Line Cytotoxic Chemotherapy Research Articles

P3.02a-018 Efficacy of Pemetrexed Based Chemotherapy Compared with Non-Pemetrexed Based Chemotherapy in Advanced, ALK-Positive NSCLC: Topic: ALK Clinical

Previous retrospective studies suggested that lung cancer patients with anaplastic lymphoma kinase (ALK) gene rearrangements are associated with sensitivity to pemetrexed chemotherapy. To determine the efficacy of pemetrexed based chemotherapy compared with non-pemetrexed based chemotherapy, we retrospectively evaluated clinical outcome in ALK positive non-small cell lung cancer (NSCLC) patients. We identified 126 patients with advanced, ALK-positive NSCLC who received 1st line cytotoxic chemotherapy from Seoul National University Hospital and Seoul National University Bundang Hospital. We compared response rate, progression-free survival, and overall survival according to chemotherapy regimens. We also analyzed the intra-cranial time to progression and proportion of ALK-positive cells as a predictive factor of pemetrexed efficacy. Forty eight patients received pemetrexed based chemotherapy and Seventy eight patients received non-pemetrexed based chemotherapy as first line systemic treatment. One hundred eighteen patients received platinum double combination chemotherapy. The pemetrexed based chemotherapy group shows superior overall response rate (44.7% versus 14.3%, p<0.001) and disease control rate (85.1% versus 62.3%, p=0.008). Pemetrexed based chemotherapy group had longer progression free survival (6.6 months versus 3.8 months, p<0.001). Exposure to pemetrexed and exposure to second generation ALK inhibitor were independent prognostic factors of overall survival (p=0.016 and p=0.011, respectively). Intra-cranial time to progression (TTP) was similar among treatment group (32.7 months versus 35.7 months, p= 0.733). Proportion of ALK positive cells was not statistically significant predictive factor of survival in pemetrexed based chemotherapy. Pemetrexed based regimen may prolong progression free survival compared with other regimens in ALK positive NSCLC in the first line setting. Exposure to pemetrexed is associated with improved survival compared with that of premetrexed-naive controls in ALK positive NSCLC.

The implication of FLT3 amplification for FLT targeted therapeutics in solid tumors.

We investigated the patients with solid cancers harboring Fms-like tyrosine kinase 3 (FLT3) amplification using targeted sequencing of tumor tissue specimen and FISH assay. Simultaneously, FLT3-amplified patient-derived cells (PDCs) were generated to evaluate the sensitivity to FLT3 inhibition. A patient with metastatic colon cancer who was previously treated with more than 3rd line cytotoxic chemotherapy was found to have FLT3 amplification and then received regorafenib showing partial response. In two PDC cell lines with FLT3 amplification, FLT3 mRNA expression was increased, however, the growth of tumor cells was not significantly inhibited by either regorafenib or sorafenib which is known to block the activity FLT3. Additional drug combinations with mTOR inhibitor did not affect the cell proliferation of PDC. FLT3 amplification in solid cancers is infrequently observed using targeted genomic profile, as yet, FLT3 amplification does not seem to be an actionable target or a proper biomarker for FLT3 inhibitor sensitivity.

Le statut KRAS n’influence pas l’efficacité de l’oxaliplatine ou de l’irinotécan, en association au bévacizumab, dans le traitement de première ligne du cancer colorectal métastatique

The identification of RAS status (KRAS and NRAS) has changed the management of metastatic colorectal cancer (mCRC). The impact of the RAS mutation on cytotoxic chemotherapy efficacy has not yet been determined. Nevertheless, several retrospective studies suggest a greater efficacy of oxaliplatin in mCRC with KRAS mutation. We analyzed retrospectively the progression free survival (PFS) and overall survival (OS) in 216patients with mCRC receiving first line treatment between 2008and 2010according to KRAS status and chemotherapy regimen used (oxaliplatin- or irinotecan-based, in association with fluoropyrimidine and bevacizumab). In KRAS mutated tumors, median OS was 23.4months with oxaliplatin-based regimen, and 23.6months with irinotecan-based regimen, with no significant difference (HR 1.30; 95% CI 0.81-2.09; P=0.27). In KRAS wild-type tumors, median OS was 30.3months with oxaliplatin-based regimen, and 25.4months with irinotecan-based regimen, with no significant difference (HR 0.81; 95% CI 0.52-1.24; P=0.33). Similarly, KRAS mutational status had no significant effect on efficacy of oxaliplatin or irinotecan regarding PFS. In this retrospective study, KRAS mutational status does not influence the efficacy of first line cytotoxic chemotherapy in association with bevacizumab.

Cytogenetics in Hairy Cell Leukemia at Diagnosis and Relapse: The Rate of Therapy-Related Myeloid Malignancies Is Low

Cytogenetic analysis of a large cohort of hairy cell leukemia (HCL) patients (pts) has never been reported. The influence on outcome of cytogenetic abnormalities is unknown.We retrospectively reviewed records of pts with HCL treated at Memorial Sloan Kettering Cancer Center between January 1973 and December 2013. 501 pts were identified and 331 were confirmed to have a diagnosis of HCL by histopathology or immunophenotyping. 170 patients were excluded, either because their final diagnosis was an alternate disease or there was inaccessible clinical data. Descriptive statistics were used to evaluate the cohort.260/331 (79%) were men, overall median age at diagnosis was 53 years (range 20-84 years) and median follow-up was 61 months. 241 had classical HCL and 18 had variant disease based on absent expression of CD25 by immunophenotyping or immunohistochemistry with median diagnostic WBC of 3.2x10^9/L and 8.4x10^9/L respectively. BRAF mutation testing was performed infrequently (<10% pts). In 72 pts we were unable to review immunophenotyping data to confirm disease type. 64 pts never received treatment, 156 received one line and 111 received at least 2 lines of therapy during follow up. The most common initial treatment was cladribine (n=215, 80%). Assessment of bone marrow cytogenetics was available in 105 of 331 patients (32%) at diagnosis with 92 cases of classical HCL, 8 variant HCL and 5 with unconfirmed disease type. Karyotype was normal in 95 patients (90.5%) and abnormal in 10 (9.5%). Abnormal karyotype was more common in patients with variant than classical disease, seen in 3/8 versus 7/92 respectively (p=0.007). 9/10 with abnormal karyotype had multiple clones identified including at least one cytogenetically normal metaphase. Sex chromosome loss was present in 4/10 pts (3 with loss of Y and 1 female with loss of X) while loss of genetic material from chromosome 7 was the most common autosomal abnormality (3/10 patients). The presence of an abnormal karyotype at diagnosis did not worsen survival compared to patients with a normal karyotype with an estimated 5 year OS of 100% and 97%, respectively.30/111 pts (24 classical and 6 variant HCL) who received two or more lines of therapy had cytogenetics evaluated at some point during disease relapse and 17/30 had cytogenetic abnormalities. 6 of these had cytogenetics at diagnosis and 4/6 were normal. Pts with an abnormal karyotype received more lines of therapy prior to identification of a cytogenetic abnormality than those with normal cytogenetics with a median of 3 and 1 lines respectively (p=0.008). Pts with variant HCL were more likely to have abnormal cytogenetics at relapse (6/6) than those with classical disease (11/24) (p=0.017).Cytogenetic abnormalities of all evaluable pts with relapsed HCL were reviewed. The most common abnormalities seen at relapse were monosomies or partial chromosome deletions seen in 14/17 cases. The most common abnormalities were loss of material from chromosome 7 (6/17 pts) and chromosomes 13 and 17 (4/17 pts each). Multiple abnormalities were present in 11/17 pts. No abnormality appeared to be specific for classical or variant disease. In particular loss of material from chromosome 7 was seen in both disease types. Only 2 of the 331 pts developed a therapy-related acute myeloid leukemia (t-AML) both had classical HCL. The first developed t-AML with a complex monosomal karyotype after prior treatment with cladribine, pentostatin, fludarabine and rituximab. The second had t-AML with monosomy 7 following 4 treatments with cladribine. There were no cases of myelodysplasia.In summary we identified cytogenetic abnormalities in 10% of newly diagnosed HCL pts and found that this did not adversely affect survival. Pts with variant HCL are more likely to have abnormal cytogenetics at diagnosis and at disease relapse compared to those with classical disease. Cytogenetic changes appear to be more common in those who received more lines of cytotoxic chemotherapy. Loss of material from chromosome 7 is the most common cytogenetic change seen at diagnosis and at disease progression. The rate of therapy-related myeloid malignancies is low and is not increased in HCL variant. Identification of new molecular mutations arising during disease relapse may be insightful. DisclosuresPark:Actinium Pharmaceuticals, Inc.: Research Funding; Juno Therapeutics: Consultancy.

World Health Organization-defined eosinophilic disorders: 2015 update on diagnosis, risk stratification, and management.

The eosinophilias encompass a broad range of non-hematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage. Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1,500/mm(3) and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ-hybridization, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder. Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2008 World Health Organization establishes a semi-molecular classification scheme of disease subtypes including 'myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1', chronic eosinophilic leukemia, not otherwise specified, (CEL, NOS), lymphocyte-variant hypereosinophilia, and idiopathic hypereosinophilic syndrome (HES), which is a diagnosis of exclusion. The goal of the therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g. < 1,500/mm(3) ) without symptoms or signs of organ involvement, a watch and wait approach with close-follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant hypereosinophilia and HES. Hydroxyurea and interferon-alpha have demonstrated efficacy as initial treatment and steroid-refractory cases of HES. In addition to hydroxyurea, second line cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive forms of HES and CEL with outcomes reported for limited numbers of patients. Although clinical trials have been performed with anti IL-5 (mepolizumab) and anti-CD52 (alemtuzumab) antibodies, their therapeutic role in primary eosinophilic diseases and HES has yet to be established.

Comprehensive Hybrid Capture-Based Genomic Profiling of T-Cell Leukemias and Lymphomas Reveals Targetable JAK1 and JAK3 Co-Existing Mutations

Background: T-cell leukemias and lymphomas (TL&Ls) are rare when compared with other hematologic malignancies, and pose a challenge for clinical management. TL&Ls are characteristically resistant to chemotherapeutic regimens used to treat other hematologic malignancies (PMID 17369126, 22649104, 25042790). Recently, activating JAK1 and JAK3 mutations have been described in a subset of mature TL&Ls including adult T-cell leukemias/lymphoma (ATLL), NK/T-cell lymphoma, and T-cell prolymphocytic leukemia (T-PLL). We used a comprehensive hybrid capture-based sequencing assay to identify genomic alterations that might suggest benefit from targeted therapy.Methods and Results.Using FoundationOne® and FoundationOne® Heme assays, we performed genomic profiling on 28 consecutive TL&Ls (leukemias, n=10; lymphomas, n=18) for all alterations in 370 or 405 cancer-related genes and select introns of 19 or 31 genes commonly rearranged in cancer, or both DNA and RNA were extracted and captured using custom baits for 405 genes and 265 frequently rearranged genes, respectively. The samples were sequenced to high uniform coverage, averaging >500X for DNA and >8M total pairs for RNA (PMID 24142049). JAK3 alterations were the most common at 25% (7/28) with an enrichment in T-cell derived leukemias (2 T-PLL, 3 T-ALL, and 1 cutaneous T-cell lymphoma (CTCL)). Other altered genes in the 28 cases included CDKN2A/B (21%), TP53 (18%), and TET2 , DNMT3A , and STAT3 (11% each). A complex rearrangement involving FCHO1 and JAK3 resulting from a ~70kb genomic segment deletion was also identified in a CTCL. The most frequently co-altered genes identified in the JAK3 mutated cases were relevant to the chromatin remodeling pathway. Focal STAT3, STAT5A, and STAT5B amplifications were identified in 2 cases (CTCL and ALCL) as well as one STAT3 D661Y in a T-cell large granular lymphocytic leukemia (T-LGL). All 3 cases with STAT gene alterations were mutually exclusive with JAK3 alterations. Additionally, 2 patients with T-PLL and T-ALL respectively were both found to harbor multiple co-existing JAK1 and JAK3mutations (2/28; 7%).One heavily pre-treated T-PLL patient harbored a major JAK1 V658F clone (40%) and a minor JAK3 M5111 clone (5%), and loss of heterozygosity for mutant ATM and TP53. Based on assay results, the patient was treated with ruxolitinib, a potent and specific inhibitor of JAK1 and JAK2. The patient had an impressive clinical response of duration of 4 months after which her T-PLL cell count rose markedly to pre-treatment levels and she developed worsening thrombocytopenia, indicating acquired resistance to therapy. The resistant T-PLL was assayed and was found to harbor an increased frequency of JAK3 M5111 (28%), decrease of JAK1 V658F (18%) and a new EZH2mutation. The patient’s disease progressed through another line of cytotoxic chemotherapy and she succumbed to her disease. Signal transduction analysis was conducted which showed in T-PLL, the JAK1 and JAK3 mutations were functionally significant as they induced constitutive phosphorylation of downstream STAT proteins. Importantly, these phosphorylations could be inhibited by JAK inhibitors. Collection of clinical outcome on additional cases is ongoing.Conclusion. In this study, we discovered a high frequency of JAK-STAT alterations in 28 T-cell neoplasms with 25% of cases harboring JAK3 missense mutations and two cases with concordant JAK1 and JAK3 mutations. In one case, treatment with the JAK1/2 inhibitor, ruxolitinib, resulted in an impressive clinical response. Our data argue for oncogene dependence upon the JAK-STAT pathway in diverse T-cell neoplasms and underscore the importance of genomic profiling by FoundationOne Heme® of rare and difficult to treat cases by revealing alterations that may be targeted by specific inhibitors, such as ruxolitinib, and may also be predictive of treatment resistance. DisclosuresOff Label Use: Ruxolitinib is FDA approved for myeloproliferative disorders.. Palma:Foundation Medicine, Inc.: Employment, Equity Ownership. Wang:Foundation Medicine Inc: Employment. Ali:Foundation Medicine, Inc.: Employment, Equity Ownership. Stephens:Foundation Medicine: Employment, Equity Ownership. Miller:Foundation Medicine, Inc.: Employment, Equity Ownership.

Clinical outcomes and survival of patients (pts) with sarcomatoid metastatic renal cell carcinoma (smRCC).

535 Background: SmRCC is a rare variant of RCC associated with poor outcome. No definitive therapeutic recommendations exist. We present survival outcomes in pts with smRCC treated with systemic therapy. Methods: From a single institutional database (years 2000-2012), we identified 21 pts with documented sarcomatoid features who received systemic therapy. Survival was assessed in the overall cohort and in subgroups divided by clinicopathologic characteristics, including the extent of sarcomatoid features, and Memorial Sloan-Kettering Cancer Center (MSKCC) risk criteria. Sarcomatoid component of the tumor was classified by predominant (≥20%) and non-predominant (&lt;20%). Immunohistochemistry (IHC) analysis was performed for mammalian target of rapamycin (mTOR) signaling, phosphorylated ribosomal protein S6, proviral integration site proteins (PIM 1,2,3), Beta-catenin, E-cadherin, phosphatase and tensin homolog (PTEN), U3 small nucleolar ribonucleoprotein (IMP-3), p53, and epithelial membrane antigen (EMA) on tumor samples, where available. Results: 21 pts were included with a median age of 62 years (range 39-74) and 13 pts were male (62%). One pt received first line cytotoxic chemotherapy, 3 pts received first line immunotherapy, and 17 pts received targeted therapy. Pts belonged to the following MSKCC risk categories: 1 (5%) favorable, 13 (62%) intermediate and 7 (33%) poor risk. Median overall survival (OS) of the entire cohort was 249 days (95% CI 161-519 days). Median OS in pts stratified as MSKCC poor, intermediate, and good risk was 2556, 430, and 137 days respectively (Poor vs Intermediate HR 4.38, p = 0.0159, CI 1.30-19.90). There was no significant difference in OS in pts with sarcomatoid predominant disease vs. non-predominant disease (234 vs 286 days, p = 0.744, HR 0.85, CI 0.31-2.39). Conclusions: Overall OS in pts with smRCC is inferior compared to that reported in clear cell variant mRCC. Although MSKCC risk scores may be useful in determining prognosis, further studies are needed to identify relevant biomarkers and define the optimal therapeutic strategy for this disease. Correlation of survival outcomes with the IHC profile of tumors will be presented.

A case of gingival candidiasis with bone destruction on gastric cancer patient receiving cytotoxic chemotherapy.

We herein report a case of gingival candidiasis in an advanced gastric cancer patient while receiving palliative cytotoxic chemotherapy. A 46-year-old male patient admitted to our hospital for known advanced gastric cancer with newly developed multiple liver metastases. While receiving 2nd line cytotoxic chemotherapy with 5FU, leucovorin, and paclitxel, he complained of gingival swelling accompanied by pain and whitish plaque. Due to lack of response to the conservative oral care, incisional biopsy of gingiva was done and the pathology confirmed gingival candidiasis. Although the lesion healed apparently after two-week antifungal therapy, pain as well as bony destruction remains. By presenting this case report, we intend to emphasize the immunocompromising effect of cancer while being on systemic chemotherapy.

Abstract OT3-2-09: FALCON: A randomised, double-blind, multicentre, phase III study comparing fulvestrant 500 mg with anastrozole 1 mg for postmenopausal women with hormone receptor-positive locally advanced or metastatic breast cancer who have not previously been treated with any hormonal therapy

Abstract Background: The Phase III CONFIRM study demonstrated that a higher dose (500 mg) of fulvestrant, an estrogen receptor (ER) antagonist for treatment of advanced breast cancer, was associated with a significant increase in progression-free survival (PFS) without increased toxicity versus fulvestrant 250 mg.Moreover, a Phase II study (FIRST) showed that first-line treatment with fulvestrant 500 mg was at least as effective as anastrozole 1 mg with a similar safety profile. The aim of the FALCON study is to investigate whether fulvestrant 500 mg is superior to anastrozole 1 mg as first-line endocrine therapy. FALCON is the only Phase III study in recent years to compare two endocrine therapies as first-line treatment in metastatic breast cancer (MBC); hence, results may potentially affect standard clinical practice in the future. Trial design: This is a randomised, double-blind, double-dummy, international, multicentre study comparing efficacy and tolerability of fulvestrant with anastrozole (NCT01602380). Eligible patients are randomised 1:1 to receive fulvestrant 500 mg or anastrozole 1 mg, and stratified at randomisation based on whether (1) they have locally advanced or MBC (2) they have received prior chemotherapy for locally advanced or MBC or not and (3) they have measurable or non-measurable disease. Eligibility criteria: Eligible are postmenopausal women with histologically confirmed, ER-positive, locally advanced or MBC who have not previously received any endocrine therapy. Patients may have received one line of cytotoxic chemotherapy but must show progressive disease prior to enrolment, have a World Health Organisation performance status of 0, 1 or 2 and at least one lesion that can be accurately assessed at baseline and is suitable for repeated assessment according to Response Evaluation Criteria in Solid Tumours (RECIST 1.1) guidelines. Specific aims: The primary objective is to demonstrate the superior PFS of patients treated with fulvestrant 500 mg versus patients treated with anastrozole 1 mg. Secondary objectives include comparison of the overall survival (OS), the objective response rate (ORR), the clinical benefit rate (CBR) and quality of life (QoL) between the treatment groups, as well as safety and tolerability assessments. Statistical methods: Comparison of PFS and OS for fulvestrant 500 mg versus anastrozole 1 mg will be performed using a stratified log-rank test. A multiple testing procedure will be used to control the overall type 1 error rate at 2.5% (1-sided). Results will be presented as an estimated hazard ratio, associated confidence interval and p-value. ORR and CBR will be analysed using a logistic regression model and examination of the odds ratio of the 2 treatment groups. A time to deterioration analysis will be performed for QoL endpoints. Present accrual and target accrual: Recruitment is currently ongoing; on June 6, 2013, 101 patients had been randomised. The recruitment target is 450 patients; 124 study sites worldwide are currently initiated. Contact information: Please contact the authors for specific information about this study. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-2-09.

Abstract S5-07: SWOG S0500 – A randomized phase III trial to test the strategy of changing therapy versus maintaining therapy for metastatic breast cancer patients who have elevated circulating tumor cell (CTC) levels at first follow-up assessment

Abstract Introduction: CTC are detectable in approximately 75% of patients with metastatic breast cancer (MBC), and are elevated (≥5CTC/7.5 ml whole blood (WB)) in about half. Elevated CTC at baseline are associated with a worse prognosis, and a decline in CTC levels suggests response to therapy. We initiated a prospective randomized clinical trial (SWOG S0500) to test whether a change in chemotherapy after failure to clear CTC after one cycle of first line chemotherapy would improve outcomes of patients starting first line cytotoxic chemotherapy for MBC. Methods: Patients initiating first-line chemotherapy for MBC were enrolled. All patients had measurable or evaluable disease that included bone metastases. Patients with elevated CTC at baseline and who continued to have elevated CTC after 21 days of therapy were randomly assigned to either continue initial therapy until progression or to change to a second line chemotherapy (physician choice) immediately at cycle 2. Patients with elevated CTC at baseline, which were not elevated at the 21-day follow-up were maintained on their initial therapy. Patients without elevated CTC at baseline were followed in an observation arm. The primary endpoint was overall survival, and progression-free survival was a secondary endpoint. It was expected that approximately 500-650 patients would have to be screened to enroll 120 patients in the randomized trial. Power was 81% with 2-sided α = 0.05 to detect a 70% increase in median overall survival for patients randomized to change therapy. Three interim analyses were planned during the course of the trial. Results: From 10/1/2006 until 3/15/2012, 624 patients were registered of whom 612 were eligible. A baseline CTC was obtained in 593 (97%) eligible patients of whom 317 (53%) had elevated CTC at baseline. Thirty-one patients (10%) with elevated baseline CTC did not complete the follow-up CTC due to death, progression, withdrawal, or assay failure. Of the 286 remaining patients, 123 patients (43%) continued to have elevated CTCs after the first cycle of chemotherapy and were randomly assigned to either maintain original chemotherapy (n = 64) or switched to new chemotherapy (n = 59). Final outcome results will be analyzed in October 2013 and will be reported if released by the SWOG Data Safety Monitoring Board. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S5-07.

Clinical benefit of second EGFR-TKI retreatment on overall survival in patients with advanced non-small-cell lung cancer harboring EGFR-mutation positive after failure of the initial EGFR-TKI treatment: A retrospective analysis.

e19164 Background: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) bring the best result to EGFR-mutation positive non-small cell lung cancer patients, but most lead to drug resistance. These acquired resistances are associated with T790M mutation or Met amplification, HGF expression. To assess whether affects overall survival in these patients, we did a retrospective study comparing survival outcomes in 2nd EGFR-TKI treated patients with controls without 2nd EGFR-TKI screened during the same time period. Methods: We examined overall survival in thirty-two of 52 patients with advanced, EGFR-mutation-positive NSCLC who treated 1st EGFR-TKI (gefitinib) from January 2009 to December 2012. We identified 16 patients who were given 2nd EGFR-TKI (erlotinib) after failure of the initial gefitinib treatment (retreatment group) with 16 patients who were not given 2nd EGFR-TKI but given only chemotherapy (control group), 20 patients who might treat with 2nd EGFR-TKI or chemotherapy at that time were excluded in progress after failure of the initial gefitinib treatment. To assess differences in overall survival, we assessed subsets of clinically comparable 2nd EGFR-TKI retreatment group. Results: Among 16 patients who were given 2nd EGFR-TKI, retreatment group who were given one or two cytotoxic chemotherapy from 1st EGFR-TKI to 2nd EGFR-TKI, median overall survival from initiation of the diagnosis with advanced IIIB/IV stage or surgical recurrent NSCLC was 24.2 months. 16 patients of control group who were given from second to seven line cytotoxic chemotherapy, overall survival was 15.8 months (p=0.021). Retreatment group who were given 2nd EGFR-TKI was significantly longer than control group in EGFR mutation positive patients. Response rate and disease control rate with 2nd EGFR-TKI retreatment are 12.5% and 31.3%. Conclusions: In patients with advanced, EGFR mutation positive NSCLC, retreatment group who were given 2nd EGFR-TKI therapy was associated with improved survival compared with control group who were given only cytotoxic chemotherapy.

Metastatic melanoma: results of ‘classical' second-line treatment with cytotoxic chemotherapies

Background: Metastatic melanoma is one of the most aggressive tumours, with a median survival that does not exceed 12 months. None of the cytotoxic first-line therapies have shown survival benefit in randomised clinical trials. Objective: To describe clinical benefit of second-line cytotoxic chemotherapy in the second line of treatment for metastatic melanoma. Methods: In a retrospective study, we analyse the outcome of patients with metastatic melanoma who had received two lines or more of cytotoxic treatments in four French dermato-oncology departments between 1999 and 2009. Results:We describe the outcomes for 109 patients. Most of these patients received dacarbazine for the first line of chemotherapy and fotemustine for the second line of chemotherapy (67.0 and 64.2%, respectively). A clinical benefit was observed in 24.1% of the patients and overall survival was 4.1 months after the second-line treatment. At least 23.8% of patients suffered from grade 3 or 4 toxicities. The presence of more than two sites of metastasis and an M1c staging according to the AJCC classification represented negative predictive factors of clinical benefit. Conclusion: This study shows the modest benefit of a second line of cytotoxic chemotherapy in a nonselected population. If eligible, these patients should be proposed for ongoing clinical trials or for targeted therapies.

World Health Organization‐defined eosinophilic disorders: 2012 update on diagnosis, risk stratification, and management

The eosinophilias encompass a broad range of nonhematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage. Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1,500/mm(3) and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ-hybridization, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder. Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2008 World Health Organization establishes a semimolecular classification scheme of disease subtypes including "myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1," chronic eosinophilic leukemia, not otherwise specified' (CEL, NOS), lymphocyte-variant hypereosinophilia, and idiopathic hypereosinophilic syndrome (HES), which is a diagnosis of exclusion. The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g., <1,500/mm(3) ) without symptoms or signs of organ involvement, a watch and wait approach with close-follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant hypereosinophilia and HES. Hydroxyurea and interferon-alpha have demonstrated efficacy as initial treatment and steroid-refractory cases of HES. In addition to hydroxyurea, second line cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive forms of HES and CEL with outcomes reported for limited numbers of patients. Although clinical trials have been performed with anti IL-5 (mepolizumab) and anti-CD52 (alemtuzumab) antibodies, their therapeutic role in primary eosinophilic diseases and HES has yet to be established.

Afatinib monotherapy in patients with metastatic squamous cell carcinoma of the lung progressing after erlotinib/gefitinib (E/G) and chemotherapy: Interim subset analysis from a phase III trial.

7558 Background: Patients with squamous NSCLC have limited treatment options. For those deriving benefit from EGFR TKIs, it is unclear whether sustained ErbB family blockade offers benefit upon progression. We evaluated afatinib, an irreversible blocker of EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptor tyrosine kinases, in patients with metastatic NSCLC who had failed chemotherapy and E/G. Here we describe a pre-specified analysis of those with squamous histology in Part A. Methods: This randomized Phase III, open-label, multi-center trial enrolled patients with pathologically confirmed metastatic NSCLC after failing ≥1 line of cytotoxic chemotherapy and E/G. In Part A, patients received oral afatinib 50 mg until disease progression. Those with clinical benefit (≥12 wks) who progressed were eligible to receive afatinib plus paclitaxel or investigator’s choice chemotherapy (Part B). Primary endpoint was PFS (RECIST 1.1). Following an amendment, an interim analysis of Part A was performed to assess afatinib monotherapy. Results: Patient enrolment into Part A was from April 2010 to May 2011. Of 1154 afatinib-treated patients, 91 (8%) had squamous histology; 18/91 and 40/91 had CR/PR and SD on prior E/G, respectively (by investigator). Median age was 63 yrs, 71% were male, 76% were current/ex-smokers. Median PFS on afatinib was 3.7 mths in the squamous histology subset. Of 91 patients, 42 had PFS ≥3 mths; 13 had PFS of ≥6 mths. In evaluable patients (n=77), 1 CR and 3 PRs were confirmed; 51 and 22 patients had best overall response of SD and PD, respectively. Of the 31 patients with PD on prior E/G with no intervening chemotherapy, 10 achieved confirmed disease control (2 PR; 8 SD) on afatinib. Most commonly reported grade 3/4 adverse events (AEs) in Part A were diarrhea (13%) and rash/acne (12%). The safety profile in the squamous histology subset was similar to that observed for the whole trial. Conclusions: Afatinib monotherapy demonstrated encouraging activity in treatment-refractory NSCLC patients with squamous histology that merits further evaluation.

World Health Organization‐defined eosinophilic disorders: 2011 update on diagnosis, risk stratification, and management

The eosinophilias encompass a broad range of non-hematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage. Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1,500/mm(3) and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ-hybridization, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder. Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2008 World Health Organization establishes a semi-molecular classification scheme of disease subtypes including myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1, chronic eosinophilic leukemia, not otherwise specified (CEL, NOS), lymphocyte-variant hypereosinophilia, and idiopathic hypereosinophilic syndrome (HES), which is a diagnosis of exclusion. The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g. < 1,500/mm(3) ) without symptoms or signs of organ involvement, a watch and wait approach with close-follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant hypereosinophilia and HES. Hydroxyurea and interferon-alpha have demonstrated efficacy as initial treatment and steroid-refractory cases of HES. In addition to hydroxyurea, second line cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive forms of HES and CEL with outcomes reported for limited numbers of patients. Although clinical trials have been performed with anti IL-5 (mepolizumab) and anti-CD52 (alemtuzumab) antibodies, their therapeutic niche in primary eosinophilic diseases and HES have yet to be established.

Prognostic and predictive impact of EGFR and K-ras mutation, and EGFR gene copy number in patients with advanced non-small cell lung cancer (NSCLC) who received first-line cytotoxic chemotherapy

8096 Background: Epidermal growth factor receptor (EGFR) mutations, amplification, and K-ras mutations are known as predictive factor of the EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy in patients (pts) with NSCLC. Prognostic influences of those biomarkers remain the matter to be discussed. Methods: Consecutive pts with advanced NSCLC who were examined EGFR genotype and received 1st line cytotoxic chemotherapy were enrolled. EGFR amplification and K-ras mutation were analyzed if sufficient tumor samples were available. Results: 87 pts were enrolled in this study. EGFR mutations or K-ras mutations were found in 26 of 87 (29.9%) or 2 of 65 (3.1%) pts, respectively. As to objective response rate (ORR), no significant differences were observed among pts with EGFR mutations, K-ras mutations, and pts without both mutations. Progression free survival (PFS) in 1st line cytotoxic chemotherapy was 8.4, 1.0, and 3.9 months in pts with EGFR mutations, with K-ras mutations, and pts without both mutations, respectively. PFS was longer in pts with EGFR mutations compared with the pts without both mutations (p=0.0234). We also found the pts with K-ras mutations had shorter PFS compared with pts without both mutations (p=0.0203). Overall survival (OS) was 29.7, 2.3 and 13.4 months in pts with EGFR mutations, with K-ras mutations, and pts without both mutations, respectively. Significant differences were found between pts with EGFR mutation and without both mutations (p=0.0001) and between pts without both mutations and with K-ras mutations (p=0.0001). Pts with EGFR amplification were found in 21 of 78 (26.9%). There were no differences between EGFR amplification positive and negative in terms of ORR, PFS and OS. 87 of 68 (78.2%) pts received EGFR-TKI therapy in the second line or later. As previously reported, both EGFR mutations and amplifications were good predictive marker of ORR, PFS and OS in pts treated with EGFR-TKI. Conclusions: EGFR mutations were good predictive marker and K-ras mutations were poor predictive marker in first line cytotoxic chemotherapy. There is the possibility that EGFR and K-ras mutations have the prognostic impact in advanced NSCLC. [Table: see text]

Activity of bevacizumab (rhuMAB VEGF) in advanced refractory epithelial ovarian cancer

Background. Angiogenesis is pivotal in the development and progression of ovarian cancer and is an ideal candidate for novel treatment approaches. Case. A case of advanced, recurrent and refractory serous carcinoma is presented that responded to bevacizumab 15 mg/m 2 intravenously every 3 weeks after failing eleventh line cytotoxic chemotherapy and radiation. An objective durable response lasting at least 5 months was documented. Conclusion. Bevacizumab has activity in epithelial ovarian carcinoma and larger scale trials are indicated.

Predictive value of topoisomerase IIα and other prognostic factors for epirubicin chemotherapy in advanced breast cancer

Although cytotoxic chemotherapy is widely used in advanced breast cancer, there are no powerful predictors for the therapy response. Because topoisomerase IIalpha (Topo IIalpha) is the molecular target for the anthracycline class of anti-cancer drugs, we compared the immunocytochemical assay of Topo IIalpha with other biomarkers in the prediction of clinical response to Topo II inhibitor chemotherapy. Fifty-five patients with advanced breast cancer were treated with a single cytotoxic drug, Topo II-inhibitor, epirubicin (30 mg m(-2) weekly up to 1000 mg m(-2)), as first line cytotoxic chemotherapy. Objective response to treatment was analysed according to UICC criteria. The predictive value of Topo IIalpha expression, c-erbB2 oncoprotein, p53 tumour-suppressor protein, oestrogen (ER) and progesterone receptor (PR), S-phase fraction and DNA ploidy were analysed from representative formalin-fixed paraffin-embedded primary tumour samples. The proportion of Topo IIalpha-positive cells (Topo IIalpha index) failed to predict response to epirubicin therapy. Mean Topo IIalpha scores in 29 responding patients were similar when compared with those with no change in disease progression (n = 13) and those with progressive disease (n = 13) (14.9% +/- 11.4% vs 15.5% +/- 7.6% vs 17.3% +/- 13.2%, not significant). Among the other biomarkers tested, overexpression of c-erbB2 oncoprotein and hormone receptor negativity were significantly associated with poor response. Response rate in patients with c-erbB2-overexpressing tumours was 32% compared with 65% in patients with no c-erbB2 overexpression (P = 0.0058). Accordingly, the response rate for ER-positive patients was 67% compared with 26% in ER-negative patients (P = 0.0021). Although both negative ER status and c-erbB2 overexpression are associated with high Topo IIalpha expression in breast cancer, step-wise logistic regression analysis showed that ER and c-erbB2 were associated with therapy response independent of Topo IIalpha expression. Histological grade, p53, DNA-ploidy, tumour proliferation rate (S-phase fraction), stage of the disease at diagnosis, age of the patient, previous anti-oestrogen therapy or site of metastasis did not predict the response to epirubicin therapy. In conclusion, despite extensive in vitro evidence, expression of Topo IIalpha is unlikely to predict the response to Topo II inhibitor chemotherapy in advanced breast cancer. Among the prognostic biomarkers, overexpression of c-erbB2 oncogene and negative ER may have predictive value in epirubicin therapy in patients with advanced breast cancer.