Phase 1b study of cobimetinib plus atezolizumab in patients with advanced BRAFV600 wild-type melanoma progressing on prior anti-programmed death-1 therapy.

OBJECTIVE: To evaluate the efficacy and safety of cobimetinib plus atezolizumab in the treatment of patients with advanced BRAFV600 wild-type melanoma who had progressed on prior anti‒programmed death-1 (PD-1) therapy. PATIENTS AND METHODS: This phase 1b, open-label, international multicentre study enrolled 3 cohorts. Herein, we report on patients in cohorts A and B who had progressed on prior anti‒PD-1 therapy. Patients in cohort A received cobimetinib 60 mg once daily for 21 days followed by a 7-day break and concurrent intravenous atezolizumab 840 mg every 2 weeks. Patients in cohort B received the same dosing regimen as cohort A except for cycle 1 in which patients received cobimetinib only for the first 14 days prior to initiation of atezolizumab on cycle 1 day 15. Coprimary end-points were objective response rate and disease control rate. Secondary end-points were duration of response, progression free survival and overall survival. RESULTS: Between 19th June 2017 and 12th December 2018, 103 patients were enrolled. Median follow-up was 6.9 months (interquartile range, 4.8-10.1 months); objective response rate was 14.6% and disease control rate was 38.8% (95% confidence interval, 29.39-48.94). The median duration of response, progression-free survival and overall survival was 12.7 months, 3.8 months and 14.7 months, respectively. The most common adverse events were diarrhoea (75/103; 72.8%), dermatitis acneiform (57/103; 55.3%) and nausea (52/103; 50.5%). Thirty-four patients (33.0%) died: 33 (91.7%) due to progressive disease and one (1%) due to treatment-related oesophagitis. CONCLUSIONS: Combination therapy with cobimetinib and atezolizumab in patients with advanced BRAFV600 wild-type melanoma with disease progression on or after prior anti‒PD-1 therapy demonstrated limited activity. CLINICAL TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov; NCT03178851.

Lung cancer patients with COVID-19 in Spain: GRAVID study.

INTRODUCTION: Patients with cancer may be at increased risk of more severe COVID-19 disease; however, prognostic factors are not yet clearly identified. The GRAVID study aimed to describe clinical characteristics, outcomes, and predictors of poor outcome in patients with lung cancer and COVID-19. METHODS: Prospective observational study that included medical records of patients with lung cancer and PCR-confirmed COVID-19 diagnosis across 65 Spanish hospitals. The primary endpoint was all-cause mortality; secondary endpoints were hospitalization and admission to intensive care units (ICU). RESULTS: A total of 447 patients with a mean age of 67.1 ± 9.8 years were analysed. The majority were men (74.3 %) and current/former smokers (85.7 %). NSCLC was the most frequent type of cancer (84.5 %), mainly as adenocarcinoma (51.0 %), and stage III metastatic or unresectable disease (79.2 %). Nearly 60 % of patients were receiving anticancer treatment, mostly first-line chemotherapy. Overall, 350 (78.3 %) patients were hospitalized for a mean of 13.4 ± 11.4 days, 9 (2.0 %) were admitted to ICU and 146 (32.7 %) died. Advanced disease and the use of corticosteroids to treat COVID-19 during hospitalization were predictors of mortality. Hospitalized, non-end-of-life stage patients with lymphocytopenia and high LDH had an increased risk of death. Severity of COVID-19 correlated to higher mortality, ICU admission, and mechanical ventilation rates. CONCLUSIONS: Mortality rate was higher among patients treated with corticosteroids during hospitalization, while anticancer therapy was not associated with an increased risk of hospitalization or death. Tailored approaches are warranted to ensure effective cancer management while minimizing the risk of exposure to SARS-CoV-2.

Combined assessment of peritumoral Th1/Th2 polarization and peripheral immunity as a new biomarker in the prediction of BCG response in patients with high-risk NMIBC.

Intravesical Bacille Calmette-Guérin (BCG) remains the most effective treatment for high-risk non-muscle-invasive bladder cancer (NMIBC), unfortunately there is no validated biomarker to predict clinical outcome. Here we tried to explore the possibility that a combination of the density of peritumoral infiltrating cells (Th1, Th2 and PD-L1) and the composition of peripheral immune cells (neutrophil and lymphocyte counts) could generate a more reliable prognostic biomarker. Twenty-two patients with high-risk NMIBC treated with BCG (10 BCG nonresponders and 12 BCG responders) were selected. BCG responders had significantly lower level of peritumoral T-bet+ cells with an associated higher GATA-3+/T-bet+ ratio (p = 0.04, p = 0.02, respectively). Furthermore, the immune polarization in tissue (GATA-3+/T-bet+ ratio) adjusted for the systemic inflammation (neutrophil-to-lymphocyte ratio) showed a significantly higher association with the BCG response (p = 0.004). A survival analysis demonstrated prolonged recurrence-free survival (RFS) in patients with a lower T-bet+/Lymphocyte ratio and higher GTR/NLR (p = 0.01). No association was observed between peritumoral PD-L1+ expression and the BCG response. In conclusion, alterations in overall immune function, both local and systemic, may influence the therapeutic response to BCG, therefore a combined analysis of tumoral (Th2/Th1 ratio) and peripheral (NLR) immune composition prior to treatment may be a promising approach to predict the BCG response in high-risk NMIBC patients.

Understanding the function and dysfunction of the immune system in lung cancer: the role of immune checkpoints.

Survival rates for metastatic lung cancer, including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), are poor with 5-year survivals of less than 5%. The immune system has an intricate and complex relationship with tumorigenesis; a groundswell of research on the immune system is leading to greater understanding of how cancer progresses and presenting new ways to halt disease progress. Due to the extraordinary power of the immune system-with its capacity for memory, exquisite specificity and central and universal role in human biology-immunotherapy has the potential to achieve complete, long-lasting remissions and cures, with few side effects for any cancer patient, regardless of cancer type. As a result, a range of cancer therapies are under development that work by turning our own immune cells against tumors. However deeper understanding of the complexity of immunomodulation by tumors is key to the development of effective immunotherapies, especially in lung cancer.

The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies.

Resistance to RAF- and MEK-targeted therapy is a major clinical challenge. RAF and MEK inhibitors are initially but only transiently effective in some but not all patients with BRAF gene mutation and are largely ineffective in those with RAS gene mutation because of resistance. Through a genetic screen in BRAF-mutant tumor cells, we show that the Hippo pathway effector YAP (encoded by YAP1) acts as a parallel survival input to promote resistance to RAF and MEK inhibitor therapy. Combined YAP and RAF or MEK inhibition was synthetically lethal not only in several BRAF-mutant tumor types but also in RAS-mutant tumors. Increased YAP in tumors harboring BRAF V600E was a biomarker of worse initial response to RAF and MEK inhibition in patients, establishing the clinical relevance of our findings. Our data identify YAP as a new mechanism of resistance to RAF- and MEK-targeted therapy. The findings unveil the synthetic lethality of combined suppression of YAP and RAF or MEK as a promising strategy to enhance treatment response and patient survival.

A critical question for cancer therapy: what new targets exist?

Designing molecular targeted therapy with high specificity based on novel tumor biomarkers is a high priority in lung cancer research. Several molecular aberrations have been already identified in non-small cell lung cancer (NSCLC), with subsequent development of drugs targeted to these aberrations. A more recent actionable target is MET, a multifaceted receptor tyrosine kinase which frequently interacts with other key oncogenic tyrosine kinases including epidermal growth factor receptor (EGFR) and ERBB3 leading to resistance to anti-EGFR therapies. However a phase III trial enrolling only patients with MET-positive tumors was stopped in early March due to futility since there was no evidence that the addition of onartuzumab to erlotinib has any positive effect. From the results of the MET lung phase III trial, we provide new pieces of information that can contribute to further preclinical validation and also be part of the armamentarium for clinical translational research.

Magnetic resonance imaging diagnosis of carcinoid heart disease.

Carcinoid tumors are associated with the production of a number of bioactive substances that might deposit on the endocardium (endocardial fibroelastosis) and produce cardiac failure. Carcinoid heart disease usually presents as right-sided valvular heart disease. Even if the diagnosis is frequently made by transthoracic echocardiography, cardiac magnetic resonance imaging adds valuable information when evaluating cardiac structures that might be difficult to analyze on echocardiography.