Identification of a central network hub of key prognostic genes based on correlation between transcriptomics and survival in patients with metastatic solid tumors.

Background: Dysregulated pathways in cancer may be hub addicted. Identifying these dysregulated networks for targeting might lead to novel therapeutic options. Objective: Considering the hypothesis that central hubs are associated with increased lethality, identifying key hub targets within central networks could lead to the development of novel drugs with improved efficacy in advanced metastatic solid tumors. Design: Exploring transcriptomic data (22,000 gene products) from the WINTHER trial (N = 101 patients with various metastatic cancers), in which both tumor and normal organ-matched tissue were available. Methods: A retrospective in silico analysis of all genes in the transcriptome was conducted to identify genes different in expression between tumor and normal tissues (paired t-test) and to determine their association with survival outcomes using survival analysis (Cox proportional hazard regression algorithm). Based on the biological relevance of the identified genes, hub targets of interest within central networks were then pinpointed. Patients were grouped based on the expression level of these genes (K-mean clustering), and the association of these groups with survival was examined (Cox proportional hazard regression algorithm, Forest plot, and Kaplan-Meier plot). Results: We identified four key central hub genes-PLOD3, ARHGAP11A, RNF216, and CDCA8, for which high expression in tumor tissue compared to analogous normal tissue had the most significant correlation with worse outcomes. The correlation was independent of tumor or treatment type. The combination of the four genes showed the highest significance and correlation with the poorer outcome: overall survival (hazard ratio (95% confidence interval (CI)) = 10.5 (3.43-31.9) p = 9.12E-07 log-rank test in a Cox proportional hazard regression model). Findings were validated in independent cohorts. Conclusion: The expression of PLOD3, ARHGAP11A, RNF216, and CDCA8 constitute, when combined, a prognostic tool, agnostic of tumor type and previous treatments. These genes represent potential targets for intercepting central hub networks in various cancers, offering avenues for novel therapeutic interventions.

Referral rates and barriers to lung transplantation based on pulmonary function criteria in interstitial lung diseases: a retrospective cohort study.

BACKGROUND: Interstitial lung diseases (ILD) unresponsive to medical therapy often require lung transplantation (LTx), which prolongs quality of life and survival. Ideal timing for referral for LTx remains challenging, with late referral associated with significant morbidity and mortality. Among other criteria, patients with ILD should be considered for LTx if forced vital capacity (FVC) is less than 80% or diffusion capacity for carbon monoxide (DLCO) is less than 40%. However, data on referral rates are lacking. OBJECTIVES: To evaluate referral rates for LTx based on pulmonary function tests (PFTs) and identify barriers associated with non-referral. DESIGN: A single-center retrospective cohort study. METHODS: The study consisted of ILD patients who performed PFT between 2014 and 2020. Patients with FVC < 80% or a DLCO < 40% were included in the study. Patients with absolute contraindications to LTx were excluded. Referral rates were computed, and a comparison was made between referred and non-referred subjects. RESULTS: Out of 114 ILD patients meeting criteria for referral to LTx, 35 were referred (30.7%), and 7 proceeded to undergo LTx. Median time from PFT to referral for assessment was 255 days [interquartile range (IQR) 35-1077]. Median time from referral to LTx was 89 days (IQR 59-143). Referred patients were younger (p = 0.003), had lower FVC (p < 0.001), DLCO (p < 0.001), and a higher rate of pulmonary hypertension (p = 0.04). Relatively better PFT, and older age, were significantly associated with non-referral of patients. CONCLUSION: There is under-referral of ILD patients who are eligible for LTx, which is associated with severe disease and missed opportunities for LTx. Further research is required to validate these findings.

Lung transplants: addressing referral gaps for lung disease patientsPatients with severe lung diseases that are unresponsive to medical treatments often require lung transplants to enhance their quality of life and survival. Determining the optimal timing for considering a transplant is challenging, as delaying it can lead to complications. Our study aimed to assess how frequently individuals with lung problems, particularly interstitial lung diseases, were referred for lung transplants based on lung function tests. We conducted a retrospective analysis of medical records for patients with lung diseases who underwent lung function tests between 2014 and 2020. We selected patients whose test results indicated impaired lung function, excluding those who were ineligible for lung transplants due to other medical reasons. Subsequently, we examined the number of patients referred for a lung transplant and compared them to those who were not referred. Our findings revealed that out of 114 patients eligible for a lung transplant, only 35 were referred, representing a referral rate of approximately 31%. Among these, only 7 patients actually underwent the transplant procedure. The time elapsed between the lung function test and the referral for a transplant assessment was notably long, averaging around 255 days. Additionally, once referred, patients waited an average of 89 days for the transplant assessment. Referred patients tended to be younger and had more severe lung disease, characterized by lower lung function test results and a higher likelihood of pulmonary hypertension. Conversely, patients who were not referred generally enjoyed better overall health and were older. This discrepancy highlights the missed opportunities for patients to improve their health and quality of life through lung transplantation. Further research is essential to verify the accuracy of these findings, but this study represents a crucial step toward ensuring that individuals with lung diseases receive the appropriate care they require.

Persistent Severe Acute Respiratory Syndrome Coronavirus 2 Pneumonia in Patients Treated With Anti-CD20 Monoclonal Antibodies.

We report 8 cases of persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia in patients previously treated with anti-CD20 monoclonal antibodies. Polymerase chain reaction of nasopharyngeal swabs for SARS-CoV-2 was negative in most cases; viral cell cultures confirmed that viable SARS-Co-2 virus was present. Four patients were treated with anti-SARS-CoV-2 hyperimmune globulins with rapid resolution of disease.

Effects of EGFR driver mutations on pathologic regression in resectable locally advanced non-small cell lung cancer treated with neoadjuvant chemoradiation and completion surgery.

OBJECTIVE: We hypothesized that driver mutations in epidermal growth factor receptor (EGFR) are associated with decreased pathologic response to neoadjuvant chemoradiation (NA-ChRT) in locally advanced non-small cell lung cancer (LA-NSCLC). METHODS: Patients with Stage IIB-IIIA NSCLC treated with NA-ChRT, completion surgery, and underwent molecular profile testing were identified in a lung cancer database. Pathologic response was quantified using: (i) major pathologic response (MPR), (ii) complete pathologic response (pCR), and (iii) mean residual viable tumor cells (MRTC). Two groups were formed based on the presence or absence of driver mutations. Clinical and pathological correlations between the groups were studied. RESULTS: Forty-seven patients underwent tumor molecular profile testing, NA-ChRT, and completion surgery. Compared to the no-driver mutation group, the driver mutation group had lower MPR (23% vs 71%, p = 0.003), pCR (0% vs 26%, p = 0.02), and higher MRTC (43.4% vs 15.8%, p = 0.009). Univariate analysis showed an increased MPR rate for smokers, squamous cell histology, ChRT-surgery interval >65 days, and no-driver mutations. Multivariate analysis showed that only no-driver mutations (OR 0.39, p = 0.02) remained significant for MPR. PD-L1 status did not affect MPR. At 2 years, the driver mutation group had lower rates of local control (Hazard ration [HR] 0.67, p = 0.17) and disease-free survival (HR 0.5, p = 0.001). Overall survival was similar for both groups (HR = 1.04, p = 0.86). CONCLUSION: Following 60 Gray NA-ChRT, tumors with a driver mutation had lower MPR and pCR rates than tumors without a driver mutation. PD-L1 was not associated with tumor regression. ADVANCES IN KNOWLEDGE: Patients with resectable LA-NSCLC and an EGFR driver mutation treated with neoadjuvant-ChRT and completion surgery have reduced pathologic regression, lower local control rates, and shorter disease-free survival than patients without a driver mutation. Evaluation of molecular testing should be introduced in LA-NSCLC intended for prognostication and treatment decisions.

Magnetic resonance imaging for prospective assessment of local recurrence of non-small cell lung cancer after stereotactic body radiation therapy.

OBJECTIVES: To evaluate multi-parametric MRI for distinguishing stereotactic body radiation therapy (SBRT) induced pulmonary fibrosis from local recurrence (LR). MATERIALS AND METHODS: SBRT treated non-small cell lung cancer (NSCLC) patients suspected of LR by conventional imaging underwent MRI: T2 weighted, diffusion weighted imaging, dynamic contrast enhancement (DCE) with a 5-minute delayed sequence. MRI was reported as high or low suspicion of LR. Follow-up imaging ≥12 months or biopsy defined LR status as proven LR, no-LR or not-verified. RESULTS: MRI was performed between 10/2017 and 12/2021, at a median interval of 22.5 (interquartile range 10.5-32.75) months after SBRT. Of the 20 lesions in 18 patients: 4 had proven LR, 10 did not have LR and 6 were not verified for LR due to subsequent additional local and/or systemic therapy. MRI correctly identified as high suspicion LR in all proven LR lesions and low suspicion LR in all confirmed no-LR lesions. All proven LR lesions (4/4) showed heterogeneous enhancement and heterogeneous T2 signal, as compared to the proven no-LR lesions in which 7/10 had homogeneous enhancement and homogeneous T2 signal. DCE kinetic curves could not predict LR status. Although lower apparent diffusion coefficient (ADC) values were seen in proven LR lesions, no absolute cut-off ADC value could determine LR status. CONCLUSION: In this pilot study of NSCLC patients after SBRT, multi-parametric chest MRI was able to correctly determine LR status, with no single parameter being diagnostic by itself. Further studies are warranted.

Timing of Lung Transplant Referral in Patients with Severe COVID-19 Lung Injury Supported by ECMO.

Severe respiratory failure caused by COVID-19 often requires mechanical ventilation, including extracorporeal membrane oxygenation (ECMO). In rare cases, lung transplantation (LTx) may be considered as a last resort. However, uncertainties remain about patient selection and optimal timing for referral and listing. This retrospective study analyzed patients with severe COVID-19 who were supported by veno-venous ECMO and listed for LTx between July 2020 and June 2022. Out of the 20 patients in the study population, four who underwent LTx were excluded. The clinical characteristics of the remaining 16 patients were compared, including nine who recovered and seven who died while awaiting LTx. The median duration from hospitalization to listing was 85.5 days, and the median duration on the waitlist was 25.5 days. Younger age was significantly associated with a higher likelihood of recovery without LTx after a median of 59 days on ECMO, compared to those who died at a median of 99 days. In patients with severe COVID-19-induced lung damage supported by ECMO, referral to LTx should be delayed for 8-10 weeks after ECMO initiation, particularly for younger patients who have a higher probability of spontaneous recovery and may not require LTx.

A Novel Artificial Intelligence Based Denoising Method for Ultra-Low Dose CT Used for Lung Cancer Screening.

RATIONALE AND OBJECTIVES: To assess ultra-low-dose (ULD) computed tomography as well as a novel artificial intelligence-based reconstruction denoising method for ULD (dULD) in screening for lung cancer. MATERIALS AND METHODS: This prospective study included 123 patients, 84 (70.6%) men, mean age 62.6 ± 5.35 (55-75), who had a low dose and an ULD scan. A fully convolutional-network, trained using a unique perceptual loss was used for denoising. The network used for the extraction of the perceptual features was trained in an unsupervised manner on the data itself by denoising stacked auto-encoders. The perceptual features were a combination of feature maps taken from different layers of the network, instead of using a single layer for training. Two readers independently reviewed all sets of images. RESULTS: ULD decreased average radiation-dose by 76% (48%-85%). When comparing negative and actionable Lung-RADS categories, there was no difference between dULD and LD (p = 0.22 RE, p > 0.999 RR) nor between ULD and LD scans (p = 0.75 RE, p > 0.999 RR). ULD negative likelihood ratio (LR) for the readers was 0.033-0.097. dULD performed better with a negative LR of 0.021-0.051. Coronary artery calcifications (CAC) were documented on the dULD scan in 88(74%) and 81(68%) patients, and on the ULD in 74(62.2%) and 77(64.7%) patients. The dULD demonstrated high sensitivity, 93.9%-97.6%, with an accuracy of 91.7%. An almost perfect agreement between readers was noted for CAC scores: for LD (ICC = 0.924), dULD (ICC = 0.903), and for ULD (ICC = 0.817) scans. CONCLUSION: A novel AI-based denoising method allows a substantial decrease in radiation dose, without misinterpretation of actionable pulmonary nodules or life-threatening findings such as aortic aneurysms.

A transcriptomics approach to expand therapeutic options and optimize clinical trials in oncology.

Background: The current model of clinical drug development in oncology displays major limitations due to a high attrition rate in patient enrollment in early phase trials and a high failure rate of drugs in phase III studies. Objective: Integrating transcriptomics for selection of patients has the potential to achieve enhanced speed and efficacy of precision oncology trials for any targeted therapies or immunotherapies. Methods: Relative gene expression level in the metastasis and normal organ-matched tissues from the WINTHER database was used to estimate in silico the potential clinical benefit of specific treatments in a variety of metastatic solid tumors. Results: As example, high mRNA expression in tumor tissue compared to analogous normal tissue of c-MET and its ligand HGF correlated in silico with shorter overall survival (OS; p < 0.0001) and may constitute an independent prognostic marker for outcome of patients with metastatic solid tumors, suggesting a strategy to identify patients most likely to benefit from MET-targeted treatments. The prognostic value of gene expression of several immune therapy targets (PD-L1, CTLA4, TIM3, TIGIT, LAG3, TLR4) was investigated in non-small-cell lung cancers and colorectal cancers (CRCs) and may be useful to optimize the development of their inhibitors, and opening new avenues such as use of anti-TLR4 in treatment of patients with metastatic CRC. Conclusion: This in silico approach is expected to dramatically decrease the attrition of patient enrollment and to simultaneously increase the speed and detection of early signs of efficacy. The model may significantly contribute to lower toxicities. Altogether, our model aims to overcome the limits of current approaches.

Driver mutation characteristics of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) in advanced non-small cell lung cancer.

OBJECTIVES: The identification and targeting of actionable genomic alterations (AGA) have revolutionized the treatment of cancer in general and mostly for non-small cell lung cancer (NSCLC). We investigated whether in NSCLC patients PIK3CA mutations are actionable. MATERIALS AND METHODS: Chart review was performed of advanced NSCLC patients. PIK3CA mutated patients were analyzed as two groups: Group A: without any non-PIK3CA established AGA; Group B: with coexisting AGA. Group A was compared to a cohort of non-PIK3CA patients (group C), using t-test and chi-square. To evaluate the impact of PIK3CA mutation on outcome, we compared Group A survival to age/sex/histology matched cohort of non-PIK3CA mutated patients (group D) by Kaplan-Meier method. A patient with a PIK3CA mutation was treated with a PI3Ka-isoform selective inhibitor BYL719 (Alpelisib). RESULTS: Of a cohort of 1377 patients, 57 are PIK3CA mutated (4.1%). Group A: n-22, group B: n-35. Group A median age is 76 years, 16 (72.7%) men, 10 (45.5%) squamous, 4 (18.2%) never smokers. Two never-smoker female adenocarcinoma patients had solitary PIK3CA mutation. One of them was treated with a PI3Ka-isoform selective inhibitor BYL719 (Alpelisib), with rapid clinical and partial radiological improvement. Group B, compared with Group A, included younger patients (p = 0.030), more females (p = 0.028) and more adenocarcinoma cases (p < 0.001). Compared to group C, group A patients were older (p = 0.030) and had more squamous histology (p = 0.011). CONCLUSION: In a small minority of NSCLC patients with PIK3CA mutation there are no additional AGA. PIK3CA mutations may be actionable in these cases.

Comorbidity between lung cancer and COVID-19 pneumonia: role of immunoregulatory gene transcripts in high ACE2-expressing normal lung.

Background: SARS-CoV-2 (COVID-19) elicits a T-cell antigen-mediated immune response of variable efficacy. To understand this variability, we explored transcriptomic expression of angiotensin-converting enzyme 2 (ACE2, the SARS-CoV-2 receptor) and of immunoregulatory genes in normal lung tissues from patients with non-small cell lung cancer (NSCLC). Methods: This study used the transcriptomic and the clinical data for NSCLC patients generated during the CHEMORES study [n = 123 primary resected (early-stage) NSCLC] and the WINTHER clinical trial (n = 32 metastatic NSCLC). Results: We identified patient subgroups with high and low ACE2 expression (p = 1.55 × 10-19) in normal lung tissue, presumed to be at higher and lower risk, respectively, of developing severe COVID-19 should they become infected. ACE2 transcript expression in normal lung tissues (but not in tumor tissue) of patients with NSCLC was higher in individuals with more advanced disease. High-ACE2 expressors had significantly higher levels of CD8+ cytotoxic T lymphocytes and natural killer cells but with presumably impaired function by high Thymocyte Selection-Associated High Mobility Group Box Protein TOX (TOX) expression. In addition, immune checkpoint-related molecules - PD-L1, CTLA-4, PD-1, and TIGIT - are more highly expressed in normal (but not tumor) lung tissues; these molecules might dampen immune response to either viruses or cancer. Importantly, however, high inducible T-cell co-stimulator (ICOS), which can amplify immune and cytokine reactivity, significantly correlated with high ACE2 expression in univariable analysis of normal lung (but not lung tumor tissue). Conclusions: We report a normal lung immune-tolerant state that may explain a potential comorbidity risk between two diseases - NSCLC and susceptibility to COVID-19 pneumonia. Further, a NSCLC patient subgroup has normal lung tissue expressing high ACE2 and high ICOS transcripts, the latter potentially promoting a hyperimmune response, and possibly leading to severe COVID-19 pulmonary compromise.

Transcriptomics in Tumor and Normal Lung Tissues Identify Patients With Early-Stage Non-Small-Cell Lung Cancer With High Risk of Postsurgery Recurrence Who May Benefit From Adjuvant Therapies.

PURPOSE: The prognosis of patients with non-small-cell lung cancer (NSCLC), traditionally determined by anatomic histology and TNM staging, neglects the biological features of the tumor that may be important in determining patient outcome and guiding therapeutic interventions. Identifying patients with NSCLC at increased risk of recurrence after curative-intent surgery remains an important unmet need so that known effective adjuvant treatments can be offered to those at highest risk of recurrence. METHODS: Relative gene expression level in the primary tumor and normal bronchial tissues was used to retrospectively assess their association with disease-free survival (DFS) in a cohort of 120 patients with NSCLC who underwent curative-intent surgery. RESULTS: Low versus high Digital Display Precision Predictor (DDPP) score (a measure of relative gene expression) was significantly associated with shorter DFS (highest recurrence risk; P = .006) in all patients and in patients with TNM stages 1-2 (P = .00051; n = 83). For patients with stages 1-2 and low DDPP score (n = 29), adjuvant chemotherapy was associated with improved DFS (P = .0041). High co-overexpression of CTLA-4, PD-L1, and ICOS in normal lung (28 of 120 patients) was also significantly associated with decreased DFS (P = .0013), suggesting an immune tolerance to tumor neoantigens in some patients. Patients with DDPP low and immunotolerant normal tissue had the shortest DFS (P = 2.12E-11). CONCLUSION: TNM stage, DDPP score, and immune competence status of normal lung are independent prognostic factors in multivariate analysis. Our findings open new avenues for prospective prognostic assessment and treatment assignment on the basis of transcriptomic profiling of tumor and normal lung tissue in patients with NSCLC.

Liquid First Is "Solid" in Naïve Non-Small Cell Lung Cancer Patients: Faster Turnaround Time With High Concordance to Solid Next-Generation Sequencing.

Purpose: Molecular profiling is crucial in naïve non-small cell lung cancer (NSCLC). While tissue-based analysis is challenged by turnaround time and scarcity of tissue, there is increasing demand for liquid biopsy. We aimed to analyze the use of upfront liquid biopsy as a molecular profiling approach. Methods: This retrospective multicenter, non-interventional study compared findings and turnaround times of liquid vs. standard-of-care (SOC) tissue-biopsy molecular profiling. The study included naïve advanced NSCLC patients with available liquid biopsy (Guardant360 CDx). Results: A total of 42 consecutive patients (60% men; median age, 69.5 [39-87] years; 86% stage IV NSCLC) were identified between September 2017 and December 2020. Liquid-biopsy analysis provided results for all 42 patients, whereas the tissue-based analysis failed in 5 (12%) patients due to insufficient tumor samples. In 17 patients, 18 actionable driver mutations were identified. Eleven mutations were detected by both approaches (i.e., concordance of 61%), 4 only by liquid biopsy and 3 only by tissue biopsy. The median time from the molecular request to receiving the molecular solid report on the last biomarker was 21 (range: 5-66) days, whereas the median time from blood draw to the liquid-biopsy results was 10.5 (7-19) days. The median time between the availability of liquid-biopsy findings and that of the last biomarker was 5 days. Treatment changes following the liquid-biopsy results were observed in 3 (7%) patients. Conclusion: Performing liquid-biopsy upfront is feasible and accurate and allows a shorter time for treatment in NSCLC, especially when tumor tissue is scarce.

The Impact of Comprehensive Genomic Profiling (CGP) on the Decision-Making Process in the Treatment of ALK-Rearranged Advanced Non-Small Cell Lung Cancer (aNSCLC) After Failure of 2nd/3rd-Generation ALK Tyrosine Kinase Inhibitors (TKIs).

Background: The use of CGP in guiding treatment decisions in aNSCLC with acquired resistance to ALK TKIs is questionable. Methods: We prospectively assessed the impact of CGP on the decision-making process in ALK-rearranged aNSCLC patients following progression on 2nd/3rd-generation ALK TKIs. Physician's choice of the most recommended next-line systemic treatment (NLST) was captured before and after receival of CGP results; the percentage of cases in which the NLST recommendation has changed was assessed along with the CGP turnaround time (TAT). Patients were divided into groups: patients in whom the NLST was initiated after (group 1) and before (group 2) receival of the CGP results. Time-to-treatment discontinuation (TTD) and overall survival (OS) with NLST were compared between the groups. Results: In 20 eligible patients (median [m]age 63 years [range, 40-89], females 75%, adenocarcinoma 100%, failure of alectinib 90%, FoundationOne Liquid CDx 80%), CGP has altered NLST recommendation in 30% of cases. CGP findings were as follows: ALK mutations 30% (l1171X 10%, G1202R, L1196M, G1269A, G1202R+l1171N+E1210K 5% each), CDKN2A/B mutation/loss 10%, c-met amplification 5%. CGP mTAT was 2.9 weeks [IQR, 2.4-4.4]. mTTD was 11.3 months (95% CI, 2.1-not reached [NR]) and 5.4 months (95% CI, 2.0-NR) in groups 1 and 2, respectively (p-0.34). mOS was 13.2 months (95% CI, 2.9-NR) and 13.0 months (95% CI, 6.0-NR) in groups 1 and 2, respectively (p-0.86). Conclusion: CGP has a significant impact on the decision-making process in ALK-rearranged aNSCLC following progression on 2nd/3rd-generation ALK TKIs.

FGFR Fusions as an Acquired Resistance Mechanism Following Treatment with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR TKIs) and a Suggested Novel Target in Advanced Non-Small Cell Lung Cancer (aNSCLC).

BACKGROUND: FGFR1/2/3 fusions have been reported infrequently in aNSCLC, including as a rare, acquired resistance mechanism following treatment with EGFR TKIs. Data regarding their prevalence and therapeutic implications are limited. METHODS: The Guardant Health (GH) electronic database (ED) was evaluated for cases of aNSCLC and FGFR2/3 fusions; FGFR2/3 fusion prevalence with and without a co-existing EGFR mutation was assessed. The ED of Tel-Aviv Sourasky Medical Center (TASMC, June 2020-June 2021) was evaluated for cases of aNSCLC and de novo FGFR1/2/3 fusions. Patients with EGFR mutant aNSCLC progressing on EGFR TKIs and developing an FGFR1/2/3 fusion were selected from the ED of Davidoff Cancer Center (DCC) and Oncology Department, Bnei-Zion hospital (BZ) (April 2014-April 2021). Clinicopathological characteristics, systemic therapies, and outcomes were assessed. RESULTS: In the GH ED (n = 57,445), the prevalence of FGFR2 and FGFR3 fusions were 0.02% and 0.26%, respectively. FGFR3-TACC3 fusion predominated (91.5%). In 23.8% of cases, FGFR2/3 fusions co-existed with EGFR sensitizing mutations (exon 19 del, 64.1%; L858R, 33.3%, L861Q, 2.6%). Among samples with concurrent FGFR fusions and EGFR sensitizing mutations, 41.0% also included EGFR resistant mutations. In TASMC (n = 161), 1 case of de novo FGFR3-TACC3 fusion was detected (prevalence, 0.62%). Of three patients from DCC and BZ with FGFR3-TACC3 fusions following progression on EGFR TKIs, two received EGFR TKI plus erdafitinib, an FGFR TKI, with clinical benefit duration of 13.0 and 6.0 months, respectively. CONCLUSIONS: Over 23% of FGFR2/3 fusions in aNSCLC may be associated with acquired resistance following treatment with EGFR TKIs. In this clinical scenario, a combination of EGFR TKIs and FGFR TKIs represents a promising treatment strategy.

Chemoradiation followed by adjuvant durvalumab in stage III non-small cell lung cancer: Real-world comparison of treatment outcomes to historical controls treated with chemoradiation alone.

OBJECTIVE: Compare outcomes in patients with stage III non-small cell lung cancer (NSCLC) treated with chemoradiation and adjuvant durvalumab to historical controls treated with chemoradiation alone. METHODS: The records of patients with stage III NSCLC treated with definitive chemoradiation ± adjuvant durvalumab were reviewed retrospectively. Primary endpoints were progression free survival (PFS), overall survival (OS), and adverse events (AE). RESULTS: Between September 2009 and September 2020, 215 patients were treated with concurrent chemoradiation (n = 144) or concurrent chemoradiation followed by adjuvant durvalumab (n = 71). Compared to historical controls, durvalumab use was associated with improved PFS: median (27 months vs. 10 months, p < 0.0001), 1-year (83.1% vs. 43.8, p < 0.0001); and improved OS; median (not reached vs. 24 months, p < 0.0001), 1-year (85.9% vs. 81.9%, p < 0.0001). Multivariate analysis showed adjuvant durvalumab was associated with increased OS (p = 0.005) and PFS (p = 0.001). Within the durvalumab group, only clinical stage IIIA versus IIIB/C was associated with improved OS (p = 0.049), but not PFS. There was no association between PFS or OS and Eastern Cooperative Oncology Group (ECOG) score, prior history of immune disease, programmed death-ligand 1 (PD-L1) receptor status, delay in starting durvalumab beyond 42 days, or development of an AE. During durvalumab treatment, 63 AE were reported in 52 patients with treatment discontinuation in 11. Pneumonitis was the most common AE reported (n = 35, 49%). Most AE were grade 1-2 (n = 57). Grade 3-4 AE were uncommon (n = 6) and none were grade 5. CONCLUSION: Treatment with adjuvant durvalumab following chemoradiation was associated with improved PFS and OS compared to chemoradiation alone.

Soluble HLA peptidome of pleural effusions is a valuable source for tumor antigens.

BACKGROUND: Soluble human leucocyte antigen (sHLA) molecules, released into the plasma, carry their original peptide cargo and provide insight into the protein synthesis and degradation schemes of their source cells and tissues. Other body fluids, such as pleural effusions, may also contain sHLA-peptide complexes, and can potentially serve as a source of tumor antigens since these fluids are drained from the tumor microenvironment. We explored this possibility by developing a methodology for purifying and analyzing large pleural effusion sHLA class I peptidomes of patients with malignancies or benign diseases. METHODS: Cleared pleural fluids, cell pellets present in the pleural effusions, and the primary tumor cells cultured from cancer patients' effusions, were used for immunoaffinity purification of the HLA molecules. The recovered HLA peptides were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) and the resulting LC-MS/MS data were analyzed with the MaxQuant software tool. Selected tumor antigen peptides were tested for their immunogenicity potential with donor peripheral blood mononuclear cells (PBMCs) in an in vitro assay. RESULTS: Mass spectrometry analysis of the pleural effusions revealed 39,669 peptides attributable to 11,305 source proteins. The majority of peptides identified from the pleural effusions were defined as HLA ligands that fit the patients' HLA consensus sequence motifs. The membranal and soluble HLA peptidomes of each individual patient correlated to each other. Additionally, soluble HLA peptidomes from the same patient, obtained at different visits to the clinic, were highly similar. Compared with benign effusions, the soluble HLA peptidomes of malignant pleural effusions were larger and included HLA peptides derived from known tumor-associated antigens, including cancer/testis antigens, lung-related proteins, and vascular endothelial growth factor pathway proteins. Selected tumor-associated antigens that were identified by the immunopeptidomics were able to successfully prime CD8+ T cells. CONCLUSIONS: Pleural effusions contain sHLA-peptide complexes, and the pleural effusion HLA peptidome of patients with malignant tumors can serve as a rich source of biomarkers for tumor diagnosis and potential candidates for personalized immunotherapy.

ALK Inhibitors or Chemotherapy for Third Line in ALK-positive NSCLC? Real-world Data.

OBJECTIVES: ALK inhibitors (ALKi) are the standard-of-care treatment for metastatic ALK-rearranged non-small cell lung cancer (NSCLC) in the first- and second-line setting. We conducted a real-world multi-institutional analysis, aiming to compare the efficacy of third-line ALKi versus chemotherapy in these patients. METHODS: Consecutive ALK-positive metastatic NSCLC patients treated with at least one ALKi were identified in the working databases of 7 Israeli oncology centers (the full cohort). Demographic and clinical data were collected. Patients receiving any systemic treatment beyond 2 ALKi comprised the third-line cohort, whether a third ALKi (group A) or chemotherapy (group B). Groups A and B were compared in terms of overall survival (OS) and time-to-next-treatment line (TNT). RESULTS: At a median follow-up of 41 months (95% confidence interval [CI]: 32-55), 80 (47.1%) have died. Median OS (mOS) in the full cohort (n = 170) was 52 months (95% CI: 32-65). Number of ALKi (hazard ratio [HR] 0.765; 95% CI: 0.61-0.95; P = .024) and age (HR 1.02, 95% CI: 1.01-1.04, P = .009) significantly associated with OS in the full cohort. The third-line cohort included 40 patients, of which 27 were treated with third ALKi (group A) and 13 treated with chemotherapy (group B). mOS from third-line initiation was 27 months in group A (95% CI: 13-NR) and 13 months for group B (95% CI: 3-NR); the difference was not significant (NS; P = .12). Chemotherapy as first line (HR 0.17, 95% CI: 0.05-0.52, P = .002) and a higher number of ALKi (HR 0.38, 95% CI: 0.20-0.86, P = .011) associated significantly with longer OS of the third-line cohort. TNT was 10 months for group A (95% CI: 5-19) and 3 months for group B (95% CI: 0-NR); the difference was NS (P = .079). CONCLUSION: We report mature real-world data of more than 4-year mOS in ALK-positive patients. The number of ALKi given was associated with a better outcome. OS and TNT demonstrated a statistically nonsignificant trend for a better outcome in patients receiving a third-line ALKi.

A WIN Consortium phase I study exploring avelumab, palbociclib, and axitinib in advanced non-small cell lung cancer.

BACKGROUND: The Worldwide Innovative Network (WIN) Consortium has developed the Simplified Interventional Mapping System (SIMS) to better define the cancer molecular milieu based on genomics/transcriptomics from tumor and analogous normal tissue biopsies. SPRING is the first trial to assess a SIMS-based tri-therapy regimen in advanced non-small cell lung cancer (NSCLC). METHODS: Patients with advanced NSCLC (no EGFR, ALK, or ROS1 alterations; PD-L1 unrestricted; ≤2 prior therapy lines) received avelumab, axitinib, and palbociclib (3 + 3 dose escalation design). RESULTS: Fifteen patients were treated (five centers, four countries): six at each of dose levels 1 (DL1) and DL2; three at DL3. The most common ≥Grade 3 adverse events were neutropenia, hypertension, and fatigue. The recommended Phase II dose (RP2D) was DL1: avelumab 10 mg/kg IV q2weeks, axitinib 3 mg po bid, and palbociclib 75 mg po daily (7 days off/21 days on). Four patients (27%) achieved a partial response (PR) (progression-free survival [PFS]: 14, 24, 25 and 144+ weeks), including two after progression on pembrolizumab. Four patients attained stable disease (SD) that lasted ≥24 weeks: 24, 27, 29, and 64 weeks. At DL1 (RP2D), four of six patients (66%) achieved stable disease (SD) ≥6 months/PR (2 each). Responders included patients with no detectable PD-L1 expression and low tumor mutational burden. CONCLUSIONS: Overall, eight of 15 patients (53%) achieved clinical benefit (SD ≥ 24 weeks/PR) on the avelumab, axitinib, and palbociclib combination. This triplet showed antitumor activity in NSCLC, including in tumors post-pembrolizumab progression, and was active at the RP2D, which was well tolerated. NCT03386929 clinicaltrial.gov.

Nivolumab in Non-Small Cell Lung Cancer: Real World Long-Term Survival Results and Blood-Based Efficacy Biomarkers.

OBJECTIVES: We aimed to examine clinical data and baseline blood test results as potential predictive biomarkers for benefit from nivolumab, in advanced non-small cell lung cancer patients (NSCLC). MATERIALS AND METHODS: A chart review was performed of 108 advanced NSCLC patients who commenced treatment with nivolumab between 2015-6 at three Israeli cancer centers, and for whom laboratory tests results were available. Data collected included sex, age, ECOG-PS, histology and number of previous lines of treatment. Baseline blood test results collected: absolute lymphocyte and neutrophil count (ANC), white blood cells (WBC), hemoglobin, platelets, albumin and lactate dehydrogenase (LDH). Neutrophil to Lymphocyte Ratio and 'derived NLR' (dNLR = (ANC/[WBC-ANC])) were calculated. Disease control at six months (DC6) was defined as any tumor shrinkage or stable disease during the first six months of nivolumab treatment. The association between clinical/laboratory variables and survival was tested with a Cox proportional hazard model. Data cut-off occurred in November 2019. RESULTS: 35 patients (32.4%) achieved DC6. Median overall survival (OS) of entire study population was 5.4 months. Four year survival rate was 16%. Achievement of DC6 strongly correlated with longer OS (HR 0.12, 95% C.I. 0.07-0.21, p<0.001). In univariate and multivariate analysis, dNLR, albumin and LDH correlated significantly with OS. No variables correlated significantly with DC6 in multivariate analysis. Based on albumin and LDH, we produced a score called CLAS (combined LDH and albumin score), including four prognostic groups of patients. Patients having low albumin and high LDH had the worst prognosis. CONCLUSION: In real-life setting, long-term efficacy of nivolumab in advanced line treatment of NSCLC is consistent with clinical trials. Response or stability of disease during first six months of treatment is associated with prolonged survival. We propose a novel score (CLAS) that may be useful for predicting outcome in nivolumab-treated NSCLC patients, but further validation is required.

Real-World Analysis of the Impact of Radiotherapy on Immunotherapy Efficacy in Non-Small Cell Lung Cancer.

BACKGROUND: Immunotherapy (IO) provides a significant benefit for a subgroup of non-small cell lung cancer (NSCLC) patients. Radiotherapy (XRT) might enhance the efficacy of IO. We evaluated the impact of the specifics of XRT treatments on the OS of IO-treated NSCLC patients. METHODS: Metastatic NSCLC patients treated with IO were retrospectively identified. Parameters included demographics, tumor characteristics, IO and XRT details. Correlation between the parameters and OS was tested with Cox regression. RESULTS: 453 patients were included. No XRT was given to 167 (36.9%) patients, whereas XRT prior and after IO had 182 (40.2%) and 104 (22.9%) patients, respectively. XRT total doses between 30 and 40 Gy had better overall survival (OS) compared to non-irradiated patients (hazard ratio (HR) 0.5, 95% CI 0.25-1.0, p = 0.049). Worse outcome was seen with total doses ≤ 10 Gy (HR 1.67, 95% 1.13-2.5, p = 0.01), XRT fractions of 4.1-8 Gy (HR 1.48, 95% CI 1.05-2.1, p = 0.027) and XRT to the bone (HR 1.36, 95% CI 1.01-1.8, p = 0.04). Several clinical parameters correlated with OS in the univariate analysis of the IO-treated patients. While, in the multivariate analysis, only ECOG-PS, treatment line, type of IO, albumin and NLR remained statistically significant. CONCLUSION: Specific doses, fractions and sites of XRT correlated with the OS of IO-treated NSCLC patients in the univariate analysis, although not in the multivariate analysis.