First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial.

BACKGROUND: First-line nivolumab plus ipilimumab has shown improved overall survival in patients with advanced non-small-cell lung cancer (NSCLC). We aimed to investigate whether the addition of a limited course (two cycles) of chemotherapy to this combination would further enhance the clinical benefit. METHODS: This randomised, open-label, phase 3 trial was done at 103 hospitals in 19 countries. Eligible patients were aged 18 years or older with treatment-naive, histologically confirmed stage IV or recurrent NSCLC, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) by an interactive web response system via permuted blocks (block size of four) to nivolumab (360 mg intravenously every 3 weeks) plus ipilimumab (1 mg/kg intravenously every 6 weeks) combined with histology-based, platinum doublet chemotherapy (intravenously every 3 weeks for two cycles; experimental group), or chemotherapy alone (every 3 weeks for four cycles; control group). Randomisation was stratified by tumour histology, sex, and PD-L1 expression. The primary endpoint was overall survival in all randomly assigned patients. Safety was analysed in all treated patients. Results reported here are from a pre-planned interim analysis (when the study met its primary endpoint) and an exploratory longer-term follow-up analysis. This study is active but no longer recruiting patients, and is registered with ClinicalTrials.gov, number NCT03215706. FINDINGS: Between Aug 24, 2017, and Jan 30, 2019, 1150 patients were enrolled and 719 (62·5%) randomly assigned to nivolumab plus ipilimumab with two cycles of chemotherapy (n=361 [50%]) or four cycles of chemotherapy alone (n=358 [50%]). At the pre-planned interim analysis (median follow-up 9·7 months [IQR 6·4-12·8]), overall survival in all randomly assigned patients was significantly longer in the experimental group than in the control group (median 14·1 months [95% CI 13·2-16·2] vs 10·7 months [9·5-12·4]; hazard ratio [HR] 0·69 [96·71% CI 0·55-0·87]; p=0·00065). With 3·5 months longer median follow-up (median 13·2 months [IQR 6·4-17·0]), median overall survival was 15·6 months (95% CI 13·9-20·0) in the experimental group versus 10·9 months (9·5-12·6) in the control group (HR 0·66 [95% CI 0·55-0·80]). The most common grade 3-4 treatment-related adverse events were neutropenia (in 24 [7%] patients in the experimental group vs 32 [9%] in the control group), anaemia (21 [6%] vs 50 [14%]), diarrhoea (14 [4%] vs two [1%]), increased lipase (22 [6%] vs three [1%]), and asthenia (tjree [1%] vs eight [2%]). Serious treatment-related adverse events of any grade occurred in 106 (30%) patients in the experimental group and 62 (18%) in the control group. Seven (2%) deaths in the experimental group (acute kidney failure, diarrhoea, hepatotoxicity, hepatitis, pneumonitis, sepsis with acute renal insufficiency, and thrombocytopenia; one patient each) and six (2%) deaths in the control group (anaemia, febrile neutropenia, pancytopenia, pulmonary sepsis, respiratory failure, and sepsis; one patient each) were treatment related. INTERPRETATION: Nivolumab plus ipilimumab with two cycles of chemotherapy provided a significant improvement in overall survival versus chemotherapy alone and had a favourable risk-benefit profile. These data support this regimen as a new first-line treatment option for patients with advanced NSCLC. FUNDING: Bristol Myers Squibb.

Analysis of EML4-ALK rearrangement in non-small cell lung cancer in Argentina.

INTRODUCTION: Identification of EML4-ALK rearrangement by FISH test has become standard in advanced NSCLC patients. There is limited information about the prevalence and clinical characteristics of ALK translocation in Latin America. The aim of our study was to evaluate this lung cancer subtype features in Argentinian patients and the factibility of FISH test with different methods used for obtaining tissue samples. METHODS: Between August 2014 and February 2017, 183 non-squamous NSCLC patients were prospectively enrolled from five Argentinian institutions. Different techniques and procedures were used to obtained tissue samples material. ALK determination was performed by FISH and immunohistochemistry (IHC). Correlation with clinico-pathological information and different biopsy procedures was assessed. RESULTS: From 183 non-squamous NSCLC samples, 131 could perform FISH test, finding 123 (93.9%) negative and 8 (6.1%) positive patients. Fifty-one samples were not evaluable by FISH, 35 because of technical problems and 16 due to not/weak signal. The difficulties in obtaining adequate FISH tests were observed significantly more frequently for fine-needle aspiration (FNA) and core-needle biopsy than for excisional and incisional biopsy (p = 0.009). Regarding the procedures, surgery was the most efficient, obtaining only 12.7% (10/79) of not evaluable samples for FISH, while CT guided biopsy and transbronchial biopsy (TBB) failed in 43.8% (21/48) and 41.3% (19/46) of patients respectively (p < 0.001). We observed a significant association between ALK translocation and never smoking habit (p = 0.004). CONCLUSION: Our ALK rearrangements frequency (6.1%) was similar to the reports worldwide. One of the major determinants for the ALK FISH test success is the quality of the tissue sample obtained.

Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial.

BACKGROUND: Src kinase-mediated interactions between prostate cancer cells and osteoclasts might promote bone metastasis. Dasatinib inhibits tyrosine kinases, including Src kinases. Data suggests that dasatinib kinase inhibition leads to antitumour activity, affects osteoclasts, and has synergy with docetaxel, a first-line chemotherapy for metastatic castration-resistant prostate cancer. We assessed whether dasatinib plus docetaxel in chemotherapy-naive men with metastatic castration-resistant prostate cancer led to greater efficacy than with docetaxel alone. METHODS: In this double-blind, randomised, placebo-controlled phase 3 study, we enrolled men of 18 years or older with chemotherapy-naive, metastatic, castration-resistant prostate cancer, and adequate organ function from 186 centres across 25 countries. Eligible patients were randomly assigned (1:1) via an interactive voice response system to receive docetaxel (75 mg/m(2) intravenously every 3 weeks, plus oral prednisone 5 mg twice daily), plus either dasatinib (100 mg orally once daily) or placebo until disease progression or unacceptable toxicity. Randomisation was stratified by Eastern Cooperative Oncology Group performance status (0-1 vs 2), bisphosphonate use (yes vs no), and urinary N-telopeptide (uNTx) value (<60 µmol/mol creatinine vs ≥60 µmol/mol creatinine). All patients, investigators, and personnel involved in study conduct and data analyses were blinded to treatment allocation. The primary endpoint was overall survival, analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00744497. FINDINGS: Between Oct 30, 2008, and April 11, 2011, 1522 eligible patients were randomly assigned to treatment; 762 patients were assigned to dasatinib and 760 to placebo. At final analysis, median follow-up was 19·0 months (IQR 11·2-25·1) and 914 patients had died. Median overall survival was 21·5 months (95% CI 20·3-22·8) in the dasatinib group and 21·2 months (20·0-23·4) in the placebo group (stratified hazard ratio [HR] 0·99, 95·5% CI 0·87-1·13; p=0·90). The most common grade 3-4 adverse events included diarrhoea (58 [8%] patients in the dasatinib group vs 27 [4%] patients in the placebo group), fatigue (62 [8%] vs 42 [6%]), and asthenia (40 [5%] vs 23 [3%]); grade 3-4 pleural effusions were uncommon (ten [1%] vs three [<1%]). INTERPRETATION: The addition of dasatinib to docetaxel did not improve overall survival for chemotherapy-naive men with metastatic castration-resistant prostate cancer. This study does not support the combination of dasatinib and docetaxel in this population of patients. FUNDING: Bristol-Myers Squibb.

Five-year outcomes with first-line nivolumab plus ipilimumab with 2 cycles of chemotherapy versus 4 cycles of chemotherapy alone in patients with metastatic non-small cell lung cancer in the randomized CheckMate 9LA trial.

BACKGROUND: We report 5-year efficacy and safety outcomes from CheckMate 9LA in patients with metastatic non-small cell lung cancer (mNSCLC) and exploratory analyses in key patient subgroups. METHODS: Adults with stage IV/recurrent NSCLC and no sensitizing EGFR/ALK alterations were randomized to receive nivolumab plus ipilimumab with chemotherapy (n = 361) or chemotherapy (n = 358). Outcomes were assessed in all randomized patients and subgroups. RESULTS: With 57.3 months' minimum follow-up, patients continued to derive overall survival (OS) benefit with nivolumab plus ipilimumab with chemotherapy over chemotherapy (HR, 0.73; 95% CI, 0.62-0.85; 5-year OS rates, 18% vs. 11%), regardless of tumor programmed death ligand 1 (PD-L1) expression (PD-L1 < 1%, 22% vs. 8%; PD-L1 ≥ 1%, 18% vs. 11%), histology (squamous, 18% vs. 7%; non-squamous, 19% vs. 12%), or presence of baseline brain metastases (20% vs. 6%). Five-year duration of response (DOR) rates were 19% versus 8% with nivolumab plus ipilimumab with chemotherapy versus chemotherapy, with consistent benefit across subgroups. Patients who discontinued nivolumab plus ipilimumab with chemotherapy due to treatment-related adverse events had a 5-year OS rate of 37%. Five-year progression-free survival and DOR rates in 5-year survivors were 55% versus 38% and 59% versus 46%, respectively. No new safety signals were observed in 5-year survivors, regardless of the number of ipilimumab doses received. CONCLUSION: This 5-year update supports the long-term, durable OS benefit and improved 5-year survivorship with nivolumab plus ipilimumab with chemotherapy over chemotherapy in patients with mNSCLC, regardless of tumor PD-L1 expression or histology. GOV REGISTRATION: NCT03215706.

Four-year clinical update and treatment switching-adjusted outcomes with first-line nivolumab plus ipilimumab with chemotherapy for metastatic non-small cell lung cancer in the CheckMate 9LA randomized trial.

BACKGROUND: In CheckMate 9LA, nivolumab plus ipilimumab with chemotherapy prolonged overall survival (OS) versus chemotherapy regardless of tumor PD-L1 expression or histology. We report updated efficacy and safety in all randomized patients with a minimum 4-year follow-up and an exploratory treatment-switching adjustment analysis in all treated patients who received chemotherapy and subsequent immunotherapy. METHODS: Adults with stage IV/recurrent non-small cell lung cancer (NSCLC), no sensitizing EGFR/ALK alterations, and ECOG performance status ≤1 were randomized 1:1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with chemotherapy (two cycles) or chemotherapy (four cycles, with optional maintenance pemetrexed for the nonsquamous population). Assessments included OS, progression-free survival, and objective response rate. Exploratory analyses included efficacy by tumor PD-L1 expression and histology and in patients who discontinued nivolumab plus ipilimumab with chemotherapy due to treatment-related adverse events (TRAEs), and a treatment-switching adjustment analysis using inverse probability of censoring weighting. RESULTS: With a 47.9-month minimum follow-up for OS, nivolumab plus ipilimumab with chemotherapy continued to prolong OS over chemotherapy in all randomized patients (HR 0.74, 95% CI 0.63 to 0.87; 4-year OS rate: 21% versus 16%), regardless of tumor PD-L1 expression (HR (95% CI): PD-L1<1%, 0.66 (0.50 to 0.86) and ≥1%, 0.74 (0.60 to 0.92)) or histology (squamous, 0.64 (0.48 to 0.84) and non-squamous, 0.80 (0.66 to 0.97)). In patients who discontinued all components of nivolumab plus ipilimumab with chemotherapy due to TRAEs (n=61), the 4-year OS rate was 41%. With treatment-switching adjustment for the 36% of patients receiving subsequent immunotherapy in the chemotherapy arm, the estimated HR of nivolumab plus ipilimumab with chemotherapy versus chemotherapy was 0.66 (95% CI 0.55 to 0.80). No new safety signals were observed. CONCLUSIONS: In this 4-year update, patients treated with nivolumab plus ipilimumab with chemotherapy continued to have long-term, durable efficacy benefit over chemotherapy regardless of tumor PD-L1 expression and/or histology. A greater estimated relative OS benefit was observed after adjustment for subsequent immunotherapy use in the chemotherapy arm. These results further support nivolumab plus ipilimumab with chemotherapy as a first-line treatment for patients with metastatic/recurrent NSCLC, including those with tumor PD-L1<1% or squamous histology, populations with high unmet needs.

First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in metastatic non-small cell lung cancer: CheckMate 9LA 2-year patient-reported outcomes.

BACKGROUND: In CheckMate 9LA (NCT03215706), first-line nivolumab plus ipilimumab with chemotherapy (2 cycles) significantly improved overall survival versus chemotherapy (4 cycles) in patients with metastatic non-small cell lung cancer and no known sensitising epidermal growth factor receptor/anaplastic lymphoma kinase alterations. We present exploratory patient-reported outcomes (PROs; minimum follow-up, 2 years). METHODS: In patients (N = 719) randomised 1:1 to nivolumab plus ipilimumab with chemotherapy or chemotherapy alone, disease-related symptom burden and health-related quality of life were assessed using the Lung Cancer Symptom Scale (LCSS) and 3-level EQ-5D (EQ-5D-3L). Treatment-phase changes in LCSS average symptom burden index (ASBI), LCSS three-item global index (3-IGI) and EQ-5D-3L visual analogue scale (VAS) and utility index (UI) over time were analysed descriptively and using mixed-effect model repeated measures. Time-to-deterioration/improvement analyses were conducted. RESULTS: Treatment-phase PRO questionnaire completion rates were >80%. Mean treatment-phase changes showed no deterioration from baseline in both arms for LCSS ASBI/3-IGI and EQ-5D-3L VAS/UI; however, minimally important differences were not met. Mixed-effect model repeated measures analyses showed overall reduction in symptom burden from baseline for both arms; changes from baseline for LCSS 3-IGI and EQ-5D-3L VAS/UI were numerically improved with nivolumab plus ipilimumab with chemotherapy versus chemotherapy, but minimally important differences were not met. Nivolumab plus ipilimumab with chemotherapy delayed time-to-definitive-deterioration versus chemotherapy (LCSS ASBI: hazard ratio, 0.62 [95% confidence interval, 0.45-0.87]); results were similar across PRO measures. CONCLUSIONS: At 2-year minimum follow-up, first-line nivolumab plus ipilimumab with chemotherapy reduced the risk of definitive deterioration in disease-related symptom burden and health-related quality of life versus chemotherapy and maintained QoL in patients with metastatic non-small cell lung cancer. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT03215706.

HOLA COVID-19 Study: Evaluating the Impact of Caring for Patients With COVID-19 on Cancer Care Delivery in Latin America.

PURPOSE: The HOLA COVID-19 study sought to evaluate the impact of COVID-19 on oncology practices across Latin America (LATAM), challenges faced by physicians, and how practices and physicians adapted while delivering care to patients with cancer. METHODS: This international cross-sectional study of oncology physicians in LATAM included a 43-item anonymous online survey to evaluate changes and adaptations to clinical practice. Multivariable logistic regression analyses were used to evaluate the association of caring for patients with COVID-19 and changes to clinical practice. RESULTS: A total of 704 oncology physicians from 19 countries completed the survey. Among respondents, the most common specialty was general oncology (34%) and 56% of physicians had cared for patients with COVID-19. The majority of physicians (70%) noted a decrease in the number of new patients evaluated during the COVID-19 pandemic when compared with prepandemic, and 73% reported adopting the use of telemedicine in their practice. More than half (58%) of physicians reported making changes to the treatments that they offered to patients with cancer. In adjusted models, physicians who had cared for patients with COVID-19 had higher odds of changing the type of chemotherapy or treatments that they offered (adjusted odds ratio 1.81; 95% CI, 1.30 to 2.53) and of delaying chemotherapy start (adjusted odds ratio 2.05; 95% CI, 1.49 to 2.81). Physicians identified significant delays in access to radiation and surgical services, diagnostic tests, and supportive care. CONCLUSION: The COVID-19 pandemic has significantly disrupted global cancer care. Although changes to health care delivery are a necessary response to this global crisis, our study highlights the significant disruption and changes to the treatment plans of patients with cancer in LATAM resulting from the COVID-19 health care crisis.

The tale of TILs in breast cancer: A report from The International Immuno-Oncology Biomarker Working Group.

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.

Efficacy and Safety of Nivolumab in Previously Treated Patients With Non-Small-cell Lung Cancer: Real World Experience in Argentina.

BACKGROUND: Nivolumab was the first anti-programmed cell death 1 drug approved in Argentina for non-small-cell lung cancer treatment in the second-line setting. MATERIALS AND METHODS: The present study was a multicenter, observational, retrospective study of patients with progression to stage IV NSCLC during platinum-based chemotherapy who had received nivolumab monotherapy in a drug-expanded access program in Argentina. RESULTS: The data from 109 patients were assessed retrospectively for safety and clinical outcomes. The follow-up period was 8.83 months (interquartile range, 3.4-12.67); 57.8% were men, 29.4% were current smokers, and 78.0% had a diagnosis of nonsquamous cell cancer. The median number of chemotherapy lines before nivolumab was 2 (range, 1-4). Also, 59.6% had received radiotherapy and 89% had received platinum-based chemotherapy. The drug-related toxicity rate was 78.9%, the grade 2-3 toxicity rate was 28.4%, and 33.9% of patients had required corticosteroids. The treatment response was evaluated in 104 patients. The best response was a complete response in 2 (2%), partial response in 28 (27%), stable disease in 33 (32%), and progressive disease in 41 (39%). Univariate analysis revealed that the absence of corticosteroid use (P = .034), toxicity grade 1-3 (P = .0025), and performance status of ≤ 1 (P = .049) were associated with longer disease-free survival, performance status of ≤ 1 (P < .001), and toxicity grade 1-3 (P = .001) were associated with longer overall survival. On multivariate Cox regression analysis, toxicity grade 1-3 (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.24-0.81; P = .008) and age ≤ 50 years (HR, 0.28; 95% CI, 0.13-0.61; P = .001) were associated with longer progression-free survival and corticosteroid use was associated with shorter progression-free survival (HR, 2.06; 95% CI, 1.22-3.48; P = .007). CONCLUSIONS: The use of nivolumab in the real world setting in patients with heavily pretreated NSCLC was well tolerated and showed promising clinical efficacy. The performance status, use of corticosteroids, and immune-mediated toxicity seem to be the conditions that can affect the clinical outcomes.

Nivolumab plus ipilimumab versus chemotherapy as first-line treatment in advanced non-small-cell lung cancer with high tumour mutational burden: patient-reported outcomes results from the randomised, open-label, phase III CheckMate 227 trial.

BACKGROUND: In the phase III CheckMate 227 study, first-line nivolumab + ipilimumab significantly prolonged progression-free survival (co-primary end-point) versus chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC) and high tumour mutational burden (TMB; ≥10 mutations/megabase). AIM: To evaluate patient-reported outcomes (PROs) in this population. METHODS: Disease-related symptoms and general health status were assessed using the validated PRO questionnaires Lung Cancer Symptom Scale (LCSS) and EQ-5D, respectively. LCSS average symptom burden index (ASBI) and three-item global index (3-IGI) and EQ-5D visual analogue scale (VAS) and utility index (UI) scores and changes from baseline were analysed descriptively. Longitudinal changes were assessed by mixed-effect model repeated measures (MMRMs) and time to first deterioration/improvement analyses. RESULTS: In the high TMB population, PRO questionnaire completion rates were ∼90% at baseline and >80% for most on-treatment assessments. During treatment, mean changes from baseline with nivolumab + ipilimumab showed early, clinically meaningful improvements in LCSS ASBI/3-IGI and EQ-5D VAS/UI; with chemotherapy, symptoms and health-related quality of life remained stable (LCSS ASBI/3-IGI, EQ-5D UI) or improved following induction (EQ-5D VAS). MMRM-assessed changes in symptom burden were improved with nivolumab + ipilimumab versus chemotherapy. Symptom deterioration by week 12 was lower with nivolumab + ipilimumab versus chemotherapy (22.3% versus 35.0%; absolute risk reduction: 12.7% [95% confidence interval 2.4-22.5]), irrespective of discontinuation. Time to first deterioration was delayed with nivolumab + ipilimumab versus chemotherapy across LCSS and EQ-5D summary measures. CONCLUSION: First-line nivolumab + ipilimumab demonstrated early, sustained improvements in PROs versus chemotherapy in patients with advanced NSCLC and high TMB. CLINICAL TRIAL REGISTRATION: NCT02477826.

Gemcitabine administered as a short infusion versus a fixed dose rate in combination with cisplatin for the treatment of patients with advanced non-small cell lung cancer.

Previous studies have indicated that, in combination with cisplatin, fixed dose rate gemcitabine may be more efficacious than standard infusion gemcitabine. This open-label, randomised phase II study was aimed to compare the efficacy and safety of these regimens as treatment for advanced non-small cell lung cancer (NSCLC) in Latin American patients. Sixty-four patients were randomised to receive up to six cycles of treatment with cisplatin 75 mg/m(2) on Day 1 plus either gemcitabine 1000 mg/m(2) over 30 min on Days 1 and 8 of a 21-day cycle (standard arm, N=33) or gemcitabine 1000 mg/m(2) at a fixed dose rate of 10 mg/m(2)/min on Days 1 and 8 of a 21-day cycle (FDR arm, N=31). In the standard arm, 9 of 33 (27%) patients responded compared with 6 of 30 (20%) patients in the FDR arm (odds ratio: 0.67, 95% CI, 0.21-2.2; p=0.56). Median overall survival was 7.5 months in the standard arm and 9.9 months in the FDR arm. One-year survival rates were 35% and 37% in the standard arm and the FDR arm, respectively. Patients in the FDR arm experienced more grade 3/4 haematological toxicity than those in the standard arm (48% versus 21%). The results of this trial do not support FDR administration of gemcitabine in preference to the standard administration in Latin American patients with NSCLC.

Challenges in Facing the Lung Cancer Epidemic and Treating Advanced Disease in Latin America.

Lung cancer, the deadliest cancer worldwide, is of particular concern in Latin America. The rising incidence poses a myriad of challenges for the region, which struggles with limited resources to meet the health care needs of its low- and middle-income populations. In this environment, we are concerned that governments are relatively unaware of the pressing need to implement effective strategies for screening, diagnosis, and treatment of lung cancer. The region has also been slow in adopting molecularly-based therapies in the treatment of advanced disease: testing for epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangements are not routine, and access to targeted agents such as monoclonal antibodies and tyrosine kinase inhibitors is problematic. In this paper, we review the current situation in the management of lung cancer in Latin America, hoping that this initiative will help physicians, patient associations, industry, governments, and other stakeholders better face this epidemic in the near future.

Melanoma: oncogenic drivers and the immune system.

Advances and in-depth understanding of the biology of melanoma over the past 30 years have contributed to a change in the consideration of melanoma as one of the most therapy-resistant malignancies. The finding that oncogenic BRAF mutations drive tumor growth in up to 50% of melanomas led to a molecular therapy revolution for unresectable and metastatic disease. Moving beyond BRAF, inactivation of immune regulatory checkpoints that limit T cell responses to melanoma has provided targets for cancer immunotherapy. In this review, we discuss the molecular biology of melanoma and we focus on the recent advances of molecularly targeted and immunotherapeutic approaches.

Comentarios sobre inmunidad en melanoma y cánceres de pulmón y de riñón ESMO 2014 - Madrid, España / Comments on immunity in melanoma and cancers of the lung and kidney ESMO 2014 - Madrid, Spain

Desde hace muchos años, se conoce que la inmunidad tiene una relación importante con las enfermedades malignas. La inmunoterapia había tenido un éxito limitado en los tumores sólidos, con la excepción de los melanomas y de los carcinomas de células renales, donde el interferón alfa y la interleuquina 2 mostraron algún tipo de actividad. El sistema inmune está preparado para la defensa de factores patógenos externos. Los cánceres en humanos someten al huésped al reconocimiento de nuevos antígenos y dan lugar a mecanismos de defensa en contra de las células productoras; sin embargo, la enfermedad desarrolla mecanismos de evasión en contra de este sistema inmune. En los últimos tiempos, se han descubierto distintos check points que, al ser inhibidos, desactivan la inhibición, valga la redundancia, para que el huésped active su sistema defensivo. Con la aprobación, en marzo de 2011, del anticuerpo ipilimumab, un inhibidor de CTLA4 para el melanoma maligno, han aumentado las opciones para el tratamiento con inmunoterapia con esta medicación y con algunas de desarrollo posterior. Además, su estudio se ha expandido a otros tumores sólidos, como los que se alojan en el pulmón, el riñón, la próstata, la mama, la vejiga, el SNC y otros. Es objetivo de este artículo revisar las presentaciones más trascendentes en ESMO 2014 sobre melanoma y cánceres de pulmón y de riñón donde las experiencias son más avanzadas.

Irinotecan, oxaliplatin plus bolus 5-fluorouracil and low dose folinic acid every 2 weeks: a feasibility study in metastatic colorectal cancer patients.

OBJECTIVES: Irinotecan or oxaliplatin combined with 5-fluorouracil (5-FU) +/- folinic acid (FA) has changed the treatment standards for metastatic colorectal cancer (CRC). The oxaliplatin and irinotecan combination has reported consistent activity. The purpose of this phase II study was to assess the efficacy and safety of the simultaneous administration of a triple chemotherapy combination of oxaliplatin, irinotecan, 5-FU bolus, and FA. MATERIALS AND METHODS: Eligible patients had metastatic CRC with no prior oxaliplatin or irinotecan-based chemotherapy. Treatment consisted of oxaliplatin 85 mg/m2 followed by irinotecan 150 mg/m2, repeated every 15 days, with 5-FU 500 mg/m2 bolus and FA 20 mg/m2 on days 1, 8, and 15. An early amendment suppressed the day 8 5-FU/FA. RESULTS: Twenty-six eligible treated patients receiving 253 doses were assessed for toxicity. Myelosuppression was the most frequent toxicity; grade 3 to 4 neutropenia and febrile neutropenia occurred in 50% and 15% of patients, respectively. The treatment schedule modification, omitting the 5-FU dosing on day 8, considerably improved treatment compliance, reducing the incidence of febrile neutropenia, diarrhea, and asthenia. Among the 25 patients evaluable for efficacy, 10 had objective responses including 1 complete response (CR) (4%) and 9 partial responses (PR) (36%), giving an overall response rate of 40%. Median time to progression was 6.20 months [95% confidence interval (CI), 5.44-6.96]. Median overall survival was 12.95 months. CONCLUSIONS: The administration of a triple combination produced promising objective responses with acceptable toxicity but does not seem to produce an evident benefit in time-related parameters.

El cístico residual: es una entidad nosológica? / Residual cystic duct: is a nosologic entity?

Creemos que el cístico residual puede ser causante del cuadro clínico que manifiesta un operado de las vías biliares, cuando se han eliminado todas las causas que puedan desencadenar una signología semejante y aun así requiere la confirmación por la anatomía patológica y el seguimiento posterior del enfermo

Colestasis extrahepáticas benignas / Benign extrahepatic cholestasis

Se refieren a las distintas causas de colestasis, considerando en este artículo las producidas por lesiones benignas de las vías biliares extrahepáticas. Se pasa revista somera a 87 pacientes estudiados y su terapéutica

Estudio de fase II de navelbine + cisplatino + etopósido en el tratamiento del cáncer de pulmón no celulas pequeñas inoperable / Phase II with navelbine + cisplatin + etoposide in the treatment of inoperable non-small cell lung carcinoma

40 pacientes con cáncer de pulmón no células pequeñas avanzado no tratados previamente fueron incluídos en un estudio en fase II con vinorelbine 20 mg/m2 días 1 y 8, etopósido 60 mg/m2 días 1-3 y cisplatino 75 mg/m2 día 1 c/28 días por 6 ciclos. Hubo 31 hombres y 9 mujeres, siendo de 54 años el promedio de edad con "performance status" grado 0-2. Todos fueron evaluables para toxicidad y 31 lo fueron para respuesta. 10 pacientes se encontraban en estadio IIIb y 21 en estudio IV. Se obtuvieron 42 por ciento de respuestas objetivas y una sobrevida global de 9 meses, lo que justifica estudios posteriores.