Background:This study was designed to compare cisplatin/docetaxel with oxaliplatin/docetaxel in patients with advanced and metastatic non-small lung cancer as a first-line treatment.Methods:Patients were randomly assigned to receive either cisplatin 75 mg m−2 and docetaxel 75 mg m−2 every 3 weeks or oxaliplatin 85 mg m−2 and docetaxel 50 mg m−2 every 2 weeks. The primary end point was response rate, and secondary end points were toxicity, time to progression and overall survival.Results:A total of 88 patients (median age: 65 (39–86) years; stage IV: 93%) were randomly assigned. Response rate (complete and partial response) was 47% (95% CI: 33–61%) in the cisplatin/docetaxel arm and 28% (95% CI: 17–43%) in the oxaliplatin/docetaxel arm (P=0.118). There was no significant difference in time to progression (6.3 vs 4.9 months, P=0.111) and median overall survival (11.6 vs 7.0 months, P=0.102) with cisplatin/docetaxel vs oxaliplatin/docetaxel, although slight trends favouring cisplatin were seen. Oxaliplatin/docetaxel was associated with significantly less (any grade) renal toxicity (56% vs 11%), any grade fatigue (81% vs 59%), complete alopecia (76% vs 27%), any grade leukopenia (84% vs 61%) and grade 3/4 leukopenia (44% vs 14%) and neutropenia (56% vs 27%).Conclusion:Oxaliplatin/docetaxel has activity in metastatic non-small cell lung cancer, but it seems to be inferior to cisplatin/docetaxel.
Background: Mantle cell lymphoma (MCL) is characterized by a recurrent chromosomal translocation t(11;14) that leads to aberrant expression of Cyclin D1 which, together with cyclin dependent kinases 4 and 6 (CDK4/6), inhibits the retinoblastoma (Rb) tumor suppressor protein and thereby induces malignant proliferation. Abemaciclib, a cell cycle inhibitor selective for CDK4/6 (Gelbert et al, 2014), has shown single agent clinical activity against multiple human tumors including lung cancer and breast cancer (Shapiro et al, ASCO 2013; Goldman et al, ASCO 2014; Patnaik et al, ASCO 2014). Based on molecular pathogenesis and single agent activity in preclinical models of human MCL, abemaciclib was evaluated in a single arm Phase II study for patients with relapsed or refractory MCL. Methods: The primary objective of this study was to estimate the disease control rate, which includes response (complete + unconfirmed complete + partial) plus stable disease, for patients who received abemaciclib for relapsed or refractory mantle cell lymphoma (MCL). Patients were scheduled to receive abemaciclib (200 mg) orally every 12 hours on Days 1 through 28 of each 28-day cycle. Eligibility criteria permitted an unlimited number of prior systemic therapies including high dose chemotherapy with stem cell transplantation, Eastern Cooperative Oncology Group (ECOG) performance status <= 2, absolute neutrophil count >= 1.5 x 109/L, and platelets >= 75 x 109/L. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 were used to grade adverse events. Response Criteria for Non-Hodgkin’s Lymphomas (Cheson et al, 1999) were used to assess clinical activity. Plasma samples for pharmacokinetics were performed both after a single oral dose and after multiple doses at steady state. Flow cytometry was used to isolate circulating MCL cells for evaluation of pharmacodynamic effect on Rb phosphorylation. Results: In this Phase II study, 22 patients with relapsed or refractory MCL received single agent oral treatment with abemaciclib. Among these patients, 91% presented at initial diagnosis with Stage III or IV disease. At the time of study entry, these patients (9 female and 13 male) had a median age of 66 years (range: 53-83), 59% had ECOG performance status of 1 or 2, and all patients had constitutional B symptoms. Eighteen patients received >= 2 prior systemic therapies, and previous treatments for the overall study population included not only high dose chemotherapy with stem cell transplantation but also rituximab (96%), cyclophosphamide-based therapy (86%), cytarabine-based therapy (64%), temsirolimus (55%), and bendamustine (41%). Patients received 1-16 cycles of treatment with abemaciclib and 8 of 22 patients (36%) completed >= 6 cycles. The most common possibly related treatment-emergent adverse events across all grades included diarrhea (55%, including 9% G3/4), nausea (23%, with no G3/4), vomiting (32%, with no G3/4), fatigue (18%, with no G3/4), thrombocytopenia (55%, including 32% G3/4), neutropenia (36%, including 32% G3/4), and anemia (18%, with no G3/4). Plasma concentrations of abemaciclib were comparable to those previously observed and associated with clinical activity in patients with advanced non-hematologic malignancies. For patients with at least one post-treatment radiographic evaluation, preliminary investigator assessment indicates that single agent therapy with abemaciclib was associated with stable disease for 9 patients and partial response for 5 patients, including durable disease control (>= 6 cycles) in 8 of these 14 patients with relapsed or refractory MCL. Conclusions: Abemaciclib, a cell cycle inhibitor, demonstrates evidence of durable disease control as a single agent for patients with relapsed or refractory MCL. Disclosures Hahka-Kemppinen: Eli Lilly and Company: Employment, Equity Ownership. Xiaohui Wang:Eli Lilly and Company: Employment. Brueck:Eli Lilly and Company: Employment. Caldwell:Eli Lilly and Company: Employment. Beckmann:Eli Lilly and Company: Employment, Equity Ownership. Gelbert:Eli Lilly and Company : Consultancy. Cronier:Eli Lilly and Company: Employment. Lin:Eli Lilly and Company: Employment. Li:Eli Lilly and Company: Employment. Chan:Eli Lilly and Company: Employment, Equity Ownership. Pfreundschuh:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boerhinger Ingelheim: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Research Funding.
Background: Mutations in the kinase domain (KD) of BCR-ABL are the predominant cause of acquired imatinib (IM) resistance in patients with CML and have also been detected at relapse in patients with advanced Ph+ ALL. The contribution of various known KD mutations to IM resistance of advanced or newly diagnosed Ph+ALL receiving different IM-based treatments has not been determined, however. We therefore studied the mutation frequency at relapse in 94 patients receiving IM-based therapy for advanced or newly diagnosed Ph+ALL or CML in lyBC using cDNA sequencing. To further investigate the frequency, distribution and prognostic significance of ABL mutations, we retrospectively analyzed bone marrow (BM) samples that had been collected pre-treatment and serially throughout IM therapy from patients by using RT-PCR based denaturing HPLC-assay. Methods: 94 pts. enrolled in a) the initial phase II trials of IM monotherapy for advanced Ph+ALL(n=57) and CML lyBC (n=9) or b) in a GMALL study of elderly pts. (>55 yrs.) with de novo Ph+ALL receiving IM in combination with chemotherapy (n=17) or c) in a GMALL study of younger pts. with de novo Ph+ALL receiving IM-based induction therapy (n=11) were screened at the time of relapse. BM and/or PB samples collected at the time of relapse were analyzed by direct sequencing of the abl KD. Samples collected pre-treatment and serially throughout IM were analyzed by denaturing HPLC. Results: Mutations were detected in 52 of 94 pts (55%). In the phase II trials of IM monotherapy, 32/57 Ph+ALL-pts. (56%) and 4/9 (44%) pts. with lyBC developed a mutation. Mutation frequency in elderly Ph+ALL pts. with de novo Ph+ALL was 82% (14/17). The overall frequencies of these mutations were: Y253F/H (n=12), Q252H (n=6), E255K (n=21), G250E (n=5), M248V(n=3) in the P-loop region and T315I (n=11) - a mutation in direct contact with IM. Only 1 mutation in the catalytic domain (F359V) and 3 mutations in the activation loop (H396R (n=2), L384M) were observed. In 13 pts. (25%) more than 1 mutation was detected. Comparison of patients with p190 bcrabl and p210 bcrabl revealed no significant difference in either the frequency or profile mutations. In pts. harbouring the T315I mutation, it was possible to detect the mutation upfront with dHPLC (sensitivity 0.5%). Summary: In Ph+ALL clinical resistance to IM is associated with a high frequency of abl KD mutations, with conspicuous predominance of mutations located in the P-loop, most of which confer high level resistance to IM. In addition in 20% of pts. The T315I mutation was detected which confers absolute resistance to IM as well as to 2nd generation ABL TK inhibitors in clinical development. The mutation profile is similar in pts. with advanced leukemia treated with IM monotherapy and in pts. with de novo Ph+ALL receiving IM in combination with chemotherapy.
Decisions on palliative chemotherapy (CT) for advanced gastric cancer require trade-offs between potential benefits and risks for patients. Healthcare providers and payers agreed that patient preferences should be considered. We conducted a CBC study in patients with mGC or mGEJ-Ca from Germany to evaluate their preferences when trading-off between treatment tolerability, quality of life and survival benefit. METHODS: German oncologists were contacted to identify patients with mGC or mGEJ-Ca who had completed ≥ 2 cycles of palliative CT (ongoing or completed). The primary objective was the quantitative evaluation of patient preferences for palliative CT in this population by CBC analysis. The CBC matrix, developed based on 6 in-depth qualitative interviews, spanned the 3 attributes ability to self-care as a key component for quality of life, treatment toxicity and survival benefit (3-4 factor levels each, 15 iterations). A minimum of 50 participants was needed. Eligible consenting patients completed the 45min standardized CBC-survey, choosing systematically among profiles. CBC models were estimated by mixed-logit regression (MLR) and hierarchical Bayes analysis (HB). Estimates of importance for each attribute and factor-level were calculated. RESULTS: Overall, 55 patients participated in the survey (78% male, median age 63yrs, 82% currently receiving CT). Patients considered low treatment toxicity as most important (45% relative importance, MLR analysis), followed by ability to self-care (32%) and an additional survival benefit of up to 3 months (3 months 23%, 2 months 18%, 1 month 11%). The MLR analysis showed high validity (certainty 37.9%, chi square p< 0.01, root likelihood 0.505). The HB analysis yielded similar results. CONCLUSIONS: Patient preferences related to palliative CT of gastric cancer can appropriately be assessed by CBC analysis. Though patients' varied experiences with chemotherapy may have impacted specific responses, across the population of patients with mGC or mGEJ-Ca improved treatment tolerability and quality of life were ranked highest.
Background: In Ph+ALL, responsiveness to single-agent imatinib (IM) is determined by the disease stage: whereas more than 90% of pts. with newly diagnosed Ph+ALL achieve a complete remission (CR), the CR rate in patients who failed previous chemotherapy is only 20–30%, with a median time to progression of only 2.2 months. Approximately 80% of pts. with Ph+ALL who relapse during IM-based therapy express a BCR-ABL Tyrosine Kinase Domain (TKD) mutation known to confer high-level IM resistance. We recently showed that in 30– 40% of pts. with de novo Ph+ALL, the same mutation found at relapse is already detectable at a low level prior to first IM exposure; in conjunction with the high response rate, this finding indicates limited growth kinetics of the mutant BCR-ABL clones. To elucidate the reasons for the low CR rate observed in advanced Ph+ALL receiving IM salvage therapy, we compared the frequency and type of up-front mutations, the level of mutant clones, and the outgrowth kinetics of mutations during the first 4 weeks of IM monotherapy in de novo Ph+ALL pts. and in pts. who had failed prior chemotherapy. Patients and methods: We employed denaturing high-performance liquid chromatography (D-HPLC) and cDNA sequencing to examine bone marrow and/or peripheral blood samples collected pre-treatment, during therapy and at the time of relapse from 54 pts. with newly diagnosed Ph+ALL (>55 yrs.) enrolled in a GMALL study of combined IM and chemotherapy (n=48) or treated analogously (n=6) and from 67 Ph+ALL pts. who were enrolled in the initial phase II studies of single-agent IM as salvage treatment after prior chemotherapy. Results: Prior to first IM exposure, TKD mutations were detected in 33% (21/63) of pts. with advanced Ph+ALL and 31% (9/29) of pts. with de novo Ph+ALL. The incidence of mutations observed at relapse was substantially higher but did not differ significantly between the two cohorts: 70% in pts. with advanced disease who relapsed on IM monotherapy (33 of 50 pts.; P-loop 48%, T315I 16%, A-loop 2%) and 84% in de novo ALL pts. (n=26), treated with combination therapy (P-loop 46%, T315I 15%, A-loop 9,5%). In contrast, the outgrowth of cells expressing mutated bcr-abl during the first four weeks of IM therapy was considerably more rapid in Ph+ALL pts who had failed prior chemotherapy: mutations were detected after 2 and/or 4 weeks IM in only 44% of patients (8/18 evaluable) with newly diagnosed Ph+ALL, whereas 69% of patients (27/39) with advanced Ph+ALL expressed mutant BCR-ABL on at least one of these timepoints. Moreover, the percentage of mutated BCR-ABL was below 1% in all 8 pts. with a mutation in the former cohort (de novo Ph+ALL), but higher than 5% (range: 5 – 100) in 16 of the 27 advanced disease pts (59%) who had a TKD mutation. Conclusions: In Ph+ALL, the incidence, distribution pattern and level of TKD mutations detected prior to - or at relapse on - IM does not differ between pts with newly diagnosed leukemia and those having failed prior chemotherapy. In contrast, patients with advanced disease are characterised by considerably more rapid outgrowth kinetics of leukemic cells expressing BCR-ABL mutations, providing clinical-translational evidence for a cooperative effect between mutational and non-mutational resistance mechanisms.
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