Michel M. van den Heuvel

First-Line Nivolumab in Stage IV or Recurrent Non–Small-Cell Lung Cancer

BACKGROUND Nivolumab has been associated with longer overall survival than docetaxel among patients with previously treated non–small‐cell lung cancer (NSCLC). In an open‐label phase 3 trial, we compared first‐line nivolumab with chemotherapy in patients with programmed death ligand 1 (PD‐L1)–positive NSCLC. METHODS We randomly assigned, in a 1:1 ratio, patients with untreated stage IV or recurrent NSCLC and a PD‐L1 tumor‐expression level of 1% or more to receive nivolumab (administered intravenously at a dose of 3 mg per kilogram of body weight once every 2 weeks) or platinum‐based chemotherapy (administered once every 3 weeks for up to six cycles). Patients receiving chemotherapy could cross over to receive nivolumab at the time of disease progression. The primary end point was progression‐free survival, as assessed by means of blinded independent central review, among patients with a PD‐L1 expression level of 5% or more. RESULTS Among the 423 patients with a PD‐L1 expression level of 5% or more, the median progression‐free survival was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio for disease progression or death, 1.15; 95% confidence interval [CI], 0.91 to 1.45; P=0.25), and the median overall survival was 14.4 months versus 13.2 months (hazard ratio for death, 1.02; 95% CI, 0.80 to 1.30). A total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy. Treatment‐related adverse events of any grade occurred in 71% of the patients who received nivolumab and in 92% of those who received chemotherapy. Treatment‐related adverse events of grade 3 or 4 occurred in 18% of the patients who received nivolumab and in 51% of those who received chemotherapy. CONCLUSIONS Nivolumab was not associated with significantly longer progression‐free survival than chemotherapy among patients with previously untreated stage IV or recurrent NSCLC with a PD‐L1 expression level of 5% or more. Overall survival was similar between groups. Nivolumab had a favorable safety profile, as compared with chemotherapy, with no new or unexpected safety signals. (Funded by Bristol‐Myers Squibb and others; CheckMate 026 ClinicalTrials.gov number, NCT02041533.)

Radiation pneumonitis in patients treated for malignant pulmonary lesions with hypofractionated radiation therapy

PURPOSE We evaluated the relationship between the mean lung dose (MLD) and the incidence of radiation pneumonitis (RP) after stereotactic body radiation therapy (SBRT), and compared this with conventional fractionated radiation therapy (CFRT). MATERIALS AND METHODS For both SBRT (n=128) and CFRT (n=142) patients, RP grade > or = 2 was scored. Toxicity models predicting the probability of RP as a function of the MLD were fitted using maximum log likelihood analysis. The MLD was NTD (Normalized Total Dose) corrected using an alpha/beta ratio of 3 Gy. RESULTS SBRT patients were treated with 6-12 Gy per fraction with a median MLD of 6.4 Gy (range: 1.5-26.5 Gy). CFRT patients were treated with 2 Gy or 2.25 Gy per fraction, the median MLD was 13.2 Gy (range: 3.0-23.0 Gy). The crude incidence rates of RP were 10.9% and 17.6% for the SBRT and CFRT patients, respectively. A significant dose-response relationship for RP was found after SBRT, which was not significantly different from the dose-response relationship for CFRT (p=0.18). CONCLUSION We derived a significant dose-response relationship between the risk of RP and the MLD for SBRT from the clinical data. This relation was not significantly different from the dose-response relation for CFRT, although statistical analysis was hampered by the low number of patients in the high dose range.

Predicting survival in malignant pleural effusion: development and validation of the LENT prognostic score

Background Malignant pleural effusion (MPE) causes debilitating breathlessness and predicting survival is challenging. This study aimed to obtain contemporary data on survival by underlying tumour type in patients with MPE, identify prognostic indicators of overall survival and develop and validate a prognostic scoring system. Methods Three large international cohorts of patients with MPE were used to calculate survival by cell type (univariable Cox model). The prognostic value of 14 predefined variables was evaluated in the most complete data set (multivariable Cox model). A clinical prognostic scoring system was then developed and validated. Results Based on the results of the international data and the multivariable survival analysis, the LENT prognostic score (pleural fluid lactate dehydrogenase, Eastern Cooperative Oncology Group (ECOG) performance score (PS), neutrophil-to-lymphocyte ratio and tumour type) was developed and subsequently validated using an independent data set. Risk stratifying patients into low-risk, moderate-risk and high-risk groups gave median (IQR) survivals of 319 days (228–549; n=43), 130 days (47–467; n=129) and 44 days (22–77; n=31), respectively. Only 65% (20/31) of patients with a high-risk LENT score survived 1 month from diagnosis and just 3% (1/31) survived 6 months. Analysis of the area under the receiver operating curve revealed the LENT score to be superior at predicting survival compared with ECOG PS at 1 month (0.77 vs 0.66, p<0.01), 3 months (0.84 vs 0.75, p<0.01) and 6 months (0.85 vs 0.76, p<0.01). Conclusions The LENT scoring system is the first validated prognostic score in MPE, which predicts survival with significantly better accuracy than ECOG PS alone. This may aid clinical decision making in this diverse patient population.

Identification of recurrent FGFR3 fusion genes in lung cancer through kinome‐centred RNA sequencing

Oncogenic fusion genes that involve kinases have proven to be effective targets for therapy in a wide range of cancers. Unfortunately, the diagnostic approaches required to identify these events are struggling to keep pace with the diverse array of genetic alterations that occur in cancer. Diagnostic screening in solid tumours is particularly challenging, as many fusion genes occur with a low frequency. To overcome these limitations, we developed a capture enrichment strategy to enable high‐throughput transcript sequencing of the human kinome. This approach provides a global overview of kinase fusion events, irrespective of the identity of the fusion partner. To demonstrate the utility of this system, we profiled 100 non‐small cell lung cancers and identified numerous genetic alterations impacting fibroblast growth factor receptor 3 (FGFR3) in lung squamous cell carcinoma and a novel ALK fusion partner in lung adenocarcinoma.

Fluid biopsy for circulating tumor cell identification in patients with early-and late-stage non-small cell lung cancer: a glimpse into lung cancer biology

Circulating tumor cell (CTC) counts are an established prognostic marker in metastatic prostate, breast and colorectal cancer, and recent data suggest a similar role in late stage non-small cell lung cancer (NSCLC). However, due to sensitivity constraints in current enrichment-based CTC detection technologies, there are few published data about CTC prevalence rates and morphologic heterogeneity in early-stage NSCLC, or the correlation of CTCs with disease progression and their usability for clinical staging. We investigated CTC counts, morphology and aggregation in early stage, locally advanced and metastatic NSCLC patients by using a fluid-phase biopsy approach that identifies CTCs without relying on surface-receptor-based enrichment and presents them in sufficiently high definition (HD) to satisfy diagnostic pathology image quality requirements. HD-CTCs were analyzed in blood samples from 78 chemotherapy-naïve NSCLC patients. 73% of the total population had a positive HD-CTC count (>0 CTC in 1 mL of blood) with a median of 4.4 HD-CTCs mL⁻¹ (range 0-515.6) and a mean of 44.7 (±95.2) HD-CTCs mL⁻¹. No significant difference in the medians of HD-CTC counts was detected between stage IV (n = 31, range 0-178.2), stage III (n = 34, range 0-515.6) and stages I/II (n = 13, range 0-442.3). Furthermore, HD-CTCs exhibited a uniformity in terms of molecular and physical characteristics such as fluorescent cytokeratin intensity, nuclear size, frequency of apoptosis and aggregate formation across the spectrum of staging. Our results demonstrate that despite stringent morphologic inclusion criteria for the definition of HD-CTCs, the HD-CTC assay shows high sensitivity in the detection and characterization of both early- and late-stage lung cancer CTCs. Extensive studies are warranted to investigate the prognostic value of CTC profiling in early-stage lung cancer. This finding has implications for the design of extensive studies examining screening, therapy and surveillance in lung cancer patients.

ERBB2 Mutations Characterize a Subgroup of Muscle-invasive Bladder Cancers with Excellent Response to Neoadjuvant Chemotherapy

UNLABELLED A pathologic complete response to neoadjuvant chemotherapy (NAC) containing platinum is a strong prognostic determinant for patients with muscle-invasive bladder cancer (MIBC). Despite comprehensive molecular characterization of bladder cancer, associations of molecular alterations with treatment response are still largely unknown. We selected pathologic complete responders (ypT0N0; n=38) and nonresponders (higher than ypT2; n=33) from a cohort of high-grade MIBC patients treated with NAC. DNA was isolated from prechemotherapy tumor tissue and used for next-generation sequencing of 178 cancer-associated genes (discovery cohort) or targeted sequencing (validation cohort). We found that 9 of 38 complete responders had erb-b2 receptor tyrosine kinase 2 (ERBB2) missense mutations, whereas none of 33 nonresponders had ERBB2 mutations (p=0.003). ERBB2 missense mutations in complete responders were mostly confirmed activating mutations. ERCC2 missense mutations, recently found associated with response to NAC, were more common in complete responders; however, this association did not reach statistical significance in our cohort. We conclude that ERBB2 missense mutations characterize a subgroup of MIBC patients with an excellent response to NAC. PATIENT SUMMARY In this report we looked for genetic alterations that can predict the response to neoadjuvant chemotherapy (NAC) in bladder cancer. We found that mutations in the gene ERBB2 are exclusively present in patients responding to NAC.

Evaluation of adapted whole-blood interferon-γ release assays for the diagnosis of pleural tuberculosis

Background: Pleural tuberculosis (TB) remains difficult to diagnose despite numerous diagnostic tools. Recently, in vitro interferon (IFN)-γ-based assays have been introduced in the diagnosis of latent TB, but these techniques have not been established in the diagnosis of active TB disease, including pleural TB. Objectives: It was the aim of this study to assess the accuracy of the commercially available QuantiFERON® TB Gold assay and adapted variants of the assay, using pleural fluid or isolated pleural fluid cells for the diagnosis of pleural TB. Methods: We recruited 66 consecutive patients with a pleural effusion of unknown cause presenting at a tertiary academic health care centre in Cape Town, South Africa, a high prevalence area of TB. Blood and pleural fluid were collected at presentation for IFN-γ assays and the results evaluated for diagnostic accuracy. Results: The clinical diagnosis was TB in 30 (46%), malignancy in 20 (30%), parapneumonic effusion/empyema in 8 (12%) and effusion due to other causes in 8 patients (12%). Ex vivo pleural fluid IFN-γ levels accurately identified TB in all patients and were superior to the QuantiFERON In Tube assay using blood and pleural fluid (73 and 57% sensitivity, with 71 and 87% specificity, respectively) and the QuantiFERON Gold assay applied to isolated pleural fluid cells (100% sensitivity and 67% specificity). Conclusion: The ex vivo pleural fluid interferon-γ level is an accurate marker for the diagnosis of pleural TB, and the QuantiFERON TB Gold assay performed with peripheral blood or adapted for pleural fluid cells does not add diagnostic value.

Differential cytokine/chemokines and KL-6 profiles in patients with different forms of tuberculosis

Cytokines are involved in the mediation and regulation of immunity, inflammation, and haematopoiesis. Secretion patterns may reflect the pathology or etiology of different diseases. In an attempt to increase our understanding of immunopathology during different forms of tuberculosis, and identify potential biological markers that may differentiate between forms of tuberculosis, we investigated the levels of 29 cytokines and KL-6 in the plasma of HIV uninfected patients with active pulmonary tuberculosis (TB) without pleural effusions and in pleural TB with and without HIV-co-infection. Healthy individuals with latent Mycobacterium tuberculosis infection and patients with non-TB pleural effusions were used as controls, We showed that pleural TB patients had increased levels of markers associated with systemic inflammation compared to pulmonary TB (EGF, G-CSF, IL-1beta IL-6, IL-8, IL-10, MCP-1, MIP-1alpha, MIP-1beta, TNF-alpha and VEGF), whereas pulmonary TB patients without effusions had higher levels of factors involved in cell-mediated immunity (IL-12p40 and sCD40L). Plasma levels of cytokines may therefore contribute to biosignatures of diseases like TB but the data also highlight systemic differences between pulmonary TB, pleural TB and other form of pleural effusion diseases.

Phase II Trial of Atezolizumab As First-Line or Subsequent Therapy for Patients With Programmed Death-Ligand 1–Selected Advanced Non–Small-Cell Lung Cancer (BIRCH)

Purpose BIRCH was designed to examine the efficacy of atezolizumab, a humanized anti-programmed death-ligand 1 (PD-L1) monoclonal antibody, in advanced non-small-cell lung cancer (NSCLC) across lines of therapy. Patients were selected on the basis of PD-L1 expression on tumor cells (TC) or tumor-infiltrating immune cells (IC). Patients and Methods Eligible patients had advanced-stage NSCLC, no CNS metastases, and zero to two or more lines of prior chemotherapy. Patients whose tumors expressed PD-L1 using the SP142 immunohistochemistry assay on ≥ 5% of TC or IC (TC2/3 or IC2/3 [TC or IC ≥ 5% PD-L1-expressing cells, respectively]) were enrolled. Atezolizumab 1,200 mg was administered intravenously every 3 weeks. Efficacy-evaluable patients (N = 659) comprised three cohorts: first line (cohort 1; n = 139); second line (cohort 2; n = 268); and third line or higher (cohort 3; n = 252). The primary end point was independent review facility-assessed objective response rate (ORR; Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Secondary end points included median duration of response, progression-free survival, and overall survival (OS). Results BIRCH met its primary objective of demonstrating a significant ORR versus historical controls. With a minimum of 12 months of follow-up, the independent review facility-assessed ORR was 18% to 22% for the three cohorts, and 26% to 31% for the TC3 or IC3 subgroup; most responses are ongoing. Responses occurred regardless of EGFR or KRAS mutation status. The median OS from an updated survival analysis (minimum of 20 month follow up) for cohort 1 was 23.5 months (26.9 months for TC3 or IC3 patients); the median OS in cohorts 2 and 3 was 15.5 and 13.2 months, respectively. The safety profile was similar across cohorts and consistent with previous atezolizumab monotherapy trials. Conclusion BIRCH demonstrated responses with atezolizumab monotherapy in patients with PD-L1-selected advanced NSCLC, with good tolerability. PD-L1 status may serve as a predictive biomarker for identifying patients most likely to benefit from atezolizumab.

Selumetinib Plus Docetaxel Compared With Docetaxel Alone and Progression-Free Survival in Patients With KRAS-Mutant Advanced Non-Small Cell Lung Cancer: The SELECT-1 Randomized Clinical Trial.

Importance There are no specifically approved targeted therapies for the most common genomically defined subset of non–small cell lung cancer (NSCLC), KRAS-mutant lung cancer. Objective To compare efficacy of the mitogen-activated protein kinase kinase (MEK) inhibitor selumetinib + docetaxel with docetaxel alone as a second-line therapy for advanced KRAS-mutant NSCLC. Design, Setting, and Participants Multinational, randomized clinical trial conducted at 202 sites across 25 countries from October 2013 through January 2016. Of 3323 patients with advanced NSCLC and disease progression following first-line anticancer therapy tested for a KRAS mutation, 866 were enrolled and 510 randomized. Primary reason for exclusion was ineligibility. The data cutoff date for analysis was June 7, 2016. Interventions Patients were randomized 1:1; 254 to receive selumetinib + docetaxel and 256 to receive placebo + docetaxel. Main Outcomes and Measures Primary end point was investigator assessed progression-free survival. Secondary end points included overall survival, objective response rate, duration of response, effects on disease-related symptoms, safety, and tolerability. Results Of 510 randomized patients (mean age, 61.4 years [SD, 8.3]; women, 207 [41%]), 505 patients (99%) received treatment and completed the study (251 received selumetinib + docetaxel; 254 received placebo + docetaxel). At the time of data cutoff, 447 patients (88%) had experienced a progression event and 346 deaths (68%) had occurred. Median progression-free survival was 3.9 months (interquartile range [IQR], 1.5-5.9) with selumetinib + docetaxel and 2.8 months (IQR, 1.4-5.5) with placebo + docetaxel (difference, 1.1 months; hazard ratio [HR], 0.93 [95% CI, 0.77-1.12]; P = .44). Median overall survival was 8.7 months (IQR, 3.6-16.8) with selumetinib + docetaxel and 7.9 months (IQR, 3.8-20.1) with placebo + docetaxel (difference, 0.9 months; HR, 1.05 [95% CI, 0.85-1.30]; P = .64). Objective response rate was 20.1% with selumetinib + docetaxel and 13.7% with placebo + docetaxel (difference, 6.4%; odds ratio, 1.61 [95% CI, 1.00-2.62]; P = .05). Median duration of response was 2.9 months (IQR, 1.7-4.8; 95% CI, 2.7-4.1) with selumetinib + docetaxel and 4.5 months (IQR, 2.3-7.3; 95% CI, 2.8-5.6) with placebo + docetaxel. Adverse events of grade 3 or higher were more frequent with selumetinib + docetaxel (169 adverse events [67%] for selumetinib + docetaxel vs 115 adverse events [45%] for placebo + docetaxel; difference, 22%). Conclusions and Relevance Among patients with previously treated advanced KRAS-mutant non–small cell lung cancer, addition of selumetinib to docetaxel did not improve progression-free survival compared with docetaxel alone. Trial Registration clinicaltrials.gov: NCT01933932