Neutrophil‐to‐lymphocyte ratio (NLR) is associated with poor prognosis in patients with lung cancer, but the predictive role of NLR on the risk of developing lung cancer is unknown. We investigated ...the association between NLR and lung cancer mortality in lung cancer‐free adults. A cohort study was performed with 527,124 Korean adults who were free of lung cancer and were followed for up to 16 years. Vital status and lung cancer‐related deaths were ascertained through national death records. Hazard ratios (HRs) and 95% confidence intervals (CIs) for lung cancer mortality were estimated using a Cox proportional hazards model. During 4,567,495.8 person‐years of follow‐up, 574 lung cancer deaths were identified. A higher NLR was positively associated with lung cancer mortality. The multivariable‐adjusted HR (95% CI) for lung cancer mortality comparing quintiles 2, 3, 4 and 5 of NLR to the lowest quintile were 1.26 (0.96–1.67), 1.23 (0.93–1.63), 1.33 (1.01–1.75) and 1.47 (1.13–1.92), respectively. The highest risk of lung cancer mortality was also observed in the highest NLR quintile among never‐smokers and low‐risk individuals after adjusting for lung function and other possible confounders. Platelet‐to‐lymphocyte ratio showed an inverse J‐shaped association with lung cancer mortality in men but the trends in women, low‐risk individuals or never‐smokers were neither linear nor U‐shaped. In this large cohort of young and middle‐aged individuals, NLR was independently associated with increased risk of lung cancer mortality in low‐risk individuals, indicating a role of systemic inflammation in lung cancer mortality in our study population.
What's new?
Neutrophil‐to‐lymphocyte ratio (NLR) is associated with poor prognosis in patients with lung cancer, but the predictive role of NLR on the risk of developing lung cancer is unknown. Here, the authors investigated the association between NLR and lung cancer mortality in a large prospective cohort study of 527,124 cancer‐free adults. The study reveals the association of elevated NLR with increased risk of lung cancer mortality, which was consistently observed in both never‐smokers and low‐risk individuals. NLR, a systemic inflammation marker, may thus play a role as an independent predictor of lung cancer mortality in never‐smokers as well as low‐risk populations.
Fentanyl buccal tablets (FBTs) are a rapid-onset opioid indicated for breakthrough cancer pain (BTcP) and FBT titration is needed to optimize BTcP management. We aimed to predict which patients could ...tolerate a high dose of FBT (400 μg or more at a time).
A retrospective analysis was performed to assess the final FBT dose. The final FBT doses were compared according to the clinical features. The prediction accuracy of patients tolerant of 400 μg or higher FBT was compared using the area under the receiver operating characteristic (ROC) curves. A risk scoring model based on the odds ratio (OR) was developed from the final multivariable model, and patients were assigned into two groups: low tolerance (0-1 point) and high tolerance (2-3 points).
Among 131 patients, the most frequently effective dose of FBT was 200 μg (54%), followed by 100 μg (30%). The median value of morphine equivalent daily doses (MEDD) was 60 mg/day, and the most common daily use was 3-4 times/day. In multivariable analysis, male sex, younger age, and use of FBTs three or more times per day were independently associated with high-dose FBT. According to the risk scoring model, the patients with a final FBT of 400 μg or higher were significantly more in the high tolerance group (17%) compared to the low tolerance group (3%; p = 0.023).
According to the dose relationship between the final FBT dose and the clinical features, three factors (sex, age, daily use of FBT) were independently associated with the final dose of FBT. Our risk score model could help predict tolerance to high-dose FBT and guide the titration plan for BTcP.
Background
Immune checkpoint inhibitors (ICIs) have shown significant improvements in patients with advanced non–small cell lung cancer (NSCLC). One of the major issues with ICIs is determining the ...optimal treatment duration.
Methods
This multicenter, retrospective study analyzed clinical outcomes in patients with NSCLC who completed 2 years of ICI therapy or were treated for more than 6 months and then discontinued ICIs without disease progression at 11 medical centers in Korea between August 2017 and December 2020.
Results
Ninety‐six patients who completed 2 years of ICIs were reviewed. The median durations of treatment and follow‐up were 24.0 and 33.9 months, respectively. The objective response rate (ORR) was 85.4%. The median progression‐free survival (PFS) and overall survival (OS) periods were not reached. After completion, the PFS and OS rates were 81.1% and 96.4%, respectively, at 12 months. Forty‐three patients were identified who discontinued ICIs without disease progression: 26 (60.5%) for adverse events and 17 (39.5%) for other causes. The median durations of treatment and follow‐up were 10.5 and 21.2 months, respectively. The ORR was 90.7%. The median PFS and OS periods were not reached. After discontinuation, the PFS and OS rates were 71.0% and 90.0%, respectively, at 12 months.
Conclusions
A significantly high proportion of patients who completed 2 years of ICI therapy continued to experience long‐term PFS. Even if ICIs are discontinued after 6 months in patients without disease progression, they may achieve a durable response and facilitate long‐term survival.
Lay Summary
The optimal treatment duration for immune checkpoint inhibitors (ICIs) remains to be determined.
This study reports the long‐term outcomes of patients with non–small cell lung cancer who completed 2 years of ICI therapy or achieved a durable response after the discontinuation of ICIs without disease progression in real‐world practice.
A significantly high proportion of patients who completed 2 years of ICIs continued to experience long‐term progression‐free survival.
In addition, even if ICIs are discontinued after 6 months in patients without disease progression, they may achieve a durable response and facilitate long‐term survival.
A significantly high proportion of patients who complete 2 years of immune checkpoint inhibitors (ICIs) continue to experience long‐term progression‐free survival. Even if ICIs are discontinued after 6 months in patients without disease progression, they may achieve a durable response and facilitate long‐term survival.
Purpose ROS1 rearrangement is a distinct molecular subset of non-small-cell lung cancer (NSCLC). We investigated the efficacy and safety of ceritinib in patients with ROS1-rearranged NSCLC. Patients ...and Methods We enrolled 32 patients with advanced NSCLC who tested positive for ROS1 rearrangement by fluorescent in situ hybridization. Ceritinib 750 mg was administered once daily. The primary end point was objective response rate. The secondary end points were disease control rate; duration of response; progression-free survival; overall survival; toxicity; and concordance among fluorescent in situ hybridization, immunohistochemistry, and next-generation sequencing. Results Between June 7, 2013, and February 1, 2016, 404 patients underwent ROS1 prescreening, and 32 patients with ROS1 rearrangement were enrolled. All patients except two were crizotinib-naïve. At the time of data cutoff, the median follow-up was 14.0 months, and 18 patients (56%) had discontinued treatment. Of the 32 patients enrolled, 28 were evaluable for response by independent radiologic review. Objective response rate was 62% (95% CI, 45% to 77%), with one complete response and 19 partial responses; duration of response was 21.0 months (95% CI, 17 to 25 months); and disease control rate was 81% (95% CI, 65% to 91%). The median progression-free survival was 9.3 months (95% CI, 0 to 22 months) for all patients and 19.3 months (95% CI, 1 to 37 months) for crizotinib-naïve patients. The median overall survival was 24 months (95% CI, 5 to 43 months). Of the eight patients with brain metastases, intracranial disease control was reported in five (63%; 95% CI, 31% to 86%). The most common adverse events (majority, grade 1 or 2) for all treated patients were diarrhea (78%), nausea (59%), and anorexia (56%). Conclusion Ceritinib demonstrated potent clinical activity in patients with ROS1-rearranged NSCLC who were heavily treated previously with multiple lines of chemotherapy.
By investigating treatment patterns and outcomes in locally advanced head and neck squamous cell carcinoma (LA-HNSCC), we aimed at providing valuable insights into the optimal therapeutic strategy ...for physicians in real-world practice.
This is a multi-institutional study enrolled the patients with stage III to IVB LA-HNSCC, except for nasopharyngeal carcinoma, from 2004 to 2015 in thirteen referral hospitals capable of multidisciplinary care.
A total of 445 LA-HNSCC patients were analyzed. The median age was 61 years (range, 24-89). The primary tumor location was the oropharynx in 191 (43%), oral cavity in 106 (24%), hypopharynx in 64 (14%), larynx in 57 (13%) and other sites in 27 (6%). The most common stage was T2 in 172 (39%), and N2 in 245 (55%). Based on treatment intents, 229 (52%) of the patients received definitive concurrent chemoradiotherapy (CCRT) and 187 (42%) underwent surgery. Approximately 158 (36%) of the study population received induction chemotherapy (IC). Taken together, 385 (87%) of the patients underwent combined therapeutic modalities. The regimen for definitive CCRT was weekly cisplatin in 58%, 3-weekly cisplatin in 28% and cetuximab in 3%. The preferred regimen for IC was docetaxel with cisplatin in 49%, and docetaxel, cisplatin plus fluorouracil in 27%. With a median follow-up of 39 months, one-year and two-year survival rates were 89 and 80%, respectively. Overall survival was not significantly different between CCRT and surgery group (p = 0.620).
In patients with LA-HNSCC, the majority of patients received combined therapeutic modalities. Definitive CCRT, IC then definitive CCRT, and surgery followed by adjuvant CCRT or radiotherapy are the preferred multidisciplinary strategies in real-world practice.
Background
The objective of the current study was to investigate the clinical activity of, safety of, and predictive biomarkers for afatinib, an irreversible pan‐ErbB kinase inhibitor, in patients ...with recurrent and/or metastatic esophageal squamous cell carcinoma (R/M‐ESCC).
Methods
Patients with R/M‐ESCC that was refractory to platinum‐based chemotherapy were enrolled in the current multicenter, single‐arm, phase 2 study and received afatinib at a dose of 40 mg/day. The primary endpoint was the objective response rate. Secondary endpoints included progression‐free survival, overall survival, the disease control rate, and the safety profile. To identify predictive biomarkers, single‐nucleotide variations, short insertions/deletions, and somatic copy number alterations were assessed using whole‐exome sequencing and their associations with clinical outcomes were analyzed.
Results
Among 49 enrolled patients, the objective response rate and disease control rate were 14.3% and 73.3%, respectively. With a median follow‐up of 6.6 months, the median progression‐free survival and overall survival were 3.4 months and 6.3 months, respectively. Treatment‐related adverse events were noted to have occurred in 33 patients (67.3%), with the majority being of grade 1 to 2 (adverse events were graded and recorded based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03). Whole‐exome sequencing demonstrated that the ESCC genomes of patients who demonstrated a response to afatinib were enriched with genomic alterations of TP53 and epidermal growth factor receptor (EGFR). As a predictive marker, a score derived from TP53 disruptive mutations and EGFR amplifications and/or missense mutations demonstrated a significant association with the response to afatinib. The score based on the mutational status of EGFR and TP53 achieved a performance of an area under the curve of 0.86 in predicting the sensitivity of afatinib.
Conclusions
The results of the current study demonstrated that afatinib can confer modest clinical benefits with manageable toxicity in patients with platinum‐resistant R/M‐ESCC. Identification of TP53 alterations and EGFR amplifications may serve as predictive markers with which to identify patients with R/M‐ESCC who may benefit from afatinib.
Lay Summary
Esophageal squamous cell carcinoma (ESCC) is a type of cancer with a dismal prognosis and very limited treatment options.
The clinical efficacy of afatinib was evaluated in patients with recurrent and/or metastatic ESCC, with adverse events demonstrating the modest efficacy with manageable toxicity of this irreversible, pan‐ErbB kinase inhibitor. Whole‐exome sequencing analysis of 41 cases of ESCC further revealed that the patients harboring epidermal growth factor receptor (EGFR) amplifications and disruptive TP53 mutations are more likely to benefit from treatment with afatinib.
The results of the current study have highlighted the clinical value of EGFR and TP53 as predictive biomarkers of platinum‐resistant recurrent and/or metastatic ESCC for afatinib sensitivity.
Patients with recurrent and/or metastatic esophageal squamous cell carcinoma have a dismal prognosis with very limited treatment options. The results of the current phase 2 trial demonstrate that afatinib has modest efficacy and manageable toxicity, but the exploratory analyses using whole‐exome sequencing indicate that EGFR amplification and TP53 disruption might serve as predictive biomarkers for treatment with afatinib.
Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor (TKI). Durvalumab is an anti–programmed death ligand 1 monoclonal antibody. The phase III open-label CAURAL trial (NCT02454933) ...investigated osimertinib plus durvalumab versus osimertinib monotherapy in patients with EGFR-TKI sensitizing and EGFR T790M mutation–positive advanced NSCLC and disease progression after EGFR-TKI therapy.
Patients were randomly assigned 1:1 to receive orally administered osimertinib (80 mg once daily) with or without durvalumab (10 mg/kg administered intravenously every 2 weeks) until progression. Treatment could continue beyond progression, providing clinical benefit continued (judged by the investigator). The amended primary objective was to assess the safety and tolerability of osimertinib plus durvalumab; efficacy was an exploratory objective.
CAURAL recruitment was terminated early because of increased incidence of interstitial lung disease–like events in the osimertinib plus durvalumab arm from the separate phase Ib TATTON trial (NCT02143466). At termination of CAURAL recruitment, 15 patients had been randomly assigned to treatment with osimertinib and 14 to treatment with osimertinib plus durvalumab. The most common AEs were diarrhea (53% grade ≥3 in 6% of patients) in the osimertinib arm and rash (67% grade ≥3 in 0 patients) in the combination arm. One patient who had been randomized to the combination arm reported grade 2 interstitial lung disease while receiving osimertinib monotherapy (after discontinuing durvalumab therapy after one dose). The objective response rates were 80% in the osimertinib arm and 64% in the combination arm.
Limited patient numbers preclude formal safety and efficacy comparisons between the two treatment arms. The combination of programmed cell death 1/programmed death ligand 1 inhibitors and EGFR-TKIs as therapy for NSCLC is not well understood, but it requires a careful approach if considered in the future.
•Predictive biomarkers are needed to optimize the use of ICI in R/M HNSCC.•Genetic alterations in PIK3CA or cell cycle pathways did not affect the efficacy of durvalumab.•NLR and PLR might be ...promising biomarker for personalized ICI therapy in HNSCC.
This study aimed to investigate whether genetic alterations in PI3KCA and the cell cycle pathways influence the efficacy of durvalumab, an immune checkpoint inhibitor, in patients with head and neck squamous cell carcinoma (HNSCC) who had previously failed platinum-based treatment.
We obtained data from a phase II umbrella trial of patients with HNSCC who failed platinum-based treatment (TRIUMPH, NCT03292250). Patients receiving durvalumab treatment comprised those with PIK3CA alterations (Group A), those with cell cycle pathway alterations such as CDKN2A (Group B), and those with no druggable genetic alterations (Group C). We analyzed the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) in each group and evaluated the potential predictive factors for durvalumab.
We analyzed the data of 87 patients: 18, 12, and 57 in groups A, B, and C, respectively. The ORRs were 27.8 %, 8.3 %, and 15.8 % in Groups A, B, and C, respectively (P = 0.329), and the median PFS for each group was 2.3, 1.6, and 1.7 months, respectively, with no significant differences between the groups (P = 0.24). Notably, patients with lower neutrophil–lymphocyte ratio (NLR) (≤5.8) had longer PFS (median, 2.8 vs 1.6 months, P < 0.001), while those with lower platelet-lymphocyte ratio (PLR) (≤491.2) exhibited longer PFS (median, 1.8 vs 1.2 months, P < 0.001).
Durvalumab’s efficacy was similar, irrespective of the presence of PIK3CA or cell cycle pathway genetic alterations in patients with platinum-resistant HNSCC. The NLR and PLR may be promising predictive biomarkers.
Background
Polypharmacy is an important issue in the care of older patients with cancer, as it increases the risk of unfavorable outcomes. We estimated the prevalence of polypharmacy, potentially ...inappropriate medication (PIM) use, and drug–drug interactions (DDIs) in older patients with cancer in Korea and their associations with clinical outcomes.
Subjects, Materials, and Methods
This was a secondary analysis of a prospective observational study of geriatric patients with cancer undergoing first‐line palliative chemotherapy. Eligible patients were older adults (≥70 years) with histologically diagnosed solid cancer who were candidates for first‐line palliative chemotherapy. All patients enrolled in this study received a geriatric assessment (GA) at baseline. We reviewed the daily medications taken by patients at the time of GA before starting chemotherapy. PIMs were assessed according to the 2015 Beers criteria, and DDIs were assessed by a clinical pharmacist using Lexi‐comp Drug Interactions. We evaluated the association between polypharmacy and clinical outcomes including treatment‐related toxicity, and hospitalization using logistic regression and Cox regression analyses.
Results
In total, 301 patients (median age 75 years; range, 70–93) were enrolled; the most common cancer types were colorectal cancer (28.9%) and lung cancer (24.6%). Mean number of daily medications was 4.7 (±3.1; range, 0–14). The prevalence of polypharmacy (≥5 medications) was 45.2% and that of excessive polypharmacy (≥10 medications) was 8.6%. PIM use was detected in 137 (45.5%) patients. Clinically significant DDIs were detected in 92 (30.6%) patients. Polypharmacy was significantly associated with hospitalization or emergency room (ER) visits (odds ratio: 1.73 1.18–2.55, p < .01). Neither polypharmacy nor PIM use showed association with treatment‐related toxicity.
Conclusion
Polypharmacy, PIM use, and potential major DDIs were prevalent in Korean geriatric patients with cancer. Polypharmacy was associated with a higher risk of hospitalization or ER visits during the chemotherapy period.
Implications for Practice
This study, which included 301 older Korean patients with cancer, highlights the increased prevalence of polypharmacy in this population planning to receive palliative chemotherapy. The prevalence of polypharmacy and excessive polypharmacy was 45.2% and 8.6%, respectively. The prescription of potentially inappropriate medications (PIMs) was detected in 45.5% and clinically significant drug–drug interaction in 30.6% of patients. Given the association of polypharmacy with increased hospitalization or emergency room visits, this study points to the need for increased awareness and intervention to minimize polypharmacy in the geriatric cancer population undergoing chemotherapy. Moreover, specific criteria for establishing PIMs should be adopted for the treatment of older adults with cancer.
There is limited information on polypharmacy in Asian older adults with metastatic cancer, especially for those undergoing palliative chemotherapy. This article reports on the prevalence of polypharmacy, potentially inappropriate medication use, and potential drug‐drug interactions in older patients with cancer in Korea.
Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) given EGFR tyrosine kinase inhibitors (TKIs) inevitably become resistant to first-generation or second-generation drugs. We assessed the ...safety, tolerability, pharmacokinetics, and activity of lazertinib—an irreversible, third-generation, mutant-selective, EGFR TKI—in patients with advanced NSCLC progressing after EGFR TKI therapy.
This first-in-human, open-label, multicentre, phase 1–2 study had three parts: dose escalation, dose expansion, and dose extension; here, we report results on dose escalation and dose expansion. The study was done in 14 hospitals in Korea. Eligible patients were aged 20 years or older and had advanced NSCLC harbouring an activating EGFR mutation and progressing after first-generation or second-generation EGFR TKI treatment, a defined tumour T790M mutation status, an Eastern Cooperative Oncology Group performance status of 0–1, at least one measurable extracranial lesion, defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and adequate organ function. Patients were enrolled to seven dose-escalation cohorts according to a rolling six design; five cohorts were expanded. Patients were given oral lazertinib 20 mg, 40 mg, 80 mg, 120 mg, 160 mg, 240 mg, or 320 mg once daily continuously in 21-day cycles. Primary endpoints were safety and tolerability and secondary endpoints included objective response in evaluable patients. This study is registered with ClinicalTrials.gov, NCT03046992, and the phase 2 extension study is ongoing.
Between Feb 15, 2017, and May 28, 2018, 127 patients were enrolled into the dose escalation group (n=38) and dose expansion group (n=89). No dose-limiting toxicities occurred. There was no dose-dependent increase in adverse events. The most commonly reported adverse events were grade 1–2 rash or acne (in 38 30% of 127 patients) and pruritus (in 34 27%). Grade 3 or grade 4 adverse events occurred in 20 (16%) patients, with the most common being grade 3 pneumonia (four 3%). Treatment-related grade 3 or 4 adverse events occurred in four (3%) patients; treatment-related serious adverse events were reported in six patients (5%). There were no adverse events with an outcome of death and no treatment-related deaths. The proportion of patients achieving an objective response by independent central review assessment was 69 (54%; 95% CI 46–63) of 127.
Lazertinib had a tolerable safety profile and showed promosing clinical activity in patients with NSCLC progressing on or after EGFR TKI therapy. Our findings provide a rationale for further clinical investigations.
Yuhan Corporation.
PDF
