bluuebunny/crossref_metadata_2025 huggingface dataset:
Atezolizumab in first-line treatment of metastatic nonsquamous non-small cell lung cancer in the real-world setting.
Authors: De Castro Javier , Campos Balea Begoña , Perez Parente Diego , Polito Letizia , Lawrance Marcus , Ruiz Gracia Pedro , Adler Leah , Marina Arroyo Marta , Socinski Mark A.
Published: June 2021

e21112

Background: The phase III IMpower150 study showed efficacy benefits with atezolizumab in combination with bevacizumab, carboplatin and paclitaxel (ABCP; arm B) as first-line (1L) treatment for patients (pts) with metastatic non-squamous (nsq) NSCLC. The FDA approved this regimen for these pts (with no EGFR or ALK mutations [WT]) on December 2018. However, to date there is limited evidence on its use in real life. This study aimed to explore the use of ABCP in the real-world setting and to describe the characteristics of early adopters (those who received ABCP in 1L). Methods: Data were extracted from the Flatiron Health database (US population). Pts with advanced stage IIIB/IV nsq NSCLC at diagnosis receiving ABCP regimen in any line were eligible for the study. Finally, early adopters were selected. Results: A total of 67 pts received the ABCP regimen in 1L. Baseline characteristics for these pts and comparisons with the IMpower150 population are summarized in Table. Real-world (rw) response in the WT group ( n = 49; 6 pts were excluded due to EGFR mutations and 12 because minimum follow-up was not reached) was similar to that of the IMpower150 series (rwRR: 55.1% [40.2-69.3] vs. 63.5% [58.2-68.5]), despite the WT population being older with a higher proportion of ECOG PS = 1. In patients who would have met the IMpower150 inclusion criteria ( n = 24), rwRR was 70.8% (48.9-87.4). Conclusions: The ABCP regimen has been adopted in the real-world setting. In terms of efficacy, response rates and current PFS data were in line with trial results, despite the population being unselected and having a worse clinical profile. Longer follow-up is required for rwOS data. vs. arm B IMpower150 results.[Table: see text]
Factors on survival for patients of EGFR mutation advanced lung adenocarcinoma with EGFR-TKIs combined with radiotherapy: Real-world data from single center.
Authors: Wang Yuxiang , Yu Wenjian , Shi Jian , Jiang Nan , Wang Zhoufan , Yang Jie , Jia Zhongfei , Song Meng
Published: June 2021

e21126

Background: The aim was to retrospectively evaluate survival and prognostic factors for patients of advanced lung adenocarcinoma with EGFR mutation by a real world data. Methods: From Jan, 2015 to Dec, 2020, lung adenocarcinoma with EGFR positive mutation, advanced (clinical stage III-IV), without surgery, received EGFR-TKIs and radiotherapy (RT) were enrolled. OS and PFS were calculated. Results: 238 patients were included, 101 in males and 137 in females; the median ages was 61. The RT was performed at the time of no-PD in 71 and PD in 167 cases. The median dose of RT was 50 Gy. The rate of acute AE during RT was 36.1% in grade 1-2 and 4.8% in grade 3-4. The follow-up ended at 30, Dec, 2020. The 1-, 2-, 3-years OS,PFS1and PFS2 were 84.4%,59.7%, 38.7%, 52.0%,29.4%, 16.3%, 86.6%, 64.6%, 45.6%. mOS, mPFS1and mPFS2 were 30.3, 14.1, 33.6 months, respectively. Multivariate analysis showed the independent factors for OS were ages (median were 34.0 and 24.9 months for ≤65 and > 65) and clinical stage (median were 22.8, 34.8 and 27.4 months for stage III (33), IVA (84) and IVB (121 cases), respectively), chemotherapy (CT) (median were 27.4, 28.1, 32.5, 44.3 months for TKIs alone(120), TKIs concurrent CT (43), TKIs sequential CT (32), CT sequential TKIs (43 cases), respectively) and total response (the medians were 32.5, 27.2, 33.3 months for CR(7)+PR(107), SD(70) and PD(54 cases), respectively); Independent factors: PFS1 was the time of RT at no-PD and PD (the median were 17.8 and13.2 months), chemotherapy, (the median were 16.1, 12.1, 11.0, 13.5 for TKIs alone, TKIs concurrent CT, TKIs sequential CT, CT sequential TKIs), and total response (the medians were 18.8, 11.7, 10.9 months for CR+PR, SD and PD); PFS2 was the total response (the medians were 58.3, 21.6, 20.9 months for CR+PR, SD and PD, respectively). Univariate analysis also showed doses of RT (the median was 12.3 months for < 50 Gy and 15.5 months for ≥ 50 Gy, p = 0.018) was associated with PFS1, the first-line drugs of TKIs (the median were 39.1, 35.0, 25.6 and 38.6 months for Gefitinib (89), Icotinib (109), Erlotinib (29) and others (11 cases), respectively, p = 0.044) and chemotherapy (the medians were 45.6, 30.6, 18.7, 41.4 months for TKIs alone, TKIs concurrent CT, TKIs sequential CT, CT sequential TKIs, respectively, p = 0.007) were related with PFS2; but the type of EGFR mutation (94 in 19 exon, 118 in 21 exon and 26 cases in others) was not related with survival. Conclusions: EGFR-TKIs combined RT was tolerable and efficient for patients of advanced lung adenocarcinoma with EGFR mutation. TKIs add RT at the time of no-PD could improve PFS1. CT sequential TKIs was probably in favour of OS, even PFS. The better total response (CR+PR) was associated with longer OS, PFS1 and PFS2. But the result need to be proved furtherly.
Efficacy and safety of anlotinib in the treatment of lung cancer.
Authors: Zhou Xinliang , Dou Yan , Jiang Da
Published: June 2021

e21129

Background: Anlotinib was approved by the National Medical Products Administration (NMPA) on 5/8/18 and 8/30/19 for the third-line treatment of patients with advanced NSCLC and SCLC. But in the real world, Anlotinib is also used in the second-line treatment of lung cancer. This study aims to evaluate the efficacy of using Anlotinib in the second-line or further treatment of lung cancer in the real-world. Methods: We conducted a retrospective case-control study of NSCLC/SCLC patients at our center from 1/1/19 to 6/30/20. Patient demographic, clinicopathologic, therapeutic and outcomes data were collected. Kaplan-Meier curve and Cox proportional hazards were utilized. Results: Of 167 patients were enrolled in this study, 106 were in Anlotinib group and 61 were in chemotherapy group. The analysis found that pathological types, ECOG PS, and therapeutic were independent factors affecting PFS and OS in lung cancer patients (P < 0.05- can be a specific value). There was a significant difference in DCR between the anlotinib group and chemotherapy group(P < 0.05), and the anlotinib group was better than chemotherapy group in mPFS (4.1 vs 3.1 months, P = 0.001) and mOS (7.682 vs 6,386 months, P = 0.011). Among the second-line treatment patients, ORR, DCR and PFS were no difference between Anlotinib group and chemotherapy group (P > 0.05). The Anlotinib group was significantly better than Chemotherapy group in mOS (10.083vs6.737 months, P = 0.026). In third-line and further treatment patients, therapeutic and ECOG PS were independent factors of PFS and OS (P < 0.05), and pathological type was an independent factor of OS (P < 0.001). There was a significant difference in DCR between anlotinib group and chemotherapy group (P = 0.011). The mPFS (3.8vs2.5 months, P < 0.001) and mOS (7.407vs5.412 months, P = 0.023) are significantly better than chemotherapy group. In terms of adverse events, the incidence of hypertension (32.80%vs9.84%) and hand-foot syndrome (28.30%vs14.75%) in anlotinib group was higher than that in chemotherapy group, but the incidence of leukopenia (4.72%vs37.7) %), fatigue (14.15%vs34.42%), anorexia (16.04%vs39.34%) and other adverse events was lower than chemotherapy group, and the incidence of III-IV adverse events is low. Conclusions: Compared with using chemotherapy alone, the second-line and further treatment of Anlotinib can significantly elevate the survival of lung cancer patients, and the safety and tolerability are better.
Performance status and activity level of lung cancer patients using wearable devices as passive monitoring: A scoping review.
Authors: Ponce Aix Santiago , Crama Leonardo , Núñez-Benjumea Francisco J. , Sánchez Sergio , Cervera-Torres Sergio , López Mar , Arnáiz Pablo , Fernández-Luque Luis
Published: June 2021

e21141

Background: Lung Cancer (LC) and particularly non-small cell lung cancer (NSCLC) is considered one of the most lethal types of cancer to date. Suitability and toxicity of treatment, or eligibility of LC patients for clinical trials usually rely on subjective indicators of Performance Status (PS) such as the Eastern Cooperative Oncology Group (ECOG) and Karnofsky indexes. In recent years, however, the use of electronic wearable devices has increasingly come to the fore with the aim of increasing objectivity of PS assessments. These devices are capable of objectively and passively monitor health-related outcomes such as daily physical activity and sleep patterns. Consequently, a comprehensive review of the current state of the art in this matter can provide further insights for future research within oncology areas in general, and lung cancer, in particular. The main goal of this scoping review is to identify and categorize scientific publications that, over the past 10 years, used wearable devices as means of monitoring activity level of LC patients. Methods: The study follows the PRISMA-ScR framework (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews). Results: A total of 32 studies were identified as suitable to be included in the review where (n = 22; 68.7%) focused on physical activity and (n = 10; 31%) in sleep or circadian patterns. Approximately half of the studies used a wrist wearable. Device output included step counts, activity counts, metabolic equivalents, time active, time spent in moderate-to-vigorous activity, sedentary time, sleep duration, sleep efficiency, total sleep time/sleep duration, sleep onset latency, wake times, and wrist movement per minute. However, step counts arose as one of the most representative outcomes of physical activity (n = 17; 53%). In general, higher levels of physical activity and circadian organization (day/night activity balance) as measured by actigraphy, are associated with less fatigue, pain, and better quality of life. Conclusions: This review shows that wearable devices, and especially wrist wearables, are increasingly used in oncology settings as a reliable method to monitor physical and sleep activity and to complement PS assessment. Further research is needed, however, to determine the extent to which this methodology can be used to more directly objectivize current PS assessment itself.
Predictors of response in EGFR-mutant metastatic non-small cell lung cancer patients treated with tyrosine kinase inhibitors.
Authors: Aydiner Adnan , Dogan Izzet , Khanmammadov Nijat , Saip Pinar , Vatansever Sezai
Published: June 2021

e21149

Background: EGFR mutations are detected in 15-62% of patients with non-small cell (NSCLC) lung cancer. We can use tyrosine kinase inhibitors (such as erlotinib, gefitinib, afatinib) to treat patients with EGFR-mutant lung cancer. Tyrosine kinase inhibitors improve the survival outcomes of the patients. This study aimed to assess predictors of overall response rate (complete or partial response) in EGFR-mutant non-small cell lung cancer patients treated with EGFR inhibitors. Methods: Data of the EGFR-mutant lung cancer patients were evaluated retrospectively. Clinical, pathological, radiological, and treatment features of the patients were recorded. SPSS 25 version was used for statistical analysis. Kaplan-Meier and Cox-regression methods were used for survival analysis. Also, predictors of overall response were evaluated with logistic regression analysis. Results: 105 patients were included in the study. The female/male patients ratio was 1.25, and the median age was 61 (range, 33-85) years. Adenocarcinoma (90.4%) was the most common histopathological type. The ratios of Exon 19, exon 21, and other (rare or multiple) mutations were 59%, 25%, and 16%, respectively. 89 (84.9%) patients were de-novo metastatic at diagnosis. Before EGFR inhibitor therapy, the patients had received chemotherapy (22.9%) and palliative radiotherapy (40%). The patients received erlotinib (83.8%) or other EGFR inhibitors (16.2%) for treatment. Median overall survival was 30.8 (range 20.2-41.4) months. Overall response rate (complete or partial response) was 61.9%, stable response 11.4%, and progressive disease 26.7%. In logistic regression analysis, we found that age (p = 0.008), number of metastasis sites (p = 0.037), pathological type (adenocarcinoma or other types) (p = 0.001) were statistically significant for the overall response rate. However, gender (p = 0.98), tumor localizations (left or right lung) (p = 0.39), de-novo metastasis (p = 0.81), EGFR mutations type (p = 0.13), and type of EGFR inhibitör (p = 0.30) were not statistically significant. Conclusions: In this study, we showed real-life outcomes of the patients with EGFR-mutant metastatic non-small cell lung cancer. The data of predictors of overall response for EGFR inhibitors is limited. We detected that age, the number of metastatic organs, and histopathological type of tumor were affected the response of treatment.
PD-1/PD-L1 inhibitors plus chemotherapy versus bevacizumab plus chemotherapy as first-line treatment for advanced nonsquamous non-small cell lung cancer: A Bayesian network meta-analysis of randomized controlled trials.
Authors: Zhang Zhibo , Zhai Jinzhao , Yan Xiang , Zhang Fan , Li Xiaoyan , Zhang Sujie , Yuan Fang , Mu Shuai , Zhi Xiaoyu , Ge Xiangwei , Lu Di , Hu Yi , Wang Jinliang
Published: June 2021

e21152

Background: Chemotherapy in combination with PD-1/PD-L1 inhibitor or bevacizumab have demonstrated superior efficacy to chemotherapy in the first-line treatment for non-squamous non-small-cell lung cancer (NS-NSCLC). However, there has been no randomized study comparing PD-1/PD-L1 inhibitors plus chemotherapy (immune-chemo) with bevacizumab plus chemotherapy (bev-chemo). Thus, we performed this network meta-analysis (NMA) to evaluate the comparative efficacy and safety of immune-chemo and bev-chemo as first-line treatment for NS-NSCLC. Methods: The randomized controlled trials (RCTs) were identified by searching PubMed, Embase, the Cochrane library, and conference abstracts until Oct 2020. Bayesian NMA with fixed effect consistency model was applied to estimate hazard ratio (HR) and Odds ratio (OR) with their 95% confidence intervals (CIs). The outcomes included progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and grade ≥3 treatment-related adverse events (TRAEs). Results: 15 RCTs involving 6541 advanced NS-NSCLC patients were eligible for analysis. For OS, immune-chemo (HR 0.70, 95% CI 0.64-0.79) and bev-chemo (0.87, 0.79-0.95) significantly prolonged survival compared with chemotherapy. For PFS, immune-chemo (0.58, 0.53-0.62) and bev-chemo (0.66, 0.61-0.71) were significantly superior to chemotherapy. For ORR, immune-chemo (2.42, 1.93-3.08) and bev-chemo (2.27, 1.75-2.92) were associated with better benefits than chemotherapy. However, immune-chemo (1.61, 1.08-2.35) and bev-chemo (1.83, 1.08-2.90) increased grade ≥3 TRATEs compared with chemotherapy. The results of Bayesian NMAs shown that immune-chemo (PFS: 0.88[0.80-0.97]; OS: 0.81[0.72-0.92]) was associated with better outcomes than bev-chemo, while there were no significant differences in ORR and the risk of grade ≥3 TRATEs (Table). Conclusions: Immune-chemo and bev-chemo are superior to chemotherapy in first-line treatment of NS-NSCLC. Immune-chemo could significantly improve clinical outcomes compared with bev-chemo without higher severe TRAEs. [Table: see text]
Real-world outcomes of patients with advanced non-small cell lung cancer and driver mutations treated with frontline immunotherapy and/or chemotherapy.
Authors: Muthusamy Bharathi , Pennell Nathan A. , Belli Andrew J. , Hansen Eric , Devincenzo Victoria , Shankaranarayana Shubha , He Ming , Wang Ching-Kun
Published: June 2021

e21156

Background: The identification of driver mutations and development of targeted therapies have significantly improved outcomes of patients with advanced non-small cell lung cancer (aNSCLC). It has been shown in clinical trials that immunotherapy (IO) has limited effectiveness in patients with aNSCLC and driver mutations, but as there is a lag in the widespread use of targeted agents for newer driver oncogenes it is important to define the efficacy of non-targeted treatments. We sought to explore the real-world treatment patterns and outcomes of patients with aNSCLC and driver mutations treated with first-line (1L) chemotherapy (chemo) as compared to chemo +/- IO. Methods: This retrospective study utilized the COTA real-world database, a de-identified database derived from the electronic health records of healthcare providers in the United States. Patients included in the study had diagnosed aNSCLC and at least one positive test result for BRAF v600, HER2 mutation, EGFR, MET, RET or ROS1 prior to the initiation of 1L therapy. Additionally, patients must have received frontline chemotherapy, IO monotherapy, or IO+chemo combination in the advanced setting. Outcomes to first-line treatment (real-world progression-free survival (rwPFS) and real-world time to next treatment (rwTTNT)) were calculated using the Kaplan-Meier method. Results: A total of 170 qualified patients were identified as having at least one positive mutation and having received frontline chemotherapy (n=119), IO monotherapy (n=28), or chemo+IO combination (n=23). Mean age was 65 yrs and patients were predominantly white (71.2%), treated in the academic setting (74.1%), and denovo metastatic (67.1%). Outcomes to 1L treatment are reported in Table. Patients treated with 1L chemo+IO combination had longer rwPFS and rwTTNT as compared to patients treated with chemo alone or IO monotherapy, though outcomes did not reach statistical significance. Conclusions: Our study showed that in a real-world population of patients with aNSCLC and driver mutations, patients treated with chemo+IO combination had longer rwPFS and rwTTNT as compared to those treated with chemo alone or IO monotherapy. The overall short duration of benefit supports the model of using targeted treatment as optimal first line therapy, and the overall lack of benefit from IO. [Table: see text]
An investigation on biomarkers of hyperprogressive disease after PD-1/PDL-1 therapies in Chinese non-small cell lung cancer patients.
Authors: Song Qingchun , Han Lei , Mao Yulong , Huang Tanxiao
Published: June 2021

e21173

Background: Immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 antibodies, are becoming standard of care for lung cancer treatment. However, low response rates to ICI antibodies and even hyperprogressive disease (HPD) have limited the clinical application of ICIs. Considering HPD for patients means shorter survival times and worse prognoses, valid biomarkers are in urgent demand to predict the occurrence of HPD and the efficacy of ICI. Here, we explored the genomic biomarkers of HPD in Chinese non-small cell lung cancer (NSCLC) patients. Methods: 749 NSCLC patients with both genomic information and PD-L1 expression data were screened from HapLab database. HaploX 605-gene panel sequencing, covering 1.31 MB genome, was performed to analyze the genomic data of patients. PDL-1 expression was detected by immunochemistry. Results: 15 genes related to HPD were detected altered in NSCLC patients. Collectively, 511 out of 749 patients (68.22%) had at least one alteration of HPD related genes. The frequent alterations were EGFR mutation (46.86%), ALK fusion (7.49%), MDM2 amplification (6.54%), KEAP1 mutation (5.34%), STK11 mutation (4.27%), FGF3/4 amplification (4.14%), DNMT3A mutation (2.14%) and MDM4 amplification (2.00%). While in EGFR wild-type and ALK-negative patients, the top 5 frequent alterations were KEAP1 mutation (8.96%), FGF3/4 amplification (7.00%), STK11 mutation (6.16%), PTEN mutation (5.32%) and MDM2 amplification (4.20%). Notably, EGFR mutation (49.27%, 68/138), ALK fusion (9.42%, 13/138) and MDM2 amplification (4.35%, 6/138) were also observed in PDL-1 positive (TPS≥1%) patients. Conclusions: It is urgent to identify specific biomarkers that could predict HPD and to develop eﬀective methods to prevent HPD. Our study investigated the genomic alterations associated with HPD in Chinese NSCLC patients.
The comparison of mutation-based biomarkers for early-stage and advanced-stage non-small cell lung caner.
Authors: Yao Jie , Zhang Xiuqin , Pan Liangbin , Wang Yuxuan , Chen Ke , Han Jiajun , Mao Guocai , Zhang Biao , Wang Nan , He Yuange , Gu Dejian , Chen Rongrong , Ma Haitao
Published: June 2021

e21176

Background: In recent years, immune checkpoint inhibitors have shown promise in the treatment of advanced-stage non-small cell lung cancer (NSCLC), more and more clinical studies have proved this treatment could also be effective for early-stage NSCLC. It’s confirmed that the count of somatic mutations (SM) and tumor mutation burden (TMB) were related to the effect of immunotherapy for advanced stage tumors but this relationship was not proved in early stage tumors, the inherent difference between early stage and advanced stage cancer is unclear. So we compared the SM count and driver mutation frequency for the ES and AS NSCLC cancer. Methods: We retrospectively analyzed the genetic aberrations in 288 patients of Chinese NSCLC patients. All the patients were detected by hybridization capture-based NGS 1021-gene panel sequencing with tumor tissue and peripheral blood control samples. Results: The genetic alterations in 288 patients with NSCLC were analyzed by defined stage categories, the tumors in clinical stage I-IIIa were classified as early-stage (ES) group and stage IIIb-IV were classified as advanced-stage (AS) group. The results showed that the actionable mutation frequency in driver genes such as EGFR/BRAF/MET/ERBB2/KRAS and structural variations called Fusions in ALK/ROS1/RET/NTRK was different in the two groups but was not statistically significant (Table). The average SM count (9.6 versus 6.25, p=0.0001) and the TMB-high (TMB-H) frequency (3.6% versus 13.2%, p=0.002) was significantly higher in AD group (Table). In other words, the driver mutation frequencies has no significant difference between the ES and AS groups but the AS group showed more somatic mutation count and TMB-H frequency, revealing there were more non-driver mutations in AS tumors. The proved relationship between SM count and TMB and the clinical effect of immunotherapy for advanced-stage patients may inapplicable for early-stage tumors, new biomarkers need to be explored for the immunotherapy of early-stage NSCLC patients. Conclusions: There was no significant variation between the early-stage and advanced-stage patients with driver mutations, but more non-driver mutations in advanced-stage patients. The immunotherapy biomarkers such as somatic mutation count and TMB for advanced-stage tumors could be inapplicable for early-stage tumors. The biomarkers for immunotherapy of early-stage NSCLC patients need further research.[Table: see text]
Effectivness of a shortened cycle of monoimmunotherapy in NSCLC.
Authors: Artemeva Elizaveta , Moiseenko Fedor Vladimirovich , Abduloeva Nuriniso , Volkov Nikita , Egorenkov Vitaly , Zhabina Albina , Artemiev Semen , Moiseyenko Vladimir
Published: June 2021

e21179

Background: Monoimmunotherapy for NSCLC is performed in all patients with a high level of PD-L1 expression ( > 50%) or patients with severe comorbidity and contraindications to therapy with platinum drugs with intermediate level of PD-L1 expression (1-49%).Therapy is carried out up to 2 years, disease progression or intolerable toxicity. An important issue is determining the optimal duration of treatment in order to find a balance between effectiveness, toxicity, cost and burden on the healthcare system. To date, there are no prospective studies with sufficient power devoted to this issue. Methods: The analysis included patients with histologically verified inoperable NSCLC who received the first line of therapy in 2018-2020. 25/230 patients received monoimmunotherapy in the first line (16 men, 9 women; mean age 65.4 years; PD-L1 level > / = 50% - 18 patients (72%), 1-49% - 3/25 ( 12%), 0% - 1/25 (4%), not assessed - 3/25 (12%), adenocarcinoma - 13 (52%), squamous cell - 12 (48%); All patients received pembrolizumab therapy 200 mg 1 once every 21 days. Results: The mean follow-up time was 5.3 months (95% CI 3.4–7.2). The average number of immunotherapy injections (min-max) is 6.4 (1–28). The objective response rate (ORR) in 1 line was 16/23 (64%) (complete regression - 2 patients (8%), partial regression - 3 (12%), stabilization - 11 (44%), progression - 3 (12 %), not assessed - 6 (24%), 2 (8%) patients died after the 1st injection of immunotherapy. Before the progression of the disease or until the end of the planned duration, 16 (64%) of 25 patients interrupted therapy: (10/16 (62%) due to the tightening of the requirements of the epidemiological situation, 6/16 (38%) refused to visit medical institutions. Average follow-up after the end of treatment 7.0 (1.3 - 12.2) months (min-max). 11/16 (68%) are observed without progression 9.3 months (4.0 - 12.1) (min-max PD in 4/16 (25%) after a mean follow-up time of 4.4 months (2.9 - 7.9) (min-max), 1 (6%) patient was lost to follow-up. Conclusions: The obtained data indirectly indicate the absence of a tendency towards a decrease in mPFS and mOS in the group of NSCLC patients who received MIT in the first line of treatment, for whom treatment was discontinued unscheduled, and not continued until 2 years or until the progression of the tumor process was recorded.
Longitudinal sequencing of TCR and circulating tumor DNA revealing radiotherapeutic efficacy and prognosis for non-small cell lung cancer patients with brain metastasis.
Authors: Dong Xiaorong , Chen Lingjuan , Tong Fan , Wei Chunhua , Wang Han , Xia Xuefeng , Xu Yaping , Liu Pian , Liao Zhongxing X. , Zhang Jianjun , Carbone David Paul
Published: June 2021

e21181

Background: This study aimed to explore cerebrospinal fluid (CSF) and peripheral blood-based liquid biopsy before and after radiotherapy of non-small cell lung cancer (NSCLC) brain metastases. Methods: Thirty NSCLC patients with brain metastases receiving brain radiotherapy were enrolled in this study. CSF and peripheral blood were collected at baseline, 24 hours (T0) and 28 days (T28) after treatment. Somatic mutations and T-cell receptor (TCR) sequences were identified by high-throughput sequencing in both compartments. Results: At baseline, identical mutations shared by paired blood and CSF emerged in nine patients (30%). Dimension reduction analysis identified distinct signatures of V and J gene recombination in blood and CSF TCR sequences. Throughout treatment, both compartments experienced a TCR diversity decrease, however, the degradation of low-abundance clones and the expansion of emerging clones might be two separate processes underwent in blood and CSF, respectively. Diversity changes and ctDNA in blood were possibly related to pulmonary responses, while the increase of maximal clone abundance in CSF might indicate a favorable intracranial response. Blood-ctDNA clearance at T28 was significantly associated with better overall survival (OS, HR = 4.027, p = 0.028) and progression-free survival (PFS, HR = 4.176, p = 0.024), and superior blood TCR diversity at T28 against baseline was associated with longer OS (HR = 5.700, p = 0.039). Combined blood factors achieved a better predictive power (OS, HR = 10.53, p < 0.001; PFS, HR = 4.843, p < 0.001). Patients with increase of maximal clone abundance ≥ 50 in CSF also had a better intracranial PFS (HR = 8.320, p = 0.011). The predictive effects of these markers were independent of other clinical factors in multivariate Cox analysis. Conclusions: CSF and peripheral blood were independent compartments showing disparate genomic and immune signatures. Longitudinal surveillance of both compartments could be a promising method to predict clinical outcomes for NSCLC patients with brain metastases.
Long-term real-world outcomes of first-line (1L) pembrolizumab (pembro) monotherapy in PD-L1 ≥50% metastatic NSCLC.
Authors: Velcheti Vamsidhar , Hu Xiaohan , Piperdi Bilal , Yang Lingfeng , Burke Thomas A.
Published: June 2021

e21184

Background: Pembro monotherapy was approved in the US in October 2016 as 1L therapy for patients with metastatic NSCLC and PD-L1 tumor proportion score (TPS) ≥50% based on findings from KEYNOTE-024. With 5-year follow-up in KEYNOTE-024, median overall survival (OS) was 26.3 months (95% CI, 18.3–40.4) in the pembro arm. With 4-year follow-up in KEYNOTE-042, median OS was 20.0 months (15.9–24.2) in the pembro PD-L1 ≥50% subgroup. Our aim was to describe long-term, real-world outcomes with 1L pembro monotherapy for patients treated at US oncology practices with disease characteristics similar to those in the KEYNOTE trials. Methods: Patients initiating 1L pembro monotherapy from December 1, 2016, through November 30, 2017, were selected from the US nationwide Flatiron Health de-identified, electronic health record-derived database if they had stage IV or recurrent metastatic NSCLC with PD-L1 TPS ≥50%, ECOG performance status 0–1, and no known EGFR/ALK/ROS1 aberration (confirmed negative EGFR/ALK for nonsquamous tumors). Enhanced manual chart review was used to determine real-world progression (rwP), tumor response (rwTR), and reasons for pembro discontinuation. OS and real-world progression-free survival (rwPFS) were estimated using the Kaplan-Meier method. Data cutoff was August 31, 2020. Results: Median study follow-up was 38.4 months (range, 33.1–44.9). Of 228 eligible patients, median age was 71 years (range, 46–82); 123 (54%) were women; 156 (68%), 12 (5%), and 60 (26%) had nonsquamous, not otherwise specified, and squamous NSCLC, respectively; and 209 (92%) were current/former smokers. History of brain metastasis was recorded for 17 (7%). Pembro was discontinued by 151 patients (66%), most commonly because of disease progression (70; 46%) and secondarily for toxic effect of therapy (35; 23%); 87 patients (38%) received ≥1 additional lines of therapy. OS, rwPFS, and rwTR results are shown below. Conclusions: In this real-world study with 3-year follow-up, patients with PD-L1 TPS ≥50% metastatic NSCLC without known EGFR/ALK aberrations and good performance status treated with 1L pembro monotherapy experienced median OS of 23 months, similar to the OS observed in phase III pivotal clinical trials, supporting the long-term OS benefits of 1L pembro monotherapy in this patient population.[Table: see text]
Clinical parameters combined with radiomics features to predict the efficacy of immunotherapy for advanced non-small cell lung cancer.
Authors: Zhao Qian , Wang Linlin
Published: June 2021

e21187

Background: Many tools have been developed to predict the efficacy of immunotherapy, such as LIPI, EPSILoN and mLIPI scores. The aim of this study was to determine the ability of to predict outcomes in Chinese aNSCLC patients treated with ICIs.With the development of imaging technology, radiomics has increasingly received a great deal of attention. We use 3D-slicer to delineat the ROI in the patient's CT image, extract a large number of features, and further screen out the radiomics features that have predictive value for the outcome. Methods: We retrospectively enrolled 317 patients with histologically proven aNSCLC (IIIB–IV) treated with ICIs. The discriminative ability of the predictive models was evaluated by AUC in the ROC analysis. Patients were randomly divided into training and validation cohorts using a 2：1 ratio. We used the semi-automatic segmentation method of the 3D-slicer platform to delineate the ROI of the tumor’s lesion area and extract 854 image features for each patient. In the training set of patients, the LASSO algorithm was used to screen the radiomic features.Hosmer-Lemeshow tests (H-L tests) were conducted to determine the fit of the prediction models. PFS and OS curves were generated using the Kaplan-Meier method and differences were assessed using log-rank tests. Univariate and multivariate analyses were performed using Cox proportional-hazards regression models. The glmnet R package was used for the LASSO regression method. The rms, Hmisc R packages used for C-index. Results: Among the 317 patients included in the study, the median OS and PFS were 14.2 months and 5.6 months, respectively and the ORR was 23.1%. The AUC values of LIPI, mLIPI, and EPSILoN scores for predicting PFS were 0.649 (95% CI: 0.588–0.709), 0.765 (95% CI: 0.713–0.818]), and 0.637 (95% CI: 0.567–0.698), respectively (P < 0.001 for all models). The AUC value of mLIPI scores was significantly higher than that of LIPI and EPSILoN scores (P < 0.05). The C-index of mLIPI was 0.645 (95% CI: 0.617-0.673). In this study, 5 radiomics features with predictive value were selected from radiomics features. The C-indexs of the radscore were 0.643 (95% CI: 0.602–0.684) and 0.632 (95% CI: 0.571–0.693). Then we combined mLIPI and radscore to obtain a mixed model. The C-index of the combination mLIPI scores with radscore for predicting PFS was 0.810 (95% CI: 0.770–0.849) and 0.706（CI: 0.633–0.778) in the training and validation cohorts, respectively. Conclusions: By externally validating LIPI, mLIPI, and EPSILoN scores, we found that all three of these predictive models could identify different prognostic subsets of patients treated with ICIs to statistically significant degrees. We also found that mLIPI had the highest accuracy among the three models. With the addition of radiomics features, the prediction performance of the mixed model has been further improved.
Real-world outcomes of toripalimab (JS001) in advanced non-small cell lung cancer: A multicenter retrospective study.
Authors: Ruan Zhihua , Zhu Bo , Wang Yi Na , Liu Baogang , Li Mengxia , Xia Guohao , Dong Xiaorong , Liu Jie
Published: June 2021

e21193

Background: In the past 3 years, immunotherapy has revolutionized the treatment paradigm of advanced non–small cell lung cancer (NSCLC). Checkpoint inhibitors showed promising results in the treatment of patients with advanced NSCLC with improved outcomes in clinical trials, but results from clinical trials can be difficult to generalize to real-world patient populations. Herein, we disclose the data of efficacy profile of toripalimab, a novel humanized IgG-4 mAb against programmed cell death protein 1 (PD-1), for NSCLC in a real-world setting in China. Methods: This retrospective study leveraged electronic health record (EHR) data collected during routine patient care in 8 cancer centers in China. The cohort included patients with mNSCLC who had received toripalimab for metastatic disease (n = 166) with > 1 EHR-documented visit from January, 2019, to June, 2020. Patients (age ≥ 18yrs) with pathologically or histologically diagnosed advanced NSCLC receiving toripalimab treatment were enrolled in this retrospective, multicenter, real-world study. The endpoints included progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR) and duration of response (DOR). Results: Between January 2019 and June 2020, 166 patients from 8 centers were eligible. The median age was 60.6 years, 134(81.7%) male, 123(76.4%) diagnosed as stage IV lung cancer, 69(42.9%) squamous histology, 25 (21.9%) underwent prior surgery and 94 (57%) received prior chemotherapy. Toripalimab was administered as first, second, and further lines of therapy in 45(28.1%), 60(37.5%) and 55(34.4%) patients, respectively. Among them, 28(17.5%) patients received toripalimab as monotherapy. 22(13.8%) received in combination with antiangiogenic agent and 132(82.5%) in combination with chemotherapy. The 164 patients were eligible for efficacy evaluation. The ORR and DCR were 21.3% and 81.7% for all the evaluable patients. The median PFS was 15.0 months (95% CI 10.2 – NA). The median PFS of adenocarcinoma and squamous cell carcinoma were 15.4 months(95% CI 10.2-NA) and 13.4 months(95% CI 10.6-NA), respectively. The PFS in first line and further-line treatment were 15.4 months(95% CI 12.6-15.4) and 13.4 months(95% CI 7.0-NA). Stratified analysis revealed that the PFS of toripalimab monotherapy and combination treatment were 15.0 months(95% CI 12.6-15.0) and 15.4 months(95% CI 8-NA). The PFS were comparable between the patients received with or without anti-angiogenesis agents (11.5m vs 15.4m). Conclusions: Toripalimab monotherapy or in combination with chemotherapy and/or antiangiogenic agent in real world were effective in advanced NSCLC patients.
Thrombotic events in patients treated with immune checkpoint inhibitors for non-small cell lung cancer: A retrospective multicentric cohort study.
Authors: Deschenes-Simard Xavier , Galland Loik , Blais Florence , Desilets Antoine , Malo Julie , Cvetkovic Lena , Belkaid Wiam , Elkrief Arielle , Gagné Andréanne , Hamel Marc-Andre , Orain Michèle , Joubert Philippe , Ghiringhelli François , Routy Bertrand , Blais Normand
Published: June 2021

e21198

Background: Venous thromboembolism is a frequent complication of non-small cell lung cancer (NSCLC) and is associated with a worse prognosis, a reduced quality of life, and increased healthcare costs. Immune checkpoint inhibitors (ICI) are revolutionizing the management of NSCLC, but little is known about their impact on thrombosis. This study aims to define the incidence and clinical relevance of thrombosis in NSCLC patients receiving these treatments. Methods: A retrospective multicentric cohort study including 593 patients from three centers in Canada and France was performed. The cumulative incidence of venous thrombotic events after ICIs was calculated, and the impact of these events on survival and response to treatment was determined. Finally, univariate log-rank tests were performed to identify thrombosis risk factors. Results: The incidence of venous thrombosis in the cohort was 9.9% for an incidence rate of 76.5 thrombosis per 1000 person-years, with most thromboses occurring rapidly after treatment initiation. Thrombosis was not correlated with overall survival, progression-free survival, or objective response to ICIs (summarized in the table below). Age ˂ 65 years old (HR = 1.66; 95 % CI = 1.00 – 2.82) and a delay of less than 12 months from diagnosis to the first ICI treatment (HR = 1.74; 95 % CI = 1.03 – 2.87) were associated with an increased risk of thrombosis. Tumors with PD-L1 > 1% were associated with more thrombosis in the first year since the beginning of therapy (HR = 3.06; 95 % CI = 1.19 – 4.76, p=0.015). Conclusions: This study suggests that the time distribution and incidence of thrombotic events in NSCLC patients treated with ICI are comparable to what is reported in other cohorts of patients treated with chemotherapy. In our cohort, thrombosis was not a prognostic factor for survival or response to therapy. Patient age < 65 and tumors with PD-L1 > 1% were associated to a higher risk of thrombotic events.[Table: see text]
Treatment of advanced mucosal melanoma in the immunotherapy era: A joint institutional case series.
Authors: Gee Abigail , Taylor Hannah , Herbert Christopher , Tillett Tania , Winter Helen
Published: June 2021

e21503

Background: Treatment pathways for malignant melanoma have changed dramatically in recent years, with the advent of immunotherapy. Mucosal melanoma is a rare subtype, representing 1-2% of melanomas in Caucasians, with higher incidence reported in other populations. They commonly present at an advanced stage due to their occult, UV naïve location. Rarity limits adequate trial exposure and the literature offers contradictory data on the benefits of immune checkpoint inhibitor (ICI) therapy in this group. Methods: Patient databases at two specialised treatment centres were searched to identify all patients with mucosal melanoma treated with ICI therapy between 01.10.15 and 30.09.19. All patients were reviewed at the regional multi-disciplinary team meeting. Patient demographics, pathology reports, mutation status, stage at start of treatment and prior treatment modalities were noted. Results: Ten patients were identified with a median age 73 years (range 32-80) and M:F ratio of 4:6. The site of the primary cancer was head and neck in 5 cases, gastrointestinal in 3 cases and genitourinary in 2 cases. All patients were BRAF wild type. C-Kit was wild type in 3 patients tested. The median number of cycles of first line ICI was 5.5 (range 1 – 45). At first radiological assessment 7 patients had progressive disease (PD), 2 patients had stable disease and one patient had a complete response (CR). Two patients progressed to second line therapy with a second ICI. One of these demonstrated a partial response after a further 9 months of treatment and had a progression-free survival (PFS) of 30.1 months on second line treatment. One patient received 3 cycles of dual ICI therapy (ipilimumab/nivolumab) but demonstrated PD after 1.5 months. The longest surviving patient currently has a PFS of 43 months. He achieved a CR after just 3 months of pembrolizumab and completed a total of 18 cycles before switching to surveillance. Conclusions: The joint institutional case series demonstrates a poor response to ICI therapy in the majority of patients, yet as commonly reported, response when it occurs can be remarkable. Recent studies have shown increased overall response rate when anti-vascular endothelial growth factor therapies are added to cytotoxics or ICI. Further investigation of this rare subtype is required to identify predictive biomarkers of response to ICI therapy and other targeted and combination treatments.
Is adjuvant treatment for melanoma in clinical practice comparable to trials? The first population-based results.
Authors: de Meza Melissa Melanie , Ismail Rawa , Blokx Willeke , Blank Christian U. , van den Eertwegh Alfonsus Johannes Maria , Aarts Maureen J.B. , Van Akkooi Alexander Christopher Jonathan , van den Berkmortel Franchette , Boers-Sonderen Marye , Kapiteijn Ellen , de Groot Jan Willem , Haanen John B. A. G. , Hospers Geke , Piersma Djura , Van Rijn Rozemarijn , Van Der Veldt Astrid Aplonia Maria , Vreugdenhil Gerard , Westgeest Hans , Suijkerbuijk Karijn , Wouters Michel W.J.M.
Published: June 2021

e21523

Background: Little is known about the outcome of adjuvant therapy in melanoma patients beyond the clinical trial setting. The Dutch Melanoma treatment Registry (DMTR) is a population-based registry, set up in July 2013 to monitor the safety and quality of melanoma care. Since 2019, adjuvant treated melanoma patients have also been registered in the DMTR, following approval and reimbursement of adjuvant treatment in the Netherlands in December 2018. Methods: Analyses were performed on melanoma patients treated with adjuvant anti-PD1 therapy included in the DMTR between 01-07-2018 and 31-12-2019. Descriptive statistics were used to analyze patient-, and treatment characteristics, and death as well as relapse rates. Results: Six hundred and fifty-seven patients treated with adjuvant systemic therapy were included in the DMTR. The majority (94%) of these patients was treated with anti-PD1. Twenty percent of the anti-PD1-treated patients developed grade ≥3 toxicity. Of the 279 patients with a minimum follow-up of one year after start of anti-PD1, 170 (61%) prematurely discontinued therapy. Relapse and death occurred in respectively, 38% and 12% of patients within one year of follow-up. Relapse was significantly more frequent in older patients, with high Breslow thickness and ulcerated melanomas. Conclusions: These data show more frequent premature discontinuation of adjuvant anti-PD1 in daily clinical practice than reported in the registration trials. Moreover, incidence of severe toxicity, relapse and death during adjuvant treatment appears higher in the real-world setting.
Prognostic pathological and clinical factors associated with overall survival in metastatic melanoma undergoing anti PD-1 treatment.
Authors: Koczka Kim , Rigo Rodrigo , Suo Aleksi , Asad Mohammad , Wang Edwin , Batuyong Eugene , Cheng Tina
Published: June 2021

e21531

Background: Anti-PD-1 immunotherapy has revolutionized metastatic melanoma treatment, as first-line monotherapy or in combination with Ipilimumab. Up to 40% of patients will progress within 3 months, with limited evidence on who derives benefit from immunotherapy. We report clinical and pathological predictive and prognostic factors from a multi-institutional cohort. Methods: Patients between 2014-2017 treated with Nivolumab and Pembrolizumab were identified from a provincial pharmacy database in Alberta, Canada. All patients had unresectable stage III or IV melanoma. Patient characteristics, investigations, treatment and clinical outcomes were obtained from electronic medical records. We utilized Cox regression and Kaplan-Meier methods to analyze progression free survival (PFS) and overall survival (OS). Results: 143 patients with either cutaneous (115) or primary unknown (28) melanoma were identified. Immunotherapy was median second line treatment and patients received a median of 7 doses. The median age was 64, and 144 (80%) were either ECOG 0 or 1 at treatment initiation. The overall response rate was 33%, with median follow up of 25 months. Ulcerated primary tumors had a lower mOS of 30 months vs. 49 months (p=0.042). Other pathologic factors (including Breslow Depth, tumor infiltrating lymphocytes, mitosis) were not associated with PFS or OS. Clinical factors associated with worsened mPFS and mOS were liver metastases, >3 sites of disease, and any visceral disease. Elevated LDH, platelets, neutrophils, and lower hemoglobin, lymphocytes, and a neutrophil/lymphocyte ratio were associated with worse mPFS and mOS. We identified 4 prognostic subgroups using LDH and number of visceral sites (Table) which was statistically significant for mPFS and mOS. Conclusions: Ulcerated primary tumors, liver metastasis, and more sites of disease had worse mPFS and mOS. We also identified 4 novel prognostic subgroups strongly associated with survival outcomes.[Table: see text]
Correlation analysis of gene and immune microenvironment for 87 melanoma cases.
Authors: Qin Lanqun , Ren Yu , Zhao Lianjun , Wu Yirong , Zhao Mengke , Huang Rong , Zou Zhengyun
Published: June 2021

e21555

Background: To map the genome of Chinese melanoma patients and explore its correlation with the expression of tumor immune microenvironmental indicators. Methods: Next generation sequencing was performed on 87 cases of primary melanoma that had been surgically removed from Nanjing Drum Tower Hospital from July 2010 to May 2017. Immunohistochemistry was carried out to detect the expressions of PD1, PDL1, CD3+TIL, MSH2, MSH6, PMS2 and MLH1. Results: BRAF mutations were the most common (26.4%), followed by KIT mutations (12.6%) in melanoma patients. RB1 gene copy number deletion (55%) and CDK4 (25%)/CCND1 (22.5%) gene copy number amplification were also common. The prognosis of patients could be distinguished by grouping the expression of PDL1 and TIL, and the difference may be related to the expression of PD1. There were more copy number amplication of genes with poor prognosis in PDL1-TIL- patients. Conclusions: The classification of tumors into four microenvironmental subtypes based on PDL1 and TIL expression is an appropriate method to stratify patients with different clinical outcomes. At the genetic level, there are more copy number amplification of the genes with poor prognosis in patients with TIL-PDL1- type, so the prognosis is always worse than that of patients with TIL+PDL1+ type. Gene may affect the prognosis of patients by affecting the tumor immune microenvironment.