Radiotherapy and Immunotherapy: The Power of the Teamwork for the Treatment of NSCLC.

Immune checkpoint inhibitors (ICPi) targeting programmed cell death 1(PD-1)/programmed cell death ligand-1 (PD-L1) have revolutionized the treatment of patients with advanced non-small cell lung cancer (NSCLC). Despite impressive success, only a small proportion of patients benefit from PD1/PDL1 inhibitors. Radiotherapy (RT) can induce a systemic anti-tumor immune response on local and distant tumors. Some preclinical and clinical evidence showed a critical role of RT to overcome acquired resistance to immunotherapy. Currently, durvalumab consolidation represents the new standard treatment for unresectable stage III NSCLC patients whose tumors express PDL1 on ≥1% of tumor cells (TC), and whose disease has not progressed following platinum-based chemoradiotherapy (CRT). In this review, we focus on the synergic effect of RT with ICPi and the new role that different RT schedules can play in combination with immunotherapy for early-stage NSCLC.

Systemic effect of radiotherapy before or after nivolumab in lung cancer: an observational, retrospective, multicenter study.

BACKGROUND: The combination of radiotherapy (RT) and programmed death 1 inhibitors seems to increase antitumor immune responses. OBJECTIVE: To assess the outcome and the role of the best combination sequence, i.e. immunotherapy given before, during, and/or after RT, in patients with non-small cell lung cancer (NSCLC). METHODS: We conducted an observational, retrospective analysis of 95 consecutive patients with advanced NSCLC who received any radiotherapy treatment and nivolumab, as clinically indicated. Median overall survival (OS) and the 95% confidence interval (CI) were estimated with the Kaplan-Meier method. Cox model was used to obtain hazard ratio (HR) and associated 95% CI with statistical inference by log-rank statistic. RESULTS: Median OS was 11.9 months (95% CI, 6.6-17.2). Patients who received radiotherapy during an immune checkpoint inhibitor treatment started more than 60 days before showed a better outcome than patients who started immunotherapy over 60 days after RT ending (HR, 2.90 [1.37-6.12], p = 0.005; median OS, 22.4 months vs 8.6 months, p = 0.005). Median progression-free survival was 6.3 months (95% CI, 4.6-8.0). CONCLUSIONS: This study shows that combining irradiation with nivolumab for the treatment of advanced NSCLC leads to improved OS. The optimal time window for the combination of RT and immunotherapy seems to play a critical role for therapeutic antitumor response derived by abscopal effect.

Regorafenib-to-trifluridine/tipiracil Versus the Reverse Sequence for Refractory Metastatic Colorectal Cancer Patients: A Multicenter Retrospective Real-life Experience.

BACKGROUND/AIM: Regorafenib (REG) and trifluridine/tipiracil (FTD/TPI) have have been shown to improve overall survival in patients with refractory metastatic colorectal cancer. The aim of our study was to evaluate the efficacy and safety profiles of these agents administered in sequence in real world practice. PATIENTS AND METHODS: Clinical data of patients treated beyond the 2°line with REG or FTD/TPI between January 2016 and August 2020, were retrospectively collected from eight institutes in the Lazio Region. RESULTS: We included 49 patients treated with both drug sequences. A total of 28 G3/G4 toxicity events (53.8%) were recorded in the FTD/TPI-to-REG sequence vs. 24 (46.1%) in the reverse sequence. Median overall survival for the patients included in the FTP/TPI-to-REG group was 20 months (95%CI=16.7-23.3) vs. 27 months in the reverse group (95%CI=17.8-36.2). The disease control rate was 45.0% for patients treated with the REG-to-FTD/TPI sequence vs. 24.1% in those treated with the FTD/TPI-to-REG sequence (p=0.18). CONCLUSION: The sequence REG-to-FTD/TPI and vice versa can extend survival, whereas only REG-to-FTD/TPI stabilizes cancer growth.

PANHER study: a 20-year treatment outcome analysis from a multicentre observational study of HER2-positive advanced breast cancer patients from the real-world setting.

BACKGROUND: The evolution of therapeutic landscape of human epidermal growth factor receptor-2 (HER2)-positive breast cancer (BC) has led to an unprecedented outcome improvement, even if the optimal sequence strategy is still debated. To address this issue and to provide a picture of the advancement of anti-HER2 treatments, we performed a large, multicenter, retrospective study of HER2-positive BC patients. METHODS: The observational PANHER study included 1,328 HER2-positive advanced BC patients treated with HER2 blocking agents since June 2000 throughout July 2020. Endpoints of efficacy were progression-free survival (PFS) and overall survival (OS). RESULTS: Patients who received a first-line pertuzumab-based regimen showed better PFS (p < 0.0001) and OS (p = 0.004) than those receiving other treatments. Median PFS and mOS from second-line starting were 8 and 28 months, without significant differences among various regimens. Pertuzumab-pretreated patients showed a mPFS and a mOS from second-line starting not significantly affected by type of second line, that is, T-DM1 or lapatinib/capecitabine (p = 0.80 and p = 0.45, respectively). Conversely, pertuzumab-naïve patients receiving second-line T-DM1 showed a significantly higher mPFS compared with that of patients treated with lapatinib/capecitabine (p = 0.004). Median OS from metastatic disease diagnosis was higher in patients treated with trastuzumab-based first line followed by second-line T-DM1 in comparison to pertuzumab-based first-line and second-line T-DM1 (p = 0.003), although these data might be partially influenced by more favorable prognostic characteristics of patients in the pre-pertuzumab era. No significant differences emerged when comparing patients treated with 'old' or 'new' drugs (p = 0.43), even though differences in the length of the follow-up between the two cohorts should be taken into account. CONCLUSION: Our results confirmed a relevant impact of first-line pertuzumab-based treatment and showed lower efficacy of second-line T-DM1 in trastuzumab/pertuzumab pretreated, as compared with pertuzumab-naïve patients. Our findings may help delineate a more appropriate therapeutic strategy in HER2-positive metastatic BC. Prospective randomized trials addressing this topic are awaited.

A 17-Gene Expression Signature for Early Identification of Poor Prognosis in Clear Cell Renal Cell Carcinoma.

The Identification of reliable Biomarkers able to predict the outcome after nephrectomy of patients with clear cell renal cell carcinoma (ccRCC) is an unmet need. The gene expression analysis in tumor tissues represents a promising tool for better stratification of ccRCC subtypes and patients' evaluation. METHODS: In our study we retrospectively analyzed using Next-Generation expression analysis (NanoString), the expression of a gene panel in tumor tissue from 46 consecutive patients treated with nephrectomy for non-metastatic ccRCC at two Italian Oncological Centres. Significant differences in expression levels of selected genes was sought. Additionally, we performed a univariate and a multivariate analysis on overall survival according to Cox regression model. RESULTS: A 17-gene expression signature of patients with a recurrence-free survival (RFS) < 1 year (unfavorable genomic signature (UGS)) and of patients with a RFS > 5 years (favorable genomic signature (FGS)) was identified and resulted in being significantly correlated with overall survival of the patients included in this analysis (HR 51.37, p < 0.0001). CONCLUSIONS: The identified Genomic Signatures may serve as potential biomarkers for prognosis prediction of non-metastatic RCC and could drive both follow-up and treatment personalization in RCC management.

Renal Cell Carcinoma: the Oncologist Asks, Can PSMA PET/CT Answer?

PURPOSE OF REVIEW: To critically review the potential clinical applications of prostate-specific membrane antigen (PSMA) radioactive ligands in renal cell carcinoma (RCC). RECENT FINDINGS: Radioactive probes targeting PSMA hold promise in several malignancies in addition to prostate cancer, owing to the expression of PSMA by tumor neovasculature. The majority of clear cell RCCs (ccRCC), the most malignant RCC subtype, express PSMA on tumor-associated neovasculature. The endothelium of less aggressive RCC subtypes is PSMA positive in a lower, but still significant percentage of cases. PSMA might therefore represent an interesting theragnostic target in RCC. The preliminary data available suggest a potential role for PSMA-targeting radiopharmaceuticals in complementing conventional imaging for staging ccRCC patients at risk of nodal involvement and oligometastatic disease. Additional applications of PSMA imaging may be the selection and the response assessment of patients receiving anti-angiogenic treatments. The effectiveness of PSMA-targeting radionuclide therapy should also be investigated.

Safety and Efficacy of Nivolumab in Patients With Advanced Non-small-cell Lung Cancer Treated Beyond Progression.

INTRODUCTION: Treatment with immune checkpoint inhibitors beyond progression is associated with improved survival in patients with melanoma and clear-cell renal carcinoma. Whether this association exists for patients with non-small-cell lung cancer (NSCLC) is currently still unclear. PATIENTS AND METHODS: We performed a multi-institutional retrospective study based on landmark and multivariable analyses to evaluate the safety and efficacy of treatment with nivolumab beyond Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 progression in patients with advanced NSCLC. Criteria for receiving nivolumab beyond progression were investigator-assessed clinical benefit, stable performance status, tolerance of treatment, and no need of immediate intervention to prevent serious complication of progression. RESULTS: Of 176 patients progressed to nivolumab according to RECIST v1.1, 60 (34.1%) were treated beyond progression (TBP) and 116 (65.9%) were not-TBP (NTBP). The median overall survival was significantly longer in the TBP group compared with the NTBP group (17.8 vs. 3.7 months; hazard ratio [HR], 0.32; 95% confidence interval [CI], 0.21-0.46; P < .0001). In a landmark analysis of evaluable patients beginning 6 weeks from first progression, the median overall survival for patients TBP was 10.7 months and for those NTBP, 3.4 months (HR, 0.48; 95% CI, 0.30-0.77; P = .002). Discontinuation of nivolumab at first progression was associated with shorter survival in multivariable analysis (HR, 2.98; 95% CI, 1.95-4.54; P < .001). No safety concerns emerged in patients who were in the TBP group. CONCLUSION: A subset of patients with NSCLC and progressive disease may continue to benefit from nivolumab beyond progression. Discontinuation of immunotherapy based only on RECIST v1.1 may be premature.

Association between CMV and Invasive Fungal Infections After Autologous Stem Cell Transplant in Lymphoproliferative Malignancies: Opportunistic Partnership or Cause-Effect Relationship?

Unlike allogeneic transplant, autologous stem cell transplantation (ASCT) represents a procedure with a low-risk of cytomegalovirus (CMV) symptomatic reactivation-infection/end-organ disease (CMV complications) and invasive fungal disease (IFD). However, novel drugs for the treatment of lymphoproliferative malignancies could cause an increase of such opportunistic infections, even after ASCT. To the best of our knowledge, there are no published data demonstrating an association between CMV and IFD in the autologous setting, while this association has been widely reported in allogeneic transplantation. We have reviewed our series of 347 ASCT in myeloma and lymphoma patients performed over a period of 14 years with the aim of investigating the descriptive and analytical epidemiology of bacterial, CMV and IFD complications, focusing on the association between CMV and IFD. Patients with myeloma have significantly fewer bacterial infections and IFD than patients with lymphoma, but a similar rate of CMV complications. Descriptive epidemiological data are consistent with the literature, indicating an overall incidence of 36%, 3.5% and 15.5% for bacterial infections, IFD and CMV complications, with a case mortality rate of 4%, 16.7% and 3.7%, respectively. A strong correlation between CMV and IFD exists, with 8 cases of IFD out of a total of 12 presenting a CMV complication. At multivariate analysis, a diagnosis of lymphoma, ≥3 previous treatment lines and age ≥60 years were found to be independent risk factors for IFD. Duration of neutropenia (ANC < 500/mm³) ≥7 days represents an independent risk factor for CMV complications, where neutropenia most likely represents a crude surrogate biomarker indicating a deeper and longer state of overall immunosuppression. From our data we conclude that (1) myeloma patients are at lower risk of bacterial infections and IFD as compared with lymphoma patients but are at equal risk of CMV complications, most likely as a consequence of a selective impact of bortezomib on Herpes Viruses infection control; (2) a significant association exists between CMV and IFD, although a possible cause-effect relationship remains to be determined; (3) IFD is a rare complication after ASCT but burdened by a mortality rate of about 17%, with peak rates in older lymphoma patients who underwent more intensive therapeutic regimens.

Molecular Basis of Drug Resistance and Insights for New Treatment Approaches in mCRPC.

Inhibiting androgen receptor (AR) signaling with androgen deprivation therapy (ADT) represents the mainstay of therapy for advanced and metastatic prostate cancer. However, about 20-60% of patients receiving first-line treatment for prostate cancer will relapse, evolving in a more aggressive and lethal form of the disease, the castration-resistant prostate cancer (CRPC), despite the use of ADT. Multiple approved systemic therapies able to prolong survival of patients with metastatic CRPC (mCRPC) exist, but almost invariably, patients treated with these drugs develop primary or acquired resistance. Multiple factors are involved in CRPC treatment resistance and elucidating the mechanisms of action of these factors is a key question and an active area of research. Due to such a complex scenario, treatment personalization is necessary to improve treatment effectiveness and reduce relapse rates in CRPC. In this review, current evidence about the major mechanisms of resistance to the available prostate cancer treatments were examined by introducing insights on new and future therapeutic approaches.

Heterogeneity of PD-L1 Expression and Relationship with Biology of NSCLC.

Immunotherapy with monoclonal antibodies against programmed cell death (PD-1), such as nivolumab and pembrolizumab, has significantly improved the survival of patients with metastatic non-small cell lung cancer (NSCLC). In order to determine the subset of patients that can benefit most from these therapies, biomarkers such as programmed death ligand-1 (PD-L1) have been proposed. However, the predictive and prognostic role of the use of PD-L1 is controversial. Anti-PD-L1 immunohistochemistry may not represent the actual status of the tumour because of individual variability and tumour heterogeneity. Additionally, there may be analytical variability due to the use of different assays and antibodies to detect PD-L1. Moreover PD-L1 expression is also regulated by oncogenic drivers in NSCLC, such as epidermal growth factor receptor (EGFR), echinoderm microtubule-associated protein-like 4 (EML4) fusion with anaplastic lymphoma kinase (ALK), and Kirsten rat sarcoma viral oncogene homolog (KRAS). Preclinical studies have shown the potential role of targeted therapy in immune escape mechanisms in NSCLC cells. This review summarizes current literature data on the heterogeneity of PD-L1 expression and the relationship with such factors and with clinicopathological features of NSCLC.

Molecular profiling in Italian patients with advanced non-small-cell lung cancer: An observational prospective study.

OBJECTIVES: Molecular profiling of advanced non-small-cell lung cancer (NSCLC) is recommended according to European and Italian guidelines. However, molecular routine assessment remains still heterogeneous. This observational study aimed to take a picture of the real clinical practice in molecular testing and therapeutic choices in advanced Italian NSCLCs. MATERIALS AND METHODS: This study prospectively enrolled newly diagnosed advanced or recurrent NSCLCs referred to 38 Italian centres, from November 2014 to November 2015. Information regarding molecular profiling and treatment choices were collected. Description of patients' outcome included overall survival (OS), progression-free survival in first (PFS1) and second-line (PFS2). RESULTS AND CONCLUSION: Among 1787 patients enrolled, 1388 (78%) performed at least one molecular analysis during the history of disease: 76% were tested for EGFR, 53% for ALK, 27% for KRAS, 16% for ROS1, 14% for BRAF, 5% for HER2, 4% for MET and 1% for FGFR. The remaining 399 patients (22.3%) did not receive any molecular test. Among patients receiving at least one molecular analysis, 583 (42%) presented a molecular alteration. Considering EGFR mutated and/or ALK rearranged patients (402), for which target agents were routinely reimbursed at time of study in Italy, the 86% received a personalized treatment as first and/or second line: the 90% (286) of EGFR mutants received an EGFR tyrosine kinase inhibitor, mostly gefitinib (41.1%) or afatinib (36.4%) while 74% (62) of ALK translocated patients received an ALK inhibitor, mostly crizotinib (64%). Median OS was 9.34 months (95% CI 8.62-10.0), median PFS1 was 4.61 months (95%CI 4.31-4.84) and median PFS2 was 2.76 months (95%CI 2.57-3.19). In the Italian clinical practice, routine molecular assessment was largely applied in NSCLC patients, according to national guidelines, but a low level of ALK test was reached. Most of EGFR mutants an ALK rearranged patients received a personalized treatment as first and/or second line.

Induction Therapy versus Initial Surgery in Advanced Thymic Tumors: Perioperative and Oncological Outcome.

Background Despite the intense debate concerning management of advanced thymic tumors, no specific oncological strategies have been yet recommended. We report our 13 years' experience to investigate this issue. Methods From 01/2001 to 12/2013, the clinical data of 28 patients treated for Masaoka stages III-IV thymic tumors were retrospectively reviewed. Eleven potentially nonresectable patients (Group A) underwent induction chemotherapy plus surgery, while immediate surgery was performed in 17 patients (Group B). The endpoint was to compare the two groups on (1) surgical resectability; (2) postoperative course; (3) disease-free survival; and (4) overall survival. Results Both groups were comparable in terms of age, gender, clinical stage, clinical tumor size, histology, and adjuvant therapy. Length of surgery was statistically longer in Group A (p = 0.015). Combined surgery and R0 resection was similarly performed in both groups (p = 0.14 and p = 0.99, respectively). The 3-year overall survival was 71.4% for Group A and 93.3% for Group B (p = 0.84). On the other hand, 3-year disease-free survival was 40.5 and 53.7% for Group A and B, respectively (p = 0.67). At multivariate analysis, gender was the strongest predictor for recurrence (hazard ratio = 5.71 [1.22; 26.67], p = 0.03). Conclusion Our results suggest that induction therapy allows obtaining acceptable clinical responses as well as resectability, survival, and recurrence rates. In selected patients with "clinically resectable" stage III-IV cancers, surgery (as first step of a multimodality therapy) could be a feasible treatment option.

Patients' Attitudes and Physicians' Perceptions Toward Maintenance Therapy for Advanced Non-Small-cell Lung Cancer: A Multicenter Italian Survey.

INTRODUCTION: Pemetrexed maintenance therapy (MT) after induction with platinum-based chemotherapy has recently become a common treatment strategy for advanced nonsquamous non-small-cell lung cancer (NSCLC). However, the benefits of MT should be weighed with consideration of the patients' perceptions and preferences. The aim of the present study was to evaluate patients' attitudes toward MT and to describe physicians' awareness of their patients' inclinations. MATERIALS AND METHODS: We administered a 12-question anonymous survey and the Distress Thermometer Questionnaire to patients with advanced or recurrent nonsquamous NSCLC. The survey was also distributed to the referring physicians. RESULTS: From December 2014 to July 2015, 92 patients and 37 physicians were enrolled. All 92 patients completed the questionnaire at T0 (before starting chemotherapy) and 56.5% also did so at T1 (after completion of induction). The physicians completed the survey only at T0. Most patients had a positive attitude toward MT at both T0 (78.9%) and T1 (86.5%), and 100% of the physicians thought their patients would be in favor of MT. The physicians believed that their patients' attitudes toward MT would decrease proportionally with the reduction in the magnitude of the overall survival increase and expected benefits. The decrease expected by the physicians was much greater than that reported by the patients. This was especially true for an overall survival increase as small as 1 month (51.9% of patients accepting MT vs. 13.5% supposed by physicians) or when the only treatment benefit was radiologic tumor stabilization (69.3% of patients accepting MT vs. 37.8% supposed by physicians). CONCLUSION: NSCLC patients have a generally positive attitude toward MT, which is not directly proportional to the expected benefits and greater than the attitude expected by physicians.

Usefulness of conventional transbronchial needle aspiration in the diagnosis, staging and molecular characterization of pulmonary neoplasias by thin-prep based cytology: experience of a single oncological institute.

BACKGROUND: Conventional transbronchial needle aspiration (c-TBNA) contributed to improve the bronchoscopic examination, allowing to sample lesions located even outside the tracheo-bronchial tree and in the hilo-mediastinal district, both for diagnostic and staging purposes. METHODS: We have evaluated the sensitivity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of the c-TBNA performed during the 2005-2015 period for suspicious lung neoplasia and/or hilar and mediastinal lymphadenopathy at the Thoracic endoscopy of the Thoracic Surgery Department of the Regina Elena National Cancer Institute, Rome. Data from 273 consecutive patients (205 males and 68 females) were analyzed. RESULTS: Among 158 (58%) adequate specimens, 112 (41%) were neoplastic or contained atypical cells, 46 (17%) were negative or not diagnostic. We considered in the analysis first the overall period; then we compared the findings of the first [2005-2011] and second period [2012-2015] and, finally, only those of adequate specimens. During the overall period, sensibility and accuracy values were respectively of 53% and 63%, in the first period they reached 41% and 53% respectively; in the second period sensibility and accuracy reached 60% and 68%. Considering only the adequate specimens, sensibility and accuracy during the overall period were respectively of 80% and 82%; the values obtained for the first period were 68% and 72%. Finally, in the second period, sensibility reached 86% and accuracy 89%. Carcinoma-subtyping was possible in 112 cases, adenocarcinomas being diagnosed in 50 cases; further, in 30 cases molecular predictive data could be obtained. CONCLUSIONS: The c-TBNA proved to be an efficient method for the diagnosis/staging of lung neoplasms and for the diagnosis of mediastinal lymphadenopathy. Endoscopist's skill and technical development, associated to thin-prep cytology and to a rapid on site examination (ROSE), were able to provide by c-TBNA a high diagnostic yield and molecular predictive data in advanced lung carcinomas.

Symptomatic toxicities experienced during anticancer treatment: agreement between patient and physician reporting in three randomized trials.

PURPOSE: Information about symptomatic toxicities of anticancer treatments is not based on direct report by patients, but rather on reports by clinicians in trials. Given the potential for under-reporting, our aim was to compare reporting by patients and physicians of six toxicities (anorexia, nausea, vomiting, constipation, diarrhea, and hair loss) within three randomized trials. PATIENTS AND METHODS: In one trial, elderly patients with breast cancer received adjuvant chemotherapy; in two trials, patients with advanced non-small-cell lung cancer received first-line treatment. Toxicity was prospectively collected by investigators (graded by National Cancer Institute Common Toxicity Criteria [version 2.0] or Common Terminology Criteria for Adverse Events [version 3]). At the end of each cycle, patients completed the European Organisation for Research and Treatment of Cancer quality-of-life questionnaires, including toxicity-related symptom items. Possible answers were "not at all," "a little," "quite a bit," and "very much." Analysis was limited to the first three cycles. For each toxicity, agreement between patients and physicians and under-reporting by physicians (ie, toxicity reported by patients but not reported by physicians) were calculated. RESULTS: Overall, 1,090 patients (2,482 cycles) were included. Agreement between patients and physicians was low for all toxicities. Toxicity rates reported by physicians were always lower than those reported by patients. For patients who reported toxicity (any severity), under-reporting by physicians ranged from 40.7% to 74.4%. Examining only patients who reported "very much" toxicity, under-reporting by physicians ranged from 13.0% to 50.0%. CONCLUSION: Subjective toxicities are at high risk of under-reporting by physicians, even when prospectively collected within randomized trials. This strongly supports the incorporation of patient-reported outcomes into toxicity reporting in clinical trials.

Thymic epithelial tumors express vascular endothelial growth factors and their receptors as potential targets of antiangiogenic therapy: a tissue micro array-based multicenter study.

OBJECTIVES: Tumor angiogenesis is an essential and complex process necessary for the growth of all tumors which represents a potential therapeutic target. Angiogenesis inhibitors targeting vascular endothelial growth factor (VEGF) or their receptor tyrosine kinases have been approved by the FDA. In thymic epithelial tumors (TET), targeted therapies have been sporadically applied due to their rarity. To ascertain the presence of potential therapeutic targets, we analyzed by immunohistochemistry the expression of angiogenesis-related biomarkers in a large series of TET arranged in Tissue Micro Arrays (TMA). MATERIALS AND METHODS: We assessed by immunohistochemistry the expression of the possible molecular target of anti-angiogenic therapy, i.e. VEGFA, VEGFC, VEGFD, VEGFR1, VEGFR2, VEGFR3, and PDGFRß, in a TMA series of 200 TET collected in the framework of a multi-institutional collaborative project for Rare Diseases. RESULTS: When compared to the low-risk tumors, high-risk TET (B2, B3, carcinomas) contained higher proportion of cancer cells expressing VEGFA, VEGFC and VEGFD (P<0.001, P<0.001, and P<0.001) growth factors, and their receptors VEGFR1 (P=0.002), VEGFR2 (P=0.013), and VEGFR3 (P=0.041). No differences were observed in terms of PDGFRß expression. CONCLUSIONS: According to our data, it is possible to hypothesize the existence of multiple paracrine and/or autocrine loops in TET, particularly in the high-risk ones, involved in TET growth and progression. Anti-angiogenic agents, directed to inhibit these loops, are therefore to be considered as potential tools in advanced TET therapy.

Advances towards the design and development of personalized non-small-cell lung cancer drug therapy.

INTRODUCTION: Non-small-cell lung cancer (NSCLC) subtypes are driven by specific genetic aberrations. For reasons such as this, there is a call for treatment personalization. The ability to instigate NSCLC fragmentation poses new methodological problems, and new 'driver' molecular aberrations are being discovered at an unprecedented pace. AREAS COVERED: This article describes the clinical development of epidermal growth factor-tyrosine kinase inhibitors (EGFR-TKIs) and crizotinib for EGFR-mutant and anaplastic lymphoma kinase (ALK)-rearranged NSCLC. Further, the authors briefly describe the emerging molecular targets in NSCLC, in terms of both rationale for therapeutic targeting and strategies, for clinical development. EXPERT OPINION: Target identification and validation in NSCLC still requires considerable effort, as not all of the molecular alterations are clear 'drivers' nor can they be efficiently targeted with available drugs. However, 50% of the NSCLC cases are without clear-defined molecular aberrations. Clinical trial methodology will need to develop novel paradigms for targeted drug development, aiming at the validation of an ideal 'biology-to-trial' approach. Despite significant challenges, a truly 'personalized' approach to NSCLC therapy appears to be within our reach.

EGFR molecular profiling in advanced NSCLC: a prospective phase II study in molecularly/clinically selected patients pretreated with chemotherapy.

INTRODUCTION: The optimal use of epidermal growth factor receptor (EGFR)-related molecular markers to prospectively identify tyrosine kinase inhibitor (TKI)-sensitive patients, particularly after a previous chemotherapy treatment, is currently under debate. METHODS: We designed a prospective phase II study to evaluate the activity of EGFR-TKI in four different patient groups, according to the combination of molecular (EGFR gene mutations, EGFR gene copy number and protein expression, and phosphorylated AKT expression, pAKT) and clinicopathological (histology and smoking habits) factors. Correlations between molecular alterations and clinical outcome were also explored retrospectively for first-line chemotherapy and EGFR-TKI treatment. RESULTS: Patients who had progressed during or after first-line chemotherapy were prospectively assigned to EGFR-TKI treatment as follows: (G1) EGFR mutation (n = 12); (G2) highly polysomic/amplified EGFR (n = 18); (G3) EGFR and/or pAKT positive (n = 41); (G4) adenocarcinoma/bronchoalveolar carcinoma and no smoking history (n = 15). G1 and G4 had the best and second-best overall response rate (25% and 20%, respectively), whereas the worst outcome was observed in G2 (ORR, 6%; p = 0.05). Disease control was highest in G1 and G4 (>50%) and lowest in G3 (<20%) (p = 0.02). Patients selected by EGFR mutation or clinical parameters (G1 and G4) also had significantly better progression-free survival and overall survival (p = 0.02 and p = 0.01, respectively). Multivariate analysis confirmed the impact of sex, smoking history, EGFR/KRAS mutation, and pAKT on outcomes and allowed us to derive an efficient predictive model. Histology, EGFR mutations, and pAKT were independent predictors of response to first-line chemotherapy at retrospective analysis, whereas pAKT and human epidermal growth factor receptor 2 expression were the only independent predictors of progression-free survival and overall survival. CONCLUSIONS: Selection of patients based on either EGFR mutation or clinical characteristics seems an effective approach to optimize EGFR-TKI treatment in chemotherapy-pretreated non-small-cell lung cancer patients.

Prognostic impact of education level of patients with advanced non-small cell lung cancer enrolled in clinical trials.

BACKGROUND: Socioeconomic status can potentially affect prognosis of cancer patients. Our aim was to describe potential differences in demographic and clinical characteristics, treatment, and survival by education level in patients with advanced non-small cell lung cancer (NSCLC) enrolled in clinical trials of first-line treatment. METHODS: Individual data of Italian patients with advanced NSCLC (stage IV, or IIIB with supraclavicular nodes or malignant pleural effusion), ECOG performance status (PS) 0-2, enrolled in four phase III randomized trials conducted between 1996 and 2005 were pooled. Information about education was available for 1680 of 1709 patients (98.3%). Patients were divided in two groups according to education level: high (patients with at least high school diploma) or low (those with less than high school diploma). Survival analyses were stratified by treatment arm within trial. RESULTS: There were 312 (19%) and 1368 (81%) patients with high and low education, respectively. Education level was significantly different among birth cohorts, with a time-trend toward higher education level. Patients with high education were significantly younger (median age 65 vs. 70), were less frequently unfit at diagnosis (ECOG PS2 5% vs. 16%), and their tumor type was more frequently adenocarcinoma (47% vs. 37%). Number of treatment cycles received was not significantly different between education groups. Median survival was 9.4 and 7.6 months in high and low education, respectively (p=0.012). At multivariable analysis, female sex, better PS and high education level (Hazard Ratio 0.85, 95%CI 0.73-0.99, p=0.03) were independently associated with longer survival. CONCLUSIONS: In Italian patients enrolled in four randomized trials of first-line chemotherapy for advanced NSCLC, high education was significantly more frequent among younger patients, and was associated with lower proportion of PS2 patients. Education level did not significantly affect number of chemotherapy cycles received. Overall survival was longer in patients with high education, after adjustment for PS and other prognostic factors. The exact underlying mechanisms of the independent prognostic role of education level are substantially unknown, but lead-time bias (anticipation in diagnosis and time to inclusion in the trial), differences in adherence to care outside the trial procedures, differences in comorbidities and life-style factors may all contribute.

Imatinib mesylate in thymic epithelial malignancies.

PURPOSE: Thymic epithelial tumors (TETs) are rare tumors of the mediastinum, with an estimated incidence of about 3 cases per 100,000 inhabitants. Although anthracycline- and platinum-based chemotherapy is an active treatment for TETs, novel systemic therapeutic options are especially needed for metastatic disease, which is virtually incurable. On the basis of the radiographic response obtained with imatinib (Novartis Pharma, Basel, Switzerland) in a patient with thymic carcinoma harboring the V560del c-KIT mutation, a phase II trial was initiated at the Department of Molecular and Clinical Oncology and Endocrinology of University "Federico II of Naples" with the purpose to test imatinib in TETs. METHODS: Imatinib was daily delivered at the dose of 400 mg to patients affected by TETs, who had progressed after at least one chemotherapy regimen. Positivity of c-KIT on immunohistochemistry was not mandatory for study entry. Radiographic responses were measured by CT scans performed every 3 months, according to the RECIST criteria. Toxicity was graded according to the Common Toxicity Criteria of the National Cancer Institute, version 3.0. RESULTS: Fifteen patients with advanced TETs were enrolled from March 2008 to May 2010. Three patients presented with thymic carcinomas. Two of these three patients presented c-kit expression on immunohistochemistry. No patient harbored a known c-kit activating mutation. Imatinib was very well tolerated, with no toxicity-related death. Diarrhea and migraine were the most frequent events, occurring both in 20% of patients, but were manageable and mild. No radiographic responses were recorded. Median progression-free survival was 3 months (interquartile range, 2.5-4). Median overall survival was not reached. The study was terminated before it reached its target accrual of 42 patients, because of the lack of responses and low accrual rate. CONCLUSIONS: This trial indicates the lack of effectiveness of imatinib in unselected patients with thymic epithelial tumors. Nevertheless, imatinib may represent a valuable option in selected patients with TETs, such as those harboring the V560del c-KIT mutation.