Prognostic Impact of Blood Lipid Profile in Patients With Advanced Solid Tumors Treated With Immune Checkpoint Inhibitors: A Multicenter Cohort Study.

BACKGROUND: Specific components of lipid profile seem to differently impact on immune activity against cancer and unraveling their prognostic role in patients with solid cancer treated with immune checkpoint inhibitors (ICIs) is needed. MATERIALS AND METHODS: We retrospectively collected baseline clinicopathological characteristics including circulating lipid profile (total cholesterol [TC], triglycerides [TG], low-density lipoproteins [LDL], high-density lipoproteins [HDL]) of patients with consecutive solid cancer treated with ICIs, and we investigated their role in predicting clinical outcomes. RESULTS: At a median follow-up of 32.9 months, among 430 enrolled patients, those with TC ≥ 200 mg/dl showed longer median progression-free survival (mPFS; 6.6 vs. 4.7 months, P = .4), although not reaching statistical significance, and significantly longer median overall survival (mOS; 19.4 vs. 10.8 months, P = .02) compared to those with TC < 200 mg/dl. Conversely, patients with TG ≥150 mg/dl displayed shorter PFS (3.4 vs. 5.1 months, P = .02) and OS (7.1 vs. 12.9 months, P = .009) compared to those with TG <150 mg/dl. TC and TG were then combined in a "LIPID score" identifying three subgroups: good-risk (GR) (TC ≥200 mg/dl and TG <150 mg/dl), intermediate-risk (IR) (TC <200 mg/dl and TG <150 mg/dl or TC ≥200 mg/dl and TG ≥150 mg/dl) and poor-risk (PR) (TC <200 mg/dl and TG ≥150 mg/dl). The mPFS of GR, IR, and PR groups was 7.8, 4.3, and 2.5 months, respectively (P = .005); mOS of GR, IR, and PR was 20.4, 12.4, and 5.3 months, respectively (P < .001). At multivariable analysis, the PR profile represented an independent poor prognostic factor for both PFS and OS. CONCLUSIONS: We developed a lipid score that defined subgroups of patients with cancer who differently benefit from ICIs. Further mechanistic insights are warranted to clarify the prognostic and predictive role of lipid profile components in patients treated with ICIs.

The role of blood cholesterol quality in patients with advanced cancer receiving immune checkpoint inhibitors.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) became the standard of care for several solid tumors. A limited fraction of patients (pts) achieves a long-term benefit. Plasmatic and intracellular cholesterol levels have emerged as promising biomarkers. The aim of the present study was to determine whether cholesterol efflux capacity (CEC), mediated by serum transporters (ABCA1 and ABCG1) and passive diffusion (PD), impacts on clinical outcome of advanced non-small cell lung cancer (NSCLC) and metastatic renal cell carcinoma (mRCC) pts treated with ICIs. MATERIAL AND METHODS: We retrospectively enrolled advanced NSCLC and mRCC pts consecutively treated with ICIs between October 2013 and October 2018. CEC and cholesterol loading capacity (CLC) were assessed by well-established specific cell models. As primary endpoint, CEC, PD and CLC were correlated with overall survival (OS) while the effects of these parameters on progression-free survival (PFS) and clinical benefit (CB), defined as complete/partial response or stable disease, represented secondary endpoints. RESULTS: NSCLC accounted for 94.2% of 70 enrolled cases, and serum sample suitable for CEC and PD determination was available in 68. Blood cholesterol and serum ABCA1, ABCG1, PD and CLC were associated with outcomes (OS, PFS and CB) at univariate analysis. At the multivariate analysis, only PD confirmed its positive prognostic value in terms of OS, PFS and CB. CONCLUSION: The favorable impact of cholesterol PD on clinical outcome might reflect its main conformation in mature HDL particles which potentially shape an inflamed context, ultimately promoting ICI efficacy. Further prospective studies are needed to support our findings and uncover targetable pathways.

Outcomes of the SARS-CoV-2 omicron (B.1.1.529) variant outbreak among vaccinated and unvaccinated patients with cancer in Europe: results from the retrospective, multicentre, OnCovid registry study.

BACKGROUND: The omicron (B.1.1.529) variant of SARS-CoV-2 is highly transmissible and escapes vaccine-induced immunity. We aimed to describe outcomes due to COVID-19 during the omicron outbreak compared with the prevaccination period and alpha (B.1.1.7) and delta (B.1.617.2) waves in patients with cancer in Europe. METHODS: In this retrospective analysis of the multicentre OnCovid Registry study, we recruited patients aged 18 years or older with laboratory-confirmed diagnosis of SARS-CoV-2, who had a history of solid or haematological malignancy that was either active or in remission. Patient were recruited from 37 oncology centres from UK, Italy, Spain, France, Belgium, and Germany. Participants were followed up from COVID-19 diagnosis until death or loss to follow-up, while being treated as per standard of care. For this analysis, we excluded data from centres that did not actively enter new data after March 1, 2021 (in France, Germany, and Belgium). We compared measures of COVID-19 morbidity, which were complications from COVID-19, hospitalisation due to COVID-19, and requirement of supplemental oxygen and COVID-19-specific therapies, and COVID-19 mortality across three time periods designated as the prevaccination (Feb 27 to Nov 30, 2020), alpha-delta (Dec 1, 2020, to Dec 14, 2021), and omicron (Dec 15, 2021, to Jan 31, 2022) phases. We assessed all-cause case-fatality rates at 14 days and 28 days after diagnosis of COVID-19 overall and in unvaccinated and fully vaccinated patients and in those who received a booster dose, after adjusting for country of origin, sex, age, comorbidities, tumour type, stage, and status, and receipt of systemic anti-cancer therapy. This study is registered with ClinicalTrials.gov, NCT04393974, and is ongoing. FINDINGS: As of Feb 4, 2022 (database lock), the registry included 3820 patients who had been diagnosed with COVID-19 between Feb 27, 2020, and Jan 31, 2022. 3473 patients were eligible for inclusion (1640 [47·4%] were women and 1822 [52·6%] were men, with a median age of 68 years [IQR 57-77]). 2033 (58·5%) of 3473 were diagnosed during the prevaccination phase, 1075 (31·0%) during the alpha-delta phase, and 365 (10·5%) during the omicron phase. Among patients diagnosed during the omicron phase, 113 (33·3%) of 339 were fully vaccinated and 165 (48·7%) were boosted, whereas among those diagnosed during the alpha-delta phase, 152 (16·6%) of 915 were fully vaccinated and 21 (2·3%) were boosted. Compared with patients diagnosed during the prevaccination period, those who were diagnosed during the omicron phase had lower case-fatality rates at 14 days (adjusted odds ratio [OR] 0·32 [95% CI 0·19-0·61) and 28 days (0·34 [0·16-0·79]), complications due to COVID-19 (0·26 [0·17-0·46]), and hospitalisation due to COVID-19 (0·17 [0·09-0·32]), and had less requirements for COVID-19-specific therapy (0·22 [0·15-0·34]) and oxygen therapy (0·24 [0·14-0·43]) than did those diagnosed during the alpha-delta phase. Unvaccinated patients diagnosed during the omicron phase had similar crude case-fatality rates at 14 days (ten [25%] of 40 patients vs 114 [17%] of 656) and at 28 days (11 [27%] of 40 vs 184 [28%] of 656) and similar rates of hospitalisation due to COVID-19 (18 [43%] of 42 vs 266 [41%] of 652) and complications from COVID-19 (13 [31%] of 42 vs 237 [36%] of 659) as those diagnosed during the alpha-delta phase. INTERPRETATION: Despite time-dependent improvements in outcomes reported in the omicron phase compared with the earlier phases of the pandemic, patients with cancer remain highly susceptible to SARS-CoV-2 if they are not vaccinated against SARS-CoV-2. Our findings support universal vaccination of patients with cancer as a protective measure against morbidity and mortality from COVID-19. FUNDING: National Institute for Health and Care Research Imperial Biomedical Research Centre and the Cancer Treatment and Research Trust.

Alarming Drop in Early Stage Colorectal Cancer Diagnoses After COVID-19 Outbreak: A Real-World Analysis from the Italian COVID-DELAY Study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has triggered the disruption of health care on a global scale. With Italy tangled up in the pandemic response, oncology care has been largely diverted and cancer screenings suspended. Our multicenter Italian study aimed to evaluate whether COVID-19 has impacted access to diagnosis, staging, and treatment for patients newly diagnosed with colorectal cancer (CRC), compared with pre-pandemic time. METHODS: All consecutive new CRC patients referred to 8 Italian oncology institutions between March and December 2020 were included. Access rate and temporal intervals between date of symptoms onset, radiological and cytohistological diagnosis, treatment start and first radiological evaluation were analyzed and compared with the same months of 2019. RESULTS: A reduction (29%) in newly diagnosed CRC cases was seen when compared with 2019 (360 vs 506). New CRC patients in 2020 were less likely to be diagnosed with early stage (stages I-II-III) CRC (63% vs 78%, P < .01). Gender and sidedness were similar regardless of the year. The percentage of tumors with any mutation among BRAF, NRAS, and KRAS genes were significantly different between the 2 years (61% in 2020 vs 50% in 2019, P = .04). Timing of access to cancer diagnosis, staging, and treatment for patients with CRC has not been negatively affected by the pandemic. Significantly shorter temporal intervals were observed between symptom onset and first oncological appointment (69 vs 79 days, P = .01) and between histological diagnosis and first oncological appointment (34 vs 42 days, P < .01) during 2020 compared with 2019. Fewer CRC cases were discussed in multidisciplinary meetings during 2020 (38% vs 50%, P = .01). CONCLUSIONS: Our data highlight a significant drop in CRC diagnosis after COVID-19, especially for early stage disease. The study also reveals a remarkable setback in the multidisciplinary management of patients with CRC. Despite this, Italian oncologists were able to ensure diagnostic-therapeutic pathways proper operation after March 2020.

Cancer patient perspective in the arena of COVID-19 pandemic.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) outbreak has been declared a global pandemic of unprecedented proportions. Italy is a country which has been heavily affected. Cancer patients are at a higher risk owing to their intrinsic fragility related to their underlying disease and oncologic treatment. Against this backdrop, we conducted a survey to investigate how patients perceived their condition, clinical management and availability of information during the pandemic. METHODS: Between 15 April and 1 May 2020 a survey was submitted to cancer patients at oncology departments in the Marche region. Questions regarding the perception of personal safety, continuity of cancer care, information quality and psychological distress. RESULTS: Seven hundred patients participated in the survey; 59% were female and 40% were aged between 46 and 65. The majority of the participants perceived compliance with appropriate safety standards by cancer care providers and 80% were reassured about their concerns during the medical interview. 40% were worried of being at a higher risk of infection and 71% felt they were at a greater risk because of chemotherapy. 55% felt that postponing cancer treatment could reduce its efficacy, however 76% declared they did not feel abandoned at the time of treatment postponement. Patients between 46 and 65 years declared a significant reduction in sleep (p < 0.01) and in concentration (p = 0.03). CONCLUSIONS: The emergency care offered to cancer patients has been deemed satisfactory in terms of both safety standards and care management. However, the majority of participants perceived the mutual negative influence between their oncologic disease and the risk of infection highlighting the need for special measures to ensure safe continuity of care.

Pachychoroid spectrum disease and choriocapillary flow analysis in patients with Cushing disease: an optical coherence tomography angiography study.

PURPOSE: To investigate the presence of pachychoroid spectrum disease (PSD) in patients with Cushing disease (CD) and to evaluate subfoveal choroidal thickness (SFCT) and choriocapillary flow using spectral domain OCT (SD-OCT) with the enhanced depth imaging (EDI) and optical coherence tomography angiography (OCT-A). METHODS: Thirty-two patients with CD and 32 age- and sex-matched healthy volunteers were enrolled in this observational study. All participants had a complete ophthalmic examination including SD-OCT with EDI and OCT-A, and were subjected to the Perceived Stress Scale test (PSS). All patients with CD had hormone test including 24-h urinary-free cortisol (UFC) and plasma adrenocorticotropic hormone (ACTH). We compared SFCT and choriocapillary vessel density (CVD) between the two groups and evaluated the presence of PSD. We investigated the association of hormone level, SFTC, CVD with the presence of CD; the association between the hormone level, SFTC, CVD, the CD disease activity, and duration with the presence of PSD in CD patients; and the association between SFTC and CVD with the hormone level, the CD disease activity, and duration in CD patients. RESULTS: Higher values of SFCT and CVD were associated with CD (ß: 0.028, 95% CI: 0.014; 0.041; ß: 0.912, 95%CI: 0.205; 1.62, respectively). Twelve patients with CD (37.5%) reported a PSD in at least one eye, whereas no subject was found in control group (p < 0.001); in particular, 11 CD patients (34%) presented pachychoroid pigment epitheliopathy (PPE) and 1 CD patient (3%) presented polypoidal choroidal vasculopathy/aneurysmal type 1 neovascularization (PCV/AT1). In patients with CD, a significant positive association between SFCT and PSD was found (ß: 0.010, 95% CI 0.001; 0.019). CONCLUSION: A chronic state of hypercortisolism may have direct implications on the choroid. Patients with CD had higher SFCT values and a significant change in the choriocapillary flow compared to healthy controls. Moreover, PSD was observed only in CD patients.

Beyond Microsatellite Instability: Evolving Strategies Integrating Immunotherapy for Microsatellite Stable Colorectal Cancer.

OPINION STATEMENT: Advanced colorectal cancer (CRC) is a heterogeneous disease, characterized by several subtypes with distinctive genetic and epigenetic patterns. During the last years, immune checkpoint inhibitors (ICIs) have revamped the standard of care of several tumors such as non-small cell lung cancer and melanoma, highlighting the role of immune cells in tumor microenvironment (TME) and their impact on cancer progression and treatment efficacy. An "immunoscore," based on the percentage of two lymphocyte populations both at tumor core and invasive margin, has been shown to improve prediction of treatment outcome when added to UICC-TNM classification. To date, pembrolizumab, an anti-programmed death protein 1 (PD1) inhibitor, has gained approval as first-line therapy for mismatch-repair-deficient (dMMR) and microsatellite instability-high (MSI-H) advanced CRC. On the other hand, no reports of efficacy have been presented in mismatch-repair-proficient (pMMR) and microsatellite instability-low (MSI-L) or microsatellite stable (MSS) CRC. This group includes roughly 95% of all advanced CRC, and standard chemotherapy, in addition to anti-EGFR or anti-angiogenesis drugs, still represents first treatment choice. Hopefully, deeper understanding of CRC immune landscape and of the impact of specific genetic and epigenetic alterations on tumor immunogenicity might lead to the development of new drug combination strategies to overcome ICIs resistance in pMMR CRC, thus paving the way for immunotherapy even in this subgroup.

Clinicopathologic correlates of first-line pembrolizumab effectiveness in patients with advanced NSCLC and a PD-L1 expression of ≥ 50.

BACKGROUND: Single-agent pembrolizumab represents the standard first-line option for metastatic non-small-cell lung cancer (NSCLC) patients with a PD-L1 (programmed death-ligand 1) expression of ≥ 50%. METHODS: We conducted a multicenter retrospective study aimed at evaluating the clinicopathologic correlates of pembrolizumab effectiveness in patients with treatment-naïve NSCLC and a PD-L1 expression of ≥ 50%. RESULTS: One thousand and twenty-six consecutive patients were included. The objective response rate (ORR) was 44.5% (95% CI 40.2-49.1), while the median progression free survival (PFS) and overall survival (OS) were 7.9 months (95% CI 6.9-9.5; 599 events) and 17.2 months (95% CI 15.3-22.3; 598 censored patients), respectively. ECOG-PS ≥ 2 (p < 0.0001) and bone metastases (p = 0.0003) were confirmed to be independent predictors of a worse ORR. Former smokers (p = 0.0002), but not current smokers (p = 0.0532) were confirmed to have a significantly prolonged PFS compared to never smokers at multivariate analysis. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a worse PFS. Previous palliative RT was significantly related to a shortened OS (p = 0.0104), while previous non-palliative RT was significantly related to a prolonged OS (p = 0.0033). Former smokers (p = 0.0131), but not current smokers (p = 0.3433) were confirmed to have a significantly prolonged OS compared to never smokers. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a shortened OS. A PD-L1 expression of ≥ 90%, as assessed by recursive partitioning, was associated with significantly higher ORR (p = 0.0204), and longer and OS (p = 0.0346) at multivariable analysis. CONCLUSION: Pembrolizumab was effective in a large cohort of NSCLC patients treated outside of clinical trials. Questions regarding the effectiveness in clinical subgroups, such as patients with poorer PS and with liver/bone metastases, still remain to be addressed. We confirmed that the absence of tobacco exposure, and the presence of bone and liver metastasis are associated with worse clinical outcomes to pembrolizumab. Increasing levels of PD-L1 expression may help identifying a subset of patients who derive a greater benefit from pembrolizumab monotherapy.

Neoadjuvant therapy in hormone Receptor-Positive/HER2-Negative breast cancer.

Neoadjuvant therapy is commonly used in patients with locally advanced or inoperable breast cancer (BC). Neoadjuvant chemotherapy (NACT) represents an established treatment modality able to downstage tumours, facilitate breast-conserving surgery, yet also achieve considerable pathologic complete response (pCR) rates in HER2-positive and triple-negative BC. For patients with HR+/HER2- BC, the choice between NACT and neoadjuvant endocrine therapy (NET) is still based on clinical and pathological features and not guided by biomarkers of defined clinical utility, differently from the adjuvant setting where gene-expression signatures have been widely adopted to drive decision-making. In this review, we summarize the evidence supporting the choice of NACT vs NET in HR+/HER2- BC, discussing the issues surrounding clinical trial design and proper selection of patients for every treatment. It is time to question the binary paradigm of responder vs non-responders as well as the "one size fits all" approach in luminal BC, supporting the utilization of continuous endpoints and the adoption of tissue and plasma-based biomarkers at multiple timepoints. This will eventually unleash the full potential of neoadjuvant therapy which is to modulate patient treatment based on treatment sensitivity and surgical outcomes. We also reviewed the current landscape of neoadjuvant studies for HR+/HER2- BC, focusing on antibody-drug conjugates (ADCs) and immunotherapy combinations. Finally, we proposed a roadmap for future neoadjuvant approaches in HR+/HER2- BC, which should be based on a staggered biomarker-driven treatment selection aiming at impacting long-term relevant endpoints.

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.

Safety of extended interval dosing immune checkpoint inhibitors: a multicenter cohort study.

BACKGROUND: Real-life spectrum and survival implications of immune-related adverse events (irAEs) in patients treated with extended interval dosing (ED) immune checkpoint inhibitors (ICIs) are unknown. METHODS: Characteristics of 812 consecutive solid cancer patients who received at least 1 cycle of ED monotherapy (pembrolizumab 400 mg Q6W or nivolumab 480 mg Q4W) after switching from canonical interval dosing (CD; pembrolizumab 200 mg Q3W or nivolumab 240 mg Q2W) or treated upfront with ED were retrieved. The primary objective was to compare irAEs patterns within the same population (before and after switch to ED). irAEs spectrum in patients treated upfront with ED and association between irAEs and overall survival were also described. RESULTS: A total of 550 (68%) patients started ICIs with CD and switched to ED. During CD, 225 (41%) patients developed any grade and 17 (3%) G3 or G4 irAEs; after switching to ED, any grade and G3 or G4 irAEs were experienced by 155 (36%) and 20 (5%) patients. Switching to ED was associated with a lower probability of any grade irAEs (adjusted odds ratio [aOR] = 0.83, 95% confidence interval [CI] = 0.64 to 0.99; P = .047), whereas no difference for G3 or G4 events was noted (aOR = 1.55, 95% CI = 0.81 to 2.94; P = .18). Among patients who started upfront with ED (n = 232, 32%), 107 (41%) developed any grade and 14 (5%) G3 or G4 irAEs during ED. Patients with irAEs during ED had improved overall survival (adjusted hazard ratio [aHR] = 0.53, 95% CI = 0.34 to 0.82; P = .004 after switching; aHR = 0.57, 95% CI = 0.35 to 0.93; P = .025 upfront). CONCLUSIONS: Switching ICI treatment from CD and ED did not increase the incidence of irAEs and represents a safe option also outside clinical trials.

Immunotherapy for mesothelioma: Moving beyond single immune check point inhibition.

Malignant pleural mesothelioma (MPM) is an aggressive neoplasm with low survival rates. Platinum-based chemotherapy has represented the cornerstone of treatment for over a decade, prompting the investigation of new therapeutic strategies both in the early stage of the disease and in the advanced setting. The advent of immune check-point inhibitors (ICIs) has recently revamped the enthusiasm for using immunotherapy also in MPM. However, results from first clinical trials using single immune check-point inhibition have been conflicting, and this may be mainly attributed to the lack of specific biomarkers as well as to intra- and inter- patient heterogeneity. The phase III Checkmate743 firstly demonstrated the superiority of an ICI combination (nivolumab plus ipilimumab) over chemotherapy in the first-line treatment of unresectable MPM, leading to FDA approval of this regimen and showing that moving beyond single immune check point inhibition might be a successful strategy to overcome resistance in the majority of MPM patients. In this review, we describe the emerging immunotherapy strategies for the treatment of MPM. We also discuss how refining the approach in pre-clinical studies towards a more holistic perspective (which takes into account not only genetic but also pathophysiological vulnerabilities) and strengthening multi-institutional collaboration in clinical trials is finally helping the clinical development of immunotherapy in MPM.

Non-small-cell lung cancer: how to manage EGFR-mutated disease.

The treatment of non-small-cell lung cancer (NSCLC) harbouring EGFR mutations has witnessed some major breakthroughs in the last years. On the one hand, the recent advent of the third-generation tyrosine kinase inhibitor (TKI) osimertinib has reshaped the therapeutic algorithm both in the first-line and adjuvant settings for patients with common activating Ex19del and L858R EGFR mutations. On the other hand, the availability of new comprehensive next-generation sequencing panels, to be used on tumour tissue or on liquid biopsy, has revealed the existence of uncommon as well as compound mutations that partially explain the onset of resistance. Nevertheless, dissecting the biological mechanisms underlying primary and secondary resistance to EGFR-TKIs is crucial to developing alternative therapeutic strategies and further improving patient outcomes. Herein, we provide an updated and comprehensive summary of the latest advancements in the quest for compounds targeting EGFR-mutant advanced non-small-cell lung cancer, discussing the biological rationale underlying the development of a forefront combination of TKI and/or new antibody-drug conjugates. We also suggest a treatment algorithm that could be followed considering the latest published data.

Management of lung cancer patients during COVID-19 pandemic: dos, don'ts and don't knows.

Aim: During the coronavirus disease 2019 (COVID-19) pandemic two needs have overlapped: on one hand continuing to provide the best care for patients with lung cancer and preventing the spread of the virus between patients and healthcare professionals on the other hand. Due to the pandemic's unpredictable duration, physicians had to evaluate the risk/benefit ratio of anti-cancer therapeutic strategy to do the best for their patients and to protect patients themselves, as well as healthcare workers. Methods: Systematic literature research was performed with the aim to assess the available guidelines for the management of lung cancer patients during the COVID-19 pandemic. Thirteen potentially relevant articles were selected and recommendations have been divided into three main categories: dos, don'ts and don't knows. Results: All guidelines and recommendations highlighted the relevance of being able to delay, if possible and based on risk stratification, and curative interventions. The selected recommendations should be considered adaptable and flexible because they might be contextualized on the basis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection prevalence and the availability of diagnostic-therapeutic resources. Conclusions: It remains of fundamental importance to discuss each diagnostic and therapeutic decision with the patient taking into account risks and benefits that might vary from case to case.

The Landscape of ALK-Rearranged Non-Small Cell Lung Cancer: A Comprehensive Review of Clinicopathologic, Genomic Characteristics, and Therapeutic Perspectives.

During the last decade, the identification of oncogenic driver mutations and the introduction of tyrosine kinase inhibitors (TKIs) in daily clinical practice have substantially revamped the therapeutic approach of oncogene-addicted, non-small cell lung cancer (NSCLC). Rearrangements in the anaplastic lymphoma kinase (ALK) gene are detected in around 3-5% of all NSCLC patients. Following the promising results of Crizotinib, a first-generation ALK inhibitor (ALK-i), other second-generation and more recently third-generation TKIs have been developed and are currently a landmark in NSCLC treatment, leading to a significant improvement in patients prognosis. As clinical trials have already demonstrated high efficacy of each ALK-i, both in terms of systemic and intracranial disease control, comparative studies between second and third generation ALK-i are still lacking, and primary or secondary ALK-i resistance inevitably limit their efficacy. Resistance to ALK-i can be due to ALK-dependent or ALK-independent mechanisms, including the activation of bypass signaling pathways and histological transformation: these findings may play an important role in the future to select patients' subsequent therapy. This review aims to provide an overview of underlying molecular alterations of ALK-i resistance and point out promising role of liquid biopsy in predicting tumor response and monitoring resistance mutations. The purpose of this review is also to summarize current approval for ALK-rearranged NSCLC patients, to help clinicians in making decisions on therapeutic sequence, and to deepen the role of clinicopathological and genomic characteristics influencing patients' prognosis during treatment with ALK-i.

Advanced non-small-cell lung cancer: how to manage EGFR and HER2 exon 20 insertion mutation-positive disease.

EGFR exon 20 insertion mutations (Ex20ins) and HER2 mutations characterize an oncogene-addicted subtype of non-small-cell lung cancer (NSCLC) typically associated with a never or light smoking history, female sex, and adenocarcinoma histology. Nevertheless, Ex20ins-mutant and HER2-mutant advanced NSCLCs are still difficult to treat for various reasons. First, there is a need for sophisticated diagnostic tools (e.g. next-generation sequencing) that could allow the identification of these relatively rare molecular drivers. Second, highly active targeted drugs that might support a significant change in patients' prognosis when used as first-line therapy are required. In fact, although a few targeted drugs have so far demonstrated antitumour activity for these patients, mainly selective human epidermal receptor-tyrosine kinase inhibitors such as poziotinib and mobocertinib (for both molecular alterations), monoclonal antibodies such as amivantamab (for Ex20ins), and antibody-drug conjugates such as trastuzumab deruxtecan (for HER2 mutants), they are mostly confined for clinical use in pretreated patients. Finally, Ex20ins-targeted or HER2-targeted drugs might be difficult to access in different countries or regions worldwide. In the present review, we provide a concise but comprehensive summary of the challenges that lie ahead as we move towards personalized treatment of Ex20ins-mutant and HER2-mutant advanced NSCLC, also suggesting a treatment algorithm that could be followed for patients with these genetic aberrations.

Lurbinectedin shows clinical activity and immune-modulatory functions in patients with pre-treated small cell lung cancer and malignant pleural mesothelioma.

PURPOSE: Lurbinectedin is a promising new drug being investigated in pre-treated patients with small cell lung cancer (SCLC) or malignant pleural mesothelioma (MPM). Its clinical activity in the real-world setting has not been investigated yet. PATIENTS AND METHODS: Clinical data of patients with SCLC and MPM who were treated with lurbinectedin were prospectively collected. Comprehensive immune cell profiling by flow cytometry was performed on screening and treating peripheral blood samples. RESULTS: A total of 95 patients (43 SCLC and 52 MPM) were treated, mostly as ≥3-line of therapy. In the SCLC cohort, a median progression-free survival (mPFS) was 1.5 months (95% CI: 1.4-3.0), and median overall survival was 7.0 months (95% CI: 4.7-not reached). Objective radiological response and disease control rate after 12 weeks were 16% and 28%, respectively. In the MPM cohort, median progression-free survival was 2.8 months (95% CI: 1.4-4.2), and median overall survival was 7.2 months (95% CI: 5.9-not reached). Disease control rate after 12 weeks was 29%, whereas no partial responses were registered. No new safety signals were observed. Lurbinectedin treatment was significantly associated with the depletion of circulating classical monocytes, which correlated with a better PFS in patients with SCLC. Lurbinectedin increased the proliferation of CD4+ and CD8+ T cells (SCLC) and natural killer and natural killer T cells (SCLC and MPM) and altered co-stimulatory and co-inhibitory receptor expression on circulating lymphocytes. CONCLUSION: Lurbinectedin has a manageable safety profile and shows clinical activity in pre-treated patients with SCLC and MPM. Its immune-modulatory functions make lurbinectedin a potential platform for immunotherapy combinations.

How to manage KRAS G12C-mutated advanced non-small-cell lung cancer.

Constitutive KRAS signalling drives tumorigenesis across several cancer types. In non-small-cell lung cancer (NSCLC) activating KRAS mutations occur in ~30% of cases, and the glycine to cysteine substitution at codon 12 (G12C) is the most common KRAS alteration. Although KRAS mutations have been considered undruggable for over 40 years, the recent discovery of allelic-specific KRAS inhibitors has paved the way to personalized cancer medicine for patients with tumours harbouring these mutations. Here, we review the current treatment landscape for patients with advanced NSCLCs harbouring a KRAS G12C mutation, including PD-(L) 1-based therapies and direct KRAS inhibitors as well as sequential treatment options. We also explore the possible mechanisms of resistance to KRAS inhibition and strategies to overcome resistance in patients with KRAS G12C-mutant NSCLC.

Rising incidence of late stage breast cancer after COVID-19 outbreak. Real-world data from the Italian COVID-DELAY study.

PURPOSE: Breast cancer (BC) patients' (pts) management was affected by a global reorganization after Coronavirus disease 2019 (COVID-19). Our multicenter study aimed to assess the impact of COVID-19 on access to diagnosis, staging and treatment for BC pts compared to pre-pandemic. METHODS: Medical records of all consecutive newly diagnosed BC pts referred to 6 Italian Institutions between March and December 2020 were assessed. Monthly access rate and temporal intervals between date of symptoms onset, radiological, cytohistological diagnosis and treatment start were analyzed and compared with 2019. RESULTS: A reduction (25%) in newly diagnosed BC was observed compared to 2019 (666 vs 890). New BC pts in 2020 were less likely to be diagnosed with early stage BC (77% vs 83%, p < 0.01), had a worse performance status according to the Eastern Cooperative Oncology Group (ECOG PS) (19.8% had PS > 0 in 2020 vs 16.5% in 2019, p < 0.01) and fewer pts were asymptomatic at diagnosis in 2020 (54% vs 71%,p < 0.01). COVID-19 did not negatively impact in terms of access to diagnosis, staging and treatment. Time intervals between symptom onset and radiological diagnosis, symptom onset and cytohistological diagnosis, cytohistological diagnosis and treatment start were maintained or improved. However, less cases were discussed in multidisciplinary tumor meetings during 2020 (60% vs 73%, p < 0.01). CONCLUSIONS: Our data proved an alarming reduction of early stage BC associated with the COVID-19 crisis in 2020. Despite the upheaval generated by the pandemic, our study shed light on the effective performance delivered by Italian Oncology Departments to guarantee diagnostic-therapeutic pathways.

Persistence of long-term COVID-19 sequelae in patients with cancer: An analysis from the OnCovid registry.

INTRODUCTION: A significant proportion of patients with cancer who recover from Coronavirus Disease 2019 (COVID-19) may experience COVID-19 sequelae in the early post-infection phase, which negatively affect their continuity of care and oncological outcome. The long-term prevalence and clinical impact of the post-COVID-19 syndrome in patients with cancer are largely unknown. METHODS: In this study, we describe the time course of COVID-19 sequelae in patients with non-advanced cancers enrolled in the OnCovid registry. RESULTS: Overall, 186 patients were included, with a median observation period of 9.9 months (95%CI:8,8-11.3) post-COVID-19 resolution. After a median interval of 2.3 months post-COVID-19 (interquartile range: 1.4-3.7), 31 patients (16.6%) reported ≥1 sequelae, including respiratory complications (14, 7.6%), fatigue (13, 7.1%), neuro-cognitive sequelae (7, 3.8%). The vast majority of the patients were not vaccinated prior to COVID-19. COVID-19-related sequelae persisted in 9.8% and 8% of patients 6 and 12 months after COVID-19 resolution. Persistence of sequelae at first oncological follow-up was associated with history of complicated COVID-19 (45.2% vs 24.8%, p = 0.0223), irrespective of oncological features at COVID-19 diagnosis. CONCLUSION: This study confirms for the first time that, in a largely unvaccinated population, post-COVID-19 syndrome can affect a significant proportion of patients with non-advanced cancer who recovered from the acute illness. COVID-19 sequelae may persist up to 12 months in some patients, highlighting the need for dedicated prevention and supportive strategies.