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Pembrolizumab; Non-small-cell lung cancer Pembrolizumab; Cáncer de pulmón de células no pequeñas Pembrolizumab; Càncer de pulmó de cèl·lules no petites Clinical trials frequently include multiple end points that mature at different times. The initial report, typically on the based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We present 5-year outcomes from the phase 3 KEYNOTE-189 study (ClinicalTrials.gov identifier: NCT02578680). Eligible patients with previously untreated metastatic nonsquamous non-small-cell lung cancer without EGFR/ALK alterations were randomly assigned 2:1 to pembrolizumab 200 mg or placebo once every 3 weeks for up to 35 cycles with pemetrexed and investigator's choice of carboplatin/cisplatin for four cycles, followed by maintenance pemetrexed until disease progression or unacceptable toxicity. Primary end points were overall survival (OS) and progression-free survival (PFS). Among 616 randomly assigned patients (n = 410, pembrolizumab plus pemetrexed-platinum; n = 206, placebo plus pemetrexed-platinum), median time from random assignment to data cutoff (March 8, 2022) was 64.6 (range, 60.1-72.4) months. Hazard ratio (95% CI) for OS was 0.60 (0.50 to 0.72) and PFS was 0.50 (0.42 to 0.60) for pembrolizumab plus platinum-pemetrexed versus placebo plus platinum-pemetrexed. 5-year OS rates were 19.4% versus 11.3%. Toxicity was manageable. Among 57 patients who completed 35 cycles of pembrolizumab, objective response rate was 86.0% and 3-year OS rate after completing 35 cycles (approximately 5 years after random assignment) was 71.9%. Pembrolizumab plus pemetrexed-platinum maintained OS and PFS benefits versus placebo plus pemetrexed-platinum, regardless of programmed cell death ligand-1 expression. These data continue to support pembrolizumab plus pemetrexed-platinum as a standard of care in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations.

Introduction: This article describes the sociodemographic, occupational, and occupational risk factors of health personnel from four hospital institutions who provided frontline emergency care in the face of the COVID-19 pandemic. The objective of this work was to characterize the health personnel of four institutions that provided frontline care for the COVID-19 pandemic. Methods: A cross-sectional descriptive study was conducted in which sociodemographic and labor variables of 362 frontline health workers who faced the COVID-19 pandemic were explored. Data collection was carried out through digital self-completion. Results: Health technicians and nursing professionals represent 61% of the population studied, in relation to sex it was found that of 100% of those infected by COVID-19, 66% correspond to women; A statistical association was found between the work performance unit and the daily hours worked. Conclusions: The health workers who participated in the study, according to the work carried out, the highest prevalence within the sample belongs to technicians and nursing professionals; being the female sex the one that predominates in these institutions and the same group with the highest frequency of contagion by COVID-19. Likewise, it was shown that in the Emergency services and in the Intensive Care Unit the shifts are extensive since they work ≥ 12 hours for 4 days a week, these being the most contagious services.

Este artículo tiene como objetivo analizar el uso de Twitter como canal de comunicación por parte delpresidente de El Salvador, Nayib Bukele (@nayibbukele), outsider, a su vez considerado el presidente‘millennial’ de dicha nación y quien emplea fuertemente esta plataforma digital para la difusión de suspolíticas de gobierno. El presente análisis se fundamenta y justifica en el contexto del COVID-19, caracterizado por la toma de medidas restrictivas de confinamiento a nivel regional y local, con una fuertepugna entre el ejecutivo y el aparato legislativo salvadoreño, así como la afectación del virus a todos losrincones del planeta. Como temporalidad se toma el trimestre abril-junio de 2020, para un corpus totalde 766 mensajes. Por medio del análisis de contenido se analiza el rol del actor político en una crisissanitaria, la presencia de pugnas con la clase política, la construcción de la categoría de pueblo de formaaplicada a la nacionalidad centroamericana, la polarización presente en su agenda y otros elementos deinterés dentro en la construcción de la dicotomía ‘nosotros-ellos’ en un entorno digital. El principal hallazgoes que Bukele se enmarca dentro de dos caracterizaciones; la primera aunada a confrontar actorespolíticos y sociales (principalmente el aparato legislativo), entorno fuertemente marcado por la polarización;y la segunda, donde conecta con la ciudadanía a través del carisma y del uso de un lenguaje cercanoy positivo, en cuyos casos la polarización se torna un elemento ausente y se apela a la integración.

Cancer patients can experience flares of pain, called breakthrough pain (BTcP), despite treatment with painkillers. Although BTcP can be excruciating, its intensity and other characteristics depend on several factors, including its treatment. However, even if treated, BTcP can impair quality of life for cancer patients. We assessed quality of life in 118 patients with advanced cancer and BTcP treated in 13 medical oncology departments across Spain. We treated BTcP with individualized therapy, taking into account both pain-related and patient-related factors. We also measured quality of life using a specific, widely-used questionnaire at the study visits: at onset of individualized pain therapy and after 3, 15 and 30 days’ treatment. At each visit, flare-up pain therapy was adjusted or maintained as necessary. Throughout the study, quality of life and sleep quality improved for all participants. Furthermore, there was a greater reduction in intensity, duration and frequency of BTcP. The most common treatments for flare-ups were low doses of rapid-onset opioids (fentanyl given by sublingual, buccal or nasal administration), which were much better tolerated than high-dose opioids. Overall, the study showed that quality of life in patients with advanced cancer and BTcP increased after individualized pain therapy, mainly with low doses of rapid-onset opioids.

We aimed to compare the efficacy and safety of maintaining or withdrawing abiraterone acetate plus prednisone (AAP) in patients with metastatic castration-resistant prostate cancer who had experienced cancer progression to this treatment and were beginning a docetaxel-based therapy. Phase II, randomised, open-label study conducted in patients with metastatic castration-resistant prostate cancer who were asymptomatic or mildly symptomatic. After open-label treatment with AAP, patients who had experienced cancer progression to AAP were randomised to 75 mg/m2 of docetaxel plus AAP or to receive 75 mg/m2 of docetaxel plus 10 mg of prednisone orally daily. The primary outcome was the radiographic progression-free survival rate at 12 months as evaluated by the investigators in all randomised patients. A total of 148 patients were included in open-label treatment with AAP, and of them, 94 patients were randomised to receive either docetaxel plus AAP (intervention group; n = 47) or docetaxel plus prednisone (control group; n = 47). The 12-month radiographic progression-free survival rates did not differ between the intervention group (34.9%; 95% CI 20.7-49.2) and the control group (33.9%; 95% CI 19.5-48.3). There were no significant differences in the time to radiographic progression and the overall survival between the intervention and control groups. Grade 3-5 neutropenia with the combination of docetaxel plus prednisone and AA was more frequent than with docetaxel plus prednisone (59.6% versus 27.7%). Our results indicate that the therapeutic strategy of maintaining AAP added to docetaxel in chemotherapy-naïve patients who have experienced cancer progression to AAP treatment should not be further evaluated and should be avoided in clinical practice. NCT02036060 https://clinicaltrials.gov/ct2/show/NCT02036060.

Background In the phase III KEYNOTE-189 study (NCT02578680), pembrolizumab plus pemetrexed and platinum-based chemotherapy (pemetrexed–platinum) significantly improved overall survival (OS) and progression-free survival (PFS) in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC) versus placebo plus pemetrexed–platinum. We report updated efficacy outcomes from the protocol-specified final analysis, including outcomes in patients who crossed over to pembrolizumab from pemetrexed–platinum and in patients who completed 35 cycles (∼2 years) of pembrolizumab. Patients and methods Eligible patients were randomized 2 : 1 to receive pembrolizumab 200 mg (n = 410) or placebo (n = 206) every 3 weeks (for up to 35 cycles, ∼2 years) plus four cycles of pemetrexed (500 mg/m2) and investigators’ choice of cisplatin (75 mg/m2) or carboplatin (area under the curve 5 mg·min/ml) every 3 weeks, followed by pemetrexed until progression. Patients assigned to placebo plus pemetrexed–platinum could cross over to pembrolizumab upon progression if eligibility criteria were met. The primary endpoints were OS and PFS. Results After a median follow-up of 31.0 months, pembrolizumab plus pemetrexed–platinum continued to improve OS [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.46-0.69] and PFS (HR, 0.49; 95% CI, 0.41-0.59) over placebo plus pemetrexed–platinum regardless of programmed death-ligand 1 expression. Objective response rate (ORR) (48.3% versus 19.9%) and time to second/subsequent tumor progression on next-line treatment (PFS2; HR, 0.50; 95% CI, 0.41-0.61) were improved in patients who received pembrolizumab plus pemetrexed–platinum. Eighty-four patients (40.8%) from the placebo plus pemetrexed–platinum group crossed over to pembrolizumab on-study. Grade 3-5 adverse events occurred in 72.1% of patients receiving pembrolizumab plus pemetrexed–platinum and 66.8% of patients receiving placebo plus pemetrexed–platinum. Fifty-six patients completed 35 cycles (∼2 years) of pembrolizumab; ORR was 85.7% and 53 (94.6%) were alive at data cut-off. Conclusions Pembrolizumab plus pemetrexed–platinum continued to show improved efficacy outcomes compared with placebo plus pemetrexed–platinum, with manageable toxicity. These findings support first-line pembrolizumab plus pemetrexed–platinum in patients with previously untreated metastatic nonsquamous NSCLC.

Purpose: Cancer and its treatments changes patients’ quality of life. The aim was to analyze quality of life, psychological distress, and life satisfaction in patients with resected versus unresectable cancer.Methods: Two prospective, multicenter (15 medical oncology departments), studies with consecutive patient recluitment were conducted, NEOetic, in individuals with unresectable advanced disease (2020-2021) and NEOcoping, in subjects with resected non-metastatic cancer (2016-2018). Participants completed quality of life (EORTC QLQ-C30), emotional distress (Brief Symptom Inventory, BSI), and life satisfaction (Satisfaction with Life Scale, SWLS) questionnaires before systemic antineoplastic treatment and after treatment. A descriptive, bivariate chi-square analysis and t-tests were performed to ascertain the differences between localized and advanced cancer.Results: A total of 1450 patients were recruited, 941 (65%) with a resected cancer and 509 with unresectable advanced cancer with a mean age of 59.0 and 64.9 years, respectively. The most common cancers were colorectal (42%) and breast (34%) in resected group and bronchopulmonary (29%), colorectal (17%), and pancreatic (11%) in unresectable advanced cancer group. Subjects with advanced disease exhibited worse scores on functional scales (physical, cognitive, emotional, and social), and had more symptoms than those with resected disease prior to initiating systemic treatment. Individuals with advanced cancer displayed better functional status and fewer symptoms, but more fatigue and nausea and those with resected cancer presented worse physical and cognitive function, more psychological distress, and more symptoms post-treatment. Conclusion: This sample reveals how antineoplastic treatment can enhance quality of life for people with unresectable advanced disease and negatively affect individuals with resected, non-metastatic cancer.Structured Abstract: Our study shows the potential quality of life benefit of systemic antineoplastic treatment in patients with unresectable advanced cancer. In addition, it shows the deterioration of quality of life in patients with resected non-metastatic cancer after completion of adjuvant treatment.

Background: 1L pembro + platinum-based chemo has shown clinical activity in metastatic NSCLC regardless of tissue tumor mutational burden (tTMB) status. bTMB assessed using circulating tumor DNA in plasma may be a surrogate for tTMB. The single-arm, phase 2 KEYNOTE-782 study (NCT03664024) evaluated the correlation of bTMB with efficacy of 1L pembro + chemo in nonsquamous NSCLC. Methods: Eligible patients (pts) had histologically or cytologically confirmed stage IV nonsquamous NSCLC with measurable disease per RECIST v1.1 and were not eligible for EGFR-, BRAF-, ROS1-, or ALK-directed therapy. Pts were not previously treated for advanced or metastatic disease, had an ECOG PS of 0 or 1, and had an evaluable biopsy sample for biomarker analysis. All pts received intravenous pembro 200 mg Q3W + platinum chemo doublet Q3W (pemetrexed 500 mg/m2 + 4 cycles of carboplatin AUC 5 mg/mL/min or cisplatin 75 mg/m2). The primary objective was to evaluate the association of baseline bTMB with ORR per RECIST v1.1 by investigator assessment. Secondary objectives were to determine safety and the association of baseline bTMB with PFS per RECIST v1.1 by investigator assessment and OS. A study-specific next-generation sequencing-based assay using a 1.9 Mb/654-gene cancer panel, which includes specific lung cancer-associated gene targets, was used to measure bTMB (continuous scale) in cell-free DNA extracted from baseline plasma samples. Paired white blood cell DNA sequencing was also performed to eliminate potential clonal hematopoiesis-derived somatic mutations. Database cutoff: November 5, 2021. Results: 117 pts were enrolled; median age was 64.0 years (range, 37-85), and the majority were male (60.7%), had an ECOG PS of 1 (69.2%), and no brain metastases at baseline (92.3%). Median time from first dose to data cutoff was 19.3 months (range, 1.0-35.5). ORR was 40.2% (95% CI, 31.2-49.6; 6 CRs, 41 PRs), median PFS was 7.2 months (95% CI, 5.6-9.8), and median OS was 18.1 months (95% CI, 13.5-25.6). Treatment-related adverse events (TRAEs) occurred in 113 pts (96.6%) and grade 3-5 TRAEs occurred in 56 (47.9%). Eight pts (6.8%) died due to a TRAE (febrile neutropenia and pneumonitis [n = 2 each], and septic shock, pulmonary sepsis, general physical health deterioration, and neutropenia [n = 1 each]). bTMB data were available for 101 pts. The area under the receiver operating curve for bTMB as a continuous variable to discriminate response was 0.47 (95% CI, 0.36-0.59). The posterior probabilities for a positive association of bTMB with PFS and OS were 16.8% and 7.8%, respectively. Conclusions: Baseline bTMB showed no evidence of an association with ORR, PFS, or OS in pts with nonsquamous NSCLC treated with 1L pembro + chemo. These findings indicate no clinical utility of bTMB in this patient population and treatment setting. No new safety signals were observed. Citation Format: Jair Bar, Emilio Esteban, Delvys Rodríguez-Abreu, Santiago Ponce Aix, Zsuzsanna Szalai, Enriqueta Felip, Maya Gottfried, Mariano Provencio Pulla, Andrew Robinson, Andrea Fülöp, Suman B. Rao, D. Ross Camidge, Giovanna Speranza, Steven M. Townson, Julie Kobie, Mark Ayers, Elisha J. Dettman, Robert McDaniel, Byoungsok Jung, David Burkhardt, Ruth Mauntz, Tibor Csőszi. Response to first-line (1L) pembrolizumab (pembro) + chemotherapy (chemo) in non-small cell lung cancer (NSCLC) by blood tumor mutational burden (bTMB): the phase 2 KEYNOTE-782 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT216.

PURPOSE In KEYNOTE-189, first-line pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus pemetrexed-platinum in patients with metastatic nonsquamous non‒small-cell lung cancer (NSCLC), irrespective of tumor programmed death-ligand 1 (PD-L1) expression. We report an updated analysis from KEYNOTE-189 (ClinicalTrials.gov: NCT02578680 ). METHODS Patients were randomly assigned (2:1) to receive pemetrexed and platinum plus pembrolizumab (n = 410) or placebo (n = 206) every 3 weeks for 4 cycles, then pemetrexed maintenance plus pembrolizumab or placebo for up to a total of 35 cycles. Eligible patients with disease progression in the placebo-combination group could cross over to pembrolizumab monotherapy. Response was assessed per RECIST (version 1.1) by central review. No alpha was assigned to this updated analysis. RESULTS As of September 21, 2018 (median follow-up, 23.1 months), the updated median (95% CI) OS was 22.0 (19.5 to 25.2) months in the pembrolizumab-combination group versus 10.7 (8.7 to 13.6) months in the placebo-combination group (hazard ratio [HR], 0.56; 95% CI, 0.45 to 0.70]). Median (95% CI) PFS was 9.0 (8.1 to 9.9) months and 4.9 (4.7 to 5.5) months, respectively (HR, 0.48; 95% CI, 0.40 to 0.58). Median (95% CI) time from randomization to objective tumor progression on next-line treatment or death from any cause, whichever occurred first (progression-free-survival-2; PFS-2) was 17.0 (15.1 to 19.4) months and 9.0 (7.6 to 10.4) months, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). OS and PFS benefits with pembrolizumab were observed regardless of PD-L1 expression or presence of liver/brain metastases. Incidence of grade 3-5 adverse events was similar in the pembrolizumab-combination (71.9%) and placebo-combination (66.8%) groups. CONCLUSION First-line pembrolizumab plus pemetrexed-platinum continued to demonstrate substantially improved OS and PFS in metastatic nonsquamous NSCLC, regardless of PD-L1 expression or liver/brain metastases, with manageable safety and tolerability.

Sunitinib and pazopanib are standard first-line treatments for patients with metastatic renal cell carcinoma (mRCC). Nonetheless, as the number of treatment options increases, there is a need to identify biomarkers that can predict drug efficacy and toxicity. In this prospective study we evaluated a set of biomarkers that had been previously identified within a secretory signature in mRCC patients. This set includes tumor expression of c-Met and serum levels of HGF, IL-6, IL-8, CXCL9, CXCL10 and CXCL11. Our cohort included 60 patients with mRCC from 10 different Spanish hospitals who received sunitinib (n = 51), pazopanib (n = 4) or both (n = 5). Levels of biomarkers were studied in relation to response rate, progression-free survival (PFS) and overall survival (OS). High tumor expression of c-Met and high basal serum levels of HGF, IL-6, CXCL11 and CXCL10 were significantly associated with reduced PFS and/or OS. In multivariable Cox regression analysis, CXCL11 was identified as an independent biomarker predictive of shorter PFS and OS, and HGF was an independent predictor of reduced PFS. Correlation analyses using our cohort of patients and patients from TCGA showed that HGF levels were significantly correlated with those of IL-6, CXCL11 and CXCL10. Bioinformatic protein–protein network analysis revealed a significant interaction between these proteins, all this suggesting a coordinated expression and secretion. We also developed a prognostic index that considers this group of biomarkers, where high values in mRCC patients can predict higher risk of relapse (HR 5.28 [2.32–12.0], p &lt, 0.0001). In conclusion, high plasma HGF, CXCL11, CXCL10 and IL-6 levels are associated with worse outcome in mRCC patients treated with sunitinib or pazopanib. Our findings also suggest that these factors may constitute a secretory cluster that acts coordinately to promote tumor growth and resistance to antiangiogenic therapy.

Five agarose types (D1LE, D2LE, LM, MS8 and D5) were evaluated in tissue engineering and compared for the first time using an array of analysis methods. Acellular and cellular constructs were generated from 0.3–3%, and their biomechanical properties, in vivo biocompatibility (as determined by LIVE/DEAD, WST-1 and DNA release, with n = 6 per sample) and in vivo biocompatibility (by hematological and biochemical analyses and histology, with n = 4 animals per agarose type) were analyzed. Results revealed that the biomechanical properties of each hydrogel were related to the agarose concentration (p < 0.001). Regarding the agarose type, the highest (p < 0.001) Young modulus, stress at fracture and break load were D1LE, D2LE and D5, whereas the strain at fracture was higher in D5 and MS8 at 3% (p < 0.05). All agaroses showed high biocompatibility on human skin cells, especially in indirect contact, with a correlation with agarose concentration (p = 0.0074 for LIVE/DEAD and p = 0.0014 for WST-1) and type, although cell function tended to decrease in direct contact with highly concentrated agaroses. All agaroses were safe in vivo, with no systemic effects as determined by hematological and biochemical analysis and histology of major organs. Locally, implants were partially encapsulated and a pro-regenerative response with abundant M2- type macrophages was found. In summary, we may state that all these agarose types can be safely used in tissue engineering and that the biomechanical properties and biocompatibility were strongly associated to the agarose concentration in the hydrogel and partially associated to the agarose type. These results open the door to the generation of specific agarose-based hydrogels for definite clinical applications such as the human skin, cornea or oral mucosa., Hispanagar SA, Burgos, Spain, through CDTI, Ministry of Science and Innovation, Spain, Programa Operativo Plurirregional de Crecimiento Inteligente (CRIN) IDI-20180052, ISCIII thorough AES AC17/00013, Junta de Andalucía PE-0395-2019, Spanish Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (I+D+i) from Ministerio de Ciencia, Innovación y Universidades (Instituto de Salud Carlos III) FIS PI17/0391, Fondo Europeo de Desarrollo Regional ERDF-FEDER, European Union PI20/0317

Background: AURA study reported 61% objective response rate and progression-free survival of 9.6 months with osimertinib in patients with EGFR/T790M+ non-small cell lung cancer. Due to lack of real-world data, we proposed this study to describe the experience with osimertinib in Spain.Methods: Post-authorization, non-interventional Special Use Medication Program, multicenter, retrospective study in advanced EGFR/T790M+ non-small cell lung cancer. 155 patients were enrolled (August 2016-December 2018) from 30 sites. Primary objective: progression-free survival. Secondary objectives: toxicity profile, objective response rate, and use of health service resources.Results: 70% women, median age 66. 63.9% were non-smokers and 99% had adenocarcinoma. Most had received at least one prior treatment (97%), 91.7% had received previous EGFR-tyrosine kinase inhibitors and 2.8% osimertinib as first-line treatment. At data cutoff, median follow-up was 11.8 months. 155 patients were evaluable for response, 1.3% complete response, 40.7% partial response, 31% stable disease and 11.6% progressive disease. Objective response rate was 42%. Median progression-free survival was 9.4 months. 49% reported an adverse event, the majority of which (78%) were grade 1 or 2. The resource cost study indicates early use is warranted. Conclusion: This study to assess the real-world clinical impact of osimertinib showed high drug activity in pretreated advanced EGFR/T790M+ non-small cell lung cancer, with manageable adverse events.Clinical trial registration number: NCT03790397

Aim: To report results from the Spanish subset included in the radium-223 international early access program (iEAP). Patients & methods: Ninety patients with castration-resistant prostate cancer and bone metastases received radium-223 55 kBq/kg every 4 weeks for six cycles. Results: The median time to disease progression was 8 months and to prostate-specific antigen progression was 4 months. The percentage of patients with ≥50% confirmed declines in prostate-specific antigen was 9%. The median overall survival was 14 months. Grade 3 or 4 treatment emergent adverse events (TEAEs) occurred in 34% of patients (serious TEAEs 28%, TEAEs leading to discontinuation 27%). Conclusion: Outcomes of the Spanish subset are consistent with the iEAP. Radium-223 was generally well tolerated with no safety concerns.

8567 Background: Clinical trial (CT) IMpower133 met both primary endpoints and is the first CT to show significant clinical improvement over standard chemotherapy (C) with a good safety profile in first line (1L) ES-SCLC. The addition of ATZ to CB + ET resulted in an OS landmark of 34% and 22% compared to 21% and 16.8% of patients alive at 18 and 24 months respectively versus C. IMfirst evaluates ATZ + CB or CP + ET in a broader patient population than the pivotal study. ECOG Performance status (PS) 2, asymptomatic untreated brain metastases, underlying stable autoimmune diseases and HIV+ pts are eligible. IMfirst also includes the possibility of 6 C induction cycles according to investigator´s choice and consolidation radiotherapy. Methods: To evaluate the safety and efficacy of ATZ added to CB or CP + ET as 1L treatment in an interventional real world setting of ES-SCLC. Exploratory endpoints include tumor biomarker analysis related to ATZ. Results: As of Oct 2020, 117 pts had been enrolled, 105 treated with ATZ + CB + ET and 12 with ATZ + CP + ET. The median age was 65 years (Y) (range 35-89); 84 males; 14 pts (12%) had CNS metastases and 66 pts were current smokers and 50 former smokers, one had never smoked. The PS was 0 in 28 pts (24%), 1 in 75 (64%) and 2 in 14 (12%). The median of cycles of ATZ received was 4 for all the pts (range 1-12) and 2 for the pts (40) in maintenance phase (range 1-8). Number of pts with adverse events (AEs) was 109, 36 with Serious Adverse Events (SAEs) and 63 with AEs. 8 pts had SAEs related to treatment, 4 had adverse events of special interest and 13 pts discontinued the treatment due to AEs: 6 to ATZ, 12 to CB or CP and 10 to ET, 1 patient discontinued ATZ due to a related AE. Table shows the treatment related AEs (TRAEs). No grade 5 TRAEs were reported. Conclusions: IMfirst induction phase analysis confirms the safety profile of ATZ plus C in a broader population of patients. Efficacy, biomarker and further safety analyses will be presented in the future with longer follow up.[Table: see text]

Updated information published up to 2016 regarding major advances in renal cancer, bladder cancer, and prostate cancer is here presented. Based on an ever better understanding of the genetic and molecular alterations that govern the initial pathogenic mechanisms of tumor oncogenesis, an improvement in the characterization and treatment of urologic tumors has been achieved in the past year. According to the Cancer Genome Atlas (ATLAS) project, alterations in the MET pathway are characteristics of type 1 papillary renal cell carcinomas, and activation of NRF2-ARE pathway is associated with the biologically distinct type 2. While sunitinib and pazopanib continue to be the standard first-line treatment in metastatic renal cell carcinoma of clear cell histology, nivolumab and cabozantinib are now the agents of choice in the second-line setting. In relation to urothelial bladder carcinoma, new potential molecular targets such as FGFR3, PI3K/AKT, RTK/RAS, CDKN2A, ARIDIA, ERBB2 have been identified. Response to adjuvant cisplatin-based chemotherapy appears to be related to basal, luminal, and p53-like intrinsic subtypes. A phase II study with eribulin and a maintenance phase II trial with vinflunine have shown promising results. Similarly, the use of the check point inhibitors in advanced disease is likely to revolutionize the management of patients who have progressed after cisplatin-based chemotherapy. In prostate cancer, seven mutually exclusive molecular subtypes have been identified by the TCGA project. Chemotherapy has been consolidated as a key treatment for castration-sensitive metastatic prostate cancer, and abiraterone, enzalutamide, cabazitaxel, and radium-223 remain standard therapeutic options for men with metastatic castration-resistant prostate cancer. All this progress will undoubtedly contribute to the development of new treatments and therapeutic strategies that will improve the survival and quality of life of our patients.

Background KRAS mutations are observed in ∼25% of lung adenocarcinomas, with some studies suggesting it is a prognostic factor in NSCLC. We assessed the prevalence of KRAS mutations and their association with efficacy in an exploratory analysis of the KEYNOTE-189 study of pembrolizumab plus pemetrexed and platinum chemotherapy vs placebo plus chemotherapy as first-line therapy for metastatic non-squamous NSCLC (NCT02578680). Methods Whole-exome sequencing (WES) was used to assess KRAS status and tumor mutational burden (TMB) in participants (pts) who had available tumor and matched-normal tissue. Descriptive analyses of the association of KRAS and KRAS G12C status with efficacy were included as part of this exploratory analysis, as was correlation between KRAS mutational status and shifts in TMB and PD-L1 expression distributions. Results 289 (47%) of 616 pts had evaluable WES data from both tumor and normal DNA. 89 (31%) of 289 pts had KRAS mutation, including 37 (13%) G12C carriers. Pts with vs without KRAS mutations tended to have higher PD-L1 TPS (median [IQR] 30% [1-71] vs 5% [0-60]) and higher TMB (median [IQR] 204 [137-276] vs 141 [85-252] mut/exome). Outcomes of pembrolizumab plus chemotherapy and of placebo plus chemotherapy in pts with and without KRAS mutation and in KRAS G12C carriers are summarized in the table. 95% CIs were wide given the modest frequency of KRAS mutation, particularly KRAS G12C, and the 2:1 randomization that resulted in small populations for placebo plus chemotherapy.TableLBA5TableWith Any KRAS MutationWith KRAS G12C MutationWithout Any KRAS MutationPembro + Chemo (N = 59)Placebo + Chemo (N = 30)Pembro + Chemo (N = 26)Placebo + Chemo (N = 11)Pembro + Chemo (N = 145)Placebo + Chemo (N = 55)ORR, % (95% CI)40.726.750.018.247.610.9(28.1-54.3)(12.3-45.9)(29.9-70.1)(2.3-51.8)(39.2-56.0)(4.1-22.3)PFS, median, mo (95% CI)9 (7-14)5 (5-9)11 (6-18)5 (5-NR)9 (7-14)5 (4-5)PFS, HR (95% CI)0.47 (0.29-0.77)0.48 (0.22-1.06)0.40 (0.29-0.57)OS, median, mo (95% CI)21 (16-NR)14 (8-NR)18 (11-NR)25 (8-NR)23 (19-NR)9 (7-17)OS, HR (95% CI)0.79 (0.45-1.38)1.14 (0.45-2.92)0.55 (0.37-0.81) Conclusion Based on this descriptive exploratory analysis, pembrolizumab plus pemetrexed and a platinum should be a standard first-line treatment for pts with metastatic non-squamous NSCLC regardless of KRAS mutation status. Clinical trial identification KEYNOTE-189, NCT02578680. Editorial acknowledgement Joanne Tomassini and Melanie Leiby, both of Merck & Co., Inc., Kenilworth, NJ, USA, for writing support. Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure S. Gadgeel: Advisory / Consultancy: Boehringer-Ingelheim; Advisory / Consultancy: Xcovery; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Novocure; Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech/Roche; Advisory / Consultancy: Takeda; Research grant / Funding (institution): Merck Sharp & Dohme; Advisory / Consultancy: Pharmamar. D. Rodriguez-Abreu: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Honoraria (self), Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis. E. Felip: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche; Advisory / Consultancy, Research grant / Funding (institution): Merck Sharp & Dohme; Advisory / Consultancy: Abbvie; Honoraria (self), lecture fees: AstraZeneca; Honoraria (self), lecture fees: Bristol Myers Squibb; Honoraria (self), lecture fees: Novartis. E. Esteban: Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Novartis; Research grant / Funding (institution): MSD. G. Speranza: Research grant / Funding (institution): MSD. M. Reck: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Merck ; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy: Eli LIlly; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Abbvie; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis. R. Hui: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Roche; Advisory / Consultancy: Eli Lilly. M. Boyer: Honoraria (self), Honoraria (institution), Research grant / Funding (institution): AstraZeneca; Honoraria (institution), Research grant / Funding (institution): MSD; Honoraria (institution): Roche; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Beigene; Research grant / Funding (institution): Ascentage Pharma; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Janssen. E.B. Garon: Honoraria (self): Dracen; Honoraria (self), Research grant / Funding (institution): EMD Serono; Honoraria (self), Research grant / Funding (institution): Novartis; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Dynavax; Research grant / Funding (institution): Iovance; Research grant / Funding (institution): Mirati; Research grant / Funding (institution): Neon; Research grant / Funding (institution): MSD. H. Horinouchi: Honoraria (self), Advisory / Consultancy: Eli LIlly; Honoraria (self), Research grant / Funding (institution): BMS; Honoraria (self), Research grant / Funding (institution): ONO; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self): Kyowa-Kirin; Honoraria (self): Taiho; Research grant / Funding (institution): Daiichi-Sankyo; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Chugai/Roche; Research grant / Funding (institution): Genomic Health. R. Cristescu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. D. Aurora-Garg: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. J. Lunceford: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. J. Kobie: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. M. Ayers: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. B. Piperdi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. M.C. Pietanza: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. M.C. Garassino: Advisory / Consultancy, Research grant / Funding (institution): MSD; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Otsuka Pharma; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Celgene; Advisory / Consultancy: Incyte; Advisory / Consultancy: Takeda; Advisory / Consultancy: Inivata; Advisory / Consultancy: Takeda; Research grant / Funding (institution): Tiziana Sciences; Research grant / Funding (institution): Clovis; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): GSK; Advisory / Consultancy: Sanofi-Aventis; Research grant / Funding (institution): Spectrum Pharmaceuticals.

Summary Background Fewer than half of the patients with completely resected non-small-cell lung cancer (NSCLC) are cured. Since the introduction of adjuvant chemotherapy in 2004, no substantial progress has been made in adjuvant treatment. We aimed to assess the efficacy of the MAGE-A3 cancer immunotherapeutic in surgically resected NSCLC. Methods In this randomised, double-blind, placebo-controlled trial, we recruited patients aged at least 18 years with completely resected stage IB, II, and IIIA MAGE-A3-positive NSCLC who did or did not receive adjuvant chemotherapy from 443 centres in 34 countries (Europe, the Americas, and Asia Pacific). Patients were randomly assigned (2:1) to receive 13 intramuscular injections of recMAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic) or placebo during 27 months. Randomisation and treatment allocation at the investigator site was done centrally via internet with stratification for chemotherapy versus no chemotherapy. Participants, investigators, and those assessing outcomes were masked to group assignment. A minimisation algorithm accounted for the number of chemotherapy cycles received, disease stage, lymph node sampling procedure, performance status score, and lifetime smoking status. The primary endpoint was broken up into three co-primary objectives: disease-free survival in the overall population, the no-chemotherapy population, and patients with a potentially predictive gene signature. The final analyses included the total treated population (all patients who had received at least one treatment dose). This trial is registered with ClinicalTrials.gov, number NCT00480025. Findings Between Oct 18, 2007, and July 17, 2012, we screened 13 849 patients for MAGE-A3 expression; 12 820 had a valid sample and of these, 4210 (33%) had a MAGE-A3-positive tumour. 2312 of these patients met all eligibility criteria and were randomly assigned to treatment: 1515 received MAGE-A3 and 757 received placebo and 40 were randomly assigned but never started treatment. 784 patients in the MAGE-A3 group also received chemotherapy, as did 392 in the placebo group. Median follow-up was 38·1 months (IQR 27·9–48·4) in the MAGE-A3 group and 39·5 months (27·9–50·4) in the placebo group. In the overall population, median disease-free survival was 60·5 months (95% CI 57·2–not reached) for the MAGE-A3 immunotherapeutic group and 57·9 months (55·7–not reached) for the placebo group (hazard ratio [HR] 1·02, 95% CI 0·89–1·18; p=0·74). Of the patients who did not receive chemotherapy, median disease-free survival was 58·0 months (95% CI 56·6–not reached) in those in the MAGE-A3 group and 56·9 months (44·4–not reached) in the placebo group (HR 0·97, 95% CI 0·80–1·18; p=0·76). Because of the absence of treatment effect, we could not identify a gene signature predictive of clinical benefit to MAGE-A3 immunotherapeutic. The frequency of grade 3 or worse adverse events was similar between treatment groups (246 [16%] of 1515 patients in the MAGE-A3 group and 122 [16%] of 757 in the placebo group). The most frequently reported grade 3 or higher adverse events were infections and infestations (37 [2%] in the MAGE-A3 group and 19 [3%] in the placebo group), vascular disorders (30 [2%] vs 17 [3%]), and neoplasm (benign, malignant, and unspecified (29 [2%] vs 16 [2%]). Interpretation Adjuvant treatment with the MAGE-A3 immunotherapeutic did not increase disease-free survival compared with placebo in patients with MAGE-A3-positive surgically resected NSCLC. Based on our results, further development of the MAGE-A3 immunotherapeutic for use in NSCLC has been stopped. Funding GlaxoSmithKline Biologicals SA.

El objetivo principal de este artículo es comentar las cartas que se enviaron Antonio Rodríguez Huéscar y José Ortega y Gasset entre 1942 y 1943. Dichas cartas se incluyen en el artículo.Palabras clave: cartas, Antonio Rodríguez Huéscar, José Ortega y Gasset

Background: Mutations in the tumor suppressor genes STK11 (also known as LKB1) and KEAP1 have been associated with poorer clinical outcomes in patients (pts) with NSCLC. In an exploratory analysis, we assessed the prevalence of STK11 and KEAP1 mutations and their association with efficacy in KEYNOTE-189 (NCT02578680). Methods: STK11 and KEAP1 status and tumor mutational burden (TMB) were assessed by whole-exome sequencing (WES) in pts who had available tumor and matched-normal tissue. PD-L1 was assessed by the PD-L1 IHC 22C3 pharmDx assay. The association of STK11 and KEAP1 status with efficacy and their correlation with TMB and PD-L1 expression distributions were evaluated descriptively. Results: WES data from both tumor and normal DNA were evaluable for 289 (47%) of 616 pts, of whom 54 (19%) had an STK11 mutation and 68 (24%) had a KEAP1 mutation; 29 (10%) had both STK11 and KEAP1 mutations. PD-L1 TPS tended to be lower in pts with vs without STK11 mutation (median [IQR] 0% [0-16] vs 15% [0-75]), whereas TMB score tended to be higher in pts with mutation (209 [132-265] vs 146 [89-264]). Similar patterns were seen for pts with vs without KEAP1 mutation (PD-L1 TPS: 1% [0-13] vs 20% [0-75]; TMB: 173 [124-267] vs 147 [89-263]). Although ORR of pembrolizumab plus chemotherapy was lower and PFS and OS shorter in pts with vs without STK11 and KEAP1 mutation, pembrolizumab plus chemotherapy was associated with numerically better outcomes than placebo plus chemotherapy regardless of mutation status (Table). 95% CIs were wide given the modest mutation frequency and the 2:1 randomization in favor of pembrolizumab plus chemotherapy. Conclusions: Data from this exploratory analysis support use of pembrolizumab plus pemetrexed and platinum as standard first-line therapy for pts with metastatic nonsquamous NSCLC regardless of STK11 or KEAP1 status. STK11KEAP1With MutationWithout MutationWith MutationWithout MutationPembro + ChemoPlacebo + ChemoPembro + ChemoPlacebo + ChemoPembro + ChemoPlacebo + ChemoPembro + ChemoPlacebo + Chemo(n = 36)(n = 18)(n = 168)(n = 67)(n = 45)(n = 23)(n = 159)(n = 62)ORR, % (95% CI)31 (16-48)17 (4-41)49 (41-57)16 (8-27)36 (22-51)17 (5-39)48 (40-56)16 (8-28)PFS, median, mo (95% CI)6 (4-9)5 (5-9)10 (8-14)5 (5-5)5 (4-11)5 (5-9)10 (8-14)5 (5-5)PFS, HR (95% CI)0.81 (0.44-1.47)0.38 (0.27-0.52)0.65 (0.38-1.12)0.38 (0.28-0.53)OS, median, mo (95% CI)17 (5-NR)8 (7-NR)23 (20-NR)12 (8-25)13 (7-NR)9 (7-NR)24 (20-NR)12 (8-NR)OS, HR (95% CI)0.75 (0.37-1.50)0.59 (0.41-0.85)0.81 (0.44-1.49)0.57 (0.39-0.84) Citation Format: Shirish M. Gadgeel, Delvys Rodriguez-Abreu, Enriqueta Felip, Emilio Esteban, Giovanna Speranza, Martin Reck, Rina Hui, Michael Boyer, Edward B. Garon, Hidehito Horinouchi, Razvan Cristescu, Deepti Aurora-Garg, Andrey Loboda, Jared Lunceford, Julie Kobie, Mark Ayers, Bilal Piperdi, M. Catherine Pietanza, Marina C. Garassino. Pembrolizumab plus pemetrexed and platinum vs placebo plus pemetrexed and platinum as first-line therapy for metastatic nonsquamous NSCLC: analysis of KEYNOTE-189 by STK11 and KEAP1 status [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-397.

Several agents have demonstrated an overall survival (OS) benefit in metastatic castration-resistant prostate cancer (mCRPC); however, optimal sequencing is unknown. Retrospective analysis of data from 574 mCRPC patients showed increasing OS with the number of therapies provided; a sequence including docetaxel, cabazitaxel (CABA), and an androgen receptor-targeted agent (ART) provided the greatest benefit. Prior administration of ART did not appear to influence CABA activity. These findings will help guide treatment decisions in daily practice. Background: Several agents have demonstrated an overall survival (OS) benefit in patients with metastatic castration-resistant prostate cancer (mCRPC); however, the optimal sequencing of these therapies is unknown as a result of a lack of prospective randomized controlled trials. This retrospective study aimed to identify clinical factors influencing outcomes and to determine optimal treatment sequencing in patients with mCRPC treated with cabazitaxel (CABA) and/or androgen receptor-targeted agents (ART) after androgen-deprivation therapy (ADT) and docetaxel (DOC). Patients and Methods: Records of 574 consecutive patients treated (2012-2016) at 44 centers in 6 countries were retrospectively examined. Results: A total of 267 patients received ADT -> DOC -> CABA (group 1), 183 patients ADT -> DOC -> ART -> CABA (group 2), and 124 patients ADT -> DOC -> CABA -> ART (group 3), with respective median OS from diagnosis of mCRPC of 38.3, 44.45, and 53.9 months (P = .012 for group 3 vs. group 1). Multivariate analysis showed response to first ADT

[Abstract] Background: A pivotal, randomized, phase III trial demonstrated a statistically significant superiority of sunitinib over interferon-α in metastatic renal cell carcinoma (mRCC) patients. Objective: To evaluate the effectiveness and safety of sunitinib in patients with advanced or mRCC in routine clinical practice. Methods: Retrospective pooled analysis of clinical data from three observational and prospective studies carried out between 2007 and 2011 in 33 Spanish hospitals. Tumor response, Progression-free survival (PFS) and overall survival (OS), and main sunitinib-related toxicities were registered. Results: 224 patients were analyzed. Median PFS 10.6 months (95% CI: 9.02–12.25), median OS 21.9 months (95% CI: 17.2–26.6). Objective response rate (ORR) 43.8% (95% CI: 36.8–50.7). Median time to PR was 3.8 months (95% CI: 3.86–5.99) and to CR 8.2 months (95% CI: 4.75–9.77). The most common ≥ grade-3 AEs were asthenia/fatigue (18.7%), hand-foot syndrome (6.2%), hypertension (5.8%) and neutropenia (4.8%). Hand-foot syndrome, diarrhea and mucositis were confirmed as independent predictors for PFS and/or OS in a multivariate analysis (p < 0.05) Conclusions: Outcomes with sunitinib in daily clinical practice resemble those obtained in clinical trials. Long-term benefit with sunitinib is possible in advanced RCC patients but the appropriate management of toxicities is mandatory to enable patients to remain on treatment.

[Abstract] Background: Several potential predictive markers of efficacy of targeted agents in patients with metastatic renal cell carcinoma (mRCC) have been identified. Interindividual heterogeneity warrants further investigation. Patients and methods: Multicenter, observational, retrospective study in patients with clear-cell mRCC treated with sunitinib. Patients were classified in two groups: long-term responders (LR) (progression-free survival (PFS)≥22 months and at least stable disease), and primary refractory (PR) (progressive disease within 3-months of sunitinib onset). Objectives were to compare baseline clinical factors in both populations and to correlate tumor expression of selected signaling pathways components with sunitinib PFS. Results: 123 patients were analyzed (97 LR, 26 PR). In the LR cohort, overall response rate was 79% and median duration of best response was 30 months. Median PFS and overall survival were 43.2 (95% confidence intervals[CI]:37.2-49.3) and 63.5 months (95%CI:55.1-71.9), respectively. At baseline PR patients had a significantly lower proportion of nephrectomies, higher lactate dehydrogenase and platelets levels, lower hemoglobin, shorter time to and higher presence of metastases, and increased Fuhrman grade. Higher levels of HEYL, HEY and HES1 were observed in LR, although only HEYL discriminated populations significantly (AUC[ROC]=0.704; cut-off=34.85). Increased levels of hsa-miR-27b, hsa-miR-23b and hsa-miR-628-5p were also associated with prolonged survival. No statistical significant associations between hsa-miR-23b or hsa-miR-27b and the expression of c-Met were found. Conclusions: Certain mRCC patients treated with sunitinib achieve extremely long-term responses. Favorable baseline hematology values and longer time to metastasis may predict longer PFS. HEYL, hsa-miR-27b, hsa-miR-23b and hsa-miR-628-5p could be potentially used as biomarkers of sunitinib response. PPfizer; SOGUG-2011-05 Ministerio de Economía, Industria y Competitividad; SAF2015-66015-R Ministerio de Economía, Industria y Competitividad; ISCIII-RETIC RD12/0036/0009 Ministerio de Economía, Industria y Competitividad; PIE 15/00076

Background Inguinal orchiectomy is curative in 70–80% of clinical stage I testicular germ cell tumours (CS I TGCT). The identification of patients who are at low risk of relapse is critical to avoid unnecessary treatment. The aim of this study is to explore EGFR, hMLH-1/hMSH-2 and microsatellite instability (MSI) as potential prognostic factors of recurrence in CS I TGCT. Methods Fifty-six CS I TGCT patients who underwent inguinal orchiectomy were included in this study. We analysed the relationship between clinicopathological and molecular factors with survival. Analysis of hMLH1, hMSH2 and EGFR expression was carried out by immunohistochemistry. Methylation status of the hMLH1 promoter was determined by pyrosequencing analysis in selected cases. EGFR exons 19, 20, 21 were analysed by PCR labeled-fragments and MSI status was determined using standard Multiplex MSI assays. Results Classical pathological factors such as lymphovascular invasion, high percentage of embryonal carcinoma, rete testis invasion or tumour size ≥4 cm showed a significant relationship with a higher risk of relapse. Additionally, it was found that an epididymis invasion proved to be a significant independent poor prognostic factor of recurrence (p = 0.001). hMLH1 or hMSH2 expression showed no significant association with risk of relapse and no MSI was found. EGFR expression was observed in 30.4% of samples and its expression was associated with higher risk of relapse (HR 3.5; 95% CI 1.3–9.8; p = 0.016). None of the cases presented EGFR kinase domain mutations. Conclusions Epididymis invasion and EGFR expression, but not hMLH-1/hMSH-2 or MSI, could be potentially useful as new prognostic factors of recurrence for CS I TGCT. Electronic supplementary material The online version of this article (doi:10.1186/s12967-017-1162-3) contains supplementary material, which is available to authorized users.

Sunitinib is the currently standard treatment for metastatic renal cell carcinoma (mRCC). Multiple candidate predictive biomarkers for sunitinib response have been evaluated but none of them has been implemented in the clinic yet. The aim of this study was to analyze single nucleotide polymorphisms (SNPs) in genes linked to mode of action of sunitinib and immune response as biomarkers for mRCC. This is a multicenter, prospective and observational study involving 20 hospitals. Seventy-five mRCC patients treated with sunitinib as first line were used to assess the impact of 63 SNPs in 31 candidate genes on clinical outcome. rs2243250 (IL4) and rs5275 (PTGS2) were found to be significantly associated with shorter cancer-specific survival (CSS). Moreover, allele C (rs5275) was associated with higher PTGS2 expression level confirming its functional role. Combination of rs5275 and rs7651265 or rs2243250 for progression free survival (PFS) or CSS, respectively, was a more valuable predictive biomarker remaining significant after correction for multiple testing. It is the first time that association of rs5275 with survival in mRCC patients is described. Two-SNP models containing this functional variant may serve as more predictive biomarkers for sunitinib and could suppose a clinically relevant tool to improve the mRCC patient management., Supported by Pfizer.

Purpose This international phase III trial (Investigating Torisel As Second-Line Therapy [INTORSECT]) compared the efficacy of temsirolimus (mammalian target of rapamycin inhibitor) and sorafenib (vascular endothelial growth factor receptor [VEGFR] tyrosine kinase inhibitor) as second-line therapy in patients with metastatic renal cell carcinoma (mRCC) after disease progression on sunitinib. Patients and Methods In total, 512 patients were randomly assigned 1:1 to receive intravenous temsirolimus 25 mg once weekly (n = 259) or oral sorafenib 400 mg twice per day (n = 253), with stratification according to duration of prior sunitinib therapy (≤ or > 180 days), prognostic risk, histology (clear cell or non–clear cell), and nephrectomy status. The primary end point was progression-free survival (PFS) by independent review committee assessment. Safety, objective response rate (ORR), and overall survival (OS) were secondary end points. Results Primary analysis revealed no significant difference between treatment arms for PFS (stratified hazard ratio [HR], 0.87; 95% CI, 0.71 to 1.07; two-sided P = .19) or ORR. Median PFS in the temsirolimus and sorafenib arms were 4.3 and 3.9 months, respectively. There was a significant OS difference in favor of sorafenib (stratified HR, 1.31; 95% CI, 1.05 to 1.63; two-sided P = .01). Median OS in the temsirolimus and sorafenib arms was 12.3 and 16.6 months, respectively. Safety profiles of both agents were consistent with previous studies. Conclusion In patients with mRCC and progression on sunitinib, second-line temsirolimus did not demonstrate a PFS advantage compared with sorafenib. The longer OS observed with sorafenib suggests sequenced VEGFR inhibition may benefit patients with mRCC.

Summary Background An unmet medical need exists for patients with metastatic renal cell carcinoma who have progressed on VEGF-targeted and mTOR-inhibitor therapies. Fibroblast growth factor (FGF) pathway activation has been proposed as a mechanism of escape from VEGF-targeted therapies. Dovitinib is an oral tyrosine-kinase inhibitor that inhibits VEGF and FGF receptors. We therefore compared dovitinib with sorafenib as third-line targeted therapies in patients with metastatic renal cell carcinoma. Methods In this multicentre phase 3 study, patients with clear cell metastatic renal cell carcinoma who received one previous VEGF-targeted therapy and one previous mTOR inhibitor were randomly assigned through an interactive voice and web response system to receive open-label dovitinib (500 mg orally according to a 5-days-on and 2-days-off schedule) or sorafenib (400 mg orally twice daily) in a 1:1 ratio. Randomisation was stratified by risk group and region. The primary endpoint was progression-free survival (PFS) assessed by masked central review. Efficacy was assessed in all patients who were randomly assigned and safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01223027. Findings 284 patients were randomly assigned to the dovitinib group and 286 to the sorafenib group. Median follow-up was 11·3 months (IQR 7·9–14·6). Median PFS was 3·7 months (95% CI 3·5–3·9) in the dovitinib group and 3·6 months (3·5–3·7) in the sorafenib group (hazard ratio 0·86, 95% CI 0·72–1·04; one-sided p=0·063). 280 patients in the dovitinib group and 284 in the sorafenib group received at least one dose of study drug. Common grade 3 or 4 adverse events included hypertriglyceridaemia (38 [14%]), fatigue (28 [10%]), hypertension (22 [8%]), and diarrhoea (20 [7%]) in the dovitinib group, and hypertension (47 [17%]), fatigue (24 [8%]), dyspnoea (21 [7%]), and palmar-plantar erythrodysaesthesia (18 [6%]) in the sorafenib group. The most common serious adverse event was dyspnoea (16 [6%] and 15 [5%] in the dovitinib and sorafenib groups, respectively). Interpretation Dovitinib showed activity, but this was no better than that of sorafenib in patients with renal cell carcinoma who had progressed on previous VEGF-targeted therapies and mTOR inhibitors. This trial provides reference outcome data for future studies of targeted inhibitors in the third-line setting. Funding Novartis Pharmaceuticals Corporation.

Background Nivolumab (N) + ipilimumab (I) has been approved for the 1st line treatment of IMDC intermediate and poor risk advanced RCC. However, administration of N+I in a fixed regimen with 4 induction cycles may result in more treatment related adverse events (AEs) compared with N alone. It is hypothesized that a tailored approach starting treatment with N alone and using N+I as immunotherapeutic boost will improve efficacy outcomes as compared to N alone and reduce AEs. Methods This multicentric European study enrolled 258 1st and 2nd line (after TKI) pts with IMDC intermediate and poor risk, advanced clear cell RCC between Oct. 2016 and Dec. 2018. Pts started with N 240 mg Q2W induction. Pts with early significant PD (week 8) or either SD or PD at week 16 received 2-4 N+I boost cycles. Responders (PR/CR) to N monotherapy continued with maintenance with N+I boosts only for progression. The primary endpoint is confirmed investigator assessed objective response rate (ORR) per RECIST independent in 1st and 2nd line. Secondary endpoints include activity of N monotherapy, remission rate with N+I boosts, safety, overall survival and QoL. Results 108 1st and 99 2nd line pts were analyzed for efficacy. Median age was 65 y (range 20-87). 70 % were intermediate and 27 % poor risk. Confirmed ORR with 1st line N monotherapy was 28.7 % (95 % CI 20 - 38). Best overall response (BOR) after N induction ± N+I boosts was 37 % (95 % CI 28 - 47) and 28 % (95 % CI 20 - 38) in 1st and 2nd line, respectively. 102 pts received N+I boosts for either SD (n = 35) or PD (n = 67) until week16. Of these, 12 (12 %) and 54 (53%) had a PR/CR and SD, respectively. Two (6%) pts entering boosts for SD had PD afterwards compared to 51% with early PD. Treatment-related AEs will be presented. Table . LBA57 1st line (n = 108) 2nd line (n = 99) n (%) Nivo mono ORR N ± N+I BOR Nivo mono ORR N ± N+I BOR Complete response 2 (1.9) 2 (1.9) 0 4 (4.0) Partial response 29 (26.9) 38 (35.2) 18 (18.2) 24 (24.2) Stable disease 26 (24.1) 26 (24.1) 23 (23.2) 25 (25.3) Progressive disease 13 (12.0) 38 (35.2) 16 (16.2) 43 (43.4) Early PD/Boost W8 22 (20.4) 26 (26.3) Not evaluable * 16 (14.8) 4 (3.7) 16 (16.2) 3 (3.0) * Including patients with early end of study e.g. due to death or immune related AEs Conclusions TITAN–RCC is the first study to assess the impact of a tailored approach using N+I as an immunotherapeutic boost. In 1st line, this significantly improved ORR compared to N mono. Further follow-up is ongoing to characterize duration and depth of response. Clinical trial identification EudraCT: 2016-002307-26. Legal entity responsible for the study AIO-Studien-gGmbH, Berlin, Germany. Funding Bristol-Myers Squibb GmbH & Co.KGaA. Disclosure M. Grimm: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self): Amgen; Honoraria (self): Apogepha; Honoraria (self): Astellas; Honoraria (self): AstraZeneca; Honoraria (self): Bayer HealthCare; Honoraria (self): Hexal; Honoraria (self), Advisory / Consultancy: Intuitive Surgical; Honoraria (self): Janssen Cilag; Honoraria (self): Ipsen Pharma; Honoraria (self): Medac; Honoraria (self): MSD; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: ONO Pharma; Honoraria (self): Pfizer; Honoraria (self): Sanofi Aventis. M. Schmidinger: Honoraria (self): Astellas; Honoraria (self): BMS; Honoraria (self): EISAI; Honoraria (self): Eusa Pharma; Honoraria (self): Exelexis; Honoraria (self): Ipsen; Honoraria (self): MSD; Honoraria (self): Pfizer; Honoraria (self): Roche. I. Duran Martinez: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Non-remunerated activity/ies: Ipsen; Honoraria (self), Research grant / Funding (self), Travel / Accommodation / Expenses: Roche Genentech; Honoraria (self), Research grant / Funding (self), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Pharmacyclyc; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: MSD. G. Baretton: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): MSD; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Pfizer. P. Barthelemy: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Novartis; Advisory / Consultancy: BMS; Advisory / Consultancy: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: Janssen Cilag; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Astellas. B. Melichar: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Pfizer. L. Albiges: Honoraria (institution): Pfizer; Honoraria (institution): Novartis; Honoraria (institution): BMS; Honoraria (institution): Ipsen; Honoraria (institution): Roche; Honoraria (institution): MSD; Honoraria (institution): AstraZeneca. All other authors have declared no conflicts of interest.

Background Post-operative platinum-based chemotherapy is the standard of care for resected NSCLC with nodal involvement. Expression of genes involved in DNA repair may have a prognostic role for the outcome. BRCA1 plays an important role in DNA repair pathways and could have a prognostic impact in this setting. The SCAT trial results found that for low BRCA1 levels subgroup Cis-Gem was superior to Cis-Doc and in high BRCA1 subgroup docetaxel single agent without platinum achieved similar survival to Cis-Doc. Risk of recurrence analysis according BRCA-1 levels has been performed. Methods From Jun/2007 to May/2013 591 patients were screened and 500 were included, 108 in the control arm treated with Cis-Docetaxel and 392 in the experimental arms treated with Cis-Gem, Cis-Doc or docetaxel alone according to terciles of BRCA1 expression level. With a cut-off September 30th 2018 and a median follow-up of 60 months, recurrence patterns were analysed for the whole group according BRCA1 levels in tumor tissue and comparison were made for risk of recurrence, single/multiple recurrence, thoracic/extrathoracic and metastatic sites (liver, bone, brain). Results Cumulative recurrence was evaluable in 232/456 patients (50.8%), 182/354 patients treated in the experimental arm and in 50/102 patients treated in the control arm (RR 1.04; 0.83-1.30) (p = 0.672). The majority of recurrences 159/232 (68.5%) were single site intrathoracic recurrences in 121/232 (52%) while 111/232 were extrathoracic (47.8%). Overall recurrence was 56.5% (113/200 p) for low tercile BRCA1 vs 48.8% (63/129) for intermediate tercile vs 44% (56/127) for high tercile (p = 0.025). No differences were seen between tercile groups for single site (p = 0.35), multiple site (p = 0.26), intrathoracic (p = 0.36), or extrathoracic (p = 0.38). More frequent distant metastatic sites were: bone (42 patients), brain (38 patients) and liver (11 patients). RIsk reduction was seen for brain metastases in patients with higher tercile BRCA1 (p = 0.003). Conclusions For NSCLC resected patients with lymph node involvement risk of recurrence remains high with a cumulative rate > 50%. Relative risk of recurrence was lower for tumors with higher BRCA1 levels. Distant metastases were seen in 47.8% of patients. Brain metastases risk was significant lower for patients with low BRCA1 expression. BRCA1 levels acts as a prognostic factor in early stages NSCLC. Clinical trial identification EudraCT: 2007-000067-15; NCT 00478699. Legal entity responsible for the study Spanish Lung Cancer Group - Grupo Espanol Cancer de Pulmon. Funding Sanofi Aventis. Disclosure All authors have declared no conflicts of interest.

Background: KEYNOTE-189 is a randomized, placebo-controlled, Phase III study of pembro plus pemetrexed-platinum versus placebo plus pemetrexed-platinum among pts with metastatic nonsquamous NSCLC. At median follow-up of 10.5 months, pts in the pembro-combination arm had improved OS (HR, 0.49; 95% CI, 0.38-0.64; P Methods: Pts with untreated metastatic nonsquamous NSCLC, ECOG PS 0/1, and without EGFR/ALK alteration were randomized 2:1 to receive up to 35 Q3W cycles of pembro 200 mg or placebo plus 4 cycles of pemetrexed 500 mg/m2 and carboplatin AUC 5 mg/mL/min or cisplatin 75 mg/m2 followed by maintenance pemetrexed. Randomization was stratified by PD-L1 TPS ( Results: 616 pts were randomized (pembro-combination, n=410; placebo-combination, n=206). At data cutoff, median follow-up was 18.7 months. At baseline, 19% of pts had liver metastases and 18% had brain metastases. HRs for OS and PFS favored the pembro-combination vs placebo-combination across all groups, and were similar for pts with/without liver or brain metastases (Table). Conclusion: Pembro plus pemetrexed-platinum provided superior outcomes vs chemotherapy alone irrespective of liver or brain metastases in pts with untreated metastatic nonsquamous NSCLC. Benefit was observed in pts with brain or liver metastases, for whom prognosis is historically poor. PFSOSN*Median, mo (95% CI)HR(95% CI)Median, mo (95% CI)HR(95% CI)Pts With Liver MetastasesPembro-combination666.1 (4.7-8.5)0.52 (0.34-0.81)12.6 (8.1-19.1)0.62 (0.39-0.98)Placebo-combination493.4 (2.8-4.7)6.6 (4.6-7.6)Pts Without Liver MetastasesPembro-combination3449.2 (8.8-11.0)0.48 (0.39-0.59)23.7 (20.1-25.9)0.58 (0.45-0.74)Placebo-combination1575.4 (4.9-6.7)13.2 (10.0-16.4)Pts With Brain MetastasesPembro-combination736.9 (5.4-11.0)0.42 (0.27-0.67)19.2 (15.0-25.9)0.41 (0.24-0.67)Placebo-combination354.7 (2.2-5.5)7.5 (4.6-10.0)Pts Without Brain MetastasesPembro-combination3379.2 (8.3-10.9)0.48 (0.39-0.59)22.4 (19.7-25.4)0.59 (0.46-0.75)Placebo-combination1714.9 (4.7-5.9)12.1 (9.1-15.0)*25 patients had both brain and liver metastases. 1 of 2 Citation Format: Marina C. Garassino, Shirish Gadgeel, Emilio Esteban, Enriqueta Felip, Giovanna Speranza, Flávia De Angelis, Manuel Domine, Philip Clingan, Maximilian J. Hochmair, Steven F. Powell, Susanna Y.-S. Cheng, Helge G. Bischoff, Nir Peled, Francesco Grossi, Ross R. Jennens, Martin Reck, Rina Hui, Edward B. Garon, Michael Boyer, Belén Rubio-Viqueira, Silvia Novello, Takayasu Kurata, Jhanelle E. Gray, Anna Cardellino, Jing Yang, M. Catherine Pietanza, Delvys Rodríguez-Abreu. Outcomes among patients (pts) with metastatic nonsquamous NSCLC with liver metastases or brain metastases treated with pembrolizumab (pembro) plus pemetrexed-platinum: Results from the KEYNOTE-189 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT043.