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.

Successful treatment with selpercatinib after pralsetinib-related pneumonitis and intracranial failure in a patient with RET-rearranged nonsmall cell lung cancer.

Pralsetinib and selpercatinib are two highly potent and selective rearranged during transfection (RET) inhibitors that substantially improved the clinical outcome of patients with RET-rearranged non-small cell lung cancer. Treatment with one RET inhibitor after failure of the other is generally not recommended because of cross-resistance mechanisms. We report the case of a patient affected by metastatic RET-rearranged non-small cell lung cancer who experienced long-lasting disease control with pralsetinib. After 13 months from treatment start, the patient developed recurrent drug-related pneumonitis, requiring temporary interruptions and dose reductions and eventually failing to control the disease. Selpercatinib was then started as an off-label treatment, allowing both clinical and radiological intracranial disease control. Selpercatinib was well-tolerated at full dosage, and no pulmonary event occurred. In our case report, after pralsetinib dose reduction due to pulmonary toxicity, the therapeutic switch to selpercatinib allowed the patient to receive a full-dose treatment, eventually restoring disease control. Our case report and a few literature data suggest that switching from pralsetinib to selpercatinib may represent a therapeutic opportunity, especially for patients with brain metastases.

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.

PD-1/PD-L1 checkpoint inhibitors during late stages of life: an ad-hoc analysis from a large multicenter cohort.

BACKGROUND: The favourable safety profile and the increasing confidence with immune checkpoint inhibitors (ICIs) might have boosted their prescription in frail patients with short life expectancies, who usually are not treated with standard chemotherapy. METHODS: The present analysis aims to describe clinicians' attitudes towards ICIs administration during late stages of life within a multicenter cohort of advanced cancer patients treated with single agent PD-1/PD-L1 checkpoint inhibitors in Italy. RESULTS: Overall, 1149 patients with advanced cancer who received single agent PD-1/PD-L1 checkpoint inhibitors were screened. The final study population consisted of 567 deceased patients. 166 patients (29.3%) had received ICIs within 30 days of death; among them there was a significantly higher proportion of patients with ECOG-PS ≥ 2 (28.3% vs 11.5%, p < 0.0001) and with a higher burden of disease (69.3% vs 59.4%, p = 0.0266). In total, 35 patients (6.2%) started ICIs within 30 days of death; among them there was a higher proportion of patients with ECOG-PS ≥ 2 (45.7% vs 14.5%, p < 0.0001) and with a higher burden of disease (82.9% vs 60.9%, p = 0.0266). Primary tumors were significantly different across subgroups (p = 0.0172), with a higher prevalence of NSCLC patients (80% vs 60.9%) among those who started ICIs within 30 days of death. Lastly, 123 patients (21.7%) started ICIs within 3 months of death. Similarly, within this subgroup there was a higher proportion of patients with ECOG-PS ≥ 2 (29.3% vs 12.8%, p < 0.0001), with a higher burden of disease (74.0% vs 59.0%, p = 0.0025) and with NSCLC (74.0% vs 58.8%, p = 0.0236). CONCLUSION: Our results confirmed a trend toward an increasing ICIs prescription in frail patients, during the late stages of life. Caution should be exercised when evaluating an ICI treatment for patients with a poor PS and a high burden of disease.

Modulating Tumor Microenvironment: A Review on STK11 Immune Properties and Predictive vs Prognostic Role for Non-small-cell Lung Cancer Immunotherapy.

OPINION STATEMENT: The quest for immunotherapy (IT) biomarkers is an element of highest clinical interest in both solid and hematologic tumors. In non-small-cell lung cancer (NSCLC) patients, besides PD-L1 expression evaluation with its intrinsic limitations, tissue and circulating parameters, likely portraying the tumor and its stromal/immune counterparts, have been proposed as potential predictors of IT responsiveness. STK11 mutations have been globally labeled as markers of IT resistance. After a thorough literature review, STK11 mutations condition the prognosis of NSCLC patients receiving ICI-containing regimens, implying a relevant biological and clinical significance. On the other hand, waiting for prospective and solid data, the putative negative predictive value of STK11 inactivation towards IT is sustained by less evidence. The physiologic regulation of multiple cellular pathways performed by STK11 likely explains the multifaceted modifications in tumor cells, stroma, and tumor immune microenvironment (TIME) observed in STK11 mutant lung cancer, particularly explored in the molecular subgroup of KRAS co-mutation. IT approaches available thus far in NSCLC, mainly represented by anti-PD-1/PD-L1 inhibitors, are not promising in the case of STK11 inactivation. Perceptive strategies aimed at modulating the TIME, regardless of STK11 status or specifically addressed to STK11-mutated cases, will hopefully provide valid therapeutic options to be adopted in the clinical practice.

Molecular basis and rationale for combining immune checkpoint inhibitors with chemotherapy in non-small cell lung cancer.

Immunotherapy has prompted a paradigm shift in advanced non-small cell lung cancer (NSCLC) treatment, by demonstrating superior efficacy to chemotherapy alone both in second- and in first-line setting. Novel insights on molecular mechanisms and regimens to enhance the efficacy of immunotherapy are warranted, as only a minority of patients (˜20%) respond to checkpoint blockade. Taking into account the multiple mechanisms adopted by tumor cells to evade the immune system through cancer immunoediting, the frontline combination of immune checkpoint inhibitors with chemotherapy appears to be a successful strategy as: 1) it enhances the recognition and elimination of tumor cells by the host immune system (immunogenic cell-death), and 2) it reduces the immunosuppressive tumor microenvironment. Remarkably, the immune checkpoint inhibitors pembrolizumab and atezolizumab have already been approved by the FDA in combination with chemotherapy for the first-line treatment of advanced NSCLC and many other chemo-immunotherapeutic regimens have been evaluated as an initial therapeutic approach in metastatic NSCLC. Concurrently, several preclinical studies are evaluating the molecular mechanisms underlying immunomodulation by conventional chemotherapeutic agents (platinum salts, antimitotic agents, antimetabolites and anthracyclines), unraveling drug- and dose/schedule-dependent effects on the immune system that should be exploited to achieve synergistic clinical activity. The current review provides a detailed overview of the immunobiological rationale and molecular basis for combining immune checkpoint inhibitors with chemotherapy for the treatment of advanced NSCLC. Moreover, current evidence and future perspectives towards a better selection of patients who are more likely to benefit from chemo-immunotherapy combinations are discussed.

The Role of c-Met as a Biomarker and Player in Innate and Acquired Resistance in Non-Small-Cell Lung Cancer: Two New Mutations Warrant Further Studies.

The c-Met receptor is a therapeutically actionable target in non-small-cell lung cancer (NSCLC), with one approved drug and several agents in development. Most suitable biomarkers for patient selection include c-Met amplification and exon-14 skipping. Our retrospective study focused on the frequency of different c-Met aberrations (overexpression, amplification and mutations) in 153 primary, therapy-naïve resection samples and their paired metastases, from Biobank@UZA. Furthermore, we determined the correlation of c-Met expression with clinicopathological factors, Epidermal Growth Factor Receptor (EGFR)-status and TP53 mutations. Our results showed that c-Met expression levels in primary tumors were comparable to their respective metastases. Five different mutations were detected by deep sequencing: three (E168D, S203T, N375S) previously described and two never reported (I333T, G783E). I333T, a new mutation in the Sema(phorin) domain of c-Met, might influence the binding of antibodies targeting the HGF-binding domain, potentially causing innate resistance. E168D and S203T mutations showed a trend towards a correlation with high c-Met expression (p = 0.058). We found a significant correlation between c-MET expression, EGFR expression (p = 0.010) and EGFR mutations (p = 0.013), as well as a trend (p = 0.057) with regards to TP53 mutant activity. In conclusion this study demonstrated a strong correlation between EGFR mutations, TP53 and c-Met expression in therapy-naïve primary resection samples. Moreover, we found two new c-Met mutations that warrant further studies.

Imatinib mesylate-induced cardiomyopathy involves resident cardiac progenitors.

Cardiovascular complications are included among the systemic effects of tyrosine kinase inhibitor (TKI)-based therapeutic strategies. To test the hypothesis that inhibition of Kit tyrosine kinase that promotes cardiac progenitor cell (CPC) survival and function may be one of the triggering mechanisms of imatinib mesylate (IM)-related cardiovascular effects, the anatomical, structural and ultrastructural changes in the heart of IM-treated rats were evaluated. Cardiac anatomy in IM-exposed rats showed a dose-dependent, restrictive type of remodeling and depressed hemodynamic performance in the absence of remarkable myocardial fibrosis. The effects of IM on rat and human CPCs were also assessed. IM induced rat CPC depletion, reduced growth and increased cell death. Similar effects were observed in CPCs isolated from human hearts. These results extend the notion that cardiovascular side effects are driven by multiple actions of IM. The identification of cellular mechanisms responsible for cardiovascular complications due to TKIs will enable future strategies aimed at preserving concomitantly cardiac integrity and anti-tumor activity of advanced cancer treatment.

Immunomodulatory effects of antiangiogenic tyrosine kinase inhibitors in renal cell carcinoma models: Impact on following anti-PD-1 treatments.

The approval of immune checkpoint inhibitors (ICIs) has revolutionized the management of metastatic renal cell carcinoma (RCC), introducing several ICI-based combinations as the new standard of care for affected patients. Nonetheless, monotherapy with antiangiogenic tyrosine kinase inhibitors (TKIs), such as pazopanib or sunitinib, still represents a first-line treatment option for selected patients belonging to the favorable risk group according to the International mRCC Database Consortium (IMDC) model. After TKI monotherapy, the main second-line option is represented by ICI monotherapy with the anti-Programmed Death Receptor 1(PD-1) nivolumab. To date, the expected clinical outcomes are similar with pazopanib or sunitinib and there is no clear indication for selecting one TKI over the other. Moreover, their impact on subsequent ICI treatment outcomes is not well defined, yet. Based on these premises, we investigated the immunomodulatory activity of these drugs in vitro and in vivo.Both TKIs induced Programmed Cell Death Ligand-1 (PD-L1) expression and soluble PD-L1 release in RCC cells, and hampered T cell activation, reducing cytokine production and the proportion of activated T cells. Nevertheless, in a syngeneic co-culture system with peripheral blood mononuclear cells (PBMCs) and tumor cells, incubation with anti-PD-1 antibody following TKIs treatment significantly restored T cell function, potentiating the cytotoxic effects against tumor cells. Pazopanib and sunitinib followed by anti-PD-1 antibody produced a comparable inhibition of tumor growth in a RCC syngeneic mouse model. Our findings suggest that pazopanib and sunitinib, showing similar immunomodulatory effects, may have a comparable impact on the subsequent effectiveness of PD-1/PD-L1 blockade.

External validation of a red cell-based blood prognostic score in patients with metastatic renal cell carcinoma treated with first-line immunotherapy combinations.

Immunotherapy combinations with tyrosine-kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) had significantly improved outcomes of patients with mRCC. Predictive and prognostic factors are crucial to improve patients' counseling and management. The present study aimed to externally validate the prognostic value of a previously developed red cell-based score, including hemoglobin (Hb), mean corpuscular volume (MCV) and red cell distribution width (RDW), in patients with mRCC treated with first-line immunotherapy combinations (TKI plus ICI or ICI plus ICI). We performed a sub-analysis of a multicentre retrospective observational study (ARON-1 project) involving patients with mRCC treated with first-line immunotherapy combinations. Uni- and multivariable Cox regression models were used to assess the correlation between the red cell-based score and progression-free survival (PFS), and overall survival (OS). Logistic regression were used to estimate the correlation between the score and the objective response rate (ORR). The prognostic impact of the red cell-based score on PFS and OS was confirmed in the whole population regardless of the immunotherapy combination used [median PFS (mPFS): 17.4 vs 8.2 months, HR 0.66, 95% CI 0.47-0.94; median OS (mOS): 42.0 vs 17.3 months, HR 0.60, 95% CI 0.39-0.92; p < 0.001 for both]. We validated the prognostic significance of the red cell-based score in patients with mRCC treated with first-line immunotherapy combinations. The score is easy to use in daily clinical practice and it might improve patient counselling.

Exploring genetic and immune underpinnings of the sexual dimorphism in tumor response to immune checkpoints inhibitors: A narrative review.

Introduction: In spite of the undisputed relevance of sex as critical biologic variable of the immune landscape, still limited is our understanding of the basic mechanisms implicated in sex-biased immune response thereby conditioning the therapeutic outcome in cancer patients. This hindrance delays the actual attempts to decipher the heterogeneity of cancer and its immune surveillance, further digressing the achievement of predictive biomarkers in the current immunotherapy-driven scenario. Body: The present review concisely reports on genetic, chromosomal, hormonal, and immune features underlying sex-differences in the response to immune checkpoint inhibitors (ICIs). In addition to outline the need of robust data on ICI pharmaco-kinetics/dynamics, our survey might provide new insights on sex determinants of ICI efficacy and suggests uncovered pathways that warrant prospective investigations. Conclusion: According to a sharable view, we propose to widely include sex among the co-variates when assessing the clinical response to ICI in cancer patients.

Upper Tract Urinary Carcinoma: A Unique Immuno-Molecular Entity and a Clinical Challenge in the Current Therapeutic Scenario.

Urothelial carcinoma (UC) is the most frequent malignancy of the urinary tract, which consists of bladder cancer (BC) for 90%, while 5% to 10%, of urinary tract UC (UTUC). BC and UTUC are characterized by distinct phenotypical and genotypical features as well as specific gene- and protein- expression profiles, which result in a diverse natural history of the tumor. With respect to BC, UTUC tends to be diagnosed in a later stage and displays poorer clinical outcome. In the present review, we seek to highlight the individuality of UTUC from a biological, immunological, genetic-molecular, and clinical standpoint, also reporting the most recent evidence on UTUC treatment. In this regard, while the role of surgery in nonmetastatic UTUC is undebated, solid data on adjuvant or neoadjuvant chemotherapy are still an unmet need, not permitting a definite paradigm shift in the standard treatment. In advanced setting, evidence is mainly based on BC literature and retrospective studies and confirms platinum-based combination regimens as bedrock of first-line treatment. Recently, immunotherapy and target therapy are gaining a foothold in the treatment of metastatic disease, with pembrolizumab and atezolizumab showing encouraging results in combination with chemotherapy as a first-line strategy. Moreover, atezolizumab performed well as a maintenance treatment, while pembrolizumab as a single agent achieved promising outcomes in second-line setting. Regarding the target therapy, erdafitinib, a fibroblast growth factor receptor inhibitor, and enfortumab vedotin, an antibody-drug conjugate, proved to have a strong antitumor property, likely due to the distinctive immune-genetic background of UTUC. In this context, great efforts have been addressed to uncover the biological, immunological, and clinical grounds in UTUC patients in order to achieve a personalized treatment.

The radiological appearances of lung cancer treated with immunotherapy.

Therapy and prognosis of several solid and hematologic malignancies, including non-small cell lung cancer (NSCLC), have been favourably impacted by the introduction of immune checkpoint inhibitors (ICIs). Their mechanism of action relies on the principle that some cancers can evade immune surveillance by expressing surface inhibitor molecules, known as "immune checkpoints". ICIs aim to conceal tumoural checkpoints on the cell surface and reinvigorate the ability of the host immune system to recognize tumour cells, triggering an antitumoural immune response.In this review, we will focus on the imaging patterns of different responses occurring in patients treated by ICIs. We will also discuss imaging findings of immune-related adverse events (irAEs), along with current and future perspectives of metabolic imaging. Finally, we will explore the role of radiomics in the setting of ICI-treated patients.

Role of Clock Genes and Circadian Rhythm in Renal Cell Carcinoma: Recent Evidence and Therapeutic Consequences.

Circadian rhythm regulates cellular differentiation and physiology and shapes the immune response. Altered expression of clock genes might lead to the onset of common malignant cancers, including Renal Cell Carcinoma (RCC). Data from Cancer Genome Atlas (TCGA) indicate that clock genes PER1-3, CRY2, CLOCK, NR1D2 and RORα are overexpressed in RCC tissues and correlate with patients' prognosis. The expression of clock genes could finely tune transcription factor activity in RCC and is associated with the extent of immune cell infiltration. The clock system interacts with hypoxia-induced factor-1α (HIF-1α) and regulates the circadian oscillation of mammalian target of rapamycin (mTOR) activity thereby conditioning the antitumor effect of mTOR inhibitors. The stimulation of natural killer (NK) cell activity exerted by the administration of interferon-α, a cornerstone of the first era of immunotherapy for RCC, relevantly varies according to circadian dosing time. Recent evidence demonstrated that time-of-day infusion directly affects the efficacy of immune checkpoint inhibitors in cancer patients. Compounds targeting the circadian clock have been identified and their role in the era of immunotherapy deserves to be further investigated. In this review, we aimed at addressing the impact of clock genes on the natural history of kidney cancer and their potential therapeutic implications.

Thirty-day mortality in hospitalised patients with lung cancer: incidence and predictors.

OBJECTIVES: Patients with lung cancer experience high rates of hospitalisation, mainly due to the high risk of complications that emerge during the natural history of the disease. We designed a retrospective, single-centre, observational study aimed at defining the clinical predictors of 30-day mortality in hospitalised patients with lung cancer. METHODS: Clinical records from the first admission of patients with lung cancer to the oncology ward of the University Hospital of Parma from 1 January 2017 to 1 January 2022 were collected. RESULTS: 251 consecutive patients were enrolled at the time of data cut-off. In the univariate analysis, baseline clinical predictors of 30-day mortality were Eastern Cooperative Oncology Group performance status (ECOG PS) (≥2 vs 0-1: 27.5% vs 14.8%, p=0.028), high Blaylock Risk Assessment Screening Score (BRASS) (high vs intermediate-low: 34.3% vs 11.9%, p<0.001), presence of pain (yes vs no: 24.4% vs 11.7%, p=0.009), number of metastatic sites (≥3 vs <3: 26.5% vs 13.4%, p=0.017) and presence of bone metastases (yes vs no: 29.0% vs 10.8%, p=0.001). In the multivariate analysis, high BRASS remained significantly associated with increased 30-day mortality (high vs intermediate-low; OR 2.87, 95% CI 1.21 to 6.78, p=0.016). CONCLUSION: Our results suggest that baseline poor ECOG PS, high BRASS, presence of pain, high tumour burden and presence of bone metastases could be used as clinical predictors of 30-day mortality in hospitalised patients with lung cancer. In particular, the BRASS scale should be used as a simple tool to predict 30-day mortality in hospitalised patients with lung cancer.

Integrating Red Blood Cell Features and Hemoglobin Levels in Metastatic Renal Cell Carcinoma Patients Treated with Pazopanib or Cabozantinib: An Easily Exploitable Prognostic Score.

BACKGROUND: The advent of immune checkpoint inhibitors (ICIs) has revolutionized the metastatic renal cell carcinoma (mRCC) therapeutic landscape. Nevertheless, tyrosine-kinase inhibitors (TKIs) targeting the vascular endothelial growth factor (VEGF) axis still play a key role. The aim of the present study was to explore the prognostic performance of an integrated blood score, based on hemoglobin (Hb) concentration, mean corpuscular volume (MCV), and red cell distribution width (RDW), in mRCC patients treated with anti-VEGF TKIs. The primary endpoint was to correlate Hb, MCV, and RDW with progression-free survival (PFS) and overall survival (OS). MATERIALS AND METHODS: Our multicenter retrospective observational study involved mRCC patients treated with pazopanib or cabozantinib from January 2012 to December 2020 in nine Italian centers. Clinical records and laboratory data, including Hb levels, MCV, and RDW, were collected at baseline. Descriptive statistics and univariate and multivariate analyses were performed. RESULTS: We enrolled 301 mRCC patients of which 179 (59%) underwent pazopanib, and 122 (41%) cabozantinib. We considered baseline Hb ≥12 g/dL, MCV >87 fL, and RDW ≤16% as good prognostic factors; hence, developing a multiparametric score capable of delineating 4 different categories. The number of good prognostic factors was associated with significantly longer PFS and OS (p < 0.001 for both). Therefore, we developed a red blood cell-based score by stratifying cases into two groups (2-3 versus 0-1, good factors). The impact on PFS and OS was even more striking (median PFS (mPFS): 16.3 vs 7.9 months; median OS (mOS): 33.7 vs 14.1 months)), regardless of the TKI agent. When challenged with univariate and multivariate analysis, the blood score maintained its high prognostic significance in terms of OS (multivariate analysis HR for OS: 0.53, 95% CI 0.39-0.75; p < 0.001, respectively), while the impact on PFS resulted in borderline significance. CONCLUSIONS: Our analyses demonstrate the prognostic role of a multiparametric score based on easily exploitable blood parameters, such as Hb concentration, MCV, and RDW. The red blood cell-based score may underlie the upregulation of the HIF-1α pathway and VEGF axis, thereby identifying a selected population who is likely to benefit from TKI therapy.

Can we identify a preferred first-line strategy for sarcomatoid renal cell carcinoma? A network meta-analysis.

Background: Combinations based on immune checkpoint inhibitors are the new first-line standard treatment for metastatic renal cell carcinoma. Sarcomatoid renal cell carcinoma (sRCC) has a dismal prognosis but good immunogenicity. Methods: The authors performed a network meta-analysis of Phase III randomized trials of immune checkpoint inhibitor-based combinations versus standard tyrosine kinase inhibitor monotherapy reporting data for sRCC. The end points were overall survival, progression-free survival and objective response rate. Results: Five trials comprising 569 sRCC patients (out of a total of 4409 metastatic renal cell carcinoma patients) were included. Nivolumab-cabozantinib was the highest ranking treatment for overall survival (p-score = 88%) and progression-free survival (p-score = 81%). Atezolizumab-bevacizumab had the highest rank for objective response rate (p-score = 80%). Conclusion: Despite some limitations, nivolumab-cabozantinib might be the preferred first-line option for sRCC in terms of efficacy.

Integrated MRI-Immune-Genomic Features Enclose a Risk Stratification Model in Patients Affected by Glioblastoma.

BACKGROUND: The aim of the present study was to dissect the clinical outcome of GB patients through the integration of molecular, immunophenotypic and MR imaging features. METHODS: We enrolled 57 histologically proven and molecularly tested GB patients (5.3% IDH-1 mutant). Two-Dimensional Free ROI on the Biggest Enhancing Tumoral Diameter (TDFRBETD) acquired by MRI sequences were used to perform a manual evaluation of multiple quantitative variables, among which we selected: SD Fluid Attenuated Inversion Recovery (FLAIR), SD and mean Apparent Diffusion Coefficient (ADC). Characterization of the Tumor Immune Microenvironment (TIME) involved the immunohistochemical analysis of PD-L1, and number and distribution of CD3+, CD4+, CD8+ Tumor Infiltrating Lymphocytes (TILs) and CD163+ Tumor Associated Macrophages (TAMs), focusing on immune-vascular localization. Genetic, MR imaging and TIME descriptors were correlated with overall survival (OS). RESULTS: MGMT methylation was associated with a significantly prolonged OS (median OS = 20 months), while no impact of p53 and EGFR status was apparent. GB cases with high mean ADC at MRI, indicative of low cellularity and soft consistency, exhibited increased OS (median OS = 24 months). PD-L1 and the overall number of TILs and CD163+TAMs had a marginal impact on patient outcome. Conversely, the density of vascular-associated (V) CD4+ lymphocytes emerged as the most significant prognostic factor (median OS = 23 months in V-CD4high vs. 13 months in V-CD4low, p = 0.015). High V-CD4+TILs also characterized TIME of MGMTmeth GB, while p53mut appeared to condition a desert immune background. When individual genetic (MGMTunmeth), MR imaging (mean ADClow) and TIME (V-CD4+TILslow) negative predictors were combined, median OS was 21 months (95% CI, 0-47.37) in patients displaying 0-1 risk factor and 13 months (95% CI 7.22-19.22) in the presence of 2-3 risk factors (p = 0.010, HR = 3.39, 95% CI 1.26-9.09). CONCLUSION: Interlacing MRI-immune-genetic features may provide highly significant risk-stratification models in GB patients.

PD-L1 SNPs as biomarkers to define benefit in patients with advanced NSCLC treated with immune checkpoint inhibitors.

OBJECTIVE: To investigate the role of CTLA-4, PD-1 (programmed death-1), and PD-L1 (programmed death-ligand 1) single nucleotide polymorphisms (SNPs) in predicting clinical outcome of patients with advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs). METHODS: A total of 166 consecutive patients were included. We correlated SNPs with clinical benefit, progression-free survival, time to treatment failure, and overall survival and evaluated the incidence of SNPs in nonresponder and long clinical benefit groups. RESULTS: Considering the entire cohort, no correlation was found between SNPs and clinical outcome; however, PD-L1 rs4143815 SNP and the long clinical benefit group showed a statistically significant association (p = 0.02). The nonresponder cohort displayed distinctive PD-L1 haplotype (p = 0.05). CONCLUSION: PD-L1 SNPs seem to be marginally involved in predicting clinical outcome of NSCLC treated with ICI, but further investigations are required.

Long-Term Response to Tyrosine Kinase Inhibitors for Metastatic Renal Cell Carcinoma.

Background: Tyrosine kinase inhibitors (TKIs) prolong progression-free survival (PFS) in patients with metastatic renal cell carcinoma (mRCC), some of which may achieve long-term responses. Herein, we report clinical and pathological characteristics of patients who achieved long-term responses during first-line TKI treatment. Methods: Patients receiving TKI as first-line therapy from January 2010 to December 2017 in seven Italian Oncology Centers were reviewed. Sixty-six patients were considered as long-term responders, as they remained progression-free for 36 months or more during TKI treatment. A logistic regression model was performed to evaluate the effect of each clinical-pathological variable on the probability of responding long-term. Results: A total of 335 patients with a median age of 66 years were included in the analysis. The median PFS and overall survival among the long-term responders was 70 and 106 months, respectively. At a landmark PFS analysis performed 36 months after the start of treatment, the median PFS was 34 months. Multivariate analysis from all patients identified previous nephrectomy, Eastern Cooperative Oncology Group Performance Status (ECOG PS) < 1, and lack of liver metastasis as favorable prognostic factors for long-term response. Female gender and lack of liver metastasis positively correlated with long-term responses in favorable-risk-score population, as well as ECOG PS < 1 in intermediate-poor risk score population. Patients Summary: Previous surgery, clinical condition, and lack of liver metastasis may predict long-term responses to tyrosine kinase inhibitors. Conclusions: TKIs can lead to a long-term response in a subset of patients with metastatic RCC. Previous nephrectomy, optimal performance status (ECOG PS = 0), and lack of liver metastasis may predict long-term responses.