Mutation profile in liquid biopsy tested by next generation sequencing in Mexican patients with non-small cell lung carcinoma and its impact on survival.

Background: Lung cancer represents a significant global health concern, often diagnosed in its advanced stages. The advent of massive DNA sequencing has revolutionized the landscape of cancer treatment by enabling the identification of target mutations and the development of tailored therapeutic approaches. Unfortunately, access to DNA sequencing technology remains limited in many developing countries. In this context, we emphasize the critical importance of integrating this advanced technology into healthcare systems in developing nations to improve treatment outcomes. Methods: We conducted an analysis of electronic clinical records of patients with confirmed advanced non-small cell lung cancer (NSCLC) and a verified negative status for the epidermal growth factor receptor (EGFR) mutation. These patients underwent next-generation sequencing (NGS) for molecular analysis. We performed descriptive statistical analyses for each variable and conducted both univariate and multivariate statistical analyses to assess their impact on progression-free survival (PFS) and overall survival (OS). Additionally, we classified genetic mutations as actionable or non-actionable based on the European Society for Medical Oncology Scale of Clinical Actionability of Molecular Targets (ESCAT) guidelines. Results: Our study included a total of 127 patients, revealing the presence of twenty-one distinct mutations. The most prevalent mutations were EGFR (18.9%) and Kirsten rat sarcoma viral oncogene homolog (KRAS) (15.7%). Notably, anaplastic lymphoma kinase (ALK) [hazard ratio (HR): 0.258, P<0.001], tumor mutation burden (TMB) (HR: 2.073, P=0.042) and brain magnetic resonance imaging (MRI) (HR: 0.470, P=0.032) demonstrated statistical significance in both the univariate and multivariate analyses with respect to PFS. In terms of OS, ALK (HR: 0.285, P<0.001) and EGFR (HR: 0.482, P=0.024) exhibited statistical significance in both analyses. Applying the ESCAT classification system, we identified actionable genomic variations (ESCAT level-1), including EGFR, ALK, breast cancer (BRAF) gene, c-ros oncogene 1 (ROS1), and rearranged during transfection (RET) gene, in 32.3% of the patients. Conclusions: Our findings from massive DNA sequencing underscore that 32.3% of patients who test negative for the EGFR mutation possess other targetable mutations, enabling them to receive personalized, targeted therapies at an earlier stage of their disease. Implementing massive DNA sequencing in developing countries is crucial to enhance survival rates among NSCLC patients and guide more effective treatment strategies.

Role of sex and sex hormones in PD-L1 expression in NSCLC: clinical and therapeutic implications.

Currently, immunotherapy based on PD-1/PD-L1 pathway blockade has improved survival of non-small cell lung cancer (NSCLC) patients. However, differential responses have been observed by sex, where men appear to respond better than women. Additionally, adverse effects of immunotherapy are mainly observed in women. Studies in some types of hormone-dependent cancer have revealed a role of sex hormones in anti-tumor response, tumor microenvironment and immune evasion. Estrogens mainly promote immune tolerance regulating T-cell function and modifying tumor microenvironment, while androgens attenuate anti-tumor immune responses. The precise mechanism by which sex and sex hormones may modulate immune response to tumor, modify PD-L1 expression in cancer cells and promote immune escape in NSCLC is still unclear, but current data show how sexual differences affect immune therapy response and prognosis. This review provides update information regarding anti-PD-1/PD-L immunotherapeutic efficacy in NSCLC by sex, analyzing potential roles for sex hormones on PD-L1 expression, and discussing a plausible of sex and sex hormones as predictive response factors to immunotherapy.

Pembrolizumab Plus Chemotherapy in Squamous Non-Small-Cell Lung Cancer: 5-Year Update of the Phase III KEYNOTE-407 Study.

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 efficacy and safety outcomes from the phase III KEYNOTE-407 study (ClinicalTrials.gov identifier: NCT02775435). Eligible patients with previously untreated, metastatic squamous non-small-cell lung cancer (NSCLC) were randomly assigned 1:1 to pembrolizumab 200 mg or placebo plus carboplatin and paclitaxel/nab-paclitaxel once every 3 weeks for four cycles, followed by pembrolizumab or placebo for up to 35 cycles. Primary end points were overall survival (OS) and progression-free survival (PFS) per RECIST version 1.1 by blinded independent central review (BICR). Five hundred fifty-nine patients were randomly assigned in the intention-to-treat population (pembrolizumab plus chemotherapy, n = 278; placebo plus chemotherapy, n = 281). The median time from random assignment to data cutoff was 56.9 (range, 49.9-66.2) months. OS and PFS were improved with pembrolizumab plus chemotherapy versus placebo plus chemotherapy (hazard ratio [95% CI], 0.71 [0.59 to 0.85] and 0.62 [0.52 to 0.74]), with 5-year OS rates of 18.4% versus 9.7%, respectively. Toxicity was manageable. Among 55 patients who completed 35 cycles of pembrolizumab, the objective response rate was 90.9% and the 3-year OS rate after completion of 35 cycles (approximately 5 years after random assignment) was 69.5%. Pembrolizumab plus chemotherapy maintained an OS and PFS benefit versus placebo plus chemotherapy in previously untreated, metastatic squamous NSCLC and is a standard-of-care first-line treatment option for metastatic squamous NSCLC regardless of programmed death ligand 1 expression.

Epirubicin, cisplatin plus ifosfamide versus standard chemotherapeutic regimens for advanced/unresectable primary thoracic sarcomas.

PURPOSE: Thoracic sarcomas are rare malignancies, with limited data for unresectable/advanced scenarios. Our goal is to provide insights of a three-drug chemotherapy regimen improving patient survival compared to standard regimens. METHODS: Retrospective cohort analysis of patients diagnosed with unresectable/advanced primary thoracic sarcoma divided between primary pulmonary sarcomas (PPS) and chest wall sarcomas (CWS) comparing chemotherapeutical regimens efficacy. Not true soft tissue sarcomas (STS) for PPS were excluded from the analysis. Univariate and multivariate analysis performed via Cox-regression model. Progression-free survival (PFS) and overall survival (OS) analysis via Kaplan-Meier with hazard ratio (HR) obtained via Mantel-Haenszel or log rank. RESULTS: 157 total cases were included, from which 50 cases were PPS and 107 cases CWS. For PPS, 4 cases were excluded from the analysis as they were not true STS. The most common histology was undifferentiated sarcomas, 63% of cases were treated with E/C/I and 37% with another regimen. The E/C/I regimen demonstrated a benefit for both OS (p = 0.020) and PFS (p = 0.010) when compared to any other regimen as well as when compared to non-platinum regimens (p = 0.016 and p = 0.001). Regarding CWS, the most common histology was synovial and undifferentiated sarcomas, 55.1% were treated with E/C/I and 44.9% treated with another regimen. The E/C/I regimen did not demonstrate a benefit for OS or PFS compared to any other regimen, neither when compared to other non-platinum regimens. However, a benefit was observed in favor of E/C/I when compared to other platinum regimens in both OS (p = 0.049) and PFS (0.015). Both analyses for PPS and CWS demonstrated a benefit in favor of cisplatin therapies compared to carboplatin in both OS and PFS. CONCLUSION: This study demonstrates that platinum therapy alone does not work, and that cisplatin must be the agent of choice and it's used in combination could increase treatment response. The E/C/I regimen demonstrated a in PPS but not for CWS, this is due do their rarity of PPS and that no standard treatment is established yet. The regimen proposed here could represent a possible new standard of treatment for PPS as long as it is validated in a prospective study.

Survival prognostic factors in unresectable/advanced primary thoracic sarcomas.

Background: Primary thoracic sarcomas (PTS) including primary pulmonary and chest wall sarcomas (CWS), are aggressive lung malignancies with limited information specially in an advanced/unresectable setting. Unfortunately, prognostic factors for these malignancies are not well identified. Methods: Retrospective cohort analysis of patients diagnosed with unresectable/advanced soft tissue PTS from a third level reference institute. Univariate and multivariate analysis performed via Cox-regression model. Progression-free survival (PFS) and overall survival (OS) analysis via Kaplan-Meier method. Results: A total of 157 patients were identified, 55.4% female, mean age 51.8 years (range, 18-90 years), 19.1% tobacco exposure and 10.8% asbestos exposure. The most common performance status was Eastern Cooperative Oncology Group (ECOG) 1 (38.9%), most common clinical presentation cough (58.4%) and thoracic pain (55.4%). Undifferentiated sarcoma (37.6%) followed by synovial sarcoma (34.4%) were the most common histologies. Most patients received five chemotherapeutic cycles (37.6%), 57.3% of patients obtained a partial response and 61.1% an overall response rate (ORR). Median PFS was 9 months [95% confidence interval (CI): 8.717-9.283 months]. The multivariable analysis identified ECOG ≥2, a poorer response to chemotherapy (less number of chemotherapy cycles) and an increase Response Evaluation Criteria in Solid Tumors (RECIST) to be associated with a shorter progression-free period. Median OS was 11 months (95% CI: 10.402-11.958 months) with an ECOG ≥2 and a poorer response to chemotherapy (less number of chemotherapy cycles) associated with a shorter survival. Conclusions: Age, gender, comorbidities, tobacco and asbestos exposure, clinical presentation and histopathological diagnosis are not useful prognostic factors in unresectable/advanced PTS, however, an adequate initial ECOG, RECIST and a better response to chemotherapy should be used as prognostic factors in the management of these tumors.

A comparative study of immunotherapy as second-line treatment and beyond in patients with advanced non-small-cell lung carcinoma.

BACKGROUND: Immunotherapy has demonstrated an improved overall survival (OS) and progression-free survival (PFS) as second-line treatment and subsequent lines compared with chemotherapy. MATERIALS & METHODS: This was a retrospective review among eight medical centers comprising 100 patients with a confirmed diagnosis of non-small-cell lung carcinoma, in their second-line treatment or beyond with immune checkpoints inhibitors treatment. The current study aimed to analyze effectiveness of immunotherapy in second-line treatment or further in the Mexican population, using PFS rate, OS rate and the best objective response to treatment by RECIST 1.1 as a surrogate of effectiveness. RESULTS: In total, 100 patients met the criteria for enrollment in the current study. From the total study population, 49 patients (49.0%) were male and 51 (51.0%) were female, with an average age of 60 years and stage IV as the most prevalent clinical stage at the beginning of the study. A total of 61 patients (61.0%) had partial response; 11 (11.0%) stable disease; 2 (2.0%), complete response, 4 (4.0%), progression; and 22 (22.0%) were nonevaluable. We found a median PFS of 4 months (95% CI: 3.2-4.7 months) and an OS of 9 months (95% CI: 7.2-10.7 months). CONCLUSION: The response to immunotherapy is similar, with an improvement in OS and PFS, independent of which drug is used. Patients using nivolumab had a better survival, although that was not statistically significant.

Outcomes With Pembrolizumab Plus Platinum-Based Chemotherapy for Patients With NSCLC and Stable Brain Metastases: Pooled Analysis of KEYNOTE-021, -189, and -407.

INTRODUCTION: This exploratory analysis retrospectively evaluated outcomes in patients with advanced NSCLC to determine whether baseline brain metastases influenced the efficacy of first-line pembrolizumab plus chemotherapy versus chemotherapy alone. METHODS: We pooled data for patients with advanced NSCLC in KEYNOTE-021 cohort G (nonsquamous), KEYNOTE-189 (nonsquamous), and KEYNOTE-407 (squamous). Patients were assigned to platinum-doublet chemotherapy with or without the addition of 35 cycles of pembrolizumab 200 mg every 3 weeks. All studies permitted enrollment of patients with previously treated or untreated (KEYNOTE-189 and KEYNOTE-407 only) stable brain metastases. Patients with previously treated brain metastases were clinically stable for 2 or more weeks (≥4 wk in KEYNOTE-021 cohort G), had no evidence of new or enlarging brain metastases, and had no steroid use at least 3 days before dosing. Patients with known untreated asymptomatic brain metastases required regular imaging of the brain. RESULTS: A total of 1298 patients were included, 171 with and 1127 without baseline brain metastases. Median (range) durations of follow-up at data cutoff were 10.9 (0.1‒35.1) and 11.0 (0.1‒34.9) months, respectively. Hazard ratios (pembrolizumab + chemotherapy/chemotherapy) were similar for patients with and without brain metastases for overall survival (0.48 [95% confidence interval (CI): 0.32‒0.70] and 0.63 [95% CI: 0.53‒0.75], respectively) and progression-free survival (0.44 [95% CI: 0.31‒0.62] and 0.55 [95% CI: 0.48‒0.63], respectively). In patients with brain metastases, median overall survival was 18.8 months with pembrolizumab plus chemotherapy and 7.6 months with chemotherapy, and median progression-free survival was 6.9 months and 4.1 months, respectively. Objective response rates were higher and duration of response longer with pembrolizumab plus chemotherapy versus chemotherapy regardless of brain metastasis status. Incidences of treatment-related adverse events with pembrolizumab plus chemotherapy versus chemotherapy were 88.2% versus 82.8% among patients with brain metastases and 94.5% versus 90.6% in those without. CONCLUSIONS: With or without brain metastasis, pembrolizumab plus platinum-based histology-specific chemotherapy improved clinical outcomes versus chemotherapy alone across all programmed death ligand 1 subgroups, including patients with programmed death ligand 1 tumor proportion score less than 1% and had a manageable safety profile in patients with advanced NSCLC. This regimen is a standard-of-care treatment option for treatment-naive patients with advanced NSCLC, including patients with stable brain metastases.

Myoepithelial Carcinoma Arising in a Plasmacytoid Myoepithelioma of the Parotid Gland Synchronized with Melanoma: A Case Report and Review of the Literature.

Myoepithelial carcinoma, also known as malignant myoepithelioma, is considered an extremely rare (0.45-1%) malignant salivary gland neoplasm. Approximately 100 cases have been reported in the English-language literature on myoepithelial carcinoma. The majority of the myoepitheliomas described in the literature have been benign, and the malignant counterpart is considered rare (<1%). Such a tumor may appear de novo or rarely develop from a preexisting pleomorphic adenoma (<20%), and in exceedingly rare cases (<0.5%), it has arisen from a benign myoepithelioma (i.e., plasmacytoid myoepithelioma). To our knowledge, no case of myoepithelial carcinoma of the parotid gland arising in a plasmacytoid myoepithelioma synchronized with melanoma has been reported to date. The treatment of myoepithelial carcinoma has been mainly surgical, including wide excision with free margins, with or without nodal dissection. The roles of chemotherapy and radiotherapy have not yet been established. We report a case of myoepithelial carcinoma of the parotid gland arising in a plasmacytoid myoepithelioma synchronized with melanoma in a 40-year-old woman. In our case, a complete response was achieved with surgery followed by adjuvant chemotherapy based on carboplatin and paclitaxel concurrent with radiotherapy.

Nivolumab and Ipilimumab as Maintenance Therapy in Extensive-Disease Small-Cell Lung Cancer: CheckMate 451.

PURPOSE: In extensive-disease small-cell lung cancer (ED-SCLC), response rates to first-line platinum-based chemotherapy are robust, but responses lack durability. CheckMate 451, a double-blind phase III trial, evaluated nivolumab plus ipilimumab and nivolumab monotherapy as maintenance therapy following first-line chemotherapy for ED-SCLC. METHODS: Patients with ED-SCLC, Eastern Cooperative Oncology Group performance status 0-1, and no progression after ≤ 4 cycles of first-line chemotherapy were randomly assigned (1:1:1) to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks for 12 weeks followed by nivolumab 240 mg once every 2 weeks, nivolumab 240 mg once every 2 weeks, or placebo for ≤ 2 years or until progression or unacceptable toxicity. Primary end point was overall survival (OS) with nivolumab plus ipilimumab versus placebo. Secondary end points were hierarchically tested. RESULTS: Overall, 834 patients were randomly assigned. The minimum follow-up was 8.9 months. OS was not significantly prolonged with nivolumab plus ipilimumab versus placebo (hazard ratio [HR], 0.92; 95% CI, 0.75 to 1.12; P = .37; median, 9.2 v 9.6 months). The HR for OS with nivolumab versus placebo was 0.84 (95% CI, 0.69 to 1.02); the median OS for nivolumab was 10.4 months. Progression-free survival HRs versus placebo were 0.72 for nivolumab plus ipilimumab (95% CI, 0.60 to 0.87) and 0.67 for nivolumab (95% CI, 0.56 to 0.81). A trend toward OS benefit with nivolumab plus ipilimumab was observed in patients with tumor mutational burden ≥ 13 mutations per megabase. Rates of grade 3-4 treatment-related adverse events were nivolumab plus ipilimumab (52.2%), nivolumab (11.5%), and placebo (8.4%). CONCLUSION: Maintenance therapy with nivolumab plus ipilimumab did not prolong OS for patients with ED-SCLC who did not progress on first-line chemotherapy. There were no new safety signals.

Prognostic factors for progression-free and overall survival in malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma is an infrequent neoplasia with a poor prognosis and the majority of patients already have advanced disease at the time of presentation. Exposure to asbestos is the most important risk factor for malignant pleural mesothelioma. Mesothelioma is a neoplasia with a long preclinical stage that can span from 15 to 40 years. METHODS: This was a descriptive, observational, retrospective study of 136 patients with a confirmed diagnosis of mesothelioma, which compared histological subtypes, immunohistochemical biomarkers, concomitant chronic degenerative diseases, tobacco use, age at the time of diagnosis, clinical stage and chemotherapy agents used or other treatments such as radiotherapy and surgery to identify all the factors that impact in the prognosis of overall survival (OS) and progression-free survival (PFS). RESULTS: A total of 136 patients were included in the study. In the total study population, 84 patients were male (61.8%) and 52 were female (38.2%). Median PFS was nine months (95% confidence interval [CI]: 8.4-9.5 months) and median OS was 12 months (95% CI: 11.3-12.6). The results indicated that the most determining prognostic factors for OS and PFS were cell differentiation measured by immunohistochemical biomarkers, the treatment chosen, and that RECIST was the most significant in the evaluation of patient response to treatment. CONCLUSIONS: Malignant pleural mesothelioma is a cancer with a poor prognosis usually diagnosed at an advanced stage of disease. Our study revealed that the prognostic factors for OS and PS were cell differentiation, the treatment chosen and RECIST.

First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Approved systemic treatments for malignant pleural mesothelioma (MPM) have been limited to chemotherapy regimens that have moderate survival benefit with poor outcomes. Nivolumab plus ipilimumab has shown clinical benefit in other tumour types, including first-line non-small-cell lung cancer. We hypothesised that this regimen would improve overall survival in MPM. METHODS: This open-label, randomised, phase 3 study (CheckMate 743) was run at 103 hospitals across 21 countries. Eligible individuals were aged 18 years and older, with previously untreated, histologically confirmed unresectable MPM, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to nivolumab (3 mg/kg intravenously once every 2 weeks) plus ipilimumab (1 mg/kg intravenously once every 6 weeks) for up to 2 years, or platinum plus pemetrexed chemotherapy (pemetrexed [500 mg/m2 intravenously] plus cisplatin [75 mg/m2 intravenously] or carboplatin [area under the concentration-time curve 5 mg/mL per min intravenously]) once every 3 weeks for up to six cycles. The primary endpoint was overall survival among all participants randomly assigned to treatment, and safety was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02899299, and is closed to accrual. FINDINGS: Between Nov 29, 2016, and April 28, 2018, 713 patients were enrolled, of whom 605 were randomly assigned to either nivolumab plus ipilimumab (n=303) or chemotherapy (n=302). 467 (77%) of 605 participants were male and median age was 69 years (IQR 64-75). At the prespecified interim analysis (database lock April 3, 2020; median follow-up of 29·7 months [IQR 26·7-32·9]), nivolumab plus ipilimumab significantly extended overall survival versus chemotherapy (median overall survival 18·1 months [95% CI 16·8-21·4] vs 14·1 months [12·4-16·2]; hazard ratio 0·74 [96·6% CI 0·60-0·91]; p=0·0020). 2-year overall survival rates were 41% (95% CI 35·1-46·5) in the nivolumab plus ipilimumab group and 27% (21·9-32·4) in the chemotherapy group. Grade 3-4 treatment-related adverse events were reported in 91 (30%) of 300 patients treated with nivolumab plus ipilimumab and 91 (32%) of 284 treated with chemotherapy. Three (1%) treatment-related deaths occurred in the nivolumab plus ipilimumab group (pneumonitis, encephalitis, and heart failure) and one (<1%) in the chemotherapy group (myelosuppression). INTERPRETATION: Nivolumab plus ipilimumab provided significant and clinically meaningful improvements in overall survival versus standard-of-care chemotherapy, supporting the use of this first-in-class regimen that has been approved in the USA as of October, 2020, for previously untreated unresectable MPM. FUNDING: Bristol Myers Squibb.

Paraneoplastic Cerebellar Degeneration with Anti-CV2/CRMP5 Antibodies in Ovarian Cancer: Case Report and Review of the Literature.

Paraneoplastic neurological syndromes (PNS) are rare presentations of an underlying oncological disease and more unusual during an oncological disease. They most likely present in small-cell lung carcinomas and thymomas, but present in <1% of the gynecological neoplasms. Acknowledging the pathophysiology is essential for management, explaining its clinical presentation, and future research. We present a patient with an underlying gynecological cancer that during her disease developed a PNS with an unusual autoantibody (anti-CV2/CRMP5) mediating the disease. We report a case of a 62-year-old female diagnosed with ovarian cancer who in the course of her disease developed neurological symptoms associated with cerebellar degeneration. After ruling out differential diagnoses such as metastases, a PNS was suspected and studied, in which anti-CV2/CRMP5 antibodies were positive. With her clinical presentation, radiological features, autoantibody positivity on cerebrospinal fluid, and an underlying oncological disease, cerebellar degeneration was diagnosed. The pathophysiology of PNS is not fully understood; therefore, its diagnosis and management are complex. Diagnosis is based on clinical presentation and specific antibodies associated. Unfortunately, patients have a bad prognosis and diminished quality of life, and therefore a multidisciplinary approach is needed. It is important to mention that the presentation of PNS does not mandatorily appear before the diagnosis of cancer, and multiple cases have been reported in which patients with an underlying oncological disease develop these syndromes. As medical oncologists and neurologists, we must consider and study these syndromes as a possible etiology in cases with an underlying cancer who develop neurological symptoms in the course of their disease.

Brigatinib in ALK-positive non-small cell lung cancer: real-world data in the Latin American population (Bri-world extend CLICaP).

Background: Brigatinib has demonstrated its efficacy as first-line therapy and in further lines for ALK-positive non-small cell lung cancer (NSCLC) patients; however, real-world data in Latin America are scarce. Methods: From January 2018 to March 2020, 46 patients with advanced ALK-positive NSCLC received brigatinib as second or further line of therapy in Mexico and Colombia. The primary end point was progression-free survival (PFS); secondary end point was time to treatment discontinuation (TTD). Results: At a median follow-up of 9.3 months, the median PFS was 15.2 months (95% CI: 11.6-18.8), and TTD was 18.46 months (95% CI: 9.54-27.38). The estimated overall survival at 12 months was 80%. Safety profile was consistent with previously published data. Conclusion: Brigatinib is an effective treatment for previously treated ALK-positive NSCLC patients in a real-world setting.

Efficacy and Safety of Nivolumab Plus Ipilimumab versus Sunitinib in First-line Treatment of Patients with Advanced Sarcomatoid Renal Cell Carcinoma.

PURPOSE: Patients with advanced renal cell carcinoma with sarcomatoid features (sRCC) have poor prognoses and suboptimal outcomes with targeted therapy. This post hoc analysis of the phase III CheckMate 214 trial analyzed the efficacy of nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib in patients with sRCC. PATIENTS AND METHODS: Patients with sRCC were identified via independent central pathology review of archival tumor tissue or histologic classification per local pathology report. Patients were randomized 1:1 to receive nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks (four doses) then nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg orally every day (4 weeks; 6-week cycles). Outcomes in patients with sRCC were not prespecified. Endpoints in patients with sRCC and International Metastatic Renal Cell Carcinoma Database Consortium intermediate/poor-risk disease included overall survival (OS), progression-free survival (PFS) per independent radiology review, and objective response rate (ORR) per RECIST v1.1. Safety outcomes used descriptive statistics. RESULTS: Of 1,096 randomized patients in CheckMate 214, 139 patients with sRCC and intermediate/poor-risk disease and six with favorable-risk disease were identified. With 42 months' minimum follow-up in patients with sRCC and intermediate/poor-risk disease, median OS [95% confidence interval (CI)] favored NIVO+IPI [not reached (NR) (25.2-not estimable [NE]); n = 74] versus sunitinib [14.2 months (9.3-22.9); n = 65; HR, 0.45 (95% CI, 0.3-0.7; P = 0.0004)]; PFS benefits with NIVO+IPI were similarly observed [median 26.5 vs. 5.1 months; HR, 0.54 (95% CI, 0.33-0.86; P = 0.0093)]. Confirmed ORR was 60.8% with NIVO+IPI versus 23.1% with sunitinib, with complete response rates of 18.9% versus 3.1%, respectively. No new safety signals emerged. CONCLUSIONS: NIVO+IPI showed unprecedented long-term survival, response, and complete response benefits versus sunitinib in previously untreated patients with sRCC and intermediate/poor-risk disease, supporting the use of first-line NIVO+IPI for this population.See related commentary by Hwang et al., p. 5.

Human skin biomarkers relationship to response to treatment with tyrosine kinase inhibitors in advanced EGFR-mutated lung adenocarcinoma.

BACKGROUND: A relationship between the EGFR signaling pathway expression in skin and the use of targeted cancer therapies has been previously demonstrated. Consistent evidence to support the use of skin biopsies as a surrogate for therapeutic evaluation is needed. The purpose of this study was to establish the relationship between the expression of EGFR signaling pathway markers in skin samples from EGFR-mutated metastatic lung adenocarcinoma patients and their response to tyrosine kinase inhibitors. METHODS: This was a prospective single blind analysis of 35 skin biopsies from 31 patients with confirmed advanced EGFR-mutated lung adenocarcinoma. Immunohistochemistry was performed: EGFR, p27, Ki67, STAT3 and MAPK, as well as H&E histopathological analysis, in order to determine their treatment response to tyrosine kinase inhibitors. RESULTS: EGFR, Ki67, STAT3, stratum corneum thickness (number of layers and millimeters) from skin samples had a statistical correlation with an adequate treatment response (P = 0.025, 0.015, 0.017, 0.041, 0.039 respectively). EGFR, p27 and number of layers of the stratum corneum were related to a better median progression-free survival (P = 0.025 and P = 0.030). CONCLUSIONS: The relationship between EGFR pathway inhibition in the skin and oncological outcomes obtained explains the parallel biological effects of tyrosine kinase inhibitors. We hope that our work incites future research to help validate and assess the use of these markers as potential prognostic and predictive factors.

Surgical care of thoracic malignancies during the COVID-19 pandemic in México: An expert consensus guideline from the Sociedad Mexicana de Oncología (SMeO) and the Sociedad Mexicana de Cirujanos Torácicos Generales (SMCTG).

To date, the impact, timeline and duration of COVID-19 pandemic remains unknown and more than ever it is necessary to provide safe pathways for cancer patients. Multiple triage systems for nonemergent surgical procedures have been published, but potentially curative cancer procedures are essential surgery rather than elective surgery. In the present and future scenario of our country, thoracic oncology teams may have the difficult decision of weighing the utility of surgical intervention against the risk for inadvertent COVID-19 exposure for patients and medical staff. In consequence, traditional pathways of surgical care must be adjusted to reduce the risk of infection and the use of resources. It is recommended that all thoracic cancer patients should be offered treatment according to the accepted standard of care until shortage of services require a progressive reduction in surgical cases. Here, we present a consensus of recommendations discussed by a multidisciplinary panel of experts on thoracic oncology and based on the best available evidence, and hope it will provide a modifiable framework of guidance for local strategy planners in thoracic cancer care services in Mexico. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: This article provides recommendations to guarantee the continuity of surgical care for thoracic oncology cases during COVID-19 pandemic, whilst maintaining the safety of patients and medical staff. WHAT THIS STUDY ADDS: This guideline is the result of an expert consensus on thoracic surgical oncology with recommendations adapted to medical, economic and social realities of Mexico.

A Randomized, Placebo-Controlled Trial of Pembrolizumab Plus Chemotherapy in Patients With Metastatic Squamous NSCLC: Protocol-Specified Final Analysis of KEYNOTE-407.

INTRODUCTION: In the randomized KEYNOTE-407 study (ClinicalTrials.gov, NCT02775435), pembrolizumab plus carboplatin and paclitaxel/nab-paclitaxel (chemotherapy) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus chemotherapy in patients with previously untreated metastatic squamous NSCLC. We report updated efficacy outcomes from the protocol-specified final analysis and, for the first time, progression on next line of treatment. METHODS: Eligible patients were randomized to chemotherapy plus either pembrolizumab (n = 278) or placebo (n = 281). After positive results from the second interim analysis, patients still receiving placebo could cross over to pembrolizumab monotherapy at the time of confirmed progressive disease. The primary end points were OS and PFS. PFS-2 (time from randomization to progression on next-line treatment/death, whichever occurred first) was an exploratory end point. RESULTS: After median (range) follow-up of 14.3 (0.1-31.3) months, pembrolizumab plus chemotherapy continued to exhibit a clinically meaningful improvement over placebo plus chemotherapy in OS (median, 17.1 mo [95% confidence interval (CI): 14.4‒19.9] versus 11.6 mo [95% CI: 10.1‒13.7]; hazard ratio [HR], 0.71 [95% CI: 0.58‒0.88]) and PFS (median, 8.0 mo [95% CI: 6.3‒8.4] versus 5.1 mo [95% CI: 4.3‒6.0]; HR, 0.57 [95% CI: 0.47‒0.69]). PFS-2 was longer for patients randomized to first-line pembrolizumab plus chemotherapy (HR, 0.59 [95% CI: 0.49‒0.72]). Grade 3 to 5 adverse events occurred in 74.1% and 69.6% of patients receiving pembrolizumab plus chemotherapy and placebo plus chemotherapy, respectively. CONCLUSIONS: Pembrolizumab plus chemotherapy continued to exhibit substantially improved OS and PFS in patients with metastatic squamous NSCLC. The PFS-2 outcomes support pembrolizumab plus chemotherapy as a standard first-line treatment in patients with metastatic squamous NSCLC.

Real-World Evidence: Multicenter Efficacy and Toxicity Analysis of Nintedanib With Docetaxel as Second-Line Treatment in Mexican Patients With Advanced Lung Adenocarcinoma.

PURPOSE: The LUME-Lung 1 study has brought consistent evidence of the effective use of nintedanib in lung adenocarcinoma as a second line of treatment; however, differences among ethnicities have been found in some studies. METHODS: This was a retrospective review among 21 medical centers of 150 patients with a confirmed diagnosis of lung adenocarcinoma, included in a compassionate use program of nintedanib from March 2014 to September 2015. The current study aimed to analyze the effectiveness of nintedanib in combination with docetaxel in the Mexican population, using progression-free survival rate and the best objective response to treatment by RECIST 1.1 as a surrogate of effectiveness. In addition, we examined the toxicity profile of our study population as a secondary end point. RESULTS: After exclusion criteria, only 99 patients met the criteria for enrollment in the current study. From the total study population, 53 patients (53.5%) were male and 46 (46.5%) were female, with an average age of 60 years and stage IV as the most prevalent clinical stage at the beginning of the compassionate use program. A total of 48 patients (48.5%) had partial response; 26 (26.3%), stable disease; 4 (4%), complete response; and 16 (16.2%), progression; and 5 (5%) were nonevaluable. We found a median progression-free survival of 5 months (95% CI, 4.3 to 5.7 months). The most common grade 3 or 4 adverse reactions were fatigue (14%) and diarrhea (13%). CONCLUSION: Nintedanib, as part of a chemotherapy regimen, is an effective option with an acceptable toxicity profile for advanced lung adenocarcinoma after first-line treatment progression.

Health-Related Quality of Life With Carboplatin-Paclitaxel or nab-Paclitaxel With or Without Pembrolizumab in Patients With Metastatic Squamous Non-Small-Cell Lung Cancer.

PURPOSE: In the phase 3 KEYNOTE-407 study, the addition of pembrolizumab to carboplatin-paclitaxel/nab-paclitaxel significantly improved overall survival, progression-free survival, and objective response rate in patients with previously untreated metastatic squamous non-small-cell lung cancer (NSCLC), with little impact on severe toxicity. We present patient-reported outcomes (PROs) from KEYNOTE-407. METHODS: Patients were randomly assigned to receive 4 cycles of pembrolizumab 200 mg or placebo once every 3 weeks plus carboplatin plus paclitaxel or nab-paclitaxel, followed by pembrolizumab or placebo for an additional 31 cycles. Health-related quality of life (HRQoL) was evaluated using the European Organisation for Research and Treatment of Cancer Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) and Quality of Life Questionnaire-Lung Cancer Module 13 (QLQ-LC13). Key PRO endpoints were change from baseline to weeks 9 and 18 (during and after platinum therapy) in the QLQ-C30 global health status/quality of life (GHS/QoL) score and time to deterioration in the composite endpoint of cough, chest pain, or dyspnea from the QLQ-C30 and QLQ-LC13. Two-sided, nominal P values are provided. RESULTS: A total of 554 and 553 patients completed ≥ 1 QLQ-C30 or ≥ 1 QLQ-LC13 assessment, respectively. GHS/QoL score improved for the pembrolizumab-combination group (least squares [LS] mean [95% CI] change from baseline: week 9, 1.8 [-0.9 to 4.4]; week 18, 4.3 [1.7 to 6.9]) and deteriorated in the placebo-combination group (week 9, -1.8 [-4.4 to 0.7]; week 18, -0.57 [-3.3 to 2.2]). Between-group differences were improved for the pembrolizumab-combination group (difference in LS mean scores: week 9, 3.6 [95% CI, 0.3 to 6.9], nominal P = .0337; week 18, 4.9 [1.4 to 8.3], nominal P = .0060). Median time to deterioration in cough, chest pain, or dyspnea was not reached in either group (hazard ratio, 0.79; 95% CI, 0.58 to 1.06]; nominal P = .125). CONCLUSION: Addition of pembrolizumab to chemotherapy maintained or improved HRQoL measurements relative to baseline and improved HRQoL versus chemotherapy alone at weeks 9 and 18. These results support use of pembrolizumab plus chemotherapy as first-line therapy for metastatic squamous NSCLC.

National Clinical Practice Guidelines for the management of non-small cell lung cancer in early, locally advanced and metastatic stages. Extended version. / Guía de Práctica Clínica Nacional para el manejo del cáncer de pulmón de células no pequeñas en estadios tempranos, localmente avanzados y metastásicos.

OBJECTIVE: Lung cancer is one the leading causes of mortality worldwide. Symptomatic manifestations of the disease generally occur in the advanced-stage setting, and therefore an important number of patients have advanced or metastatic disease by the time they are diagnosed. This situation contributes to a poor prognosis in the treatment of lung cancer. Evidencebased clinical recommendations are of great value to support decision-making for daily practice, and thus improving health care quality and patient outcomes. MATERIALS AND METHODS: This document was an initiative of the Mexican Society of Oncology (SMEO) in collaboration with Mexican Center of Clinical Excellence (Cenetec) according to Interna- tional Standards. Such standards included those described by the IOM, NICE, SIGN and GI-N. An interdisciplinary Guideline Development Group (GDG) was put together which included medical oncologists, surgical oncologistsc, radiation therapists, and methodologists with expertise in critical appraisal, sys- tematic reviews and clinical practice guidelines development. RESULTS: 62 clinical questions were agreed among members of the GDG. With the evidence identified from systematic reviews, the GDG developed clinical recommendations using a Modified Delphi Panel technique. Patients' representatives validated them. CONCLUSIONS: These Clinical Practice Guideline aims to support the shared decision-making process for patients with different stages of non-small cell lung cancer. Our goal is to improve health-care quality on these patients.

OBJETIVO: El cáncer de pulmón es una de las principales causas de mortalidad alrededor del mundo. Su historia natural, con la manifestación de síntomas en etapas avanzadas y el retraso en su diagnóstico hacen que una gran proporción de pacientes se diagnostiquen en estadios tardíos de la enfermedad, lo que hace muy complicado el tratamiento exitoso de la misma. De esto deriva la importancia de dar origen a recomendaciones basadas en evidencia para soportar la toma de decisiones clínicas por parte de los grupos interdisicplinarios que se encargan del manejo de este padecimiento. MATERIAL Y MÉTODOS: Este documento se desarrolló por parte de la Sociedad Mexicana de Oncología en colaboración con el Centro Nacional de Excelencia Tec- nológica de México (Cenetec) a través de la dirección de integración de Guías de Práctica Clínica en cumplimiento a estándares internacionales como los descritos por el Ins- tituto de Medicina de EUA (IOM, por sus siglas en inglés), el Instituto de Excelencia Clínica de Gran Bretaña (NICE, por sus siglas en inglés), la Red Colegiada para el Desarrollo de Guías de Escocia (SIGN, por sus siglas en inglés), la Red Internacional de Guías (G-I-N, por sus siglas en inglés); entre otros. Se integró en representación de la Sociedad Mexicana de Oncología un Grupo de Desarrollo de la Guía (GDG) de manera interdisciplinaria, considerando oncólogos médicos, cirujanos oncólogos, cirujanos de tórax, radio-oncólogos, y metodólogos con experiencia en revisiones sistemáticas de la literatura y guías de práctica clínica. RESULTADOS: Se consensuaron 62 preguntas cllínicas que abarcaron lo establecido previamente por el GDG en el documento de alcances de la Guía. Se identificó la evidencia científica que responde a cada una de estas preguntas clínicas y se evaluó críticamente la misma, antes de ser incorporada en el cuerpo de evidencia de la Guía. El GDG acordó mediante la técnica de consenso formal de expertos Panel Delphi la redacción final de las recomendaciones clínicas. C. CONCLUSIONES: Esta Guía de Práctica Clínica pretende proveer recomendaciones clínicas para el manejo de los distintos estadios de la enfermedad y que asistan en el proceso de toma de decisiones compartida. El GDG espera que esta guía contribuya a mejorar la calidad de la atención clínica en las pacientes con cáncer de pulmón de células no pequeñas.