Therapeutic strategies for BRAF mutation in non-small cell lung cancer: a review

Lung cancer is the leading cause of cancer related deaths. Among the two broad types of lung cancer, non-small cell lung cancer accounts for 85% of the cases. The study of the genetic alteration has facilitated the development of targeted therapeutic interventions. Some of the molecular alterations which are important targets for drug therapy include Kirsten rat sarcoma (KRAS), Epidermal Growth Factor Receptor (EGFR), V-RAF murine sarcoma viral oncogene homolog B (BRAF), anaplastic lymphoma kinase gene (ALK). In the setting of extensive on-going clinical trials, it is imperative to periodically review the advancements and the newer drug therapies being available. Among all mutations, BRAF mutation is common with incidence being 8% overall and 1.5 – 4% in NSCLC. Here, we have summarized the BRAF mutation types and reviewed the various drug therapy available - for both V600 and nonV600 group; the mechanism of resistance to BRAF inhibitors and strategies to overcome it; the significance of comprehensive profiling of concurrent mutations, and the role of immune checkpoint inhibitor in BRAF mutated NSCLC. We have also included the currently ongoing clinical trials and recent advancements including combination therapy that would play a role in improving the overall survival and outcome of NSCLC

Efficacy and outcomes of ramucirumab and docetaxel in patients with metastatic non-small cell lung cancer after disease progression on immune checkpoint inhibitor therapy: Results of a monocentric, retrospective analysis

Current first-line standard therapy for metastatic non-small cell lung cancer without driver mutations involves chemotherapy and immunotherapy combination. Prior to the advent of immune checkpoint inhibition, REVEL, a randomized phase III trial demonstrated improved progression-free and overall survival with ramucirumab and docetaxel (ram+doc) in patients who failed platinum-based first-line therapy. Long-term outcomes related to second-line ramucirumab and docetaxel after first-line immunotherapy exposure remain unknown. We analyzed outcomes for 35 patients from our center whom received ramucirumab and docetaxel following disease progression on chemotherapy and immunotherapy combination. Median progression-free survival among patients who received ram+doc after exposure to immunotherapy was 6.6 months (95% CI = 5.5 to 14.9 months; p<0.0001), and median overall survival was 20.9 months (95% CI = 13.4 months to infinity; p<0.0001). These outcomes suggest that there may a synergistic benefit to combining chemotherapy with anti-angiogenic therapy after immunotherapy exposure. Future analyses should be evaluated prospectively and among a larger patient subset

Umbilical cord mesenchymal stem cells for COVID-19 acute respiratory distress syndrome: A double-blind, phase 1/2a, randomized controlled trial

Acute respiratory distress syndrome (ARDS) in COVID-19 is associated with high mortality. Mesenchymal stem cells are known to exert immunomodulatory and anti-inflammatory effects and could yield beneficial effects in COVID-19 ARDS. The objective of this study was to determine safety and explore efficacy of umbilical cord mesenchymal stem cell (UC-MSC) infusions in subjects with COVID-19 ARDS. A double-blind, phase 1/2a, randomized, controlled trial was performed. Randomization and stratification by ARDS severity was used to foster balance among groups. All subjects were analyzed under intention to treat design. Twenty-four subjects were randomized 1:1 to either UC-MSC treatment (n = 12) or the control group (n = 12). Subjects in the UC-MSC treatment group received two intravenous infusions (at day 0 and 3) of 100 ± 20 × 106 UC-MSCs; controls received two infusions of vehicle solution. Both groups received best standard of care. Primary endpoint was safety (adverse events [AEs]) within 6 hours; cardiac arrest or death within 24 hours postinfusion). Secondary endpoints included patient survival at 31 days after the first infusion and time to recovery. No difference was observed between groups in infusion-associated AEs. No serious adverse events (SAEs) were observed related to UC-MSC infusions. UC-MSC infusions in COVID-19 ARDS were found to be safe. Inflammatory cytokines were significantly decreased in UC-MSC-treated subjects at day 6. Treatment was associated with significantly improved patient survival (91% vs 42%, P =.015), SAE-free survival (P =.008), and time to recovery (P =.03). UC-MSC infusions are safe and could be beneficial in treating subjects with COVID-19 ARDS

Abstract PO-256: Factors determining adherence to lung cancer screening in a Hispanic urban population

Abstract Background: The National Lung Screening Trial (NLST) demonstrated that lung cancer screening reduces lung cancer mortality by 20% in high risk individuals. The rate of adherence to screening was more than 90% in the NSLT in a predominant non- Hispanic White (NHW) population, with only 1.8% Hispanics. Concerns regarding adherence in lung cancer screening have been widely reported. The goal of our study was to investigate the attributes of a Lung Cancer (LC) screening program and factors associated with screening adherence in a largely Hispanic urban population and compare with the NLST population. Methods: We performed a retrospective analysis of 421 consecutive cases who underwent LDCT screening from 2016-2019 at the University of Miami (UM), with similar inclusion criteria as the NLST. Annual adherence was defined as returning for imaging within 1 year and 90 days after an initial negative scan. Screening results, LC detection and screening adherence were examined and compared with the NLST cohort using summary statistics and X2 test for categorical variables. Association between adherence and baseline factors including age, gender, race/ethnicity, insurance, smoking history, and COPD was analyzed. Results: A total of 421 patients underwent screening from 2016-2019. UM cohort had a different racial and ethnic profile, with a higher percentage of Hispanics (47.3% vs 1.8%) and African Americans (15% vs 4.5%) in the UM than the NLST cohort respectively. Compared with NLST Low-Dose Computed Tomography (LDCT) arm, the UM cohort had fewer active smokers and a lighter smoking history. The proportion of positive LDCT screens (Lung-RADS Class 3/4) in the UM cohort (14.1%) was comparable to the NLST cohort (13.7%). Eighty-five percent of initial scans (359 of 421) were benign (Lung-RADS Class 1/2). The no-show rate for the LDCT screening shared-decision visit was 26% (228 of 891 visits). Early adherence rate to repeat annual imaging was 31.4% (81/258) Factors associated with early adherence included gender smoking, and race/ethnicity, with greater adherence in men than women, former smokers, and patients of NHW ethnicity. Despite, lower adherence to screening, the UM cohort had higher LC detection rate (3.3%) than the NLST cohort (1.1%) (p<0.001). Conclusion: Nonadherence to LDCT screening recommendations and non-compliance to shared decision making visits is common in a urban-based LDCT screening program. More data is needed to understand obstacles to compliance with screening in minority populations nationwide. Citation Format: Estelamari Rodriguez, Marie Jeanette Charles, Sophie Torrents, Richa Dawar, Nestor Villamizar, Dao Minh Nguyen, Kunal Gawri. Factors determining adherence to lung cancer screening in a Hispanic urban population [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-256

Clinical attributes and outcomes in metastatic non-small cell lung cancer bearing BRAF mutations treated with targeted therapy versus immunotherapy

e21219 Background: Mutations in BRAF oncogene have been identified in about 2-4% of non-small cell lung cancer (NSCLC) patients. Combination of tyrosine kinase inhibitors (TKI), dabrafenib and trametinib has shown improved and enduring results in both first line and second line setting. Given the rarity of BRAF mutations, and the approval of TKI, the role of Immune Checkpoint Inhibitors (ICI) still needs to be ascertained. Methods: We conducted a retrospective review of 19 BRAF-mutant lung cancer patients from 2013-2020 at the University of Miami. Clinicopathologic features, and patient’s response to chemotherapy/ICI vs anti-BRAF targeted therapy (ABTT) was investigated. Duration of response (DOR) was calculated from the initiation of therapy, and Overall survival (OS) was calculated from the diagnosis of metastatic disease. OS was estimated by Kaplan-Meier method and log-rank test was used to compare groups. Hazard ratio (HR) and corresponding 95% confidence interval were estimated using Cox proportional hazards regression model. All tests were two sided and statistical significance was considered when p<0.05. Results: Total 19 patients with a median age of 63 (range 54-87) were identified from a cohort of 575 sequenced lung cancer patients (prevalence of 3.3%). 6 patients were never-smokers, 13 former/current smokers; 10 were women; 10 were Non-Hispanic White, 8 Hispanic, and 1 African American. Majority had adenocarcinoma (n=17) and non-V600E BRAF mutation (n=13)). PD-L1 expression testing (n=11) was negative in 55% (n=6 of 11), low in 9% (n=1 of 11), and high in 36% (n=4 of 11). All patients presented with metastatic disease; lung (16), bone (7), brain (5), and liver (4). 47.4% (n=9) of patients received platinum-based doublet chemotherapy as first-line (FL) treatment; 21.1% (n=4) received combined chemotherapy+ICI as FL; 5% (n=1) received ABTT as FL. Overall, 47% (n=9) received ABTT; 11.1% (n=1) as FL, 33.3% (n=3) as second line, 44.4% (n=4) as third line, and 11.1% (n=1) as fourth line. Median OS in the entire cohort was 1.86 years (95 % CI :1.26-2.32). Median DOR to ICI as first line or second line agent was 3 months (mos) (range 0.5-25mos). Median DOR to TKI in BRAFV600E cases was 13 mos (range 7-53mos), as second line agent or beyond. Among patients with BRAFV600E mutation, median OS was 4.89 years (95% CI 4.31-NA) in recipients of ABTT, and 1.68 years (95% CI not estimable) in patients who did not receive ABTT. Conclusions: In our BRAF-mutant NSCLC cohort, median DOR was greater in patients treated with ABTT, than those with ICI. ABTT treated BRAFV600E-mutant patients had longer OS, in comparison to those treated without ABTT. Our analysis highlights a potentially significant benefit of ABTT, and an unsatisfactory response with ICI, in patients harboring BRAFV600E mutation; therefore, the role of ICI in this subgroup needs further investigation

Outcomes of a lung cancer screening program in a Hispanic urban population: The University of Miami experience

e19011 Background: The National Lung Screening Trial (NLST) revealed a 20% reduction in lung cancer (LC) mortality when low-dose computed tomography (LDCT) was utilized for LC screening vs chest radiography. NLST participants were predominantly Non-Hispanic Whites, with only 1.8% Hispanics. The goal of our study was to investigate the attributes of a LC screening program in a largely Hispanic urban population and compare with NLST. Methods: We performed a retrospective analysis of 421 consecutive cases who underwent LDCT screening from 2016-2019 at University of Miami (UM), with similar inclusion criteria as the NLST. Demographic characteristics, smoking status, lung RADS, LC detection and compliance were examined & compared with NLST cohort using summary statistics and χ2 tests for categorical variables. Results: Demographic and smoking characteristics of the UM cohort didn’t resemble those of NLST LDCT cohort. UM cohort had a different racial and ethnic profile, with a higher percentage of Hispanics (47.3% vs 1.8%) and African Americans (15% vs 4.5%) in the UM cohort vs NLST cohort respectively (p < 0.001). UM cohort generally had lesser smoking intensity, and significantly fewer active smokers when compared to the NSLT cohort; 38.5% vs 48.1% respectively. The proportion of positive LDCT screens (Lung-RADS Class 3 or 4) in the UM cohort (14.1%) was almost similar to the NLST cohort (13.7%) (p = 0.81). The UM cohort had a higher LC detection rate (3.3%) than the NLST cohort (1.1%) (p < 0.001). In keeping with goals of screening, both cohorts had 50% or more LC cases detected at an early curable stage. Overall patient adherence to screening guidelines was more than 90% in NLST cohort; whereas almost a quarter of referred patients in UM cohort didn’t show for their initial decision-making visit and only 45% completed two or more scans. Conclusions: Our LDCT screening program was based in a Hispanic urban location (UM) with 47.3% Hispanics. Compared to NLST LDCT arm, the UM cohort had fewer active smokers, lighter smoking history, a more diverse population, somewhat higher LC detection rate, weaker adherence to screening related visits. More data is needed to understand obstacles to compliance with screening in minority populations

Umbilical cord mesenchymal stem cells for COVID-19 acute respiratory distress syndrome: A double-blind, phase 1/2a, randomized controlled trial

Acute respiratory distress syndrome (ARDS) in COVID-19 is associated with high mortality. Mesenchymal stem cells are known to exert immunomodulatory and anti-inflammatory effects and could yield beneficial effects in COVID-19 ARDS. The objective of this study was to determine safety and explore efficacy of umbilical cord mesenchymal stem cell (UC-MSC) infusions in subjects with COVID-19 ARDS. A double-blind, phase 1/2a, randomized, controlled trial was performed. Randomization and stratification by ARDS severity was used to foster balance among groups. All subjects were analyzed under intention to treat design. Twenty-four subjects were randomized 1:1 to either UC-MSC treatment (n = 12) or the control group (n = 12). Subjects in the UC-MSC treatment group received two intravenous infusions (at day 0 and 3) of 100 ± 20 × 10 UC-MSCs; controls received two infusions of vehicle solution. Both groups received best standard of care. Primary endpoint was safety (adverse events [AEs]) within 6 hours; cardiac arrest or death within 24 hours postinfusion). Secondary endpoints included patient survival at 31 days after the first infusion and time to recovery. No difference was observed between groups in infusion-associated AEs. No serious adverse events (SAEs) were observed related to UC-MSC infusions. UC-MSC infusions in COVID-19 ARDS were found to be safe. Inflammatory cytokines were significantly decreased in UC-MSC-treated subjects at day 6. Treatment was associated with significantly improved patient survival (91% vs 42%, P = .015), SAE-free survival (P = .008), and time to recovery (P = .03). UC-MSC infusions are safe and could be beneficial in treating subjects with COVID-19 ARDS