Outcomes in Patients With Non–small-cell Lung Cancer With Brain Metastases Treated With Pembrolizumab-based Therapy

BackgroundPatients with metastatic non–small-cell lung cancer (mNSCLC) and untreated brain metastases (BM) have been excluded from most trials of immune checkpoint inhibitors (ICIs). Real-world evidence on efficacy and survival outcomes of ICIs in patients with BM is limited.Patients and MethodsWe conducted a single-center retrospective study of patients with mNSCLC treated with pembrolizumab with or without chemotherapy and compared progression-free survival (PFS) and overall survival (OS) between patients with and without BM using Kaplan-Meier and Cox methodology. We also characterized systemic and intracranial objective response rate (ORR) and treatment details, including timing of cranial irradiation.ResultsBetween Augutst 2013 and December 2018, 570 patients with mNSCLC treated with pembrolizumab-based therapy were analyzed. Of 126 (22.1%) patients with BM, 96 (76.2%) had treated BM (local therapy prior to pembrolizumab), and 30 (23.8%) had untreated BM. Of patients with untreated BM, 17 (56.7%) underwent radiation within 30 days after pembrolizumab initiation. In the remaining 13 (43.3%) treated with pembrolizumab-based therapy alone, intracranial ORR was 36.4%. Patients with and without BM did not have significantly different systemic ORR (27.8% vs. 29.7%; P = .671), PFS (mPFS 9.2 vs. 7.7 months; P = .609), or OS (mOS 18.0 vs. 18.7 months; P = .966). Factors associated with improved survival on Cox analysis included female gender, performance status, adenocarcinoma histology, and first-line therapy.ConclusionsPatients with BM did not have inferior survival to patients without BM after treatment with pembrolizumab-based therapy. In the current era, BM may not automatically confer inferior survival, and should not exclude patients from receiving pembrolizumab-based therapy.     

Cell-Free Plasma DNA-Guided Treatment With Osimertinib in Patients With Advanced EGFR-Mutated NSCLC

Introduction

Osimertinib is standard treatment for patients with advanced EGFR T790M-mutated non–small-cell lung cancer who have been pre-treated with EGFR–tyrosine kinase inhibitors (TKIs). We studied whether cell-free plasma DNA for T790M detection can be used to select patients for osimertinib treatment in the clinical routine.

Challenges With Serum Protein Electrophoresis in Assessing Progression and Clinical Response in Patients With Waldenström Macroglobulinemia

Accurate determination of the immunoglobulin (Ig) M paraprotein concentration is crucial to evaluating response in patients with Waldenström macroglobulinemia (WM). In most clinical laboratories, M-spike quantitation is performed by serum protein electrophoresis, which is the same method used to quantitate IgG and IgA paraproteins in patients with multiple myeloma (MM). However, the migration pattern and propensity of IgM paraproteins to form higher-order complexes in serum makes laboratory evaluation of samples from patients with WM especially challenging. We review examples of patients whose IgM paraprotein is particularly ill-suited to M-spike quantitation by serum protein electrophoresis: a case of “sticky M,” a case of IgM multimers that cannot be resolved, and a case of an IgM in the β region. In these and similar cases, a method other than M-spike quantitation, such as IgM heavy chain nephelometry, should be considered in laboratory evaluation of paraprotein concentration.     

How Do I Deal With the Axilla in Patients With a Positive Sentinel Lymph Node?

Optimal management of the axilla in a patient with a positive sentinel node biopsy is not yet defined.     

Neoadjuvant Chemotherapy With Docetaxel-Cisplatin in Patients With Stage III N2 Non–Small-Cell Lung Cancer

IntroductionTo assess the efficacy and potential prognostic factors of patients with stage III N2 non–small-cell lung cancer (NSCLC) treated with neoadjuvant docetaxel-cisplatin (DP) chemotherapy followed by surgical resection.MethodsSixty-two patients with NSCLC treated with DP as neoadjuvant chemotherapy between November 2003 and December 2009 were identified and reviewed in this study. Tumor response, survival, and clinicopathologic data were collected retrospectively. The time to event was analyzed by fitting Cox proportional hazards models.ResultsFifty-eight (94%) of 62 patients eventually underwent surgical resection after DP. The overall clinical response rate to induction DP chemotherapy was 42%. Patients with squamous cell carcinoma (SCC) histology were more likely to response to the DP regimen than those with adenocarcinoma histology (68% vs. 33%, P = .006). With a median follow-up of 82.4 months among the 58 patients, there were 41 (71%) tumor relapses and 27 (47%) deaths. The median event-free survival was 27.5 months (95% CI, 22.3-32.7 months), and the median overall survival was 66.7 months (95% CI, 35.1-98.3 months). In multivariate analysis, when fitting the Cox proportional hazards model, SCC histology (hazard ratio [HR] 0.234 [95% CI, 0.098-0.560]; P = .001) and mediastinal downstaging to N0 (HR 0.451 [95% CI, 0.226-0.898]; P = .024) were independent predictors of better event-free survival.ConclusionsNeoadjuvant chemotherapy with the DP regimen is both active and well tolerated in patients with stage III N2 NSCLC. SCC histology predicted a better treatment response and survival outcome than adenocarcinoma histology in this patient group. Further investigation of combined-modality treatment is warranted to improve survival in the adenocarcinoma subset of stage III N2 NSCLC.     

Analysis of Early Death in Japanese Patients With Advanced Non–small-cell Lung Cancer Treated With Nivolumab

Background

The increased risk for early death owing to anti-programmed cell death 1 inhibitors is a major disadvantage that requires special management. We evaluated the frequency, causes, and risk factors of early death during nivolumab treatment for non-small cell lung cancer (NSCLC) in a Japanese clinical setting.

Racial Disparities in Prostate Cancer–Specific Mortality in Men With Low-Risk Prostate Cancer

BackgroundMen with low-risk prostate cancer (CaP) are considered unlikely to die of CaP and have the option of active surveillance. This study evaluated whether African American (AA) men who present with low-risk disease are at higher risk for death from CaP than white men.Patients and MethodsThe authors identified 56,045 men with low-risk CaP (T1-T2a, Gleason score ≤ 6, prostate-specific antigen ≤ 10 ng/mL) diagnosed between 2004 and 2009 using the Surveillance, Epidemiology, and End Results (SEER) database. Fine-Gray competing-risks regression analyses were used to analyze the effect of race on prostate cancer–specific mortality (PCSM) after adjusting for known prognostic and sociodemographic factors in 51,315 men (43,792 white; 7523 AA) with clinical follow-up information available.ResultsAfter a median follow-up of 46 months, 258 patients (209 [0.48%] white and 49 [0.65%] AA men) died from CaP. Both AA race (adjusted hazard ratio [AHR], 1.45; 95% CI, 1.03-2.05; P = .032) and noncurative management (AHR, 1.49; 95% CI, 1.15-1.95; P = .003) were significantly associated with an increased risk of PCSM. When analyzing only patients who underwent curative treatment, AA race (AHR, 1.62; 95% CI, 1.04-2.53; P = .034) remained significantly associated with increased PCSM.ConclusionAmong men with low-risk prostate cancer, AA race compared with white race was associated with a higher risk of PCSM, raising the possibility that clinicians may need to exercise caution when recommending active surveillance for AA men with low-risk disease. Further studies are needed to ultimately determine whether guidelines for active surveillance should take race into account.     

Soluble c-Met Levels Correlated With Tissue c-Met Protein Expression in Patients With Advanced Non–Small-Cell Lung Cancer

Background

Immunohistochemistry (IHC) and fluorescent in situ hybridization are reliable methods for identifying c-Met protein expression or c-Met gene amplification. However, each technique requires a high-quality tissue sample, which might not be available. The aim of the present study was to investigate the correlation between the soluble c-Met level and tissue c-Met protein expression and the relationship between these markers and patient prognosis.

A Phase 1–2 Study of Rovalpituzumab Tesirine in Combination With Nivolumab Plus or Minus Ipilimumab in Patients With Previously Treated Extensive-Stage SCLC

IntroductionThis open-label, phase 1–2 study evaluated the safety and efficacy of rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate targeting DLL3, plus immune checkpoint inhibitors nivolumab plus or minus ipilimumab in previously treated extensive-stage SCLC (ES SCLC).MethodsPatients with histologically or cytologically confirmed, previously treated (two or more lines of therapy) ES SCLC were enrolled into two cohorts. Cohort 1 received 0.3 mg/kg Rova-T (once every 6 wk for two cycles) plus 360 mg nivolumab (two 3-wk cycles beginning on week 4). Cohort 2 received the same dosage of Rova-T as cohort 1 plus 1 mg/kg nivolumab (four 3-wk cycles) and 1 mg/kg ipilimumab (beginning week 4). Both cohorts received 480 mg nivolumab every 4 weeks starting at week 10. Key objectives were to evaluate safety and tolerability and efficacy (per Response Evaluation Criteria in Solid Tumors version 1.1). The response-related results are based on centrally read data.ResultsA total of 42 patients received therapy: cohort 1, n = 30; cohort 2, n = 12. Overall, 43% received two or more previous lines of therapy. All patients experienced one or more treatment-emergent adverse event (TEAE); 41 patients reported AEs considered related to the study drug by the investigator. The most frequent TEAE was pleural effusion (n = 20, 48%); most common grade greater than or equal to 3 was anemia (n = 9, 21%). Three grade 5 TEAEs considered related to the study drug were reported (cohort 1): pneumonitis (n = 2), acute kidney injury (n = 1). The objective response rate was 30% (12 of 40): cohort 1, 27.6% (8 of 29); cohort 2, 36.4% (4 of 11); all partial responses.ConclusionsDespite encouraging antitumor activity in previously treated ES SCLC, combination therapy with Rova-T and nivolumab plus or minus ipilimumab was not well tolerated at the dose levels and administration schedules evaluated.     

Distinct MET Protein Localization Associated With MET Exon 14 Mutation Types in Patients With Non–small-cell Lung Cancer

Background

The MET gene has been recognized as a potential important therapeutic target in non–small-cell lung cancer (NSCLC). We sought to investigate the MET exon 14 mutations in a cohort of Chinese patients with 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

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.

Polymorphisms in the Von Hippel–Lindau Gene Are Associated With Overall Survival in Metastatic Clear-Cell Renal-Cell Carcinoma Patients Treated With VEGFR Tyrosine Kinase Inhibitors

Background

Clear-cell renal-cell carcinoma (ccRCC) is characterized by loss of a functional Von Hippel–Lindau (VHL) protein. We investigated the potential of 3 single nucleotide polymorphisms (SNPs) in VHL as biomarkers in metastatic ccRCC (m-ccRCC) patients treated with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs).

Is There a Flare Phenomenon on Bone Scintigraphy in Men With Advanced Prostate Cancer Treated With Radium-223?

Introduction

Radium-223 is an approved survival-prolonging treatment option in men with castration-resistant prostate cancer (mCRPC) and bone metastases. In the registration trial (ALSYMPCA), no regular imaging was mandated. We aimed to analyze men with metastatic mCRPC treated with radium-223 who had bone scintigraphy for staging and treatment monitoring.

A Phase Ib,Dose-Finding Study of Erlotinib in Combination With a Fixed Dose of Pertuzumab in Patients With Advanced Non–Small-Cell Lung Cancer

BackgroundPertuzumab, a dimerization inhibitor of human epidermal growth factor receptor 2 (HER2), has demonstrated pharmacodynamic activity, with stable disease in non–small-cell lung cancer. Combining erlotinib and pertuzumab may enhance antitumor activity. This study aimed to establish the recommended dosing of the erlotinib and pertuzumab combination; assess safety, preliminary efficacy, and pharmacokinetics; and analyze biomarkers.Patients and MethodsFifteen patients with stage IIIb/IV non–small-cell lung cancer who failed chemotherapy were recruited. The patients received erlotinib (days ?8 to ?1), then combination therapy (21-day cycles for 6 cycles). Pertuzumab was given intravenous at 840 mg, then 420 mg once every three weeks, with erlotinib given daily (100 or 150 mg).ResultsNo dose-limiting toxicities were observed. Adverse events were generally grade 1/2 and manageable. The objective response rate was 20% (3/15 patients; 2 responders had mutant HER1, 1 responder had wild-type HER1), median overall progression-free survival was 9.3 weeks. High HER1, HER2, and HER3 messenger RNA expression correlated with increased progression-free survival. Combination therapy did not affect erlotinib's pharmacokinetics; however, pertuzumab mean exposures (maximum concentration, 231 mg/L; area under the concentration-time curve from 0 to 21 days, 1780 mg*d/L) were slightly higher than in previous studies.ConclusionsCombination therapy was well tolerated in patients with good performance status, with encouraging efficacy. A loading dose of pertuzumab 840 mg followed by 420 mg once every three weeks plus daily erlotinib 150 mg appears to be the most appropriate regimen for this combination.     

Prognostic Value of Thyroid Hormone Ratios in Patients With Advanced Metastatic Colorectal Cancer Treated With Regorafenib: The TOREADOR Study

Background

The impact of free triiodothyronine (FT₃)/free thyroxine (FT₄) ratio on survival in hospitalized geriatric patients was recently described. Up today, there are no data regarding the prognostic role of FT₃/FT₄ ratio in patients with advanced cancer. We evaluated the impact of FT₃/FT₄ ratio on survival in patients with refractory colorectal cancer (CRC) treated with regorafenib.

The Impact of Beta Blockers on Survival Outcomes in Patients With Non–small-cell Lung Cancer Treated With Immune Checkpoint Inhibitors

BackgroundBeta blockers have been associated with anti-tumorigenic effects, potentially by reducing adrenergic-mediated stress responses. Preclinical studies have additionally shown that beta blockade may enhance the efficacy of cancer immunotherapy. We investigated patients with lung cancer who concomitantly used beta blockers and immune checkpoint inhibitors (ICIs), with the hypothesis that beta blockade would positively impact clinical outcomes.Patients and MethodsWe retrospectively reviewed the health records of 109 patients who were treated at Northwestern University from January 2014 through August 2018 with ICIs for non–small-cell lung cancer (NSCLC). Comparisons of overall survival and progression-free survival (PFS) were performed using Kaplan-Meier analysis with log-rank test, and a univariate regression analysis was performed with a Cox proportional hazards model.ResultsAmong 109 patients treated with ICIs for NSCLC, 28 of them were concomitantly prescribed beta blockers. Use of beta blockers was associated with increased PFS, with a hazard ratio of 0.58 and 95% confidence interval of 0.36 to 0.93. There was not a significant increase in overall survival among patients who took beta blockers (hazard ratio, 0.66; 95% confidence interval, 0.38-1.17). In a regression model, beta blockers were identified as predictive of PFS, as were non-squamous histology, tumor programmed death-ligand 1 positivity, and lower line of treatment.ConclusionsOur data suggests beta blocker use may be associated with improved PFS among patients treated with ICIs for NSCLC. This was a small study, and these findings should be further validated in prospective clinical studies.