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Importance Thymic carcinoma (TC) is a rare aggressive tumour occurring in adults characterised by one of the lowest tumor mutational burdens (TMB). Microsatellite instability (MSI) is a mutational signature, caused by defects in the DNA MisMatch Repair (MMR) system, that predicts benefit from immunotherapy and causes high TMB. Fragmentary and unstructured evidence of these conditions co-occurring are reported in literature. Objective Review available data on the co-occurrence of these two conditions and determine its frequency in our institute case series. Design We performed a systematic analysis of literature and a retrospective evaluation of all the cases of TET treated at our institution from 2000 to 2020, selecting patients with a medical history of multiple tumours to enhance a priori probability of identifying cases with underlying predisposition. Results Literature yielded 3 cases of patients with MSI TC, for which MMR gene alteration was reported. None of them received immunotherapy. Of 366 patients with TETs treated in our institute, 32 had a medical history of multiple tumours and 25 of 32 (19 thymomas and 6 TCs) had available tissue for MMR analysis. One patient with TC showed a high TMB, and MSI due to MLH1 mutation and was treated in a phase II study with avelumab and axitinib combination obtaining a long-lasting partial response. MLH1 alterations are shared across MSI TC cases. Conclusions and relevance This analysis highlights the usefulness of MSI testing in patients with TC. The observation of cases of TC occurring in patients with Lynch syndrome and the unexpected homogeneity of gene alterations support further investigation.

We present a case of a woman with epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma who received gefitinib for 2 years and obtained a partial response. The patient then developed liver metastasis and a breast lesion, displaying high estrogen receptor (ER) expression and harboring the same EGFR mutation. From the radiological studies, it was not possible to make a differential diagnosis between primary breast cancer and breast metastasis from lung cancer. After the removal of the breast nodule, thanks to the clinical history, radiology, and above all, molecular and immunohistochemical investigations, a diagnosis of breast metastasis from lung adenocarcinoma was made. This case emphasizes the importance of a comprehensive clinical, pathological, and molecular analysis in the differential diagnosis between primary breast cancer and metastases from extramammary tumor to guide adequate treatment decision making.

BACKGROUND/AIM The role of anti-PD1/PD-L1 therapy (IO) in NSCLC harboring driver mutations is questionable. This study aimed to examine the efficacy of IO in patients with non-small cell lung cancer (NSCLC) with a KRAS mutation (KRAS+). PATIENTS AND METHODS We retrospectively identified NSCLC patients harboring KRAS mutation treated with IO in our Institution. We analyzed the results in comparison to non-KRAS patients. RESULTS Among 328 consecutive KRAS+ NSCLC patients, 43 (13.1%) received IO in our Institution. In parallel 117 non-KRAS NSCLC patients treated with IO were selected for comparison. The baseline characteristics were similar between the two groups. No significant difference was observed between KRAS+ and non-KRAS patients in terms of mPFS (4.6 vs. 3.3 months, p=0.58) or OS (8.1 vs. 13.0 months, p=0.38). CONCLUSION KRAS mutations seem to be irrelevant for selecting patients for IO that could be therefore considered an effective therapy for NSCLC patients, independently of KRAS status.

Surgery is the best option for patients with early stage non-small cell lung cancer (NSCLC). However, the rate of local and metastatic recurrences following surgery alone is high, especially in NSCLC patients with N2 lymph node involvement. A recent American study [1] showed that 60% of lung cancers are diagnosed in an advanced stage, and less than 20% are diagnosed in an early, resectable stage. The same study reported the 5-year survival of patients with stage IV NSCLC was 6% compared to 50% in patients with resectable NSCLC depending by stage. The addition of adjuvant or neoadjuvant chemotherapy only improves 5-year survival by 5-10%. Recently, immunotherapy with or without chemotherapy and novel targeted therapies have yielded excellent results, in terms of both progression-free survival and overall survival, in advanced NSCLC. Published studies have shown a benefit in using immunotherapy and targeted therapy in both the adjuvant and neoadjuvant settings with many further studies still ongoing. Here we review the published data on immunotherapy and targeted therapy in the adjuvant and neoadjuvant settings in patients with operable NSCLC.

Background Primary enteric adenocarcinoma of the thymus (EAT) is a recently proposed rare subtype of thymic carcinoma. Unlike thymic carcinomas with squamous histology, for which clinical guidelines are available, little knowledge is available regarding the clinical and pathological features of EAT, and there is no consensus on the best treatment algorithm for such tumors. Methods We performed a systematic review of the literature, searching for all cases of EAT reported. We also retrospectively reviewed all cases of EAT treated at the European Institute of Oncology (IEO) between January 2000 and January 2020. Individual patient data were extracted and analyzed in order to delineate clinical and pathological features, as well as patients’ prognosis and treatments outcome, evaluated in terms of Disease free Survival (DFS), Progression free survival (PFS) and overall survival (OS). Results Thirty-three cases (29 reported in literature and 4 new cases treated at IEO) of thymic adenocarcinoma deploying enteric differentiation as defined by WHO-criteria were analyzed. All tumors showed positive immunoreactivity for cytokeratin (CK) 20 and/or caudal type homeobox 2 (CDX2). Data on molecular profiling by next-generation sequencing were available in only 3 cases, and did not show actionable findings. At diagnosis, 11 pts had an early-stage (Masaoka I-II) and 22 a locally advanced (10 pts) or metastatic (12 pts) disease. Median-DFS of patients with localized disease was 12 months (95% CI, 7–19). Patients who received systemic chemotherapy were mostly treated with regimens commonly used for thymic epithelial tumors, with a discouraging PFS of 3–5 months for patients with stage IV disease. Median OS of the whole population was 34 months (95% CI, 24–NA:. mOS was not reached for patients with stage I-II disease versus 34 months in stage III-IV (p Conclusion Available evidence suggests that EAT represents a distinct entity in the context of thymic epithelial tumors, characterized by aggressive clinical behavior, poor responsiveness to chemotherapy and dismal patients prognosis. More research is needed to better define optimal management strategies for patients with such rare disease.

Immune checkpoint inhibitors (ICIs) represent one of the main steps forward for the treatment of advanced or metastatic non-small-cell lung cancer (NSCLC), without oncogenic driver alterations. Despite this recent progress, only a minority of patients achieve a broad and durable benefit and another proportion report poor survival and sometimes fast disease progression, confirming the need to optimise the patient's selection. To date, several issues are unsolved about how to personalise the immunotherapy treatment for individual patients. In this review, analysing data from pivotal randomised clinical trials (RCTs), we discuss patient baseline clinical and demographic features, including sex, age, ECOG performance status, smoking habit and specific site of metastases (liver, bone and brain) that may influence the efficacy outcomes in patients treated with ICIs. The high performance of the ICIs blurred the vision on different efficacy-limiting factors, which require extensive evaluation to improve the understanding ofthe tumour-specificimmune response, in which clinical drivers could be useful for better patient stratification.

Background Results of several randomized clinical trials (RCTs) testing the combination of an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) plus an anti-angiogenic drug in advanced EGFR-mutated non–small cell lung cancer were reported. Methods We first report a systematic review and meta-analysis of all RCTs to estimate effectiveness and toxicity of this new therapeutic approach compared with first-generation EGFR-TKI monotherapy. Subsequently, we present a network meta-analysis comparing the combination of an EGFR-TKI plus an anti-angiogenic drug with 2 new treatment options: combination of an EGFR-TKI plus chemotherapy or new EGFR-TKIs of second or third generation as monotherapy. Results Five RCTs were included in the first meta-analysis. The progression-free survival (PFS) was statistically significantly larger in patients treated with an EGFR-TKI plus an anti-angiogenic drug compared with EGFR-TKI monotherapy: the pooled PFS–hazard ratio (HR) was 0.59 (95% confidence interval [CI] = 0.51 to 0.69). The pooled median-PFS was 17.8 months (95% CI = 16.5 to 19.3 months) for the combination vs 11.7 months (95% CI = 11.1 to 12.7 months) for EGFR-TKI as monotherapy. No statistically significant differences between the 2 treatment arms were observed in overall survival or objective response rate. The rate of grade equal or higher than 3 adverse events was statistically significantly higher in patients treated with EGFR-TKI plus an anti-angiogenic drug: the pooled-relative risk was 1.72 (95% CI = 1.43 to 2.06). Ten RCTs were included in the network meta-analysis. All 3 experimental treatments were associated with a statistically significant improvement in PFS compared with first-generation EGFR-TKIs. When compared to each other, none of the 3 experimental treatments were statistically significantly associated with larger PFS or lower rate of grade 3 or higher adverse events. Conclusion Patients with EGFR-mutated non small-cell lung cancer derived clinically meaningful larger PFS benefit from the addition of an anti-angiogenic drug to a first-generation EGFR-TKI at the cost of an increase of toxicities.

// Francesca Toffalorio 1, 2, * , Mariacarmela Santarpia 1, 3, * , Davide Radice 4 , Christopher Adrian Jaramillo 5 , Gianluca Spitaleri 1, 6 , Michela Manzotti 7 , Chiara Catania 1, 6 , Lars Petter Jordheim 8 , Giuseppe Pelosi 9, 10 , Godefridus J. Peters 5 , Carmelo Tibaldi 11 , Niccola Funel 12, 13 , Lorenzo Spaggiari 14 , Filippo de Braud 9, 10, * , Tommaso De Pas 1, * and Elisa Giovannetti 5, 12, 13, * 1 Medical Oncology Unit of Respiratory Tract and Sarcomas, New Drugs Development Division, European Institute of Oncology, Milan, Italy 2 Medical Affairs, Roche Spa, Monza, Italy 3 Medical Oncology Unit, Department of Human Pathology, University of Messina, Messina, Italy 4 Epidemiology and Biostatistics Division, European Institute of Oncology, Milan, Italy 5 Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands 6 Thoracic Oncology Division, European Institute of Oncology, Milan, Italy 7 Division of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy 8 Centre de Recherche en Cancerologie de Lyon, INSERM 1052/CNRS UMR 5286, Lyon, France 9 Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy 10 Inter-Hospital Pathology Division, Science and Technology Park, IRCCS MultiMedica, Milan, Italy 11 Division of Oncology, Department of Oncology, S. Luca Hospital, Lucca, Italy 12 CNR-Nano, Institute of Nanoscience and Nanotechnology, Pisa, Italy 13 Cancer Pharmacology Laboratory, AIRC Start-Up Unit, University of Pisa, Pisa, Italy 14 Thoracic Surgery Division, European Institute of Oncology, Milan, Italy * These authors equally contributed to the work Correspondence to: Elisa Giovannetti, email: elisa.giovannetti@gmail.com Keywords: lung cancer; pharmacogenetics; response; gemcitabine; nucleotidase Received: May 30, 2017 Accepted: February 02, 2018 Epub: February 16, 2018 Published: March 27, 2018 ABSTRACT A number of pharmacogenetic studies have been carried out in non-small-cell lung cancer (NSCLC) to identify and characterize genes involved in chemotherapy activity. However, the results obtained so far are controversial and no reliable biomarker is currently used to predict clinical benefit from platinum-based chemotherapy, which represents the cornerstone of treatment of advanced NSCLC. This study investigated the expression levels of ERCC1 and of six genes (RRM1, RRM2, hENT1, dCK, cN-II and CDA) involved in gemcitabine metabolism in locally/advanced NSCLC patients treated with gemcitabine/platinum combination. Gene expression was assessed by quantitative-PCR in laser-microdissected specimens and correlated with tumor response. Frequency distribution of responses above and below the median expression level of biomarkers was compared using a two-sided Fisher’s test. 5′-nucleotidase (cN-II) was the only gene differently expressed ( p = 0.016) in the responders (complete/partial-response) compared to non-responders (stable/progressive disease). In the multivariate analysis, overexpression of this catabolic enzyme of gemcitabine remained a significant negative predictive factor. Patients with low cN-II had a modest trend toward increased survival, while both survival and progression-free survival were significantly longer in a more homogenous validation cohort of 40 advanced NSCLC (8.0 vs. 5.1 months, p = 0.026). Moreover, in vitro studies showed that silencing or pharmacological inhibition of cN-II increased the cytotoxicity of gemcitabine. This is the first study demonstrating the role of cN-II as a predictor of response to gemcitabine/platinum combinations in NSCLC. Its validation in prospective studies may improve clinical outcome of selected patients.

Background In our previous works, we demonstrated that patients’ sex affects the efficacy of immune checkpoint inhibitors (ICIs) in patients with several advanced solid tumors. Here, we assessed the sex-based heterogeneity of efficacy of anti-programmed cell death protein 1 (anti-PD-1)/anti-programmed death-ligand 1 (anti-PD-L1) given as monotherapy, for advanced non-small-cell lung cancer (NSCLC) expressing high PD-L1 levels, to evaluate if available evidence supports this therapeutic option for both women and men. Methods We carried out a systematic review and meta-analysis including all randomized, controlled trials testing anti-PD-1/anti-PD-L1 drugs in monotherapy, as first-line treatment of advanced NSCLC expressing high PD-L1 levels. The primary endpoint was the difference in efficacy of anti-PD-1/anti-PD-L1 drugs versus chemotherapy, between men and women, measured in terms of the difference in overall survival (OS) log [hazard ratio (HR)] reported in male and female study participants. Results We analyzed four randomized, controlled trials, including 1672 patients, of whom 1224 (73.2%) were men and 448 (26.8%) were women. The pooled OS-HR comparing anti-PD-1/anti-PD-L1 versus chemotherapy was 0.59 [95% confidence interval (CI), 0.50-0.69] for men and only 0.84 (95% CI, 0.64-1.10) for women. The pooled ratio of the OS-HRs reported in men versus women was 0.71 (95% CI, 0.52-0.98; P-heterogeneity: 0.04), indicating a significantly greater effect for men. No heterogeneity among single-study estimates was observed in either male patients (Q = 2.39, P = 0.50, I2 = 0%) or in female patients (Q = 1.13, P = 0.50, I2 = 0%). Conclusion Evidence available indicates anti-PD-1/anti-PD-L1 monotherapy as highly effective in men but not in women, even in NSCLCs expressing high PD-L1 levels. Prospective trials testing sex-based tailored immunotherapy strategies are needed., Highlights • Sex-based heterogeneity of efficacy of immune checkpoint inhibitors. • Sex-tailored immunotherapy strategies. • NSCLC expressing high PD-L1 levels.

Engineered cytokine products represent promising agents for the treatment of immunogenic tumors, such as malignant melanoma, in addition to immune checkpoint inhibitors. Here we describe the results of a controlled, randomized phase II clinical trial, aimed at assessing the therapeutic potential of L19IL2, a fully human fusion protein consisting of the L19 antibody specific to the alternatively spliced extra-domain B of fibronectin, fused to human interleukin-2 in advanced metastatic melanoma. In one arm, patients received dacarbazine (DTIC; 1000mg/m2 of body surface on day 1 of 21-day cycles) as single agent, while in two other arms L19IL2 (22.5 million international units of IL2 equivalents) was added, based on two different schedules of administration. In total, 69 patients with stage IV melanoma were enrolled (24 in the dacarbazine arm, 23 and 22 in the other combination arms, respectively) and 67 received treatment. Analyses of efficacy results show a statistically significant benefit in terms of overall response rate and median progression-free survival for patients receiving L19IL2 in combination with DTIC, compared to DTIC as single agent. In light of these results, further clinical investigations with L19IL2 (alone or in combination with other agents) are warranted.

Immunotherapy is a new standard first-line treatment for non-small cell lung cancers (NSCLC) with high programmed cell death-ligand 1 (PD-L1) expression (≥ 50%) and second-line treatment regardless of PD-L1 status, though not all patients benefit from this approach. Much effort is ongoing to identify robust prognostic and predictive biomarkers of response to immune checkpoint inhibitors, overcoming PD-L1 that appears limited in its ability to discriminate patient candidates to this new class of anticancer agents. The purpose of this research study is to identify potential new biomarkers for immunotherapy in lung cancer.Fifty-three consecutive patients with advanced NSCLC treated with nivolumab were enrolled in the study. All the patients received a blood analysis looking for the relationship between different populations of baseline white blood cells and granulocytic myeloid-derived suppressor cells (Gr-MDSC) detected by flow cytometry, to identify and characterize patients with poor likelihood of benefit from nivolumab in NSCLC second-line setting, regardless of clinical feature and PDL1 expression.Univariate analysis showed that high baseline levels of Gr-MDSC and low baseline CD8/Gr-MDSC ratio are associated with significantly better (P = 0.02) response to immunotherapy treatment. Log-rank tests suggested a significant improvement in OS and PFS with high baseline levels of Gr-MDSC levels (≥ 6 cell/μl), low absolute neutrophil count ( 5840/μl), high eosinophil count ( 90 /μl), and NLR 3. The multivariate analysis showed a statistically significant improvement for PFS (P = 0.003) and OS (P = 0.05) in favour of the identified good prognostic Gr-MDSC-linked asset group, compared with the poor prognosis group.The role of Gr-MDSC appears interesting as a potential biomarker in NSCLC patients receiving immune-checkpoint inhibitors. Further analyses are needed to confirmed and study in deep the role of these particular cells and their role in cancer response and progression during ICI therapy.

Background: There is a pressing need to expand the evidence base in geriatric lung oncology. Most non-small cell lung cancers (NSCLCs) are diagnosed in the elderly, with approximately 15% of cases affecting octogenarians. Treatment-related decisions are challenging in this population, and the role of biologically driven therapies is still underrated. Methods: A single-institution cohort of 76 NSCLCs from octogenarian patients was submitted to molecular analysis using a next-generation sequencing (NGS) multigene panel, fluorescence in situ hybridization (FISH) analyses, and immunohistochemistry for PD-L1 assessment. Treatment and clinical outcome data were available for 33 patients. Results: Most cases (n = 66, 87%) harbored at least one genomic alteration. EGFR and KRAS mutations were detected in 18 (24%) and 20 (26%) patients, respectively. No ALK alterations were found, but in two patients ROS1 translocation was identified. Of 22 cases tested, 17 were positive for PD-L1 staining. Octogenarian patients who received tyrosine kinase inhibitors (TKIs) based on molecular analysis showed clinical benefits, with long progression-free survival as expected in TKI-treated younger cohorts. Conclusions: This study highlights the utility of molecular profiling in all advanced-stage NSCLCs, regardless of the age at diagnosis, to drive personalized treatment. The prevalence of druggable alterations and the clinical benefits obtained by biologically-driven therapies in octogenarians were comparable to those of the younger NSCLC population.

The discovery of anaplastic lymphoma kinase (ALK) gene rearrangements and the development of tyrosine kinase inhibitors (TKI) that target them have achieved unprecedented success in the management of patients with ALK-positive non-small cell lung cancer (NSCLC). Despite the high efficacy of crizotinib, the first oral ALK TKI approved for the treatment of ALK-positive NSCLC, almost all patients inevitably develop acquired resistance, showing disease progression in the brain or in other parenchymal sites. Second- or third-generation ALK TKIs have shown to be active in crizotinib-pretreated or crizotinib-naïve ALK-positive patients, even in those with brain metastases. In this review, the current knowledge regarding ALK-positive NSCLC, focusing on the biology of the disease and the available therapeutic options are discussed.

HER2 mutations are uncommon molecular mutations in nonesmall-cell lung cancer (NSCLC) (4%). Tyrosine kinase inhibitors, such as erlotinib or gefitinib, have demonstrated promising results in patients with advanced NSCLC who harbor epidermal growth factor receptor mutations. Human epidermal growth factor 2 (HER2/ERBB2/neu) is a member of the ERBB family of tyrosine kinase receptors, and is activated by homodimerisation or heterodimerisation with other ERBB receptors. It is possible that NSCLC patients with HER2 mutations could benefit from targeted therapy. There are some data on afatinib and trastuzumab activity in this subgroup of patients. There are no data on the efficacy of immunotherapy in patients harboring epidermal growth factor receptor or ERB2 mutations. The results of CheckMate 057 suggested that, among patients harboring druggable mutations, better outcomes were achieved with docetaxel treatment than with nivolumab (84 patients). We report the first case of a patient with a HER2 mutation treated with nivolumab: this case suggests that nivolumab has strong activity even in patients with targeting biomarkers, in particular with advanced HER2-positive lung cancer.

e21114 Background: Patients (pts) with advanced B3 thymoma (B3T) and thymic carcinoma (TC) resistant to chemotherapy have limited treatment options. Treatment with Anti-PD1 showed not negligible toxicity and limited activity, and anti-VEGFR drugs obtained limited and short lasting antitumor responses. No data on combined anti-PD1/PD-L1 with antiangiogenic drugs are available in B3T/TC. We report preliminary results on safety and activity of avelumab combined with axitinib in this pts population. Methods: The CAVEATT is a single arm, multicentric, phase II trial in immunotherapy-naive pts with advanced B3T or TC, progressing after at least one line of platinum based chemotherapy. Prior therapy with antiangiogenic drugs is allowed. Pts received Avelumab 10 mg/kg iv every 2 weeks and Axitinib 5 mg twice a day until progression or toxicity. The primary objective of the study is overall response rate (ORR) by RECIST 1.1; secondary endpoints include ORR by irRC and ITMIG, and QoL by EORTC QLQ-C30. An interim futility analysis is planned after the enrollment of the first 18 patients. If at least 5 out of 18 patients will obtain a PR, the accrual will continue to reach the total number of 33 pts, according with a Simon’s minimax design. Tumor and blood samples are collected at baseline and whenever feasible at disease progression, to identify predictive biomarkers of response and mechanisms of resistance to treatment. Results: 1 pt with B3T and 12 with TC were enrolled from April 2019 to January 2020. Median age was 59 years (range 33-77). 8 pts received ≥2 previous line of therapies, and 6 pts were pretreated with an antiangiogenic drug. The median follow-up was 5.1 months. 10 pts were evaluable for response. The proportions of patients who achieved a partial response (PR) or a stable disease (SD) were respectively 40% (95% CI 17%–69%) and 60% (95% CI 30%–83%). The median PFS was 7.9 months (95% CI 2.5–NA) 12 pts were evaluable for toxicity. Treatment-related adverse events (AE) of grade 1 or 2 occurred in 7 (58%) pts, and the most common was diarrhea (3 pts). Grade ≥3 AEs occurred in 2 (17%) pts: 1 had G3 hyperthension and 1 G3 hand foot syndrome, both leading to axitinib drug reduction. No immune-related AEs (irAEs) were observed. No patient stopped treatment for toxicity, 5 pts stopped for progressive disease, and 8 pts are still on treatment. Conclusions: Preliminary results suggest promising antitumor activity and a good toxicity profile of the combination of axitinib and avelumab in pts with advanced B3T and TC. Accrual is ongoing to reach the target of 33 pts Clinical trial information: 2017-004048-38 .

Brigatinib (AP-26113, Alunbrig) is a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) that is highly active in non-small cell lung cancer (NSCLC) harboring ALK translocation. Brigatinib was found to be very active against different ALK resistance mutations that mediate acquired resistance biology processes, particularly G1269A ALK C1156Y, I1171S/T, V1180L and others. Different clinical trials evaluated the activity of brigatinib in crizotinib-resistant patients, confirming high activity with durable response not only in parenchymal disease, but also in intracranial disease. Nowadays, brigatinib is under evaluation in different clinical trials exploring TKI-naive patients in the first-line setting. On the basis of its significant activity results, brigatinib received approval by the FDA for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib.

The discovery of EML4-ALK fusion gene in a subgroup of patients with lung adenocarcinoma led to the development of a new class of agents, the ALK inhibitors, and dramatically improved the clinical outcome of these patients. The striking results from clinical trials with crizotinib, the first ALK inhibitor evaluated, allowed the accelerated approval of crizotinib from the USA Food and Drug Administration (FDA). Despite the high initial results, patients acquire resistance to crizotinib, and different next generation ALK kinase inhibitors have been developed. In the current review, we will analyze the biology of EML4-ALK gene, the acquired resistance mechanisms to crizotinib, the therapeutic strategies, currently under evaluation, designed to overcome crizotinib resistance, and the open issues that need to be addressed in order to improve outcome in ALK+ Non Small Cell Lung Cancer (NSCLC) patients.

Acknowledgements section was missing.

Introduction: Epidermal growth factor receptor (EGFR) mutations are detected in about 10–15% of Caucasian and 30–40% of Asian patients with advanced or metastatic non-small-cell lung cancer (NSCLC). In patients harbouring EGFR mutations, the treatment with different available EGFR tyrosine kinase inhibitors (TKIs) showed to be more effective and safe than platinum-based chemotherapy regimens.Areas covered: The current evidences about the role of afatinib for patients with EGFR-positive NSCLC are reviewed and discussed. We report a review based on a MEDLINE/PubMed, searched for randomized phase II or III trials evaluating afatinib in EGFR-positive NSCLC.Expert commentary: Afatinib is the third EGFR TKI approved for the treatment of NSCLC harbouring EGFR mutations, showing high efficacy in this setting of patients.

http://hdl.handle.net/20.500.11768/96439 Background: During the period that randomized clinical trials were establishing the role of adjuvant therapy in tumors larger than 5 cm without lymph-node invasion, which shifted from stage IB (6th TNM) to stage II (7th TNM), we derived the rate of shifted patients in our series and analyzed the relationship between specific patient- and tumor-characteristics, and clinical outcome, to identify putative prognostic factors. Methods: We retrospectively collected data (age, sex, smoking status, type of surgery grading, and histological type) from 467 patients who underwent radical surgery for primary 6th TNM-T2N0 non-small cell lung cancer patients between 1998 and 2009 at our institute. Categorical variables were cross-tabulated by tumor staging according to the 7th TNM edition, and they were tested both for association with stage and survival. Results: One hundred and eighteen patients shifted to stage II, mainly older patients and patients with a sarcomatoid or a poorly differentiated carcinoma. Median overall survival time was significantly different across stages. Among the factors investigated, only the tumor dimension resulted in being statistically significant in multivariate analysis. Conclusions: Nearly a quarter of patients shifted from stage I (6th TNM) to stage II (7th TNM), raising a major need for information on the effects of adjuvant chemotherapy in this group of patients. Our findings suggest that randomized clinical trials aimed at addressing this topic should consider only tumor dimensions as principal selection criteria.

Breast cancer during pregnancy is increasingly being encountered, and establishing the safety of trastuzumab in this setting is important. The case of a 29-year-old woman diagnosed with node-positive, HER2-positive breast cancer is described. She underwent surgery followed by chemotherapy and radiotherapy and then received trastuzumab. The authors suggest that short-term trastuzumab exposure may be safe and they recommend careful monitoring of the amniotic fluid and cardiac assessment of the mother and fetus. Background. A 29-year-old woman was diagnosed with lymph-node-positive, steroid-hormone-receptor-negative and HER2/neu-positive breast cancer. She underwent surgery followed by cyclophosphamide, epirubicin, and 5-fluorouracil chemotherapy, and received radiotherapy followed by trastuzumab therapy for 1 year. During the tenth month of trastuzumab therapy, the patient reported a missed period and had a positive pregnancy test. Investigations. Physical examination, pregnancy test, echocardiography. Diagnosis. Unintended pregnancy during adjuvant trastuzumab therapy. Management. Cessation of trastuzumab and close monitoring of mother and fetus during pregnancy.

A phase Ib/II trial was performed to evaluate safety, tolerability, recommended dose (RD) and efficacy of F16-IL2, a recombinant antibody-cytokine fusion protein, in combination with doxorubicin in patients with solid tumors (phase Ib) and metastatic breast cancer (phase II). Six patient cohorts with progressive solid tumors (n = 19) received escalating doses of F16-IL2 [5-25 Million International Units (MIU) of IL2 equivalent dose] in combination with escalating doses of doxorubicin (0-25 mg/m(2)) on day 1, 8 and 15 every 4 weeks. Subsequently, patients with metastatic breast cancer (n = 10) received the drug combination at the RD. Clinical data and laboratory findings were analyzed for safety, tolerability, and activity. F16-IL2 could be administered up to 25 MIU, in combination with the RD of doxorubicin (25 mg/m(2)). No human anti-fusion protein antibodies (HAFA) response was detected. Pharmacokinetics of F16-IL2 was dose-dependent over the tested range, with half-lives of ca. 13 and ca. 8 hours for cohorts dosed at lower and higher levels, respectively. Toxicities were controllable and reversible, with no combination treatment-related death. After 8 weeks, 57% and 67% disease control rates were observed for Phase I and II, respectively (decreasing to 43% and 33% after 12 weeks), considering 14 and 9 patients evaluable for efficacy. One patient experienced a long lasting partial response (45 weeks), still on-going at exit of study. F16-IL2 can be safely and repeatedly administered at the RD of 25 MIU in combination with 25 mg/m(2) doxorubicin; its safety and activity are currently being investigated in combination with other chemotherapeutics, in order to establish optimal therapy settings.

Objective: To report a case of erlotinib-induced breast cancer regression. Case Summary: A 38-year-old woman developed bilateral locoregional malignant cutaneous lymphangitis following a right subcutaneous mastectomy and 3 months of adjuvant chemotherapy. After several systemic chemotherapy regimens, the lymphangitis worsened rapidly, with progressive skin ulceration. Morphine and dexamethasone were given, with suboptimal pain control. A chemotherapy regimen of gemcitabine and vinorelbine was started. After 2 full-dose administrations, while lymphangitis continued to worsen, erlotinib 150 mg/day was added to the regimen. After 10 weeks of treatment, pain subsided and analgesics were discontinued. Physical examination revealed a partial regression of malignant cutaneous lymphangitis and pulmonary metastases, with resolution of ulceration. Discussion: There has been increased interest in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in the treatment of breast cancer. Gefitinib has shown a low level of efficacy, while preliminary clinical data on erlotinib were not conclusive and suggested lack of clinical activity. Molecular analysis of the tumor in our patient revealed a profile predictive of response to EGFR selective inhibitors in some patients with lung cancer. Conclusions: The addition of erlotinib to our patient's chemotherapy regimen resulted in antitumor activity in breast cancer in which an activated EGFR pathway was demonstrated. This finding is consistent with available preclinical and clinical data on EGFR tyrosine kinase inhibitors across tumor types and supports the efforts to optimize EGFR selective inhibitors in treating breast cancer and other malignancies.

Background The combination of capecitabine and vinorelbine is a potentially valuable treatment regimen for patients with advanced-stage breast cancer. The drugs are easy to administer and do not cause significant alopecia. In order to identify the spectrum of toxicity of a regimen containing 2 drugs, we conducted an extended phase I study aimed at defining maximum tolerated doses, recommended doses, safety, and efficacy in patients with pretreated advanced-stage breast cancer. Patients and Methods Forty-nine patients with advanced-stage breast cancer were treated with escalating doses of oral capecitabine from 500 mg/m 2 to 1375 mg/m 2 twice daily on days 1-14 and escalating doses of vinorelbine from 12.5 mg/m 2 to 25 mg/m 2 intravenously (I.V.) on days 1 and 3 every 3 weeks. Almost all patients (90%) had received ≥ 3 previous treatments for metastatic disease (anthracyclines, 76%; 5-flourouracil, 76%; taxanes, 29%). Results Dose level 9 (capecitabine 1250 mg/m 2 twice daily on days 1-14 and vinorelbine 22.5 mg/m 2 I.V. on days 1 and 3) was identified as the maximum tolerated dose. The most frequent clinical adverse events were nausea (78%), asthenia (59%), constipation (51%), mucositis (47%), and hand-foot syndrome (41%). The majority of events were mild to moderate; the only grade 4 clinical adverse events were diarrhea, fever, and thromboembolism, each of which occurred in 1 patient (2%) at dose level 8. Objective confirmed responses were observed in 18 patients (37%), including 1 complete response (2%) and 17 partial responses (35%). Disease was stable in an additional 10 patients (20%), with a median duration of 6.3 months (range, 4-24 months). Conclusion The combination of the 2 drugs is very well tolerated and effective, especially considering the previous exposure to chemotherapy. The recommended dose for further phase II studies should be capecitabine 1250 mg/m 2 twice daily on days 1-14 and vinorelbine 22.5 mg/m 2 I.V. on days 1 and 3.

The anti-PD-1 monoclonal antibody nivolumab is clinically active in a variety of tumor types including squamous (sq) and non-squamous (non-sq) NSCLC in second-line, where randomized phase III trials have shown a survival benefit. However, no predictive/prognostic or dynamic biomarkers have been found so far to correlate with clinical benefit in patients treated with anti-PD-1 antibodies. The aim of the present study is to investigate the potential role of baseline peripheral blood cell counts in relation to survival and response rate in NSCLC patients treated with nivolumab in a second-line setting. From July to May 2016 we evaluated 45 patients with Sq (n = 10) and non-Sq (n = 35) NSCLC, previously treated with first-line platinum-based chemotherapy, who received nivolumab 3 mg/kg IV on day 1 of each 2 week treatment cycle. Clinical characteristics (T-Stage, lymph nodes involvement, M-Stage) were assessed. Total numbers of white blood cells, myeloid-derived suppressor cells (MDSCs, including both monocytic [Mo-MDSC]) and polymorphonuclear [PMN-MDSC] types), regulatory T cells (T-regs), and serum lactate dehydrogenase (LDH) were assessed. Endpoints were correlations with objective response rate (RR), progression-free survival (PFS, categorized as ≤ 3 or > 3 months) and overall survival (OS). Tumor response was assessed using RECIST criteria, version 1.1, at week 9 and every 6 weeks thereafter until disease progression. Statistical investigations were based on univariate analyses by the Wilcoxon rank test. The median PFS of the overall study population was 3 months. Data about PMN-MDSCs (identified by flow cytometry as Lin-CD15+CD14-CD11b+HLA-DRlow/-), Mo-MDSCs (Lin-CD14-CD11b+HLA-DRlow/-) and absolute eosinophil count (AEC) were available in 37/45 patients (82% of treated patients). Baseline absolute numbers of PMN-MDSCs, Mo-MDSCs and AEC were greater in patients with a good prognosis (PFS > 3 months) and a better RR. In particular, among patients with shorter PFS and lower RR, the median numbers of PMN-MDSCs, Mo-MDSCs and AEC were significantly lower than those detected in patients with longer PFS (4 vs 13 cell/µl, p=0.01; 4 vs 21 cell/µl, p=0.06; 55 vs 155 cell/µl; p=0.02, respectively). Our data suggest that a baseline blood signature characterized by low levels of PMN-MDSCs, Mo-MDSCs and AEC is associated with a poor clinical outcome (median PFS ≤ of 3 months and low RR) in 67.6% of patients treated with nivolumab. In contrast, patients with high levels of these three biomarkers showed a median PFS significantly longer than 3 months and a higher RR. The OS analysis is ongoing, and further studies have been planned to understand whether this signature has a biomarker potential also in chemotherapy-naïve, first line NSCLC patients. Citation Format: Patrizia Mancuso, Antonio Passaro, Valentina Labanca, Sara Gandini, Gianluca Spitaleri, Elena Guerini, Massimo Barberis, Cristina Noberasco, Ester del Signore, Alessia Pochesci, Chiara Catania, Filippo De Marinis, Francesco Bertolini. Baseline myeloid-derived suppressor cell and eosinophil cell counts predict clinical efficacy in patients with non-small cell lung cancer (NSCLC) treated with nivolumab in second line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2635. doi:10.1158/1538-7445.AM2017-2635

Introduction Recent data show that EGFR pathway and its inhibition maintain their role after progression of disease during EGFR TKI therapy in NSCLCs. We conducted a retrospective study with the aim of evaluating efficacy and feasibility of prosecution of EGFR TKI therapy beyond focal progression associated to locoregional radiotherapy. Methods We retrospectively analyzed the data of all NSCLC patients treated with EGFR TKIs in our institution from 2004 to 2012. We included in the analysis patients that after a focal disease progression, meant as a single lesion RECIST progression, have been treated with definitive locoregional radiotherapy, associated to continuation of EGFR TKI therapy until further progression. Results 15 out of 147 patients (10%) satisfied inclusion criteria. The median progression free survival, measured from the date of focal progression until further progression of disease or death by any cause, was 10,9 months (range 3–32 months). The corresponding 6 and 12 months PFS rates were 73% and 33%, respectively. Conclusion The longer disease control observed in our patients suggests that continuation of EGFR TKI beyond focal progression associated to a locoregional treatment is an efficacious therapeutic strategy.

10053Background: More than 40% of NSCLCs are diagnosed in patients older than 70 years. Elderly have more comorbidities and are less tolerant to chemio-radiotherapies than younger but targeted trea...

http://hdl.handle.net/20.500.11768/96638 Non-small cell lung cancer (NSCLC) remains the leading cause of cancer related mortality worldwide and despite some advances in therapy the overall prognosis remains disappointing. New therapeutic approaches like vaccination have been proposed and several clinical trials are ongoing. Many tumor antigens have been identified so far and specific tumor vaccines targeting these antigens have been developed. Even if the ideal setting for vaccine therapy might be the adjuvant one, vaccines seem to be potentially beneficial also in advanced disease and combination therapy could be a promising treatment option. In the advanced setting anti-MUC-1 vaccine (belagenpumatucel) and anti-TGF-beta(2) vaccine (BPL-25) have entered in phase III trials as maintenance therapy after first line chemotherapy. In the adjuvant setting the most relevant and promising vaccines are directed against MAGE-A3 and PRAME, respectively. We will review the key points for effective active immunotherapies and combination therapies, giving an update on the most promising vaccines developed in NSCLC. (C) 2012 Published by Elsevier Ireland Ltd.

Introduction: The pemetrexed-gemcitabine combination is effective in patients with non-small cell lung cancer (NSCLC). Preclinical data suggest that pemetrexed may synergistically interact with gemcitabine by enhancing the expression of human equilibrative nucleoside transporter 1 (hENT1) and deoxycytidine kinase (dCK), increasing the uptake and intracellular activation of gemcitabine. A pharmacogenetic approach was adopted to evaluate hENT1 and dCK expressions in humans and to identify the potential best time interval to administer gemcitabine after pemetrexed in patients with advanced NSCLC. Methods: The dCK and hENT1 expressions, examined by quantitative real-time polymerase chain reaction, were analyzed during each cycle before and at 1, 2, 4, 6, 24, and 48 hours after pemetrexed administration. The relative differences from baseline to each planned time, for peak values and for the relative difference at peak, were measured. Results: Nineteen patients were treated with pemetrexed single agent (500 mg/m every 15 or 21 days). Quantitative real-time polymerase chain reaction analysis revealed a statistically significant (p < 0.001) biphasic increase in both hENT1 and dCK genes at 1 to 2 and 24 to 48 hours after pemetrexed administration. Conclusions: This is the first evidence of dCK and hENT1 induction by pemetrexed in humans, suggesting that the pemetrexed→gemcitabine combination should be optimized by the administration of gemcitabine 1 to 2 or 24 to 48 hours after pemetrexed. These results support further studies to validate the role of dCK/hENT1 in vivo modulation for the optimization of gemcitabine-pemetrexed combination in patients with NSCLC.

Objectives To document the preliminary validity of a new informed consent form (ICF) model in terms of face/content validity and feasibility, to collect patients’ and oncologists’ opinions on it, and to explore physicians’ and patients’ “knowledge”, “opinions” about “the information exchanged”. Methods The working group for informed consent promoted by the Italian Association of Medical Oncology developed a new ICF model which was tested in ten Italian cancer centers. Patients and physicians received questionnaires on the new ICF model. Twenty-six independent oncologists were interviewed to collect their opinions. Results Seventy eight cancer patients were enrolled: about 90% reported having received information about diagnosis and therapy and 80% about prognosis. About 63% of oncologists had no difficulty in administering the ICF. Oncologists used “correct terms” about diagnosis in 92% of patients with localized disease and in 90% with metastasis and about therapy in respectively 75.7% and 80%. About prognosis, oncologists used “vague” and “no information–no pertinent terms” in 79% of patients with localized disease and 92.5% of patients with metastasis. Conclusions The ICF seemed to have sufficient validity and feasibility. Practice implication This ICF model could mean that patients require oncologists to spend more time explaining the diagnosis, prognosis and treatment, increasing patient's opportunities to participate actively in the care process

Background: Ifosfamide and doxorubicin combination is an active regimen for patients with advanced soft tissue sarcomas (STS) but is burdened by high toxicity. A phase II trial was designed to assess the activity of continuous infusion ifosfamide and doxorubicin combination. Patients and Methods: Thirty-four chemotherapy-naive patients with advanced STS were treated with ifosfamide (13 g/m2/12 days as continuous infusion) and doxorubicin (75 mg/m2 on day 8) every 28 days with granulocyte colony-stimulating factor. Results: The major toxicity was hematological: grade 3/4 neutropenia, anemia and thrombocytopenia occurred in 63, 30 and 12% of patients, respectively. The disease control rate was 68% and the median time to progression was 7.1 months. Among leiomyosarcomas, 2 partial responses and 4 stable diseases were observed. Conclusions: Our study confirms that the ifosfamide and doxorubicin combination has a very low non-hematological toxicity profile. This regimen attained a high disease control rate with moderate activity. Further investigation into leiomyosarcoma is warranted.

Background: despite the fact that the combination of gemcitabine (GCB) and docetaxel shows an increased benefit for disease-free survival and overall survival compared to GCB alone in patients with soft-tissue sarcoma, GCB mono-chemotherapy should be considered as a preferable option with respect to the combination because of its lower toxicity profile and the possibility of it being administered continuously for a long time period. Case report: we report a clinical case of a woman with advanced high-grade uterine leiomyosarcoma, refractory to ifosfamide, doxorubicin and trabectedin, who experienced a sustained and progressive response to GCB alone. Conclusions: GCB given as mono-chemotherapy can obtain long-lasting tumour control in patients heavily pre-treated with various chemotherapeutic regimes for uterine LMS and should be considered as a possible option for this subset of patients.

Background Advance directives, acceleration of death, euthanasia and ‘life-sustaining treatment’ have sparked much heated debate among the media, the public, doctors and political leaders. We evaluate the personal opinions of Italian Association of Medical Oncology (AIOM) members. Patients and methods A 30-item questionnaire was developed and delivered to all 1832 AIOM members. Results Six-hundred and eighty-five (37%) oncologists completed and returned the questionnaires. Sixty-three per cent felt culturally and psychologically prepared to face these issues. Fifty-four per cent believed that what had been decided while the patient enjoyed good health is no longer applicable in an advanced state of terminal illness. Thirty-nine per cent believed that doctors should abide by these directives, while 49% believed that this should be discussed on a case-by-case basis. Fourteen per cent of oncologists were favourable towards euthanasia and 42% only in particular circumstances. Fifty-six per cent had received at least one request for accelerating death: 15% consented, 50% discussed it with the patient and 31% refused. Conclusion Advance directives, euthanasia, accelerated death and life-sustaining treatment represent considerable challenges for Italian oncologists. Although prepared to face these issues, AIOM members ask for a debate within the medical world and for a shared judicial regulation.

Background: Trastuzumab (T) combined with i.v. vinorelbine (i.v.VNR) is an active regimen for patients with advanced breast cancer (ABC). In order to further improve quality of life of patients undergoing treatment for ABC, a new regimen using oral vinorelbine (oVNR) (d1 + d3) plus q3wks T was tested (ToVNR). Patients and methods: Thirty-nine patients with ABC, human epidermal growth factor receptor 2/neu 3+ or FISH positive received 288 treatment cycles with T 6 mg/kg (loading dose, 8 mg/kg) on d1 and oVNR 55 mg/m 2 on d1 + d3, q3wks until disease progression or unacceptable toxicity. Results: Thirty-seven patients and 286 treatment cycles were evaluated (two patients were lost to follow-up). Treatment was very well tolerated. Two patients had complete response (CR), 14 partial response (PR), 17 stable disease (SD) and four disease progression (PD) (overall response rate: 43%). Clinical benefit rate (CR + PR + SD >24 months) was 73%. Median time to progression was 8.9 months (range 2–27) and median duration of response was 10.9 months (range 2–27). Conclusions: The ToVNR combination is active and very well tolerated. It favorably compares with the combination of T and weekly i.v. administered VNR, allowing a more convenient once every three weeks hospital admission and leaving patients and care providers free from the unpleasant effect of i.v.VNR.

Fulvestrant ('Faslodex') is an oestrogen receptor (ER) antagonist with no agonist effects. The drug was administered to heavily pre-treated patients with advanced breast cancer (ABC). Patients received Fulvestrant after disease progression (PD) on a previous endocrine treatment or as maintenance treatment after chemotherapy.Fifty-seven postmenopausal women with ER and/or progesterone receptor-positive ABC resistant to previous endocrine treatments prospectively received fulvestrant 250 mg via intramuscular injection q 28.Twenty-seven patients received fulvestrant after PD and 30 received it as maintenance therapy after chemotherapy. All patients received fulvestrant as second-up to eight-line endocrine treatment for ABC. One patient (2%) had a partial response (PR) and 24 patients (42%) had stable diseaseor =12 weeks (SD), including 11 patients who had SDor =24 weeks. Thirty-two patients (56%) had de novo PD. Clinical benefit (CB; PR + SDor =24 weeks) occurred in 12 patients (21%). Patients treated as maintenance and treated upon PD had 0 and 4% PR, 43 and 41% SD (including 20 and 19% SDor =24 weeks), 57 and 55% PD, respectively. Overall, median time to progression (TTP) was 3 months. No differences in CB rate (20% vs. 23%), TTP (3 months vs. 3 months) and time to treatment failure (3 months vs. 3 months) were observed between patients receiving fulvestrant as maintenance therapy and those treated at PD on prior endocrine treatment. No grade 2-4 NCI-CTC toxicity was recorded.Fulvestrant treatment was associated with prolonged CB and was well tolerated in this group of heavily pre-treated patients with ABC. The outcomes appeared to be similar for patients treated upon PD and those receiving fulvestrant as maintenance therapy.

Summary Background In a previous phase I dose-escalation study, we showed a weekly administration of paclitaxel (TAX) and gemcitabine (GEM) to be active and very well tolerated in non-small-cell lung cancer (NSCLC) patients, with the lack of interaction between drugs. The dose of GEM 1500mg/m 2 and TAX 100mg/m 2 was selected for phase II studies due to its predictable kinetic behaviour and less severe thrombocytopenia. Patients and methods Fifty-four chemo-naive patients with advanced NSCLC (53 patients: stage IV) received TAX (100mg/m 2 i.v. infusion over 1h) followed by GEM 1500mg/m 2 over 30min) on days 1, 8, 15 and 21 of a 28-day cycle. Results The objective response rate was 46% (95% CI 32–61), median OS of 10.4ms (95% CI 6.5–4.3), and a 1-year survival rate of 53%. Grades 3 and 4 haematological toxicity consisted of non-febrile neutropenia and thrombocytopenia in 13 and 4% of the cycles, respectively. Grade 3 non-haematological toxicities were observed in three patients (asthenia, diarrhoea and neuropathy), and were always reversible. Conclusions This weekly schedule of TAX and GEM is highly active in chemo-naive NSCLC patients and confirms the low toxicity profile already observed in a previous phase I study.

Purpose: A phase I study was performed to determine the maximal tolerated dose, recommended doses (RDs), safety and efficacy of oral vinorelbine when combined with capecitabine in an all-oral chemotherapy regimen in patients with metastatic breast cancer (MBC), with pharmacokinetic blood sampling to investigate potential drug–drug interactions. Patients and methods: Forty-four patients with MBC received as first- or second-line chemotherapy, oral vinorelbine at a dose of 60 or 80 mg/m2 on days 1 and 8 (and 15) with escalating doses of capecitabine from 1650 to 2500 mg/m2/day days 1–14 every 3 or 4 weeks. Three schedules were tested: day 1, day 8 and weekly regimens of oral vinorelbine with a 14-day course of capecitabine every 3 weeks; and a days 1 and 8 regimen of oral vinorelbine with a 14-day course of capecitabine every 4 weeks. Results: With oral vinorelbine at 60 mg/m2, the RDs were established as oral vinorelbine 60 mg/m2 on days 1 and 8 plus capecitabine 2250 mg/m2/day days 1–14 and oral vinorelbine 60 mg/m2/week plus capecitabine 2000 mg/m2/day days 1–14. With oral vinorelbine at 80 mg/m2, the RD was oral vinorelbine 80 mg/m2 on days 1 and 8 plus capecitabine 2000 mg/m2/day days 1–14. Neutropenia was the main dose-limiting toxicity of the combination; it was reported in 40 patients (90.9%), with grade 3 in 14 patients (31.8%) and 6.2% of cycles, and grade 4 in 12 patients (27.3%) and 4.3% of cycles. Complications were rare with only three patients experiencing febrile neutropenia (one episode each). The most frequent non-haematological toxicity was gastrointestinal; however, the incidence of grade 3 was low, with no episode of grade 4. Hand–foot syndrome was reported in 14 patients (31.8%) and 22.6% of cycles, with grade 2 in two patients (4.5%) and 1.2% of cycles (two episodes each). No episode of grade 3 was observed. Objective responses were reported in 18 patients (three complete responses and 15 partial responses), yielding a response rate of 40.9% in the intention-to-treat population according to the investigator assessment. Results from the pharmacokinetic study demonstrated the absence of mutual pharmacokinetic interactions when both drugs were co-administered. Conclusions: The combination of oral vinorelbine and capecitabine is safe and easy to administer in an outpatient setting. This all-oral combination chemotherapy may offer a good alternative to the intravenous route for patients with MBC. Based on these promising results, a phase II study has started using oral vinorelbine 60 mg/m2/week with capecitabine 2000 mg/m2/day days 1–14 every 3 weeks as first-line chemotherapy in patients with MBC.

We developed and pilot tested a 12-item questionnaire, to approach the issue of patients’ perception on efficacy of oral chemotherapy. An additional question was on ‘trade-off’ between treatment efficacy and the ease of oral administration. The motivating underlying hypothesis was that oral drugs might be perceived by patients as less effective than when drugs were delivered by injection. The questionnaire was given to 59 patients with advanced breast cancer who received oral chemotherapy. Ninety-percent of patients considered clear and completed the questionnaire. Oral chemotherapy was positively viewed by most patients, perceiving it as advantageous (58%), able to help them feel less ill (77%) and to reduce the effort in coping with the disease (67%). The most important feeling elicited was the sense of freedom. Younger patients (

The aim of the study was to evaluate the activity of cisplatin (CDDP) plus vinorelbine (VNR) in patients with advanced non-small cell lung cancer (NSCLC) progressing after paclitaxel plus gemcitabine. Treatment consisted of CDDP 80 mg/m 2 administered on day 1 and VNR 25 mg/m 2 administered on day 1 and 8, repeated every 3 weeks. Nine patients who relapsed after partial response and eight patients refractory to prior CT received a minimum of two treatment cycles: three patients achieved a PR (18%; 95% CI: 4–43%), four had stable disease and 10 had disease progression. All responses were observed among the nine patients responsive to prior treatment. Median survival was 35 weeks. No patients required dose-reduction, treatment discontinuation or delay because of toxicity. Our results indicate a reasonable antitumor efficacy and no relevant toxicity of a second-line CDDP-based chemotherapy in patients with advanced NSCLC. We recommend the use of this regimen for patients not refractory to primary treatment.

Duodenal adenocarcinoma is an unusual and aggressive tumor, with an overall 5-year survival rate of about 25% [1].Very few data on the activity of anticancer agents are available for patients with ...

The therapeutic strategy used for elderly affected by malignant neoplasms should take into account the common variables present in oncological patients, and the specific alteration of the elderly metabolism and their possible morbidity. Ifosfamide is an active drug for various tumors with elevated incidence in the elderly. We analyze the principle criteria in the selection of these patients and the alterations of metabolism which correlates to aging with their consequences on the pharmacokinetics of ifosfamide. Finally, we propose clinical guidelines to optimize the use of ifosfamide in elderly patients affected by malignant tumors.

Background: L19TNF-α is a tumor targeted immunocytokine composed of a single chain variable fragment (scFv) directed against the ED-B domain of fibronectin and the human recombinant cytokine tumor necrosis factor-α. It was created to selectively localize TNF-α to tumor tissues and to minimize systemic toxicity. We evaluated safety, early signs of clinical activity and pharmacokinetic properties of L19TNF-α in patients with refractory solid tumors. Patients and Methods: Six cohorts of patients with refractory solid tumors were planned to receive escalating doses of L19TNF-α (60 minute-intravenous infusion of 1.3, 2.6, 5.2, 7.8, 10.4, e 13 g/kg) on days 1, 3 and 5 of a 21-days treatment cycle (maximum 6 cycles). Serum samples were taken for pharmacokinetic assessment and the analysis of 5-hydroxyindoleacetic acid (5-HIAA; surrogate marker of vascular disruption) during the first treatment cycle. Immunophenotyping (marker panels: CD71/CD8/CD3/CD4 for T-cell; CD71/CD19/CD3/CD56 for NK/B; CD25/CD122/CD3/CD4 for IL-2 expression on T-cell) on blood mononuclear cells was performed on days 1, 5, and 15 of each cycle for the first consecutive patients. The formation of human antifusion protein antibodies to L19 (HAFA) was analyzed at screening and on day 1 of each cycle. Data on safety and activity were collected. Results: Eightheen patients with solid tumors were recruited into the trial between January 2008 and September 2009. Patient's median age was 59 years (range 35–74), 8 were male and 9 female. Eight patients had colorectal cancer, 3 cholangiocarcinoma, 2 thymoma, 1 gastric carcinoma, 1 papilla Vater adenocarcinoma, and 1 parotid adenoidocystic carcinoma. A maximum tolerated dose was not yet reached. At the highest dose level achieved so far (10.4 g/kg) severe lumbar pain occurred in one patient during the L19TNF-infusion constituting a DLT. Most common (> 20%) toxicities included G1 Chills (100%), G2 Chills (41%), febricula (47%), G1 fever (70%), G1 asthenia (41%), headache (41%), G1 Nausea (52%), G1 vomiting (52%), G1 constipation (30%), herpes simplex recurrence (30%), G1 pain (58%), G2 pain (30%). Eight of the 18 patients achieved confirmed disease stabilization, lasting for 5 months (range: 1.5 to 8 months). All other patients progressed. Baseline and post-treatment 5′HIAA values were measured in patients of the first two cohorts (6 patients). A significant increase of 5′-HIAA levels on day 1 of the treatment (within 12 hours after end of infusion) as compared to baseline was found in most patients. Immunophenotyping, pharmacokinetic, HAFA and 5′HIAA analyses will be presented at the meeting. Conclusions: L19TNF- up to a dose of 10.4 g/kg was found safe when intravenously administered to patients with advanced progressive solid tumors in an outpatient setting. The observed toxicity profile was mild and reversible. Encouraging long-lasting disease stabilization was found in a larger fraction of patients, in particular in patients suffering from upper tract gastrointestinal adenocarcinomas. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B55.

10571 Background: The anti-angiogenic efficacy of chemotherapy (CT) is probably best obtained by administration of low doses of cytotoxics on a frequent or continuous schedule. The aim of this pilot study was to assess feasibility, clinical efficacy and tolerability of PLA, using a “metronomic” schedule in ABC. This schedule has been previously tested in the treatment of Kaposi sarcoma. Methods: From January to November 2005, 36 pts with ABC were treated with PLA, at a dose 20 mg/m2 q14. Almost all the pts were heavily pretreated for ABC and 44% of them received previous anthracycline therapy in adjuvant or metastatic setting. Results: Thirty-four pts were evaluable for toxicity and 29 for response. One pt (3%) had CR, 3 (11%) PR, 12 (41%) NC and 13 (45%) PD, for an overall clinical benefit of 28%. Median response duration was 2.59 mos; median TTP was 3.38 mos (95% CI 2.11–4.64). Treatment was well tolerated with neither G3-G4 NCI-CTC hematological toxicity. Only one pt experienced G3 palmar-plantar erythrodysesthesia (PPE). PPE was observed in other 15 pts (39%), with G2 occurring in 7 (21%). Other common G2 non-hematological toxicities were mucositis in 3 pts (9%) and constipation in 3 pts (9%) Dose reduction, due to subjective or hematological toxicity, was required in 10 pts (36%). No decrease in LVEF > 10% from baseline was observed. Conclusions: Metronomic PLA schedule in pretreated ABC pts seems to be an active and well-tolerated regimen. As to dose-dense CT, targets of metronomic CT might be, in addition to malignant cells, also endothelial and other stromal cells of the progressing metastasis, leading ultimately to the stability and eventually regression of the neoplastic lesion. The lower toxicity profile of the metronomic schedules make their use in pts with ABC very attractive and their testing in the adjuvant setting extremely challenging. No significant financial relationships to disclose.

666 Background: The study investigated oral vinorelbine (NBV oral) and Capecitabine (CAP) combination, which offers the convenience of an all-oral regimen. Methods: to determine maximal tolerated d...