RESUMEN
Key Clinical Message: Conventional treatments of anaplastic meningioma include surgery and radiotherapy. Temozolomide is also an option. Metastases to extracerebral organs are very rare and hardly manageable. Antiangiogenic drugs could represent a salvage therapy. Abstract: Anaplastic meningioma is an unusual tumor subtype that rarely involves organs outside the brain. In our case, a patient with cerebral meningioma developed lung metastases after 19 years from the initial tumor appearance. This unpredictable behavior could make complex the diagnosis.
RESUMEN
RAF family proteins are serine-threonine kinases that play a central role in the MAPK pathway which is involved in embryogenesis, cell differentiation, cell proliferation and death. Deregulation of this pathway is found in up to 30% of all human cancers and BRAF mutations can be identified in 1.5-3.5% of NSCLC patients. Following the positive results obtained through the combination of BRAF and MEK inhibitors in BRAF-mutant melanoma, the same combination was prospectively assessed in BRAF-mutant NSCLC. In cohort B of the BRF113928 trial, 57 pretreated NSCLC patients were treated with dabrafenib plus trametinib: an ORR of 68.4%, a disease control rate of 80.7%, a median PFS of 10.2 months and a median OS of 18.2 months were observed. Similar results were reported in the first-line setting (cohort C), with an ORR of 63.9%, a DCR of 75% and a median PFS and OS of 10.2 and 17.3 months, respectively. The combination was well tolerated: the main adverse events were pyrexia (64%), nausea (56%), diarrhoea (56%), fatigue (36%), oedema (36%) and vomiting (33%). These positive results led to the approval of the combination of dabrafenib and trametinib for the treatment of BRAF V600E metastatic NSCLC patients regardless of previous therapy. Ongoing research should better define the role of new generation RAF inhibitors for patients with acquired resistance, the activity of chemo-immunotherapy or the combination of TKIs with chemotherapy or with immunotherapy in patients with BRAF-mutated cancers.
RESUMEN
Few treatment options are available for patients with small cell lung cancer (SCLC) in progression after a first-line therapy. A novel therapeutic approach is represented by lurbinectedin, a synthetic derivative of trabectedin that works by inhibiting oncogenic transcription and promoting apoptosis in tumor cells. A phase II basket trial demonstrated the activity of lurbinectedin at the dose of 3.2 mg/m2 in patients with SCLC who had failed a previous chemotherapy, with a response rate of 35.2%, a median progression-free survival (mPFS) of 3.5 months, and a median overall survival (mOS) of 9.3 months. Common severe adverse events (grades 3-4) were hematological disorders, including anemia (9%), leukopenia (29%), neutropenia (46%), and thrombocytopenia (7%). On the basis of the positive results of this phase II study, on June 2020, lurbinectedin was approved by the Food and Drug Administration as second line for SCLC patients in progression on or after platinum-based therapy. The subsequent phase III trial comparing the combination of lurbinectedin plus doxorubicin vs. CAV (cyclophosphamide, Adriamycin, and vincristine) or topotecan did not demonstrate an improvement in overall survival, although the experimental arm showed a superior safety profile. Combinations of lurbinectedin with other drugs, cytotoxic agents and immune checkpoint inhibitors, are currently under investigation. The results of these studies should better define the optimal clinical application of lurbinectedin.
RESUMEN
RET rearrangements are observed in 1-2% of non-small-cell lung cancer (NSCLC) patients and result in the constitutive activation of downstream pathways normally implied in cell proliferation, growth, differentiation and survival. In NSCLC patients, RET rearrangements have been associated with a history of non-smoking, a higher rate of brain metastasis at initial diagnosis and a low immune infiltrate. Traditionally, RET fusions are considered mutually exclusive with other oncogenic drivers, even though a co-occurrence with EGFR mutations and MET amplifications has been observed. Cabozantinib, vandetanib and lenvatinib are the first multi-kinase inhibitors tested in RET-rearranged NSCLC patients with contrasting results. More recently, two selective RET inhibitors, selpercatinib and pralsetinib, demonstrated higher efficacy rates and good tolerability and they were approved for the treatment of patients with metastatic RET fusion-positive NSCLC on the bases of the results of phase II studies. Two ongoing phase III clinical trials are currently comparing selpercatinib or pralsetinib to standard first line treatments and will definitively establish their efficacy in RET-positive NSCLC patients.
RESUMEN
Inhibition of angiogenesis has been demonstrated to be an efficacious strategy in treating several tumors. Vascular endothelial growth factor (VEGF) is the most important protein with proangiogenic functions and it is overexpressed in small cell lung cancer (SCLC). Bevacizumab, a monoclonal antibody directed against VEGF, showed a promising activity in combination with etoposide and cisplatin as first-line treatment of patients with extended stage (ES)-SCLC and two randomized studies confirmed that bevacizumab improved PFS, but failed to prolong OS. Instead, disappointing results have been observed with endostar, sunitinib, sorafenib, vandetanib, and thalidomide in combination with chemotherapy in the first-line setting, with sunitinib in the maintenance setting, with sunitinib, cediranib and nintedanib as single agents or ziv-aflibercept in combination with topotecan in second-line setting. Only anlotinib improved OS and PFS as third-line therapy in Chinese patients with SCLC, and it was approved with this indication in China. Future challenges are the evaluation of the role of angiogenesis inhibitors in combination with immune- checkpoint inhibitors and chemotherapy in SCLC patients and the identification of predictive biomarkers of response to both agents.
RESUMEN
Small-cell lung cancer (SCLC) is an aggressive tumor type with limited therapeutic options and poor prognosis. Chemotherapy regimens containing platinum represent the cornerstone of treatment for patients with extensive disease, but there has been no real progress for 30 years. The evidence that SCLC is characterized by a high mutational burden led to the development of immune-checkpoint inhibitors as single agents or in combination with chemotherapy. Randomized phase III trials demonstrated that the combination of atezolizumab (IMpower-133) or durvalumab (CASPIAN) with platinum-etoposide chemotherapy improved overall survival of patients with extensive disease. Instead, the KEYNOTE-604 study demonstrated that the addition of pembrolizumab to chemotherapy failed to significantly improve overall survival, but it prolonged progression-free survival. The safety profile of these combinations was similar with the known safety profiles of all single agents and no new adverse events were observed. Nivolumab and pembrolizumab single agents showed anti-tumor activity and acceptable safety profile in Checkmate 032 and KEYNOTE 028/158 trials, respectively, in patients with SCLC after platinum-based therapy and at least one prior line of therapy. Future challenges are the identification predictive biomarkers of response to immunotherapy in SCLC and the definition of the role of immunotherapy in patients with limited stage SCLC, in combination with radiotherapy or with other biological agents.
RESUMEN
INTRODUCTION: Atezolizumab is a humanized monoclonal antibody against PD-L1 capable of enhancing antitumor immune activity, with a demonstrated activity as single agent in patients with advanced non-small-cell lung cancer (NSCLC). AREAS COVERED: This review summarizes the clinical data emerging from randomized clinical studies with atezolizumab in NSCLC and small-cell lung cancer (SCLC), focusing in particular on the efficacy and safety data regarding the combinations of atezolizumab plus chemotherapy in the IMpower studies. EXPERT OPINION: A significant improvement in progression-free survival and in overall survival was observed in IMpower 130 and 150 (NSCLC non-squamous) and 133 (SCLC), with an acceptable safety profile. In particular, the most common immune-related adverse events were rash (18-28% of patients), hypothyroidism (8-15%), hepatitis (5-17%), pneumonitis (2-7%), and colitis (1.5-2.3%). The safety profile of atezolizumab in combination with chemotherapy was consistent with the known adverse events related to single-agent atezolizumab and no new adverse events were observed. Ongoing studies will evaluate the role of atezolizumab in other settings (adjuvant and neoadjuvant) and in combination with chemotherapy and radiotherapy for patients with locally advanced NSCLC and the role of predictive factors (B-FAST study).
Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígeno B7-H1/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Supervivencia sin Enfermedad , Humanos , Neoplasias Pulmonares/patología , Ensayos Clínicos Controlados Aleatorios como Asunto , Tasa de SupervivenciaRESUMEN
Several preclinical studies suggested a potential benefit from combined treatment with inhibitors of epidermal growth factor receptor (EGFR) and angiogenesis, both effective in patients with advanced non-small-cell lung cancer (NSCLC). In pretreated patients with advanced EGFR wild type NSCLC, bevacizumab plus erlotinib improved progression-free survival as second-line therapy in the BeTa study and as maintenance therapy in the ATLAS trial, although the benefit was modest and did not translate into an advantage in overall survival. Disappointing results were reported with oral VEGF inhibitors plus erlotinib in pretreated patients with EGFR wild type NSCLC. On the contrary, erlotinib plus bevacizumab or ramucirumab showed a clinically relevant improvement of progression-free survival in naïve patients with EGFR mutations, leading to the approval of these two regimens as first-line treatment of NSCLC patients with EGFR mutant tumors. Several clinical studies are evaluating the feasibility and activity of osimertinib plus bevacizumab or ramucirumab. However, limits that could affect its use in clinical practice are the need of an intravenous infusion for angiogenesis inhibitors, the increased incidence of treatment associated adverse events, the exclusion of patients with tumors located in central position or at risk of hemorrhage. The identification of predictive biomarkers is an important goal of research to optimize the combined use of these agents.
RESUMEN
Pembrolizumab is a humanized monoclonal antibody against PD-1 capable of enhancing antitumor immune activity. The KEYNOTE-001 study showed that pembrolizumab has activity in advanced non-small-cell lung cancer patients and identified programmed death ligand 1 (PD-L1) as a companion test to select patients most likely to benefit from pembrolizumab. Five randomized clinical trials showed the efficacy of pembrolizumab in non-small-cell lung cancer: in second-line setting PD-L1 ≥1% (KEYNOTE-010), in first-line setting PD-L1 ≥50% (KEYNOTE-024 and KEYNOTE-042) and in first-line setting in combination with platinum doublets, any expression of PD-L1 (KEYNOTE-189 and KEYNOTE-407). Future challenges are the identification of the role of pembrolizumab in adjuvant, neoadjuvant, locally advanced disease or oncogene-addicted patients, in combination with radiotherapy or other biological agents.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Receptores de Estrógenos/metabolismo , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Animales , Anticuerpos Monoclonales Humanizados/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/patología , Docetaxel/administración & dosificación , Evaluación de Medicamentos , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/patología , Ratones , Nivolumab/administración & dosificación , Pronóstico , Carcinoma Pulmonar de Células Pequeñas/patología , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Kaposi's sarcoma involving the digestive tract in isolated form before the appearance of diffuse skin lesions is very rare in HIV-negative patients and is a condition requiring watchful waiting.
RESUMEN
Malignant melanoma is a very aggressive tumor. Immune and targeted therapy could prolong patient's clinical benefit and survival, but the correct sequence of therapies has still to be defined.
RESUMEN
Angiogenesis is a complex biological process that plays a relevant role in sustaining the microenvironment, growth, and metastatic potential of several tumors, including non-small cell lung cancer (NSCLC). Bevacizumab was the first angiogenesis inhibitor approved for the treatment of patients with advanced NSCLC in combination with chemotherapy; however, it was limited to patients with non-squamous histology and first-line setting. Approval was based on the results of two phase III trials (ECOG4599 and AVAIL) that demonstrated an improvement of about two months in progression-free survival (PFS) in both trials, and in the ECOG4599 trial, an improvement in overall survival (OS) also. Afterwards, other antiangiogenic agents, including sunitinib, sorafenib, and vandetanib have been unsuccessfully tested in first and successive lines. Recently, two new antiangiogenic agents (ramucirumab and nintedanib) produced a significant survival benefit in second-line setting. In the REVEL study, ramucirumab plus docetaxel prolonged the median OS of patients with any histology NSCLC when compared with docetaxel alone (10.4 versus 9.1 months, hazard ratio (HR) 0.857, p = 0.0235). In the LUME-Lung 1 study, nintedanib plus docetaxel prolonged the median PFS of patients with any tumor histology (p = 0.0019), and improved OS (12.6 versus 10.3 months) in patients with adenocarcinoma. As a result, it became a new option for the second-line treatment of patients with advanced NSCLC and adenocarcinoma histology. Identifying predictive biomarkers to optimize the benefit of antiangiogenic drugs remains an ongoing challenge.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Inhibidores de la Angiogénesis/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Bevacizumab/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Ensayos Clínicos Fase III como Asunto , Supervivencia sin Enfermedad , Docetaxel , Humanos , Indoles/uso terapéutico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Neovascularización Patológica/metabolismo , Neovascularización Patológica/mortalidad , Neovascularización Patológica/patología , Niacinamida/análogos & derivados , Niacinamida/uso terapéutico , Compuestos de Fenilurea/uso terapéutico , Piperidinas/uso terapéutico , Pirroles/uso terapéutico , Quinazolinas/uso terapéutico , Sorafenib , Sunitinib , Taxoides/uso terapéutico , RamucirumabRESUMEN
Unlike chemoimmunotherapy regimens, which are given for a defined period, ibrutinib, a first-in-class Bruton's kinase inhibitor, allows most patients with CLL to remain on treatment for an extended period. Our experience, supported by sequential CT scan images, suggests that long-term ibrutinib promotes a high response rate that improves in quality with time.
RESUMEN
Nintedanib is a new triple angiokinase inhibitor that potently blocks the proangiogenic pathways mediated by vascular endothelial growth factor receptors, platelet-derived growth factor receptors, and fibroblast growth factor receptors. Evidence about its efficacy in addition to second-line chemotherapy in non-small cell lung cancer (NSCLC) has been produced by two large randomized phase III clinical trials (LUME-Lung 1 and LUME-Lung 2), conducted in patients with pretreated NSCLC, without major risk factors for bleeding. In the LUME-Lung 1, the addition of nintedanib to docetaxel significantly improved progression-free survival, which was the primary end point of the trial (3.4 vs. 2.7 months, hazard ratio: 0.79; p = 0.0019). Furthermore, a significant improvement in median overall survival (from 10.3 to 12.6 months) was observed in patients with adenocarcinoma histology, with a greater advantage in patients who progressed within 9 months after start of first-line treatment (from 7.9 to 10.9 months) and in patients who were most refractory to first-line chemotherapy (from 6.3 to 9.8 months). Adverse events were more common in the docetaxel plus nintedanib group, and they included diarrhea and increased liver enzymes, while no statistically significant increase in the incidence of bleeding and hypertension events by the addition of nintedanib was observed. On these bases, the combination of docetaxel and nintedanib can be considered a new option for the second-line treatment for patients with advanced NSCLC with adenocarcinoma histology. Future challenges are the identification of predictive factors to help the decision of using nintedanib in eligible patients.
RESUMEN
Afatinib is an oral, irreversible, tyrosine kinase inhibitor (TKI) of EGFR, HER2 and HER4. According to phase I studies, the recommended dose of afatinib was 50mg daily. Rash, acne, diarrhea and stomatitis were the most common adverse events. Afatinib failed to demonstrate an improvement in overall survival in unselected heavily pretreated NSCLC patients (Lux-Lung-1). On the contrary, the Lux-Lung-3 and -6 trials met the primary end point, demonstrating a significant increase in terms of PFS with afatinib compared with chemotherapy in the first line treatment of EGFR mutant patients. Moreover, in both studies, afatinib improved overall survival in patients with exon 19 EGFR deletion (31.7 vs 20.7 months; HR: 0.59, p=0.0001). The results of ongoing randomized trials should further clarify the efficacy of afatinib compared with first-generation TKIs in advanced NSCLC, its activity in the adjuvant and neoadjuvant settings, as well as its efficacy in other tumors.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/uso terapéutico , Afatinib , Receptores ErbB/antagonistas & inhibidores , Humanos , Inhibidores de Proteínas Quinasas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Treatment of small cell lung cancer (SCLC) remains a significant challenge for the oncologists. Attempts to improve the results of first-line treatment have all failed so far and no real progress has been made in last years, emphasizing the need for novel strategies of treatment and the development of validated biomarkers. Patients with limited disease and good performance status should be considered for concomitant chemoradiotherapy, followed by prophylactic cranial irradiation. Patients with extensive disease should be treated with a platinum-based chemotherapy (cisplatin or carboplatin); chest radiotherapy can be considered in patients achieving extra-thoracic complete response and prophylactic cranial irradiation is recommended for patients responsive to initial chemotherapy. A large number of molecular-targeted drugs and immunomodulators are currently in clinical development: however, only a better understanding of molecular biology of SCLC and the identification of molecular markers predictive of response to targeted agents will lead to advances in the treatment of SCLC.
Asunto(s)
Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Pulmonares/terapia , Carcinoma Pulmonar de Células Pequeñas/terapia , Carboplatino/uso terapéutico , Cisplatino/uso terapéutico , Ensayos Clínicos como Asunto , Terapia Combinada , Irradiación Craneana , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Radioterapia Adyuvante , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/cirugíaRESUMEN
Treatment of locally advanced non-small cell lung cancer (NSCLC) remains a significant challenge for oncologists, despite progress made in recent years in early diagnosis and therapy. This review focuses on integrated therapeutic approaches of patients with locally advanced NSCLC, summarizing the available evidence for patients with potentially resectable disease (stage IIIA-0/3) and with unresectable disease (stage IIIA-4/IIIB) and discussing several key questions related to the use of integrated approaches in NSCLC. Based on current evidence, neoadjuvant platinum-based combination chemotherapy is a treatment option in patients with potentially resectable stage IIIA-0/3: a 2-drug combination of platinum combined with a third-generation drug seems preferable, and at least 3 cycles of chemotherapy should be administered. There are no definitive evidences of clear superiority of surgery compared to radiotherapy for patients obtaining a response with neoadjuvant treatment: however, surgery is associated with a better local control, and subgroup analyses of randomized trials suggest improved outcome in patients in whom a complete resection could be obtained with a lobectomy, avoiding the increased surgical mortality associated with pneumonectomy. Standard treatment for patients with locally advanced, unresectable NSCLC is currently represented by combination of chemotherapy and radiotherapy. Concomitant approach has been proven superior to the sequential administration, although it is associated with higher risk of toxicity. All patients should be evaluated by a multidisciplinary team, skilled in multimodality treatment and should be counselled about risks and potential benefits of the different therapeutic approaches.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/terapia , Terapia Combinada/métodos , Neoplasias Pulmonares/terapia , Pulmón/patología , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Neoplasias Pulmonares/patologíaAsunto(s)
Ácidos Borónicos/uso terapéutico , Resistencia a Antineoplásicos , Inmunosupresores/uso terapéutico , Leishmaniasis Visceral/inmunología , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/inmunología , Infecciones Oportunistas/inmunología , Pirazinas/uso terapéutico , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Antiprotozoarios/uso terapéutico , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/parasitología , Células de la Médula Ósea/patología , Ácidos Borónicos/efectos adversos , Bortezomib , Humanos , Inmunosupresores/efectos adversos , Italia , Leishmania donovani/efectos de los fármacos , Leishmania donovani/aislamiento & purificación , Leishmaniasis Visceral/complicaciones , Leishmaniasis Visceral/tratamiento farmacológico , Leishmaniasis Visceral/parasitología , Masculino , Persona de Mediana Edad , Mieloma Múltiple/complicaciones , Infecciones Oportunistas/complicaciones , Infecciones Oportunistas/tratamiento farmacológico , Infecciones Oportunistas/parasitología , Inhibidores de Proteasoma/efectos adversos , Inhibidores de Proteasoma/uso terapéutico , Pirazinas/efectos adversos , Resultado del TratamientoRESUMEN
Cetuximab is a chimeric human-mouse anti-EGF receptor monoclonal antibody. In Phase I studies, no dose-limiting toxicities were observed with cetuximab as a single agent or combined with chemotherapy; pharmacokinetic and pharmacodynamic analyses supported 250 mg/m(2) weekly administration. Skin toxicity, diarrhea and fatigue were the most common toxicities. The positive results obtained in Phase II trials in patients with advanced non-small-cell lung cancer prompted two randomized Phase III trials evaluating cetuximab in addition to first-line chemotherapy. Both trials showed a small benefit in overall survival for the experimental treatment, which was considered insufficient by the EMA for marketing approval. However, a subgroup analysis of the FLEX Phase III trial recently demonstrated a larger survival benefit from the experimental treatment in patients with high immunohistochemical EGF receptor expression. This finding, if confirmed prospectively, could represent a new opportunity for positioning cetuximab into the standard treatment of advanced non-small-cell lung carcinoma.