressive disease is not recommended. Imatinib interruption in non-progressing patients with GIST was associated with rapid progression, faster resistance to imatinib, and shorter overall survival in the long-term follow-up when compared with imatinib continuation in patients after 3 years and 5 years of imatinib. FUNDING: Centre Léon Bérard, INCa, CONTICANET, Ligue Contre le Cancer, and Novartis.
Asunto(s)
Tumores del Estroma Gastrointestinal , Mesilato de Imatinib , Inhibidores de Proteínas Quinasas , Humanos , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/patología , Tumores del Estroma Gastrointestinal/mortalidad , Mesilato de Imatinib/administración & dosificación , Mesilato de Imatinib/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios de Seguimiento , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Francia , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/patología , Neoplasias Gastrointestinales/mortalidad , Supervivencia sin Progresión , Adulto , Factores de Tiempo , Resistencia a Antineoplásicos , Privación de Tratamiento/estadística & datos numéricos , Esquema de MedicaciónRESUMEN
RATIONALE: We report a phase II trial (OSAD93) testing CDDP with ifosfamide (IFO), without doxorubicin in neoadjuvant phase, in adult osteosarcoma with a 25 years follow-up. PATIENTS AND METHODS: This is a multicentric phase II study of neoadjuvant chemotherapy with IFO and CDDP in localized high-grade osteosarcoma of patients. Patients received 4 pre-operative courses of IFO 9 g/m2 and CDDP 100 mg/m2 on day 4 (SHOC regimen), followed by local treatment. Doxorubicin was added post-operatively (HOCA regimen) in patients with > 10 % residual tumor cells. A Good Histological Response (GHR), ie ≤ 10 % residual tumor cells in > 30 % of patients, was the primary objective. Disease-free survival (DFS), overall survival (OS) and toxicity were secondary objectives. RESULTS: From Jan 1994 to Jun 1998, 60 patients were included. Median age was 27 (range: 16-63). Primary tumor sites were limbs (76 %), trunk, head or neck (24 %). After neoadjuvant SHOC, grade 3-4 and febrile neutropenia, thrombopenia, and re-hospitalization occurred in 58 %, 17 %, 17 % and 22 % of SHOC courses and in 76 %, 28 %, 47 %, 47 % of HOCA courses, respectively. GHR was obtained in 16/60 (27.5 %) patients. With a median follow-up of 322 months, the DFS and OS were 51.8 % and 64.4 % at 5 years. At 10 years, DFS and OS were 49.9 % and 64.4 %. At 25 years, DFS and OS were 47.8 % and 55.9 %. No long-term cardiac toxicity was observed. Three patients developed a second malignancy (one fatal) after 300 months. CONCLUSION: Though the primary endpoint of OSAD93 was not met, this pre-operative doxorubicin-free regimen led to excellent long-term survival with limited toxicity in localized osteosarcoma.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Óseas , Ifosfamida , Osteosarcoma , Humanos , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/mortalidad , Osteosarcoma/patología , Adulto , Masculino , Femenino , Persona de Mediana Edad , Adulto Joven , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Ifosfamida/administración & dosificación , Ifosfamida/efectos adversos , Ifosfamida/uso terapéutico , Terapia Neoadyuvante/efectos adversos , Terapia Neoadyuvante/mortalidad , Cisplatino/administración & dosificación , Cisplatino/uso terapéutico , Cisplatino/efectos adversos , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Doxorrubicina/uso terapéutico , Supervivencia sin Enfermedad , Estudios de SeguimientoRESUMEN
BACKGROUND: ABBV-184, a novel survivin peptide-targeting T-cell receptor (TCR)/anti-CD3 bispecific protein, demonstrated preclinical T-cell activation and cytotoxicity toward HLA-A2:01-positive tumor lines. This first-in-human trial evaluated ABBV-184 monotherapy in patients with acute myeloid leukemia (AML) and non-small cell lung cancer (NSCLC). RESEARCH DESIGN AND METHODS: This phase 1 multicenter, open-label, dose escalation trial (NCT04272203) enrolled adult patients with relapsed/refractory AML or NSCLC with an HLA-A2:01 restricted genotype. Patients received ABBV-184 at 0.07 ug/kg initially, with 2- to 3-fold dose increases. The primary objective was determining the ABBV-184 recommended phase 2 dose. Secondary objectives included safety, tolerability, pharmacokinetics, and immunogenicity assessments. RESULTS: Fifteen patients enrolled in the dose escalation (8 AML and 7 NSCLC). ABBV-184 doses ranged from 0.07 mg/kg-0.7 µg/kg, with a half-life of approximately 13-29 hours. Transient cytokine increases were observed at all dose levels, and in patients with NSCLC, transient peripheral blood lymphocyte decreases were observed. The most frequently reported treatment-emergent adverse events (TEAEs) were anemia, diarrhea, and headache. Grade 1-2 infusion-related reaction (IRR) and cytokine release syndrome (CRS) TEAEs were reported. CONCLUSIONS: ABBV-184 was well tolerated and demonstrated preliminary evidence of CD3 engagement with transient cytokine increases and peripheral lymphocyte decreases. CLINICAL TRIAL REGISTRATION: NCT04272203.
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Anticuerpos Biespecíficos , Complejo CD3 , Carcinoma de Pulmón de Células no Pequeñas , Relación Dosis-Respuesta a Droga , Leucemia Mieloide Aguda , Neoplasias Pulmonares , Receptores de Antígenos de Linfocitos T , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Persona de Mediana Edad , Masculino , Anticuerpos Biespecíficos/administración & dosificación , Anticuerpos Biespecíficos/efectos adversos , Anticuerpos Biespecíficos/farmacología , Anciano , Femenino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/inmunología , Adulto , Antígeno HLA-A2RESUMEN
BACKGROUND: Novel treatments are needed for patients with advanced, triple-negative breast cancer (TNBC) that progresses or recurs after first-line treatment with chemotherapy. The authors report results from the TNBC cohort of the multicohort, open-label, single-arm, phase 2 LEAP-005 study of lenvatinib plus pembrolizumab in patients with advanced solid tumors (ClinicalTrials.gov identifier NCT03797326). METHODS: Eligible patients had metastatic or unresectable TNBC with disease progression after one or two lines of therapy. Patients received lenvatinib (20 mg daily) plus pembrolizumab (200 mg every 3 weeks; up to 35 cycles). The primary end points were the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1, and safety (adverse events graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0). Duration of response, progression-free survival, and overall survival were secondary end points. RESULTS: Thirty-one patients were enrolled. The objective response rate by investigator assessment was 23% (95% confidence interval [CI], 10%-41%). Overall, the objective response rate by blinded independent central review (BICR) was 32% (95% CI, 17%-51%); and, in patients who had programmed cell death ligand 1 combined positive scores ≥10 (n = 8) and <10 (n = 22), the objective response rate was 50% (95% CI, 16%-84%) and 27% (95% CI, 11%-50%), respectively. The median duration of response by BICR was 12.1 months (range, from 3.0+ to 37.9+ months). The median progression-free survival by BICR was 5.1 months (95% CI, 1.9-11.8 months) and the median overall survival was 11.4 months (95% CI, 4.1-21.7 months). Treatment-related adverse events occurred in 94% of patients (grade 3, 52%; grade 4, 0%). One patient died due to a treatment-related adverse event of subarachnoid hemorrhage. CONCLUSIONS: The combination of lenvatinib plus pembrolizumab demonstrated antitumor activity with a manageable safety profile in patients with previously treated, advanced TNBC.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Compuestos de Fenilurea , Quinolinas , Neoplasias de la Mama Triple Negativas , Humanos , Quinolinas/administración & dosificación , Quinolinas/uso terapéutico , Quinolinas/efectos adversos , Femenino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/uso terapéutico , Compuestos de Fenilurea/efectos adversos , Persona de Mediana Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adulto , Anciano de 80 o más Años , Supervivencia sin Progresión , Estudios de CohortesRESUMEN
OBJECTIVES: The phase 2, multicohort, open-label LEAP-005 study evaluated lenvatinib plus pembrolizumab in patients with previously treated advanced solid tumors. We report outcomes from the ovarian cancer cohort. METHODS: Eligible patients had metastatic/unresectable ovarian cancer and had received 3 previous lines of therapy. Patients received lenvatinib 20 mg/day plus pembrolizumab 200 mg every 3 weeks. Treatment continued until progression, unacceptable toxicity, or (for pembrolizumab) completion of 35 cycles. Primary endpoints were objective response rate (ORR) per RECIST version 1.1 and safety. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). RESULTS: Thirty-one patients were enrolled. 39% had high grade serous ovarian cancer, 23% were platinum-sensitive, 55% were platinum-resistant, 23% were platinum-refractory, and 84% had tumors that had a PD-L1 combined positive (CPS) score ≥1. ORR (95% CI) was 26% (12%-45%) by investigator assessment and 35% (19%-55%) by blinded independent central review (BICR). Per BICR, median DOR was 9.2 (1.5+ to 37.8+) months. ORRs (95% CI) by BICR were 35% (9/26 patients; 17%-56%) for PD-L1 CPS ≥ 1 disease and 50% (2/4 patients; 7%-93%) for PD-L1 CPS < 1 disease. Median (95% CI) PFS by BICR and OS were 6.2 (4.0-8.5) months and 21.3 (11.7-32.3) months, respectively. Treatment-related AEs occurred in 94% of patients (grade 3-4, 77%). One patient died from treatment-related hypovolemic shock. CONCLUSIONS: Lenvatinib plus pembrolizumab demonstrated antitumor activity as fourth line therapy in patients with advanced ovarian cancer, and no unanticipated safety signals were identified. Responses were observed regardless of PD-L1 status.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Ováricas , Compuestos de Fenilurea , Quinolinas , Humanos , Femenino , Quinolinas/administración & dosificación , Quinolinas/efectos adversos , Quinolinas/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/efectos adversos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Persona de Mediana Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Adulto , Supervivencia sin Progresión , Anciano de 80 o más Años , Estudios de CohortesRESUMEN
BACKGROUND: A standard treatment for fit, older patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) is yet to be established. In the previous EXTREME trial, few older patients were included. We aimed to evaluate the efficacy and tolerance of an adapted EXTREME regimen in fit, older patients with recurrent or metastatic HNSCC. METHODS: This single-arm, phase 2 study was done at 22 centres in France. Eligible patients were aged 70 years or older and assessed as not frail (fit) using the ELAN Geriatric Evaluation (EGE) and had recurrent or metastatic HNSCC in the first-line setting that was not eligible for local therapy (surgery or radiotherapy), and an Eastern Cooperative Oncology Group performance status of 0-1. The adapted EXTREME regimen consisted of six cycles of fluorouracil 4000 mg/m2 on days 1-4, carboplatin with an area under the curve of 5 on day 1, and cetuximab on days 1, 8, and 15 (400 mg/m2 on cycle 1-day 1, and 250 mg/m2 subsequently), all intravenously, with cycles starting every 21 days. In patients with disease control after two to six cycles, cetuximab 500 mg/m2 was continued once every 2 weeks as maintenance therapy until disease progression or unacceptable toxicity. Granulocyte colony-stimulating factor was systematically administered and erythropoietin was recommended during chemotherapy. The study was based on the two-stage Bryant and Day design, combining efficacy and toxicity endpoints. The primary efficacy endpoint was objective response rate at week 12 after the start of treatment, assessed by central review (with an unacceptable rate of ≤15%). The primary toxicity endpoint was morbidity, defined as grade 4-5 adverse events, or cutaneous rash (grade ≥3) that required cetuximab to be discontinued, during the chemotherapy phase, or a decrease in functional autonomy (Activities of Daily Living score decrease ≥2 points from baseline) at 1 month after the end of chemotherapy (with an unacceptable morbidity rate of >40%). Analysis of the coprimary endpoints, and of safety in the chemotherapy phase, was based on the per-protocol population, defined as eligible patients who received at least one cycle of the adapted EXTREME regimen. Safety in the maintenance phase was assessed in all patients who received at least one dose of cetuximab as maintenance therapy. The study is registered with ClinicalTrials.gov, NCT01864772, and is completed. FINDINGS: Between Sept 27, 2013, and June 20, 2018, 85 patients were enrolled, of whom 78 were in the per-protocol population. 66 (85%) patients were male and 12 (15%) were female, and the median age was 75 years (IQR 72-79). The median number of chemotherapy cycles received was five (IQR 3-6). Objective response at week 12 was observed in 31 patients (40% [95% CI 30-51]) and morbidity events were observed in 24 patients (31% [22-42]). No fatal adverse events occurred. Four patients presented with a decrease in functional autonomy 1 month after the end of chemotherapy versus baseline. During chemotherapy, the most common grade 3-4 adverse events were haematological events (leukopenia [22 patients; 28%], neutropenia [20; 26%], thrombocytopenia [15; 19%], and anaemia [12; 15%]), oral mucositis (14; 18%), fatigue (11; 14%), rash acneiform (ten; 13%), and hypomagnesaemia (nine; 12%). Among 44 patients who received cetuximab during the maintenance phase, the most common grade 3-4 adverse events were hypomagnesaemia (six patients; 14%) and acneiform rash (six; 14%). INTERPRETATION: The study met its primary objectives on objective response and morbidity, and showed overall survival to be as good as in younger patients treated with standard regimens, indicating that the adapted EXTREME regimen could be used in older patients with recurrent or metastatic HNSCC who are deemed fit with use of a geriatric evaluation tool adapted to patients with head and neck cancer, such as the EGE. FUNDING: French programme PAIR-VADS 2011 (sponsored by the National Cancer Institute, the Fondation ARC, and the Ligue Contre le Cancer), Sandoz, GEFLUC, and GEMLUC. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.
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Protocolos de Quimioterapia Combinada Antineoplásica , Fluorouracilo , Neoplasias de Cabeza y Cuello , Recurrencia Local de Neoplasia , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Anciano , Masculino , Femenino , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Anciano de 80 o más Años , Fluorouracilo/administración & dosificación , Fluorouracilo/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/uso terapéutico , Carboplatino/efectos adversos , Cetuximab/administración & dosificación , Cetuximab/uso terapéutico , Cetuximab/efectos adversosRESUMEN
BACKGROUND: At present, there is no established standard treatment for frail older patients with recurrent or metastatic head and neck squamous cell carcinoma. We aimed to compare the efficacy and safety of cetuximab to those of methotrexate (the reference regimen) in this population. METHODS: This randomised, open-label, phase 3 trial was done at 20 hospitals in France. Patients aged 70 years or older, assessed as frail by the ELAN Geriatric Evaluation, with recurrent or metastatic head and neck squamous cell carcinoma in the first-line setting and with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were eligible for inclusion. Patients were randomly assigned (1:1) to receive cetuximab 500 mg/m2 intravenously every 2 weeks or methotrexate 40 mg/m2 intravenously every week, with minimisation by ECOG performance status, type of disease evolution, Charlson Comorbidity Index score, serum albumin concentration, and geriatrician consultation. To avoid deterministic minimisation and assure allocation concealment, patients were allocated with a probability of 0·80 to the treatment that most reduced the imbalance. Treatment was continued until disease progression or unacceptable toxicity, whichever occurred first. The primary endpoint was failure-free survival (defined as the time from randomisation to disease progression, death, discontinuation of treatment, or loss of 2 or more points on the Activities in Daily Living scale, whichever occurred first) and was analysed in the intention-to-treat population. 151 failures expected out of 164 patients were required to detect a hazard ratio (HR) of 0·625 with 0·05 alpha error, with 80% power. A futility interim analysis was planned when approximately 80 failures were observed, based on failure-free survival. Safety analyses included all patients who received at least one dose of the study drug. This study is registered on ClinicalTrials.gov (NCT01884623) and was stopped for futility after the interim analysis. FINDINGS: Between Nov 7, 2013, and April 23, 2018, 82 patients were enrolled (41 to the cetuximab group and 41 to the methotrexate group); 60 (73%) were male, 37 (45%) were aged 80 years or older, 35 (43%) had an ECOG performance status of 2, and 36 (44%) had metastatic disease. Enrolment was stopped for futility at the interim analysis. At the final analysis, median follow-up was 43·3 months (IQR 30·8-52·1). At data cutoff, all 82 patients had failure; failure-free survival did not differ significantly between the groups (median 1·4 months [95% CI 1·0-2·1] in the cetuximab group vs 1·9 months [1·1-2·6] in the methotrexate group; adjusted HR 1·03 [95% CI 0·66-1·61], p=0·89). The frequency of patients who had grade 3 or worse adverse events was 63% (26 of 41) in the cetuximab group and 73% (30 of 41) in the methotrexate group. The most common grade 3-4 adverse events in the cetuximab group were fatigue (four [10%] of 41 patients), lung infection (four [10%]), and rash acneiform (four [10%]), and those in the methotrexate group were fatigue (nine [22%] of 41), increased gamma-glutamyltransferase (seven [17%]), natraemia disorder (four [10%]), anaemia (four [10%]), leukopenia (four [10%]), and neutropenia (four [10%]). The frequency of patients who had serious adverse events was 44% (18 of 41) in the cetuximab group and 39% (16 of 41) in the methotrexate group. Four patients presented with a fatal adverse event in the cetuximab group (sepsis, decreased level of consciousness, pulmonary oedema, and death of unknown cause) as did two patients in the methotrexate group (dyspnoea and death of unknown cause). INTERPRETATION: The study showed no improvement in failure-free survival with cetuximab versus methotrexate. Patients with an ECOG performance status of 2 did not benefit from these systemic therapies. New treatment options including immunotherapy should be explored in frail older patients with recurrent or metastatic head and neck squamous cell carcinoma, after an initial geriatric evaluation, such as the ELAN Geriatric Evaluation. FUNDING: French programme PAIR-VADS 2011 (sponsored by the National Cancer Institute, the Fondation ARC and the Ligue Contre le Cancer), GEMLUC, GEFLUC, and Merck Santé. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.
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Neoplasias de Cabeza y Cuello , Metotrexato , Humanos , Masculino , Anciano , Femenino , Metotrexato/efectos adversos , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Cetuximab/efectos adversos , Anciano Frágil , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Progresión de la Enfermedad , FatigaRESUMEN
There is no strong and reliable predictive biomarker in head and neck squamous cell carcinoma (HNSCC) for EGFR inhibitors. We aimed to identify predictive and pharmacodynamic biomarkers of efficacy of afatinib, a pan-HER tyrosine kinase inhibitor, in a window-of-opportunity trial (NCT01415674). Multi-omics analyses were carried out on pre-treatment biopsy and surgical specimen for biological assessment of afatinib activity. Sixty-one treatment-naïve and operable HNSCC patients were randomised to afatinib 40 mg/day for 21-28 days versus no treatment. Afatinib produced a high rate of metabolic response. Responders had a higher expression of pERK1/2 (P = 0.02) and lower expressions of pHER4 (P = 0.03) and pRB1 (P = 0.002) in pre-treatment biopsy compared to non-responders. At the cellular level, responders displayed an enrichment of tumor-infiltrating B cells under afatinib (P = 0.02). At the molecular level, NF-kappa B signaling was over-represented among upregulated genes in non-responders (P < 0.001; FDR = 0.01). Although exploratory, phosphoproteomics-based biomarkers deserve further investigations as predictors of afatinib efficacy.
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Neoplasias de Cabeza y Cuello , Quinazolinas , Humanos , Afatinib/uso terapéutico , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Quinazolinas/farmacología , Quinazolinas/uso terapéutico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/genética , Biomarcadores , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
BACKGROUND: The REGOBONE multi-cohort study explored the efficacy and safety of regorafenib for patients with advanced bone sarcomas; this report details the Ewing sarcoma (ES) cohort. METHODS: Patients with relapsed ES progressing despite prior standard therapy, were randomised (2:1) to receive regorafenib or placebo. Patients on placebo could crossover to receive regorafenib after centrally confirmed progression. The primary endpoint was the progression-free rate at 8 weeks. With one-sided α of 0.05, and 80% power, at least 14/24 progression-free patients at 8 weeks were needed for success. RESULTS: From September 2014 to November 2019, 41 patients were accrued. 36 patients were evaluable for efficacy: 23 on regorafenib and 13 on placebo. Thirteen patients (56%; one-sided 95% CI [37.5%-[)) were progression-free at 8 weeks on regorafenib vs. 1 (7.7%; 95% CI [0.4%-[) on placebo. Median PFS was 11.4 weeks on regorafenib, and 3.9 weeks on placebo. Ten placebo patients crossed over to receive regorafenib after progression. The most common grade ≥3 regorafenib-related adverse events were pain (22%), asthenia (17%), thrombocytopenia (13%) and diarrhoea (13%). CONCLUSION: Although the primary endpoint was not met statistically in this randomised cohort, there is evidence to suggest that regorafenib might modestly delay tumour progression in relapsed ES after failure of prior chemotherapy.
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Sarcoma de Ewing , Sarcoma , Humanos , Sarcoma de Ewing/tratamiento farmacológico , Estudios de Cohortes , Sarcoma/tratamiento farmacológico , Compuestos de Fenilurea/efectos adversos , Método Doble CiegoRESUMEN
BACKGROUND: Patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) have a poor prognosis and limited therapeutic options. Immune checkpoint inhibitors (ICIs) are effective in patients with tumor progression < 6 months following first-line, platinum-based chemotherapy (PBC), but data are missing for patients with progression ≥ 6 months after the last platinum dose. METHODS: Retrospective analysis (six French centers, 2008-2019) of all consecutive R/M-HNSCC patients. treated first-line with PBC and tumor progression ≥ 6 months after the last platinum dose. PRIMARY ENDPOINT: progression-free survival after second-line therapy (PFS2). Additional endpoints: overall survival from Day 1 of first-line (OS1) and second-line (OS2) therapy. RESULTS: R/M-HNSCC patients (n = 144) received cisplatinum (n = 67, 47%) or carboplatinum (n = 77, 53%) first-line. Response after first-line: complete response (CR; n = 16, 11%); partial response (PR; n = 77, 53%); stable disease (n = 22, 15%). Second-line therapy: PBC (n = 95, 66%); platinum-free regimen (PFR) (n = 25, 17%); ICI (n = 24, 17%). Median [95% confidence interval] PFS (months): PBC 5.0 [3.8-6.2]; PFR 4.0 [1-7.0]; ICI 2.0 [0.4-3.6] (p = 0.16). For PBC, PFR, and ICI, respectively: OS1 30, 23, and 29 months (p = 1.02); OS2 14, 10, and 16 months (p = 0.25); PR, 26%, 16%, and 21% patients; CR, 0%, 8%, and 4% patients. For subsequent lines, ICIs were administered for PBC (n = 11, 12%) and PFR (n = 2, 8%). No predictive factor for efficacy (PFS, OS) was identified. CONCLUSIONS: Our retrospective study suggests similar efficacy regarding OS2 for second-line chemotherapy or ICI in R/M-HNSCC patients with progression ≥ 6 months after the last first-line platinum dose.
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Neoplasias de Cabeza y Cuello , Inhibidores de Puntos de Control Inmunológico , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Estudios Retrospectivos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Platino (Metal)/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
BACKGROUND: Sarcoma is a heterogeneous group of diseases with few treatment options. Immunotherapy has shown little activity in studies including unselected sarcomas, but immune checkpoint blockers have shown activity in specific histotypes. We evaluated the activity of pembrolizumab in rare and ultra-rare sarcomas. METHODS: AcSé Pembrolizumab is an ongoing phase 2, basket, multitumour study investigating the activity of pembrolizumab monotherapy in rare cancers. Here, we report the results obtained in patients with selected histotypes of rare sarcomas (incidence of less than one case per 1 000 000 people per year) recruited at 24 French hospitals. Key inclusion criteria were age 15 years or older, Eastern Cooperative Oncology Group performance status of 0-1, and advanced disease that was untreated and resistant to treatment. Patients were given pembrolizumab 200 mg intravenously on day 1 of every 21-day cycle for a maximum of 24 months. The primary endpoint was objective response rate at week 12 using Response Evaluation Criteria in Solid Tumours version 1.1, assessed by local investigators. The primary endpoint and safety were analysed in the intention-to-treat population. The AcSé Pembrolizumab study is registered with ClinicalTrials.gov, NCT03012620. FINDINGS: Between Sept 4, 2017, and Dec 29, 2020, 98 patients were enrolled, of whom 97 received treatment and were included in analyses (median age 51 years [IQR 35-65]; 53 [55%] were male; 44 [45%] were female; no data were collected on race or ethnicity). 34 (35%) patients had chordomas, 14 (14%) had alveolar soft part sarcomas, 12 (12%) had SMARCA4-deficient sarcomas or malignant rhabdoid tumours, eight (8%) had desmoplastic small round cell tumours, six (6%) had epithelioid sarcomas, four (4%) had dendritic cell sarcomas, three (3%) each had clear cell sarcomas, solitary fibrous tumours, and myxoid liposarcomas, and ten (10%) had other ultra-rare histotypes. As of data cutoff (April 11, 2022), median follow-up was 13·1 months (range 0·1-52·8; IQR 4·3-19·7). At week 12, objective response rate was 6·2% (95% CI 2·3-13·0), with no complete responses and six partial responses in the 97 patients. The most common grade 3-4 adverse events were anaemia (eight [8%] of 97), alanine aminotransferase and aspartate aminotransferase increase (six [6%]), and dyspnoea (five [5%]). 86 serious adverse events were reported in 37 patients. Five deaths due to adverse events were reported, none of which were determined to be related to treatment (two due to disease progression, two due to cancer, and one due to unknown cause). INTERPRETATION: Our data show the activity and manageable toxicity of pembrolizumab in some rare and ultra-rare sarcoma histotypes, and support the PD-1/PD-L1 pathway as a potential therapeutic target in selected histotypes. The completion of the basket study will provide further evidence regarding the activity and toxicity of pembrolizumab in identified rare types of cancer. FUNDING: The Ligue contre le cancer, INCa, MSD. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.
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Sarcoma de Parte Blanda Alveolar , Neoplasias de los Tejidos Blandos , Humanos , Masculino , Femenino , Persona de Mediana Edad , Adolescente , Anticuerpos Monoclonales Humanizados/efectos adversos , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/patología , Sarcoma de Parte Blanda Alveolar/tratamiento farmacológico , Criterios de Evaluación de Respuesta en Tumores Sólidos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , ADN Helicasas , Proteínas Nucleares , Factores de TranscripciónRESUMEN
Nutritional support during radiotherapy is crucial to tolerating and completing oropharyngeal squamous cell carcinoma (OPSCC) treatment. The impact of HPV status on nutritional support is debated. The objective was to evaluate the rate of Reactive Feeding Tube (RFT) use and determine its prognostic factors during definitive radiotherapy for OPSCC. All OPSCC patients treated from 2009 to 2014 were included in this multicentric retrospective study. The impact of tumor p16 status on the risk of RFT was assessed through multivariate analyses. Among the 543 patients, 103 patients required an RFT (19.0%). The use of RFT differed between centers (5% to 32.4%). In multivariate analysis, only tongue base involvement and concurrent chemotherapy were significantly associated with RFT (OR = 2.18 and 3.7, respectively). Tongue base involvement and concomitant chemotherapy were prognostic factors for RFT. HPV status was not a prognostic factor for enteral nutrition during radiotherapy for OPSCC.
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PURPOSE OF REVIEW: Clinical data on salvage chemotherapy used after checkpoints inhibitors in oncology are reviewed, with a special focus on recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). RECENT FINDINGS: Converging evidence is emerging about high response and/or disease control rates associated with salvage chemotherapy after immunotherapy failure in advanced solid tumours. This phenomenon is mainly reported in retrospective studies for "hot tumours" such as R/M HNSCC, melanoma, lung, urothelial or gastric cancers, but also in haematological malignancies. Some physiopathological hypotheses have been raised. SUMMARY: Several independent series show increased response rates associated with postimmuno chemotherapy when compared with retrospective series in similar settings. Several mechanisms could be involved such as a "carry-over" allowed by a persistence of the checkpoint inhibitor, a modulation of tumour microenvironment components but also an intrinsic immunomodulatory effect of chemotherapy, increased by a specific immunologic state induced by the therapeutic pressure of checkpoint inhibitors. These data establish a rationale for prospectively evaluating the features of postimmunotherapy salvage chemotherapy.
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Neoplasias de Cabeza y Cuello , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Estudios Retrospectivos , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Inmunoterapia , Microambiente TumoralRESUMEN
PURPOSE OF REVIEW: Despite recent advances, treatment personalization remains an issue for recurrent metastatic head and neck squamous cell carcinoma (RM HNSCC) patients. After human papilloma virus (HPV) and programmed death ligand 1 (PDL1) expression, Harvey rat sarcoma viral oncogene homolog (HRAS) appears as an emerging target in this field. In this review, we summarize the features of HRAS -mutated HNSCC and its targeting by farnesyl transferase inhibitors. RECENT FINDINGS: HRAS mutations define a small subgroup of RM HNSCC patients with a poor prognosis and often refractory to the standard treatments. Posttranslational processing of HRAS being dependent on farnesylation, farnesyl transferase inhibitors have been evaluated in HRAS -mutated tumors. Tipifarnib, a first in class farnesyl transferase inhibitor, has shown efficacy in phase 2 trials with HRAS -mutated tumors. Despite reported high response rates in selected population, the efficacy of Tipifarnib is inconsistent and always transient, probably because of limiting hematological toxicities leading to dose reduction and occurrence of secondary resistance mutations. SUMMARY: Tipifarnib is the first in the class of farnesyl transferase inhibitors to show efficacy in HRAS -mutated RM HNSCC. The understanding of mechanisms of resistance will pave the way for the design of second-generation farnesyl transferases inhibitors.
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Carcinoma , Neoplasias de Cabeza y Cuello , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/genética , Transferasas , OncogenesRESUMEN
BACKGROUND: Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor beta receptor II (a TGF-ß "trap") fused to a human immunoglobulin G1 monoclonal antibody blocking programmed cell death 1 ligand 1 (PD-L1). We report the efficacy and safety in patients with non-small cell lung cancer (NSCLC) that progressed following anti-PD-(L)1 therapy. MATERIALS AND METHODS: In this expansion cohort of NCT02517398-a global, open-label, phase I trial-adults with advanced NSCLC that progressed following chemotherapy and was primary refractory or had acquired resistance to anti-PD-(L)1 treatment received intravenous bintrafusp alfa 1200 mg every 2 weeks until confirmed progression, unacceptable toxicity, or trial withdrawal. The primary endpoint was best overall response (by Response Evaluation Criteria in Solid Tumors version 1.1 adjudicated by independent review committee); secondary endpoints included safety. RESULTS: Eighty-three eligible patients (62 [74.7%] treated with ≥3 prior therapies) received bintrafusp alfa. Four patients (3 primary refractory, 1 acquired resistant) had confirmed partial responses (objective response rate, 4.8%; 95% CI, 1.3%-11.9%), and 9 had stable disease. Tumor cell PD-L1 expression was not associated with response. Nineteen patients (22.9%) experienced grade ≥3 treatment-related adverse events, most commonly asthenia (3 [3.6%]) and fatigue, eczema, and pruritus (2 each [2.4%]). One patient had grade 4 amylase increased. One patient died during treatment for pneumonia before initiation of bintrafusp alfa. CONCLUSION: Although the primary endpoint was not met, bintrafusp alfa showed some clinical activity and a manageable safety profile in patients with heavily pretreated NSCLC, including prior anti-PD-(L)1 therapy. Tumor responses occurred irrespective of whether disease was primary refractory or had acquired resistance to prior anti-PD-(L)1 therapy.
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Antineoplásicos Inmunológicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Adulto , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Antígeno B7-H1 , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Factores InmunológicosRESUMEN
Local or metastatic relapse following surgery, radiotherapy, and cisplatin is the leading cause of death in patients with head and neck squamous cell carcinoma (HNSCC). Our study shows overexpression of c-MET and AXL in HNSCC cells and patients resistant to radiotherapy and cisplatin. We demonstrate that cabozantinib, an inhibitor of vascular endothelial growth factor receptor (VEGFR), c-MET, and AXL, decreases migration, invasion, and proliferation and induces mitotic catastrophe and apoptotic cell death of naive and radiotherapy- and cisplatin-resistant HNSCC cells. Cabozantinib inhibits the growth and metastatic spread of experimental HNSCC in zebrafish and the growth of experimental HNSCC in mice by blocking tumor cell proliferation and angiogenesis. The efficacy of cabozantinib is also confirmed on viable sections of surgically removed specimens of human HNSCC and on a patient who relapses after five lines of treatment. These results suggest that cabozantinib is relevant for the treatment of patients with HNSCC after relapse under radiotherapy and cisplatin.
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Carcinoma , Neoplasias de Cabeza y Cuello , Anilidas , Animales , Línea Celular Tumoral , Cisplatino/farmacología , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Humanos , Ratones , Recurrencia Local de Neoplasia , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , Piridinas , Proteínas Tirosina Quinasas Receptoras/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular , Ensayos Antitumor por Modelo de Xenoinjerto , Pez CebraRESUMEN
PURPOSE: Act.In.Sarc (NCT02379845) demonstrated that the first-in-class radioenhancer NBTXR3, activated by preoperative radiation therapy (RT), doubled the rate of pathologic complete response after resection compared with preoperative RT alone in adult patients with locally advanced soft tissue sarcoma of the extremity or trunk wall (16.1% vs 7.9%, P = .045), and more patients achieved R0 resections (77.0% vs 64.0%, P = .042). These are the toxicity and health-related quality of life (HRQoL) results. METHODS AND MATERIALS: Act.In.Sarc randomized eligible patients 1:1 to either NBTXR3 (single intratumoral injection, volume equivalent to 10% of baseline tumor volume, at 53.3 g/L) activated by external-beam RT (arm A) or external-beam RT alone (arm B) (50 Gy in 25 fractions), followed by surgery in both arms. Here, we report the safety analyses in the all-treated population with a long-term follow-up of at least 2 years, and HRQoL in the intention-to-treat full analysis set. RESULTS: During the on-treatment period, serious adverse events (SAEs) of all grades related to NBTXR3 occurred in 10.1% (9/89) of patients (arm A), and SAEs related to RT occurred in 5.6% (5/89) (arm A) versus 5.6% (5/90) (arm B); postsurgery hospitalization owing to SAEs occurred in 15.7% (14/89) (arm A) versus 24.4% (22/90) (arm B). During the follow-up period, posttreatment SAEs (regardless of relationship) occurred in 13.5% (12/89) (arm A) versus 24.4% (22/90) (arm B). NBTXR3 did not negatively affect HRQoL; during the follow-up period, there was an improvement in most mean Toronto extremity salvage, EuroQoL 5-dimension (EQ-5D), EQ5D02-EQ visual analog scale, reintegration to normal living index, and musculoskeletal tumor rating scale scores. CONCLUSIONS: NBTXR3 did not negatively affect safety or HRQoL. Long-term safety results reinforce the favorable benefit-risk ratio of NBTXR3 plus RT.
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Antineoplásicos , Sarcoma , Neoplasias de los Tejidos Blandos , Adulto , Antineoplásicos/uso terapéutico , Humanos , Terapia Neoadyuvante , Calidad de Vida , Radiofármacos/uso terapéutico , Sarcoma/tratamiento farmacológico , Sarcoma/radioterapia , Sarcoma/cirugía , Neoplasias de los Tejidos Blandos/radioterapia , Neoplasias de los Tejidos Blandos/cirugíaRESUMEN
PURPOSE OF REVIEW: The treatment of recurrent and/or metastatic head and neck squamous cell carcinoma patients is revolutionized by the advent of anti-PD1 checkpoint inhibitors. RECENT FINDINGS: Indeed, Pembrolizumab is approved as monotherapy or used in combination with platin and fluorouracil for first-line patients with tumors expressing PD-L1. Nivolumab and Pembrolizumab are also approved in second line of recurrent/metastatic head and neck squamous cell carcinoma. Moreover, the substitution of fluorouracil for a taxane in the TPEx regimen has shown improvement in safety profile when compared with EXTREME regimen. SUMMARY: Here we carry out a review of the main results of pivotal trials and discuss the pros and cons of the three possible scenarios when considering the therapeutic sequence (first and second line).
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Neoplasias de Cabeza y Cuello , Recurrencia Local de Neoplasia , Fluorouracilo/uso terapéutico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Humanos , Inhibidores de Puntos de Control Inmunológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Nivolumab/uso terapéutico , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológicoRESUMEN
Missense mutations in the polymerase epsilon (POLE) gene have been reported to generate proofreading defects resulting in an ultramutated genome and to sensitize tumors to checkpoint blockade immunotherapy. However, many POLE-mutated tumors do not respond to such treatment. To better understand the link between POLE mutation variants and response to immunotherapy, we prospectively assessed the efficacy of nivolumab in a multicenter clinical trial in patients bearing advanced mismatch repair-proficient POLE-mutated solid tumors. We found that only tumors harboring selective POLE pathogenic mutations in the DNA binding or catalytic site of the exonuclease domain presented high mutational burden with a specific single-base substitution signature, high T-cell infiltrates, and a high response rate to anti-PD-1 monotherapy. This study illustrates how specific DNA repair defects sensitize to immunotherapy. POLE proofreading deficiency represents a novel agnostic biomarker for response to PD-1 checkpoint blockade therapy. SIGNIFICANCE: POLE proofreading deficiency leads to high tumor mutational burden with high tumor-infiltrating lymphocytes and predicts anti-PD-1 efficacy in mismatch repair-proficient tumors. Conversely, tumors harboring POLE mutations not affecting proofreading derived no benefit from PD-1 blockade. POLE proofreading deficiency is a new tissue-agnostic biomarker for cancer immunotherapy. This article is highlighted in the In This Issue feature, p. 1397.
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ADN Polimerasa II , Neoplasias , ADN Polimerasa II/genética , Humanos , Inmunoterapia , Mutación Missense , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Neoplasias/genética , Proteínas de Unión a Poli-ADP-Ribosa/genética , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/genéticaRESUMEN
A prevalence of around 26% of human papillomavirus (HPV) in head and neck squamous cell carcinoma (HNSCC) has been previously reported. HPV induced oncogenesis mainly involving E6 and E7 viral oncoproteins. In some cases, HPV viral DNA has been detected to integrate with the host genome and possibly contributes to carcinogenesis by affecting the gene expression. We retrospectively assessed HPV integration sites and signatures in 80 HPV positive patients with HNSCC, by using a double capture-HPV method followed by next-generation Sequencing. We detected HPV16 in 90% of the analyzed cohort and confirmed five previously described mechanistic signatures of HPV integration [episomal (EPI), integrated in a truncated form revealing two HPV-chromosomal junctions colinear (2J-COL) or nonlinear (2J-NL), multiple hybrid junctions clustering in a single chromosomal region (MJ-CL) or scattered over different chromosomal regions (MJ-SC) of the human genome]. Our results suggested that HPV remained episomal in 38.8% of the cases or was integrated/mixed in the remaining 61.2% of patients with HNSCC. We showed a lack of association of HPV genomic signatures to tumour and patient characteristics, as well as patient survival. Similar to other HPV associated cancers, low HPV copy number was associated with worse prognosis. We identified 267 HPV-human junctions scattered on most chromosomes. Remarkably, we observed four recurrent integration regions: PDL1/PDL2/PLGRKT (8.2%), MYC/PVT1 (6.1%), MACROD2 (4.1%) and KLF5/KLF12 regions (4.1%). We detected the overexpression of PDL1 and MYC upon integration by gene expression analysis. In conclusion, we identified recurrent targeting of several cancer genes such as PDL1 and MYC upon HPV integration, suggesting a role of altered gene expression by HPV integration during HNSCC carcinogenesis.