Phase I Results from a Study of Crizotinib in Combination with Erlotinib in Patients with Advanced Nonsquamous Non–Small Cell Lung Cancer

IntroductionThis phase I trial was conducted to determine the safety, maximum tolerated dose (MTD)/recommended phase II dose, and efficacy of crizotinib plus erlotinib in patients with advanced NSCLC.MethodsPatients with NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 2 after failure of one or two prior chemotherapy regimens were eligible. Erlotinib, 100 mg, was given continuously once daily starting between day −14 and −7; crizotinib, 200 mg twice daily (dose level 1) or 150 mg twice daily (dose level −1), was added continuously beginning on day 1 of treatment cycle 1. Potential pharmacokinetic interactions between crizotinib and erlotinib were evaluated.ResultsTwenty-seven patients received treatment; 26 received crizotinib plus erlotinib. Frequent adverse events were diarrhea, rash, decreased appetite, and fatigue. Dose-limiting toxicities were dehydration, diarrhea, dry eye, dysphagia, dyspepsia, esophagitis and vomiting. The MTD was crizotinib, 150 mg twice daily, with erlotinib, 100 mg once daily. Crizotinib increased the erlotinib area under the concentration-time curve 1.5-fold (dose level −1) and 1.8-fold (dose level 1). The plasma level of crizotinib appeared to be unaffected by coadministration of erlotinib. Two patients whose tumors harbored activating EGFR mutations achieved confirmed partial responses, one at each crizotinib dose level.ConclusionsThe MTD of the combination of crizotinib and erlotinib in patients with advanced NSCLC was crizotinib, 150 mg twice daily, with erlotinib, 100 mg once daily, which is less than the approved dose of either agent. The phase II portion of the study was not initiated.     

Ceritinib plus Nivolumab in Patients with Advanced ALK-Rearranged Non–Small Cell Lung Cancer: Results of an Open-Label,Multicenter, Phase 1B Study

IntroductionInduction of programmed death ligand 1 (PD-L1) expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring echinoderm microtubule associated protein like 4 gene (EML4)–ALK receptor tyrosine kinase gene (ALK) rearrangements. We assessed the safety and activity of ceritinib plus nivolumab in these patients.MethodsIn this open-label, phase 1B, multicenter, dose escalation and expansion study, previously treated (with ALK receptor tyrosine kinase [ALK] inhibitor [ALKI]/chemotherapy) or treatment-naive patients with stage IIIB or IV ALK-rearranged NSCLC received nivolumab, 3 mg/kg intravenously every 2 weeks, plus ceritinib, 450 mg/300 mg daily, with a low-fat meal.ResultsIn total, 36 patients were treated (a 450-mg cohort [n=14] and a 300-mg cohort [n=22]). In the 450-mg cohort, four patients experienced dose-limiting toxicities. In the 300-mg cohort, two patients experienced dose-limiting toxicities. Among ALKI-naive patients, the overall response rate (ORR) was 83% (95% confidence interval [CI]: 35.9–99.6) in the 450-mg cohort and 60% (95% CI: 26.2–87.8) in the 300-mg cohort. Among ALKI-pretreated patients, the ORR was 50% (95% CI: 15.7–84.3) in the 450-mg cohort and 25% (95% CI: 5.5–57.2) in the 300-mg cohort. The ORR point estimate was observed to be greater in patients who were positive for PD-L1 than in those who were negative for PD-L1, with overlapping CIs (e.g., at a cutoff ≥1% PD-L1, 64% of patients [95% CI: 35.1–87.2] had confirmed responses as compared with those with negative PD-L1 staining (31% [95% CI: 11.0–58.7]). The most frequently reported grade 3 or 4 adverse events were increased alanine aminotransferase level (25%), increased gamma-glutamyl transferase level (22%), increased amylase level (14%), increased lipase level (11%), and maculopapular rash (11%). The incidence of all-grade rash (grouped term) was 64% in both cohorts; grade 3 rash was reported in 29% and 14% of patients in the 450-mg and 300-mg cohorts, respectively; no grade 4 rash was reported.ConclusionCeritinib plus nivolumab has activity; ORR appears to correlate with PD-L1 at baseline. Toxicity, especially rash, is more common than with either single agent.     

Importance of Quality of Life in Patients with Non–Small-Cell Lung Cancer

The therapeutic options for patients with advanced non–small-cell lung cancer (NSCLC) are palliative. Therefore, the quality of life in oncology is considered as an endpoint in clinical trials, and several scales have been accepted for its measurement in parallel with other clinical determinations. However, its use in clinical practice is hindered by various obstacles that need to be overcome. In this article we examine the concept of the quality of life in patients with NSCLC, as well as giving an evaluation and interpretation of the results of various clinical trials. We describe the new technological methods used in daily clinical practice to measure the quality of life.     

Updated Efficacy Analysis Including Secondary Population Results for OAK: A Randomized Phase III Study of Atezolizumab versus Docetaxel in Patients with Previously Treated Advanced Non–Small Cell Lung Cancer

Introduction

The efficacy and safety of atezolizumab versus the efficacy and safety of docetaxel as second- or third-line treatment in patients with advanced NSCLC in the primary (n = 850) and secondary (n = 1225) efficacy populations of the randomized phase III OAK study (respectively referred to as the intention-to-treat [ITT] 850 [ITT850] and ITT1225) at an updated data cutoff were assessed.

Prognostic Impact of the Findings on Thin-Section Computed Tomography in Patients with Subcentimeter Non–Small Cell Lung Cancer

IntroductionSubcentimeter NSCLC is not always an early-stage disease despite its small tumor size. We investigated the prognostic impact of such cancers on the basis of the findings of thin-section computed tomography (CT).MethodsWe evaluated the clinicopathological features and prognosis of 328 surgically resected clinical-N0 NSCLCs 1.0 cm or less in size. Consolidation-to-tumor ratio (CTR) was evaluated for all, and tumors were classified into three groups, namely, pure ground glass opacity (GGO) (CTR = 0 [n = 139]), part solid (0 < CTR < 1.0 [n = 123]), and pure solid (CTR = 1.0 [n = 66]).ResultsPathological nodal involvement was observed in seven patients, with all cases found exclusively in pure solid subcentimeter NSCLC (10.9%). Furthermore, a multivariate analysis revealed that the presence of GGO was an independently significant clinical factor in overall survival (OS) and recurrence-free survival (RFS) (OS: p = 0.0340; RFS: p = 0.0018). Histological examination revealed that 134 of the 139 cases of pure GGO (97%), 99 of the 123 cases of part solid tumor (81%), and 16 of the 66 cases of pure solid tumor (25%) were lepidic predominant lung adenocarcinoma. Evaluation of the oncological outcomes on the basis of CTR revealed that 5-year OS and RFS rates were significantly better in patients with nonsolid tumors (OS and RFS = 100%) or part solid tumors (OS = 97.5% and RFS=94.9%), whereas the OS and RFS rates of patients with pure solid subcentimeter NSCLC were 87.6% and 79.3%, respectively (OS: p = 0.0015; RFS: p < 0.0001).ConclusionsThe findings of thin-section CT are extremely important when considering the prognosis of subcentimeter NSCLC. Radiologically determined solid subcentimeter NSCLCs should be treated as invasive tumors regardless of their small size.     

Peripheral Blood Biomarkers Associated with Clinical Outcome in Non–Small Cell Lung Cancer Patients Treated with Nivolumab

Objective

The aim of this study was to identify baseline peripheral blood biomarkers associated with clinical outcome in patients with NSCLC treated with nivolumab.

Veliparib Plus Carboplatin and Paclitaxel Versus Investigator's Choice of Standard Chemotherapy in Patients With Advanced Non–Squamous Non–Small Cell Lung Cancer

BackgroundThis open-label Phase III trial (NCT02264990) evaluated the PARP inhibitor, veliparib, combined with carboplatin/paclitaxel versus chemotherapy alone for first-line treatment of patients with advanced non–squamous non–small cell lung cancers (NSCLC). A 52-gene expression classifier (LP52) previously shown to identify patients more likely to respond to veliparib was evaluated as a planned correlative analysis.Materials and MethodsAdult current or former smokers with advanced non–squamous NSCLC were randomized 1:1 to veliparib (120 mg daily for 7 days/cycle) with carboplatin and paclitaxel or to investigators’ choice of platinum doublet chemotherapy (up to 6, 21-day cycles), with optional pemetrexed maintenance. Prospective analysis of the LP52 signature was conducted using a clinical Qiagen/HTG assay. The primary endpoint was overall survival (OS) in LP52+ patients.ResultsOverall, 595 patients received veliparib + carboplatin/paclitaxel (n = 298) or chemotherapy alone (n = 297); 13% (n = 40) in each arm were LP52+. The primary endpoint was not met; median OS was 11.2 months with veliparib + carboplatin/paclitaxel versus 9.2 months with chemotherapy alone in the LP52+ subgroup (hazard ratio [HR] 0.644, 95% confidence interval [CI]: 0.396-1.048; P = .113). In the overall population, median OS was 12.1 months in both arms (HR 0.986, 95% CI: 0.827-1.176; P = .846). No new safety signals were observed.ConclusionIn patients with non–squamous NSCLC, there was no significant improvement in OS with veliparib + carboplatin/paclitaxel versus chemotherapy alone, although a trend toward improved OS in the LP52+ population suggests this subgroup may benefit from veliparib. Statistical power was limited due to the small sample size.     

Early Immune-Related Adverse Events and Association with Outcome in Advanced Non–Small Cell Lung Cancer Patients Treated with Nivolumab: A Prospective Cohort Study

IntroductionRetrospective studies have shown immune-related adverse events (irAEs) to be associated with better prognosis. However, no prospective clinical trials have been conducted, and little is known regarding the association between irAEs and the outcome of patients with NSCLC after treatment with immunotherapy.MethodsWe conducted a prospective cohort study of patients with advanced NSCLC who were treated with nivolumab between January and December 2016. The association between clinical outcome and irAEs 2 to 6 weeks after commencement of nivolumab treatment was investigated. IrAEs were assessed by at least three independent medical professionals.ResultsA total of 43 patients were enrolled, including 19 patients with irAEs 2 weeks after commencement of nivolumab treatment. Common irAEs included rash, pyrexia, and diarrhea. Programmed cell death ligand 1–positive tumor cell expression was not significantly different between patients with and without irAEs. The objective response and disease control rates were higher in patients with irAEs than in those without irAEs (37% versus 17% and 74% versus 29% [p = 0.17 and p < 0.01], respectively]). Patients with irAEs were associated with a significantly longer median progression-free survival than those without (6.4 months [95% confidence interval: 2.5–not reached] versus 1.5 months [95% confidence interval: 1.2–2.3] [p = 0.01]). These findings were comparable to those for patients with and without irAEs 6 weeks after commencement of nivolumab treatment.ConclusionsEarly irAEs are associated with a better outcome after treatment with immunotherapy. We predicted responses to nivolumab by using early irAEs. Further research is needed to elucidate the mechanisms of these associations.     

Next Generation Sequencing of Advanced Non–Small Cell Lung Cancer: Utilization Based on Race and Impact on Survival

BackgroundNext generation sequencing (NGS) of tumor of patients with advanced non–small cell lung cancer (NSCLC) is now a standard of care that informs the clinician on the best therapeutic approach for their patients. The purpose of our study was to investigate the overall impact of NGS testing on survival as well as potential racial differences in utilization, therapeutic decision, and genomic alterations.MethodUsing a large institutional database, 928 patients with stage IV NSCLC were identified. NGS testing using Foundation One platform was used. Clinical and genomic characteristics were compared by race. We used a propensity-modeling technique to compare groups that were sequenced or not in terms of overall survival. Time to event data was analyzed using Kaplan-Meier method and Cox model.ResultsA total of 295 patients underwent NGS. Patients undergoing NGS testing had significantly longer survival of 25.3 months versus those who did not undergo sequencing with a median survival of 14.6 months (P = .002) irrespective if they received targeted therapy or not. There was no difference in terms of NGS utilization based on race (P = .32). African American individuals had significantly higher rates of ALK rearrangements and mutations in PBRM1, SETD2, TSC2, and FBXW7.ConclusionOur study demonstrates that within a large single institution there is no racial difference in NGS utilization and that NGS testing directly impacts survival. We identify a number of differences in genomic findings between African American and white individuals.     

Italian Nivolumab Expanded Access Program in Nonsquamous Non–Small Cell Lung Cancer Patients: Results in Never-Smokers and EGFR-Mutant Patients

Introduction

Nivolumab is the first checkpoint inhibitor approved for the treatment of nonsquamous NSCLC. We report results from the nivolumab Italian expanded access program focusing on never-smokers and patients with EGFR-mutant nonsqamous NSCLC.

Outcome of Patients with Non–Small Cell Lung Cancer and Brain Metastases Treated with Checkpoint Inhibitors

IntroductionAlthough frequent in NSCLC, patients with brain metastases (BMs) are often excluded from immune checkpoint inhibitor (ICI) trials. We evaluated BM outcome in a less-selected NSCLC cohort.MethodsData from consecutive patients with advanced ICI-treated NSCLC were collected. Active BMs were defined as new and/or growing lesions without any subsequent local treatment before the start of ICI treatment. Objective response rate (ORR), progression-free survival, and overall survival (OS) were evaluated. Multivariate analyses were performed by using a Cox proportional hazards model and logistic regression.ResultsA total of 1025 patients were included; the median follow-up time from start of ICI treatment was 15.8 months. Of these patients, 255 (24.9%) had BMs (39.2% active, 14.3% symptomatic, and 27.4% being treated with steroids). Disease-specific Graded Prognostic Assessment (ds-GPA) score was known for 94.5% of patients (35.7% with a score of 0–1, 58.5% with a score of 1.5–2.5, and 5.8% with a score of 3). The ORRs with BM versus without BM were similar: 20.6% (with BM) versus 22.7% (without BM) (p = 0.484). The intracranial ORR (active BM with follow-up brain imaging [n = 73]) was 27.3%. The median progression-free survival times were 1.7 (95% confidence interval [CI]: 1.5–2.1) and 2.1 (95% CI: 1.9–2.5) months, respectively (p = 0.009). Of the patients with BMs, 12.7% had a dissociated cranial-extracranial response and two (0.8%) had brain pseudoprogression. Brain progression occurred more in active BM than in stable BM (54.2% versus 30% [p < 0.001]). The median OS times were 8.6 months (95% CI: 6.8–12.0) with BM and 11.4 months (95% CI: 8.6–13.8) months with no BM (p = 0.035). In the BM subgroup multivariate analysis, corticosteroid use (hazard ratio [HR] = 2.37) was associated with poorer OS, whereas stable BMs (HR = 0.62) and higher ds-GPA classification (HR = 0.48–0.52) were associated with improved OS.ConclusionIn multivariate analysis BMs are not associated with a poorer survival in patients with ICI-treated NSCLC. Stable patients with BM without baseline corticosteroids and a good ds-GPA classification have the best prognosis.     

Predictive Performance of Four Programmed Cell Death Ligand 1 Assay Systems on Nivolumab Response in Previously Treated Patients with Non–Small Cell Lung Cancer

Introduction

Nivolumab has demonstrated efficacy against metastatic NSCLC. Four programmed cell death ligand 1 (PD-L1) immunohistochemistry (IHC) assay systems are available for identification of responders among patients with NSCLC, and these assays show some differing characteristics. Accordingly, in this study, we evaluated the ability of these assays to identify responders to nivolumab therapy.

Results of PROFILE 1029, a Phase III Comparison of First-Line Crizotinib versus Chemotherapy in East Asian Patients with ALK-Positive Advanced Non–Small Cell Lung Cancer

Introduction

The phase III randomized PROFILE 1014 study demonstrated superiority of crizotinib to first-line chemotherapy in prolonging progression-free survival (PFS) in previously untreated patients with ALK receptor tyrosine kinase gene (ALK)-positive advanced nonsquamous NSCLC. This result was consistent with that in the smaller subset of East Asian patients in PROFILE 1014. The subsequent study reported here prospectively evaluated crizotinib in a larger East Asian patient population.