bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II trial of bicalutamide in combination with palbociclib for the treatment of androgen receptor (+) metastatic breast cancer.
Authors: Gucalp Ayca , Boyle Leigh Ann , Alano Tina , Arumov Artavazd , Gounder Mrinal M. , Patil Sujata , Feigin Kimberly , Edelweiss Marcia , D'Andrea Gabriella , Bromberg Jacqueline , Goldfarb Shari Beth , Ligresti Louise , Wong Serena Tsan-Lai , Traina Tiffany A. 
Published: May 2020

1017 Background: Genome-wide transcriptional analysis has identified a unique subset of androgen receptor (AR) +, estrogen receptor (ER)/progesterone receptor (PR)- breast cancer (BC). The functional role of AR was confirmed initially in preclinical models demonstrating that androgen-driven growth could be abrogated by antiandrogen therapy. TBCRC011 established the safety and efficacy of inhibiting AR with bicalutamide (B) in patients (pts) with AR+/ER/PR- metastatic BC (MBC) with a median progression free survival (PFS) of 12 weeks (wks) (95% CI, 11–22 wks). In preclinical data, palbociclib (P) has been shown to reduce growth of AR+/ER/PR- MDA-MB-453 BC cells. It has been shown that AR+ triple negative BC (TNBC) expresses a luminal profile and has intact Rb protein, the target of P activity. We conducted this Phase I/II trial of the AR inhibitor B in combination with the CDK4/6 inhibitor P in pts with AR+/ER/PR/HER2- BC (NCT02605486) to test the hypothesis that androgen blockade, paired with CDK4/6 inhibition would have increased efficacy in pts with androgen-dependent BC. Methods: Postmenopausal pts with AR+ TN MBC defined as IHC ≥ 1% nuclear staining (DAKO, Clone AR441 (5/2016-11/2016) then Ventana AR SP107 (11/2016-6/2018), ECOG ≤2, measurable/non-measurable disease were eligible for enrollment. Any number of prior regimens was permitted. Pts received B 150 mg daily and P 125 mg daily 3 wks on 1 wk off. Pts were evaluated for toxicity every 2-4 wks and for response every 8-12 wks. Primary endpoint: 6 month (mo) PFS. Secondary endpoints: clinical benefit rate, toxicity, correlative studies to better characterize AR+ TNBC. A Simon 2-stage minimax design that discriminates between 6 mo PFS rates of 20% and 40% was used. If ≥ 11/33 pts were PF at 6 mo then B+P would warrant further study. Results: As of 1.1.20 33 pts were enrolled on study with median (med) age 67 (42-79), performance status 0 (0-1). Number of pts with visceral metastases: 20, measurable disease: 22. AR% 1-9: 3, 10-50: 6; 51-100: 24. Med prior lines for MBC: 3 (0-9). Best response: (31 evaluable pts): 11 pts PF at 6mo: 10 SD > 6mo, 1 PR. Med wks on study: 14 (2-101). Toxicity > 10% grade >3 related: Number of pts with leukopenia: 21, neutropenia: 21, lymphocytopenia: 6, thrombocytopenia: 3. One pt with febrile neutropenia. One death due to disease progression within 30 days off study. Conclusions: In this selected subset of pts with AR+ TN MBC, this study met its prespecified endpoint with 11 pts PF at 6 mo on B 150 mg + P 125 mg. B+P has been well tolerated with no unexpected toxicity observed. Clinical trial information: NCT02605486 .
Clinical efficacy and molecular effects of lenvatinib (Len) and letrozole (Let) in hormone receptor-positive (HR+) metastatic breast cancer (MBC).
Authors: Lim Joline Si Jing , Wong Andrea , Ow Samuel Guan Wei , Ngoi Natalie , Ang Yvonne Li'en , Chan Gloria , Eng Lim Siew , Chong Wan Qin , Choo Joan , Lee Matilda , Tan Hon Lyn , Jan Yi-hua , Tan Kien Thiam , Sundar Raghav , Tan David Shao Peng , Soo Ross A. , Chee Cheng Ean , Yong Wei-Peng , Goh Boon C. , Lee Soo-Chin 
Published: May 2020

1019 Background: Preclinical studies show cross talk between RET and estrogen receptor, with at least additive treatment (Tx) effect of Len, a RET inhibitor, with Let. Our previous work concluded a recommended phase 2 dose (RP2D) of Len 14mg daily and Let 2.5mg daily (Lim, ASCO 2019). We present efficacy data from dose escalation and expansion cohorts. Methods: Safety, tolerability and efficacy data of MBC patients in both dose escalation (Len dose level 1 [DL]:20mg, DL -1:16mg and DL -2:14mg) and expansion (Len 14mg) cohort of this phase Ib/II study of combination Len+Let study was analysed. Patients were treated with single-agent Len for 2 weeks, followed by Len+Let until disease progression (PD). Serial tumor biopsies at baseline, after Len alone, 4 weeks post Len+Let, and upon PD, were sequenced for 440 genes with the ACTOnco+ platform. Results: A total of 33 pts (DL1 6pts, DL-1 6pts, DL-2 + expansion 21pts) with median 5 lines of prior Tx (range 0-11) were enrolled; 87.9%, 75.8%, and 75.8% had prior endocrine therapy (ET), ET+CDK4/6 inhibitor (i), and chemotherapy (CT) respectively. Objective response rate (ORR), disease control rate (DCR) ≥6 months (m), median duration of response (DOR), and percentage progression-free (PPF) at 12m were 33.3%, 45.5%, 11.5m (range 6.3-22.4), and 27.2% respectively. Among patients who previously progressed on CDK4/6i (n = 25), ORR, DCR ≥6m, median DOR, and PPF at 12m were 24.0%, 40.0%, 13.7m (range 6.3-18.2), and 12.0% respectively. Of note, 3/25 (12%) patients had durable response to Len+Let lasting ≥12m, despite having only modest PFS on ET+CDK4/6i (3, 7, and 12 months respectively). Most frequent all-grade toxicities (tox) were HTN (n = 15, G3:15), hypothyroidism (n = 20, G3:0) and fatigue (n = 13, G3:2), with no G4/5 tox. No new toxicity signals were observed compared to dose escalation phase. Pre-treatment tumor molecular profiling showed responders to be more likely to harbor NEFH, USH2A and PTCH1 mutations, while non-responders were more likely to carry PIK3R1, APC and PALB2 mutations. Sequencing of serial biopsies showed downregulation of BRD4, PTCH1, KIT, NTRK1 and CREBBP after Len treatment. Conclusions: Len+Let showed significant anti-tumor activity with meaningful duration of response, even in pts who failed prior CT or ET+CDK4/6i. The results support further investigation in randomized studies. Tumor profiling identified mutations associated with response and insights on molecular effects of lenvatinib. Clinical trial information: NCT02562118 .
Prognostic and predictive value of ESR1 mutations in postmenopausal metastatic breast cancer (MBC) patients (pts) resistant to aromatase inhibitors (AI), treated with palbociclib (PAL) in combination with endocrine therapy (ET) or capecitabine (CAP) in the PEARL study.
Authors: Martin Miguel , Zielinski Christoph , Ruiz-Borrego Manuel , Carrasco Eva Maria , Ciruelos Eva , Muñoz Montserrat , Bermejo Begoña , Vila Mireia Margeli , Turner Nicholas C. , Casas Maribel , Anton Antonio , Murillo Jaso Laura , Lang Istvan , Bartlett Cynthia Huang , Koehler Maria , Martin Nuria , Corsaro Massimo , Swift Claire , Nisenbaum Bella , Gil Gil Miguel J. 
Published: May 2020

1022 Background: Prior retrospective data has shown ESR1 mutation is an acquired resistant mechanism to AI. However, little is known about ist prognostic and predictive value to endocrine-based therapy and chemotherapy. PEARL study compared PAL+ET vs CAP in AI resistant patients. Here we wxplored prospectively the ESR1 mutational status based on updated PFS and OS. Methods: PEARL is a phase 3 study with 2 subsequent cohorts: cohort 1 with 296 pts randomized to PAL+Exemestane (EXE) vs CAP and cohort 2 with 305 pts randomized to PAL+ Fulvestran (FUL) vs CAP. ESR1 hotspot mutations were analyzed in circulating free DNA at baseline by digital PCR. Cox regresion analysis for PFS and OS were performed. Adjusted hazard ratios (aHR) and interaction test between treatment and ESR1 status were calculated. Results: ESR1 mutational status was assessed in 557 pts, 91% and 94% treated with CAP and PAL+ET, respectively; 164 (29%) had ESR1 mutations. Characteristics between ESR1 wild-type (WT) and mutated pts were balanced except for ECOG, prior sensitivity to ET, treatment line, prior AI for metastatic disease and time from first metastatic diagnosis to randomization. Median follow-up was 22.5 months (m). Median PFS was 9.6 vs. 7.5 m (HR: 1.06 [0.88 - 1.28], p = 0.522) and median OS was 30.2 vs 30.3 (HR: 0.99 [0.78 - 1.26] p = 0.934), for CAP vs. PAL+ET, respectively. No interaction was seen between treatment arm and ESR1 status either for PFS (p = 0.538) or OS (p = 0.957). Conclusions: In luminal MBC, ESR1-mutated pts had poorer OS than ESR1-WT pts regardless of treatment received. Clinical trial information: NCT02028507 . [Table: see text]
NOMINATOR: Feasibility of genomic testing of rare cancers to match cancer to treatment.
Authors: Kee Damien , Kondrashova Olga , Ananda Sumitra , Brown Michael Paul , Cohen Paul Andrew , Dean Andrew , Desai Jayesh , Fellowes Andrew , Fox Stephen B. , Hadley Alison , Lindsay Dianne , Mileshkin Linda R. , O'Byrne Kenneth John , Prall Owen W.J. , Scott Hamish , Thomas David Morgan , Vines Richard , Waddell Nic , Papenfuss Anthony , Scott Clare L. 
Published: May 2020

103 Background: Rare cancers (RCs) often lack proven treatments and consequently have poorer outcomes. Identification of molecular biomarkers can facilitate treatment selection and trials access for RC patients (pts) where histology-based trials are not feasible. We assessed the potential for next-generation sequencing (NGS) to impact RC care. Methods: Pts with a rare histology, poor-prognosis solid-tumor and no standard of care therapy underwent NGS genomic profiling of paired FFPE tumor and blood (PMCC comprehensive cancer panel; 391 genes). A virtual molecular tumour board (MTB) reviewed curated results regarding diagnosis, actionability (OncoKB) and treatment recommendations. Results: Between July 2017 and Nov 2019, 121 pt were prospectively enrolled across 4 Australian sites. 109 (91%) pts had a tumour with an incidence of < 1/100,000 person/years with 83 diverse RC histologies represented. 100 (83%) cases were successfully sequenced. The most commonly aberrant genes ( > 10%) were: TP53 (45%), CDKN2A/B, RB1, PTEN and NF1. 51 (51%) had at least one potentially actionable finding, with 27 matched to a clinically validated drug (OncoKB level 3 or better) [Table]. In 6 cases NGS resulted in a revised diagnosis (includes 4 with FDA approved therapy). Actionable germline mutations were detected in 3 individuals of which 2 were previously known. The majority of pts remain in follow-up, however, 8 died prior to or within 28 days of NGS result availability. Drug access remains a limitation with only 12 receiving therapy based on NGS/MTB guidance. Clinical trial information: ACTRN12616001000493 . Conclusions: NGS in RCs is feasible with potential impact in half of cases. Earlier testing and improved off-label/trial drug access is necessary to increase the likelihood that RC patients may benefit from molecularly guided therapy. [Table: see text]
A phase I dose escalation study evaluating the safety and tolerability of a novel anti-HER2 antibody-drug conjugate (PF-06804103) in patients with HER2-positive solid tumors.
Authors: Meric-Bernstam Funda , Calvo Emiliano , Moreno Victor , Chung Hyun Cheol , Park Yeon Hee , Bang Yung-Jue , Rosen Lee S. , Mita Monica M. , Garrido-Laguna Ignacio , Leung Abraham C.F. , Dube Harman , Zhong Wei , Chen Xiaoying , Dawaher Rula , Curigliano Giuseppe 
Published: May 2020

1039 Background: PF-06804103 is an anti-HER2 immunoglobulin G1 antibody-drug conjugate (ADC), comprising an anti-HER2 monoclonal antibody conjugated with a cleavable linker to the cytotoxic agent Aur0101. PF-06804103 demonstrated strong activity in low to high HER2-expressing preclinical tumor models. In this study, the safety and tolerability of PF-06804103 was assessed in patients with advanced breast cancer (BC) or gastric cancer (GC). Methods: This multi-center, open-label, first-in-patient, phase I study (NCT03284723) has two parts: dose escalation (Part 1) and dose expansion (Part 2). In Part 1, groups of adult patients (pts) with HER2+ BC or HER2+ GC, who are resistant or intolerant to standard therapy or for which no standard therapy is available, received PF-06804103 intravenously once every 21 days (Q3W); dosage was escalated per cohort. Primary objectives were to evaluate the safety and tolerability of PF-06804103, characterize its dose-limiting toxicities (DLTs), and determine the recommended phase 2 dose. Response was assessed using RECIST v1.1. Objective response rate (ORR) was calculated for response-evaluable pts with target lesions at baseline and ≥1 post-baseline assessment (including unconfirmed responses). Results: A total of 35 pts (BC: n = 20; GC: n = 15) received PF-06804103 at escalating dose levels (0.15 mg/kg: n = 2; 0.5 mg/kg: n = 2; 1.2 mg/kg: n = 2; 2 mg/kg: n = 4; 3 mg/kg: n = 10; 4 mg/kg: n = 9; 5 mg/kg: n = 6). The median (range) number of prior therapies was 6 (3–18) and 3 (1–6) for BC and GC groups, respectively (all pts had prior HER2-targeted therapy). The 3 most common, drug-related adverse events (any grade) were alopecia (n = 17, 48.6%), fatigue (n = 15, 42.9%), and neuropathy (n = 9, 25.7%). DLTs (mostly grade 3) occurred in 3 pts and included arthralgia, neuropathy, myalgia, fatigue, and osteomuscular pain. Preliminary ORR in the patients treated with doses ≥3mg/kg was 52.4% (11/21). Conclusions: The PF-06804103 ADC demonstrated manageable toxicity and promising anti-tumor activity in this small, heavily pretreated study population. Clinical trial information: NCT03284723 .
Different response to ALK inhibitors in EML4-ALK positive mediastinal cancer of unknown primary.
Authors: Hu Chunhong , Zhao Lishu , Wu Fang 
Published: May 2020

104 Background: With the development of next-generation sequencing (NGS) and precision medicine, targeted therapy especially molecule-driven therapy irrespective of tumor site may play an important role in cancer patients with druggable targets. Cancer of unknown primary (CUP) especially mediastinal CUP (MCUP) has poor prognosis with empirical chemotherapy but may harbor targetable genetic alterations. In the study, we evaluate the response to ALK inhibitors in ALK-positive MCUP. Methods: We queried the cancer database of the Second Xiangya hospitalfrom 2018.10 to 2019.12 for patients with ALK-positive cancers regardless of tumor site.Then we selected ALK-positive MCUP patients treated with ALK inhibitors, on which both NGS and programmed death-ligand 1 (PD-L1) testing were performed. Results: Forty-eightpatients with ALK-positive cancers were registered in the database. Two MCUP patients were found and showed different response. The first MCUP patient obtaining remarkable response to alectinib harbored ALK/TP53 co-mutation and TERT wild type accompanied by low PD-L1 expression, while the second one showing stable disease with crizotinib carried ALK/TP53/TERT co-mutation and high PD-L1 expression. Conclusions: We reveal for the first time that ALK inhibitors are applied to MCUP as first-line therapy and alectinib is firstly reported to treat MCUP patients. ALK inhibitor alectinib is expected to improve outcomes of patients with ALK-positive MCUP. NGS and PD-L1 testing should be recommended for MCUP to get more information about therapy and efficacy. [Table: see text]
SOPHIA analysis by chemotherapy (Ctx) choice: A phase III (P3) study of margetuximab (M) + Ctx versus trastuzumab (T) + Ctx in patients (pts) with pretreated HER2+ metastatic (met) breast cancer (MBC).
Authors: Escrivá Santiago , Im Seock-Ah , Cardoso Fatima , Cortes Javier , Curigliano Giuseppe , Gradishar William John , Pegram Mark D. , Wright Gail Lynn Shaw , Levy Christelle , De Laurentiis Michelino , Ferrero Jean-Marc , Bahadur Shakeela Wazeen , Kim Sung-Bae , Petráková Katarína , Riseberg David A. , Yardley Denise A. , Edlich Sutton , Hong Sam , Rock Edwin P. , Rugo Hope S. 
Published: May 2020

1040 Background: Despite advances, pretreated HER2+ MBC remains incurable with ongoing need for new therapies. Investigational M has similar HER2 binding and antiproliferative effects as T. Relative to T, M Fc engineering increases binding affinity for both variants of activating Fc receptor (FcR) CD16A and decreases affinity for inhibitory FcR CD32B, coordinately activating innate and adaptive immunity. In a Phase 3 (P3) trial, M prolonged PFS over T (Table). Second interim OS results from Sept 2019 also favor M (hazard ratio [HR], 0.89; 95% CI 0.69–1.13; nominal P=0.326). Methods: SOPHIA (NCT02492711), an open-label P3 trial, enrolled pts with HER2+ MBC after pertuzumab and 1–3 lines of prior treatment (Tx) for MBC. Randomization was 1:1 to M (15 mg/kg IV q3w + Ctx) or T (6 [8 for loading dose] mg/kg IV q3w + Ctx), stratified by met sites (≤2, >2), lines of Tx for met disease (≤2, >2), and Ctx choice, including capecitabine (Cap), eribulin (Eri), gemcitabine (Gem), or vinorelbine (Vin). Primary endpoints were central blinded PFS and OS, assessed sequentially using the stratified log-rank test. Results: Investigator chemotherapy choices and results by chemotherapy are shown in the table. Subjects receiving Eri and Gem had the lowest PFS hazards ratios (HRs), favoring M over T, although no statistical significance of individual chemotherapy subgroups was seen. There was variable toxicity among Ctx subgroups, and fewer subjects receiving Cap had Ctx related Grade 3 or higher (>=Gr 3) AEs. In this unblinded study, more subjects on M than T in all subgroups discontinued Ctx while continuing study antibody. Conclusions: In combination with chemotherapy in pretreated HER2+ MBC, M improved PFS over T. Safety was manageable in all Ctx subgroups. Differences among HRs for chemotherapy subgroups may be driven by selection bias and/or sensitivity differences. Clinical trial information: NCT02492711 . [Table: see text]
Pyrotinib plus capecitabine for HER2-positive, trastuzumab-resistant metastatic breast cancer: A pooled analysis of three randomized controlled trials.
Authors: Jiang Zefei , Xu Binghe , Yan Min , Ouyang Quchang , Hu Xi-Chun , Li Wei , Feng Ji Feng , Zhang Qingyuan , Tong Zhongsheng , Yan Ping , Zhu Xiaoyu , Rong Shangyi , Zou Jianjun 
Published: May 2020

1048 Background: Trastuzumab is the most widely used anti-HER2 agent in patients (pts) with HER2-positive breast cancer, both in (neo)adjuvant and metastatic settings; however, drug resistance is inevitable. This pooled study aimed to investigate the efficacy of pyrotinib plus capecitabine in pts with HER2-positive, trastuzumab-resistant relapsed or metastatic breast cancer. Methods: Data were derived from three randomized controlled trials, including a phase II (NCT02422199) and the PHOEBE phase III (NCT03080805) study comparing pyrotinib plus capecitabine vs lapatinib plus capecitabine and the PHENIX phase III (NCT02973737) study comparing pyrotinib plus capecitabine vs placebo plus capecitabine. Pts with trastuzumab-resistant disease were included in the analyses, including 39 pts who had relapsed within six months after adjuvant trastuzumab and 57 pts who had progressed within three months of trastuzumab treatment for metastatic disease. The pooled tumor response data (per blinded independent central review) were reported herein. Results: In the pooled analysis of all three studies, 63 pts received pyrotinib plus capecitabine. Among them, 28 (44.4%) pts had disease progression or died. The median progression free survival (PFS) was 12.4 months (95% CI, 6.9 to not reached). In total, 40 pts (63.5% [95% CI, 50.4% to 75.3%]) achieved objective response, and the estimated median duration of response (DoR) was 11.1 months (95% CI, 6.9 to not reached). In the pooled analysis involving the phase II and PHOEBE phase III, 43 pts were treated with pyrotinib plus capecitabine and 33 pts with lapatinib plus capecitabine. In total, 18 (41.9%) pts with pyrotinib plus capecitabine and 17 (51.5%) pts with lapatinib plus capecitabine had disease progression or died. The PFS tended to be prolonged with pyrotinib plus capecitabine vs lapatinib plus capecitabine (median, 12.4 months [95% CI, 6.9 to not reached] vs 6.9 months [95% CI, 5.5 to not reached]; hazard ratio, 0.62 [95% CI, 0.31 to 1.24]; p=0.0864). The objective response rate was 67.4% (95% CI, 51.5% to 80.9%) with pyrotinib plus capecitabine compared with 54.5% (95% CI, 36.4% to 71.9%) with lapatinib plus capecitabine. The estimated median DoR was 11.1 months [95% CI, 6.9 to not reached] vs not reached [95% CI, 4.2 months to not reached], respectively. Conclusions: Pyrotinib plus capecitabine showed favorable efficacy in pts with HER2-positive, trastuzumab-resistant relapsed or metastatic breast cancer. This combination could be a treatment option for this population.
Randomized phase II trial of MIBG versus MIBG/vincristine/irinotecan versus MIBG/vorinostat for relapsed/refractory neuroblastoma: A report from the New Approaches to Neuroblastoma Therapy Consortium.
Authors: DuBois Steven G. , Granger Meaghan , Groshen Susan G. , Tsao-Wei Denice , Shamirian Anasheh , Czarnecki Scarlett , Goodarzian Fariba , Berkovich Rachel , Shimada Hiroyuki , Mosse Yael P. , Shusterman Suzanne , Cohn Susan Lerner , Goldsmith Kelly C. , Weiss Brian D. , Yanik Gregory A. , Twist Clare , Irwin Meredith , Park Julie R. , Marachelian Araz , Matthay Katherine K. 
Published: May 2020

10500 Background: 131I-metaiodobenzylguanidine (MIBG) remains one of the most active agents for neuroblastoma. It is not clear if putative radiation sensitizers improve upon this activity. The primary aim of this trial was to identify the MIBG treatment regimen with highest response rate among: MIBG monotherapy (Arm A); MIBG/Vincristine/Irinotecan (Arm B); MIBG/Vorinostat (Arm C). The secondary aim was to compare toxicity across arms. Methods: We conducted a multicenter, randomized phase II trial. Patients 1-30 years with relapsed/refractory high-risk neuroblastoma were eligible with at least one MIBG-avid site and adequate autologous stem cells (ASCs). All patients received MIBG 18 mCi/kg on Day 1 and ASC on day 15. Patients on Arm A received only MIBG; patients on Arm B also received vincristine (2 mg/m2) IV on Day 0 and irinotecan (50 mg/m2) IV daily on Days 0-4; patients on Arm C also received vorinostat (180 mg/m2) orally once daily on days -1 to 12. The primary endpoint was response after one course according to NANT response criteria. The trial was designed as a pick-the-winner study with a maximum of 105 eligible and evaluable patients to ensure an 80% chance that the arm with highest response rate is selected, if that response rate is at least 15% higher than the other arms. Results: 114 patients enrolled. Three patients were ineligible and 6 eligible patients never received MIBG, leaving 105 eligible and evaluable patients (36 Arm A; 35 Arm B; and 34 Arm C; 55 boys; median age 6.5 years). 9 patients had received prior MIBG monotherapy, 65 prior irinotecan, and 7 prior vorinostat. After one course, the response rates (Partial Response or better) on Arms A, B, and C were 17% (95% CI 7-33%), 14% (5-31%), and 32% (18-51%). An additional 4, 4, and 7 patients met NANT Minor Response criteria [partial response in one disease category (e.g., bone marrow) and stable disease in other categories] on Arms A, B, and C, respectively. On Arms A, B, and C, rates of any grade 3+ non-hematologic toxicity were 19%, 49% and 32%; rates of grade 3+ diarrhea were 0%, 11%, 0%; and rates of grade 3+ febrile neutropenia were 6%, 11%, and 0%. Conclusions: The combination of vorinostat/MIBG had the highest response rate, with manageable toxicity. Vincristine and irinotecan do not improve the response rate to MIBG and are associated with increased toxicity. These data provide response rates for MIBG monotherapy in a contemporary patient population assessed with current response criteria. Clinical trial information: NCT02035137.