bluuebunny/crossref_metadata_2025_split huggingface dataset:
TIVO-3: Subgroup analysis of progression-free survival of tivozanib compared to sorafenib in subjects with refractory advanced renal cell carcinoma (RCC).
Authors: Porta Camillo , Verzoni Elena , Escudier Bernard , Pal Sumanta K. , Atkins Michael B. , Hutson Thomas E. , Needle Michael N. , McDermott David F. , Rini Brian I. 
Published: May 2019

4572 Background: Tivozanib (T) is a biochemically potent and highly selective VEGF tyrosine kinase receptor inhibitor in clinical development in RCC. The TIVO-3 trial in 3rd and 4th line subjects with metastatic (m) RCC showed a median progression free survival (mPFS) of 5.6 months (mos) for T compared to 3.9 mos for sorafenib (S) (p = 0.017, HR = 0.73). Methods: Subjects with mRCC who failed 2 or 3 prior systemic regimens, one of which included a VEGFR TKI other than S or T, were stratified by IMDC risk category and type of prior therapy (two TKIs; TKI plus checkpoint; TKI + other) then randomized in a 1:1 ratio to T or S. The primary objective was to compare PFS by blinded independent radiological review. Pre-specified subgroups included prior treatment, IMDC prognostic group, and demographic characteristics. Results: Tivozanib demonstrated PFS benefit in all subgroups including men, women, patients over 65, and under 65. The hazard ratio was the same for patients enrolled in North America and the EU. Patients with ECOG performance status (PS) of 0 had a lower HR than patients with ECOG PS of 1. There was an increase in HR from IMDC favorable vs IMDC intermediate vs IMDC poor. PFS favored tivozanib in patients who had two prior lines of therapy, those treated with three prior lines, those with a prior checkpoint inhibitor, or with two prior VEGFR TKIs. Conclusions: Tivozanib improved PFS vs. sorafenib across several subgroups in TIVO-3. Patients with favorable and intermediate IMDC risk and ECOG PS 0 seemed to derive the most benefit. Patients treated with a prior checkpoint inhibitor or two VEGFR-TKIs had a longer PFS than patients treated on sorafenib. Clinical trial information: NCT02627963. [Table: see text]
Adjuvant axitinib dose modification in renal cell carcinoma (RCC): Analysis of the ATLAS study.
Authors: Quinn David I. , Kwon Tae Gyun , Eto Masatoshi , Ye Dingwei , Miyake Hideaki , Seo Seong Il , Byun Seok-Soo , Lee Jae-Lyun , Master Viraj A. , Ng Chi-Fai , Linke Rolf Gerhard , Rosbrook Brad , Thakur Mahgull Nazar , Grande Enrique , Gross-Goupil Marine , Chang Chao-Hsiang 
Published: May 2019

4573 Background: The ATLAS trial compared axitinib vs placebo in patients (pts) with locoregional RCC at risk of recurrence after nephrectomy. ATLAS was stopped due to futility at a pre-planned interim analysis; results showed no difference in disease-free survival (DFS) between the treatment arms. We explored whether pts treated longer with axitinib achieved better outcomes and the impact of axitinib dose reduction or increase on DFS – the trial required dose reduction for toxicity and allowed dose escalation in the event of no or minimal toxicity. Methods: Pts in ATLAS received a maximum of 3 y of study treatment. A landmark analysis was conducted comparing pts treated with axitinib ≤1 y vs > 1 y. Pts who recurred or censored prior to 1 y were excluded. An analysis of daily dose characteristics was undertaken to compare patients whose dose was reduced and whose dose was increased to those with a stable dose of axitinib. Cox proportional hazard model was used for DFS analysis. Toxicity analysis using a 90-day landmark was also conducted. Results: Overall, 264 axitinib-treated pts were included in this analysis. Of these 42 pts were treated for ≤1 y and 222 pts for > 1 y. Pts remaining on axitinib > 1 y vs ≤1 y did not have different DFS (hazard ratio [HR] = 0.572, 95% confidence interval [CI]: 0.247–1.327, P= 0.1874). Pts with dose reduction had longer DFS than those with a stable dose (HR = 0.458, CI: 0.305–0.687, P= 0.0001). Pts with dose increase did not have DFS different to stable dose pts (HR = 1.936, CI: 0.937–3.997, P= 0.0685). No difference in DFS in pts experiencing grade ≥2 adverse events (AEs) vs grade < 2 AEs within 90 d of start of treatment was observed (HR = 0.885, CI: 0.419–1.869, P= 0.7488). Pts experiencing grade ≥3 AEs within 90 d of start of treatment had shorter DFS compared to those that did not (HR = 1.643, CI: 0.963–2.801, P= 0.0653). Conclusions: DFS did not vary based on duration of axitinib treatment, however, pts with dose reductions had longer DFS vs pts with stable dose or dose increases. This difference suggests that there is a relation between axitinib exposure and DFS as seen with sunitinib in the advanced setting and pazopanib in the PROTECT study.
Interest of short hormonotherapy (HT) associated with radiotherapy (RT) as salvage treatment for metastatic free survival (MFS) after radical prostatectomy (RP): Update at 9 years of the GETUG-AFU 16 phase III randomized trial (NCT00423475).
Authors: Carrie Christian , Magné Nicolas , Burban-Provost Patricia , Sargos Paul , Latorzeff Igor , Supiot Stephane , Belkacemi Yazid , Peiffert Didier , Allouache Nedla , Dubray Bernard M. , Servagi Vernat Stephanie , Suchaud Jean-Philippe , Crehange Gilles , Guerif Stéphane , Brihoum Meryem , Barbier Nicolas , Graff-Cailleaud Pierre , Ruffion Alain , Chabaud Sylvie 
Published: May 2019

5001 Background: RT is the standard salvage treatment after RP. The role of HT is not formally demonstrated to date. This trial assessed the efficacy of RT alone vs RT+HT in terms of progression-free survival (PFS), metastase-free survival (MFS) and overall survival (OS) in patients with biological relapse (BR) after RP. After a median follow-up (FU) duration of 5.3 years, we previously reported [Carrie C, Lancet Oncol 2016] a benefit in PFS (80% vs 62% PFS free at 5 years; p < 0.0001) in the combined arm, whatever the risk subgroups. Methods: Patients (pts) were randomized (1:1) to RT alone or RT+HT (goserelin, for 6 months). The randomization was stratified according to radiotherapy modality and risk group. Low risk was defined as Gleason score < 8, surgical margins+, psa doubling time > 8 months and no seminal vesicle involment. Assuming a 45% 5-year PFS of 45% in the RT arm, the trial required 369 pts per arm to detect an improvement of 12% on PFS in RT+HT arm (90% power and 5% bilateral alpha risk), possibly translating into a 10% gain in OS (75% to 85% with 80% power). Biological relapse (BR) was defined according to ASTRO-consensus. Results: At the time of data cutoff (March 2019), the median duration follow-up was 112 months. We confirm the benefit of RT+HT on PFS (HR = 0.54 [CI95% = 0.43-0.68] ; p < 0.0001) whatever the risk subgroup (HR = 0.47 [CI95% = 0.28-0.80] and 0.56 [CI95% = 0.44-0.73] for low and high risk patients, respectively. Metastatic free survival (MFS) is significantly improved in the combined arm (HR = 0.73 [CI95% = 0.54-0.98] ; p = 0.034) with 69% [CI95% = 63-74] versus 75% [CI95% = 70-80] of MFS at 10 years for RT alone and RT+HT, respectively. Conclusions: Salvage radiotherapy combined with short term HT significantly improved 10-years metastatic free survival compared with salvage radiotherapy alone. GETUG-16 considered in the context of previously published results from RTOG-9601, confirm that this strategy can be considered as the new standard for salvage treatment after radical prostatectomy. Clinical trial information: NCT00423475.
Alliance A031201: A phase III trial of enzalutamide (ENZ) versus enzalutamide, abiraterone, and prednisone (ENZ/AAP) for metastatic castration resistant prostate cancer (mCRPC).
Authors: Morris Michael J. , Heller Glenn , Bryce Alan Haruo , Armstrong Andrew J. , Beltran Himisha , Hahn Olwen Mary , McGary Eric C. , Mehan Paul Tracy , Goldkorn Amir , Roth Bruce J. , Xiao Han , Watt Colleen , Hillman David W. , Taplin Mary-Ellen , Ryan Charles J. , Halabi Susan , Small Eric Jay 
Published: May 2019

5008 Background: Androgen receptor (AR) signaling is an important growth mechanism in mCRPC, providing the rationale for treatment with AR axis inhibitors such as ENZ and AAP. Targeting AR with anti-androgens such as ENZ can result in compensatory autocrine and paracrine androgenic stimulation. Therefore, using ENZ with the androgen biosynthesis inhibitor AAP to dampen these resistance mechanisms could improve clinical outcomes relative to ENZ alone. Methods: Men with progressive mCRPC by Prostate Cancer Working Group 2 criteria were eligible. Prior treatment with taxanes for mCRPC and any prior treatment with ENZ or AAP was exclusionary. Patients (pts) were randomized 1:1 to ENZ or ENZ/AAP at standard FDA-approved doses. Randomization was stratified by prior chemotherapy and Halabi prognostic three risk groups. Castrating therapy was maintained. The primary endpoint was overall survival (OS) defined as the date of randomization from date of death or last follow-up. The log-rank test had 90% power to detect a hazard ratio for OS of 0.77 with a one-sided type I error rate of 0.025. Secondary endpoints included radiographic progression free survival (rPFS) and on-treatment PSA declines. Exploratory endpoints included imaging changes, and changes in serum biomarkers such as androgens, angiokines, and circulating microRNA and RNA. The primary analysis was based on the stratified log-rank test adjusting on the stratification factors. Results: Between January 2014 and August 2016, 1311 men were randomized: 657 to ENZ and 654 to ENZ/AAP. Groups were well balanced between arms, including stratification variables. 15.6% of pts were high risk, 35.3% intermediate, and 48.1% low. Median OS was 33.6 mo (95% CI 30.5-36.4) and 32.7 mo (29.9-35.4) respectively, two-sided p = 0.53. Fifty percent PSA decline rate was 80% vs. 76.5%. Grade 3-5 adverse events (AE) (all attributions) were 55.6% and 68.8% respectively. Treatment discontinuation due to AEs occurred in 5% and 12%, pt withdrawal in 5% and 13%, and progression or death in 57% and 48% of pts respectively. Conclusions: Addition of abiraterone acetate to enzalutamide did not prolong survival in men with mCRPC. The combination resulted in more AEs than enzalutamide alone. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org . Clinical trial information: NCT01949337.
Docetaxel, trastuzumab, pertuzumab versus trastuzumab emtansine as neoadjuvant treatment of HER2-positive breast cancer: Results from the Swedish PREDIX HER2 trial identifying a new potential de-escalation standard?
Authors: Bergh Jonas C. S. , Andersson Anne , Bjohle Judith , Bosch Ana , Carlsson Lena , Dreifaldt Ann Charlotte , Einbeigi Zakaria , Fredholm Hanna , Isaksson-Friman Erika , Foukakis Theodoros , Elinder Ellinor , Hellstrom Mats , Johansson Hemming , Lekberg Tobias , Lindman Henrik , Maes Claudia , Brandberg Yvonne , Hatschek Thomas 
Published: May 2019

501 Background: Neoadjuvant therapy produces high rates of pathological complete response (pCR) and is the standard of care in HER2 positive breast cancer; however, the optimal treatment regimen remains to be established. Methods: In this randomized phase II study patients ≥18 years with HER2 positive breast cancer > 20mm or verified lymph node metastases were randomized to 6 courses of docetaxel, trastuzumab and pertuzumab (DTP, group A) or trastuzumab emtansine (T-DM1, group B), q 21 days. The protocol allowed switch to the competing treatment upon lack of response or drug-related severe toxicity. Patients received postoperative epirubicin+cyclophosphamide, trastuzumab for a total of one year and endocrine therapy. Accrual was completed in October 2018 after randomization of 202 patients, data on pCR were available for 190 at the time for this abstract submission. Median age, 52 years (26-74), menopausal status, histological type and grade were well balanced between the treatment groups. 62.6% of the tumors were hormone receptor (HR) positive. Results: Primary endpoint was pathological objective response. 190 patients completed the protocol-specified preoperative treatment. pCR was achieved in 45.3% of patients, 46.4% in patients treated with DTP and 44.1% with T-DM1 (chi-sq., p = 0.75). In HR-positive tumors, pCR was obtained in 35.3% of patients, 35.9% in group A vs. 34.6% in group B (p = 0.87); in HR-negative tumors, the overall pCR rate was 62.0%, 66.7% in group A vs. 57.9% in group B (p = 0.45). Severe (grade 3/4) toxicity was reported at 68 occasions related to DTP, compared with 16 related to T-DM1, 26 vs. 3 caused by febrile neutropenia. Significantly better quality of life was reported by patients treated with T-DM1. Conclusions: Our data on TDM-1 demonstrates similar efficacy and less toxicity, in particular for patients with HER2 and HR positive cancers, being a potential new standard for neoadjuvant therapy. Clinical trial information: NCT02568839.
Pembrolizumab (pembro) plus enzalutamide (enza) in abiraterone (abi)-pretreated patients (pts) with metastatic castrate resistant prostate cancer (mCRPC): Cohort C of the phase 1b/2 KEYNOTE-365 study.
Authors: Fong Peter C.C. , Retz Margitta , Drakaki Alexandra , Massard Christophe , Berry William R. , Romano Emanuela , De Bono Johann S. , Feyerabend Susan , Appleman Leonard Joseph , Conter Henry Jacob , Sridhar Srikala S. , Shore Neal D. , Linch Mark David , Joshua Anthony M. , Gurney Howard , Wu Helen , Schloss Charles , Poehlein Christian Heinrich , Yu Evan Y. 
Published: May 2019

5010 Background: Pembro has activity as monotherapy in pts with pretreated advanced mCRPC. A phase 2 study suggested that pembro + enza after progression on enza may have clinical activity. Data from cohort C (pembro + enza) of KEYNOTE-365 (NCT02861573), a phase 1b/2 umbrella study to test combinations in mCRPC, are presented. Methods: Pts who were unsuccessful with or became intolerant to ≥4 weeks of abi in the prechemotherapy mCRPC state, with either PSA or radiologic progression within 6 mo before screening were included. Pts received pembro 200 mg IV Q3W with enza 160 mg/day orally. Primary end points were safety and PSA response rate (confirmed PSA decrease ≥50%). Key secondary end points were investigator-assessed ORR (RECIST v1.1), disease control rate (DCR: CR+PR+SD ≥6 mo), time to PSA progression, rPFS, and OS. Results: 69 pts began treatment (median age, 69 y; visceral disease, 26%; measurable disease, 36%). Median (95% CI) follow-up was 9 (7-13) mo. Efficacy is outlined in the table. Treatment-related AEs occurred in 63 (91%) pts; most frequent (≥20%) were fatigue (30%), rash (23%), and nausea (22%). Grade 3/4 treatment-related AEs occurred in 28 (41%) pts; most common was rash (10%); no deaths were from treatment-related AEs. Conclusions: The pembro + enza combination showed sustained activity in abi-pretreated chemotherapy-naive mCRPC. AEs were considered tolerable for the treatment combination; incidence of rash resolved with standard-of-care treatment. Clinical trial information: NCT02861573. [Table: see text]
Copy number analysis to identify tumor suppressor genes associated with enzalutamide (Enza) resistance and poor prognosis in metastatic castration-resistant prostate cancer (mCRPC) patients.
Authors: Guan Xiangnan , Sun Duan-Chen , Lu Eric , Urrutia Joshua A. , Reiter Robert Evan , Rettig Matthew , Evans Christopher P. , Lara Primo , Gleave Martin , Beer Tomasz M. , Thomas George V. , Huang Jiaoti , Xia Zheng , Alumkal Joshi J. 
Published: May 2019

5011 Background: Although enza prolongs life in mCRPC pts, the development of drug resistance and subsequent disease progression is nearly universal. Seeking to clarify molecular mechanisms that underlie enza resistance, we analyzed whole genome sequencing (WGS) and RNA sequencing (seq) of tumors obtained from patients with enza-naive or -resistant mCRPC. Methods: One hundred and one men with mCRPC who underwent image-guided biopsy and subsequent WGS were included (n = 64 with enza-naive and n = 37 with enza-resistant mCRPC). The differential copy number alteration (CNA) events enriched in enza-resistant vs. naïve samples were determined, and the prognostic significance of differential CNAs was assessed. RNA-seq data were evaluated to confirm that CNAs correlated with changes in gene expression of relevant loci and to identify potentially druggable targets selectively activated in tumors with specific CNAs. Results: Copy number loss was more common than gain in enza-resistant tumors. Specifically, we identified 123 protein-coding genes that were more commonly lost in enza-resistant samples—eight of which were previously described tumor suppressor genes. There was a strong concordance of copy number loss and reduced mRNA expression of these genes. We identified one gene from this list of eight genes whose copy number loss was associated with poor overall survival (median overall survival from date of CRPC was 19.1 months in tumors with gene loss vs. 42.0 months in intact tumors, hazard ratio 3.8 [1.46–9.8], log-rank p = 0.003). Finally, Master Regulator analysis determined that tumors with copy number loss of this poor prognosis gene had activation of several potentially targetable factors, including the kinases Akt and PLK1. Conclusions: Copy number loss of specific tumor suppressor genes is associated with enza resistance in mCRPC patients. Previously unappreciated molecular subsets of enza-resistant CRPC were identified, including one subset associated with poor clinical outcome.
HER2 heterogeneity as a predictor of response to neoadjuvant T-DM1 plus pertuzumab: Results from a prospective clinical trial.
Authors: Metzger Filho Otto , Viale Giuseppe , Trippa Lorenzo , Li Tianyu , Yardley Denise A. , Mayer Ingrid A. , Abramson Vandana Gupta , Arteaga Carlos L. , Spring Laura , Waks Adrienne Gropper , Janiszewska Michalina , Wrabel Eileen , Demeo Michelle , Bardia Aditya , King Tari A. , Polyak Kornelia , Winer Eric P. , Krop Ian E. 
Published: May 2019

502 Background: HER2 targeted therapy without chemotherapy may be insufficient to completely eradicate a HER2+ cancer in cases of significant intratumor HER2 heterogeneity (ITH-HER2). Methods: We conducted a single-arm phase II study enrolling centrally confirmed HER2+ breast cancer. Pts received 6 cycles of T-DM1 plus Pertuzumab before surgery. Central ITH-HER2 was assessed on baseline ultrasound-guided core biopsies from 2 distinct areas of each tumor (3 cores/site). ITH-HER2 was defined as at least one of the six areas demonstrating either 1) HER2 positivity by FISH in > 5% and < 50% of tumor cells (i.e., CAP guideline) or 2) an area of tumor that tested HER2 negative. The primary objective is the association between pathologic complete response (pCR) and ITH, stratified by ER status. pCR defined as residual cancer burden (RCB) 0. Results: 164 pts with centrally confirmed HER2+ tumors were enrolled from 1/2015 to 1/2018. 2 pts withdrew consent. Median tumor size by imaging was 2.8 cm (IQR 2.1-3.8cm); 111 (69%) were ER+ and 51 (32%) ER-. 8 pts discontinued tx (6 due to disease progression, 2 due to toxicity). 49% of pts had a pCR (RCB-0), 14% RCB-I, 26% RCB-II and 11% RCB-III. Higher rates of RCB-0 were seen in ER- (65%) versus ER+ (42%). ITH-HER2 was detected in 10% (16/157) of evaluable cases. No pCR was observed among cases classified as heterogeneous (RCB-I 25%, RCB-II 25%, RCB-III 50%). The study met its primary endpoint by demonstrating a significant association between ITH-HER2 and pCR stratified by ER status (p < .0001). Secondary analysis also demonstrated a significant association between ITH-HER2 and pathologic response defined as RCB 0 or I (OR = 5.6, p = 0.004). Exploratory analysis revealed higher rates of RCB-0 among tumors centrally classified as HER2 3+ (56% [66/118]) versus HER2 2+ (27% [10/37]), (OR = 3.4, p = 0.002). The association of ITH-HER2 and pCR was maintained when stratifying by ER status and HER2 IHC (2+ vs. 3+), (p = 0.002). Conclusions: ITH-HER2 assessed by routine pathology evaluation is a strong predictor of pCR to a dual-HER2 targeted therapy regimen. If validated, ITH-HER2 may need to be considered in selection of pts for HER2-targeted regimens without chemotherapy in the curative setting. Clinical trial information: NCT02326974.
Concurrent or layered treatment with radium-223 (Ra-223) and enzalutamide (Enza) or abiraterone plus prednisone/prednisolone (Abi/pred): A retrospective study of real-world clinical outcomes in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Shore Neal D. , Sartor A. Oliver , Sternberg Cora N. , Saad Fred , Tombal Bertrand F. , Miller Kurt , Kalinovsky Jan , Jiao XiaoLong , Tangirala Krishna , Higano Celestia S. 
Published: May 2019

5026 Background: In clinical practice, Ra-223 is often combined with Enza or Abi/pred. ERA 223 (NCT02043678) showed increased fracture risk with concurrent Ra-223+Abi/pred. We assessed real-world symptomatic skeletal events (SSEs) and overall survival (OS) of pts with mCRPC who received concurrent or layered Ra-223+Enza or Abi/pred. Methods: Patients with mCRPC treated with Ra-223 in US cancer clinics from 1/01/2013 to 6/30/2017 were identified from a Flatiron prostate cancer registry of electronic health records. Treatment initiation defined subgroups: concurrent (both started within 30 days) or layered (1 started ≥30 days after the other). Baseline (BL) was the first dose of Ra-223. Descriptive analysis was performed for BL characteristics, SSEs, and OS (Kaplan–Meier). Results: Of 625 pts treated with Ra-223, 48% received Ra-223+Enza or Abi/pred. Layered treatment was more common (73%) than concurrent (27%). BL characteristics and clinical outcomes were summarized [Table]. Conclusions: In a real-world setting, Ra-223+Enza or Abi/pred treatment was mainly layered. SSE rates with layered vs concurrent Ra-223+Abi/pred varied between subgroups; results must be treated cautiously given small pt numbers and a non-randomized study. The ongoing PEACE III trial is investigating concurrent Ra-223+Enza; a Phase III study (ESCALATE) exploring layered Ra-223+Enza is planned. [Table: see text]