Laila C. Roisman

BRAF Mutant Lung Cancer: Programmed Death Ligand 1 Expression, Tumor Mutational Burden, Microsatellite Instability Status, and Response to Immune Check-Point Inhibitors

Introduction: The efficacy of immune checkpoint inhibitors (ICPi) in BRAF mutant NSCLC is unknown. Methods: Multi‐institutional retrospective chart review identified 39 patients with BRAF mutant NSCLC. The patients were divided into two groups: V600E (group A, n = 21) and non‐V600E (group B, n = 18). Programmed death ligand 1 (PD‐L1) expression, tumor mutational burden (TMB) and microsatellite instability status were assessed in 29 (74%), 11 (28%), and 12 (31%) patients, respectively. Objective response rate, progression‐free survival (PFS) with ICPi, and overall survival were analyzed. Results: High (≥50%), intermediate (1–49%), and no (<1%) PD‐L1 expression was observed in 8 of 19 (42%), 6 of 19 (32%), 5 of 19 (26%), and 5 of 10 (50%), 1 of 10 (10%), and 4 of 10 (40%) cases in groups A and B, respectively. Two tumors in group A showed high TMB (25%); none were microsatellite instability status–high. Twenty‐two patients (group A, n = 12; group B, n = 10) received ICPi. Objective response rate with ICPi was 25% and 33% in groups A and B, respectively (p = 1.0). Median PFS with ICPi was 3.7 months (95% confidence interval [CI]: 1.6–6.6), and 4.1 months (95% CI: 0.1–19.6) in groups A and B, respectively (log‐rank test = 0.81, p = 0.37). Neither BRAF mutation type nor PD‐L1 expression affected the response probability/PFS. Median overall survival was not reached (95% CI: 13–NR) and comprised 21.1 months (95% CI: 1.8–NR) for patients who were and were not exposed to ICPi, respectively (log‐rank test = 5.58, p = 0.018). Conclusions: BRAF mutant NSCLC is associated with high level of PD‐L1 expression, low/intermediate TMB and microsatellite‐stable status. ICPi have favorable activity both in BRAF V600E and BRAF non‐V600E mutant NSCLC.

Effectiveness and safety of nivolumab in advanced non-small cell lung cancer: the real-life data

OBJECTIVES Nivolumab has recently received regulatory approval as a 2nd-line treatment of non-small cell lung cancer (NSCLC). The data regarding its effectiveness and safety in real life setting is lacking. MATERIALS AND METHODS 260 consecutive patients with advanced NSCLC treated with nivolumab at five Israeli cancer centers between January 2015 and March 2016 were evaluated for overall survival (OS) and toxicity. OS was analyzed by the Cox proportional-hazards regression model. Overall response rate (ORR) and progression-free survival (PFS) were assessed in 49 patients using RECIST, v.1.1. RESULTS Median age was 67y (41-99); males 68%; smokers 76%; ECOG PS ≥2 46%; non-squamous/squamous/other/NR 70%/23%/6%/1%; brain metastases 21%; liver metastases 21%; treatment line: 1st/2nd/3rd+-line/NR 6%/64%/26%/4%. With median survival follow-up of 18.5 months (range, 12.0-26.9), 155 (60%) patients died; median OS comprised 5.9 months (95% CI 4.7-7.4). In univariate and multivariate analysis, the only variable which significantly correlated with OS was ECOG PS. Median OS of patients with ECOG PS 0/1 and ECOG PS ≥2 comprised 9.5 months (95% CI, 6.7-NR) and 3.5 months (95% CI, 2.6-4.5), respectively. For 49 patients evaluable for response (median follow-up of 8.4 months (range, 2-16.8), ORR was 35%, median PFS was 2.8 months (95% CI, 1.8-7.7), incidence of pseudo-progression was 9%. The nivolumab safety profile was in accordance with the literature data, except for febrile neutropenia and pericarditis (observed in 1 case each). CONCLUSION In real life setting, the effectiveness of nivolumab is reasonable yet less prominent than it has been demonstrated in clinical trials. ECOG PS ≥2 is associated with poor prognosis.

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.

Abstract LB-041: Novel platform to profile variants of uncertain significant (VUS) with preliminary retrospective clinical validation in non-small cell lung cancer (NSCLC)

Background: With the expanding usage of next generation sequencing (NGS) during treatment of NSCLC, an increasing number of variants of uncertain significance are being detected. Therefore, exists an urgent unmet need for a functional assay to reveal the significance of these findings both for naive patients and those with acquired resistance to targeted therapy. We present feasibility data and retrospective clinical validation for a novel high-throughput cell-based assay (FACT) which profiles alterations by measuring downstream activation of signaling pathways to determine oncogenic grading and prioritize treatment with targeted therapies. Methods: Patients with NSCLC adenocarcinoma that underwent NGS test (tissue based/cell-free tumor DNA) were consented and enrolled. Alterations were profiled using the FACT platform to quantify oncogenic signaling activity and inhibition by targeted therapies. Patient outcomes were compared to in vitro drug sensitivities retrospectively. Results: 9 patients with NSCLC were analyzed using the FACT platform. 17 alterations were functionally profiled (EGFR - 12, ERBB2 - 2, BRAF - 1, PDGFRA - 1 and JAK2 - 1). 12 (70%) mutations were found to be oncogenic, 11 (65%) oncogenic alterations were in actionable genes (EGFR/ERBB2), 7 patients (78%) were treated with targeted therapies. 3 patients had uncommon double point mutations in EGFR profiled on the same DNA construct (cis) and separately (trans) showing distinct oncogenic profiles. Drug inhibition was measured with used targeted therapies and showed concordance with retrospective clinical responses. Conclusions: Functional profiling of alterations found in NSCLC is feasible through the FACT platform and can provide useful insights on the oncogenicity of uncommon variants. Profiling of drug sensitivity was successfully performed in the majority of patients and in vitro sensitivity correlated with observed clinical outcomes. Citation Format: Benjamin Miron, Gabi Tarcic, Oded Edelheit, Nitza Burck, Michael Vidne, Laila Roisman, Nir Peled. Novel platform to profile variants of uncertain significant (VUS) with preliminary retrospective clinical validation in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-041. doi:10.1158/1538-7445.AM2017-LB-041

Abstract 5394: The clinical impact of multiplex ctDNA gene analysis in lung cancer

Background: Next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) enables a non-invasive option for comprehensive genomic analysis of lung cancer patients. Currently there is insufficient data in regard to the impact of ctDNA analysis on clinical decision making. In this study, we evaluated the clinical utility of ctDNA sequencing on treatment strategy and progression-free survival. Methods: In this retrospective study, data was collected from files of 92 NSCLC patients monitored between the years 2014-2016 at the Thoracic Center Unit at Davidoff Cancer Center, Rabin Medical Center, Israel. Plasma samples from stage IIIb/IV non-small cell lung cancer (NSCLC) patients were analyzed by a commercial test (Guardant 360), using hybrid capture, single molecule barcoding and massively parallel paired-end synthesis to sequence a targeted gene panel. This test allows the detection of somatic alterations such as point mutations, indels, fusions and copy number amplifications. Results: 92 consecutive NSCLC patients were included in this study. Median age at diagnosis was 63 years, male:female ratio was 1:1.6. 40% (37/92) were never-smokers, 84% (77/92) had adenocarcinoma. 38% (35/92) performed ctDNA analysis before 1st line therapy and 62% (57/92) on progression. ctDNA analysis yielded lung cancer related actionable mutations in total 39% (36/92) of the patients; 31% (11/35) among upfront testing and 44% (25/57) among patients at progression on matched therapy. Treatment decision was taken toward targeted therapy subsequent to NGS analysis in 23% (8/35) and 26% (15/57) respectively (total 25%; 23/92). 53 individual actionable genomic alterations were found. The most common genes were sensitizing EGFR mutations (47.2%; 25/53), MET amplifications and/or exon 14 skipping mutations (17%; 9/53) and resistance EGFR mutations (13.2%; 7/53). Response assessment (RECIST) for 18 patients with evaluable response to targeted therapy showed complete response in 6% (1/18), partial response in 39% (7/18), stable disease in 22% (4/18) and progressive disease in 33% (6/18). Total objective response rate (ORR) was 45% and disease control rate was 67%. Conclusions: Comprehensive ctDNA testing revealed possible treatment options for two-thirds of patients analyzed. ctDNA analysis impacted clinical decision making in a quarter of the patients. Although this topic needs to be further assessed in large randomized controlled trials, these positive results emphasize the utility of liquid biopsy analysis to guide clinicians to select the right therapy for the right patient. Citation Format: Smadar Geva, Anna Belilovski Rozenblum, Tal Twito, Addie Dvir, Lior Soussan-Gutman, Maya Ilouze, Laila C. Roisman, Elizabeth Dudnik, Alona Zer, Richard B. Lanman, Nir Peled. The clinical impact of multiplex ctDNA gene analysis in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5394. doi:10.1158/1538-7445.AM2017-5394