Biphenotypic lung carcinoma with coexpression of TTF-1 and ΔNP63/P40 within most of the same individual cells: a further case confirming poor prognosis and a review of literature.

The WHO Classification of Tumors, Thoracic Tumors, 5th edition, has outlined the use of TTF-1 and ΔNP63/P40 to discriminate between adenocarcinoma and squamous cell carcinoma. In 2015, the first description of a rare non-small cell lung carcinoma featuring co-expression of glandular and squamous differentiation within most of the same individual tumor cells was reported on, with ultrastructural and molecular demonstration of such a biphenotypic differentiation. We herein describe an additional case of this rare tumor entity, which is confirmed to be an aggressive neoplasm despite potential targets of therapy.

APOLLO 11 Project, Consortium in Advanced Lung Cancer Patients Treated With Innovative Therapies: Integration of Real-World Data and Translational Research.

INTRODUCTION: Despite several therapeutic efforts, lung cancer remains a highly lethal disease. Novel therapeutic approaches encompass immune-checkpoint inhibitors, targeted therapeutics and antibody-drug conjugates, with different results. Several studies have been aimed at identifying biomarkers able to predict benefit from these therapies and create a prediction model of response, despite this there is a lack of information to help clinicians in the choice of therapy for lung cancer patients with advanced disease. This is primarily due to the complexity of lung cancer biology, where a single or few biomarkers are not sufficient to provide enough predictive capability to explain biologic differences; other reasons include the paucity of data collected by single studies performed in heterogeneous unmatched cohorts and the methodology of analysis. In fact, classical statistical methods are unable to analyze and integrate the magnitude of information from multiple biological and clinical sources (eg, genomics, transcriptomics, and radiomics). METHODS AND OBJECTIVES: APOLLO11 is an Italian multicentre, observational study involving patients with a diagnosis of advanced lung cancer (NSCLC and SCLC) treated with innovative therapies. Retrospective and prospective collection of multiomic data, such as tissue- (eg, for genomic, transcriptomic analysis) and blood-based biologic material (eg, ctDNA, PBMC), in addition to clinical and radiological data (eg, for radiomic analysis) will be collected. The overall aim of the project is to build a consortium integrating different datasets and a virtual biobank from participating Italian lung cancer centers. To face with the large amount of data provided, AI and ML techniques will be applied will be applied to manage this large dataset in an effort to build an R-Model, integrating retrospective and prospective population-based data. The ultimate goal is to create a tool able to help physicians and patients to make treatment decisions. CONCLUSION: APOLLO11 aims to propose a breakthrough approach in lung cancer research, replacing the old, monocentric viewpoint towards a multicomprehensive, multiomic, multicenter model. Multicenter cancer datasets incorporating common virtual biobank and new methodologic approaches including artificial intelligence, machine learning up to deep learning is the road to the future in oncology launched by this project.

Repotrectinib Overcomes F2004V Resistance Mutation in ROS1-Rearranged NSCLC: A Case Report.

ROS1 tyrosine kinase inhibitors (TKIs) were found to provide a substantial clinical benefit for patients with advanced ROS1-positive (ROS1+) NSCLC. Nevertheless, TKI resistance inevitably develops with different mechanisms, preventing prolonged responses. For this reason, next-generation compounds are under clinical development. ROS1 F2004 substitutions have been previously detected on circulating tumor DNA of patients progressing to entrectinib. Hereby, we report the case of a patient with ROS1+ NSCLC in which F2004V-acquired mutation was detected on a site of disease progression, after entrectinib and crizotinib failure. A subsequent treatment with next-generation TKI repotrectinib led to disease response, providing the first clinical evidence of activity of repotrectinib against F2004V resistance mutation.

Association Between Lung Immune Prognostic Index and Durvalumab Consolidation Outcomes in Patients With Locally Advanced Non-Small-Cell Lung Cancer.

INTRODUCTION: The LIPI, based on pretreatment derived neutrophils/[leukocytes-neutrophils] ratio (dNLR) and LDH, is associated with immune checkpoint inhibitors (ICI) outcomes in advanced non-small-cell lung cancer (NSCLC). We aimed to assess baseline LIPI correlation with durvalumab consolidation outcomes in the locally advanced setting. MATERIAL AND METHODS: Multicentre retrospective study (330 patients) with stage III unresectable NSCLC treated with durvalumab after chemo-radiotherapy between April 2015 and December 2020; 65 patients treated with chemo-radiotherapy only. Baseline LIPI characterized 3 groups: good (dNLR≤3+LDH≤ULN), intermediate (dNLR>3/LDH>ULN) and poor (dNLR>3+LDH>ULN). Primary endpoint was overall survival (OS). RESULTS: In the durvalumab cohort, median age was 67 years, 95% smokers, 98% with a performance status of 0-1; 60% had nonsquamous histology and 16% a PD-L1 expression <1%. Radiotherapy was delivered concurrently in 81%. LIPI was evaluable in 216 patients: 66% good, 31% intermediate, 3% poor. LIPI significantly correlated with median OS (median follow-up: 19 months): 18.1 months vs. 47.0 months vs. not reached in poor, intermediate and good LIPI groups, respectively (P = .03). A trend between objective response rate and LIPI groups was observed: 0% vs. 41% vs. 45%, respectively (P = .05). The pooled intermediate/poor LIPI group was associated with shorter OS (HR 1.97; P = .03) and higher risk of progressive disease (OR 2.68; P = .047). Survivals and response were not influenced in the control cohort. CONCLUSION: Baseline LIPI correlated with outcomes in patients with locally advanced NSCLC treated with durvalumab consolidation, but not in those who only received chemo-radiotherapy, providing further evidence of its prognostic and potential predictive role of ICI benefit in NSCLC.

High bone tumor burden to identify advanced non-small cell lung cancer patients with survival benefit upon bone targeted agents and immune checkpoint inhibitors.

BACKGROUND: Bone-targeted agents (BTA), such as denosumab (DN) and zoledronic acid (ZA), have historically reduced the risk of skeletal related events in cancer patients with bone metastases (BM), with no improvement in survival outcomes. In the immunotherapy era, BM have been associated with poor prognosis upon immune-checkpoint inhibitors (ICI). Currently, the impact of bone tumor burden on survival upon BTAs in advanced non-small cell lung cancer (aNSCLC) patients treated with ICI remains unknown. METHODS: Data from ICI-treated aNSCLC patients with BM (4/2013-5/2022) in one institution were retrospectively collected. BTA-ICI concurrent treatment was defined as BTA administration at any time before or within 90 days from ICI start. High bone tumor burden (HBTB) was defined as ≥ 3 sites of BM. Median OS (mOS) was estimated with Kaplan-Meier. Aikaike's information criterion (AIC) was used to select the best model for data analysis adjusted for clinical variables. RESULTS: Of 134 patients included, 51 (38 %) received BTA. At a mFU of 39.6 months (m), BTA-ICIs concurrent treatment did not significantly impact on mOS [8.3 m (95% CI 3.9-12.8) versus (vs) 6.8 m (95% CI 4.0-9.6) p = 0.36]; these results were confirmed after adjustment for clinical variables selected by AIC. A multivariate model showed a significant interaction between BTA use and HBTB or radiation therapy to BM. In subgroup analyses, only HBTB confirmed to be associated with significantly longer mOS [8.3 m (95% CI 2.4-14.2) vs 3.5 m (95% CI 2.9-4.1), p = 0.003] and mPFS [3.0 m (95% CI 1.6-4.4) vs 1.8 m (95% CI 1.6-2.0) p = 0.001] upon BTA-ICI concurrent treatment, with the most pronounced OS benefit observed for DN-ICI concurrent regimen [15.2 m (95% CI 0.1-30.7) vs 3.5 m (95% CI 2.9-4.1) p = 0.002]. CONCLUSIONS: In the immunotherapy era, HBTB can identify patients experiencing survival benefit with BTA, especially with DN-ICI combination. HBTB should be included as a stratification factor in the upcoming trials assessing BTA and ICI combinations in patients with aNSCLC and BM.

What to do after immune-checkpoint inhibitors failure in advanced non-small cell lung cancer: an expert opinion and review.

INTRODUCTION: Immune-checkpoint inhibitors (IO) have significantly improved outcomes of patients with non-oncogene-addicted non-small cell lung cancer (NSCLC), becoming the first-line agents for advanced disease. However, resistance remains a significant clinical challenge, limiting their effectiveness. AREAS COVERED: Hereby, we addressed standard and innovative therapeutic approaches for NSCLC patients experiencing progression after IO treatment, discussing the emerging resistance mechanisms and the ongoing efforts to overcome them. In order to provide a complete overview of the matter, we performed a comprehensive literature search across prominent databases, including PubMed, EMBASE (Excerpta Medica dataBASE), and the Cochrane Library, and a research of the main ongoing studies on clinicaltrials.gov. EXPERT OPINION: The dynamics of progression to IO, especially in terms of time to treatment failure and burden of progressive disease, should guide the best subsequent management, together with patient clinical conditions. Long-responders to IO might benefit from continuation of IO beyond-progression, in combination with other treatments. Patients who experience early progression should be treated with salvage CT in case of preserved clinical conditions. Finally, patients who respond to IO for a considerable timeframe and who later present oligo-progression could be treated with a multimodal approach in order to maximize the benefit of immunotherapy.

Exploring the Role of Immunotherapy-Based Treatments for Advanced Non-Small-Cell Lung Cancer With Novel Driver Alterations.

BACKGROUND: Immunotherapy (IO) single agent or combined with chemotherapy (CT-IO) is the standard treatment for advanced non-small-cell lung cancer (aNSCLC) without driver alterations. IO efficacy in patients with novel driver alterations is not well reported. MATERIALS AND METHODS: Data of aNSCLC patients treated with IO or CT-IO in any line from January 2016 to September 2022 were retrospectively collected. Patients harboring novel driver alterations (m-cohort), including MET exon 14 skipping, BRAF (V600E or atypical), RET rearrangements, HER2 point mutations/exon 20 insertions or uncommon EGFR mutations/EGFR exon 20 insertions, and wild type patients (wt-cohort) were eligible. Clinico-pathological data were extracted from Institutional databases and compared through chi square or Fisher's exact test. Survivals were estimated through Kaplan-Meier method and compared by log-rank test. RESULTS: m-cohort and wt-cohort included 84 and 444 patients, respectively. Progression free survival (PFS) was 5.53 vs. 4.57 months (P= .846) and overall survival (OS) was 25.1 vs. 9.37 months, (P < .0001) for m-cohort compared to wt-cohort. Within the m-cohort, BRAF atypical mutations had the better outcomes (Overall Response Rate [ORR], PFS), targeted agents timing did not affect response to IO and CT-IO had better ORR and disease control rate (DCR) compared to IO single agent (P = .0160 and P = .0152). In the PD-L1≥50% group, first line IO single agent resulted in inferior ORR (P = .027) and PFS (P = .022) in m-cohort compared to wt-cohort. CONCLUSION: IO based treatments seem not detrimental for patients harboring novel driver alteration. Adding CT could improve modest responses to IO alone. Confirmation on larger datasets is required.

A systematic review and meta-analysis on the optimal treatment duration of checkpoint inhibitoRS in solid tumors: The OTHERS study.

No clear evidence supports the advantage of fixed (up to two years (2yICI)) or continuous treatment (more than two years (prolonged ICI)) in cancer patients achieving stable disease or response on immune checkpoint inhibitors (ICIs). We performed a systematic review and meta-analysis of randomized controlled trials reporting the duration of ICIs (alone or in combination with standard of care (SoC)) across various solid tumors. Overall, we identified 28,417 records through database searching. Based on the eligibility criteria, 57 studies were identified for the quantitative synthesis, including 22,977 patients receiving ICIs (with or without SoC). Prolonged ICI correlated with better overall survival (OS) than 2yICI in patients with melanoma (HR:1.55; 95%CI: 1.22,1.98), while 2yICI-SoC led to better OS than prolonged ICI-SoC in patients with NSCLC (HR: 0.84; 95%CI: 0.68,0.89). Prospective randomized trials are needed to assess the most appropriate duration of ICIs. OBJECTIVE: No clear evidence supports the advantage of fixed (up to two years (2yICI)) or continuous treatment (more than two years (prolonged ICI)) in cancer patients achieving stable disease or response on immune checkpoint inhibitors (ICIs). Here, we assessed the optimal treatment duration for ICIs in solid tumors. CONCLUSIONS: Prolonged ICIs administration does not seem to improve the outcomes of patients with NSCLC an RCC.

Immune Checkpoint Inhibitors and the Exposome: Host-Extrinsic Factors Determine Response, Survival, and Toxicity.

Cancer immunotherapy, largely represented by immune checkpoint inhibitors (ICI), has led to substantial changes in preclinical cancer research and clinical oncology practice over the past decade. However, the efficacy and toxicity profiles of ICIs remain highly variable among patients, with only a fraction achieving a significant benefit. New combination therapeutic strategies are being investigated, and the search for novel predictive biomarkers is ongoing, mainly focusing on tumor- and host-intrinsic components. Less attention has been directed to all the external, potentially modifiable factors that compose the exposome, including diet and lifestyle, infections, vaccinations, and concomitant medications, that could affect the immune system response and its activity against cancer cells. We hereby provide a review of the available clinical evidence elucidating the impact of host-extrinsic factors on ICI response and toxicity.

STYLE (NCT03449173): A Phase 2 Trial of Sunitinib in Patients With Type B3 Thymoma or Thymic Carcinoma in Second and Further Lines.

INTRODUCTION: Thymic malignancies are rare tumors with few therapeutic options. The STYLE trial was aimed to evaluate activity and safety of sunitinib in advanced or recurrent type B3 thymoma (T) and thymic carcinoma (TC). METHODS: In this multicenter, Simon 2 stages, phase 2 trial, patients with pretreated T or TC were enrolled in two cohorts and assessed separately. Sunitinib was administered 50 mg daily for 4 weeks, followed by a 2-week rest period (schedule 4/2), until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Progression-free survival, overall survival, disease control rate and safety were secondary endpoints. RESULTS: From March 2017 to January 2022, 12 patients with T and 32 patients with TC were enrolled. At stage 1, ORR was 0% (90% confidence interval [CI]: 0.0-22.1) in T and 16.7% (90% CI: 3.1-43.8) in TC, so the T cohort was closed. At stage 2, the primary endpoint was met for TC with ORR of 21.7% (90% CI: 9.0%-40.4%). In the intention-to-treat analysis, disease control rate was 91.7% (95% CI: 61.5%-99.8%) in Ts and 89.3% (95% CI: 71.8%-97.7%) in TCs. Median progression-free survival was 7.7 months (95% CI: 2.4-45.5) in Ts and 8.8 months (95% CI: 5.3-11.1) in TCs; median overall survival was 47.9 months (95% CI: 4.5-not reached) in Ts and 27.8 months (95% CI: 13.2-53.2) in TCs. Adverse events occurred in 91.7% Ts and 93.5% TCs. Grade 3 or greater treatment-related adverse events were reported in 25.0% Ts and 51.6% TCs. CONCLUSIONS: This trial confirms the activity of sunitinib in patients with TC, supporting its use as a second-line treatment, albeit with potential toxicity that requires dose adjustment.

Comparative assessment of early mortality risk upon immune checkpoint inhibitors alone or in combination with other agents across solid malignancies: a systematic review and meta-analysis.

BACKGROUND: The early crossing of survival curves in randomised clinical trials (RCTs) with immune checkpoint blockers suggests an excess of mortality in the first months of treatment. However, the exact estimation of the early death (ED) rate, the comparison between ED upon immune checkpoint inhibitors (ICI) alone or in combination with other agents and the impact of tumour type, and PD-L1 expression on ED are unknown. METHODS: RCTs comparing ICI alone (ICI-only group) or in combination with other non-ICI therapies (ICI-OT group) (experimental arms) versus non-ICI treatments (control arm) were included. ED was defined as death within the first 3 months of treatment. The primary outcome was the comparison of ED between experimental and control arms, and the secondary outcome was the comparison of ED risk between ICI-only and ICI-OT. ED rates estimated by risk ratio (RR) were pooled by random effect model. RESULTS: A total of 56 RCTs (40,215 participants, 14 cancer types) were included. ED occurred in 14.2% and 6.7% of patients in ICI-only and ICI-OT groups, respectively. ED risk significantly increased with ICI-only (RR: 1.29, 95% CI 1.05-1.57) versus non-ICI therapies, while it was lower with ICI-OT versus non-ICI treatments (RR: 0.81, 95% CI 0.73-0.90). ED risk was significantly higher upon ICI-only compared to ICI-OT (RR: 1.57, 95% CI 1.26-1.95). Gastric and urothelial carcinoma were at higher risk of ED. PD-L1 expression and ICI drug classes were not associated with ED. CONCLUSIONS: ED upon first-line ICI is a clinically relevant phenomenon across solid malignancies, not predictable by PD-L1 expression but preventable through the addition of other treatments to ICI.

RET rearrangements in non-small cell lung cancer: Evolving treatment landscape and future challenges.

The Rearranged during Transfection (RET) oncogene has been extensively investigated in solid malignancies, particularly thyroid cancer and non-small cell lung cancer (NSCLC), and represents an attractive therapeutic target. RET rearrangements occur in 1-2% of lung adenocarcinomas, where they function as potent oncogenic drivers. Importantly, tumors harboring RET fusions are particularly sensitive to RET tyrosine kinase inhibitors. Results of the LIBRETTO-001 and ARROW clinical trials led to the approval of novel potent and selective RET inhibitors, selpercatinib and pralsetinib, able to overcome the limits of previously used multikinase inhibitors. Herein, we review the most relevant evidences about the role of RET signaling in NSCLC. In addition, we interrogated the Project GENIE database to investigate common clinical and molecular features of RET-fusion positive NSCLC. This analysis revealed that RET rearrangements occurred more frequently in younger and light smoker patients and were associated with a lower tumor mutational burden, compared to RET-fusion negative tumors. Moreover, we assessed and described the differences between RET genomic alterations in NSCLC and thyroid cancers. Finally, we summarized how the treatment landscape of RET-rearranged NSCLC has changed in the last few years, which are the available data about the recognized mechanisms of resistance to RET inhibitors and the challenges for future development of novel therapeutic strategies, aiming to improve management of patients with RET-fusion positive NSCLC.

Circulating CD81-expressing extracellular vesicles as biomarkers of response for immune-checkpoint inhibitors in advanced NSCLC.

PD-L1 in tumor cells is the only used biomarker for anti PD1/PD-L1 immune-checkpoints inhibitors (ICI) in Non Small Cell Lung Cancer (NSCLC) patients. However, this parameter is inaccurate to predict response, especially in patients with low tumor PD-L1. Here, we evaluated circulating EVs as possible biomarkers for ICI in advanced NSCLC patients with low tumoral PD-L1. EVs were isolated from plasma of 64 PD-L1 low, ICI-treated NSCLC patients, classified either as responders (R; complete or partial response by RECIST 1.1) or non-responders (NR). EVs were characterized following MISEV guidelines and by flow cytometry. T cells from healthy donors were triggered in vitro using patients' EVs. Unsupervised statistical approach was applied to correlate EVs' and patients' features to clinical response. R-EVs showed higher levels of tetraspanins (CD9, CD81, CD63) than NR-EVs, significantly associated to better overall response rate (ORR). In multivariable analysis CD81-EVs correlated with ORR. Unsupervised analysis revealed a cluster of variables on EVs, including tetraspanins, significantly associated with ORR and improved survival. R-EVs expressed more costimulatory molecules than NR-EVs although both increased T cell proliferation and partially, activation. Tetraspanins levels on EVs could represent promising biomarkers for ICI response in NSCLC.

Circulating Fatty Acid Profile as a Biomarker for Immunotherapy in Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Lipid metabolism impacts immune cell differentiation, activation, and functions, modulating inflammatory mediators, energy homeostasis, and cell membrane composition. Despite preclinical evidence, data in humans lack concerning tumors and immunotherapy (IO). We aimed at investigating the correlations between circulating lipids and the outcome of non-small cell lung cancer (NSCLC) patients treated with IO. MATERIALS AND METHODS: We identified all patients with advanced NSCLC treated with IO at our Institution with available baseline plasma samples. Fatty acids (FAs) were analyzed through gas chromatography. Survival curves were estimated by the Kaplan-Meier method. Cox multivariate models were constructed through a stepwise procedure, with entry and exit P value set at .2. RESULTS: We identified 112 patients, mostly with performance status 1 (65.2%) and PD-L1≥1% (75.3%). Median progression-free survival (PFS) and overall survival (OS) were 2.8 and 11.0 months, respectively. Multivariable model for survival identified a positive association of circulating free (FFA) C16:0 (P .005) and esterified (EFA) C16:1 (P .030) with PFS, and a positive association of EFA C16:1 (P .001) and EFA C18:0 (P .020) with OS. EFA C16:0 was negatively associated with PFS (P .008). CONCLUSION: FFA C16:0 and FAs derived from its unsaturation (EFA C16:1) and elongation (EFA C18:0) are associated with a better outcome in NSCLC patients treated with IO. It is conceivable that the ratio among those FAs may modify membrane fluidity and receptor activity, influencing IO efficacy. These data pave the way for the investigation of lipid-modulating strategies in association with IO in NSCLC.

Durvalumab consolidation in patients with unresectable stage III non-small cell lung cancer with driver genomic alterations.

INTRODUCTION: Durvalumab is the standard-of-care as consolidation therapy after chemo-radiotherapy in stage III unresectable non-small cell lung cancer (NSCLC); however, its activity across patients with NSCLC harbouring driver genomic alterations (dGA) is poorly characterised. MATERIAL AND METHODS: Multicentre retrospective study including patients with stage III unresectable NSCLC treated with durvalumab after chemo-radiotherapy between April 2015 and October 2020 at 26 centres in Europe and America. Clinical and biological data were collected; dGA included: EGFR/BRAF/KRAS mutations (m) and ALK/ROS1 rearrangements (r). We evaluated progression-free survival (PFS) and overall survival (OS) based on dGA. RESULTS: Out of 323 patients included, 43 patients had one dGA: KRASm (n = 26; 8 G12C), EGFRm (n = 8; 6 del19/ex21), BRAFm (n = 5; 4 V600E) and ALKr (n = 4). The median age was 66 years [39-84], gender ratio 1:1, with 98% performance status (PS) 0-1 and 19% non-smokers; 88% had adenocarcinoma. PD-L1 was positive in 85% (n = 4 missing). In the whole cohort, the median PFS was 17.5 months (mo.) (95% CI, 13.2-24.9) and median OS 47 mo (95%CI, 47-not reached [NR]). No statistically significant differences in terms of the median PFS were observed between patients with dGA vs. non-dGA: 14.9 mo (95% CI, 8.1-NR) vs. 18 mo. (95% CI, 13.4-28.3) (P = 1.0); however, when analysed separately: the median PFS was NR (11.3-NR) in the KRASm G12C vs. 8.1 mo (5.8-NR) in the EGFRm del19/ex21 vs. 7.8 mo (7.7-NR) in the BRAFm V600E/ALKr (P = 0.02). CONCLUSIONS: We observed limited activity of durvalumab consolidation in patients with stage III unresectable NSCLC with EGFR/BRAFm and ALKr but not for those harbouring KRASm. Larger prospective studies are needed to confirm these findings.

Real-world data to build explainable trustworthy artificial intelligence models for prediction of immunotherapy efficacy in NSCLC patients.

Introduction: Artificial Intelligence (AI) methods are being increasingly investigated as a means to generate predictive models applicable in the clinical practice. In this study, we developed a model to predict the efficacy of immunotherapy (IO) in patients with advanced non-small cell lung cancer (NSCLC) using eXplainable AI (XAI) Machine Learning (ML) methods. Methods: We prospectively collected real-world data from patients with an advanced NSCLC condition receiving immune-checkpoint inhibitors (ICIs) either as a single agent or in combination with chemotherapy. With regards to six different outcomes - Disease Control Rate (DCR), Objective Response Rate (ORR), 6 and 24-month Overall Survival (OS6 and OS24), 3-months Progression-Free Survival (PFS3) and Time to Treatment Failure (TTF3) - we evaluated five different classification ML models: CatBoost (CB), Logistic Regression (LR), Neural Network (NN), Random Forest (RF) and Support Vector Machine (SVM). We used the Shapley Additive Explanation (SHAP) values to explain model predictions. Results: Of 480 patients included in the study 407 received immunotherapy and 73 chemo- and immunotherapy. From all the ML models, CB performed the best for OS6 and TTF3, (accuracy 0.83 and 0.81, respectively). CB and LR reached accuracy of 0.75 and 0.73 for the outcome DCR. SHAP for CB demonstrated that the feature that strongly influences models' prediction for all three outcomes was Neutrophil to Lymphocyte Ratio (NLR). Performance Status (ECOG-PS) was an important feature for the outcomes OS6 and TTF3, while PD-L1, Line of IO and chemo-immunotherapy appeared to be more important in predicting DCR. Conclusions: In this study we developed a ML algorithm based on real-world data, explained by SHAP techniques, and able to accurately predict the efficacy of immunotherapy in sets of NSCLC patients.

Immune-Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer With Uncommon Histology.

BACKGROUND: Immune-checkpoint inhibitors (ICIs) have significantly improved outcome of advanced non-small cell lung cancer (aNSCLC) patients. However, their efficacy remains uncertain in uncommon histologies (UH). MATERIALS AND METHODS: Data from ICI treated aNSCLC patients (April,2013-January,2021) in one Institution were retrospectively collected. Univariate and multivariate survival analyses were estimated by Kaplan-Meier and Cox proportional hazards regression model, respectively. Objective response rate (ORR) and disease control rate (DCR) were assessed. RESULTS: Of 375 patients, 79 (21.1%) had UH: 19 (24.1%) sarcomatoid carcinoma, 15 (19.0%) mucinous adenocarcinoma, 10 (12.6%) enteric adenocarcinoma, 8 (10.1%) adenocarcinoma not otherwise specified, 7 (8.9%) large-cell neuroendocrine carcinoma, 6 (7.6%) mixed histology non-adenosquamous, 5 (6.3%) adenosquamous carcinoma, 9 (11.4%) other UH. In UH group, programmed death-ligand 1 (PD-L1) <1%, 1-49%, ≥50% and unknown expression were reported in 27.8%, 22.8%, 31.7% and 17.7% patients respectively and ICI was the second/further-line in the majority of patients. After a median follow-up of 35.64 months (m), median progression-free survival (mPFS) was 2.5 m in UH [95% CI 2.2-2.9 m] versus (vs.) 2.7 m in CH [95% CI 2.3-3.2 m, P-value = .584]; median overall survival (mOS) was 8.8 m [95% CI 4.9-12.6 m] vs. 9.7 m [95% CI 8.0-11.3 m, P-value = .653]. At multivariate analyses only ECOG PS was a confirmed prognostic factor in UH. ORR and DCR were 25.3% and 40.5% in UH vs. 21.6% and 49.5% in CH [P-value = .493 and .155 respectively]. CONCLUSIONS: No significant differences were detected between UH and CH groups. Prospective trials are needed to understand ICIs role in UH population.

Tocilizumab for the treatment of immune-related adverse events: a systematic literature review and a multicentre case series.

OBJECTIVE: Research is moving towards a more personalized management of immune-related adverse events (irAEs) due to immune checkpoint inhibitors (ICI). Our objective was to evaluate the efficacy and safety of tocilizumab in the treatment of these clinical manifestations. METHODS: A systematic literature review was performed to retrieve data about the use of tocilizumab in the treatment of irAEs. Additionally, data from cancer patients referred to our Immune-related Adverse Event Clinic and treated with tocilizumab were collected. RESULTS: Our literature review identified 20 articles and 11 meeting abstracts. Data about 91 cancer patients who received tocilizumab for the treatment of irAEs were collected. In 85% of cases, this therapy was associated with clinical benefit and no case of disease progression was reported. ICI therapy was continued following irAE onset and biologic therapy initiation in only three patients. Five patients developed irAEs upon ICI initiation and were subsequently treated with tocilizumab at our Centre. At a median follow-up of eight months, tocilizumab was safely continued along with ICI in three out of five patients, and an adequate control of irAE was obtained in all cases. No significant adverse reactions to tocilizumab were reported. Only one patient experienced a disease progression 18 months after ICI discontinuation. CONCLUSION: Both our systematic literature review and case series highlight the efficacy and safety of tocilizumab in the treatment of irAEs. Furthermore, they both support the possibility of a combined approach with tocilizumab and ICI, to guarantee an effective irAEs management without losing the oncologic response.

Novel patterns of progression upon immunotherapy in other thoracic malignancies and uncommon populations.

In the immunotherapy era, considering the prolonged survival benefit and responses observed with immunecheckpoint inhibitors (ICI) in many cancer types, the identification of patients with rapid progression (PD) and deaths upon ICI has found some skepticism and resistance among the scientific community. Nevertheless, an acceleration of tumour during ICI, defined as hyperprogressive disease (HPD), has been recognized across different cancer types and evidence regarding rapid PDs and deaths are emerging in patients with malignant pleural mesothelioma (MPM), small cell lung cancer (SCLC) and thymic malignancies and in uncommon non-small cell lung cancer (NSCLC) populations. Of note, PD and early deaths (ED) rates upon single agent ICI were up to 60% and 30% in MPM and 70% and 38% in SCLC patients, respectively. Similarly, rapid PDs and deaths were observed in clinical trials and retrospective studies including patients with poor performance status (PS), HIV infection and rare NSCLC histologies. Atypical patterns of response, such as pseudoprogression (PsPD) may also occur in other thoracic malignancies (MPM) and in some uncommon populations (i.e., HIV patients), however probably at lower rate compared to HPD. The characterizations of HPD and PsPD mechanisms and the identification of common definition criteria are the next future challenges in this area of cancer research.

Liquid Biopsy for Small Cell Lung Cancer either De Novo or Transformed: Systematic Review of Different Applications and Meta-Analysis.

BACKGROUND: The potential added value of liquid biopsy (LB) is not well determined in the case of small cell lung cancer (SCLC), an aggressive tumor that can occur either de novo or from the histologic transformation of non-small cell lung cancer (NSCLC). METHODS: A systematic review of studies adopting LB in patients with SCLC have been performed to assess the clinical utility of circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs). RESULTS: After a screening of 728 records, 62 studies (32 evaluating CTCs, 27 ctDNA, and 3 both) met predetermined eligibility criteria. Only four studies evaluated LB in the diagnostic setting for SCLC, while its prognostic significance was evaluated in 38 studies and prominently supported by both ctDNA and CTCs. A meta-analysis of 11 studies as for CTCs enumeration showed an HR for overall survival of 2.63 (1.71-4.05), with a potential publication bias. The feasibility of tumor genomic profiling and the predictive role of LB in terms of response/resistance to chemotherapy was assessed in 11 and 24 studies, respectively, with greater consistency for those regarding ctDNA. Intriguingly, several case reports suggest that LB can indirectly capture the transition to SCLC in NSCLC treated with EGFR tyrosine kinase inhibitors. CONCLUSIONS: While dedicated trials are needed, LB holds potential clinical roles in both de novo and transformed SCLC. CtDNA analysis appears the most valuable and practicable tool for both disease monitoring and genomic profiling.