Catherine Labbe

Monitoring and Management of Immune-Related Adverse Events Associated With Programmed Cell Death Protein-1 Axis Inhibitors in Lung Cancer

Monoclonal antibodies targeting programmed cell death protein-1 (PD-1) represent a new treatment paradigm in non-small cell lung cancer. Three phase III trials have demonstrated a survival benefit and improved tolerability of nivolumab and pembrolizumab when compared with standard second-line chemotherapy. Nevertheless, the adverse events associated with PD-1 inhibitors are unique; early recognition and treatment are essential. This review summarizes the required monitoring and appropriate management of immune-related adverse events in lung cancer patients receiving these agents. THE ONCOLOGIST 2017;22:70-80 IMPLICATIONS FOR PRACTICE: : The potential adverse events of immune checkpoint inhibitors differ from conventional chemotherapy and can require a multidisciplinary approach. Continued education is important for all physicians to ensure optimal care for patients.

Prognostic and predictive effects of TP53 co-mutation in patients with EGFR-mutated non-small cell lung cancer (NSCLC).

INTRODUCTION TP53 mutations are common in non-small cell lung cancer (NSCLC) and have been reported as prognostic of poor outcome. The impact of TP53 co-mutations in epidermal growth factor receptor (EGFR)-mutated NSCLC is unclear. MATERIALS AND METHODS Tissue from 105 patients with EGFR-mutated NSCLC at Princess Margaret Cancer Centre was analyzed by next-generation or Sanger sequencing to determine TP53 mutational status. Associations between TP53 status and baseline patient and tumor characteristics, treatments and outcomes (relapse-free survival [RFS] after surgical resection, overall survival [OS], overall response rate [ORR] and progression-free survival [PFS] on EGFR tyrosine kinase inhibitors [TKIs]), were investigated. RESULTS Dual TP53/EGFR mutations were found in 43/105 patients (41%). Among 76 patients who underwent surgical resection, neither RFS (HR 0.99, CI 0.56-1.75, p=0.96) nor OS (HR 1.39, CI 0.70-2.77; p=0.35) was associated with TP53 status. Sixty patients (24 TP53 MUT; 36 TP53 WT) received first-generation EGFR TKIs for advanced disease. ORR was not significantly different (TP53 MUT 54%, WT 66%, p=0.42). There was a non-significant trend towards shorter PFS on EGFR TKIs with TP53 mutation (HR 1.74, CI 0.98-3.10, p=0.06). When limited to TP53 missense mutations (n=17), PFS was significantly shorter (HR 1.91, CI 1.01-3.60, p=0.04). Among 11 evaluable patients treated with T790M inhibitors, ORR was not significantly different (TP53 MUT 3/3 [100%], WT 7/8 [88%]). CONCLUSIONS Patients with dual TP53/EGFR mutations, especially missense mutations, had marginally lower response rates and shorter PFS when treated with EGFR TKI therapy. Larger datasets are required to validate these observations.

Treatment options for patients with brain metastases from EGFR/ALK-driven lung cancer

INTRODUCTION Brain metastases in EGFR/ALK-driven NSCLC frequently pose treatment dilemmas. Tyrosine kinase inhibitors (TKIs) can control extracranial disease, but radiotherapy is often required for intracranial control. We aimed to evaluate the impact of first-line whole brain radiotherapy (WBRT), stereotactic radiotherapy (SRS) or TKI alone on outcomes of patients with brain metastases from EGFR/ALK-driven NSCLC. METHODS This single center retrospective review included 184 patients with brain metastases from EGFR/ALK-driven NSCLC, and analyzed effect of treatment choice on time to intracranial progression (TTIP) and overall survival (OS). RESULTS First-line treatment for brain metastases consisted of WBRT in 120 patients, SRS in 37 and TKI alone in 27. WBRT-treated patients had more brain metastases, and more baseline symptoms. Median TTIP was longer in the WBRT group at 50.5months than SRS or TKI groups at 12 and 15months (p=0.0038). No significant difference was seen in median OS: 21.6months in the WBRT group, 23.9months in the SRS group and 22.6months in the TKI group (p=0.67). In multivariable analysis, age>65years (HR 2.2, p=0.0014), greater number of brain metastases (HR 2.48, p=0.0002) and greater number of extracranial metastatic sites (2 vs 0-1 HR=2.05, p=0.014 and 3+ vs 0-1 HR=2.95, p=0.0001 were associated with shorter OS. No independent effect was seen from first-line CNS treatment choice. CONCLUSIONS First-line WBRT for brain metastases from EGFR/ALK-driven NSCLC was associated with longer TTIP than SRS or TKI alone, with no difference in OS. These results could support deferral of WBRT until intracranial progression in selected patients who are closely monitored.

The prognostic effect of single and multiple cancer-related somatic mutations in resected non-small-cell lung cancer

INTRODUCTION Somatic mutations are becoming increasingly important biomarkers for treatment selection and outcome in patients with non-small-cell lung cancer (NSCLC). The role of multiple somatic mutations in early-stage NSCLC is unclear. METHODS Tissue from 214 patients with resected NSCLC at the Princess Margaret Cancer Centre was analyzed by next-generation sequencing by Mi-SEQ or Sequenom multiplex platforms. Associations between mutation status, baseline patient characteristics and outcomes (disease-free survival (DFS) after surgical resection and overall survival (OS)) were investigated. RESULTS Somatic mutations were identified in 184 patients with resected stage I-III NSCLC: None (n = 30), single (n = 101) and multiple (≥2, n = 83). Multiple mutations were significantly associated with younger age (p = 0.0006), female sex (p = 0.012), smoking status (p = 0.002) and adenocarcinoma histology (p = 0.0001).TP53, KRAS and EGFR were the most common mutations. TP53 mutation was the most frequent co-mutation occurring in 72% of patients with multiple mutations. In resected stage I-III patients, multiple mutations were significantly associated with worse DFS (HR = 2.56, p = 0.003) but not OS on univariate analysis. Patients with KRAS and EGFR mutations were also associated with shorter DFS (HR = 2.52, p = 0.016 and HR = 4.37, p = 0.001 respectively) but no OS difference. TP53 mutation was associated with both shorter DFS (HR = 2.21, p = 0.02) and OS (HR = 3.08, p = 0.02). In subgroup univariate analysis, poorer DFS was associated with multiple mutations (p = 0.0015), EGFR (HR = 3.14, p = 0.006), and TP53 (HR = 2.46, p = 0.018) in patients with stage I disease. CONCLUSION The presence of known somatic mutations is associated with worse DFS in resected NSCLC. The differences are both statistically significant and clinically relevant. The presence of EGFR, KRAS and TP53 mutations was also associated with adverse outcomes. Larger datasets are required to validate whether mutational status is an independent prognostic factor in early stage NSCLC.

Correlation of Neutrophil to Lymphocyte Ratio and Absolute Neutrophil Count With Outcomes With PD-1 Axis Inhibitors in Patients With Advanced Non–Small-Cell Lung Cancer

Micro‐Abstract: Programmed death‐1 (PD‐1) axis inhibitors have become standard therapy in advanced Non–Small‐Cell Lung Cancer (NSCLC). The relationship between clinical outcomes and neutrophil to lymphocyte ratio (NLR) and absolute neutrophil count (ANC) was explored in 88 advanced NSCLC patients treated with PD‐1 axis inhibitors. Patients with baseline NLR ≤4 had superior disease control rate, treatment duration, and survival. Lower NLR and ANC during treatment were associated with response and treatment duration. Introduction: Programmed death‐1 (PD‐1) axis inhibitors have become standard therapy in advanced non–small‐cell lung cancer (NSCLC). Response might be delayed and pseudo‐progression occasionally occurs in patients who eventually benefit from treatment. Additional markers beyond programmed death ligand 1 (PD‐L1) expression are needed to assist in patient selection, response evaluation, and treatment decisions. Materials and Methods: The relationship between prospectively collected clinical outcomes (response, disease control rate [DCR], treatment duration, overall survival) and hematologic parameters (neutrophil to lymphocyte ratio [NLR], absolute neutrophil count [ANC], and platelet to lymphocyte ratio [PLR]) was explored retrospectively in advanced NSCLC patients treated with PD‐1 axis inhibitors at a major cancer center from May 2013 to August 2016. Hematologic parameters at baseline and during treatment (week 2 or 3 and week 8) were included. Results: Of 88 patients treated with PD‐1 axis inhibitors, 22 (25%) experienced partial response. Baseline NLR ≤4 was associated with superior DCR (74% vs. 50%; P = .025), treatment duration (P = .037), time to progression (P = .053), and overall survival (P = .019), with no differential association according to PD‐L1 tumor expression. Lower NLR and ANC during treatment were also associated with response to treatment (P = .025 and P = .017, respectively), and treatment duration (P = .036 and P = .008). No association was found between baseline PLR and DCR, response, treatment duration, nor overall survival. Conclusion: Baseline NLR ≤4 and lower NLR and ANC during treatment might correlate with disease control and treatment response and should be explored further as potential predictors of treatment benefit in larger studies.

Real-World EQ5D Health Utility Scores for Patients With Metastatic Lung Cancer by Molecular Alteration and Response to Therapy.

Introduction Economic analyses of upcoming treatments for lung cancer benefit from real‐world health utility scores (HUSs) in an era of targeted therapy. Methods A longitudinal cohort study at Princess Margaret Cancer Centre evaluated 1571 EQ5D‐3L‐derived HUSs in 475 outpatients with metastatic lung cancer across various disease states. Patients with epidermal growth factor receptor (EGFR) (n = 183) and anaplastic lymphoma kinase (ALK) (n = 38) driver alterations were enriched through targeted enrolment; patients with wild‐type non–small‐cell lung cancer (WT NSCLC) (n = 224) and small‐cell lung cancer (SCLC) (n = 30) were sampled randomly. Results For patients stable on most appropriate treatment, the mean HUSs were 0.81 and 0.82 in patients receiving EGFR and ALK tyrosine kinase inhibitors (TKIs) respectively (with similar HUSs across agents), which were higher than patients with WT NSCLC (0.78; P = .04) and SCLC receiving chemotherapy (0.72; P = .06). In mutation‐specific comparisons, disease stability on appropriate therapy resulted in significantly higher mean HUSs (P < .002‐.02) than when disease was progressing (mean HUS: EGFR, 0.70; ALK, 0.69; WT NSCLC, 0.66; SCLC, 0.52). When evaluating treatment‐related toxicities, significant inverse relationships were observed between HUS and the severity of fatigue and decreased appetite in the EGFR group. There was also a significant inverse relationship between the total number of clinically significant symptoms and HUS, both in patients who were EGFR‐mutated and patients with WT NSCLC. Conclusions In a North American setting, HUSs generated from patients with metastatic lung cancer are higher in treated, stable patients carrying driver mutations. This is partially explainable by treatment toxicity and patient symptom differences. Such differences in scores should be considered in economic analyses. Micro‐Abstract There is limited data outside of clinical trials on health utility scores in patients with metastatic lung cancer. This longitudinal cohort study evaluated EQ5D‐3L‐derived health utility scores in 475 outpatients. Mean scores were higher in patients carrying driver mutations stable on targeted treatments than in patients without alterations stable on chemotherapy. Such differences should be considered in economic analyses of upcoming treatments.