bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of TGFBR2 mutation as a negative predictor of immunotherapy in NSCLC.
Authors: Li Teng , Wang Han , Xu Jiachen , Li Chengcheng , Zhang Yudong , Wang Guoqiang , Cai Shangli , Junling Li , Wang Zhijie
Published: June 2021

e21002

Abstract Background: Immune adaptive resistance is one of the reasons contributing to the resistance of immune checkpoint inhibitors (ICIs). Previous studies have demonstrated the role of TGFβ-SMAD signaling in the dysfunction of immune response. We hypothesized that transforming growth factor beta receptor 2 (TGFBR2) mutation in non-small cell lung cancer (NSCLC) might be a predictor of immunotherapeutic resistance. Methods: Genomic and transcriptomic data of NSCLC patients from The Cancer Genome Atlas (TCGA) were analyzed by the in silico Pathway Activation Network Decomposition Analysis (iPNADA) to study the association between TGFBR2 mutation and intracellular signaling pathway activation. Clinical and genomic data from public cohorts with patients treated with ICIs including POPLAR/OAK, MSKCC and Van Allen cohorts were obtained and analyzed. An independent China cohort was used to demonstrate the association between TGFBR2 mutation and immunotherapeutic efficacy and we further demonstrated a case with mutated TGFBR2 treated with ICI. Results: TGF-β signaling was decreased and JAK-STAT signaling was increased in patients with mutated TGFBR2 (P < 0.05). The immune checkpoints including CD274, LAG3, TIGHT, CTLA-4, PDCD1 and PDCD1LG2 were significantly increased in patients with mutated TGFRB2 (P < 0.05). The immune dysfunction score tended to be increased in patients with mutated TGFBR2 though no significant difference was observed (P = 0.23). In the POPLAR/OAK cohort, patients with mutated TGFBR2 had shorter progression-free survival (P = 0.004; HR, 2.83; 95% CI, 1.34-6.00) and overall survival (OS) (P = 0.0006; HR, 3.46; 95% CI, 1.63-7.35) than patients with wild-type TGFBR2 when treated with ICIs. While in patients treated with chemotherapy, there was no difference in PFS (P = 0.69; HR, 0.86; 95% CI, 0.41-1.82) and OS (P = 0.61; HR, 1.21; 95% CI, 0.57-2.57) between patients with mutated and wild-type TGFBR2. In the merged MSKCC and Van Allen cohorts, similar result was observed that the OS was shorter in patients with mutated TGFBR2 (P = 0.007; HR, 2.53; 95% CI, 1.25-5.12). At last, we demonstrated a 39-year-old case with TGFBR2 mutation who was treated with 3 mg/kg nivolumab as second-line treatment. The patient progressed after three cycles of nivolumab and the PFS was only 1.3 months. Conclusions: We identified TGFBR2 mutation as a negative predictor for ICIs in NSCLC and the clinical use of ICIs needs to be cautious in those patients, highlighting the importance of genomic profiling in the treatment of ICIs. Combination ICIs and TGF-β signaling inhibitors may overcome the resistance for those patients harboring TGFBR2 mutation and need to be developed in the future.
Why are oncologists not testing all NSCLC patients for biomarkers in the U.S. market?
Authors: Winkelman Daniel F. , Varkhedkar Vaibhav M. , Stellander-Amato Holly , Bailey Lesley , Kachadourian Anise
Published: June 2021

e21003

Background: NSCLC has the greatest number of biomarkers of any tumor type. If a patient is not biomarker tested, he or she may not receive access to targeted therapies that often offer greater efficacy through personalized therapy. The purpose of this research study is to examine the reasons certain lung cancer patients are not tested in the United States for biomarkers. Methods: This study followed market research best practices. The study was based on a survey of the BrandImpact Oncology panel conducted on patient visits during Q4 2020 at the point-of-prescribing. Results: The baseline measure of NSCLC patients that were being treated but had a biomarker status that was unknown ranges from 9% to 12% of patient visits. The biomarkers examined included ALK, ROS-1, EGFR and PD-L1. The Oncologists who treat NSCLC patients received the following question: When treating patients in your practice with NSCLC cancer what are your top 3 reasons for not conducting biomarker testing? As outlined in the table below which reflects all survey responses, the top four reasons for not conducting biomarker testing are: not enough tumor sample for testing purposes, patient has early stage of disease, patient is not healthy enough and patient cost associated with testing. Conclusions: The overall results indicate the absence of biomarker testing for lung cancer patients is mainly due to two different patient types. The early-stage patient was a key reason for not testing despite advances in early stage indications and diagnostic technology which provide increasing evidence that testing should be done earlier in the treatment journey. The late-stage patient which is seen more often in Academic institutions and who often has more aggressive cancer. The speed of receiving the biomarker test results for these more severe patients likely needs to be addressed. In the Community, setting cost of branded therapies can be an issue and in some cases biomarker testing is not readily available in all practices. It should also be noted that “not enough tumor sample for testing” was the number one reason for not conducting biomarker testing, but this issue can now be addressed through liquid NGS technology.[Table: see text]
Effect of PDL1 expression [exp] on overall survival [OS] in patients [pts] with metastatic adenocarcinoma lung [MAC]: Illinois CancerCare [ILCC] analysis.
Authors: Kumar Nikhil , Gomez Patrick Leigh , Harper Jamie
Published: June 2021

e21005

Background: Effect of PDL1 on OS in patients with MAC is controversial. This relationship has not been studied systematically in U.S. midwestern population, a largely homogenous Caucasian group. We examined the effect of PDL1 expression on OS in MAC pts at ILCC, one of the largest practices in U.S. Midwest. Methods: We conducted a retrospective analysis of all MAC pts who presented at ILCC in 2018. PDL1 status was defined as high if PDL1 was ≥50%, low if 1≤50% & -ve if 0≤1%. High and low groups together were called +. Statistical analysis was performed using the log rank Kaplan Meier method. Results: Results were available in 104/125 pts [83%]. 68/104 pts [65%] received anti PDL1 antibodies Nivolumab, Pembrolizumab, Durvalumab, & Atezolizumab. 43/68 pts were PDL1+ and 25/68 were -ve. Median OS of PDL1+ high exp was 10.78 months [m] & of low exp was 9.7 m. There was no statistical difference in OS in these groups [p = 0.984778]. We also evaluated this relationship between all PDL1+ pts [high and low expressers together] and PDL1- ve pts. We did not find any difference between these groups either. Median OS of all PDL1+ was 9.77 m & PDL1 -ve was 6.67 m [p = 0.435038]. Conclusions: Our study suggests that OS of MAC in our pt population is not influenced by PDL1 status. The potential influence of patient ethnic, genetic & molecular biomarker traits on OS needs to be explored further.[Table: see text]
Comprehensive cancer genomics-based screening of new therapeutic targets and biomarkers for lung cancer.
Authors: Daigo Yataro , Takano Atsushi , Nakamura Yusuke
Published: June 2021

e21031

Background: Since the clinical outcome of advanced lung cancer patients is still poor after standard therapies, development of new anti-cancer drugs with minimum risk of adverse effects and cancer biomarkers for precision medicine is urgently required. Methods: We have been screening new therapeutic target molecules and molecular biomarkers for lung cancers as follows; i) To identify overexpressed genes in lung cancers by the gene expression profile analysis, ii) To verify the target genes for their scarce expression in normal tissues, iii) To validate the clinicopathologic importance of their protein expression by tissue microarray covering 263 lung cancers, and iv) To confirm their function for the growth and/or invasive ability of the lung cancer cells by siRNAs and gene transfection assays. Results: We identified dozens of candidate target molecules and selected a gene encoding protein with a GAP domain, LAPG1 (lung cancer-associated protein with Gap domain 1). Immunohistochemical analysis showed that LAPG1 expression was observed in 69.9% of lung cancers. Moreover positivity of LAPG1 expression was associated with poor prognosis of lung cancer patients. Knockdown of LAPG1 expression by siRNAs suppressed growth of lung cancer cells. Introduction of LAPG1 increased the invasive activity of mammalian cells, indicating that LAPG1 could be a prognostic biomarker and therapeutic target for lung cancers. Conclusions: Comprehensive cancer genomics-based screening could be useful for selection of new cancer biomarkers and molecular targets for developing small molecules, antibodies, nucleic acid drugs, and immunotherapies.
Antifungal imidazole: Potential new antineoplastic agent-cytotoxic effects on non-small cell lung cancer cell lines (A549).
Authors: Kahraman Erkan , Goker Erdem
Published: June 2021

e21037

Background: There are many drugs that can be applied to the treatment of lung cancer. These therapeutics include classical chemotherapeutics, targeted drugs against driver mutations, and immunotherapeutics. However, still, new agents are required to better results and patients outcomes. Recently, imidazole and its compounds, a type of antifungal drugs, were found to have antitumor efficacy in several cancer types. Its effects on non-small-cell lung cancer cells are yet known. This study aimed to detect anti-cancer properties of imidazole on non-small-cell lung cancer cells and suitability for clinical usage as an anti-cancer agent. Methods: We used A549 cell lines that are non-small-cell lung cancer cells in this study. A549 cells were treated with imidazole (molecular grade) at 1, 5, 10, 20, 40, 80 mM doses for 24, 48 and 72 hours. Cytotoxicity and IC50 values (the half-maximal inhibitory concentration) were calculated using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) analysis. Colony formation assay was performed to detect the effect of imidazole on cancer cell colony formation ability. The cellular morphological alterations were observed on bright-field microscopy using Giemsa staining. Cellular migration status of A549 cells was defined with in vitro scratch assay up to 48th hour. Results: Cytotoxicity assay results showed that low-level imidazole induced cell proliferation. However, high-level imidazole treatment decreased the cell viability of A549 cells in a dose and time-dependent manner. The IC50 value was calculated as 60 mM, 28 mM, and 15,9 µM doses respectively at 24, 48, 72 hours in A549 cells. Also, we determined that the number of colonies (number of colonies: 42.7 ± 3.06) formed in A549 cell lines treated with imidazole at IC50 dose was statistically less than the colony number of the control group (number of colonies: 70.7 ± 5.13) (p < 0.01). Interestingly, we observed that colony number increased at a low dose (at 5 mM) imidazole treated group, statistically significant (p < 0.05). Cellular morphology was not affected at low doses; however, at the IC50 dose, A549 cells changed their cellular morphology, lost cell-cell contact, decreased cytoplasmic volume, and differentiated from parental morphology. In addition to these effects, we observed that imidazole treated cells decreased their migration capabilities compared with control group cells (p < 0.05). Conclusions: Our results have shown that antifungal imidazole treatment inhibits cancer cell biological responses such as proliferation, colony formation ability, and motility in non-small lung cancer cell lines in a dose and time-dependent manner. These results suggest that imidazole would be the right candidate for the synergy with other therapeutic options such as immunotherapy. This introductory study allows us further studies exploring the synergy and its mechanism.
Does denosumab offer survival benefits? Our experience with denosumab in metastatic non-small cell lung cancer patients treated with immune-checkpoint inhibitors.
Authors: Cao Yenong , Afzal Muhammad Zubair , Shirai Keisuke
Published: June 2021

e21039

Background: Lung cancer is the leading cause of cancer-related death in the United States. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small-cell lung cancer (NSCLC). Denosumab is a humanized monoclonal antibody to RANK ligand used to prevent skeletal-related events of bone metastases in solid tumors. In preclinical and some clinical studies, denosumab have shown to have some anti-tumor properties. We are reporting the clinical outcomes in our NSCLC patients who received RANKL inhibitor in combination with ICIs. Methods: This observational study used retrospective data from a tertiary cancer center from 2015-2020. Stage IV non-small cell lung cancer patients who received denosumab within 30 days of ICIs (pembrolizumab, nivolumab, atezolizumab, ipilimumab) were included. Median overall survival (OS), progression free survival (PFS), best radiographic responses were obtained. Univariate, multivariate analyses and logistic regression analyses were done, and Kaplan-Meier curves were obtained for survival analysis. Results: We identified 69 patients and all had skeletal metastasis, and 37.7% had brain metastases. Median duration of concomitant use of denosumab and ICI was 1.5 months. Median OS was 6.3 months and median PFS was 2.8 months. Overall response rate was 18.8% and disease control rate was 40.6%. Median OS in patients with concomitant denosumab and ICIs more than 3 months was 11.5 months, comparing to 3.6 months in patients with < 3 months of concomitant therapy (P=0.0005). OS and PFS did not differ with respect to brain metastases or number of skeletal metastases. However, the duration of ICIs and denosumab overlap was associated with improved OS and PFS. Among the 18.8% of patients who achieved complete response (CR) and partial response (PR), six-month survival rate was 100% and one-year survival rate was 69.2%. Conclusions: Patients receiving combination therapy did not perform poorly despite of poor prognostic features such as brain metastases and numerous skeletal metastases. Although we did notice potential benefit of the longer duration of concomitant use of ICI and denosumab, future prospective clinical trials are needed to evaluate the synergistic effect of RANKL inhibitors/ICI and if duration of RANKL inhibitors matters.
Myocarditis as a rare, yet serious adverse event associated with immune checkpoint inhibitors in patients with non-small cell lung cancer: Case series from a large community-based cancer center.
Authors: Hendawi Mohamed , Peterson Luke , Tadesse Eyob ale , Wolf Frank M. , Brown Thomas D. , Thompson Michael A.
Published: June 2021

e21047

Background: Patients (pts) with lung cancer and other cancers treated with immune checkpoint inhibitors (ICI) may experience immune related adverse events (irAE). These can present with variable severity and with single- or multi-organ involvement including pneumonitis, colitis, hepatitis, and myocarditis/pericarditis. The incidence of myocarditis has been reported between 0.06% and 2.4% and is associated with a high mortality (25% to 50%). This retrospective review of real-world data (RWD) investigates myocarditis as a high-grade adverse event in pts with lung cancer treated with ICIs. Methods: Pts were identified and characterized using RWD in the Syapse Learning Health Network platform from 2010 to 2020 at Advocate Aurora Health Care. Eligible pts included: ≥18 years old; histologically confirmed NSCLC; and myocarditis diagnosis by ICD codes. Additional chart review was performed to confirm timing of ICI treatment and myocarditis. All pts identification and review were performed after IRB review. Results: 12,686 pts with non-small cell lung cancer were eligible for review. The median age at diagnosis was 70; 54% were female; 86% were White and 12% were Black; 1,975 (15.6%) were treated with an ICI and of those 4 cases (0.2%) of myocarditis were identified. All 4 pts were White females, ages 46, 59, 65, and 74 years. Pathology included lung adenocarcinoma (3) and an undifferentiated lung carcinoma (1). All pts had metastatic disease, and none had a prior history of cardiac disease. ICIs were pembrolizumab (2), durvalumab (1), and nivolumab (1). Median time from initial dose of ICI to diagnosis of myocarditis was 62 days [range: 42-185]. All 4 pts presented with chest pain and elevated troponin T [median 0.07 ng/ml (range: 0.06-0.08)]. All pts had echocardiography at the time of diagnosis, and 2 pts had cardiac MRI that confirmed myocarditis. 3 pts were treated with a prednisone taper. 1 pt died of recurrent congestive heart failure and ventricular tachycardia despite rescue attempt with high dose corticosteroids. 2 pts had additional concomitant irAEs of hypothyroidism/colitis, and thyroiditis/pneumonitis, respectively. Conclusions: Many irAEs are reversible. This RWD analysis confirms that clinically evident myocarditis is a rare but serious adverse event of ICI therapy. Early consideration, diagnosis, and intervention may help prevent poor outcomes. Termination of ICI therapy along with initiation of corticosteroids constitute the current standard of management. Further research is warranted to better identify high risk groups, surveillance measures, and improved management of ICI associated myocarditis.
The relationship between evolving sarcopenia and efficacy of immune checkpoint inhibitor in non-small cell lung cancer patients.
Authors: Makiguchi Tomonori , Tanaka Hisashi , Taima Kageaki , Tatsuo Soichiro , Iida Saya , Kakeda Shingo , Tasaka Sadatomo
Published: June 2021

e21049

Background: Sarcopenia has been receiving attention due to its association with prognoses in patients with cancer. We investigated the association between evolving sarcopenia assessed with computed tomography (CT) and outcome of non-small cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs). Methods: In this retrospective study, 47 NSCLC patients who received ICIs at our Hirosaki University Hospital were enrolled. Skeletal muscle area at the level of the third lumbar vertebra (L3-SMA) was measured from CT images before and 90 days after the ICI treatment. The factor related to the poor efficacy of ICIs was determined by logistic regression analysis. The prognostic cut-off value was estimated by a receiver operating characteristic (ROC) curve. As covariate factors, age, gender, smoking history, histology, performance status (PS), PD-L1 tumor proportion score (TPS), status of driver mutations, body mass index (BMI), serum protein and albumin levels, and lymphocyte count were included. Results: In the univariate analysis, reduction rate of L3-SMA, PS, BMI, serum protein and albumin levels, and lymphocyte count were significantly associated with efficacy. In the multivariate analysis, only reduction rate of L3-SMA was significant. The cut-off value was estimated to be 6%. The study subjects were divided into two groups by the cut-off value. In both of progression free and overall survival analysis, those with more than 6% of reduction had significantly shorter period being free of events than that of the other. Conclusions: Evolving sarcopenia assessed with CT images is promising as a prognostic factor in Japanese NSCLC patients receiving ICIs.
Surrogates of response to treatment of non-small cell lung cancer with immunotherapy: Toxicity and leukocyte ratios—Experience of a center.
Authors: Moratiel Pellitero Alba , Ruiz Moreno Ines , Cruellas Mara , Alonso Marin Natalia , Ocáriz Maitane , Gascon Ruiz Marta , Sesma Goñi Andrea , Zapata-Garcia Maria , Zurera Berjaga Maria , Marti Pi Maria , Goas Gomez Ana , Camacho Fuentes Carlos , Sanchez Cortes Carla , Alvarez Maria , Quilez Elisa , Torres Irene , Lambea- Sorrosal Julio Jose , Isla Dolores , Lastra Rodrigo
Published: June 2021

e21052

Background: Immunotherapy is proposed as a therapeutic novelty in metastatic non-small cell lung cancer (NSCLC), in many cases already in front line. It presents different adverse effects than traditional schemes, due to the stimulation of the immune system. There is a possible relationship between toxicity and response. Neutrophil-to-lymphocyte ratio (NLR) as a possible predictive factor of response. Objectives: Evaluating the response according to the toxicity degree in NSCLC patients in real clinical practice. Analyze whether pretreatment NLR high patients have a worse prognosis. Methods: Observational, retrospective, analytical, single-center study. HCULB stage IV NSCLC patients with inmunotherapy treatment during 2016-2018. Descriptive and multivariate analysis. Toxicity grade: CTCAE version 4.0. Response assessment: RECIST 2.0 and immunorelated criteria. Toxicity degree and response (global and individualized results according to treatment and histology). Neutrophil-to-lymphocyte ratio and response. Results: N = 43 patients (35 men, 8 women). Average age 64 years. Response: 3 complete response (CR) (toxicity ≥2), 13 partial response (PR) (toxicity ≥1), 13 stable disease (SD), 12 progression (P) (only 4 toxicity and ≤2), 2 not evaluated. Hypothyroidism as the most common irAE. Relationship between toxicity and response: the absence of irAEs conditions worse prognosis p < 0.05. Histology: 25 adenocarcinoma [18 with irAES (1 CR, 7 PR, 8 SD,) and 7 without (1 SD, 5 P, 1 no ev.)]; 17 squamous [13 with irAES (1 CR, 6 PR, 4 SD) and 4 without (3 P, 1 no ev.)]; 1 adenosquamous with irAES and CR. Drug: Atezolizumab N = 8 [6 with irAES (2 PR, 3 SD, 1 P) and 2 without (both P)], Nivolumab N = 16 [9 with irAES (1 CR, 3 PR, 3 SD, 2 P) and 7 without (1 SD, 4 P, 2 no ev.)], Pembrolizumab N = 19 [17 with irAEs (2 CR, 8 PR, 6 SD, 1 P) and 2 without (both P)]. Significant positive correlation between toxicity and response (p < 0.001) R = 0.067, (CI 99% 0.378-0.837), regardless of histology and drug. It is observed a better response in those patients who presented a NRL close to 3 or less at the beginning of treatment. On the contrary, it is observed that subjects with NRL greater than 4 obtained worse results when they were treated with immunotherapy. Conclusions: The appearance of irAES like a response indicator of immune system, seem to conditione better evolution. In contrast, the absence of toxicity predicts a worse prognosis. Further studies with a larger sample are needed to confirm our findings about the predictive value of NLR and optimize therapeutic regimens if necessary.
A real-world study of camrelizumab in the treatment of advanced lung cancer patients.
Authors: Gu Kangsheng , Bi Minghong , Zhao Dong , Cheng Huaidong , Wang Genhe , Qian Hong , Min Xuhong , Xia Xiaoyang , Wang Fan , Hu Zhiqiang
Published: June 2021

e21056

Background: Camrelizumab, as a humanized antibody against PD-1, has shown high efficiency and survival benefits in clinical studies on lung cancer treatment. This study aims to observe the efficacy and safety of Camrelizumab in the treatment of advanced lung cancer in the real world. Methods: This is a prospective, open, multi-center observational study that includes patients with advanced lung cancer who are older than 18 years of age, regardless of gender, with an ECOG score of 0-2. Results: As of November 18, 2020, a total of 253 patients have been enrolled. Males accounted for 187 cases (74.2%). The ECOG PS score was 0 in 44 cases (17.3%), 1 in 162 cases (64.0%), and 2 in 47 cases (18.6%). There were 181 patients (71.5%) of stage IV, 96 patients (37.9%) of adenocarcinoma, and 98% of patients did not undergo PD-L1 testing. A history of radiotherapy accounted for 31.2%, and a history of surgery on the primary lesion accounted for 20.2%. Camrelizumab accounted for 29.6% of the first-line treatment, 27.2% of the second-line treatment, and 43.1% of the third-line and above. Camrelizumab monotherapy accounted for 20.1%, camrelizumab combined with chemotherapy accounted for 56.3%, combined anti-angiogenesis therapy accounted for 22.1%, and combined anti-angiogenesis + chemotherapy accounted for 1.5%. Among the 199 patients with evaluable efficacy, 4 were CR, 46 were PR, 116 were SD, and 33 were PD. The ORR reached 25.1% and the DCR reached 83.4%. The overall adverse event rate was 33.7%, the major adverse event RCCEP rate was 22.6%, appetite loss was 5%, and fatigue was 3.5%. There were 4 cases (2%) of RCCEP with adverse events greater than or equal to grade 3. Conclusions: In this real-world study of lung cancer, most of the patients enrolled were patients with poor PS score and late stage, but the efficacy and safety of camrelizumab in patients with advanced lung cancer were still confirmed. The dominant population and combination therapy are still under study. Clinical trial information: ChiCTR2000034595.
Association of MUC16 mutations with immunotherapy biomarkers in Chinese non-small cell lung cancer patients.
Authors: Han Tao , Guo Taiyan , You Xia , He Qianru , Zhang Qin , Qi Chuang
Published: June 2021

e21061

Background: MUC16 is frequently mutated in non-small cell lung cancer (NSCLC). Previous studies showed MUC16 mutation were associated with TMB and prognostic outcome in gastric cancer patients and may benefits for patients with immunotherapy. Herein, we aimed to characterize the association of MUC16 with immunotherapy biomarkers in Chinese and Western NSCLC patients. Methods: Next-generation sequencing data and clinical data were collected from 1053 TCGA NSCLC patients (Western cohort). A 539-gene panel targeted sequencing assay was performed on FFPE tumor samples from 1056 Chinese pan-cancer patients (Chinese cohort). Both MUC16 mutation ratio and TMB were calculated on the two cohorts following the same criteria. Results: In total, 269 (25%) of the 1056 Chinese patients and 494 (47%) of the 1053 Western patients had at least one mutation of MUC16 genes ( MUC16 mutant group). The Chinese cohort had a higher mutation frequency of MUC16 gene than the Western cohort (25% vs. 47%, p＜0.001). In both cohorts, TMB was higher in the MUC16 mutant group compared to non- MUC16 mutant group. In Chinese cohort, PD-L1 positive was not associated with MUC16 mutation. However, patients with MUC16 mutation were not associated with prolonged survival in Western immunotherapy cohort. Conclusions: Our study provided a landscape of MUC16 mutations in a much larger Chinese NSCLC group, which could be a valuable complement to TCGA dataset. Both in Chinese and Western cohorts, the higher TMB in MUC16 mutant patients suggested potential efficacy from immunotherapy of MUC16 mutant group. A larger validation cohort of MUC16 mutant is required to confirm these findings in the further.
Successful treatment of pulmonary lymphangitic carcinomatosis by anlotinib in 14 Chinese patients with advanced non-small cell lung cancer.
Authors: Fang Shencun , Cheng Wanwan , Zhang Yingming , Zhang Haitao , Li Si , Xiao Mingzhe
Published: June 2021

e21064

Background: Pulmonary lymphangitic carcinomatosis (PLC) occurs in 6%-8% of intrathoracic metastases among malignant tumor. The median survival was only 2.0 months from time of pulmonary symptoms to death in cases during 2000-2018, which is a poor prognosis. Effective interventions were needed besides standard chemotherapy and symptomatic support. Anlotinib showed a critical effect on lymphangiogenesis, and lymphatic metastasis in mouse models of lung adenocarcinoma, it might be a therapeutic option for tumor lymphatic metastasis. In this study, we retrospectively analyzed the efficacy and safety of anlotinib for PLC in patients with Non-small Cell Lung Cancer (NSCLC). Methods: We retrospectively investigated NSCLC patients with PLC at our hospital between May 2018 and November 2020, who received anlotinib monotherapy or combined therapy for PLC. Data were analyzed for progression-free survival (PFS), overall survival (OS), objective response rate(ORR), disease control rate(DCR) and adverse events (AE). The impact of clinical and genomic factors on PFS and OS were also assessed. Results: A total of 14 patients were enrolled with a median age of 64 years. 10(71.4%) were male, 4(28.6%) has smoking history, 10(71.4%) of patients had a performance status of 2-3. 9, 3, 2 patients had TP53 mutation, EGFR mutation, ALK fusion respectively. 9(64.3%) patients received anlotinib monotherapy. Of 14 patients, 8 achieved partial response (PR), 5 presented stable disease (SD), 1 had progressed disease. The ORR and DCR were 57.1% and 92.9% respectively. The median PFS was 3.1 months (95% CI: 2.0-4.2), the median OS for 1, 2, ≥3 line were 13 months, 7.2 months, 5.2 months, respectively. Median PFS and OS (≥3 line) were significantly longer for patients with TP53-mutant tumors compared with those with TP53–wild-type tumors (median PFS: 7 vs. 1.1 months, median OS (≥3 line): 6.8 vs. 1.9 months). No difference of PFS and OS (≥3 line) was found between EGFR or ALK alteration and the corresponding wild type patients. The most frequently reported AEs were high blood pressure (11, 78.6%), hand foot syndrome (6, 42.9%), diarrhea (5, 35.7%), fatigue (4, 28.6%), hoarseness (3, 21.4%), proteinuria (2, 14.3%) and stomatitis (2, 14.3%). Conclusions: Anlotinib presented favorable efficacy in patients with pulmonary lymphangitic carcinomatosis and conferred considerable survival benefit compared with previous studies, especially in patients harboring TP53 mutations. The AEs were manageable. These indicated that anlotinib can be a promising therapeutic treatment of PLC. More clinical data is needed to validate this finding.
Spectrum of adipokines, batokines, myokines, and growth factors in blood serum of patients with various stages of lung cancer and with immunotherapy with PD-1/PD-L1 inhibitors.
Authors: Zlatnik Elena Yu. , Sagakyants Aleksandr B. , Kit Oleg I. , Shulgina Oksana G. , Kalabanova Elena A. , Teplyakova Maria A. , Vladimirova Liubov Yu , Storozhakova Anna E. , Novikova Inna A. , Kharagezov Dmitry A. , Milakin Anton G. , Konstantinova Yulia S.
Published: June 2021

e21069

Background: Metabolites of the intestinal microbiota, including adipokines, batokins, and myokines, are involved in carcinogenesis, antitumor immune defense and ensuring the effectiveness of antitumor treatment, including chemotherapy and immunotherapy. Methods: The study included 100 patients with lung cancer (LC), 70% males and 30% females: stage I – 10%, II - 14%, III – 50%, IV – 26%. 21 patients (12 males and 9 females) received treatment with PD-1/PD-L1 inhibitors: stage I - 2 (9%), II - 1 (5%), III - 5 (24%), IV - 12 (62%). Therapy included atezolizumab and pembrolizumab – 9 patients each (43%), nivolumab – 3 (14%). Complete response was registered in 2 (9%), partial response in 5 (24%), stabilization - 4 (19%), progression - 8 (38%). One patient developed an immune-mediated adverse event (Guillain-Barré syndrome), so checkpoint inhibitors (CPI) were canceled. Serum levels of adipokines, myokines, batokines, and growth factors were determined by ELISA before and during treatment. The control group included 100 healthy donors. Results: Levels of VEGF and NGF were statistically significantly higher in patients with lung cancer than in donors, without differences in other parameters. Differences were revealed depending on the LC stage: leptin was higher in stages I and IV (Me 52.8 and 46.3 ng/ml, respectively) compared with stages II and III (Me 27.4 and 16.4 ng/ml, respectively) and with donors (Me 12.5 ng/ml). In stages III and IV, levels of VEGF increased (Me 504 and 473 pg/ml, respectively; in donors Me 239 pg/ml), while BDNF decreased (Me 2.7 and 0.4, respectively, in donors Me 12.6 μg/ml); NGF in stages I and II was not detected, unlike stages III and IV. Immunotherapy with CPI elevated levels of adiponectin (Me 12.5 and 16 μg/ml, respectively), and reduced levels of myostatin (Me 26.4 and 2.8 μg/ml, respectively) and NGF (Me 130 and 53 pg/ml, respectively). Only NGF could be regarded as a predictive factor of the response to CPI, since it was detected in high amounts only in patients with subsequent LC progression, while in patients with a positive response to treatment or stabilization, it was absent both before and after immunotherapy. Conclusions: Serum levels of some adipokines, myokines, batokins, and growth factors in LC patients differ depending on the cancer stage and the result of CPI immunotherapy; thus, NGF can be used as a predictor of the immunotherapy effectiveness. The study was performed with financial support from the Federal Medical and Biological Agency of Russia under contract No. 0373100122120000017 dated 20.05.2020.
Efficacy and safety of anti-EGFR monoclonal antibody (SCT200) as third-line or further treatment in advanced lung squamous cell cancer.
Authors: Dong Xiaorong , Wu Lin , Huang Dingzhi , Cheng Ying
Published: June 2021

e21070

Background: Treatment strategies for advanced lung squamous cell cancer (LSCC) of third-line or further-line are limited. We assessed the efficacy and safety of recombinant anti-EGFR monoclonal antibody SCT200 in patients with advanced LSCC in a phase 1b study. Methods: Advanced LSCC Patients previously treated with at least two chemotherapy regimens were randomly assigned to intravenous injection of SCT200 9 or 12 mg/kg every week (QW) for a maximum of 6 cycles, followed by 12 or 15 mg/kg every two weeks (Q2W). The primary endpoint was objective response rate (ORR). The secondary endpoint was progression free survival (PFS), overall survival (OS) and safety. This study was registered at ClinicalTrials.gov (NCT03808701). Results: Between March 19, 2019 and October 19, 2019, a total of 25 patients were enrolled and 23 were included in the final analysis (10 low dose [9mg/kg] and 13 high dose [12mg/kg]). The median age was 57 years old, and 21 (91.3%) patients were males. 22 patients (95.6%) had ECOG performance status of 1, and 17 (74%) were stage IV. The baseline characteristics were similar between the two dose groups. While no patients were evaluated as complete response or partial response, 5 and 6 patients achieved stable disease in the 9mg/kg and 12mg/kg dose groups respectively. However, the mOS was 5.96m (2.14 ̃ NR) and 9.59m (2.86 ̃ NR) in the low and high dose groups respectively. The mPFS was 2.23 (0.23 ̃ 5.26) and 1.38 (1.25 ̃ 3.02) in each group. The most common grade ≥3 treatment-related AEs were hypomagnesemia (13%), rash (13%) and anemia (4.3%). Conclusions: In this trial, a clinical benefit in OS was observed in the high dose group. SCT200 was shown to be safe and well tolerated in all patients. Our study indicated that SCT200 could serve as a potential single treatment or in combination with other therapy for advanced LSCC. Clinical trial information: NCT03808701. [Table: see text]
The prognostic role of body-mass index (BMI) for advanced EGFR positive non-small cell lung cancer (NSCLC) patients treated with osimertinib.
Authors: De Giglio Andrea , Di Federico Alessandro , Donati Giada , Deiana Chiara , Nuvola Giacomo , Fragomeno Benedetta , Sperandi Francesca , Melotti Barbara , Gelsomino Francesco , Ardizzoni Andrea
Published: June 2021

e21078

Background: In advanced EGFR-mutated non-small cell lung cancer (NSCLC) population, osimertinib represents the standard of care both for EGFR tyrosine kinase (TK) inhibitor-naive patients and for those with EGFR-mutated NSCLC harboring the T790M mutation and progressed following prior EGFR-TK inhibitor. No clear data supports the relationship between body mass index (BMI) and osimertinib's efficacy. Methods: We conducted a single-center, retrospective study including advanced EGFR-mutated NSCLC patients treated with Osimertinib as second or subsequent lines from February 2016 to December 2020. We examined survival outcomes according to BMI among a BMI-low group ( < 25 Kg/mq2) and BMI-high group (≥25 Kg/mq2). Results: A total of 37 consecutive patients received osimertinib as second- or subsequent line at our Institution. The mean age was 63.5 years (range 34-83 years), 24 (65%) patients were female, 16 (59%) were former or never smokers, and 25 (67%) had three or more metastatic sites at the start of therapy. The BMI-low group includes 25 (67%) patients and the BMI-high group 12 (33%), respectively. Globally, the median overall survival (mOS) was 29.9 mo. (95% CI, 18.2 – NR) and median progression-free survival (mPFS) was 17.5 mo. (95% CI, 15.7-33.3). The median follow-up was 32.5 mo. (IQR, 13.35-42.06). The mPFS was 21.0 mo. (95 CI, 16.8 – NR) within the BMI-low group and 16.8 mo. (95 CI, 4.4 – NR) within the BMI-high group, respectively (p = 0.03). Analogously, the mOS within the BMI-low group was 29.9 mo. (95 CI, 20.8 – NR) versus 18.2 mo. (95 CI, 11.7- NR) for the BMI-high group (p = 0.01). A BMI ≥25 Kg/mq2 constituted an independent risk factor for mortality [HR 3.99, (95 CI, 1.2 – 13.2), p 0.02] at multivariate analysis, including also age and number of metastatic sites. The BMI-high group showed a non-significant tendency to progression [HR 2.76, (95 CI, 0.9 - 8.3), p 0.06] at the same multivariate analysis. Conclusions: In our experience, a BMI ≥25 Kg/mq2 negatively influenced survival outcomes of 2nd-line osimertinib' treated NSCLC patients. More comprehensive studies are warranted to confirm these findings.
An exploratory clinical study of gefitinib combined with anlotinib in the first-line treatment of stage ⅢB-Ⅳ EGFR gene mutant non-small cell lung cancer patients with slow progress.
Authors: Wang Pengyuan
Published: June 2021

e21089

Background: Anlotinib is a new type of small molecule anti-angiogenic drug that can inhibit the activity of a variety of tyrosine kinase receptors. Based on the initial efficacy of the combination of anti-angiogenic drugs and EGFR-TKIs and a clearer definition of people who are sensitive to EGFR-TKIs treatment, this study explores the slow progress of first-line use of gefitinib in patients with non-small cell lung cancer slowly progress, the efficacy and safety of combined Anlotinib. Methods: Fifteen patients with first-line non-small cell lung cancer who received gefitinib treatment and slowly progressed after enrolled in Xuchang Central Hospital, 15 received anlotinib(12mg/d from day 1 to day 14 in a 21-day cycle) combined with gefitinib（250mg /d） treatment until the disease progressed or died or was intolerable Adverse events. The primary endpoint was the progression-free survival(PFS), and the secondary endpoints were objective response rate (ORR), disease control rate( DCR) and safety. Results: As of January 4, 2021, a total of 15 patients have been enrolled and 14 patients can be evaluated. 0CR, 5PR, 8SD, 1PD. The median progression-free survival was 13.3 months (95% Cl, 3.71-4.89), and the most common adverse reactions were Grade 1, including hypertension (42.86%) and fatigue (21.42%). No higher-grade adverse reactions. Conclusions: Gefitinib combined with Anlotinib Hydrochloride Capsules is safe, effective and well tolerated when the first-line treatment of EGFR gene mutant non-small cell lung cancer patients progresses slowly.
Network meta-analysis (NMA) of immuno-oncology (IO) monotherapy as first-line (1L) treatments (txs) for advanced non-small cell lung cancer (NSCLC) with PD-L1 expression ≥50%.
Authors: Freemantle Nicholas , Xu Yingxin , Wilson Florence , Guyot Patricia , Chen Chieh-I , Keeping Sam , Konidaris Gerasimos , Chan Keith , Kuznik Andreas , Atsou Kokuvi , Glowienka Emily , Stow Lisa , Pouliot Jean-Francois , Gullo Giuseppe , Rietschel Petra , Rizvi Naiyer A.
Published: June 2021

e21091

Background: For advanced NSCLC patients (pts) with high (≥50%) PD-L1 expression, effective IO mono options with survival benefits are approved (pembrolizumab mono, current standard of care) and emerging (cemiplimab). In a recent Phase 3 trial, cemiplimab, a high-affinity, highly potent human PD-1 inhibitor approved for tx of advanced cutaneous squamous cell carcinoma, demonstrated significantly improved overall survival (OS) and progression-free survival (PFS) vs chemotherapy (CT) in advanced NSCLC pts with PD-L1 ≥50%. A systematic literature review and NMA were conducted to identify/compare the efficacy/safety from randomized controlled trials (RCTs) for cemiplimab vs pembrolizumab or other IO mono published 2010–19. Methods: Relevant RCTs were identified by searching Embase, MEDLINE, Cochrane, and conference proceedings with predefined search strategies according to ISPOR, NICE, and PRISMA guidelines. An NMA with time-varying hazard ratios (HRs) was performed for OS and PFS. Analyses were conducted for objective response rate (ORR), Grade (G) 3–5 all-cause adverse events (AE), G3–5 immune-mediated AE (IMAE) and discontinuation due to AEs (DAE). Fixed-effect models were used due to limited evidence. Results with standard constant HRs and various sensitivity analyses were conducted to account for differences in RCT designs and other txs. Results: The feasibility assessment determined that EMPOWER-Lung 1, KEYNOTE-024, and KEYNOTE-042 trials were eligible. IMpower110 was excluded since an incompatible PD-L1 assay (SP142) was used for pt selection. For 1L advanced NSCLC with PD-L1 ≥50%, cemiplimab was associated with significantly greater PFS and ORR, and comparable OS, G3–5 AEs, IMAEs, and all-cause DAEs vs pembrolizumab (Table). At 2 yrs, numerically more pts receiving cemiplimab vs pembrolizumab were alive (59% vs 49%) and significantly more were alive w/o progression (37% vs 18%). Conclusions: In advanced NSCLC pts with PD-L1 ≥50%, cemiplimab mono demonstrated significant improvements in PFS and ORR, and comparable OS, safety/tolerability vs pembrolizumab.[Table: see text]
Interaction effect between mutational events on predicting efficacious immunotherapy in nonsquamous NSCLC: Results from 1,083 patients.
Authors: Zhang Fan , Zhao Lei , Li Tao , Xu Yu , Li Chengcheng , Wang Guoqiang , Cai Shangli , Hu Yi , Wang Jinliang
Published: June 2021

e21100

Background: Despite that the biomarkers of single mutational events predicting efficacy of immune checkpoint inhibitors (ICIs) have been intensively studied in non-squamous NSCLC, the interaction effects between mutations on prediction were scarcely investigated due to the limited sample size. Deeper understanding of these inter-relations could optimize the prediction model and provide insights for basic research on anti-tumor immunity. Methods: In total, 1083 patients with non-squamous NSCLC were included. 288 patients with both PFS and OS data receiving monotherapy from the MSKCC, DFCI, and SNCC cohorts were included in the training set-1. 304 and 294 patients from the POPLAR/OAK cohort treated with atezolizumab or docetaxel were included in the training set-2 and the control set respectively. Validation set-1 and validation set-2 respectively consists of 104 patients receiving monotherapy with only OS data and 93 patients treated with combination therapy from the MSKCC cohort. Risk models using single mutations (uni-model) and both single mutations and interactions (inter-model) were developed via multivariable Cox proportional hazards regression model. Results: By cross-validation in training set-1/2, five single mutational events, including mutations of EGFR, STK11, PTPRD, members in PI3K pathway, and members in HRR pathway, and five interactions ( EGFR* PI3K pathway, TP53* KRAS, TP53* ERBB4, cell cycle pathway*HRR pathway, and PI3K pathway*chromatin remodeling pathway) were identified as predictive biomarkers. The score of inter-model exhibited higher correlation with immunotherapeutic PFS in the training sets, compared to the uni-model ( Dxy: 0.173 vs. 0.139). Uni-score low was moderately associated with longer OS in the validation set-1 (HR = 0.62, 95% CI 0.35-1.08, P = 0.092), and PFS in the validation set-2 (HR = 0.32, 95% CI 0.18-0.60, P < 0.001). Inter-score low showed better predictive utility in the validation set-1 (HR = 0.53, 95% CI 0.30-0.94, P = 0.030), and the validation set-2 (HR = 0.23, 95% CI 0.10-0.50, P < 0.001). On the contrary, inter-score low was associated with worse PFS and OS in the control set, indicating that inter-score low might be a negative prognostic biomarker, but positive predictive biomarker to efficacious immunotherapy. Conclusions: Our study suggests that the predictive biomarkers might not be similarly predictive in every single subpopulation, and they might be merely valid under certain circumstances, which is termed by “interaction effect”. Given this, the future researches probing into immunotherapeutic predictor should focus on the mutual influence between distinct biomarkers, for instance, adding an interaction term in the Cox proportional hazards regression model.
Economic evaluation of crizotinib, alectinib, ceritinib, and brigatininb in anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC) as second-line treatment.
Authors: Alkhatib Nimer S. , Choi Briana , Halawah Hala , Calamia Matthias , Gulick Dexter , Manasrah AlMothana , Alkhdour Odai , McBride Ali , Abraham Ivo
Published: June 2021

e21104

Background: Crizotinib, alectinib, ceritinib, and brigatinib are approved as second line treatment for ALK+ NSCLC. Crizotinib was the first ALK inhibitor for first line therapy approved by Food and Drug Administration (2011) then ceritinib (2014), alectinib (2015), and brigatinib (2017) were approved as second line drugs. Following more data, these agents were approved as the first line therapy (2017 for ceritinib and alectinib; 2020 for brigatinib). These remain as a treatment option in patients who fail the first line therapy. Cost-effectiveness/utility analyses were conducted to assess clinical efficacy with varying costs of the agents. Methods: A three state Markov model were assumed (progression free, progression and death). Progression free survival (PFS) curves were digitized and fitted with exponential function. US payer perspective, a lifetime horizon, and discount rate of 3% were applied. Drug costs were Redbook wholesale acquisition cost. Other costs included were monitoring, adverse events and disease progression from published data (US$ 2020). Adverse events reported >5% in patients were included. Measured outcomes were PFS life years (PFSLY) and quality adjusted life years (PFSQALY). Crizotinib was the reference drug. Incremental cost-effectiveness and utility ratios (ICER/ICUR) of PFSLY and PFSQALY gained (PFSLYG, PFSQALYG) and lost were estimated. Base case (BCA) and probabilistic sensitivity analyses (PSA) were conducted. Results: Crizotinib was the reference drug for the following outcomes. For alectinib, with the decremental cost of -$14,653 (-$14,712), the incremental PFSLY of 0.16 (0.16) and PFSQALY of 0.05 (0.05) resulted in an ICER / PFSLYG of -$89,337 (-$88,604) and an ICUR / PFSQALYG of -$269,835 (-$266,510). For brigatinib, with the decremental cost of -$14,975 (-$14,954), the incremental PFSLY of 0.01 (0.01) and PFSQALY of ̃0.01 (0.02) yielded an ICER / PFSLYG of -$1,982,962 (-$1,431,631) and an ICUR / PFSQALYG of -$2,140,534 (-$570,538). For ceritinib, with the incremental cost of $7,590 ($7,514), there were decremental PFSLY of -0.01 (-0.01) and PFSQALY of -0.03 (-0.03). Conclusions: As second line treatment, crizotinib, ceritinib, and brigatinib had comparable PFSLYs and PFSQALYs while alectinib had the most PFSLY and PFSQALY and the lowest cost. Therefore, alectinib is the most cost-effective treatment for treating ALK+ NSCLC as the second line therapy.[Table: see text]