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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically 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 report 5-year results from the phase III KEYNOTE-042 study (ClinicalTrials.gov identifier: NCT02220894 ). Eligible patients with locally advanced/metastatic non–small-cell lung cancer (NSCLC) without EGFR/ALK alterations and with programmed death ligand-1 (PD-L1) tumor proportion score (TPS) ≥ 1% received pembrolizumab 200 mg once every 3 weeks for 35 cycles or chemotherapy (carboplatin + paclitaxel or pemetrexed) for 4-6 cycles with optional maintenance pemetrexed. Primary end points were overall survival (OS) in PD-L1 TPS ≥ 50%, ≥ 20%, and ≥ 1% groups. Patients who completed 35 cycles of pembrolizumab with ≥ stable disease could begin second-course pembrolizumab upon progression. One thousand two hundred seventy‐four patients were randomly assigned (pembrolizumab, n = 637; chemotherapy, n = 637). Median follow-up time was 61.1 (range, 50.0-76.3) months. OS outcomes favored pembrolizumab ( v chemotherapy) regardless of PD-L1 TPS (hazard ratio [95% CI] for TPS ≥ 50%, 0.68 [0.57 to 0.81]; TPS ≥ 20%, 0.75 [0.64 to 0.87]; TPS ≥ 1%, 0.79 [0.70 to 0.89]), with estimated 5-year OS rates with pembrolizumab of 21.9%, 19.4%, and 16.6%, respectively. No new toxicities were identified. Objective response rate was 84.3% among 102 patients who completed 35 cycles of pembrolizumab and 15.2% among 33 patients who received second-course pembrolizumab. First-line pembrolizumab monotherapy continued to show durable clinical benefit versus chemotherapy after 5 years of follow-up in PD-L1–positive, locally advanced/metastatic NSCLC without EGFR/ALK alterations and remains a standard of care.

The Chilean census of 2017 reported that 11.4% of the local population are 65 years or older, and according to the National Institute of Statistics (INE) by 2025 20% of the Chilean population will be in this group. Cancer in Chile is a major public health problem. Aging is a significant risk factor for cancer development which added to the improved life expectancy, it increases the incidence of cancer. In 2040, new cancer cases will increase from 19.3 to 30.2 million worldwide. Older people are a heterogeneous group requiring specialized and individualized management. Chronological age does not necessarily correlate with physiological age. More than half of the geriatric patients with cancer have at least one comorbidity which is relevant when defining a cancer treatment. Likewise, polypharmacy is frequent and is an important issue to consider in people with cancer due to the risk associated with drug interactions. Oncogeriatric assessment consists of a comprehensive multidimensional evaluation, including functional and biopsychosocial issues, addressing aspects of the neoplastic disease such as the risk of toxicities due to systemic therapy and life expectancy. This tool has proven to be helpful in the diagnosis of conditions that are not evident in a routine oncological evaluation, such as geriatric syndromes, frailty, functional dependence, and cognitive impairment among others, which have an impact when deciding on therapy, predicting risks of treatment toxicity and mortality.

BACKGROUND: In the phase III KEYNOTE-061 trial (NCT02370498), pembrolizumab did not significantly improve overall survival versus paclitaxel as second-line therapy for gastric/gastroesophageal junction (GEJ) adenocarcinoma with programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥1 tumors. The association of tissue tumor mutational burden (tTMB) status and clinical outcomes was determined, including the relationship with CPS and microsatellite instability-high (MSI-H) status. PATIENTS AND METHODS: In patients with whole exome sequencing (WES) data [420/592 (71%); pembrolizumab, 218; paclitaxel, 202], the association of tTMB with objective response rate (ORR; logistic regression), progression-free survival (PFS; Cox proportional hazards regression), and overall survival (OS; Cox proportional hazards regression) were measured using one-sided (pembrolizumab) and two-sided [paclitaxel] P values. tTMB was also evaluated using FoundationOne®CDx [205/592 (35%)]. Prespecified equivalent cut-offs of 175 mut/exome for WES and 10 mut/Mb for FoundationOne®CDx were used. RESULTS: WES-tTMB was significantly associated with ORR, PFS, and OS in pembrolizumab-treated (all P < 0.001) but not paclitaxel-treated patients (all P > 0.6) in univariate analysis. The area under the receiver operating characteristics curve for WES-tTMB and response was 0.68 [95% confidence interval (CI) 0.56-0.81] for pembrolizumab and 0.51 (95% CI 0.39-0.63) for paclitaxel in univariate analysis. There was low correlation between WES-tTMB and CPS in both treatment groups (r ≤ 0.16). WES-tTMB remained significantly associated with all clinical endpoints with pembrolizumab after adjusting for CPS and with PFS and OS after excluding known MSI-H tumors (n = 26). FoundationOne®CDx-tTMB demonstrated a positive association with ORR, PFS, and OS in pembrolizumab-treated patients (all P ≤ 0.003) but not PFS or OS in paclitaxel-treated patients (P > 0.1). CONCLUSION: This exploratory analysis from KEYNOTE-061 is the first to demonstrate a strong association between tTMB and efficacy with pembrolizumab but not paclitaxel in patients with gastric/GEJ adenocarcinoma in a randomized setting. Data further suggest tTMB is a significant and independent predictor beyond PD-L1 status. ispartof: ANNALS OF ONCOLOGY vol:32 issue:9 pages:1127-1136 ispartof: location:England status: published

Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

During the last several years, multiple gene rearrangements with oncogenic potential have been described in NSCLC, identifying specific clinic-pathological subgroups of patients that benefit from a targeted therapeutic approach, including anaplastic lymphoma kinase (ALK), c-ros protooncogene 1 (ROS1) and, more recently, REarranged during Transfection (RET) and neurotrophic tyrosine receptor kinases (NTRK) genes. Despite initial impressive antitumor activity, the use of targeted therapies in oncogene-addicted NSCLC subgroups is invariably associated with the development of acquired resistance through multiple mechanisms that can include both on-target and off-target mechanisms. However, the process of acquired resistance is a rapidly evolving clinical scenario that constantly evolves under the selective pressure of tyrosine kinase inhibitors. The development of increasingly higher selective and potent inhibitors, traditionally used to overcome resistance to first generation inhibitors, is associated with the development of novel mechanisms of resistance that encompass complex resistance mutations, highly recalcitrant to available TKIs, and bypass track mechanisms. Herein, we provide a comprehensive overview on the therapeutic strategies for overcoming acquired resistance to tyrosine kinase inhibitors (TKIs) targeting the most well-established oncogenic gene fusions in advanced NSCLC, including ALK, ROS1, RET, and NTRK rearrangements.

Background First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater. Methods This randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries. Eligible patients were adults (≥18 years) with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation was computer generated, accessed via an interactive voice-response and integrated web-response system, and stratified by region of enrolment (east Asia vs rest of world), ECOG performance status score (0 vs 1), histology (squamous vs non-squamous), and PD-L1 TPS (≥50% vs 1-49%). Enrolled patients were randomly assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles or the investigator's choice of platinum-based chemotherapy for four to six cycles. Primary endpoints were overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater (one-sided significance thresholds, p=0·0122, p=0·0120, and p=0·0124, respectively) in the intention-to-treat population, assessed sequentially if the previous findings were significant. This study is registered at ClinicalTrials.gov, number NCT02220894. Findings From Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women, median age 63 years [IQR 57-69]) with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n=637) or chemotherapy (n=637) and included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up was 12·8 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (≥50% hazard ratio 0·69, 95% CI 0·56-0·85, p=0·0003; ≥20% 0·77, 0·64-0·92, p=0·0020, and ≥1% 0·81, 0·71-0·93, p=0·0018). The median surival values by TPS population were 20·0 months (95% CI 15·4-24·9) for pembrolizumab versus 12·2 months (10·4-14·2) for chemotherapy, 17·7 months (15·3-22·1) versus 13·0 months (11·6-15·3), and 16·7 months (13·9-19·7) versus 12·1 months (11·3-13·3), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively. Interpretation The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS. Funding Merck Sharp & Dohme.

Background: In the phase 3 KEYNOTE-061 study (NCT02370498), second-line pembro did not significantly prolong OS vs pac in patients with PD-L1-positive (CPS ≥1) GC (N = 395) but did elicit a longer DOR and offered a favorable safety profile. We explored the association between tumor gene expression signatures and clinical outcomes. Methods: In patients with tumor RNA-sequencing data, we analyzed the association of the 18-gene T-cell-inflamed gene expression profile (TcellinfGEP) and 10 other signatures (angiogenesis, glycolysis, gMDSC, hypoxia, mMDSC, MYC, proliferation, RAS, stroma/EMT/TGFβ, WNT) on a continuous scale with outcomes using logistic (ORR) and Cox proportional hazards (PFS; OS) regression. For TcellinfGEP, 1-sided (pembro) and 2-sided (pac) P values were calculated (prespecified significance, α = 0.05). For the 10 non-TcellinfGEP signatures, 1-sided (pembro) and 2-sided (pac) multiplicity-adjusted P values were calculated (prespecified significance, α = 0.10). Clinical data cutoff was October 26, 2017. Results: There were 274 patients with tumor RNA-sequencing data (n = 137 in each arm). Association with clinical outcomes for gene expression signatures are reported in the Table. Conclusions: In this exploratory analysis of patients with previously treated GC from KEYNOTE-061, tumor TcellinfGEP showed some association with clinical outcomes for pembro (ORR and PFS) but not pac (ORR, PFS, and OS). The TcellinfGEP-adjusted mMDSC signature was negatively associated with clinical outcomes for pembro (ORR, PFS, and OS), while the TcellinfGEP-adjusted glycolysis, MYC, and proliferation signatures were negatively associated with OS for pac. This exploratory biomarker analysis suggests that myeloid-driven suppression may play a role in resistance to PD-1 inhibition and supports a strategy of considering immunotherapy combinations intended to target this myeloid axis. Association between clinical outcomes and TcellinfGEP and non-TcellinfGEP signatures adjusted for TcellinfGEP Pembrolizumabn = 137 Paclitaxeln = 137 ORR PFS OS ORR PFS OS TcellinfGEPa 0.041 0.026 0.178 0.822 0.207 0.644 Angiogenesisb 0.077 0.298 0.623 0.220 0.462 0.263 Glycolysisb 0.934 0.861 0.956 0.223 0.097 0.018 gMDSCb 0.626 0.573 0.623 0.694 0.352 0.263 Hypoxiab 0.934 0.861 0.956 0.223 0.220 0.440 mMDSCb 0.077 0.057 0.033 0.694 0.932 0.263 MYCb 0.934 0.861 0.956 0.223 0.327 0.057 Proliferationb 0.934 0.861 0.956 0.223 0.071 0.002 RASb 0.934 0.861 0.956 0.223 0.327 0.440 Stroma/EMT/TGFβb 0.306 0.366 0.522 0.694 0.462 0.263 WNTb 0.934 0.861 0.956 0.097 0.327 0.440 aBolded P values (1-sided for pembrolizumab with hypothesized positive association and 2-sided for paclitaxel with no hypothesized association) indicate nominal statistical significance (α = 0.05); model includes additional covariates of ECOG PS. bBolded P values (1-sided for pembrolizumab with hypothesized negative association except for proliferation and 2-sided for paclitaxel with no hypothesized association) indicate multiplicity-adjusted statistical significance (α = 0.10); model includes additional covariates of ECOG PS and TcellinfGEP. Citation Format: Kohei Shitara, Maria Di Bartolomeo, Mario Mandala, Min-Hee Ryu, Christian Caglevic, Tomasz Olesinski, Hyun C. Chung, Kei Muro, Eray Goekkurt, Raymond S. McDermott, Wasat Mansoor, Zev A. Wainberg, Chie-Schin Shih, Julie Kobie, Michael Nebozhyn, Razvan Cristescu, Z. Alexander Cao, Andrey Loboda, Mustafa Özgüroğlu. Association between gene expression signatures and outcomes of pembrolizumab (pembro) and paclitaxel (pac) in advanced gastric cancer (GC): Exploratory analysis from KEYNOTE-061 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2140.

Background: Safe, effective treatment options for advanced melanoma that progressed on a PD-1/PD-L1 inhibitor is an unmet medical need. Results of the phase 1b KEYNOTE-029 trial showed promising antitumor activity in advanced melanoma with pembro combined with a CTLA-4 inhibitor. This ongoing, open-label, multiarm phase 1/2 study (NCT03179436) evaluating the CTLA-4 inhibitor Qmab + pembro showed antitumor activity as first-line treatment for advanced NSCLC and for previously treated extensive-stage SCLC. Data from the efficacy expansion phase in pts with advanced melanoma that progressed on a PD-1/PD-L1 inhibitor are presented. Methods: Pts with unresectable stage III-IV melanoma and confirmed progressive disease (PD) per iRECIST within 12 wk of the last dose of a PD-1/PD-L1 inhibitor given alone or in combination for ≥2 doses (combinations with CTLA-4 inhibitors were not allowed) were randomly assigned (1:1) to receive Qmab 25 mg IV Q6W with or without pembro 400 mg IV Q6W; 100 pts in the Qmab + pembro arm and 40 pts in the Qmab monotherapy arm were planned for enrollment. Treatment in both arms was given for up to 18 cycles (~2 y) or until PD, toxicity, or pt withdrawal. Pts who had PD after ≥2 Qmab monotherapy cycles could crossover to Qmab + pembro. Tumor imaging was assessed Q9W to wk 54 and Q12W thereafter. Primary end points were safety and ORR by BICR per RECIST v1.1. Secondary and exploratory end points included DOR and PFS by BICR per RECIST v1.1 and OS. Results: 151 pts were enrolled (n = 111, Qmab + pembro; n = 40, Qmab monotherapy); median time from first dose to database cutoff was 7.7 mo. In all pts, median age was 64 y; 66% of pts were male, 33% had BRAF-mutant tumors, and 50% had elevated LDH. Treatment-related adverse events (TRAEs) were reported in 87 pts (78%) in the Qmab + pembro arm and 24 pts (60%) in the Qmab monotherapy arm; grade 3/4 TRAEs were reported in 16 pts (14%) and 3 pts (8%), respectively. The most common TRAEs were pruritus (26%), fatigue (14%), diarrhea (14%), and rash (13%). No treatment-related deaths occurred in either arm; 5% of pts discontinued because of TRAEs. Confirmed ORR was 9% (95% CI, 4.4-15.9) with Qmab + pembro (1 CR, 9 PRs) and 3% (95% CI, 0.1-13.2) with Qmab monotherapy (1 PR). Median DOR was not reached (NR; range, 2.0+ to 13.8+ mo) with Qmab + pembro. DOR was 1.9+ with Qmab monotherapy. Median PFS was 2.1 mo (95% CI, 2.1-3.2) with Qmab + pembro and 2.1 mo (95% CI, 2.1-2.5) with Qmab monotherapy; 6-mo PFS rates were 21% and 13%, respectively. Median OS was NR (95% CI, 11.2 mo to NR) with Qmab + pembro and 7.8 mo (95% CI, 6.3 to NR) with Qmab monotherapy; 6-mo OS rates were 74% and 73%, respectively. Conclusions: Qmab + pembro was generally well tolerated and provided modest antitumor activity in pts with advanced melanoma that progressed on a PD-1/PD-L1 inhibitor. This combination and a coformulation of Qmab + pembro will be further investigated in the KEYMAKER-U02 study. Citation Format: Sanjeev Deva, Jacek Mackiewicz, Stephane Dalle, Helen Gogas, Iwona Lugowska, Alfonso Berrocal, Alexander M. Menzies, Michele Maio, Adnan Nagrial, Karmele Mujika Eizmendi, Jean-Jacques Grob, Christian Caglevic, Megan Lyle, Juan Martin-Liberal, Rachel Altura, Yixin Ren, Anuradha Khilnani, Jobin Cyrus, Shabana Siddiqi, Michal Lotem. Phase 1/2 study of quavonlimab (Qmab) + pembrolizumab (pembro) in patients (pts) with advanced melanoma that progressed on a PD-1/PD-L1 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT557.

Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2 and has been a pandemic since March 2020. Currently, the virus has infected more than 50 million people worldwide and more than half a million in Chile. For many coronaviruses, Spike (S) and Nucleocapsid (N) proteins are described as major antigenic molecules, inducing seroconversion and production of neutralizing antibodies. In this work, we evaluated the presence in serum of IgM, IgA and IgG antibodies against N and S proteins of SARS-CoV-2 using western blot, and developed an ELISA test for the qualitative characterization of COVID-19 patients. Patients with an active infection or who have recovered from COVID-19 showed specific immunoblotting patterns for the recombinants S protein and its domains S1 and S2, as well as for the N protein of SARS-CoV-2. Anti-N antibodies were more frequently detected than anti-S or anti-S1-RBD antibodies. People who were never exposed to SARS-CoV-2 did not show reactivity. Finally, indirect ELISA assays using N and S1-RBD proteins, alone or in combination, were established with variable sensitivity and specificity depending on the antigen bound to the solid phase. Overall, Spike showed higher specificity than the nucleocapsid, and comparable sensitivity for both antigens. Both approaches confirmed the seroconversion after infection and allowed us to implement the analysis of antibodies in blood for research purposes in a local facility.

Background Gastric cancer is the fifth cause of cancer incidence worldwide. Multidisciplinary approaches that improve the survival are needed. Perioperative chemotherapies show improvement in pathological complete remission (pCR) and overall survival (OS), but less than 50% of the patients completed the chemotherapeutic regimen. The recent 5-fluorouracil, leucovorin, oxaliplatin, docetaxel-4 (FLOT4) study shows OS 50 months and pCR 16.6%, but only 46% of the patients completed pre- and postoperative treatment. This case series report evaluated pCR and safety in patients that received complete preoperative chemotherapeutic with FLOT. Methods Patients received eight cycles FLOT regimen before surgery. Each cycle comprised 50 mg/m2 docetaxel intravenous (iv) on day 1, 85 mg/m2 oxaliplatin iv on day 1, 200 mg/m2 leucovorin iv on day 1 and 2,600 mg/m2 5-fluorouracil iv in a 24-hour infusion on day 1, every 2 weeks. Results Fifty-nine patients were evaluated, 58 patients received preoperative cycles. Thirty-one patients received all eight cycles of preoperative therapy. 65.5% patients presented any major adverse event. Thirty-nine patients underwent surgery. Thirty-three biopsy reports were obtained. Six patients (18.2%) presented pCR, 13 patients (39.4%) had no lymph node involvement. OS was 21.32 months. Patients with histology of signet ring carcinoma cells had a shorter survival than other histologies. Conclusion Total neoadjuvant with FLOT chemotherapy presents an adequate safety profile, a similar pathologic regression rate, and a slightly higher rate of completing treatment to report in perioperative FLOT regimen studies. A prospective clinical study with suitable diagnostic, staging tools and an adequate follow-up may prove total neoadjuvant chemotherapy's efficacy.

Background In the phase 3 KEYNOTE-061 study (cutoff: 10/26/2017), pembrolizumab did not significantly prolong OS vs paclitaxel as second-line (2L) therapy in PD-L1 combined positive score (CPS) ≥ 1 gastric/GEJ cancer. We present results in CPS ≥ 1, ≥ 5, and ≥ 10 populations after two additional years of follow-up (cutoff: 10/07/2019). Methods Patients were randomly allocated 1:1 to pembrolizumab 200 mg Q3W for ≤ 35 cycles or standard-dose paclitaxel. Primary endpoints: OS and PFS (CPS ≥ 1 population). HRs were calculated using stratified Cox proportional hazards models. Results 366/395 patients (92.7%) with CPS ≥ 1 died. Pembrolizumab demonstrated a trend toward improved OS vs paclitaxel in the CPS ≥ 1 population (HR, 0.81); 24-month OS rates: 19.9% vs 8.5%. Pembrolizumab incrementally increased the OS benefit with PD-L1 enrichment (CPS ≥ 5: HR, 0.72, 24-month rate, 24.2% vs 8.8%; CPS ≥ 10: 0.69, 24-month rate, 32.1% vs 10.9%). There was no difference in median PFS among treatment groups (CPS ≥ 1: HR, 1.25; CPS ≥ 5: 0.98; CPS ≥ 10: 0.79). ORR (pembrolizumab vs paclitaxel) was 16.3% vs 13.6% (CPS ≥ 1), 20.0% vs 14.3% (CPS ≥ 5), and 24.5% vs 9.1% (CPS ≥ 10); median DOR was 19.1 months vs 5.2, 32.7 vs 4.8, and NR vs 6.9, respectively. Fewer treatment-related AEs (TRAEs) occurred with pembrolizumab than paclitaxel (53% vs 84%). Conclusion In this long-term analysis, 2L pembrolizumab did not significantly improve OS but was associated with higher 24-month OS rates than paclitaxel. Pembrolizumab also increased OS benefit with PD-L1 enrichment among patients with PD-L1-positive gastric/GEJ cancer and led to fewer TRAEs than paclitaxel. Trial registration ClinicalTrials.gov, NCT02370498

Objectives Head and neck mucosal melanoma (HNMM) is a rare disease with a poor prognosis. The aim of this research was to analyze clinical characteristics and prognostic factors in a Latin American cohort. Study Design A retrospective chart review of patients with HNMM treated between 2008 and 2019 was conducted. Demographic characteristics, tumor characteristics, surgical treatment, adjuvant therapy, and oncologic outcomes were recorded. Results Twenty HNMMs were identified; 60% were in men. The most frequent primary location was the nasal cavity (10; 50%). Regional disease was uncommon and limited to the oral cavity. The median overall survival was 29 months; the 3- and 5-year overall survival rates were 37.2% and 26.6%, respectively. Univariate analysis revealed that predictors of a worse overall survival were paranasal location (hazard ratio [HR], 4.61; 95% confidence interval [CI], 1.61-18.40; P = .030), positive lymph nodes (HR, 6.00; 95% CI, 1.30-27.7; P = .022), positive margins (HR, 4.32; 95% CI, 1.08-17.2; P = .039), bone invasion (HR, 3.27;95% CI, 1.05-10.1; P = .041), and lymphovascular invasion (HR, 3.82; CI, 1.03-14.2; P = .045). Three-year recurrence-free survival was 17.3%, and most of the recurrences were with distant disease. Conclusions HNMM is an infrequent disease with an aggressive behavior. Survival outcomes are related to location of the primary disease, regional spread, lymphovascular invasion, and bone invasion.

BackgroundThe use of convalescent plasma (CP) to treat COVID-19 has shown promising results; however, its effectiveness remains uncertain. The purpose of this study was to determine the safety and mortality of CP among patients hospitalized with COVID-19.Study Design and MethodsThis multicenter, open-label, uncontrolled clinical trial is currently being conducted at nine hospitals in Chile. Patients hospitalized due to COVID-19 who were still within 14 days since symptom onset were classified into four groups: Patients with cancer and severe COVID-19. Patients with cancer and non-severe COVID-19. Patients with severe COVID-19 and patients with non-severe COVID-19 only. The intervention involved two 200-cc. CP transfusions with anti-SARS-CoV-2 IgG titers ≥ 1:320 collected from COVID-19-recovered donors.Results192 patients hospitalized for COVID-19 received CP transfusions. At the first transfusion, 90.6% fulfilled the criteria for severity, and 41.1% required mechanical ventilation. 11.5% of the patients had cancer. Overall 7-day and 30-day mortality since the first CP transfusion was 5.7% and 16.1% respectively. There were no differences at either time point in mortality between the four groups. Patients on mechanical ventilation when receiving CP had higher mortality rates than those who were not (22.8% vs. 11.5%; p = 0.037). Overall 30-day mortality was higher in patients over 65 than in younger patients (p = 0.019). Severe adverse events were reported in four patients (2.1%) with an overall transfusion-related lung injury rate of 1.56%. No CP-related deaths occurred.DiscussionCP is safe when used in patients with COVID-19 even when also presenting severity criteria or risk factors. Our mortality rate is comparable to reports from larger studies. Controlled clinical trials are required to determine efficacy.RegistrationNCT04384588

The use of PD-1/PD-L1 checkpoint inhibitors in advanced NSCLC is associated with longer survival. However, many patients do not benefit from PD-1/PD-L1 blockade, largely because of immunosuppression. New immunotherapy-based combinations are under investigation in an attempt to improve outcomes. Id1 (inhibitor of differentiation 1) is involved in immunosuppression. In this study, we explored the potential synergistic effect of the combination of Id1 inhibition and pharmacological PD-L1 blockade in three different syngeneic murine KRAS-mutant lung adenocarcinoma models. TCGA analysis demonstrated a negative and statistically significant correlation between PD-L1 and Id1 expression levels. This observation was confirmed in vitro in human and murine KRAS-driven lung cancer cell lines. In vivo experiments in KRAS-mutant syngeneic and metastatic murine lung adenocarcinoma models showed that the combined blockade targeting Id1 and PD-1 was more effective than each treatment alone in terms of tumor growth impairment and overall survival improvement. Mechanistically, multiplex quantification of CD3+/CD4+/CD8+ T cells and flow cytometry analysis showed that combined therapy favors tumor infiltration by CD8+ T cells, whilst in vivo CD8+ T cell depletion led to tumor growth restoration. Co-culture assays using CD8+ cells and tumor cells showed that T cells present a higher antitumor effect when tumor cells lack Id1 expression. These findings highlight that Id1 blockade may contribute to a significant immune enhancement of antitumor efficacy of PD-1 inhibitors by increasing PD-L1 expression and harnessing tumor infiltration of CD8+ T lymphocytes.

Lung cancer frequency has been progressively increasing; this has been linked to the use of inhaled tobacco and air pollution. In Chile, air pollution has reached alarming levels due to motor vehicle traffic, firewood burning for heating and minerals in urban areas; for this reason, our objective was to evaluate the association between the incidence of lung cancer and the concentration of the main air pollutants monitored in the country. We carried out a cross-sectional ecological study that evaluated the association between the average incidence of lung cancer in a 5-year period (2015-2019) with the average annual concentration of six atmospheric pollutants in the 5 years prior in 14 Chilean boroughs, using the population of beneficiaries of the Fundacion Arturo-Lopez-Perez Cancer Institute. The annualised incidence of lung cancer was 9.77 per 100,000 and it varied significantly within the boroughs studied. When evaluating the relationship between lung-cancer incidence and the average concentration of atmospheric pollutants, we only found a direct and significant correlation between the level of respirable particulates 2.5 and the incidence of adenocarcinomas (β: 0.16; p: 0.023).

Metastatic and local advanced unresectable pancreatic cancers are lethal conditions that always carry a poor prognosis with rare exceptions. Currently, the mainstay of therapy is cytotoxic chemotherapy plus best supportive care. First-line therapy for patients with a good performance status includes FOLFIRINOX or gemcitabine plus nab-paclitaxel regimens. Patients carrying a deleterious germline BRCA mutation can be treated with maintenance olaparib after FOLFIRINOX. Patients with a poor performance status, but still fit enough for chemotherapy, may be treated with single agent gemcitabine. Second-line therapy will depend on previous therapy and current performance status. Options for patients treated with gemcitabine-based regimens are 5-fluorouracil plus leucovorin plus either nanoliposomal irinotecan, irinotecan or oxaliplatin. Patients that were treated with first line FOLFIRINOX may benefit from a gemcitabine-based chemotherapy, but evidence from randomized trials is lacking. Other options like immunotherapy and targeted therapies yield benefit only in very selected cases, and it is still an area of research.

BackgroundConvalescent plasma (CP), despite limited evidence on its efficacy, is being widely used as a compassionate therapy for hospitalized patients with COVID-19. We aimed to evaluate the efficacy and safety of early CP therapy in COVID-19 progression.MethodsOpen-label, single-center, randomized clinical trial performed in an academic center in Santiago, Chile from May 10, 2020, to July 18, 2020, with final follow-up August 17, 2020. The trial included patients hospitalized within the first 7 days of COVID-19 symptoms onset, presenting risk factors for illness progression and not on mechanical ventilation. The intervention consisted in immediate CP (early plasma group) versus no CP unless developing pre-specified criteria of deterioration (deferred plasma group). Additional standard treatment was allowed in both arms. The primary outcome was a composite of mechanical ventilation, hospitalization for >14 days or death. Key secondary outcomes included: time to respiratory failure, days of mechanical ventilation, hospital length-of-stay, mortality at 30 days, and SARS-CoV-2 RT-PCR clearance rate.ResultsOf 58 randomized patients (mean age, 65.8 years, 50% male), 57 (98.3%) completed the trial. A total of 13 (43.3%) participants from the deferred group received plasma based on clinical aggravation. We found no benefit in the primary outcome (32.1% vs 33.3%, OR 0.95, 95% CI 0.32-2.84, p>0.99) in the early versus deferred CP group. In-hospital mortality rate was 17.9% vs 6.7% (OR 3.04, 95% CI 0.54-17.2, p=0.25), mechanical ventilation 17.9% vs 6.7% (OR 3.04, 95% CI 0.54-17.2, p=0.25), and prolonged hospitalization 21.4% vs 30% (OR 0.64, 95%CI, 0.19-2.1, p=0.55) in early versus deferred CP group, respectively. Viral clearance rate on day 3 (26% vs 8%, p=0.20) and day 7 (38% vs 19%, p=0.37) did not differ between groups. Two patients experienced serious adverse events within 6 or less hours after plasma transfusion.ConclusionImmediate addition of CP therapy in early stages of COVID-19 -compared to its use only in case of patient deterioration-did not confer benefits in mortality, length of hospitalization or mechanical ventilation requirement.Clinical Trials RegistrationNCT04375098

The world currently faces a pandemic due to SARS-CoV-2. Relevant information has emerged regarding the higher risk of poor outcomes in lung cancer patients. As such, lung cancer patients must be prioritized in terms of prevention, detection and treatment. On May 7th, 45 experts in thoracic cancers from 11 different countries were invited to participate. A core panel of experts regarding thoracic oncology care amidst the pandemic gathered virtually, and a total of 60 initial recommendations were drafted based on available evidence, 2 questions were deleted due to conflicting evidence. By May 16th, 44 experts had agreed to participate, and voted on each of the 58 recommendation using a Delphi panel on a live voting event. Consensus was reached regarding the recommendations (>66 % strongly agree/agree) for 56 questions. Strong consensus (>80 % strongly agree/agree) was reached for 44 questions. Patients with lung cancer represent a particularly vulnerable population during this time. Special care must be taken to maintain treatment while avoiding exposure.

Cancer is one of the leading causes of death worldwide. The success rate of conventional anticancer therapeutic approaches such as chemotherapy is limited by the non-specific toxicity and low specificity towards specific tumors, which are highly dependent on the mutational burden present on each patient. Similarly, targeted therapies have proven to induce resistance in numerous malignancies. Therefore, immunotherapy has emerged as a better approach to discriminate between “the own” and “the non-own”, which occurs through two types of mechanisms, innate and acquired immunity. Acquired immunity is one of the targets for new immunotherapeutic treatments, unleashing the power of antigen-specific T cells as a potential therapeutic weapon for cancer treatment. Thus, immunotherapy modifies the own immune system to increase the recognition and elimination of cancer cells by identifying these cancer antigens. One of the advantages of immunotherapy, when compared to conventional anticancer approaches, is the generation of long-term immunity (immunological memory). Currently, there are different potential types of immunotherapy in cancer to promote the modulation of the immune response. Among them, the use of cytokines, vaccines, viruses, monoclonal antibodies, and the generation of adaptive immune response cells have achieved successful results in some types of cancer.

Platinum-based compounds are widely used for the treatment of different malignancies due to their high effectiveness. Unfortunately, platinum-based treatment may lead to ototoxicity, an often-irreversible side effect without a known effective treatment and prevention plan. Platinum-based compound-related ototoxicity results mainly from the production of toxic levels of reactive oxygen species (ROS) rather than DNA-adduct formation, which has led to test strategies based on direct ROS scavengers to ameliorate hearing loss. However, favorable clinical results have been associated with several complications, including potential interactions with chemotherapy efficacy. To understand the contribution of the different cytotoxic mechanisms of platinum analogues on malignant cells and auditory cells, the particular susceptibility and response of both kinds of cells to molecules that potentially interfere with these mechanisms, is fundamental to develop innovative strategies to prevent ototoxicity without affecting antineoplastic effects. The n-3 long-chain polyunsaturated fatty acids (n-3 PUFAs) have been tried in different clinical settings, including with cancer patients. Nevertheless, their use to decrease cisplatin-induced ototoxicity has not been explored to date. In this hypothesis paper, we address the mechanisms of platinum compounds-derived ototoxicity, focusing on the differences between the effects of these compounds in neoplastic versus auditory cells. We discuss the basis for a strategic use of n-3 PUFAs to potentially protect auditory cells from platinum-derived injury without affecting neoplastic cells and chemotherapy efficacy.

Summary Background Patients with advanced gastric or gastro-oesophageal junction cancer that progresses on chemotherapy have poor outcomes. We compared pembrolizumab with paclitaxel in patients with advanced gastric or gastro-oesophageal junction cancer that progressed on first-line chemotherapy with a platinum and fluoropyrimidine. Methods This randomised, open-label, phase 3 study was done at 148 medical centres in 30 countries. Eligible patients were randomised (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive either pembrolizumab 200 mg every 3 weeks for up to 2 years or standard-dose paclitaxel. Primary endpoints were overall survival and progression-free survival in patients with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or higher. Safety was assessed in all patients, irrespective of CPS. The significance threshold for overall survival was p=0·0135 (one-sided). This trial is registered at ClinicalTrials.gov, number NCT02370498. Findings Between June 4, 2015, and July 26, 2016, 592 patients were enrolled. Of the 395 patients who had a PD-L1 CPS of 1 or higher, 196 patients were assigned to receive pembrolizumab and 199 patients were assigned to receive paclitaxel. As of Oct 26, 2017, 326 patients in the population with CPS of 1 or higher had died (151 [77%] of 196 patients in the pembrolizumab group and 175 [88%] of 199 patients in the paclitaxel group). Median overall survival was 9·1 months (95% CI 6·2–10·7) with pembrolizumab and 8·3 months (7·6–9·0) with paclitaxel (hazard ratio [HR] 0·82, 95% CI 0·66–1·03; one-sided p=0·0421). Median progression-free survival was 1·5 months (95% CI 1·4–2·0) with pembrolizumab and 4·1 months (3·1–4·2) with paclitaxel (HR 1·27, 95% CI 1·03–1·57). In the total population, grade 3–5 treatment-related adverse events occurred in 42 (14%) of the 294 patients treated with pembrolizumab and 96 (35%) of the 276 patients treated with paclitaxel. Interpretation Pembrolizumab did not significantly improve overall survival compared with paclitaxel as second-line therapy for advanced gastric or gastro-oesophageal junction cancer with PD-L1 CPS of 1 or higher. Pembrolizumab had a better safety profile than paclitaxel. Additional trials of pembrolizumab in gastric and gastro-oesophageal cancer are ongoing. Funding Merck Sharp & Dohme, a subsidiary of Merck & Co.

Summary Background Immunotherapy combination treatments can improve patient outcomes. Epacadostat, an IDO1 selective inhibitor, and pembrolizumab, a PD-1 inhibitor, showed promising antitumour activity in the phase 1–2 ECHO-202/KEYNOTE-037 study in advanced melanoma. In this trial, we aimed to compare progression-free survival and overall survival in patients with unresectable stage III or IV melanoma receiving epacadostat plus pembrolizumab versus placebo plus pembrolizumab. Methods In this international, randomised, placebo-controlled, double-blind, parallel-group, phase 3 trial, eligible participants were aged 18 years or older, with unresectable stage III or IV melanoma previously untreated with PD-1 or PD-L1 checkpoint inhibitors, an ECOG performance status of 0 or 1, and had a known BRAFV600 mutant status or consented to BRAFV600 mutation testing during screening. Patients were stratified by PD-L1 expression and BRAFV600 mutation status and randomly assigned (1:1) through a central interactive voice and integrated web response system to receive epacadostat 100 mg orally twice daily plus pembrolizumab 200 mg intravenously every 3 weeks or placebo plus pembrolizumab for up to 2 years. We used block randomisation with a block size of four in each stratum. Primary endpoints were progression-free survival and overall survival in the intention-to-treat population. The safety analysis population included randomly assigned patients who received at least one dose of study treatment. The study was stopped after the second interim analysis; follow-up for safety is ongoing. This study is registered with ClinicalTrials.gov , number NCT02752074 . Findings Between June 21, 2016, and Aug 7, 2017, 928 patients were screened and 706 patients were randomly assigned to receive epacadostat plus pembrolizumab (n=354) or placebo plus pembrolizumab (n=352). Median follow-up was 12·4 months (IQR 10·3–14·5). No significant differences were found between the treatment groups for progression-free survival (median 4·7 months, 95% CI 2·9–6·8, for epacadostat plus pembrolizumab vs 4·9 months, 2·9–6·8, for placebo plus pembrolizumab; hazard ratio [HR] 1·00, 95% CI 0·83–1·21; one-sided p=0·52) or overall survival (median not reached in either group; epacadostat plus pembrolizumab vs placebo plus pembrolizumab: HR 1·13, 0·86–1·49; one-sided p=0·81). The most common grade 3 or worse treatment-related adverse event was lipase increase, which occurred in 14 (4%) of 353 patients receiving epacadostat plus pembrolizumab and 11 (3%) of 352 patients receiving placebo plus pembrolizumab. Treatment-related serious adverse events were reported in 37 (10%) of 353 patients receiving epacadostat plus pembrolizumab and 32 (9%) of 352 patients receiving placebo plus pembrolizumab. There were no treatment-related deaths in either treatment group. Interpretation Epacadostat 100 mg twice daily plus pembrolizumab did not improve progression-free survival or overall survival compared with placebo plus pembrolizumab in patients with unresectable or metastatic melanoma. The usefulness of IDO1 inhibition as a strategy to enhance anti-PD-1 therapy activity in cancer remains uncertain. Funding Incyte Corporation, in collaboration with Merck Sharp & Dohme.

Cancer is one of the leading causes of death worldwide. The success rate of conventional anticancer therapeutic approaches such as chemotherapy is limited by the non-specific toxicity and low specificity towards specific tumors, which are highly dependent on the mutational burden present on each patient. Similarly, targeted therapies have proven to induce resistance in numerous malignancies. Therefore, immunotherapy has emerged as a better approach to discriminate between "the own" and "the non-own", which occurs through two types of mechanisms, innate and acquired immunity. Acquired immunity is one of the targets for new immunotherapeutic treatments, unleashing the power of antigen-specific T cells as a potential therapeutic weapon for cancer treatment. Thus, immunotherapy modifies the own immune system to increase the recognition and elimination of cancer cells by identifying these cancer antigens. One of the advantages of immunotherapy, when compared to conventional anticancer approaches, is the generation of long-term immunity (immunological memory). Currently, there are different potential types of immunotherapy in cancer to promote the modulation of the immune response. Among them, the use of cytokines, vaccines, viruses, monoclonal antibodies, and the generation of adaptive immune response cells have achieved successful results in some types of cancer.

Pancreatic cancer is a malignancy of great impact in developed countries and is having an increasing impact in Latin America. Incidence and mortality rates are similar for this cancer. This is an important reason to offer to the patients the best treatments available. During the Latin American Symposium of Gastroenterology Oncology (SLAGO) held in Viña del Mar, Chile, in April 2015, a multidisciplinary group of specialists in the field met to discuss about this disease. The main conclusions of this meeting, where practitioners from most of Latin American countries participated, are listed in this consensus that seek to serve as a guide for better decision making for patients with pancreatic cancer in Latin America.

Importance Safe and effective therapies for untreated, advanced gastric/gastroesophageal junction (G/GEJ) cancer remain an unmet need. Objective To evaluate the antitumor activity of pembrolizumab, pembrolizumab plus chemotherapy, or chemotherapy alone in patients with untreated, advanced G/GEJ cancer with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or greater. Design, Setting, and Participants The phase 3 KEYNOTE-062 randomized, controlled, partially blinded interventional trial enrolled 763 patients with untreated, locally advanced/unresectable or metastatic G/GEJ cancer with PD-L1 CPS of 1 or greater from 200 centers in 29 countries between September 18, 2015, and May 26, 2017. Interventions Patients were randomized 1:1:1 to pembrolizumab 200 mg, pembrolizumab plus chemotherapy (cisplatin 80 mg/m2/d on day 1 plus fluorouracil 800 mg/m2/d on days 1 to 5 or capecitabine 1000 mg/m2twice daily), or chemotherapy plus placebo, every 3 weeks. Main Outcomes and Measures Primary end points were overall survival (OS) and progression-free survival (PFS) in patients with PD-L1 CPS of 1 or greater or 10 or greater. Results A total of 763 patients were randomized to pembrolizumab (n = 256), pembrolizumab plus chemotherapy (n = 257), or chemotherapy (n = 250). The median (range) age of all patients in the study cohort was 62 (20-87) years; 554 of 763 (72.6%) were men. At final analysis, after a median (range) follow-up of 29.4 (22.0-41.3) months, pembrolizumab was noninferior to chemotherapy for OS in patients with CPS of 1 or greater (median, 10.6 vs 11.1 months; hazard ratio [HR], 0.91; 99.2% CI, 0.69-1.18). Pembrolizumab monotherapy was not superior to chemotherapy in patients with CPS of 1 or greater. Pembrolizumab prolonged OS vs chemotherapy in patients with CPS of 10 or greater (median, 17.4 vs 10.8 months; HR, 0.69; 95% CI, 0.49-0.97), but this difference was not statistically tested. Pembrolizumab plus chemotherapy was not superior to chemotherapy for OS in patients with CPS of 1 or greater (12.5 vs 11.1 months; HR, 0.85; 95% CI, 0.70-1.03;P = .05) or CPS of 10 or greater (12.3 vs 10.8 months; HR, 0.85; 95% CI, 0.62-1.17;P = .16) or for PFS in patients with CPS of 1 or greater (6.9 vs 6.4 months; HR, 0.84; 95% CI, 0.70-1.02;P = .04). Grade 3 to 5 treatment-related adverse event rates for pembrolizumab, pembrolizumab plus chemotherapy, and chemotherapy were 17%, 73%, and 69%, respectively. Conclusions and Relevance This phase 3 randomized clinical trial found that among patients with untreated, advanced G/GEJ cancer, pembrolizumab was noninferior to chemotherapy, with fewer adverse events observed. Pembrolizumab or pembrolizumab plus chemotherapy was not superior to chemotherapy for the OS and PFS end points tested. Trial Registration ClinicalTrials.gov Identifier:NCT02494583

4512 Background: KEYNOTE-061 (NCT02370498) was a randomized, open-label, phase 3 study of pembrolizumab vs paclitaxel in patients with advanced gastric or gastroesophageal junction adenocarcinoma with tumor progression after first-line therapy (N =592). We explored the association of tissue tumor mutational burden (tTMB) status and clinical outcomes in patients with GC enrolled in KEYNOTE-061, including the relationship with PD-L1 combined positive score (CPS) and microsatellite instability-high (MSI-H) status. Methods: In patients from KEYNOTE-061 with evaluable tumor and matched normal whole exome sequencing (WES) data (N = 420; pembrolizumab, 218; paclitaxel, 202), the association of tTMB (continuous log10 scale) with confirmed ORR and PFS by blinded central radiology review per RECIST v1.1, and OS was evaluated within each treatment arm using logistic regression (ORR) and Cox proportional hazards regression (PFS; OS). The clinical utility of tTMB was assessed using the prespecified cutoff of 175 mut/exome. Clinical data cutoff: October 26, 2017. Results: tTMB was significantly associated (α=0.05) with ORR, PFS, and OS in patients treated with pembrolizumab (one-sided P0.600). The area under the receiver operating characteristics curve for tTMB and response (pembrolizumab vs paclitaxel) was 0.68 (95% CI, 0.56-0.81) vs 0.51 (95% CI, 0.39-0.63). Patient outcomes by tTMB cutoff are reported in Table. There was low correlation between tTMB and PD-L1 CPS in both treatment arms (r

Breast cancer (BC) is a highly prevalent malignancy in Latin American women, most cases being diagnosed at locally advanced or metastatic stages when options for cancer care are limited. Despite its label as a public health problem in the region, Latin American BC patients face several barriers in accessing standard of care treatment when compared with patients from developed countries. In this review, we analyse the landscape of the four main identified barriers in the region: i) high burden of locally advanced/advanced BC; ii) inadequate access to medical resources; iii) deficient access to specialised cancer care and iv) insufficient BC research in Latin America. Unfortunately, these barriers represent the main factors associated with the BC poor outcomes seen in the region. Targeted actions should be conducted independently by each country and as a region to overcome these limitations and create an enhanced model of BC care.

Background: Immunotherapy combination treatments may improve patient outcomes. Epacadostat, an indoleamine 2,3-dioxygenase 1 (IDO1) selective inhibitor, and pembrolizumab, a programmed death protein (PD)-1 inhibitor, showed promising antitumour activity in the phase 1/2 ECHO-202/KEYNOTE-037 advanced melanoma study. Methods: In the phase 3 ECHO-301/KEYNOTE-252 (NCT02752074) study, patients with unresectable stage III or IV melanoma previously untreated with checkpoint inhibitors were stratified by PD-ligand-1 expression and BRAF mutation status, and randomised (1:1) to epacadostat 100 mg twice-daily (BID) plus pembrolizumab 200 mg every 3 weeks (Q3W) or placebo plus pembrolizumab 200 mg Q3W for up to 2 years. Primary endpoints were progression-free survival (PFS) per modified Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 and overall survival (OS). Secondary endpoints included objective response rate (ORR) per modified RECIST v1.1, duration of response (DOR), and safety. We report PFS final and OS interim analyses. Findings: 706 patients were randomised (n=354 epacadostat plus pembrolizumab, n=352 placebo plus pembrolizumab). Median follow-up was 12·4 months. No significant difference was found between epacadostat plus pembrolizumab versus placebo plus pembrolizumab for PFS (median 4·7 vs 4·9 months, respectively; HR=1·00; CI, 0·83-1.21; one-sided p=0·517) or OS (HR=1·13; 95% CI 0·86 1·49; one-sided p=0·807). Twelve-month OS rate was 74% (both groups). ORR was 34·2% (epacadostat plus pembrolizumab) and 31·5% (placebo plus pembrolizumab). Median DOR was not reached (both groups). Grade ≥3 treatment-related adverse events were reported in 21·8% of patients receiving epacadostat plus pembrolizumab; 17·0% receiving placebo plus pembrolizumab. Interpretation: Epacadostat 100 mg BID plus pembrolizumab did not improve PFS or OS versus pembrolizumab alone in unresectable or metastatic melanoma patients. Utility of IDO1 inhibition as a strategy to enhance anti-PD-1 therapy activity in cancer remains uncertain. Funding: Incyte Corporation (Wilmington, DE, USA) in collaboration with Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Declaration of Interest: GVL has served as a consultant/advisor for Amgen, Array, Bristol-Myers Squibb, Incyte, Merck Sharp and Dhome, Novartis, Pierre Fabre, and Roche; has received honoraria from Bristol-Myers Squibb, Incyte, Merck Sharp and Dhome, Novartis, and Roche; and personal fees for travel to conferences from Merck Sharp and Dhome and Roche. RD has served as a consultant/advisor for Amgen, Bristol-Myers Squibb, Merck Sharp and Dhome, Novartis, Pierre Fabre, Roche, Sanofi, Sun Pharma, and Takeda. OH has served as a consultant/advisor for and/or received honoraria from Amgen, Bristol-Myers Squibb, Incyte, Merck, Novartis, and Roche; served on speakers bureau for Amgen, Array, Bristol-Myers Squibb, Genentech, Novartis, and Sanofi; and his institution has received research funding from AstraZeneca, Bristol-Myers Squibb, Celldex, Genentech, Immunocore, Incyte, Merck, Merck Serono, Medimmune, Novartis, Pfizer, and Rinat. TFG has served on advisory boards for Merck and his institution has received research grants from Merck and Incyte. CC has served as a consultant for AstraZeneca, Bayer, Bristol-Myers Squibb, and Merck Sharp and Dhome; served on speakers bureau for Bayer, Bristol-Myers Squibb, Eli Lilly, and Merck Sharp and Dhome; received personal fees and for travel and non-financial support from Boehringer Ingelheim and Bristol-Myers Squibb; and has received research grants from Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Medivation, Merck Sharp and Dhome, and Roche. SD received personal fees from Sanofi; non-financial support for travel and research from Bristol-Myers Squibb and Merck Sharp and Dhome; and research grant from Bristol-Myers Squibb. AA has served as a consultant and on speakers bureau for Bristol-Myers Squibb, Merck Sharp and Dhome, Novartis, and Roche. MSC has served as a consultant for Amgen, Bristol-Myers Squibb, Merck Sharp and Dhome, Novartis, and Pierre Fabre. J-JG has served as a consultant/advisor for and/or received honoraria from Amgen, Bristol-Myers Squibb, Incyte, Merck/Pfizer, Merck Sharp and Dhome, Novartis, Pierre Fabre, Roche, Sanofi, and Sun Pharma; has served on speakers bureau for Novartis; and received other support for travel from Amgen, Bristol-Myers Squibb, Merck Sharp and Dhome, Pierre Fabre, and Roche. TMK declares no competing interests. LD has served as a consultant for and received honoraria and research grants from Bristol-Myers Squibb, Merck Sharp and Dhome, Novartis, and Roche. CR has served as a consultant/advisor for and received honoraria from Amgen, Bristol-Myers Squibb, Merck, Novartis, Pierre Fabre, and Roche. JL has served as a consultant for Achilles, AstraZeneca, Boston Biomedical, Bristol-Myers Squibb, Eisai, EUSA Pharma, GlaxoSmithKline, Ipsen, Imugene, Incyte, iOnctura, Kymab, Merck Serono, Merck Sharp and Dhome, Nektar Therapeutics, Novartis, Pierre Fabre, Pfizer, Roche/Genentech, Secarna, and Vitaccess; his institute has received grants from Achilles Therapeutics, Aveo, Bristol-Myers Squibb, Covance, Immunocore, Merck Sharp and Dhome, Nektar Therapeutics, Novartis, Pfizer, Pharmacyclics, and Roche; and has received non-financial support from NIHR RM/ICR Biomedical Research Centre for Cancer. JRA is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. JM and MJ are employees and stockholders of Incyte. SJD is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and stockholder of Merck & Co., Inc., Kenilworth, NJ, USA. TCM has served as a consultant/advisor for Bristol-Myers Squibb, Incyte, Merck, and Novartis. Ethical Approval: The study was conducted in accordance with the protocol, Declaration of Helsinki, and International Council for Harmonisation guidelines for Good Clinical Practice. The protocol and amendments were approved by the institutional review boards or independent ethics committees of participating institutions. All patients provided written informed consent.

The management of Non-Small Cell Lung Cancer (NSCLC) has changed dramatically in the last 10 years with an increase in the understanding of the biology and with the development of new and multiple treatments. Chemotherapy being the first systemic treatment used in the setting of advanced disease, proving benefit for patients over palliative care. With the identification of oncogenic drivers, innovative targeted therapies were developed and tested, leading to important changes in the management of certain patients and giving to some of them the possibility to be treated in first line with oral inhibitors. Immunotherapy was then explored as a potential option, with promising results, and data of impact in important endpoints in lung cancer treatments. This chapter explores the different CTLA-4 inhibitors that have been investigated in NSCLC: ipilimumab and tremelimumab, as well as the different immune checkpoint inhibitors: anti PD-1 (nivolumab and pembrolizumab) and PD-L1 (atezolizumab, durvalumab, avelumab, BMS-936559) medications. It also analyzes the different studies that have been developed for NSCLC with these medications, the evidence obtained, and the possible role in the management of patients. Immunotherapy has definitely changed the paradigm on NSCLC treatment, and the future is promising for the benefit of patients.

According to data from recent studies from Europe, a large percentage of patients have restricted access to innovative medicines for metastatic melanoma. Melanoma World Society and European Association of Dermato-oncology conducted a Web-based survey on access to first-line recommended treatments for metastatic melanoma by current guidelines (National Comprehensive Center Network, European Society for Medical Oncology [ESMO] and European Organization for Research and Treatment of Cancer/European Association of Dermato-oncology/European dermatology Forum) among melanoma experts from 27 European countries, USA, China, Australia, Argentina, Brazil, Chile and Mexico from September 1st, 2017 to July 1st, 2018. Data on licencing and reimbursement of medicines and the number of patient treated were correlated with the data on health expenditure per capita (HEPC), Mackenbach score of health policy performance, health technology assessment (HTA), ASCO and ESMO Magnitude of clinical benefit scale (ESMO MCBS) scores of clinical benefit and market price of medicines. Regression analysis for evaluation of correlation between the parameters was carried out using SPSS software. The estimated number of patients without access in surveyed countries was 13768. The recommended BRAFi+MEKi combination and anti-PD1 immunotherapy were fully reimbursed/covered in 19 of 34 (55.8%) and 17 of 34 (50%) countries, and combination anti-CTLA4+anti-PD1 in was fully covered in 6 of 34 (17.6%) countries. Median delay in reimbursement was 991 days, and it was in significant correlation with ESMO MCBS (p=0.02), median market price (p=0.001), HEPC and Mackenbach scores (p&nbsp

Several drinkable water sources worldwide have been highly contaminated with arsenic, which means that an estimated 160 million people have been exposed to this chemical agent. If we analyse exposure by region, we will find a high correlation between arsenic contamination and the incidence of lung cancer (among other malignancies). In order to determine what the risks of these exposures are, we need to understand how this chemical is processed in our body and how it is linked to cancer. In this article we reviewed how biotransformation of ingested arsenic may lead to cancer by modulating the activation of several essential signalling pathways such as EGFR, PI3K/AKT, RTK/Ras/PI3K, JNK/STAT3 and Nrf2-KEAP1; by producing epigenetics modifications and by disrupting normal expression of miRNAs. In order to design effective health policies, educational strategies, decontaminations plans and effective medical treatments are necessary to understand the impact of arsenic pollution and the relevance of the environment in our health.

Breast cancer is the leading cause of cancer death among women worldwide. While triple-negative breast cancer is less common among various sub-types of breast cancer, it tends to affect younger women and is more aggressive, having a higher rate of early recurrence and mortality compared to other sub-types. We know about the association between triple-negative breast cancer and BRCA mutations, which are highly prevalent in founding populations of European origin, but the true prevalence of these mutations in Latin American populations is unknown. There is also very little information about the demographic and epidemiological aspects of triple-negative breast cancer in Latin America, which we will try to summarise in this article. In addition, we will try to provide a brief introduction to the most common recommendations for treating this histological class in Latin America.

Lapatinib plus capecitabine (lap+cap) is approved as treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), who have progressed on prior trastuzumab in the metastatic setting.We previously reported progression-free survival (PFS), overall survival (OS) and safety results from this open-label, multicentre, phase II study (VITAL; NCT01013740) conducted in women with HER2 positive MBC, to evaluate the efficacy and safety of lap plus vinorelbine (lap+vin), an important chemotherapy option for MBC, compared with lap+cap. In total, 112 patients were randomised 2:1 to treatment with lap+vin (N = 75) or lap+cap (N = 37). Results showed that the median PFS (primary endpoint) and OS (secondary endpoint) post-randomisation were comparable between treatment arms, with no new safety signals detected.Here, we assessed the final OS in this study at 40 months post-randomisation. At the time of final analyses, 24 (32%) patients were ongoing in the lap+vin arm, compared with 14 (38%) patients in the lap+cap arm (92% in both arms had discontinued treatment). Median OS in the lap+vin arm was 23.3 months (95% confidence intervals [CI]: 18.5, 31.1), compared with 20.3 months (95% CI: 16.4, 31.8) in the lap+cap arm. The median follow-up in the lap+vin arm was 18.86 months (95% CI: 10.68, 26.02), compared with 19.38 (95% CI: 25.56) months in the lap+cap arm. Similar rates of death (56–57%) were observed in both arms.The final OS was consistent with the previously reported data and suggest that lap+vin offers an effective treatment option for women with HER2-positive MBC.

Lung cancer is a public health problem worldwide and Latin America (LATAM) cannot escape this reality. This malignant disease has not only a high prevalence in the region, but is also the main cause of cancer related deaths, and in other emerging countries, the incidence rates are still on the rise. Interestingly in most LATAM countries, lung cancer mortality has been decreasing in men but not in women, reflecting smoking patterns in countries such as Chile, Bolivia, and Brazil. Despite the fact that these issues are well known to government agencies, physicians and patients in the region, current efforts still fall behind those needed in order to face this problem of epidemic proportions. Tobacco control and smoking cessation are the most important interventions against lung cancer, but even with their optimal implementation (which is far from reality at this time) the number of cases in the foreseeable future would still be significant. Beyond tobacco control, advances in our understanding of the molecular component of lung cancer have resulted in new targeted therapies and immune check point inhibitors, which have improved clinical outcomes but at a considerably higher financial cost. LATAM has not widely and speedily adopted these strategies, including new technology and approved novel drugs, due to a number of facts, and therefore only a dismal proportion of LATAMs patient population have benefited from these new advances. A keen focus on a heterogeneous education system for caregivers in lung cancer treatment would likely help standardize care and improve future potential gains from domestic research. In this review we discuss the challenges of treatment implementation, focusing on new technologies.