Activity of EGFR Tyrosine Kinase Inhibitors in NSCLC With Refractory Leptomeningeal Metastases

IntroductionLeptomeningeal metastases (LMs) are associated with dismal prognosis in NSCLC. Optimal management remains unknown in patients with EGFR-mutated NSCLC after initial tyrosine kinase inhibitor (TKI) failure.MethodsWe conducted a multicenter retrospective study including patients with EGFR-mutated NSCLC and LM. TKI failure was defined as diagnosis of LM on TKI, or progression of known LM on TKI.ResultsNinety-two patients were included, median age of 60 years, predominantly female (68%), never-smokers (74%). EGFR mutations included L858R (45%), exon 19 deletions (28%), or other mutations (14%). Median time to LM diagnosis was 18.5 months after initial diagnosis of advanced NSCLC. LM was diagnosed after a median of 2 (range: 0–9) systemic therapies. Median overall survival from LM diagnosis was 6.1 months (95% confidence interval [CI]: 4.2–7.6 months). Among 87 patients with TKI failure, patients rechallenged with TKI (n = 50) had a median LM overall survival of 7.6 months (95% CI: 5.7–10.9) compared to 4.2 months (95% CI: 1.6–6.7) in patients without further therapy. Overall, 60% of patients rechallenged with TKI experienced clinical benefit (clinical response or stable disease >2 months), and 23% were treatment failure-free at 6 months. Clinical benefit was reported in 11 of 20 (55%) patients treated with erlotinib after afatinib or gefitinib. Strategies based on increasing dose intensity (n = 17) yielded clinical benefit in 59% of patients. All four patients who received osimertinib after first- and second-generation TKI experienced clinical benefit.ConclusionsTKI rechallenge strategies, including dosing intensification, may improve clinical outcomes of patients with LM from EGFR-mutated NSCLC after initial TKI failure.     

Long-term Follow-up and Patterns of Recurrence of Patients With Oligometastatic NSCLC Treated With Pulmonary SBRT

IntroductionThis multicenter study aims to analyze outcome as well as early versus late patterns of recurrence following pulmonary stereotactic body radiotherapy (SBRT) for patients with oligometastatic non–small-cell lung cancer (NSCLC).Materials and MethodsThis analysis included 301 patients with oligometastatic NSCLC treated with SBRT for 336 lung metastases. Although treatment of the primary tumor consisted of surgical resection, radiochemotherapy, and/or systemic therapy, pulmonary oligometastases were treated with SBRT.ResultsThe median follow-up time was 16.1 months, resulting in 2-year overall survival (OS), local control (LC), and distant control (DC) of 62.2%, 82.0%, and 45.2%, respectively. Multivariate analysis identified age (P = .019) and histologic subtype (P = .028), as well as number of metastatic organs (P < .001) as independent prognostic factors for OS. LC was superior for patients with favorable histologic subtype (P = .046) and SBRT with a higher biological effective dose at isocenter (P = .037), whereas DC was inferior for patients with metastases in multiple organs (P < .001) and female gender (P = .027). Early (within 24 months) local or distant progression was observed in 15.3% and 36.5% of the patients. After 24 months, the risk of late local failure was low, with 3- and 4-year local failure rates of only 4.0%, and 7.6%. In contrast, patients remained at a high risk of distant progression with 3- and 4-year failure rates of 13.3% and 24.1%, respectively, with no plateau observed.ConclusionSBRT for pulmonary oligometastatic NSCLC resulted in favorable LC and promising OS. The dominant failure pattern is distant with a continuously high risk of disease progression for many years.     

Treatment Patterns and Clinical Outcomes Among Patients With ROS1-rearranged Non–small-cell Lung Cancer Progressing on Crizotinib

BackgroundROS1 rearrangements define a subset of non–small-cell lung cancers (NSCLCs) that are susceptible to therapeutic ROS1 kinase inhibition. Despite the fact that most patients initially respond to the first-generation ROS1 tyrosine kinase inhibitor (TKI) crizotinib, relapse invariably occurs, and therapeutic options upon disease progression are limited.Patients and MethodsWe conducted a multicenter study of patients with ROS1-rearranged NSCLC who progressed on ROS1 TKIs and examined the clinical outcomes based on the post-progression treatment approaches.ResultsAmong 29 patients with ROS1-rearrangement who received at least 1 ROS1 inhibitor, the median age was 51 years (range, 30-80 years), 70.8% of patients were female, and 68.9% were never-smokers. Upon progression to the first TKI, 11 patients (37.9%) received treatment with TKIs beyond progression. The median second progression-free survival to TKIs in patents treated beyond progression was 5.5 months (95% confidence interval [CI], 4.1-9.1 months), whereas the post-progression survival was 21.0 months (95% CI, 5.5 months-not reached [NR]). Eleven (37.9%) patients received a sequential treatment with lorlatinib ROS1 TKIs following a first generation ROS1 TKI. The overall response rate, median progression-free survival, and median overall survival (OS) to next-generation TKIs were 41.7% (95% CI, 15.2%-72.3%), 12.7 months (95% CI, 8.5 months-NR), and 17.0 months (95% CI, 15.8 months-NR), respectively. Patients treated with sequential ROS1 TKIs had a significantly longer median OS compared with those who were not (NR vs. 16.1 months; hazard ratio, 0.26; 95% CI, 0.10-0.78; P = .017).ConclusionIn this study, we reported that a subset of patients with ROS1-rearranged NSCLC may benefit from treatment with TKIs beyond progression and that sequential treatment with crizotinib followed by lorlatinib is associated with improved OS in patients with ROS1-rearranged NSCLC.     

EGFR Tyrosine Kinase Inhibitor (TKI) Combined With Concurrent or Sequential Chemotherapy for Patients With Advanced Lung Cancer and Gradual Progression After First-Line EGFR-TKI Therapy: A Randomized Controlled Study

IntroductionContinuing tyrosine kinase inhibitor (TKI) therapy may be beneficial when patients with non–small-cell lung cancer and EGFR mutations experience gradual disease progression after initial EGFR-TKI treatment. We aimed to compare the efficacy of simultaneous EGFR-TKI and chemotherapy with that of sequential treatment after patients’ disease gradually progressed after first-line EGFR-TKI treatment.Patients and MethodsPatients with gradual progression who were EGFR-T790M mutation negative were randomly divided into two groups. In the concurrent group, patients were treated with pemetrexed plus cisplatin along with the same EGFR-TKI. In the sequential group, patients continued with EGFR-TKI until the disease progressed again, according to RECIST, then switched to chemotherapy. We evaluated the patients’ progression-free survival (PFS) and overall survival times.ResultsNinety-nine patients were enrolled: 49 in the concurrent group and 50 in the sequential group. The median PFS (mPFS) was 7.7 months (95% confidence interval [CI], 3.6-11.7) in the concurrent group and 5.7 months (95% CI, 3.5-7.9) in the sequential group (hazard ratio = 0.66; 95% CI, 0.44-1.00; P = .026), respectively. For the sequential group, the mPFS1 and mPFS2 were 1.8 months (95% CI, 1.4-2.3) and 3.8 months (95% CI, 3.1-4.5), respectively. The median overall survival of the concurrent group was longer than that of the sequential group (20.0 vs. 14.7 months; hazard ratio = 0.52; 95% CI, 0.32-0.85; P = .038).ConclusionFor patients with advanced non–small-cell lung cancer and gradual progression who are EGFR-T790M mutation negative after initial EGFR-TKI therapy, EGFR-TKI combined with chemotherapy confers longer PFS and overall survival than sequential EGFR-TKI and chemotherapy does.     

Is Elective Inguinal or External Iliac Irradiation During Neoadjuvant (Chemo)radiotherapy Necessary for Locally Advanced Lower Rectal Cancer With Anal Sphincter Invasion?

PurposeTo investigate the impact of excluding irradiation of inguinal lymph nodes (ILNs) and external iliac lymph nodes (ELNs) during neoadjuvant (chemo)radiotherapy in a locally advanced lower rectal cancer (LALRC) with anal sphincter invasion.Methods and MaterialsA total of 214 LALRC patients with anal sphincter invasion according to pre-treatment magnetic resonance imaging who underwent neoadjuvant (chemo)radiotherapy followed by surgery between September 2010 and May 2019 were enrolled. ILNs and ELNs were clinically negative pre-treatment and were excluded from irradiation. Failure rates and patterns of ILNs and ELNs and survival were analyzed. Nomograms for predicting ILN and ELN failure risk were also constructed.ResultsThe median follow-up was 53.3 months. The 3-year failure rates were 3.7% for ILNs and 3.3% for ELNs. Only 1 patient developed isolated ILN failure, and no patient experienced isolated ELN failure. Multivariate analyses demonstrated that lower edge of tumors invaded or located below the dentate line (odds ratio [OR], 7.513; P = .013), high histological grade (OR, 6.892; P = .017), and perineural invasion (OR, 7.111; P = .023) were significantly related to ILN failure. Both perineural invasion (OR, 8.923; P = .011) and high histological grade (OR, 8.129; P = .011) showed a strong correlation with ELN failure. The concordance index of nomograms for predicting ILN and ELN failure risk were 0.842 and 0.880, respectively. The 3-year local recurrence free survival, disease-free survival, and overall survival were 94.6% (95% confidence interval [CI], 91.3%-97.9%), 77.7% (95% CI, 71.8%-83.6%), and 91.9% (95% CI, 87.8%-96.0%), respectively, for the whole cohort.ConclusionsExcluding ILNs and ELNs from irradiation was associated with an acceptably low failure risk for LALRC invading the anal sphincter. These findings help to refine existing guidelines for clinical target volume delineation of ILNs and ELNs during neoadjuvant (chemo)radiotherapy in rectal cancer.     

Characteristics and outcomes of women with adenocarcinoma versus squamous cell carcinoma of the vulva: A Japanese Gynecologic Oncology Group study

ObjectiveStudies on vulvar adenocarcinoma are lacking. Thus, we aimed to compare the characteristics and survival outcomes between vulvar adenocarcinoma and squamous cell carcinoma (SCC).MethodsThis was a preplanned sub-analysis of a previously organized nationwide retrospective observational study in Japan conducted between 2001 and 2010 (JGOG-1075S). Surgically treated women with stage I-IV vulvar invasive adenocarcinoma were compared to those with SCC. Multivariable analysis was performed to identify patient and tumor characteristics related to adenocarcinoma. Inverse probability of treatment weighting was used to balance the background differences, and a Cox proportional hazards regression model was fitted to estimate the effect of the histological type on survival.ResultsForty-eight women with adenocarcinoma were compared with 537 women with SCC. On multivariable analysis, women with adenocarcinoma were younger (median age, 64.5 vs. 70 years, adjusted odds ratio [OR] per age 0.975, 95% confidence interval [CI] 0.955–0.995, P = 0.016) and had higher positive surgical margin rates (31.2% vs. 18.4%, adjusted OR 2.376, 95% CI 1.188–4.754, P = 0.014) than those with SCC. However, according to the weighted model, the survival outcomes were comparable (hazard ratio for progression-free survival, 1.088, 95% CI 0.740–1.601, P = 0.667 and hazard ratio for overall survival, 1.008, 95% CI 0.646–1.573, P = 0.973). Similar associations were observed when the cohort was stratified by age (≤70 or >70 years), stage (I-II or III-IV), and surgical margin (negative or positive) (all, P > 0.05).ConclusionVulvar adenocarcinoma is characterized by a younger age at diagnosis and higher positive surgical margin rates than SCC, but the survival outcomes are comparable.     

Management of Central Nervous System Metastases in Patients With Advanced Anaplastic Lymphoma Kinase-Rearranged Non–Small-Cell Lung Cancer During Crizotinib Treatment

BackgroundCentral nervous system (CNS) progression is a common manifestation of acquired resistance to crizotinib in anaplastic lymphoma kinase (ALK)-rearranged non–small-cell lung cancer (NSCLC). However, an optimal tailored treatment approach has not been established in patients with CNS failure during crizotinib treatment.Patients and MethodsPatients with ALK-rearranged NSCLC with CNS progression during crizotinib treatment between January 2013 and December 2016 were included for analysis. Clinical data for different treatments after CNS failure during crizotinib treatment were retrospectively collected.ResultsAmong the 44 patients who had CNS progression during crizotinib treatment, 19, 15, 8, and 2 patients received crizotinib treatment beyond progressive disease (CBPD), a second ALK tyrosine kinase inhibitor (TKI), chemotherapy, and best supportive care, respectively. Post progression survival offered by treatment with a second ALK TKI was significantly more favorable than that of chemotherapy (P < .001) or CBPD (P = .045). In addition, patients who received sequential treatment with a second ALK TKI had significantly longer intracranial time to progression (IC-TTP) compared with those treated with chemotherapy (P < .01) or CBPD after radiotherapy (P = .003). In the 7 patients who received brigatinib, the median IC-TTP was 21.8 months (95% confidence interval, 11.7-32.0). The additional use of CNS radiotherapy in patients treated with a second ALK TKI showed no significance in terms of IC-TTP (P = .54).ConclusionAlthough CBPD is an option in patients with isolated CNS progression during crizotinib treatment, sequential treatment with a second ALK TKI, particularly brigatinib, might be preferable. The newly approved TKI, brigatinib, showed promise in the control of brain metastases, even without radiotherapy.     

Patterns of Failure and Optimal Treatment Paradigm for Large,Inoperable, Node-Negative Non–small Cell Lung Cancer

ObjectivesThe ideal non-operative treatment for patients with large, node-negative non–small cell lung cancer (NSCLC) is poorly defined. To inform optimal treatment paradigms for this cohort, we examined patterns of failure and the impact of radiation therapy (RT) and chemotherapy receipt.Materials and MethodsNode-negative NSCLC patients with 5+ cm primary tumors receiving definitive RT at our institution were identified. Sites of initial progression were analyzed. Local progression, regional/distant progression, progression-free survival, and overall survival were analyzed via cumulative incidence function and Kaplan-Meier. Associations between local vs. regional/distant progression with treatment and clinicopathologic variables were assessed via univariable and multivariable competing risks regression.Results and ConclusionWe identified 88 patients for analysis. Among patients with recurrent disease (N = 36), initial patterns of failure analysis showed that isolated distant (27.8%) and isolated regional progression (22.2%) were most common. Distant or regional failure as a component of initial failure was seen in 88.9% of patients who progressed, while isolated local failure was uncommon (11.1%). Univariable and multivariable competing risks regression showed that receipt of SBRT was associated with reduced risk of local progression (HR 0.23, P = .012), and receipt of chemotherapy was associated with reduced risk of regional/distant progression (HR 0.12, P = .040). In conclusion, patients with large, node-negative NSCLC treated with definitive RT are at high risk of regional and distant progression. SBRT correlates with a reduced risk of local failure while chemotherapy is associated with reduced regional/distant progression in this patient population. Ideal treatment may include SBRT when feasible with appropriate systemic therapy.     

Survival of Asian Females With Advanced Lung Cancer in the Era of Tyrosine Kinase Inhibitor Therapy

Introduction

We examined the effect of access to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy on survival for Asian female (AF) EGFR mutation-enriched patients with advanced lung adenocarcinoma.

Factors Associated With Acute Toxicity in Pediatric Patients Treated With Proton Radiation Therapy: A Report From the Pediatric Proton Consortium Registry

PurposeLimited prospective information regarding acute toxicity in pediatric patients receiving proton therapy (PT) exists. In this study, Pediatric Proton Consortium Registry (PPCR) data was analyzed for factors associated with development of acute toxicity in children receiving passively scattered or pencil beam scanning PT.Methods and MaterialsPediatric patients treated with PT and enrolled on the PPCR from 2016 to 2017 at 7 institutions were included. Data were entered on presence versus absence of acute general, cardiac, endocrine, eye, gastrointestinal, genitourinary, hematologic, mouth, musculoskeletal, neurologic, psychological, respiratory, and skin toxicities before (baseline) and at the end of PT (acute). Associations between patient and treatment variables with development of acute toxicity were assessed with multivariable modeling.ResultsOf 422 patients included, PT technique was passively scattered in 241 (57%), pencil beam scanning in 180 (43%), and missing in 1 (<1%) patient. Median age was 9.9 years. Daily anesthesia for treatment was used in 169 (40%). Treatments were categorized as craniospinal irradiation (CSI; n = 100, 24%), focal central nervous system PT (n = 157, 38%), or body PT (n = 158, 38%). Passively scattered PT was associated with increased risk of hematologic toxicity compared with pencil beam scanning PT (odds ratio [OR]: 3.03; 95% confidence interval [CI], 1.38-6.70; P = .006). There were no other differences toxicities between PT techniques. Uninsured patients had increased risk of GI (OR: 2.71; 95% CI, 1.12-6.58; P = .027) and hematologic toxicity (OR: 10.67; 95% CI, 2.68-42.46; P <.001). Patients receiving concurrent chemotherapy were more likely to experience skin (OR: 2.45; 95% CI, 1.23-4.88; P = .011), hematologic (OR: 2.87; 95% CI, 1.31-6.25; P = .008), GI (OR: 2.37; 95% CI, 1.33-4.21; P = .003), and mouth toxicities (OR: 2.03; 95% CI, 1.10-3.73; P = .024). Patients receiving 49 to 55 Gy were more likely to experience skin (OR: 2.18; 95% CI, 1.06-4.44; P = .033) toxicity than those receiving <49 Gy.ConclusionsThe PPCR registry highlights broad differences in acute toxicity rates in children receiving PT, and identifies opportunities for improvements in prevention, monitoring, and treatment of toxicities.     

Prognostic Role of Biologically Active Volume of Disease in Patients With Metastatic Lung Adenocarcinoma

BackgroundNumber of metastatic sites can identify patient populations with non–small cell lung cancer (NSCLC) that benefit from aggressive therapy. Total volume of disease is also relevant. We evaluated the prognostic impact of biologically active volume of disease (BaVD) on patients with metastatic lung adenocarcinoma.Materials and MethodsPositron emission tomography/computerized tomography (PET/CT) scans from patients with newly diagnosed lung adenocarcinoma prior to starting any therapy were identified. SUV thresholds of 3 and 4 were used to auto-contour all FDG avid areas. Kaplan-Meier analysis and Cox regression were performed to examine influence on OS.ResultsOne hundred forty-eight patients were included in the analysis. The median BaVD when using an SUV threshold of 3 was 122.8 mL. The median BaVD when using an SUV threshold of 4 was 46.2 mL When stratified by median BaVD using an SUV of 3, median OS was higher for patients with <=122.8 mL (2.12 years) compared to patients with >122.8 mL (1.46 years) (log-rank P = .001). Similarly, when stratified by median BaVD using an SUV of 4, median OS was higher for patients with <=46.2 mL (1.91 years; 95% CI: 1.65-3.22 years) compared to patients with >46.2 mL (1.48 years; 95% CI: 1.07-1.80 years) (log-rank P = .007). On multivariable analysis, BaVD was significantly associated with OS when using an SUV threshold of 3 (HR: 20.169, P < .001) and 4 (HR: 4.117, P < .001).ConclusionBaVD is an important prognostic factor in metastatic lung adenocarcinoma and may aid identification of patients with limited disease who may be candidates for more aggressive therapies.     

Comparison of Chemotherapy Plus Pembrolizumab vs. Chemotherapy Alone in EGFR-Mutant Non–small-Cell Lung Cancer Patients

IntroductionPlatinum doublet chemotherapy is the standard of care in patients with non–small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation who had disease progression after tyrosine kinase inhibitor (TKI). We aimed to assess immune checkpoint inhibitors efficacy in EGFR-mutant advanced NSCLC.Materials and MethodsWe retrospectively reviewed the data of sensitive EGFR-mutant NSCLC patients who progressed after EGFR-TKIs and received platinum doublet chemotherapy plus immunotherapy between 2015 and 2021. Efficacy outcomes, including overall response rate, progression-free survival, and overall survival, were assessed and compared with those of patients who had received platinum-based doublet chemotherapy.ResultsOf the total 869 patients, 82 treated with pembrolizumab and chemotherapy and 82 with only chemotherapy were selected. The median progression-free survival in patients administered pembrolizumab was significantly longer than those not administered pembrolizumab (6.7 months; 95% confidence interval [CI] 5.0-8.5 vs. 4.2 months; 95% CI 3.3-5.0, hazard ratio [HR] 0.64, 95% CI 0.46-0.89, P = .0076). Improved median overall survival was also observed in patients receiving pembrolizumab plus chemotherapy (26.7 [95% CI 22.6-30.8] vs. 13.4 months [95% CI 10.4-16.4], HR, 0.49 [95% CI 0.31-0.75], P = .0052). In addition, the overall response rate was higher in patients treated with than patients treated without pembrolizumab (34.1% and 20.7%, respectively).ConclusionThe combination of pembrolizumab with chemotherapy is associated with improved efficacy and survival in patients with EGFR-mutant NSCLC after TKI resistance, but these findings need to be confirmed in further prospective studies.     

Clinical Features and Progression Pattern of Acquired T790M-positive Compared With T790M-negative EGFR Mutant Non–small-cell Lung Cancer: Catching Tumor and Clinical Heterogeneity Over Time Through Liquid Biopsy

BackgroundClinical-pathologic predictors of acquired T790M epidermal growth factor receptor (EGFR) mutation in Caucasian patients with non–small-cell lung cancer (NSCLC) progressing after first-/second-generation tyrosine kinase inhibitors (TKIs) is an open field for research. Similarly, the best time point for T790M detection by liquid or tissue biopsy after disease progression is currently matter of debate.Patients and MethodsThis is an observational study at 7 Italian centers enrolling patients with EGFR-mutant NSCLC progressing after first-/second-generation EGFR TKIs, between 2014 and 2018, aiming at comparing baseline clinical-pathologic features and progression patterns in acquired T790M-positive compared with T790M-negative cases.ResultsA total of 235 patients received first-line treatment with gefitinib (N = 126; 53%), erlotinib (N = 51; 22%), or afatinib (N = 58; 25%). In 120 (51%) cases, T790M was detected in liquid biopsy, tissue biopsy, or both. Age younger than 65 years (P = .037), the presence of common mutations (P = .004), and better response to first-line TKI (P = .023) were correlated with T790M positivity. T790M detection was associated with higher number of new progressing sites (P = .04), liver progression (P = .002), and a lower frequency of lung metastases (P = .027). When serial liquid biopsies were performed (N = 15), an oligoprogressive disease was correlated with a negative test outcome, whereas systemic progression was observed at the time of T790M positivity.ConclusionThis study on a Caucasian population showed that age, type of EGFR mutation at diagnosis, response to first-line treatment, and peculiar progression pattern are associated with T790M status. Serial liquid biopsy might be useful for treatment selection, especially when tissue rebiopsy is not feasible.     

Steroid Use Independently Predicts for Poor Outcomes in Patients With Advanced NSCLC and High PD-L1 Expression Receiving First-Line Pembrolizumab Monotherapy

BackgroundReal-world data have suggested a detrimental effect of steroid use in patients with advanced non–small-cell lung cancer (NSCLC) receiving immunotherapy. However, previous studies included heterogeneous cohorts of patients receiving different lines of treatment with several immuno-oncology agents and various combinations of chemotherapy and immuno-oncology agents.Patients and MethodsA comprehensive clinicopathologic database of patients with NSCLC and programmed cell death ligand 1 >50% treated with frontline pembrolizumab monotherapy was constructed in 14 centers in Italy, Spain, Greece, and Switzerland. A multivariate analysis adjusting for the established prognostic factors was performed using a Cox regression model.ResultsFor the 265 eligible patients, the median age at diagnosis was 67 years, 66% were male, 90% were current or former smokers, 18% had had an Eastern Cooperative Oncology Group performance status of 2 or 3. Of the NSCLC subtypes, 64% were adenocarcinoma and 25% were squamous cell. Of the patients, 18% had had brain metastases at diagnosis and 24% had received steroids before or during pembrolizumab treatment. The median time to progression was 4.4 months with and 13.7 months without steroid use (hazard ratio [HR], 2.55; 95% confidence interval [CI], 1.69-3.85; log-rank P < .001). The median survival was 22.5 months for the whole cohort, 7.7 months for the steroid group, and not reached for the non-steroid group (HR, 3.64; 95% CI, 2.34-5.68; log-rank P < .001). On multivariate analysis accounting for all established prognostic variables, steroid use was still independently associated with a high risk of progression (HR, 1.864; 95% CI, 1.179-2.949; P = .008) and death (HR, 2.292; 95% CI, 1.441-3.644; P < .001)ConclusionsIn patients with advanced NSCLC and programmed cell death ligand 1 expression > 50% receiving frontline pembrolizumab monotherapy, any use of steroids before or during treatment was associated with an 86% increase in the risk of progression and a 2.3-fold increase in the risk of death, even accounting for palliative indication-related bias, including the presence of central nervous system metastasis. The use of steroids for palliative indications should be restricted to absolutely necessary for patients receiving immuno-oncology monotherapy.     

Clinical and molecular characteristics of non-small-cell lung cancer (NSCLC) harboring EGFR mutation: results of the nationwide French Cooperative Thoracic Intergroup (IFCT) program

BackgroundEGFR mutations cause inconsistent response to EGFR tyrosine-kinase inhibitors (TKI). To better understand these features, we reviewed all cases of EGFR-mutated non-small-cell lung cancer collected in the Biomarkers France database.Patients and methodsOf 17 664 patients, 1837 (11%) with EGFR-mutated non-small-cell lung cancer were retrospectively analyzed for clinical and molecular characteristics. Results were correlated with survival and treatment response for the 848 stage IV patients.ResultsEGFR exon 18, 19, 20 and 21 mutations were found in 102 (5.5%), 931 (51%), 102 (5.5%) and 702 (38%) patients, respectively. Over 50% of exon 18 and 20 mutated patients were smokers. The median follow-up was 51.7 months. EGFR mutation type was prognostic of overall survival (OS) versus wild-type {exon 19: hazard ratio (HR)=0.51 [95% confidence interval (CI): 0.41–0.64], P < 0.0001; exon 21: HR = 0.76 (95% CI: 0.61–0.95), P = 0.002; exon 20: HR = 1.56 (95% CI: 1.02–2.38), P = 0.004}. EGFR mutation type was prognostic of progression-free survival versus wild-type [exon 19: HR = 0.62 (95% CI: 0.49–0.78), P < 0.0001; exon 20: HR = 1.46 (95% CI: 0.96–2.21), P = 0.07]. First-line treatment choice did not influence OS in multivariate analysis. First-line TKI predicted improved progression-free survival versus chemotherapy [HR = 0.67 (95% CI: 0.53–0.85), P = 0.001]. OS was longer for del19 versus L858R, which was associated with better OS compared with other exon 21 mutations, including L861Q. TKI improved survival in patients with exon 18 mutations, while chemotherapy was more beneficial for exon 20-mutated patients.ConclusionEGFR mutation type can inform the most appropriate treatment. Therapeutic schedule had no impact on OS in our study, although TKI should be prescribed in first-line considering the risk of missing the opportunity to use this treatment.     

Access to Tyrosine Kinase Inhibitors and Survival in Patients with Advanced EGFR+ and ALK+ Positive Non–small-cell Lung Cancer Treated in the Real-World

IntroductionWe assessed the proportion of patients with advanced epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) positive non–small-cell lung cancer (NSCLC) who receive tyrosine kinase inhibitors (TKIs) in the real-world, predictors of TKI use, and impact of TKI therapy on overall survival (OS).Materials and MethodsWe identified patients diagnosed with stage IV EGFR⁺ and ALK⁺ positive NSCLC from January 1, 2010 to December 31, 2018, in the Cancer Surveillance System registry and linked their records to Medicare and commercial insurance claims. We reported the proportions of patients with 1 or more TKI claims versus no TKI claims and used logistic regression to identify predictors of TKI use. We evaluated the effect of TKI use on OS by applying extended Cox proportional hazard models with TKI use as a time-dependent exposure and landmark analysis in a subcohort (N = 105). We adjusted Cox models for confounding patient characteristics.ResultsOf 117 eligible patients (median age = 69; 62% women; 88% EGFR⁺), 21 (17.9%) had no TKI claims. Diagnosis in 2015 to 2018 was independently associated with lower likelihood of TKI therapy compared with 2010 to 2014 (adjusted odds ratio, 0.29; P = .020). TKI use was associated with longer OS in a multivariate extended Cox model and in the landmark analysis (adjusted hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.33; 0.99; P = .048; adjusted HR, 0.55; 95% CI, 0.30; 1.00; P = .050).ConclusionApproximately 18% of patients with advanced EGFR⁺ and ALK⁺ positive NSCLC do not receive TKIs and have inferior survival. Further studies need to investigate barriers of access to TKIs in biomarker-selected patients.     

Validation of the Combination Gleason Score as an Independent Favorable Prognostic Factor in Prostate Cancer Treated With Dose-Escalated Radiation Therapy

PurposePrognostic factors for prostate cancer include tumor, node, metastases stage, pretreatment prostate-specific antigen, and pathology (via Gleason score [GS] or grade group). Of these, GS yields the largest effect on prostate cancer specific mortality. It was previously determined that those with cores with a mix of higher and lower GS at biopsy (which was termed a “ComboGS”) had decreased risk for prostate cancer specific mortality after either surgical or radiation treatment. We validate the effect of ComboGS in an independent cohort of patients with prostate cancer treated with definitive dose-escalated radiation therapy (DE-RT) at 2 institutions.Methods and MaterialsDE-RT was administered to 2539 men, of which 687 men had a ComboGS. To further ascertain the ComboGS effect we employed the modified Cancer of the Prostate Risk Assessment (mCAPRA) score. Rates of biochemical event-free survival and distant metastasis-free survival were compared across CAPRA scores, with and without modification, and the prognostic value of the CAPRA scores was compared using Harrel's concordance index.ResultsOn univariate analysis in Gleason 7 to 10 patients the presence of ComboGS improved 10-year biochemical event-free survival from 76.6% to 82.4% (hazard ratio [HR], 0.75; confidence interval [CI], 0.59-0.96; P = .021), 10-year distant metastasis-free survival from 89.3% to 93.2% (HR, 0.57; CI, 0.39-0.85; P = .005), 10-year prostate cancer specific survival from 93.9% to 97.4% (HR, 0.39; CI, 0.21-0.7; P = .001), and 10-year overall survival from 65.7% to 75.6% (HR, 0.69; CI, 0.57-0.83; P < .001). Multivariable analysis also supported that ComboGS is protective for biochemical failure (HR, 0.64; CI, 0.50-0.83; P < .001), distant metastasis (HR, 0.42; CI, 0.28-0.63; P < .001), death from prostate cancer (HR, 0.32; CI, 0.17-0.58; P < .001), and overall mortality (HR, 0.65; CI, 0.54-0.79; P < .001). Additionally, adjusting the mCAPRA score for ComboGS decreased the risk of biochemical failure by nearly 30% (HR, 0.70; 95% CI, 0.55-0.88; P = .003) and by 50% (HR, 0.54; 95% CI, 0.37-0.80; P = .002) for distant metastasis.ConclusionsComboGS is a useful and readily available independent prognostic factor for all clinical endpoints evaluated. Moreover, the ComboGS can be used in conjunction with the extensively validated CAPRA scoring to better risk stratify patients being treated with definitive DE-RT for GS 7 to 10 disease.     

Determinants of Guideline-Based Treatment in Patients With cT1 Bladder Cancer

IntroductionClinical T1 (cT1) bladder cancer is associated with high rates of recurrence, upstaging, and progression. Guidelines recommend that these patients be treated with adjuvant intravesical Bacillus Calmette-Guérin immunotherapy (BCG) or upfront radical cystectomy (RC). We analyzed the National Cancer Database (NCDB) to identify demographic and clinical determinants of guideline-based treatment (GBT) and RC.Patients and MethodsWe identified 47,694 patients in the NCDB with cT1 bladder cancer diagnosed in 2004-2013. Those who did not receive any treatment or underwent primary chemotherapy were excluded. Mixed effects logistic regression adjusted for facility-level variation was used to identify factors associated with receipt of GBT.ResultsThe median age of the cohort was 72 years (interquartile range, 63-79). Of the patients, 22.4% were female, 5.1% were African American, and 2.7% had variant histology. Nearly one-third of patients received GBT: 11,453 (24%) were initially treated with BCG and 3320 (7%) were initially treated with RC. Recent year of diagnosis (odds ratio [OR], 1.67; 95% confidence interval [CI], 1.52-1.85; P < .001), treatment at an academic center (OR, 2.42; 95% CI, 2.27-2.59; P < .001), and private insurance status (OR, 1.41; 95% CI, 1.19-1.66; P < .001) were associated with increased odds of GBT. Of patients who received GBT, variant histology (OR, 5.89; 95% CI, 4.65-7.47; P < .001), and recent year of diagnosis (OR, 1.89; 95% CI, 1.50-2.39; P < .001) were associated with greater odds of RC.ConclusionThere is low treatment-guideline compliance for patients with cT1 disease. However, there appears to be a temporal trend toward increased use of GBT. Efforts should be made to understand why many cT1 bladder cancer patients do not receive GBT.     

Progression-free Survival Outcome Is Independent of Objective Response in Patients With Estrogen Receptor-positive,Human Epidermal Growth Factor Receptor 2-negative Advanced Breast Cancer Treated With Palbociclib Plus Letrozole Compared With Letrozole: Analysis From PALOMA-2

BackgroundIn PALOMA-2, palbociclib + letrozole significantly prolonged progression-free survival (PFS) versus placebo + letrozole in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER⁺/HER2⁻) advanced breast cancer (ABC). We investigated clinical outcomes of patients who achieved or did not achieve a confirmed objective response (OR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (data cutoff: May 31, 2017).Patients and MethodsPostmenopausal patients untreated for ER⁺/HER2⁻ ABC were randomized 2:1 to palbociclib + letrozole or placebo + letrozole. Median PFS, median duration of OR, baseline characteristics, and palbociclib exposure were compared in patients with or without OR by treatment arm.ResultsIn the intent-to-treat population, OR was achieved by 194 (44%) of 444 and 77 (35%) of 222 patients in the palbociclib and placebo arms, respectively (odds ratio, 1.5; 95% confidence interval [CI], 1.0-2.1; P = .0156). Regardless of treatment, more OR than non-OR patients had de novo metastatic disease (47%-50% and 28%-31%, respectively) and no prior endocrine therapy (55% and 35%-37%, respectively). Rates of palbociclib dose reduction owing to adverse events were similar regardless of OR (41% and 38%, respectively). Among the patients with OR during the study, approximately 50% achieved OR within the first 3 months regardless of treatment. The median PFS was significantly prolonged with palbociclib + letrozole versus placebo + letrozole in patients with measurable disease in both OR (37.2 months; 95% CI, 28.1 months to not estimable vs. 27.4 months; 95% CI, 22.2-31.1 months; hazard ratio, 0.66; 95% CI, 0.47-0.94; P = .009) and non-OR groups (10.9 months; 95% CI, 8.2-11.2 months vs. 5.6 months; 95% CI, 5.3-8.3 months; hazard ratio, 0.72; 95% CI, 0.54-0.97; P = .016).ConclusionsPalbociclib + letrozole provided significant clinical benefit versus placebo + letrozole to patients with ER⁺/HER2⁻ ABC regardless of achieving RECIST-defined OR.Pfizer; ClinicalTrials.gov: NCT01740427     

Differential Relapse Patterns for Non-small Cell Lung Cancer Subtypes Adenocarcinoma and Squamous Cell Carcinoma: Implications for Radiation Oncology

AimsCurative-intent (radical) radiotherapy aims to control local disease and cure non-small cell lung cancer (NSCLC). The predominant subtypes of NSCLC are adenocarcinoma and squamous cell carcinoma (SCC). The radiotherapy paradigm offered to patients does not differ according to these two subtypes. Relapse patterns and disease control rates for adenocarcinoma and SCC treated with radical radiotherapy were determined.Materials and methodsA radical radiotherapy database covering the period from 2004 to June 2016 was examined to determine the first sites of relapse and the actuarial local and distant control rates.ResultsIn total, 537 patients with known pathological subtype were treated over the period. In 39 (7%), the site of first relapse was uncertain. Of the remainder, 203 (41%) had adenocarcinoma and 295 (59%) had SCC. At a median follow-up of 16.4 months, 58% had relapsed. There was a difference in relapse patterns (chi-squared test P < 0.0005), with a higher rate of first relapse locally in SCC (42% of all patients versus 24%) and a higher rate of first relapse in the brain for adenocarcinoma (14% versus 3%). The actuarial local control rate was worse for SCC (hazard ratio 0.6, 95% confidence interval 0.5–0.9, P = 0.002). The brain metastasis-free survival was worse for adenocarcinoma (hazard ratio 4.1, 95% confidence interval 2.2–7.5, P < 0.0001).ConclusionThere is a difference in relapse patterns between NSCLC histological subtypes, indicating that these are distinct entities. This may have implications for follow-up policy and strategies to improve disease control.