Rare targetable drivers (RTDs) in non-small cell lung cancer (NSCLC): Outcomes with immune check-point inhibitors (ICPi).

OBJECTIVES: Efficacy of immune check-point inhibitors (ICPi) in NSCLC with rare targetable drivers (RTDs) is largely unknown. MATERIALS AND METHODS: Consecutive patients with NSCLC and RTDs (non-EGFR/ALK, n-82) were selected from the Davidoff Cancer Center database. ORR, PFS, OS with ICPi, OS since advanced disease diagnosis, TMB, MSI, and PD-L1 expression were analyzed; uni- and multivariate PFS and OS analyses were done. OS with ICPi was compared between the RTD cohort and the non-selected NSCLC cohort (n-278). RESULTS: Of 50 tumors tested, 32%, 38%, and 30% were associated with ≥50%, 1-49% and <1% PD-L1 expression, respectively. Median TMB (n-48) comprised 4 muts/Mb (0-57); TMB ≥ 10 muts/Mb was seen in 19% of tumors. Both TMB and PD-L1 expression varied across different RTDs. All the 47 tumors were MSI stable. ORR with ICPi (n-44) was 16%, median PFS was 3.2 months (95% CI, 2.6-5.0), median OS was 16.2 months (95% CI, 8.4-NR). No correlation was seen between OS with ICPi and PD-L1 expression (p > 0.4), TMB (p > 0.8), or RTD type (p > 0.3). In the multivariate analysis, ECOG PS (p-0.005), targeted agents exposure (p-0.005), and ICPi exposure (p-0.04) were the only variables which correlated with OS since advanced disease diagnosis. Median OS since advanced disease diagnosis comprised 32 months (95% CI, 19.9-44.9) and 13 months (95% CI, 6.6-15.9) for patients who were and were not exposed to ICPi, respectively (log-rank test-6.3; p-0.01). In the inter-cohort comparison, for patients matched for ECOG PS (0/1), median OS with ICPi comprised 17.5 months (95% CI, 8.1-NR) and 8.6 months (95% CI, 6.7-NR) for RTD and non-selected patients, respectively (log-rank test-2.4, p-0.1). CONCLUSION: In NSCLC with RTD, ICPi have favorable efficacy and independent impact on OS. NSCLC with RTD is associated with MSI stable status and variable levels of PD-L1 expression and TMB; their predictive value remains to be determined.

The Clinical Impact of Comprehensive Genomic Testing of Circulating Cell-Free DNA in Advanced Lung Cancer.

INTRODUCTION: Next-generation sequencing (NGS) of cell-free circulating tumor DNA (cfDNA) enables noninvasive genomic analysis of NSCLC patients. Although plasma-detected genomic alterations (GAs) have been shown to predict targeted therapy response, evidence of durability of response is lacking or limited to small cohorts as is the impact of cfDNA NGS results on clinical decisions. METHODS: This retrospective study of stage IIIB/IV NSCLC patients between the years 2014 and 2017 in Israel used cfDNA NGS (Guardant360; Guardant Health, Inc., Redwood City, California) to identify targetable GAs. RESULTS: We consecutively tested 116 NSCLC patients, 41.4% before first-line therapy (group A), 34.5% upon progression on chemotherapy or immunotherapy (group B1), and 24.1% upon progression on EGFR tyrosine kinase inhibitors (group B2). Targetable GAs were found in 31% of group A (15 of 48 patients), 32.5% in group B1 (13 of 40 patients) and 71% in group B2 (20 of 28 patients). Treatment decision was changed to targeted therapy in 23% (11 of 48 patients), 25% (10 of 40 patients) and 32% (9 of 28 patients), respectively (total cohort 26%; 30/116). Objective response rate (Response Evaluation Criteria in Solid Tumors) was 43% (12 of 28 patients) including one complete response, partial response in 39% (11 of 28 patients), stable disease in 32% (9 of 28 patients), and progressive disease in 25% (7 of 28 patients). Disease control rate was 75% for 5 months median treatment duration. CONCLUSIONS: Comprehensive cfDNA testing impacted clinical decisions in one-quarter to one-third of initial and subsequent lines of treatment in advanced NSCLC patients. This retrospective study extends previous reports by showing that responses based on cfDNA are durable and change treatment decisions at initial presentation and at progression.

Clinical Impact of Hybrid Capture-Based Next-Generation Sequencing on Changes in Treatment Decisions in Lung Cancer.

INTRODUCTION: Targeted therapy significantly prolongs survival in lung adenocarcinoma. Current diagnostic guidelines include only EGFR and anaplastic lymphoma receptor tyrosine kinase gene (ALK) testing. Next-generation sequencing (NGS) reveals more actionable genomic alterations than do standard diagnostic methods. Data on the influence of hybrid capture (HC)-based NGS on treatment are limited, and we investigated its impact on treatment decisions and clinical outcomes. METHODS: This retrospective study included patients with advanced lung cancer on whom HC-based NGS was performed between November 2011 and October 2015. Demographic and clinicopathologic characteristics, treatments, and outcome data were collected. RESULTS: A total of 101 patients were included (median age 63 years [53% females, 45% never-smokers, and 85% with adenocarcinoma]). HC-based NGS was performed upfront and after EGFR/ALK testing yielded negative or inconclusive results in 15% and 85% of patients, respectively. In 51.5% of patients, HC-based NGS was performed before first-line therapy, and in 48.5%, it was performed after treatment failure. HC-based NGS identified clinically actionable genomic alterations in 50% of patients, most frequently in EGFR (18%), Ret proto-oncogene (RET) (9%), ALK (8%), Mesenchymal-epithelial transition factor (MET) receptor tyrosine kinase gene (6%), and erb-b2 receptor tyrosine kinase 2 gene (ERBB2) (5%). In 15 patients, it identified EGFR/ALK aberrations after negative results of prior standard testing. Treatment strategy was changed for 43 patients (42.6%). The overall response rate in these patients was 65% (complete response 14.7%, partial response 50%). Median survival was not reached. Immunotherapy was administered in 33 patients, mostly without an actionable driver, with a presenting disease control rate of 32%, and with an association with tumor mutation burden. CONCLUSIONS: HC-based NGS influenced treatment decisions in close to half of the patients with lung adenocarcinoma and was associated with an overall response rate of 65%, which may translate into a survival benefit.

[LUNG CANCER TREATMENT IN 2015: ADVANCES AND FUTURE OUTLOOK].

Every third cancer death in Israel is due to lung cancer. Still, 80% of the lung cancer cases are related to tobacco smoking; and therefore, more must be done for primary prevention, screening for lung cancer among risk cohort and against the tobacco industry. In the last decade, significant progress in the molecular understanding of this disease brought to a marked improvement in the overall survival and in the quality of life of these patients. The treatment paradigm is shifting from "one treatment fits all" regimens to personalized treatment strategies that allow patients to be treated with a variety of novel drugs that prolong their survival and maintain their quality of life. The latest revolutionary concept of immunotherapy in lung cancer is emerging and promises further hope to this population