bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanism-based peripheral blood biomarkers to evaluate anticancer effects of the plinabulin/docetaxel combination (plin/doc) vs. doc alone in second/third line EGFR wild-type (WT) NSCLC.
Authors: Feinstein Trevor , Lu Y. June , Duprez Stephen , Bai Lore , Huang Lan , Mohanlal Ramon W.
Published: June 2023

e21017

Background: Pretreatment neutrophil to lymphocyte (L) (NLR), platelet to L (PLR), and L to monocyte (LMR) levels are established prognostic biomarkers for advanced NSCLC. Plinabulin (Plin) is a well-tolerated, differentiated tubulin-binding agent being developed for neutropenia prevention as a monotherapy and in combination, and for improving the efficacy of anticancer agents. DUBLIN-3 (NCT02504489) was a randomized, single-blinded (pts only), active-controlled Ph3 study in 2nd/3rd line stage IIIB/IV, EGFR WT NSCLC with a measurable lung lesion (RECIST 1.1). Pts (N = 559) were randomized 1:1 to Plin/Doc or Doc (21-day (D) cycle (C)). Doc (75 mg/m2) on D1 and Plin (30 mg/m2) on D1/D8 were given by IV infusion with steroid premedication (8 mg PO BID x 3D). Differential WBCs and platelet counts were collected at baseline (pre-steroid), D1, and D8. We analyzed the posttreatment effects of Plin on NLR, PLR, and LMR. Methods: All evaluable Plin/Doc vs Doc pts were included. NLR/PLR/LMR ratios and their respective change from baseline (cNLR/cPLR/cLMR) were obtained from blood draws taken at predose, C1D8, and/or C2D8. For intra/inter-arm overall survival (OS) stratification, baseline median NLR (3.2), PLR (177), and LMR (3.5) values were selected as thresholds. By examining responders & long-term survivors in both arms, posttreatment NLR/LMR and cNLR/cLMR thresholds were established for C1D8 and C2D8. Finally, PFS/OS benefits were stratified to determine the statistical significances of Plin/Doc vs Doc. Results: In agreement with literature, baseline threshold levels for NLR = 3.2, PLR = 177, LMR = 3.5 were statistically significantly predictive of OS in both the Plin/Doc and Doc arms (p values ranging from 0.05 to 0.0001). Plin prevents Doc-induced neutropenia, and post-Doc neutrophil counts were higher on D8 with Plin/Doc vs Plin (p < 0.001). Despite Doc-induced myelosuppression, Plin/Doc responding pts maintained similar NLR/LMR values as baseline at C1D8 and C2D8. After a single Plin dose at C1D8, lower NLR (cutoff = 3.0; 1.2x median value of all pts) and higher LMR (cutoff = 4.5; median value of all pts) thresholds independently predicted PFS/OS benefits of Plin/Doc vs Doc. Further, a higher cNLR threshold (cutoff = 0.25) at C2D8, best predicted Plin/Doc vs Doc in PFS and OS (p < 0.0001 and p = 0.0035 respectively). Conclusions: Bone marrow suppression remains a common serious risk of classical/non-classical cancer drugs. Under these conditions, the addition of Plin offers rapid protection of GMP lineage cells which can be captured by simple blood cell counts. Incorporation of blood-based biomarkers may help enrich NSCLC pts with better sensitivity to Plin/Doc combination than Doc alone. Clinical trial information: NCT02504489 .
Prognostic value of baseline immune suppressive biomarkers to select non-small cell lung cancer (NSCLC) patients (pts) likely to benefit from the plinabulin/docetaxel (Plin/Doc) combination.
Authors: Feinstein Trevor , Legaspi Gabrielle , Duprez Stephen , Huang Lan , Mohanlal Ramon W.
Published: June 2023

e21018

Background: Baseline Neutrophil-to-Lymphocyte (L) ratio (NLR), Platelet-to-L ratio (PLR), and L-to-Monocyte ratio (LMR) are biomarkers that can predict anticancer outcomes. Plin, a novel small molecule immune-enhancing agent, exerts anticancer activity by GEF-H1-dependent activation of dendritic cells, and hence T-cells. We evaluated the correlation of Plin’s anticancer effects with NLR, PLR, LMR immune suppressive (IS) signature. We correlated baseline NLR, PLR, and LMR (broken down in quartiles [Q]) with overall survival (OS) in NSCLC pts from the DUBLIN-3 trial, which had met the primary OS endpoint in favor of Plin/Doc vs Doc alone (Han ESMO 2021). Methods: DUBLIN-3 (NCT02504489) was a global Phase 3 study in 2nd/3rd line EGFR-wild type, stage IIIB/IV NSCLC pts (N = 559) randomized 1:1 to Plin/Doc or Doc alone. Doc (75 mg/m2 on D1) and Plin (30 mg/m2 on D1/D8) were given by IV infusions. Baseline (i.e., prior to dexamethasone premedication, Doc and Plin) blood draws were taken from each pt within 28 days prior to any study medication given to obtain baseline NLR, PLR, and LMR. The survival duration of each pt was obtained. NLR, PLR, and LMR values for Plin/Doc and Doc were divided into Qs, and the corresponding median OS for each Q was calculated. Only 2nd line pts were included in this analysis to avoid confounding with multiple lines. Results: Increasing Qs of baseline NLR and PLR (thus with increasing IS signature) were associated with decreasing median OS for both Plin/Doc and Doc. Increasing Qs for LMR (thus with decreasing IS signature) were associated with increasing median OS in both Plin/Doc and Doc. Median OS in each Q was consistently higher with Plin/Doc vs Doc alone, except for Qs with an IS signature. With baseline NLR ≤3.6, PLR≤194, or LMR≥5.9, thus avoiding an IS signature, median OS was on average 2.5 Mo (range 0.6-4.5 Mo) longer with Plin/Doc vs Doc alone. For each of the Qs in the table, the n = 52 ± 2 pts. Conclusions: Baseline IS biomarkers were predictive of median OS with both Plin/Doc and Doc alone. Baseline NLR, PLR, and LMR, at cut-off levels to avoid IS levels, could serve as prognostic markers to identify likely responders to the immune-enhancing agent Plin in combination with Doc in NSCLC. Clinical trial information: NCT02504489 . [Table: see text]
Preclinical evidence for synergistic effects of autophagy inhibitor and alpelisib in PI3KCA mutated non-small cell lung cancer: Implications for future clinical trials.
Authors: Shim Byoung Yong , Lee Sang-Bin , Kim Hyunho , Park Hyung Soon , An Ho Jung
Published: June 2023

e21022

Background: The PI3K pathway is frequently activated in a variety of cancers including non-small cell lung cancer (NSCLC). PI3K mutation is associated with worse response to chemotherapy and consequently decrease the effectiveness of single administration of anticancer drugs. In this study, we checked the therapeutic efficacy of alpelisib either alone or in combination with an autophagy inhibitor for the treatment of NSCLC. Methods: We treated alpelisib and autophagy inhibitors in human NSCLC cell lines and measured the cell viability and protein expression of autophagy indicators, p62 and LC3B. Co-treatment of alpelisib and autophagy inhibitors significantly decrease the cell viability and proliferation compared to alpelisib alone. Based on the results of the combination experiment of alpelisib and autophagy inhibitors, Chloroquine (CQ) was selected for further study. Co-treatment of alpelisib and CQ significantly increase apoptosis and decrease tumor-related protein expression in in vitro and in vivo. Results: Our data demonstrates that alpelisib and autophagy inhibitor have a synergistic efficacy against NSCLC in vitro and in vivo. Conclusions: Based on these results, a Phase 1 clinical trial is currently being planned.
Effects of different immune microenvironment characteristics on predictive efficacy of PTCH1 mutations in immune checkpoint inhibitor therapy of solid tumors.
Authors: Zhu Guangyu
Published: June 2023

e21026

Background: The PTCH1 gene encoding the protein corticosteroid receptor, which regulates the activity of the Sonic Hedgehog (SHH) signaling pathway. Mutations in PTCH1 result in disruption of the SHH signaling pathway and are closely related to the development of various solid tumors. Previous research has shown that mutations of the PTCH1 gene may result in decreased of antigen expression on the surface of tumor cells. However, relevant correlation with the efficacy of ICI therapy and immune microenvironment are still lacking. Methods: NGS data from an independent cohort (the MSKCC study cohort) of 1661 patients and Chinese clinical dataset (panel on 381/733-gene) of 35337 patients with pan-cancer to explore the association between PTCH1 mutations and immune biomarkers. TMB was defined as total number of somatic non-synonymous mutations in coding region. MSI was evaluated by NGS of 500 known MSI loci. PD-L1 expression was evaluated using immunohistochemistry (Dako 22C3). Patients from three independent cohorts (OAK, POPLAR and MSKCC study cohort) and were used to analyze the correlation between PTCH1 mutations and the efficacy of immune checkpoint blockade immunotherapies (ICIs). Estimation of immune filtration cells scores were conducted via TIMER2.0 (http://timer.cistrome.org/). Results: In Chinese cohort, there were 1384 (3.91%) patients harboured PTCH1 mutation ( PTCH1mut), slightly more than the MSKCC cohort (2.52%, 42/1661). For the TMB, both Chinese (median, 24.14 Muts/Mb vs 8.52 Muts/Mb, P ＜0.0001) and MSKCC (median, 22.30 Muts/Mb vs 5.90 Muts/Mb, P = 0.0035) cohort were associated with higher TMB than the wild-type. Supplemental analysis of MSI in the Chinese cohort showed significant differences between the PTCH1mut and PTCH1wt groups (P ＜0.0001), but not on PD-L1 levels (P = 0.64). In terms of prognostic effect with ICIs therapy, PTCH1mut were significantly associated with the overall survival (OS) of NSCLC (median, 5 months vs 11 months; HR = 1.61; 95% CI, 1.00-2.60; P = 0.049) and colorectal (median, 11 months vs 8 months; HR = 0.27; 95% CI, 0.08–0.90; P = 0.023). Interestingly, PTCH1mut in NSCLC was inversely associated with ICIs efficacy, as opposed to other solid tumors. Exploring the correlation between PTCH1 and immune microenvironment, it was found that CD4+ T cell (P＜0.001), macrophages (P＜0.001), NK cells (P＜0.001), and CD8+ T cells (P = 0.015) infiltration was significantly positively correlated in colorectal. But the infiltration of most immune cells was negatively correlated with PTCH1mut in NSCLC, that the B cells (P = 0.005), macrophages (P = 0.049), and NK cells (P = 0.022) had a significant difference. Conclusions: The results showed that the PTCH1 had a high correlation in solid tumors with TMB and MSI. The PTCH1 might a potential biomarker for ICIs therapy, and the immune microenvironment may be a factor affecting of it.
Effects of different immune microenvironment characteristics on effect of immune checkpoint inhibitors in solid tumors with TGFBR2 mutation.
Authors: Yao Rongrong
Published: June 2023

e21027

Background: TGFBR2 is a member of the TGF-β receptor family, the protein encoded by it was involved in the regulation of cell proliferation, apoptosis, differentiation and other biological processes. TGFBR2 mutation can affect the occurrence of tumors. previous research showed that the TGF-β signaling pathway suppresses the tumor immune response, so TGFBR2 mutations may lead to tumor resistance to immunotherapy. However, effect of TGFBR2 mutations on ICIs and its correlation with immune microenvironment are rarely explored. Methods: NGS data from an independent cohort (the MSKCC study cohort) of 1661 patients and Chinese clinical dataset (panel on 733-gene) of 35337 patients with pan-cancer to explore the association between PTCH1 mutations and immune biomarkers. TMB was defined as total number of somatic non-synonymous mutations in coding region. MSI was evaluated by NGS of 500 known MSI loci. PD-L1 expression was evaluated using immunohistochemistry (Dako 22C3). Patients from three independent cohorts (OAK, POPLAR and MSKCC study cohort) and were used to analyze the correlation between PTCH1 mutations and the efficacy of immune checkpoint blockade immunotherapies (ICIs). Estimation of immune filtration cells scores were conducted via TIMER2.0 (http://timer.cistrome.org/). Results: In Chinese cohort, there were 831 (4.32%) patients harboured TGFBR2 mutation ( TGFBR2mut), in which the most number patients with TGFBR2mut were gastric carcinoma (10.53%), followed by colorectal (8.63%) and NSCLC (2.98%). Same as the MSKCC cohort (2.77%). For the TMB, both Chinese (median, 28.64 Muts/Mb vs 8.39 Muts/Mb, P ＜0.001) and MSKCC (median, 28.53 Muts/Mb vs 6.89 Muts/Mb, P = 0.030) cohort were associated with higher TMB than the wild-type. Supplemental analysis of MSI in the Chinese cohort showed significant differences between the TGFBR2mut and TGFBR2wt groups (P ＜0.001), but not on PD-L1 levels (P = 0.50). In terms of prognostic effect with ICIs therapy, TGFBR2mut were significantly associated with the overall survival (OS) of NSCLC (median, 2 months vs 11 months; HR = 3.46; 95% CI, 1.63-7.35; P ＜0.001) in OAK and POPLAR cohort, same as MSKCC cohort (median, 3 months vs 10 months; HR = 2.21; 95% CI, 1.04-4.71; P = 0.034). Interestingly, In the MSKCC cohort, opposite with NSCLC, majority tumors with TGFBR2mut had a longer survival value, showing a trend toward longer survival. Exploring the correlation between TGFBR2 and immune microenvironment. The results showed NK cell (P = 0.042) and CD4+ T cell (P = 0.036) infiltration were significantly negatively correlated in NSCLC. However, other solid tumors such as colorectal and melanoma are opposite. Conclusions: The results showed that the TGFBR2 had a high correlation in solid tumors with TMB and MSI. The TGFBR2 might a potential biomarker for ICIs therapy in NSCLC, and the immune microenvironment may be a factor affecting of it.
Genomic mechanisms of RET inhibitor sensitivity and resistance in RET-fusion positive cancer cells.
Authors: Heymach John , Nilsson Monique B. , Huo Xiaofang , Kumar Ashwani , He Jun , Kittler Ralf
Published: June 2023

e21029

Background: RET fusions occur in 2-3% of lung cancer cases, and there are currently two FDA-approved RET-specific inhibitors (RETi), selpercatinib and pralsetinib. RET fusions are heterogeneous and the impact of specific fusion partners and their unique breakpoints on drug sensitivity is poorly understood. Moreover, while patients may be initially sensitive to RETi treatment, therapeutic resistance eventually emerges, and studies have shown that RET-dependent mechanisms of resistance include acquired resistance mutations that alter drug binding. We sought to investigate mechanisms of sensitivity and resistance to RET inhibitors in RET-fusion positive lung cancer in effort to improve treatment options and clinical outcomes in this patient population. Methods: We characterized the landscape of RET-fusions and -mutations in non-small cell lung cancer (NSCLC). KIF5B-RET, CCDC6-RET, and NCOA4-RET were the most frequently observed RET fusions in NSCLC. To investigate the drug sensitivity profile of individual RET fusion variants, we generated a panel of Ba/F3 cells expressing various RET fusion variants and evaluated in vitro sensitivity to RETi including selpercatinib, pralsetinib, vandetinib, cabozantinib, TPX-0046, lovatinib, and ponatinib. We observed that unique RET fusions impart differential sensitivities to RET inhibitors. For example, cells expressing KIF-RET (K15, R12) were highly sensitive to selpercatinib, pralsetinib, and ponatinib, whereas cells expressing KIF-RET (K22, R12) were likewise sensitive to selpercatinib and pralsetinib but were less sensitive to ponatinib. We next established a cell line (MDA-L-30) from a patient harboring a RET-fusion (KIF-RET; K15, R12) and observed a RETi sensitivity profile similar to that observed using the BaF3 system. Results: Next, we employed the LentiMutate approach to rapidly identify genomic mechanisms of RETi resistance. In cells expressing the KIF5B-RET (K15, R12) fusion, the G810S mutation was associated with acquired resistance to both selpercatinib and pralsetinib, consistent with prior reports and clinical observations. However, V804M/E and M918T mutations were associated with acquired resistance to selpercatinib but not pralsetinib, and L730I/V and E732K mutations were associated with resistance to pralsetinib but not selpercatinib. Conclusions: Taken together, these data indicate that individual RET fusion variants with diverse fusion partner breakpoints have distinct drug sensitivity profiles and that secondary resistance mutations may be non-overlapping between RETi. These findings support the need to comprehensively characterize RET-dependent mechanisms of resistance in order to provide therapeutic recommendations for treating RET-fusion driven cancers.
Association of docetaxel efficacy with cancer gene mutation status in patients with metastatic non-small-cell lung cancer who progressed on platinum doublets and immunotherapy.
Authors: Qin Kang , Wang Kaiwen , Li Shenduo , Hong Lingzhi , Rinsurongkawong Waree , Hubert Shawna Marie , Le Xiuning , Vokes Natalie I , Altan Mehmet , Gibbons Don Lynn , Heymach John , Lee J. Jack , Lou Yanyan , Zhang Jianjun
Published: June 2023

e21030

Background: Docetaxel +/- ramucirumab remains the standard of care therapy after progression on platinum doublet and immune checkpoint blockade (ICB) in patients with metastatic non-small cell lung cancer (NSCLC). However, the clinical benefit from docetaxel is short-lived with substantial toxicity. Additionally, whether cancer gene mutation status impacts the benefit from docetaxel has not been systemically studied. In this real-world study, we aim to investigate whether cancer gene mutation status is associated with benefit from docetaxel. We also explored whether IMPOWER150-based regimens (ABCP-atezolizumab + bevacizumab + carboplatin + paclitaxel; ACP-atezolizumab + carboplatin + paclitaxel; BCP-bevacizumab + carboplatin+paclitaxel) may serve as alternative options with better efficacy in this patient population. Methods: We retrospectively queried MD Anderson Cancer Center GEMINI database for patients with metastatic NSCLC who received docetaxel, docetaxel+ramucirumab, or one of the above-mentioned IMPOWER150-based regimens after progression on concomitant or sequential platinum-doublet and ICI. Primary endpoints include progression-free survival (PFS) and overall survival (OS). Results: 274 patients were analyzed (docetaxel n = 99; docetaxel +ramucirumab n = 142; ABCP n = 28; BCP n = 4, ACP n = 1). No significant difference was observed in mPFS (3.00m versus 3.93m, P = 0.156) or mOS (8.40m vs.8.67m, P = 0.737) between patients from docetaxel monotherapy group and docetaxel+ ramucirumab group. Cancer gene mutations in EGFR, KRAS, TP53 or PD-L1 expression (0-1%; 1-49%; ≥50%) were not associated with PFS or OS in the 241 patients treated with docetaxel +/- ramucirumab. Furthermore, there was no difference in mPFS (5.50m versus 3.47m, P = 0.516) or mOS (10.40m versus 8.83m, P = 0.737) in patients who received IMPOWER 150-based regimens compared to those who were treated with docetaxel+/- ramucirumab. The median treatment duration was 1.60m (0.70m-20.23m), 1.90m (0.70m-32.90m), 4.80m(0.70m-33.47m) and 11 patients (11.11%), 20 patients (14.08%), and 3 patients (9.09%) discontinued treatment due to adverse events in the patients treated with docetaxel monotherapy, docetaxel+ramucirumab combined therapy, and the IMPOWER150 regimens, respectively. Conclusions: These results from this real-world study suggested that unlike for ICI therapy, where onco-driver mutations have profound impact on the clinical benefit, the cancer gene mutation status does not impact the benefit from docetaxel +/- ramucirumab in NSCLC patients who progressed on platinum doublets and ICI. Furthermore, the clinical benefit from docetaxel +/- ramucirumab is short-lived. Novel treatment regimens are urgently needed in this clinical setting.
Clinical outcomes of patients with advanced NSCLC with different EGFR exon 19 deletion subtypes treated with first-line tyrosine kinase inhibitors.
Authors: Gu Yangchun , Yu JinYu , Hu Haifeng , Zhang Hua , Cao Baoshan , Liang Li
Published: June 2023

e21034

Background: Epidermal growth factor receptor (EGFR) exon 19 deletion (Ex19del) in non-small cell lung cancer (NSCLC) consists of many subtypes, and their sensitivity to tyrosine kinase inhibitors (TKIs) has not been clearly defined. This study aimed to investigate the clinical outcomes of advanced NSCLC patients with different EGFR ex19del subtypes treated with different TKIs. Methods: We retrospectively analyzed stage IIIB-IV NSCLC patients with EGFR Ex19del and first-line TKIs therapy. E746_A750del was defined as classic group, and the others as non-classic group, which was further divided into subgroups according to deletion with or without insertion, starting codon or length of deletion. The primary endpoint was progression free survival (PFS). Results: There were 17 Ex19del subtypes identified in 101 patients. The frequency of E746_A750del was 64.4% (65/101), and the top three frequent non-classic subtypes were L747_T751del (6.9%, 7/101), L747_P753delinsS (5.9%, 6/101) and E746_S752delinsV (5.0%, 5/101). In all patients, the median PFS (mPFS) of first-line TKIs in classic and non-classic groups were 14.3 months (m) and 19.3 m ( p > 0.05). In non-classic group, the mPFS in deletion with insertion (delins) and without insertion subgroups were 25.3 m and 11.2 m; in deletion starting with E746 and with other codon subgroups were 29.7 m and 19.3 m; and in deletion length of 15 nucleotides (n) and of other length subgroups were 11.2 m and 25.3 m. The mPFS of these non-classic subgroups were not statistically different with that of classic group ( p > 0.05). In all patients, the mPFS of first-line therapy with the 1st, 2nd and 3rd generation TKIs were 17.4 m, 15.6 m and 20.5 m, respectively ( p＞0.05); in classic group, the mPFS were 14.3 m, 16.9 m and 20.5 m, respectively ( p＞0.05). However, in non-classic delins subgroup (29.7 m, 15.6 m and 11.9 m) and in deletion length of ≥18 n subgroup (25.3 m，12.3 m and 11.9 m), the 1st generation TKIs had an insignificantly longest mPFS ( p＞0.05). When resistant to 1st or 2nd generation TKIs, patients in classic group showed a trend of higher incidence of T790M mutation than non-classic group (72.0% vs 43.8%, p = 0.070). In multivariant analysis, pleural metastasis (PM) had interaction with Ex19del grouping, warranting stratification analysis. In patients without PM, the mPFS of first-line TKIs in classic group was significantly shorter than non-classic group (13.8 m and 29.7 m, p = 0.026). However, in patients with PM, the mPFS of classic group was numerically longer than non-classic group (16.9 m and 11.7 m, p > 0.05), with the shortest mPFS in non-classic without insertion subgroup, and in non-classic with 15 n deletion subgroup. Conclusions: In advanced NSCLC patients with EGFR Ex19del, the efficacy of first-line TKIs therapy was affected by the presence of pleural metastasis, Ex19del subtypes and different generation of TKIs.
Artificial neural network model analysis in T790M detection after failure of first- and second-generation epidermal growth factor receptor tyrosine kinase inhibitors.
Authors: Pluzanski Adam , Świetlik Dariusz , Krzakowski Maciej Jerzy
Published: June 2023

e21041

Background: Despite osimertinib availability, first or second generation (1st/2nd gen.) epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are commonly used in many countries. Clinical factors identified before first line EGFR TKIs treatment that correlate with T790M occurrence are not well-known. In this single center retrospective study we define the artificial intelligence-based model that support T790M detection in daily practice. Methods: In 80 patients (pts) consecutively progressed on 1st/2nd generation EGFR TKIs T790M mutation was assessed. In multivariate logistic regression factors predictive to T790M mutation were identified. Based on clinical and molecular factors present before EGFR TKIs initiation multi-layer perceptron (MLP) neural network was used for building model classifying patients according to T790M status. The artificial neural network consisted of three layers: input, hidden and output layers of 36, 6 (optimally due to the result of the neural network) and 1 neurons, respectively. During the learning process the weight links between the neurons were modified using Broyden-Fletcher-Goldfarb-Shanno algorithm. To calculate the diagnostic quality of the artificial neural network, we divided at random of all patients for two groups: training and testing. The training group contained 65 and testing group 15 cases. Sensitivity and specificity for both models were assessed. TIBCO Software Inc., Statistica (data analysis software system), version 13 software was used for all calculations. Results: In 49/80 pts (61.3%) T790M was present. In logistic regression model: del19 EGFR mutation, chest or liver metastases and 1st gen. TKI treatment correlated with T790M presence. Parameters included in building neural network model were: del19/L858R/other EGFR mutation status, sex, age, 1st/2nd gen. TKI in first line, clinical stage, metastases location, ECOG PS, smoking history. Learning and testing phase models detected T790M with sensitivity-94.7%, specificity – 91.3% and sensitivity-77.8%, specifity-83.3%. In testing set (15 pts) proposed neural network model achieved 80% accuracy in predicting correctly T790M status. Clinical stage, TKI generation in first line, metastases location, EGFR mutation were the most valuable entrance parameters. After conducting a sensitivity analysis for all 8 the analysed variables the observed error quotients were above 1, therefore, they are all significance and should be entered as input to the developed network. Conclusions: The proposed artificial neural network model used parameters identified before start of TKI treatment and achieved high accuracy in T790M status prevalence. Although this model need to be validated in large cohort it can be an useful tool to support clinicians decision.
Impact of SPARC expression on pembrolizumab treatment response and prognostic role in advanced stage non-small cell lung cancer.
Authors: Goktas Aydin Sabin , Bilici Ahmet , Calis Elif , Olmez Omer Fatih , Karci Ebru
Published: June 2023

e21042

Background: Secreted protein acidic and cysteine-rich (SPARC) was highly expressed in non-small cell lung cancer (NSCLC) tissue. Studies have indicated the association between SPARC expression and immune-cell infiltration and the prognosis of lung cancer. Despite the optimal first-line treatment approach in advanced NSCLC that lacks a driver mutation includes immunotherapy with or without chemotherapy, a well-defined tool or test for predicting response has yet to be created. We aimed to elucidate the influence of SPARC expression terms of clinicopathology, pembrolizumab response and prognosis in metastatic NSCLC patients. Methods: Thirty-six patients diagnosed with advanced-stage NSCLC without actionable driver mutation and recieved pembrolizumab in the first line setting were included in this study. Programmed death ligand-1(PD-L1) and SPARC expression were assessed by means of PD-L1 IHC 22C3 pharmDx and BenchMark ULTRA assay(Ventana Medical Systems, Tucson, AZ) in paraffin-embedded blocks. The expressions were categorised according to the tumor proportion score. Staining intensity of SPARC was graded according to the following criteria: 1+ (weak), 2+ (moderate), and 3+(strong). Results:The median age was 62 (range 45-81). One patient was female, and four patients did not have a smoking history.Twenty-seven of tumor were adenocarcinoma, and six were squamous cell carcinoma. PDL-1 status was < 1% in 4 (11.4%), 1-49% in 12 (34.3%), and > 50% in 20 (54.3%) patients.There was no significant correlation between SPARC expression and smoking status, histologic type of tumour, T and N status, and liver and bone metastasis. Central nervous system (CNS) metastasis and progression was seen in 8 (57.1%), 2 (12.5%), and 1 (16.7%) and in 6 (16.7%), 0, and 6 (37.5%) patients with SPARC 1+,2+, and 3 +, respectively. Controversially, higher SPARC expression was significantly correlated with lower rates of brain metastasis but higher rates of CNS progression (p = 0.022 and p = 0.011, respectively). While PD-L1 and SPARC expression were not significantly correlated, a trend toward low SPARC expression was seen in patients with PD-L1 > 50%. The objective response rate (ORR) trended to be higher in the SPARC 1+ group (85.7%, 43.8%, and 50.0% in SPARC 1+, 2+ and 3+ group, respectively, p = 0.052). Univariate analysis revealed that SPARC expression was not a significant prognostic factor for both PFS (p = 0.7) and OS (p = 0.07). But, low SPARC expression was a significant predictive factor for the first-line pembrolizumab treatment response (p = 0.04, OR:0.11, 95%CI 0.01-0.92) in NSLC patients. Conclusions: Our study lightened a new area in the literature that SPARC expression might predict the pembrolizumab response and might be a marker for CNS progression in NSLC patients. These results should be explored in further studies to address the potential therapeutic implications of SPARC expression.
Efficacy and safety analysis of immune checkpoint inhibitors plus angiogenesis inhibitors for treatment of advanced driver-negative NSCLC in elderly patients: A retrospective study.
Authors: Zhang Jian , Wang Hao , Zhou Jundong , Zou Zhonghua , Tan Jie , Shi Jianping , Yang Hui , Xue Jing
Published: June 2023

e21044

Background: Immune checkpoint inhibitors (ICIs) combined with antiangiogenic drugs may have synergistic effects in elderly patients with advanced driver-gene wild-type non-small cell lung cancer (NSCLC), but its true efficacy remains unclear. In addition, the chemotherapy tolerance of elderly NSCLC patients is poor, and the precise identification of the population who can benefit from ICIs combined with angiogenesis inhibitors is also the focus of current research. Methods: We retrospectively compared the clinical efficacy and safety of ICIs combined with or without antiangiogenic agents in elderly patients with advanced driver-gene negative NSCLC who were ≥65 years old in the Cancer Center of the Affiliated Suzhou Hospital of Nanjing Medical University. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), objective response rate (ORR), and immune-related adverse events (irAEs). Results: A total of 36 patients in the IA group（Immune checkpoint inhibitors plus angiogenesis inhibitors group) and 43 patients in the NIA group（Immune checkpoint inhibitors without angiogenesis inhibitors group) were enrolled in the study between January 1, 2019 and December 31, 2021. The median follow-up time for patients in IA group and NIA group was 18.2 months (95%CI: 14 - 22.5 months) and 21.4 months (95%CI: 16.7 -26.1 months), respectively. The median PFS and median OS were longer in the IA group compared to the NIA group（8.1 months vs 5.3 months；HR for PFS: 0.778, 95%CI: 0.474-1.276, P = 0.32; NA vs 30.9 months; HR for OS: 0.795, 95%CI: 0.396-1.595, P = 0.519). Subgroup analysis showed that patients in the IA group had significantly longer PFS in the subgroup with PD-L1 expression ≥50% (P = 0.017), and the relationship between treatment regimens and outcomes was still discrepant in different PD-L1 expression levels (P for interaction = 0.002). There was no significant difference in ORR between the two groups (23.3% vs 30.5%, P = 0.465). The incidence of adverse events in IA group was lower than that in NIA group (39.5% vs 19.4%, P = 0.05), and the cumulative incidence of treatment interruptions due to adverse events was significantly reduced (P = 0.045). Conclusions: In elderly patients with advanced driver-gene wild-type NSCLC, the addition of antiangiogenic agents to ICIs therapy did not provide significant clinical benefit, but the incidence of treatment interruptions due to adverse events was significantly reduced. In the subgroup analysis, we found that the clinical benefit of this combination therapy was observed in patients with PD-L1 expression ≥50%, which warrants further exploration. Clinical trial information: NCT05688046 .
Epidemiology and survival trends of lung carcinoids in the veteran population.
Authors: Tehzeeb Javaria , Mahmood Fatima , Gemoets Darren , Azem Amin , Mehdi Syed Arzoo
Published: June 2023

e21049

Background: Lung carcinoids (LC) continue to increase in prevalence and existing data shows a female predominance of these tumors, but relevant epidemiologic data for heterogeneous populations is limited. In this study, we describe the epidemiology of LC in the United States (US) Veteran population. Methods: In this retrospective study, we searched Veteran Affairs Cancer Cube Registry (VACCR) for LC cases diagnosed between 2000 and 2017 and their baseline characteristics. Survival rates were analyzed across all baseline characteristics to identify important prognostic factors and results were compared with Surveillance, Epidemiology, and End Results cancer database (SEER). Data was analyzed via chi-square and Fischer exact probability tests (level of significance at < 0.05). Results: We identified 846 LC cases in VACCR (91% males), and 8,851 LC cases in SEER (32% males). Compared to SEER, VACCR data had more black patients (12% vs 8%), less cases with loco-regional disease (56% vs 84% in SEER) and same proportion of lower lobe tumors (40%). The annual incidence rate of LC among all lung cancers in Veterans tripled from 2000 to 2017 (0.3% to 0.9%). No racial disparities in treatment were noted among the Veterans. Male-specific 5-year survival rate was 18% lower in VACCR compared to SEER (61% vs 79%). Univariate analysis of both databases showed a statistically significant association of survival with age, primary tumor site and gender (p < 0.05 for all) (Table 1), with advanced age, upper lobe LC and male gender associated with worse survival. SEER subgroup analyses also showed lower 5-year survival rates for males across all baseline characteristics. Overall, black race appeared to be associated with worse prognosis, but the results did not reach statistical significance for VACCR data. Conclusions: Our study showed that US Veteran population, consisting of older males with more comorbidities, LC have lower survival rates than SEER population with more female LC cases. Advanced age, upper lobe predominant disease, and advanced stage were associated with worse survival. Both SEER and VACCR data suggest that male sex is a poor prognostic factor for LC. [Table: see text]
Gut microbiota profiling and clinical response in patients with metastatic non-small cell lung cancer receiving endothelial growth factor-tyrosine kinase inhibitors (EGFR-TKI).
Authors: Zhao Jing , Rao Jie , Li Qianxia , Yang Lin , Hu Guangyuan
Published: June 2023

e21050

Background: Pre-clinical mouse models have suggested that gut microbiota in immune relates with inflammation and modulates tumor response, while it remains uncertain in lung cancer patients with EGFR mutation. We aimed to evaluate the relationship between gut microbiota and early tumor response after EGFR-TKI treatment in metastatic non-small cell lung cancer (NSCLC) patients. Methods: NSCLC patients haboring EGFR exon 19del or 21L858R mutation were enrolled in this study in Tongji Hospital, Wuhan, China. Early response was assessed at 12 weeks after EGFR-TKI initiation per RECIST 1.1, and patients were categorized as responders (CR+PR) and non-responders (SD+PD). Stool sample was collected prior to EGFR-TKI treatment. The V3–V4 region of the 16S rRNA gene was amplified for the characterization of the gut microbiota profiling. Data were analyzed on the online tool of Majorbio Cloud Platform to compare microbiota community structure and abundance at α- and β-diversity levels. Linear discriminant analysis with effect size (LEfSe) was used to to identify biomarkers using a taxonomic bar chart. PICRUSt2 was used to predict the functional profiling of microbial communities. P-values < 0.05 were considered statistically significant. Results: From June 2020 to Sep 2022, 24 patients were included. CR, PR, SD and PD were recorded in 2 (8.3%), 14(58.3%), 6(25%) and 2(8.3%) patients, respectively. The four most abundant bacteria at phylum level were Firmicutes (64.4%), Bacteroidota (15.1%), Proteobacteria(14.7%), and Actinobacteriota (4.6%). The relative abundance of Actinobacteriota counts were significantly higher in responders than those with no-responders ( p= 0.032). There was a significant difference in the Sob index (α-diversity) between responders and no-responders (60.062 vs. 86.250, p= 0.043). β-diversity was similar between the two groups ( p= 0.087). Differential analysis using LEfSe identified that genus Rothia was significantly enriched in responders; phyla Actinobacteria and Deinococcota, genera Ruminococcus, Collinsella, Holdemanella were significantly enriched in non-responders. PICRUSt2 based on KEGG prediction identified that Transketolase and Carbamoyl-phosphate synthase were significantly enriched enzymes in non-responders compared with responders, the p values were 0.019 and 0.022, respectively. Conclusions: The early response of EGFR-TKI was associated with alteration of specific genera and metabolic function of gut microbiota. Further research with larger cohorts is needed to validate this pilot study. [Table: see text]
Efficacy and safety of immune checkpoint inhibitor without pemetrexed for first-line maintenance therapy in advanced lung adenocarcinoma.
Authors: Gao Ming , Yang Wenyu , Wang Chunyu , Wang Ting , Jing Fangfang , Zhang Fan , Tao Haitao , Ma Junxun , Hu Yi , Wang Lijie
Published: June 2023

e21058

Background: Currently, the standard first-line treatment for driver gene-negative advanced lung adenocarcinoma (LUAD) is chemotherapy plus immune checkpoint inhibitor (ICI) therapy followed by pemetrexed and ICI. However, pemetrexed is prone to certain adverse reactions and needs to be pretreated. At present, there is no relevant study on the efficacy between pemetrexed combined with ICI and ICI monotherapy in maintenance treatment. The object of this study is to explore the efficacy and safety of ICI as maintenance therapy in such patients. Methods: The study retrospectively analyzed patients with driver gene-negative advanced LUAD in PLA General Hospital from January 2019 to June 2022. These patients had received pemetrexed and platinum-based chemotherapy combined with ICI for 4-6 cycles. Patients who didn’t progress were subsequently entered into maintenance stage. The primary endpoint was progression-free survival (PFS) and overall survival (OS), and the secondary endpoint was objective response rate (ORR) and safety. Results: A total of 93 patients with advanced LUAD who received first-line chemotherapy combined with ICI were collected, including 39 patients receiving pemetrexed plus ICI of maintenance therapy, 30 patients receiving ICI maintenance therapy, and 24 patients who failed to enter the maintenance treatment. Baseline characteristics of ICI group and pemetrexed plus ICI group were as follows: median age, 61.5 (42~81) years vs. 63 (35~74) years; male, 66.7% (20/30) vs. 79.5% (31/39); Smoking history, 63.3% (19/30) vs. 74.4% (29/39); Brain metastases, 10% (3/30) vs. 23.1% (9/39). ORR was 60.0% (95%CI 42.5-77.5) in the ICI monotherapy group and 69.2% (95%CI 54.7~83.7) in the pemetrexed plus ICI group. By November 30, 2022, the median follow-up time was 19.2 months. The median PFS of the two groups were 15.8 months (95%CI 9.84-21.70) in ICI group and 22.8 months (95%CI 4.57-40.97) in pemetrexed plus ICI group and there was no statistical difference between the two groups (P = 0.50). Neither group achieved OS. The incidence of all grade treatment-related adverse events (TRAEs) was 90.0% (27/30) in ICI monotherapy group and 92.3% (36/39) in pemetrexed plus ICI group. Grade 3/4 TRAEs occurred in 23.3% (7/30) and 23.1% (9/39) of each cohort and no grade 5 TRAE occurred. Conclusions: ICI maintenance therapy without pemetrexed showed great therapeutic efficacy in first-line maintenance stage and can be a feasible regimen in advanced lung adenocarcinoma.
Pretreatment radiomic biomarker for immunotherapy responder prediction in IB-IV stage NSCLC: A multi-center retrospective study.
Authors: Wu Shaowei , Zhou HaiYu , Xie Daipeng , Yao Lintong
Published: June 2023

e21060

Background: The current biomarker of immune checkpoint inhibitors (ICIs) efficacy is not sufficient. This study investigated the correlation between radiomic biomarker and immunotherapy responder in patients with IB-IV stage non-small-cell lung cancer (NSCLC), including its biological explanation for ICIs treatment response prediction. Methods: CT images from 319 pretreatment NSCLC patients receiving immunotherapy between January, 2015 and November, 2021 were retrospectively collected and were distributed into a discovery (n = 214), independent validation (n = 54), and external test cohort (n = 51). 851 features were extracted from both tumoral and each peri-tumoral VOIs. The reference standard is the durable clinical benefit (DCB) and the crucial exclusion criteria are missing pretreatment CT scans. The predictive value of combined radiomic signature (CRS) was assessed in a cohort of 98 resectable NSCLC patients receiving ICIs. The association of radiomic features and tumor immune landscape on the online dataset (n = 60) was also evaluated. A clinical model was constructed and incorporated with radiomic signature to improve performance further. Results: CRS discriminated between DCB and non-DCB patients in the training cohort (area under the curve (AUC): 0.82, 95% CI: 0.75 to 0.88)) and independent cohort (AUC: 0.75, 95%CI: 0.62 to 0.88). In this study, the predictive value of CRS was better than PD-L1 expression (AUC of PD-L1 subset: 0.59, 95%CI: 0.50 to 0.69) or clinical model (AUC of validation cohort: 0.66, 95%CI: 0.51 to 0.81). When predicting pathological response, CRS divided patients into a major pathological response (MPR) and non-MPR group (AUC: 0.76, 95%CI: 0.67 to 0.81). Moreover, CRS showed a promising stratified ability on overall survival (OS; HR: 0.48, 95%CI: 0.27 to 0.89; p = 0.020) and progression-free survival (PFS; HR: 0.43, 95%CI: 0.26 to 0.74; p = 0.002). Biological pathway analysis on online dataset revealed that dysregulation of Hedgehog and Hippo signaling pathways got involved in the prediction of radiomic features. Conclusions: By analyzing both tumoral and peri-tumoral regions of CT images in a radiomic strategy, we developed a non-invasive biomarker distinguishing responder from ICIs therapy, which might inform clinical decisions on the use of ICIs in advanced as well as resectable NSCLC patients.
Post-double lung transplantation survival outcomes of bilateral lung cancer and incidence of post-transplant lung cancer.
Authors: Lee Jeeyeon , Yu Jisang , Schellenberg Samuel , Chung Il-Young , Bharat Ankit , Chae Young Kwang
Published: June 2023

e21061

Background: To evaluate the role of double lung transplantation (DLT) for lung cancer, the survival outcomes of patients who underwent DLT for lung cancer and the incidence of lung cancer after DLT were assessed. Methods: Data from case series reported in the literature were pooled and collected from the Organ Procurement Transplantation Network (OPTN) and the International Society of Heart and Lung Transplantation (ISHLT) registries. We evaluated the recurrence-free survival (RFS), overall survival (OS), and cancer-specific survival (CSS) of patients who underwent DLT for lung cancer. Moreover, the incidence and OS of post-transplant lung cancer in patients who received transplants for the non-cancerous disease were examined. Results: Regarding patients who underwent DLT for lung cancer, in the pooled (n = 19), OPTN (n = 15), and ISHLT (n = 25) data, 5-year RFS was 52.6%, 66.7%, and 80.0%, and 5-year OS was 57.9%, 26.7%, and 36.0%, respectively. The median CSS was 48.0 (range, 6.0–144.0), 27.7 (range, 0.2–66.6), and 24.0 (range, 0.1–145.1) months. Additionally, the application of cardiopulmonary bypass was associated with lower tumor recurrence in the pooled data (p = 0.004). The incidence and 5-year OS post-transplant lung cancer in patients who underwent DLT for the non-cancerous disease were 0.8% and 47.3% in the OPTN data and 0.6% and 50.7% in the ISHLT data, respectively. Conclusions: We demonstrated that reasonable survival outcomes can be achieved with DLT in patients with bilateral lung cancer. Further studies are required to evaluate the risk of post-transplant lung cancer in patients undergoing DLT for bilateral lung cancer.
Clinical efficacy of frontline immunotherapy (IO) in ethnic-minority patients (pts) with metastatic NSCLC.
Authors: Lee Matthew , Liu Jianyou , Miao Emily , Wang Shuai , Zhang Frank , Wei John X , Chung Julie , Xue Xiaonan , Halmos Balazs , Hosgood Dean , Cheng Haiying
Published: June 2023

e21063

Background: Since minority pts have been historically underrepresented in key IO trials, knowledge on the clinical use of IO in ethnic-minority pts with non-small cell lung cancer (NSCLC) remains limited. This study aims to evaluate race/ethnicity and other demographic, socioeconomic and clinical factors of pts with metastatic NSCLC treated with first-line IO. Methods: A retrospective cohort study of 5920 pts diagnosed with lung cancer within the Montefiore Health system from 1/1/2013 to 6/1/2022 was conducted. Pts with metastatic NSCLC without EGFR or ALK alterations and underwent first-line IO use were identified. The primary endpoint was overall survival (OS) with secondary endpoints of progression-free survival (PFS) and time to discontinuation (TTD) from the start of IO. Results: In total, 248 pts were identified with median follow-up time of 10.7 months (mons), median age of 66 years and 39.1% as Non-Hispanic Black (NHB), 30.2% as Hispanic and 30.7% as non-Hispanic White (NHW). OS (p = 0.39), PFS (p = 0.29) and TTD (p = 0.98) were similar among races/ethnic groups. ECOG < 2 at the start of IO was associated with longer OS summarized in Table 1. Significantly higher PFS and TTD were noted respectively in pts with Medicare insurance and PD-L1 status (TPS>1), while lower PFS and TTD with lower BMI. These results were remained after adjusting for biological sex, smoking status, histology, and IO regimen. Conclusions: Our study demonstrates that race/ethnicity does not impact the benefits of IO. However, factors such as ECOG status impact OS, and BMI, insurance and PD-L1 significantly impact PFS and TTD. These findings help identify potential factors that can be addressed to optimize outcomes and supportive care while undergoing IO.[Table: see text]