Search

Supplementary Methods, Supplementary Figure Legends, Supplementary Table

Kaplan-Meier estimated progression-free survival (PFS) in the intention-to-treat population

Major molecular response by 12 months, by Sokal risk group. bid, twice daily; MMR, major molecular response (defined as BCR-ABL1 transcript level {less than or equal to}0.1% [MR3.0]); qd, daily.

Purpose: Radotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) approved in Korea for chronic phase chronic myeloid leukemia (CML-CP) in patients newly diagnosed or with insufficient response to other TKIs. This study was conducted to evaluate the efficacy and safety of radotinib as first-line therapy for CML-CP.Experimental Design: This multinational, open-label study assigned patients (1:1:1) to one of two twice-daily radotinib doses, or imatinib daily. The primary endpoint was major molecular response (MMR) by 12 months.Results: Two hundred forty-one patients were randomized to receive radotinib 300 mg (n = 79) or 400 mg twice-daily (n = 81), or imatinib 400 mg daily (n = 81). MMR rates by 12 months were higher in patients receiving radotinib 300 mg (52%) or radotinib 400 mg twice-daily (46%) versus imatinib (30%; P = 0.0044 and P = 0.0342, respectively). Complete cytogenetic response (CCyR) rates by 12 months were higher for radotinib 300 mg (91%) versus imatinib (77%; P = 0.0120). Early molecular response at 3 months occurred in 86% and 87% of patients receiving radotinib 300 mg and radotinib 400 mg, respectively, and 71% of those receiving imatinib. By 12 months, no patients had progression to accelerated phase or blast crisis. Most adverse events were manageable with dose reduction.Conclusions: Radotinib demonstrated superiority over imatinib in CCyR and MMR in patients newly diagnosed with Philadelphia chromosome–positive CML-CP. This trial was registered at www.clinicaltrials.gov as NCT01511289. Clin Cancer Res; 23(23); 7180–8. ©2017 AACR.

Achievement of MMR by 12 months according to 3-month EMR (< 10% of BCR-ABL1IS). (c) Radotinib 300 mg bid (n = 79 patients with evaluable molecular data at 3 months).

Achievement of MMR by 12 months according to 3-month EMR (< 10% of BCR-ABL1IS).EMR at 3 months.

Introduction: Multiple myeloma remains to be an incurable hematologic entity, but with the advent of novel agents more patients experience significantly longer survival. In a third world country like the Philippines, autologous bone marrow transplant after chemotherapy for newly diagnosed cases which is the standard of care is difficult to comply. The management paradigm for myeloma has shifted over the years, hence this study. Objective: Determine the clinical profile and treatment outcome of Filipino multiple myeloma patients diagnosed and managed at a tertiary institution from January 2013 to December 2018. Methodology: Retrospective, observational and cross-sectional study of eligible symptomatic myeloma patients. Results: Data for six years were retrospectively collected from a single tertiary institution. The clinical characteristics at diagnosis, treatment and survival rates of 109 active myeloma patients were described. The median age was 61 years (range, 28–83), with 51.4% being female. Median overall survival was 49.5 months (95% CI 42.7–56.2). The frontline treatments of patients were also analyzed. The combined deep response (complete and very good partial) of our patients at 31.7% was higher than of Asian Myeloma Network Study at 30.9%. None of them yet underwent autologous bone marrow transplantation as of date. Novel agents, especially bortezomib was used in 35.7% and significantly affected overall and progression-free survivals when used as a first line treatment. Conclusion: This retrospective analysis demonstrated the paradigm shift in the treatment modality of myeloma and the survival outcomes has significantly improved, especially on the best response to chemotherapy. Short of the ideal management in a third world country like the Philippines, we can now set our new standard of care based on the treatments available including novel agents like bortezomib, and the best practices that our institution offers. Keywords: Multiple Myeloma, Profile, Outcomes, Tertiary

Summary In the phase 3 study RERISE, patients with newly diagnosed chronic myeloid leukaemia in chronic phase demonstrated significantly faster and higher rates of major molecular response (MMR) with twice‐daily radotinib 300 mg (n = 79) or 400 mg (n = 81) than with once‐daily imatinib 400 mg (n = 81) after 12 months. With ≥48 months’ follow‐up, MMR was higher with radotinib 300 mg (86%) or 400 mg (83%) than with imatinib (75%). Among patients with BCR‐ABL1 ≤ 10% at three months, MMR and molecular response 4·5 (MR4·5) were achieved within 48 months by more radotinib‐treated patients (300 mg: 84% and 52%, respectively; 400 mg: 74% and 44%, respectively) than imatinib‐treated patients (71% and 44%, respectively). Estimated overall and progression‐free survival rates at 48 months were not significantly different between imatinib (94% and 94%, respectively) and radotinib 300 mg (99% and 97%, respectively) or 400 mg (95% and 93%, respectively). The treatment failure rate was significantly higher with imatinib (19%) than with radotinib 300 mg (6%; P = 0·0197) or 400 mg (5%; P = 0·0072). Safety profiles were consistent with previous reports; most adverse events occurred within 12 months. Radotinib continues to demonstrate robust, deep molecular responses, suggesting that treatment‐free remission may be attainable.

Purpose: Radotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) approved in Korea for chronic phase chronic myeloid leukemia (CML-CP) in patients newly diagnosed or with insufficient response to other TKIs. This study was conducted to evaluate the efficacy and safety of radotinib as first-line therapy for CML-CP. Experimental Design: This multinational, open-label study assigned patients (1:1:1) to one of two twice-daily radotinib doses, or imatinib daily. The primary endpoint was major molecular response (MMR) by 12 months. Results: Two hundred forty-one patients were randomized to receive radotinib 300 mg (n = 79) or 400 mg twice-daily (n = 81), or imatinib 400 mg daily (n = 81). MMR rates by 12 months were higher in patients receiving radotinib 300 mg (52%) or radotinib 400 mg twice-daily (46%) versus imatinib (30%; P = 0.0044 and P = 0.0342, respectively). Complete cytogenetic response (CCyR) rates by 12 months were higher for radotinib 300 mg (91%) versus imatinib (77%; P = 0.0120). Early molecular response at 3 months occurred in 86% and 87% of patients receiving radotinib 300 mg and radotinib 400 mg, respectively, and 71% of those receiving imatinib. By 12 months, no patients had progression to accelerated phase or blast crisis. Most adverse events were manageable with dose reduction. Conclusions: Radotinib demonstrated superiority over imatinib in CCyR and MMR in patients newly diagnosed with Philadelphia chromosome–positive CML-CP. This trial was registered at www.clinicaltrials.gov as NCT01511289. Clin Cancer Res; 23(23); 7180–8. ©2017 AACR.

Background Thyroid cancer is the most common endocrine-related malignancy in the Philippines. It ranks seventh overall based on the latest Department of Health statistics. Its incidence increases every year, noted especially in females and in the reproductive age group. This study determined the incidence and the profile of all thyroid carcinomas encountered in a tertiary teaching hospital in the Philippines. Methods Data were collected from the University of Santo Tomas Hospital in 2015 to 2018 from different specialties, including the Pathology Department. All information gathered were kept confidential in respect to the data privacy act. Results A total of 1618 thyroid specimens were sent for histopathologic examination from 2015-2018 and 35.6% (n = 576) of these were malignant. Fine needle aspiration was the most frequent form of biopsy done. Eight hundred eighty patients underwent thyroidectomy and 43% (n = 378) of them had malignancy based on final histopathology. Eighty one percent (81%) were females and 19% were males. The most common type of malignancy was papillary thyroid carcinoma (74.6%), followed by papillary microcarcinoma (18.4%), follicular carcinoma (4.8%), anaplastic carcinoma (0.7%), squamous cell (0.7%) and poorly differentiated carcinoma (0.9%). The most frequent subtype of papillary carcinoma seen was the conventional type (31.7%). Majority of the patients had no extrathyroidal extension (41%), no lymphovascular invasion (38%), had clear margins (70%) and had no lymph node involvement (21%). Of the patients diagnosed with papillary and follicular carcinoma and papillary microcarcinoma, 30% underwent RAI in the same institution. There were 17 patients who underwent radiation therapy, mostly for palliative intent because of RAI-refractory disease. There was one case who underwent concurrent chemoradiation for anaplastic thyroid carcinoma. Conclusions This study showed that one-third of thyroid specimens received in the institution turned out to be malignant, with papillary carcinoma still the most frequent type. Total thyroidectomy is the most common form of curative surgery done. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Within the spectrum of lymphoproliferative malignancies, Hodgkin and Non-Hodgkin Lymphomas (NHL) are amongst the most common lymphoid cancers. The objective of this study is to describe the clinical profile and treatment outcomes of patients with lymphoma seen at a tertiary institution. A total of 135 lymphoma patients were included in the analysis. Total of 23 (17.04%) subjects had a diagnosis of HL, while 112 (82.96%) subjects had NHL. The median age at diagnosis was 59 years (18-86 years). There were a total of 51 males and 67 females (ratio 0.76:1). Among patients with HL, the most frequent stage at diagnosis was stage IV (35%), same incidence was obtained with NHL (44%) at Stage IV at diagnosis. The most common first-line chemotherapy used for HL was ABVD (96%), while for NHL was CHOP (34%). Both for HL and NHL, 48% achieved complete response after first-line chemotherapy. The most frequent second-line treatment given in HL were BV, COPP and ICE (all 9%), while that for NHL was R-COP (4%). The PFS for HL is 87% and for NHL is 67.9%, while the OS achieved for HL is 91.3% and for NHL is 90.2%. The results of the analysis showed that the outcome of patients receiving chemotherapy in a developing country has similar outcome as developed countries.

Patients with primary immune thrombocytopenia (ITP) from the Asia-Pacific region often exhibit characteristics distinct from those of patients from the West. Moreover, as the region itself is heterogeneous, the ITP landscape among individual Asia-Pacific countries can be diverse. The recently released international consensus report on ITP places new emphasis on ITP, but does not address the unique ITP landscape in the Asia-Pacific region, which is home to 60% of the world’s population. In an attempt to characterize how the ITP landscape differs between the West and the Asia-Pacific region, an expert panel with representatives from Northeast Asia, Southeast Asia, and Australia was convened. Important differences were identified between the guidance provided in the international consensus report and experience in the Asia-Pacific region, namely diagnostic practices, incidence and approach to ITP secondary to H. pylori infection, systemic lupus erythematosus-related ITP, the use of bone marrow examination, initial treatment strategies, and the role of splenectomy, rituximab, and thrombopoietin receptor agonists.

Background: In RERISE phase 3 study, radotinib demonstrated significantly higher and faster rates of major molecular response (MMR) than imatinib in patients with newly diagnosed CML-CP. By 36 months follow up, MMR (BCR-ABL1IS ≤ 0.1%) and MR4.5 (BCR-ABL1IS ≤ 0.0032%) in radotinib 300 mg twice daily (bid) were higher than imatinib group. Also, early molecular response (EMR) at 3 months could predict better long term outcomes in both radotinib and imatinib groups. Here, authors updated 48 months long-term benefits and risks of 300mg bid and imatinib 400mg qd from RERISE phase 3 study (NCT01511289). Methods: RERISE study was randomized trial of radotinib 300 mg bid (n=79), radotinib 400 mg bid (n=81), or imatinib 400 mg once daily (qd) (n=81) in patients with newly diagnosed CML-CP. We evaluated long-term MMR and MR4.5, overall survival (OS), and progression-free survival (PFS) including safety data by 48 months. Results: At the study completion, 53% of patients with radotinib and 44% of patients with imatinib treated were remained. MMR and MR4.5 continued to be higher in patients receiving radotinib 300 mg bid compared with imatinib 400mg qd (Table). Especially, MMR rate by 48 months was significantly higher for radotinib compared to imatinib (76% vs 56%; P=0.0070, Figure). Also, early molecular response (EMR) at 3 months were observed in 86% of patients in the radotinib 300 mg bid group and 68% in the imatinib group (P = 0.0179). More patients treated with radotinib 300mg bid who had EMR at 3 months achieved MMR and MR4.5 by 48 months: 84% and 53% in the radotinib 300 mg bid group and 71% and 44% in the imatinib group, respectively. 48 months estimated OS and PFS rate were not significantly different in two groups (99% vs 94%; P=0.3224, 97% vs 94%; P=0.4328). Treatment failure was lower in radotinib group compared with imatinib group (Table). The safety profiles were consistent with those previously reported and most of adverse events (AEs) developed within 12 months. No new or unexpected safety events were reported in both arms by 48 months and no serious CVE related with radotinib reported. Conclusions: With a minimum 48 months follow-up, radotinib continued to demonstrate higher rates of MMR and MR4.5 than imatinib in newly diagnosed CML-CP. Also, these responses with radotinib were earlier and deeper compared with imatinib. Up to 48 months, no new and serious safety events related with radotinib reported. These results demonstrate that radotinib may have higher possibility of treatment- free remission (TFR) on frontline therapy as well as it can be one of the standards of care in newly diagnosed CML-CP. Figure. Figure. Disclosures Bunworasate: IL-YANG: Research Funding. Comia:IL-YANG: Research Funding. Mun:IL-YANG: Research Funding. Caguioa:IL-YANG: Research Funding. Kim:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Ilyang: Research Funding.

Overexpression of the epidermal growth factor receptor-related gene ErbB2 occurs in 18% to 25% of patients with breast cancer in Western countries and is associated with a poor prognosis. The prevalence of ErbB2-positive tumors in Asia is unclear, partly because data are limited. The objective of this review was to summarize the reported prevalence of ErbB2-positive tumors from a large sample of Asian patients and to examine ErbB2 assessment methods in Asia. From searches of MEDLINE, local language journals, and local and international conference proceedings as well as locoregional breast cancer experts' recommendations, the authors selected up to 5 studies each from India, Korea, Malaysia, the Philippines, Singapore, Taiwan, and Thailand that reported ErbB2 results based on assessment with immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH). The reported prevalence of ErbB2-positive tumors in 22 studies on 24,671 patients, of whom 14,398 patients were assessed for ErbB2 status, varied widely (range, 6%-65%) as did the assessment methods used. Most studies (n = 21) used IHC to assess ErbB2 status, but definitions for positivity varied. When robust assessment methods were used, the median prevalence was 19% based on strong IHC staining (IHC3+; n = 9812 patients) and 25% based on FISH (n = 681 patients). Data on the prevalence of ErbB2-positive breast cancer in Asia are limited. The current survey indicated that the prevalence in Asia may be similar to that in Western countries; thus, up to 1 in 4 Asian patients with breast cancer potentially could benefit from ErbB2-targeted treatment. A standard, reliable ErbB2 assessment method available to patients across Asia is urgently required. Cancer 2010;116:5348–57. © 2010 American Cancer Society.

Resistance and intolerance to imatinib are of particular clinical relevance to Asian patients because of their lower body surface area. Dasatinib is 325-fold more potent than imatinib in inhibiting BCR-ABL in vitro and is indicated for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant or intolerant to imatinib. Data from a series of phase I/II research trials were analyzed to compare the efficacy, safety and pharmacokinetic profile of dasatinib 70 mg twice daily in Asian and non-Asian patients. Results from 55 Asian and 615 non-Asian patients demonstrated that the efficacy and safety of dasatinib was comparable. Dasatinib was well tolerated, with no observed toxicities exclusive to Asian patients. A higher incidence of adverse events and lower rate of response observed among Asian patients with myeloid blast phase CML reflected the aggressive nature of the disease. Analyses of noncompartmental pharmacokinetics (5 Asian and 49 non-Asian patients) and population pharmacokinetics (17 Asian and 382 non-Asian patients) were also comparable. The efficacy, safety and pharmacokinetic profile of dasatinib 70 mg twice daily is similar in Asian and non-Asian patients with CML. Dasatinib is therefore an important therapeutic option for this patient population.

e20580 Background: Lung cancer is the most commonly diagnosed cancer worldwide and its incidence continues to grow. Lung cancer mortality and survival rates vary markedly by race and ethnicity resulting into a public health burden that differs by population subgroups. This study determined the association of the clinical profile, pathological characteristics and mutational profile with the disease outcome of Non Small Cell Lung Cancer patients at the Benavides Cancer Institute – University of Santo Tomas Hospital from January 1, 2007 to December 31, 2011. Methods: This is a retrospective descriptive study. Medical records of all of patients diagnosed with non-small cell lung cancer were included. Results: A total of 80 patients with non small cell lung cancer were treated, 78.75% (63) were adenocarcinoma and 13.75% (11) were squamous cell carcinoma. Overall 5-year survival rate was at 5%. The 1 year, 2-year, 3-year survival rates were 38.75%, 21.25% and 12.5% respectively with the mean survival time of 1.6 years. The mean survival time of patients who received adjuvant treatment was 26 months, while for metastatic patients was 18 months. Only the stage at time of diagnosis was correlated with overall survival. Age, gender, family history, smoking history, number of pack years smoking history, histologic subtype, response after first line of treatment and sites of metastases were not associated with overall survival. EGFR mutational analysis was not performed in this study since it was not the standard of care and had limited availability in low to middle income countries at the time of the study period. Conclusions: Similar to global incidence, adenocarcinoma remains the most common type of lung cancer in our center. Stage at diagnosis predicts overall survival among lung cancer patients. There is a need for molecular immunotyping to further characterize patients and response to treatment.

Introduction: Myelofibrosis is characterized by bone marrow fibrosis, cytopenias and extramedullary hematopoiesis. Ruxolitinib is a Janus Kinase-2 inhibitor recently approved for myelofibrosis. In the Philippines, it was made available through the compassionate use program. Methods: This is a multicentre, retrospective case series of eleven patients in the compassionate use program and eleven age-matched historical controls on best available therapy. Results: The median age was 54.5+7.33, 82% females. Using the International Working Group on Myelofibrosis Research and Treatment (IWG-MRT) consensus criteria of 2013, 1 out of the 11 patients had both spleen response and anemia response, achieving transfusion independence for > 12 weeks. Nine patients experienced clinical improvement specifically spleen response. Decrease in spleen size was seen in the first 3 months of ruxolitinib use with a mean of 53.5% from baseline. Hematologic toxicities were anemia and thrombocytopenia while nonhematologic were gastrointestinal disorders 5(45%) and hepatic dysfunction 4(36%). These patients were matched by age with historical controls on best available therapy. There was a remarkable decrease in spleen size with ruxolitinib (53.5%) compared to BAT group (18% from baseline). Thrombocytopenia and anemia occurred more frequently in the ruxolitinib group. Conclusion: Ruxolitinib is a viable treatment option for Intermediate-2 to high risk myelofibrosis with massive splenomegaly. Anemia and thrombocytopenia were common hematologic toxicities during therapy.

Breast cancer is a clinically heterogeneous disease. Approximately 10–15 % of breast cancer patients develop distant metastases within 2 years of diagnosis with a poor 5-year survival rate of 21 %. Little data have been gathered about how some breast cancer metastasizes earlier than expected. The study aimed to identify predictors of distant metastases among breast cancer patients in relation to their clinical and tumour characteristics. The results of the study may have important implications in our understanding of the disease process allowing more aggressive treatment and monitoring of certain subgroups of patients. Retrospective review of 215 patients (54 % early stage and 46 % locally advanced stage) who fulfilled the specified criteria was performed. Twelve variables were considered. Univariate and multivariate logistic regression analyses were performed to identify independent predictors of developing distant metastasis within 24 months after surgery and adjuvant therapy. Of the 215 patients, 27.9 and 17.7 % developed bone and visceral metastasis, respectively. Bone metastasis was significantly dependent on stage, tumour size, lymph node involvement, lymphovascular invasion, estrogen receptor, progesterone receptor and Her/2-neu pattern (p

[Graphic][1] Background Radotinib is a second generation BCR-ABL1 tyrosine kinase inhibitor (TKI) developed by IL-YANG Pharm. Co., Ltd (Seoul, South Korea) and approved by the Korea FDA for the treatment of chronic phase chronic myeloid leukemia (CML-CP) patients who have failed prior TKIs. We conducted the randomized, open-label, phase 3 study to assess the efficacy and safety of radotinib, as compared with imatinib, for the first-line treatment of newly diagnosed CML-CP. Methods Based on baseline demographics and Sokal risk score, 241 patients were randomized 1:1:1 to radotinib 300 mg twice daily (bid) (n=79), radotinib 400 mg bid (n=81), or imatinib 400 mg once daily (qd) (n=81). The primary endpoint was the rate of major molecular response (MMR) by 12 months and molecular response was assessed by RQ-PCR at baseline and every 3 months. Secondary endpoints were the rate of complete cytogenetic response (CCyR), MR4.5 by 12 months, and the rate of progression to accelerate phase or blast crisis. Results All three study groups were well balanced with baseline age, gender, race and Sokal risk score. With minimum follow-up of 12 months, the proportions of patients receiving a study drug were 86.3% (69/79) in radotinib 300 mg bid group, 71.6% (58/81) in radotinib 400 mg bid group, and 81.5% (66/81) in imatinib 400 mg qd group. By 12 months, rates of MMR were significantly higher in patients receiving radotinib 300 mg bid (51.9%, P = .0044) and radotinib 400 mg bid (45.7%, P = .0342) compared with imatinib (29.6%). The median time to MMR among responders were shorter on radotinib 300 mg bid (5.7 months) and radotinib 400 mg bid (5.6 months) than imatinib group (8.2 months). The MR4.5 rates by 12 months were also higher for both radotinib 300 mg bid (15.2%) and 400 mg bid (13.6%) compared to imatinib (8.6%). The CCyR rates by 12 months were also higher for radotinib 300 mg bid (91.1%, P = .0120) compared with imatinib (76.5%). There was no progression to accelerated phase or blast crisis in all groups by 12 months. Discontinuation due to adverse events (AEs) or laboratory abnormalities occurred in 7 (8.8%), 16 (19.8%), and 5 (6.2%) patients for radotinib 300 mg bid, radotinib 400 mg bid and imatinib, respectively. Grade 3/4 thrombocytopenia occurred in 16.5% of patients receiving radotinib 300 mg bid, in 13.6% for radotinib 400 mg bid, and in 19.8% receiving imatinib. And grade 3/4 neutropenia occurred in 19.0%, 23.5%, and 29.6% for radotinib 300 mg bid, 400 mg bid and imatinib, respectively. The most common any grade non-laboratory AEs were skin rash (35.4% and 33.3%), nausea/vomiting (22.8% and 23.5%), headache (19.0% and 30.9%), and pruritus (19.0% and 30.0%) in radotinib 300 mg bid and radotinib 400 mg bid, respectively; AEs in the imatinib group were edema (34.6%), myalgia (28.4%), nausea/vomiting (27.2%), and skin rash (22.2%). Overall, grade 3/4 non-laboratory AEs were uncommon in all groups. Conclusions With minimum 12 months follow-up, radotinib demonstrated significantly higher and faster rates of CCyR and MMR than imatinib in patients with newly diagnosed CML-CP. The safety profiles of the radotinib and imatinib were different, and most AEs were manageable with optimal dose reduction. The results of this trial support that radotinib can be one of the standard of care in newly diagnosed CML-CP. | | Radotinib 300mg BID | Radotinib 400mg BID | Imatinib 400mg QD | | --------------------------------------------- | --------------------------- | --------------------------- | ------------------------- | | | (N=79) | (N=81) | (N=81) | | Age, median (range), years | 45 (20-75) | 43 (18-84) | 45 (18-83) | | Gender, n (%) | | | | | Male | 52 (65.8) | 47 (58.0) | 52 (64.2) | | Female | 27 (34.2) | 34 (42.0) | 29 (35.8) | | Sokal risk, n (%) | | | | | Low | 21 (26.6) | 22 (27.2) | 22 (27.2) | | Intermediate | 38 (48.1) | 38 (46.9) | 39 (48.2) | | High | 20 (25.3) | 21 (25.9) | 20 (24.7) | | MMR by 12 months, % | 51.9 | 45.7 | 29.6 | | | P = .0044 | P = .0342 | | | Cumulative Incidence of MMR by 12 months¢O, % | 57.0 | 58.0 | 35.0 | | | P = .0040 | P = .0037 | | | MR4.5 by 12 months, % | 15.2 | 13.6 | 8.6 | | CCyR by 12 months, % | 91.1 | 81.5 | 76.5 | * ¢O Kaplan-Meier estimates of MMR Table. Baseline Characteristics, Molecular and Cytogenetic Response Rates Disclosures Kim: IL-YANG Pharm. Co. Ltd: Research Funding. Kim: Alexion Pharmaceuticals: Research Funding. Chung: Alexion Pharmaceuticals: Research Funding. Choi: Alexion Pharmaceuticals: Research Funding. [1]: /embed/inline-graphic-2.gif

Background: Recent studies have demonstrated that early molecular milestones were able to identify high-risk chronic myeloid leukemia patients treated with frontline imatinib (IM) and second generation tyrosine kinase inhibitors (2G TKIs) such as nilotinib and dasatinib. However, whether a single measurement of BCR-ABL1 transcripts level after 3 months of treatment is sufficient to define failure necessitating a change of treatment is not confirmed. Radotinib (RAD) is a 2G TKI for BCR-ABL1 tyrosine kinase, which was approved by the Korea FDA for the second-line therapy, and the phase 3 study comparing the efficacy and safety of RAD 300 and 400 mg twice daily and IM 400 mg once daily in patients with newly diagnosed CP CML was performed. The aim of this study was to identify the predictive value of 3-month molecular milestone for an achievement of major molecular response (MMR) by 12 months to RAD therapy. Additionally, in the same population, predictive factors for achieving MMR by 12 months were analyzed. Methods: Among 241 patients who were enrolled in the randomized, open-label, phase 3 study of RAD, 236 patients with available 3-month qRT-PCR on study therapy [RAD 300 mg twice (n = 79), RAD 400 mg twice (n = 79), IM 400 mg once (n = 78)] were evaluated. Molecular responses were monitored using a qRT-PCR assay in 3-month intervals by 12 months. All qRT-PCR were tested with at least 4.5-log sensitivity in the central laboratory (Cancer Research Institute, The Catholic University of Korea, Seoul, Korea) and MMR was defined as a BCR-ABL1 transcript level of 0.1% or lower on the international scale (IS). Results: 236 patients (including 149 men and 87 women) with available 3-month qRT-PCR on study therapy were evaluated. With a median age of 45 years (range, 18-84 years), the distribution of low, intermediate and high Sokal risk scores were 27%, 47% and 26%, respectively. At 3 months, BCR-ABL1 ≤10% [RAD 300 mg twice (n = 68), RAD 400 mg twice (n = 69), IM 400 mg once (n = 55)] and >10% [RAD 300 mg twice (n = 11), RAD 400 mg twice (n = 10), IM 400 mg once (n = 23)] were observed. In the IM 400 mg once group, patients with BCR-ABL1 ≤10% at 3 months showed a significant higher rate of MMR by 12 months compared with that of patients with BCR-ABL1 >10% (38.2% vs 13.0%, P = 0.028). In the RAD 300 and 400 mg twice group, an achievement of 3-month EMR was associated with a higher rate of MMR by 12 months [57.4% vs 18.2%, P = 0.016 (RAD 300 mg twice) and 50.7% vs 10.0%, P = 0.018 (RAD 400 mg twice)]. After adjusting for factors affecting achievement of MMR by 12 months on univariate analyses, multivariate analyses showed that b2a2 transcript type (RR of 0.46, P = 0.023), large spleen size (RR of 0.91, P = 0.001), and no achievement of 3-month EMR (RR of 0.24, P = 0.004) were predictor for not achieving MMR by 12 months. Significance of 3-month EMR for achieving MMR by 12 months was observed in the separated treatment groups: RR of 0.24, P = 0.037 in the IM 400 mg once group, RR of 0.17 P = 0.028 in the RAD 300 mg twice group, and RR of 0.11, P = 0.040 in the RAD 400 mg twice group. Conclusions: Our results suggest that 3-month EMR can play key roles for 12-month MMR achievement in CP CML patients treated with IM and RAD. In addition, some factors for achieving 12-month MMR were detected. To evaluate the long-term prognostic value of 3-month EMR, further clinical investigations in a larger patient population with longer follow-up are needed. Disclosures Kim: IL-YANG Pharm.Co.Ltd: Research Funding. Chung:Alexion Pharmaceuticals: Research Funding.

Background Treatment options for advanced non-small-cell lung cancer are inadequate. There remains a critical need for more effective systemic therapies. Methods Forty-one patients with advanced non-small-cell lung cancer were treated on a 28-day cycle with a very high-dose, cisplatin-based three-drug regimen. A treatment cycle consisted of an intravenous (IV) injection of cisplatin 100 mg/m2 on days 1 and 8; etoposide 60 mg/m2 IV over 30 minutes on days 1, 2, 8, and 9 (cycles 1 and 3 only); and mitomycin C 8 mg/m2 IV bolus on day 1 (cycles 2 and 4 only) (PEM regimen). Results The median dose intensity of cisplatin delivered was 49 mg/m2/wk, or 98% of the planned dose. One patient achieved a complete response and 16 patients a partial response or regression, yielding an overall objective response rate of 41%. The median duration of response was 21 weeks. Median survival of all patients was 38 weeks. Neurologic toxicity was dose limiting. The frequency of peripheral neuropathy and ototoxicity was directly related to cumulative cisplatin dose. In five patients, a progressive peripheral neuropathy developed after discontinuation of cisplatin. Hematologic toxicity also was significant. Conclusions This very high-dose, cisplatin-based chemotherapy regimen has appreciable activity in advanced non-small-cell lung cancer. In comparison with previous reports on the use of very high-dose cisplatin alone, however, this combination appears at best to be only marginally more active, to confer no additional survival advantage, and to be considerably more toxic.

Chronic myeloid leukemia (CML) in Asia has an incidence rather lower than in Western countries yet tends to afflict a younger population. As in the West, imatinib mesylate (IM, Glivec) has supplanted busulphan, hydroxyurea and interferon-alpha as first-line treatment. Its use has resulted in a dramatic decline in the number of hematopoietic stem cell transplantations (HSCT) performed. Although it is expensive, IM induces a complete cytogenetic response in 60-90% of newly diagnosed patients, and up to 10% for those in blastic phase. The standard dose of 400 mg is well tolerated by most patients, although adverse events have been observed, including drug-induced cytopenia. Through the Glivec International Patient Assistance Program, the majority of CML patients has access to IM and can expect prolonged survival, even in the absence of HSCT. However, just as in Western countries, resistance to imatinib has emerged in Asian countries. They will require the novel tyrosine kinase inhibitors (dasatinib, nilotinib) becoming available through either clinical trials or market approval. This review examines the available data on CML in China, Hong Kong, India, the Philippines, Singapore, South Korea, Taiwan and Thailand.

Background KW-2478 is a potent Hsp 90 inhibitor that binds to Hsp 90 with an IC50 value of 3.8 nmol/L. In preclinical studies, KW-2478 inhibited the in vitro growth of myeloma cell lines at GI50 values of 0.12 – 0.39 µM and markedly inhibited the growth of myeloma xenografts in SCID mice in a dose-dependent manner. In vitro, KW-2478 and BTZ demonstrated synergistic activity against OPM-2/GFP cells and in the NCI-H929 xenograft model, the combination of KW-2478 and BTZ showed greater anti-growth activity than either agent alone. A single-agent Phase 1 study (KW-2478 administered daily x 5 every 14 days), showed no dose limiting toxicity (DLT) and Hsp90 inhibition was observed at doses >71 mg/m2. Aim To establish safety, tolerability and recommended Phase 2 dose (RP2D) of KW-2478 plus BTZ in pts with R/R myeloma and assess overall response rate (ORR) based on International Myeloma Working Group (IMWG) response criteria. The PK and PD of KW-2478 plus BTZ were characterized and progression-free survival (PFS) was investigated. Methods All patients had MM by IMWG criteria, had received at least 1 and no more than 3 prior MM regimens and had not responded or had relapsed, and had adequate renal function. Patients who received prior BTZ could not be refractory. This open-label study had 2 parts: A Phase 1 dose escalation (3 + 3 design) part followed by a Simon 2-stage Phase 2. KW-2478 and BTZ were administered on Days 1, 4, 8 and 11 of a 21-day cycle. In Phase 1, the doses of KW-2478 and BTZ were sequentially escalated until observation of DLT, MTD, or achievement of the maximal planned dose levels (KW-2478 175 mg/m2, BTZ 1.3 mg/m2). PK and PD samples were collected in C1 on Days 1 and 11, and Days 1, 4, 8, and 11, respectively. In Phase 2, if 11 or more responses were observed in the first 27 evaluable pts, then an additional 50 evaluable pts would be enrolled. Response was assessed at the end of each cycle and safety was assessed continuously. Results The study enrolled 95 pts who received at least one dose of study drug: 15 in Phase 1 and 80 in Phase 2; 86 pts received the RP2D (highest planned dose of KW-2478 175 mg/m2 /bortezomib 1.3 mg/m2). Median age was 65; 57% of pts were male. There was 1 DLT (presyncope) in Phase 1. The most common adverse events (AEs) were diarrhea (74%), nausea (61%), fatigue (55%), constipation (46%), vomiting (40%) and peripheral neuropathy (30%). Most AEs were Grade 2; 5 pts had Grade 4 AEs. Five pts had a Grade 4 thrombocytopenia and 3 pts had a Grade 4 neutropenia. The PK profiles for KW-2478 plus BTZ in combination were comparable to each agent’s individual PK profile. In the Phase 1 portion of the trial, Hsp70 levels, a marker of Hsp90 inhibition, increased in the peripheral blood mononuclear cells in all subjects (N = 13). Of the pts who received the RP2D, 79 pts were evaluable for IMWG response. The ORR was 39% (4% CR, 14% VGPR, and 22% PR); in pts who were bortezomib naïve (n = 50), the ORR was 48%. Median PFS was 26.4 weeks and median duration of response had not been reached at the time of this report. Six pts continue treatment at the time of data cut-off. Conclusions KW-2478 plus BTZ was well-tolerated when administered at the doses and schedule studied. Clinical activity was demonstrated in pts with R/R MM (ORR of 39%). PFS was 26.4 weeks Disclosures: Akinaga: Kyowa Kirin Pharmaceuticals: Employment, Equity Ownership. Kurman:Kyowa Kirin Pharmaceuticals: Consultancy. Novak:Kyowa Kirin Pharmaceuticals: Employment.

629 Background: CT-P6(C) is an anti-HER2 MoAb, a biosimilar to trastuzumab (T). This trial is a global phase III study to compare C with T, both in combination with paclitaxel (P) as first-line treatment in women with HER2+ MBC. Methods: 475 patients with centrally confirmed HER2+ MBC were randomized to receive either C+P (n=244) or T+P (n=231). Patients had to have a baseline LVEF ≥50% and no history of serious cardiac disease. Study medication was as follows: C or T 8 mg/kg i.v. (day 1), followed by 3-weekly C or T 6 mg/kg. P (175 mg/m23-weekly) was co-administered. The primary endpoint was overall response rate (ORR) as determined by independent review. Pooled analysis with data from phase I/IIb (NCT01084863) and III studies (NCT01084876) was predefined and endorsed by the EMA. Patient safety was monitored throughout the study by an independent data monitoring committee. Treatment was continued until disease progression, death or patient’s withdrawal. Results: In the pooled ITT population, ORR was 57% for C+P and 62% for T+P (difference: 5%; 95% CI: -0.14, 0.04) during the first 8 cycles of treatment. The limits of the 95% CIs for the difference in the proportions of responders were contained within the pre-defined range [-0.15, 0.15] required for equivalence. Median time to progression and median time to response were 11.07 vs. 12.52 months (P =0.10), and 1.38 vs. 1.38 months (P =0.37) for C+P and T+P, respectively. Frequency of treatment-related AEs is shown in the Table. Conclusions: Equivalence of C and T was observed for ORR in patients with HER2+ MBC in combination with P as first-line therapy. Secondary efficacy endpoints also supported the comparability between C and T. C was well tolerated with a safety profile comparable to that of T. Clinical trial information: NCT01084876. [Table: see text]

PURPOSE A phase I trial in patients with refractory hematologic malignancies was performed at our institution to test the clinical relevance of the selective cytotoxic activity of the interleukin-2 (IL-2)-diphtheria toxin fusion protein, DAB486IL-2. A subset of five patients from this trial, all with cutaneous T-cell lymphomas (CTCL), forms the basis of this report. PATIENTS AND METHODS Two treatment schedules were used. One patient received DAB486IL-2 at a dose of 0.075 mg/kg/d intravenous (i.v.) bolus over 15 minutes daily for 5 consecutive days. The other four patients received DAB486IL-2 at a dose of 0.1 mg/kg as an i.v. infusion over 180 minutes weekly for 5 consecutive weeks. RESULTS Three of the five CTCL patients achieved significant tumor responses. One patient attained a complete clinical and pathologic response (CR), which has been sustained without any interval treatment for 33+ months. Two other patients achieved partial responses (PRs) of 17+ and 4 months' duration, respectively. Treatment was well tolerated. The most common adverse effect was a transient increase in hepatic transaminases experienced by all five patients. CONCLUSION The growth factor-cytotoxin fusion protein DAB486IL-2 demonstrated significant clinical activity with acceptable toxicity in a group of heavily pretreated patients with CTCL.

e22164 Background: Breast cancer incidence is increasing throughout Asia. However, the characteristics of Asian breast cancer are not always well understood due to the limited availability of local data and their inadequate inclusion in global literature databases. Effective breast cancer treatment in this region requires a better understanding of Asian breast cancer biology, including ErbB2 status. Methods: We performed a literature search in seven Asian countries on breast cancer studies in which tumour ErbB2 overexpression was assessed. The keywords erbB2 OR HER2 OR ErbB-2 OR HER-2 AND breast cancer AND (country) were used to search PubMed, international and local conference abstracts and local-language journals from the year 2000 onwards. Where available, we selected up to five representative studies from each country on the basis of population size, multi-institution patient populations, institution reputation and journal impact factor. We excluded studies containing only mRNA, serum, or cell line data or those conducted on biased populations or in western countries on Asian populations. Results: ErbB2 data from 26 Asian breast cancer studies are summarized in the table . The mean or median age of the study populations ranged from 46–56 years, with one exception. In most studies that evaluated tumour ErbB2 and hormone status, ErbB2 over-expression correlated negatively with ER positivity. Conclusions: The larger studies in particular confirm that the proportion of ErbB2-positive breast cancer in Asia is generally similar to the 20–30% reported for western women. Definitions of ErbB2 positivity using IHC vary between institutions and FISH is not routinely performed in several Asian countries. This may contribute to the fact that reliable, representative data on breast tumour ErbB2 status is scarce in Malaysia, the Philippines, India and Thailand. The increased availability of accurate ErbB2 testing and data would aid improved treatment of ErbB2-positive breast cancer in these countries. [Table: see text] [Table: see text]