ABSTRACT
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 TCâ ≥â 200 mg/dl showed longer median progression-free survival (mPFS; 6.6 vs. 4.7 months, Pâ =â .4), although not reaching statistical significance, and significantly longer median overall survival (mOS; 19.4 vs. 10.8 months, Pâ =â .02) compared to those with TCâ <â 200 mg/dl. Conversely, patients with TG ≥150 mg/dl displayed shorter PFS (3.4 vs. 5.1 months, Pâ =â .02) and OS (7.1 vs. 12.9 months, Pâ =â .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 (Pâ =â .005); mOS of GR, IR, and PR was 20.4, 12.4, and 5.3 months, respectively (Pâ <â .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.
Subject(s)
Immune Checkpoint Inhibitors , Neoplasms , Humans , Retrospective Studies , Prognosis , Lipids , Triglycerides , Neoplasms/drug therapyABSTRACT
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.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Pneumonia , Proto-Oncogene Proteins c-ret , Pyrazoles , Pyridines , Humans , Middle Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/administration & dosage , Brain Neoplasms/drug therapy , Brain Neoplasms/secondary , Brain Neoplasms/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Gene Rearrangement , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Pneumonia/chemically induced , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/administration & dosage , Proto-Oncogene Proteins c-ret/genetics , Pyrazoles/adverse effects , Pyrazoles/therapeutic use , Pyrazoles/administration & dosage , Pyridines/adverse effects , Pyridines/therapeutic use , Pyridines/administration & dosage , Pyrimidines , FemaleABSTRACT
The combination of BRAF and MEK inhibitors demonstrated significant clinical benefit in patients with BRAF-mutant non-small cell lung cancer (NSCLC). However, the molecular mechanisms of acquired resistance to BRAF and MEK inhibition in NSCLC are still unknown. Herein, we report a case of a 76-year-old man with a history of smoking who was diagnosed with BRAF V600E-mutant lung adenocarcinoma (PD-L1â >â 50%) and subsequently candidate to first-line therapy with pembrolizumab. After 18â months since the start of immunotherapy, computed tomography scan showed disease progression and a second-line therapy with dabrafenib and trametinib was initiated. Seven months later, due to a suspect disease progression, a left supraclavicular lymphadenectomy was performed and next-generation sequencing analysis revealed the appearance of MET exon 14 skipping mutation, while fluorescence in situ hybridization analysis showed MET amplification. The patient is still on BRAF and MEK inhibitor treatment. Our case highlights the relevance of performing tumor tissue rebiopsy at the time of progression during treatment with BRAF/MEK inhibition with the aim of identifying putative mechanisms of resistance.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Carcinoma, Non-Small-Cell Lung , Drug Resistance, Neoplasm , Imidazoles , Lung Neoplasms , Mutation , Oximes , Proto-Oncogene Proteins B-raf , Proto-Oncogene Proteins c-met , Pyridones , Pyrimidinones , Humans , Pyridones/administration & dosage , Pyrimidinones/administration & dosage , Male , Oximes/administration & dosage , Aged , Proto-Oncogene Proteins B-raf/genetics , Imidazoles/administration & dosage , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Proto-Oncogene Proteins c-met/genetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
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.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Carcinoma, Renal Cell , Kidney Neoplasms , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/pathology , Immune Checkpoint Inhibitors/therapeutic use , Retrospective Studies , Carcinoma, Renal Cell/drug therapy , Biomarkers, Tumor/analysis , Kidney Neoplasms/drug therapy , CholesterolABSTRACT
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.
Subject(s)
B7-H1 Antigen , Lung Neoplasms , Humans , Immune Checkpoint Inhibitors , Italy , Lung Neoplasms/drug therapy , Programmed Cell Death 1 ReceptorABSTRACT
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.
Subject(s)
Carcinoma, Non-Small-Cell Lung/etiology , Carcinoma, Non-Small-Cell Lung/pathology , Immunomodulation , Lung Neoplasms/etiology , Lung Neoplasms/pathology , Tumor Microenvironment/immunology , AMP-Activated Protein Kinase Kinases/genetics , AMP-Activated Protein Kinase Kinases/metabolism , Animals , Antineoplastic Agents, Immunological/pharmacology , Antineoplastic Agents, Immunological/therapeutic use , Biomarkers , Biomarkers, Tumor , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/therapy , Disease Management , Disease Susceptibility , Energy Metabolism , Gene Expression Regulation, Neoplastic , Humans , Immunomodulation/genetics , Immunotherapy , Lung Neoplasms/metabolism , Lung Neoplasms/therapy , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mutation , Prognosis , Signal Transduction , Treatment Outcome , Tumor Escape/genetics , Tumor Microenvironment/drug effects , Tumor Microenvironment/geneticsABSTRACT
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 (Ë20%) 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.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/therapy , Immunity/drug effects , Lung Neoplasms/drug therapy , Lung Neoplasms/therapy , Carcinoma, Non-Small-Cell Lung/immunology , Humans , Immunity/immunology , Immunotherapy/methods , Lung Neoplasms/immunology , Tumor Microenvironment/immunologyABSTRACT
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.
Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma, Non-Small-Cell Lung/genetics , Drug Resistance, Neoplasm/genetics , Lung Neoplasms/genetics , Mutation/genetics , Proto-Oncogene Proteins c-met/genetics , Adult , Aged , ErbB Receptors/genetics , Female , Gene Amplification , Gene Expression Regulation, Neoplastic , Humans , Male , Middle Aged , Neoplasm Metastasis , Tumor Suppressor Protein p53/geneticsABSTRACT
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.
Subject(s)
Cardiomyopathies/chemically induced , Imatinib Mesylate/toxicity , Myocardium/pathology , Stem Cells/drug effects , Animals , Cell Death/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Hemodynamics/drug effects , Humans , Male , Myocardium/ultrastructure , RatsABSTRACT
The study investigated the relationship between serum proinflammatory cytokine levels, cholesterol metabolism, and clinical outcome in cancer patients undergoing immune checkpoint inhibitors (ICIs). Peripheral blood was collected before therapy from ICI-treated advanced cancer patients. We retrospectively assessed plasma total cholesterol (TC), ABCA1- and ABCG1-mediated cholesterol efflux (CE), passive diffusion (PD), cholesterol loading capacity (CLC), and serum IL-6, IL-10, and TNF-α. The association between blood cholesterol parameters and inflammatory cytokines and their effect on overall survival (OS), progression-free survival (PFS), and clinical benefit (CB) from ICIs were statistically assessed. Among 70 consecutively enrolled patients (nonsmall cell lung cancer: 94%; renal cell carcinoma: 6%), TC, CLC, and cholesterol PD resulted significantly higher in IL-6low and IL-10low cases (P<0.05), whereas ABCA1-mediated CE was increased in IL-10high patients (P=0.018). Uni- and multivariable analysis revealed meaningfully longer OS and PFS in IL-6low (HR 2.13 and 2.97, respectively) and IL-10low (HR 3.17 and 2.62) groups. At univariate analysis all cholesterol-related indices significantly correlated with OS and PFS, whereas at multivariate only high PD was validated as a protection factor (OS, HR 0.75; PFS, HR 0.84). Finally, uni- and multivariable showed a statistically significant inverse association of CB with ABCG1-CE (OR 0.62), as with IL-6 (OR 0.13) and IL-10 (OR 0.10). In-depth characterization of the interplay between blood cholesterol metabolism and immune-inflammatory cytokines might provide novel insights into the complex relationship among cancer, inflammation, lipids profile, and response to immunotherapy.
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Aim: To investigate the different impact of each component of lipid profile in advanced cancer patients treated with immune checkpoints inhibitors (ICIs) according to neutrophil-to-lymphocyte ratio (NLR) value. Methods: We retrospectively collected total cholesterol (TC), triglycerides (TGs), low-density lipoproteins (LDL), high-density lipoproteins (HDL). Results: 407 patients were enrolled. In NLR <4 subgroup, TGs <150 mg/dl led to longer PFS (p = 0.01) and OS (p = 0.02) compared with TGs ≥150 mg/dl; LDL <100 mg/dl led to longer PFS (p = 0.004) and OS (p = 0.007) compared with LDL ≥100 mg/dl. In NLR ≥4 subgroup, TC >200 mg/dl led to longer PFS (p = 0.008) and OS (p = 0.004) compared with TC <200 mg/dl. Conclusion: We showed a distinct prognostic impact of lipid profile according to NLR.
[Box: see text].
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Aims: Anemia, mean corpuscular volume and red cell distribution width may have some effects on survival outcomes of metastatic renal cell carcinoma (mRCC) patients and are incorporated in a red blood cell (RBC)-based score. Its validity in prognostication of mRCC patients treated with second-line nivolumab was assessed. Patients and methods: Retrospective analysis using Meet-URO-15 cohort of mRCC patients receiving nivolumab in the second-line setting or beyond. Outcomes were overall survival (OS) and progression-free survival (PFS). Results: A total of 390 patients were included. Significant differences in OS and PFS between RBC-based score groups, with group 1 (2 or 3 of the RBC-related prognostic factors) having longer OS (median 29.5 months, 95% CI: 23.1-35.9, versus 11.5 months, 95% CI: 8.5-22.6; p < 0.001) and PFS (7.5 months, 95% CI: 5.5-10.2, versus 4.2 months, 95% CI: 3.3-5.9; p = 0.040) than those in group 0 (0 or 1 RBC-related prognostic factors). Belonging to group 1 independently predicted OS (hazard ratio: 0.65, 95% CI: 0.50-0.85; p = 0.002) but not PFS (hazard ratio: 0.89, 95% CI: 0.70-1.14, p = 0.370) or disease response (OR 0.68, 95% CI: 0.41-1.10; p = 0.118) at multivariable analysis. Conclusion: RBC-based group scores independently predicted OS in mRCC patients treated with nivolumab.
This study looked at how certain blood cell measurements (anemia, mean corpuscular volume, red cell distribution width) affect survival in patients with metastatic renal cell carcinoma who are treated with nivolumab, an immunotherapy drug. Researchers analyzed data from 390 patients who received nivolumab as a second-line treatment or beyond. They divided patients into groups based on their blood cell scores. They found that patients with higher scores had better overall survival and progression-free survival compared with those with lower scores. Specifically, patients with better scores lived longer. The study concluded that these scores can help predict survival in these patients treated with nivolumab.
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PURPOSE: This study aims to determine whether longitudinal changes in CT radiomic features (RFs) and systemic inflammatory indices outperform single-time-point assessment in predicting survival in advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs). MATERIALS AND METHODS: We retrospectively acquired pretreatment (T0) and first disease assessment (T1) RFs and systemic inflammatory indices from a single-center cohort of stage IV NSCLC patients and computed their delta (Δ) variation as [(T1-T0)/T0]. RFs from the primary tumor were selected for building baseline-radiomic (RAD) and Δ-RAD scores using the linear combination of standardized predictors detected by LASSO Cox regression models. Cox models were generated using clinical features alone or combined with baseline and Δ blood parameters and integrated with baseline-RAD and Δ-RAD. All models were 3-fold cross-validated. A prognostic index (PI) of each model was tested to stratify overall survival (OS) through Kaplan-Meier analysis. RESULTS: We included 90 ICI-treated NSCLC patients (median age 70 y [IQR=42 to 85], 63 males). Δ-RAD outperformed baseline-RAD for predicting OS [c-index: 0.632 (95%CI: 0.628 to 0.636) vs. 0.605 (95%CI: 0.601 to 0.608) in the test splits]. Integrating longitudinal changes of systemic inflammatory indices and Δ-RAD with clinical data led to the best model performance [Integrated-Δ model, c-index: 0.750 (95% CI: 0.749 to 0.751) in training and 0.718 (95% CI: 0.715 to 0.721) in testing splits]. PI enabled significant OS stratification within all the models (P-value <0.01), reaching the greatest discriminative ability in Δ models (high-risk group HR up to 7.37, 95% CI: 3.9 to 13.94, P<0.01). CONCLUSION: Δ-RAD improved OS prediction compared with single-time-point radiomic in advanced ICI-treated NSCLC. Integrating Δ-RAD with a longitudinal assessment of clinical and laboratory data further improved the prognostic performance.
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OBJECTIVES: Despite the outstanding results achieved by osimertinib for the treatment of advanced EGFR-mutated NSCLC, the development of resistance is almost inevitable. While molecular mechanism responsible for osimertinib resistance are being mostly revealed, the definition of predictive biomarkers is crucial in order to identify patients at higher risk of progression and optimize treatment strategy. MATERIALS AND METHODS: This is a prospective single-center study aimed to assess the potential role of liquid biopsy and 18F-FDG PET/CT derived metabolic parameters as noninvasive predictive biomarkers of osimertinib outcomes in advanced EGFR-mutated NSCLC patients. Patients underwent blood samples for ctDNA analysis at baseline, after 15 days and 1 month (t1) of osimertinib. 18F-FDG PET/CT was performed at baseline and after 1 month of osimertinib. RESULTS: Seventy-two advanced EGFR-mutated NSCLC patients treated with osimertinib in first (n = 63) and in second-line (n = 9) were prospectively enrolled. Baseline positive shedding status was significantly associated with a shorter progression-free survival (PFS) (9.5 vs. 29.2 months, P = .031). Early metabolic response (MR) led to improved PFS (16.8 vs. 5.5 months, P = .038) and OS (35.2 vs. 15.3 months, P = .047). Early MR was significantly correlated with subsequent radiologic response (P = .010). All 18F-FDG PET/CT baseline parameters were significantly related to baseline EGFR activating mutation allele frequency. Both clearance and no detection of EGFR at t1 were significantly associated with MR (P = .001 and P = .004, respectively). CONCLUSION: Molecular and 18F-FDG PET/CT derived metabolic parameters might represent a useful tool to predict osimertinib outcome in advanced EGFR-mutated NSCLC patients.
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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.
Subject(s)
Angiogenesis Inhibitors , Carcinoma, Renal Cell , Kidney Neoplasms , Programmed Cell Death 1 Receptor , Protein Kinase Inhibitors , Pyrimidines , Sulfonamides , Sunitinib , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/pathology , Kidney Neoplasms/drug therapy , Kidney Neoplasms/pathology , Animals , Humans , Mice , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/therapeutic use , Angiogenesis Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Sunitinib/pharmacology , Sunitinib/therapeutic use , Cell Line, Tumor , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/metabolism , Indazoles/pharmacology , Indazoles/therapeutic use , Indazoles/administration & dosage , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Female , Xenograft Model Antitumor Assays/methods , Nivolumab/pharmacology , Nivolumab/therapeutic use , Nivolumab/administration & dosage , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/metabolismABSTRACT
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.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Carcinoma, Renal Cell/secondary , Prognosis , Kidney Neoplasms/pathology , Progression-Free Survival , Immunotherapy , Retrospective StudiesABSTRACT
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.
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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.
Subject(s)
Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , Urinary Tract , Humans , Retrospective Studies , ImmunotherapyABSTRACT
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.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/therapy , Carcinoma, Non-Small-Cell Lung/diagnostic imaging , Carcinoma, Non-Small-Cell Lung/therapy , Prognosis , Radiography , Immunotherapy/methodsABSTRACT
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.