bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase IV, randomized, double-blind, placebo (PBO)-controlled study of continued enzalutamide (ENZA) post prostate-specific antigen (PSA) progression in men with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC).
Authors: Attard Gerhardt , Borre Michael , Gurney Howard , Loriot Yohann , Andresen Corina , Kalleda Ranjith , Pham Trinh , Taplin Mary-Ellen
Published: September 2018

5004

Background: We hypothesized resistance to the androgen receptor inhibitor ENZA is due to increases in androgens and can be overcome by combination with the androgen synthesis inhibitor abiraterone (abi). The phase 4 PLATO trial (NCT01995513) is evaluating the safety and efficacy of continued ENZA + abi/prednisone (abi/P) vs PBO + abi/P after PSA progression on ENZA. Methods: In Period (P) 1, men with chemotherapy-naïve mCRPC received ENZA (160 mg); men with no PSA increase from baseline at wk 13 and 21 continued treatment until PSA progression (≥ 25% increase and ≥ 2 ng/mL above nadir). Eligible men were then randomized 1:1 in P2 to ENZA + abi/P (1000 mg/10 mg) or PBO + abi/P. The primary endpoint (EP) was progression-free survival (PFS; radiographic or unequivocal clinical progression, or death on study) in P2, with a prespecified sensitivity analysis of radiographic PFS (rPFS); protected secondary EPs were time to PSA progression (TTPP) and PSA response ≥ 50% in P2. Results: 509 men enrolled in P1. At data cutoff (Oct 7, 2016), 84 were active, 174 discontinued, and 251 were randomized in P2 (ENZA + abi/P, n = 126; PBO + abi/P, n = 125). Median treatment duration in P2 was 5.6 mo for both arms. PFS event by radiographic/clinical/death was 38%/25%/2% for ENZA + abi/P and 55%/18%/1% for PBO + abi/P. Median PFS was 5.7 mo for ENZA + abi/P and 5.6 mo for PBO + abi/P (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.61, 1.12; P = 0.22). Median TTPP was 2.8 mo for both arms (HR, 0.87; 95% CI, 0.62, 1.24; P = 0.45). PSA response rate was 0.8% for ENZA + abi/P and 2.5% for PBO + abi/P ( P = 0.31). Median rPFS was 10.0 mo for ENZA + abi/P and 7.0 mo for PBO + abi/P (HR, 0.67; 95% CI, 0.47, 0.94; P = 0.02). The most common (≥ 15%) adverse events for ENZA + abi/P vs PBO + abi/P were back pain (21% vs 23%), hypertension (20% vs 7%), nausea (17% vs 9%), and fatigue (14% vs 15%). Conclusions: ENZA + abi/P post PSA progression on ENZA was associated with increased hypertension and nausea and did not result in a statistically significant improvement in composite PFS. The signal seen in rPFS needs further evaluation. Clinical trial information: NCT01995513.
Duration of androgen deprivation therapy in high risk prostate cancer: Final results of a randomized phase III trial.
Authors: Nabid Abdenour , Garant Marie-Pierre , Martin André-Guy , Bahary Jean-Paul , Lemaire Celine , Vass Sylvie , Bahoric Boris , Archambault Robert , Vincent Francois , Bettahar Redouane , Carrier Nathalie , Duclos Marie , Souhami Luis
Published: September 2018

5008

Background: Long-term androgen deprivation therapy (ADT) combined with radiotherapy (RT) is a standard treatment for patients with high-risk prostate cancer (HRPC). However, the optimal duration of ADT is not yet defined. The aim of this randomized trial (Clinical Trials.gov, #NCT00223171) was to compare outcomes of RT combined with either 36 or 18 months of ADT. Methods: Patients with HRPC were randomized to pelvic and prostate RT combined with 36 (arm 1) or 18 months (arm 2) of ADT. Overall survival (OS) and quality of life (QoL) were primary end points. OS rates were compared with Cox Regression model and QoL data were analyzed through mixed linear model. Results: 630 patients were randomized, 310 to arm 1 and 320 to arm 2. With a median follow-up of 9.4 years, 290 patients had died (147 arm 1 vs. 143 arm 2). The 10-year OS rate was 62.4% (95% confidence interval [CI] 56.4%, 67.8%) for arm 1 and 62.0% (95% CI 56.1%, 67.3%) for arm 2 (p = 0.8412) with a global hazard ratio (HR) of 1.024 (95% CI 0.813-1.289, p = 0.8411). QoL analysis showed a significant difference (p < 0.001) in 6 scales and 13 items favoring 18 months ADT with two of them presenting a clinically relevant difference in mean scores of ≥10 points. Conclusions: In HRPC, ADT combined with RT can be safely reduced from 36 to 18 months without compromising outcomes or QoL. 18 months of ADT represents a new standard of care in HRPC. Funded by AstraZeneca Pharmaceuticals Clinical trial information: NCT00223171.
9 weeks vs 1 year adjuvant trastuzumab in combination with chemotherapy: Results of the phase III multicentric Italian study Short-HER.
Authors: Conte Pier Franco , Bisagni Giancarlo , Frassoldati Antonio , Brandes Alba Ariela , Anselmi Elisa , Giotta Francesco , Aieta Michele , Gebbia Vittorio , Musolino Antonino , Garrone Ornella , Taverniti Cristiana , Cavazzini Giovanna , Turletti Anna , Rubino Daniela , Picardo Elisa , Ferro Antonella , Piacentini Federico , Balduzzi Sara , D'Amico Roberto , Guarneri Valentina
Published: September 2018

501

Background: 1-year trastuzumab with chemotherapy is the standard adjuvant treatment for HER2+ breast cancer patients (pts). The efficacy of less extended trastuzumab exposure is still under investigation. The Short-HER study is an independent, non-profit study aimed to test the non-inferiority of 9 weeks vs 1 year of adjuvant trastuzumab. Methods: This is a phase III, multicenter, Italian trial where pts with HER2+ breast cancer were randomly assigned to: Arm A (Long) AC or ECx4 followed by 4 courses of 3-weekly docetaxel in combination with trastuzumab, followed by 14 additional courses of 3-weekly trastuzumab; or Arm B (Short) 3 courses of 3-weekly docetaxel plus weekly trastuzumab for 9 doses followed by FEC x3. When indicated, radiation therapy was administered after the completion of chemotherapy. Hormonal therapy started at the completion of chemotherapy for pts with hormone receptor positive tumors. This is a non-inferiority trial with disease-free survival (DFS) as primary end-point.Overall survival (OS) is evaluated as second primary analysis outcome. The sample size of 1250 pts has been estimated based on a hazard ratio <1.29 for the short arm to be non-inferior. The definitive analysis will take place after 198 DFS events. Secondary aims include 2-yrs failure rate, cardiac toxicity, correlative biomarkers analyses. Hazard ratio for DFS and OS (90% CI) will be estimated according to the Cox model. Data will also be analyzed by the Bayesian approach. Results: from Dec-2007 to Oct-2013, 1254 pts from 82 centers have been randomized. Pts characteristics are the following: median age 55 yrs (25-78), stage I 37.3%, IIA 40%, IIB 20.6%, III 2.1%. 30% of the pts had 1-3 positive nodes, 16% >=4. Sixty-eight% of the pts had ER+ tumors. Characteristics were balanced between the two arms. At the time of this writing, 95% of the planned DFS events have been reported. 105 Grade ≥2 cardiac events have been reported, 78 in arm A (long) and 27 in arm B (short). Grade 3-4 cardiac events were 20 in arm A and 11 in arm B. Conclusions: Shorter trastuzumab administration almost halves the rate of severe cardiac toxicity. Final DFS data will be available at the time of the meeting. Clinical trial information: NCT00629278.
Combination of PDL-1 and PARP inhibition in an unselected population with metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Karzai Fatima , Madan Ravi Amrit , Owens Helen , Hankin Amy , Couvillon Anna , Cordes Lisa M , Fakhrejahani Farhad , Houston Nicole D. , Trepel Jane B. , Chen Clara , Edelman Daniel C. , Meltzer Paul S. , Steinberg Seth M. , Gulley James L. , Dahut William L. , Lee Jung-min
Published: September 2018

5026

Background: About 30% of sporadic mCRPC has defects in DNA repair pathways which may confer sensitivity to PARP inhibition. There is limited data about PDL1 inhibition in mCRPC. We hypothesize increased DNA damage by olaparib (O) will complement anti-tumor activity of immune checkpoint blocking antibody, durvalumab (D), in mCRPC:NCT02484404. Methods: Single arm pilot study with accrual of 25 patients (pts) with mCRPC and biopsiable disease. Prior treatment with enzalutamide and/or abiraterone is required. D is given at 1500 mg iv q28 days + O 300 mg po q12 h. Primary endpoint is PFS. Pretreatment and on-study core biopsies undergo mutational analysis. Results: 10 pts have enrolled (median age 65 yr [range 51-79], median baseline PSA: 85.78 [22.17-809.9 ng/mL]). 7 pts have GS ≥ 8. Grade 3/4 adverse events include anemia 2/7 (29%), thrombocytopenia, lymphopenia, neutropenia, nausea, fatigue, UTI, and lung infection [1/7 each, (14%)]. 5/7 pts (71%) on-study >2 months (mos) have PSA declines > 50%. Median PFS is 7.8 mos (95% CI: 1.8 mos-undefined). Conclusions: Preliminary data shows D+O is well tolerated with activity in an unselected population. Accrual is ongoing with biomarker analysis. Clinical trial information: NCT02484404. [Table: see text]
Efficacy of cabazitaxel (CABA) rechallenge in heavily-treated patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Thibault Constance , Eymard Jean-Christophe , Hardy-Bessard Anne-Claire , Birtle Alison J. , Krainer Michael , Baciarello Giulia , Flechon Aude , Le Moulec Sylvestre , Spaeth Dominique , Laguerre Brigitte , Caffo Orazio , Deville Jean-Laurent , Beuzeboc Philippe , Hasbini Ali , Gross-Goupil Marine , Helissey Carole , Bennamoun Mostefa , Oudard Stephane
Published: September 2018

5033

Background: Only 2 chemotherapies have shown an overall survival (OS) benefit in mCRPC: docetaxel (DOC) and CABA. In patients (pts) previously treated with a new hormonal therapy (NHT: enzalutamide or abiraterone), DOC and CABA, therapeutic options are limited. We previously reported some activity of DOC rechallenge in good responders to first-line DOC. We present here the results of a retrospective study evaluating the efficacy and safety of CABA rechallenge. Methods: Records of 70 mCRPC pts rechallenged with CABA were collected in 17 centers (France, Italy, UK, Austria). To be included, pts should have previously received DOC, NHT and CABA with a good response to CABA. Results: Of these 70 pts, 52 received DOC-NHT-CABA, 15 DOC-CABA-NHT and 3 NHT-DOC-CABA. At rechallenge, 83% had a high-volume disease (CHAARTED definition), 10% had visceral mets, 66% consumed narcotic analgesics, 68 % were ECOG 0-1 and median neutrophil/lymphocyte ratio (NLR) was 3.1. CABA was rechallenged for a median of 6 cycles (25 mg/m2 q3w, 59%; 20 mg/m2, 27%; 16 mg/m2q3w 11%) with prophylactic G-CSF in 47%. Median time from last CABA cycle was 8.6 months (mo). CABA rechallenge had an acceptable tolerability: 7 pts (10%) had grade 3-4 toxicity (neutropenia). Data on efficacy are reported in Table 1. Median progression-free survival (PFS) was 11.3 mo with DOC, 12 mo with NHT, 11.9 mo with first CABA (median 8 cycles), and 7.8 mo with CABA rechallenge. Median OS calculated from the first life-extending therapy was 59.9 mo (95% CI 47.8; 66.4). Conclusions: This retrospective cohort of heavily treated mCRPC pts suggests that CABA rechallenge has a good activity with a manageable toxicity. CABA rechallenge might be an option in heavily treated pts still fit to receive chemotherapy. [Table: see text]
Linking tumor mutational load to clinical responses to ipilimumab (IPI) in men with advanced prostate cancer (PCa).
Authors: Subudhi Sumit Kumar , Aparicio Ana , Troncoso Patricia , Zhang Jianhua , Gumbs Curtis , Wu Chang-jiun , Gao Jianjun , Vence Luis M , Blando Jorge M , Corn Paul Gettys , Araujo John C. , Zurita Amado J. , Prokhorova Ina N. , Van Alstine Michael , Logothetis Christopher , Futreal Andrew , Allison James Patrick , Sharma Padmanee
Published: September 2018

5065

Background: Tumor mutational load and neoantigens have been associated with responses to immune checkpoint therapies in patients (pts) with melanoma and lung cancer. We designed a clinical trial (NCT02113657) in advanced PCa to determine whether the induction of antitumor responses by IPI correlate with T cell responses to PCa neoantigens. Methods: All advanced PCa pts enrolled into this study had sufficient DNA/RNA from tumor tissue obtained prior to receiving IPI (3 mg/kg every 21 days for up to 4 doses) for whole-exosome sequencing (WES) and RNA-seq. Results: Twenty-one of 30 pts have been enrolled. Nine (43%) have received all 4 doses of IPI. IPI was discontinued prematurely in 9 pts (43%) due to drug-related toxicities and in 3 (14%) due to disease progression. All 3 of the latter had liver metastases. To date, tumors from 13 pts have been comprehensively analyzed by WES and RNA-seq. The median time from IPI #1 to the next systemic therapy for these pts was 24 weeks (IQR, 18.3 – 54.3). Responders (R) were defined as pts whose time to next systemic therapy was > 24 weeks. The median time to next systemic therapy for R (n = 7, 54%) is 55 weeks (IQR, 52.0 – 89.0; 2 pts with ongoing responses) versus 18 weeks (IQR, 10.5 – 23.0) for non-responders (NR; n = 6, 46%). In an analysis of all 13 pts, including those with liver metastases, tumor mutational load and frequency of expressed non-synonymous mutations were similar for R and NR pts. However, a subset analysis, excluding pts with liver metastases, revealed > 100 total mutations and/or > 10 expressed non-synonymous mutations in 7/7 R versus 1/4 NR. Conclusions: For advanced PCa pts without liver metastases, tumor mutational load may be associated with responses to IPI. Identification of immunodominant neoantigens may lead to the development of personalized vaccines to be combined with immune checkpoint therapies for the effective treatment of pts with PCa. Clinical trial information: NCT02113657.
Phase 1-2 study of progesterone receptor (PR) inhibition with extended-release (ER) onapristone (ONA) alone or in combination with abiraterone (AA) in patients (pts) with castration-resistant prostate cancer (CRPC) incorporating plasma DNA analysis to define androgen receptor (AR) status.
Authors: Jayaram Anuradha , Nowakowska Karolina , Mateo Joaquin , Kumar Sanjeev , Hernandez Tatiana , Fulton Ben , Nava Rodrigues Daniel , Riisnaes Ruth , Zukiwski Alexander , Bexon Alice Susannah , Proniuk Stefan , Barranco Charles , Bianchini Diletta , Zafeirou Zafeiris , Perez Lopez Raquel , Tunariu Nina , Pacey Simon , Jones Robert J. , De Bono Johann S. , Attard Gerhardt
Published: September 2018

5071

Background: An urgent need exists for new therapies after progression (PD) onAA and enzalutamide (ENZ). Increased PR expression or progesterone-activating AR mutations have been associated with resistance to AR targeting. We aimed to test ONA, a type I PR antagonist with clinical activity in PRpos cancers, in AA/enz-resistant CRPC. In a prospectively defined exploratory analysis, we aimed to report outcome by plasma AR status ( pAR). Methods: This was a multi-institution, open label phase I/II clinical trial in pts progressing after ENZ/AA. Pts were first treated with single agent (SA) ONA using a randomised dose escalation design. ONA at 2 doses was then combined with AA (1000mg od with pred 5mg bid) in pts progressing on AA. The primary end-points were safety, pharmacokinetics (PK) and anti-tumor activity split by p AR. Archival and metastatic biopsies were collected when possible and tested for PR status. p AR was studied using previous methods (Romanel STM 2015). Results: 21 pts received SA ONA (5 = 10mg/ 5 = 20mg/ 4 = 30mg/ 4 = 40mg /3 = 50mg BID) and 15 pts received ONA-AA combination (5 = 30mg ONA BID, 10 = 50mg ONA BID). There were not DLTs or significant LFT abnormalities and no G3/4 adverse events (AE), no treatment discontinuations due to AEs and no SAEs considered related to ONA. PK in SA ONA observed active plasma concentrations and no interaction with AA. Of 32 evaluated pts 15 had a 2105T > A (p.L702H) or 2632A > G (p.T878A) AR mutation detected in plasma pre-treatment and 1 had AR copy number gain. PSA declines were not observed with SA ONA but in 2 pts with combination (-30%, -7%) who were AR normal. The rPFS on SA ONA was 2.8 months for AR normal and 2.6 for AR aberrant (Hazard ratio (HR) 1.41; 95% CI, 0.62-3.72; P 0.48) and on combination was 4.4 months for AR normal (8/15) and 2.2 for AR aberrant (7/15) (HR 6.08; 95%CI, 6.32-221.9; P < 0.001). Conclusions: ONA is safe in CRPC as SA and in combination with AA. There was no difference in rPFS by p AR status for SA ONA but on the combination with AA, pts who were plasma AR normal had a significantly longer rPFS. Clinical trial information: NCT02049190.
A randomized, double-blind, phase III study comparing SB3 (trastuzumab biosimilar) with originator trastuzumab in patients treated by neoadjuvant therapy for HER2-positive early breast cancer.
Authors: Pivot Xavier B. , Bondarenko Igor , Dvorkin Mikhail , Trishkina Ekaterina , Ahn Jin-Hee , Im Seock-Ah , Sarosiek Tomasz , Chattopadhyay Sanjay , Wojtukiewicz Marek , Moiseyenko Vladimir , Shparyk Yaroslav V. , Bello Maximino De Guzman , Semiglazov Vladimir , Song Sujeong , Lim Jae Yun
Published: September 2018

509

Background: SB3, a proposed biosimilar to the originator trastuzumab (TRZ), demonstrated similarity to its originator in terms of biological activities and pharmacokinetic (PK) equivalence. This study compared SB3 to TRZ in terms of efficacy, safety, PK, and immunogenicity in patients treated by neoadjuvant therapy for HER2 positive early breast cancer (NCT02149524). Methods: Phase III, randomized, double blind, multicenter study compared neoadjuvant SB3 or TRZ for 8 cycles concurrently given with chemotherapy (docetaxel followed by 5-fluorouracil/epirubicin/cyclophosphamide). Then patients underwent surgery followed by 10 cycles of SB3 or TRZ. The primary endpoint was breast pathologic complete response (bpCR) rate. Equivalence was declared if the 90% confidence interval (CI) of the ratio or the 95% CI of the difference of the bpCR rates in the per-protocol set (PPS) were contained within the pre-defined equivalence margins (0.785, 1.546) and (-13%, 13%), respectively. Secondary endpoints were total pathologic complete response (tpCR), overall response rate (ORR), event-free survival, PK, immunogenicity, and safety. Results: 800 patients were included in PPS. The bpCR rates were 51.7% for SB3 and 42.0% for TRZ. The ratio of bpCR rate was 1.259 and its 90% CI was 1.112-1.426, within the pre-defined equivalence margin. The difference of bpCR rate was 10.70% and its 95% CI was 4.13-17.26; the lower margin was contained within, the upper margin was outside the pre-defined equivalence margin. Secondary endpoints were comparable between SB3 vs TRZ: tpCR rate (45.8% vs 35.8%); ORR (96.3% vs 91.2%). Safety was comparable between SB3 vs TRZ during neoadjuvant period: incidence of treatment-emergent adverse events (96.6% vs 95.2%), most commonly neutropenia, alopecia, and nausea; incidence of serious adverse events (10.5% vs 10.7%). PK equivalence was demonstrated and immunogenicity between SB3 vs TRZ was comparable (0.7% vs 0.0%). Conclusions: Equivalence was demonstrated between SB3 and TRZ based on the ratio of bpCR rates. Safety, PK, and immunogenicity were similar. Complete safety and survival data will follow. Clinical trial information: NCT02149524.
Double-blind, randomized phase III study to compare the efficacy and safety of CT-P6, trastuzumab biosimilar candidate versus trastuzumab as neoadjuvant treatment in HER2 positive early breast cancer (EBC).
Authors: Stebbing Justin , Baranau Yauheni Valerievich , Baryash Valery , Manikhas Alexey , Moiseyenko Vladimir , Dzagnidze Giorgi , Javrid Edvard , Boliukh Dmytro , Stroyakovskiy Daniil , Pikiel Joanna , Eniu Alexandru E. , Komov Dmitry , Zautashvili Zakaria , Morar-Bolba Gabriela , Li Rubi Khaw , Lifirenko Igor , Rusyn Andriy V. , Lee Sang Joon , Lee Sung Young , Esteva Francisco J.
Published: September 2018

510

Background: CT-P6 (C) is a proposed biosimilar to trastuzumab. This trial (NCT02162667) evaluated the similarity of C and trastuzumab in efficacy and safety for HER2+ EBC. Methods: 549 patients with HER2+ EBC were randomized to receive C (n=271) or trastuzumab (n=278) in combination with docetaxel (Cycles 1-4) and 5-fluorouracil, epirubicin, and cyclophosphamide (Cycles 5-8). C or trastuzumab was administered at 8 mg/kg (Cycle 1 only) followed by 6 mg/kg every 3 weeks. The primary endpoint was pathological complete response (pCR) rate at surgery. Secondary endpoints were overall response rate (ORR), PK, PD and safety. After surgery, patients received adjuvant C or trastuzumab to complete a total of 1-year treatment. Results: The pCR rate was 46.8% for C and 50.4% for trastuzumab. The 95% CIs for the risk ratio estimate were within the equivalence margin (0.74, 1.35) in PPS and ITT analyses. Other efficacy endpoints were similar between C and trastuzumab. The proportion of patients with at least 1 treatment-emergent SAE was 6.6% for C and 7.6% for trastuzumab. Only 1 patient in each group withdrew treatment due to significant LVEF decrease. Infusion-related reaction was reported for 8.5% of patients in C and 9.0% of patients in trastuzumab. Conclusions: This study demonstrated the similarity of efficacy in terms of pCR between CT-P6 and trastuzumab in EBC patients. Secondary efficacy endpoints also supported the similarity between CT-P6 and trastuzumab. CT-P6 was well tolerated with a similar safety profile to that of trastuzumab during the neoadjuvant period. Clinical trial information: NCT02162667. [Table: see text]
Seven-year (yr) follow-up of adjuvant paclitaxel (T) and trastuzumab (H) (APT trial) for node-negative, HER2-positive breast cancer (BC).
Authors: Tolaney Sara M. , Barry William Thomas , Guo Hao , Dillon Deborah , Dang Chau T. , Yardley Denise A. , Moy Beverly , Marcom P. Kelly , Albain Kathy S. , Rugo Hope S. , Ellis Matthew James , Shapira Iuliana , Wolff Antonio C. , Carey Lisa A. , Overmoyer Beth , Partridge Ann H. , Hudis Clifford A. , Krop Ian E. , Burstein Harold J. , Winer Eric P.
Published: September 2018

511

Background: Retrospective data suggest that patients (pts) with small HER2+ cancers have more than just minimal risk of disease recurrence. The APT trial was designed to address treatment for such pts. We have previously reported 3-yr disease-free survival (DFS) and here we provide an updated analysis with 7-yr DFS. Methods: APT is a single arm multicenter, phase II study of TH. Pts with HER2+ BC (IHC 3+ and/or FISH ratio > 2.0) with negative nodes (a single axillary lymph node micrometastasis was allowed) and tumor size < 3 cm were eligible. Pts received T (80 mg/m2) with H x 12 weekly (w), followed by H (weekly or q3w) x 39w. The primary endpoint was DFS. Recurrence Free Interval (RFI), Breast Cancer Specific Survival (BCSS), and overall survival (OS) were also analyzed. Intrinsic subtyping by PAM50 was performed on the nCounter Analysis system on archival tissue. Results: 410 pts were enrolled from September 2007 to September 2010 and 406 began protocol therapy. 67% had hormone-receptor (HR)+ tumors. Distribution by tumor size: 2% T1mi; 17% T1a; 30% T1b; 42% T1c, and 9% T2 ≤ 3 cm. 6 pts had a nodal micrometastasis. With a median follow-up of 6.5 yrs, there were 23 DFS events observed: 4 (1.0%) distant recurrences, 5 local/regional recurrences (1.2%), 6 new contralateral BC (1.5%), and 8 deaths without documented recurrence (2.0%). The 7-yr DFS was 93.3% (95% CI 90.4-96.2); 7-yr DFS for HR+ pts was 94.6% (95% CI 91.8-97.5) and for HR- pts was 90.7% (95% CI 84.6-97.2). 7-yr RFI was 97.5% (95% CI 95.9-99.1); 7-year BCSS is 98.6% (95% CI 97.0-100); and 7-yr OS was 95.0% (95% CI 92.4-97.7). Ongoing PAM50 testing (n = 227 pts) identified 142 (63%) HER2-enriched; 22 (10%) luminal A, 26 (11%) luminal B, and 20 (9%) basal-like; 17 samples had a poor quality assay. Additional testing and associations with clinical outcomes will be presented at the meeting. Conclusions: These data suggest that TH as adjuvant therapy for node-negative HER2+ BC is associated with few recurrences and only 4 distant recurrences with longer follow-up. Based on these data, if chemotherapy/trastuzumab is given to a pt with stage I HER2+ breast cancer, the TH regimen should be considered a standard treatment. Clinical trial information: NCT00542451.
A phase III, open label, prospective, randomized, multicenter, neoadjuvant study of chemotherapy versus endocrine therapy in premenopausal patient with hormone responsive, HER2 negative, breast cancer (KBCSG 012).
Authors: Kim hee Jeong , Noh Woo Chul , Lee Eun Sook , Kim Leesu , Jung Yongsik , Han Wonshik , Nam Seok Jin , Ahn Sei-Hyun
Published: September 2018

517

Background: Neoadjuvant endocrine therapy has shown efficacy in hormone-responsive postmenopausal breast cancer patients. We aimed to assess the efficacy and safety of cytotoxic chemotherapy versus endocrine therapy for hormone-responsive lymph node-positive premenopausal breast cancer patients in a neoadjuvant setting. (NCT01622361). Methods: In this phase 3, randomized, double blind, parallel group, multicenter study, we enrolled premenopausal women with estrogen receptor (ER)-positive, HER2-negative, and lymph node-positive premenopausal breast cancer patients. Patients were randomized to either 24 weeks of neoadjuvant chemotherapy with adriamycin plus cyclophosphamide (AC) followed by taxane (T) or neoadjuvant endocrine therapy with zoladex and tamoxifen. Results: 187 patients were randomly assigned to chemotherapy (n=95) or endocrine therapy (n=92), and 174 patients completed the 24 week neoadjuvant treatment period (n=87, both). More patients in the chemotherapy group had a complete or partial response than did those in endocrine therapy arm on both caliper (chemotherapy 83.9% vs endocrine therapy 71.3%, OR 0.476 95% CI 0.228 to 0.994) and MRI (chemotherapy 83.7% vs endocrine therapy 52.9%, OR 0.219, 95% CI 0.107 to 0.447). Three patient on chemotherapy group (3.4%) and 1 patients (1.15%) on endocrine treatment group showed complete pathologic response. In the patients who had breast cancer with low Ki 67 expression (<20%) on initial biopsy, clinical response on caliper were shown similar on both treatment group (HR 0.958, 95%CI 0.296 to 3.101). Five patients who had no tumor on the breast or lymph node after 24 week neoadjuvant endocrine therapy had higher ER score (all allred score >6), all low grade (1or 2) low Ki 67(≤20%) expression (4/5 patients) on initial biopsy specimen. Conclusions: In premenopausal breast cancer patients, 24 weeks neoadjuvant chemotherapy showed better clinical response than endocrine therapy. Low Ki 67 expression could be a parameter of the endocrine treatment. Clinical trial information: NCT01622361.
Independent validation of stromal uPA in archived tumor samples from the prospectively randomized ABCSG8 trial to provide level 1b evidence for a prognostic value of uPA immunohistochemistry in endocrine-treated postmenopausal breast cancer patients.
Authors: Singer Christian F. , Jahn Stephan W , Rudas Margaretha , Bago-Horvath Zsuzsanna , Fitzal Florian , Greil Richard , Mlineritsch Brigitte , Schmitt Manfred , Filipits Martin , Gnant Michael ,   ABCSG
Published: September 2018

536

Background: We have recently demonstrated that urokinase Plasminogen Activator (uPA), together with its inhibitor PAI-1, have prognostic value in hormone-receptor positive early breast cancer, and can be measured in FFPE archived tumor samples. We have now aimed to validate the prognostic role of uPA protein expression in FFPE archived tumor samples in an independent cohort of endocrine-treated breast cancer patients. Methods: 303 postmenopausal women with hormone receptor–positive, early breast cancer who had received 5 years of endocrine therapy in the prospectively designed ABCSG-08 trial, and in whom FFPE tumor tissue was available, were included in this analysis. Stromal uPA and PAI-1 protein expression was evaluated by immunohistochemistry and correlated with distant recurrence-free survival (DRFS) and overall survival (OS). Results: Stromal uPA was detected in 132 of 297 tumors (44.4%), and 74 out of 269 samples (27.5%) exhibited stromal PAI-1, while co-expression of both proteins was found in 48 of 294 (16.3%) samples. Neither uPA nor PAI-1 expression were associated with tumor size, age, nodal status, grading, or receptor status. Patients whose tumor stroma expressed uPA protein were more likely to have a shorter DRFS (adjusted HR for relapse: 2.78; 95% CI 1.31-5.93; p=0.008 Cox regression analysis) and OS (adjusted HR for death: 1.29; 95% CI 0.86-12.50; p=0.161) than women without uPA expression. No such association was observed for PAI-1 and for the uPA/PAI1 ratio. After a median follow-up of 5.6 years women with uPA-positive tumors experienced a significantly shorter DRFS (93.3% vs 84.8%; p<0.013 log rank test) and tended to have a worse OS (83.0.4% vs 77.3%; p=0.106) compared to women with uPA negative tumors. Conclusions: By confirming the clinical utility of stromal uPA IHC in archived breast cancer samples from an independent prospective randomized trial, we now provide level 1b evidence for a prognostic role of stromal uPA in women with endocrine-responsive early breast cancer.
Which patient characteristics drive treatment decisions in elderly patients with early stage hormone receptor–positive breast cancer?
Authors: Satram-Hoang Sacha , Reyes Carolina M. , Stein Alisha , Hoang Khang Q. , Momin Faiyaz , Cortazar Patricia
Published: September 2018

538

Background: Hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) is the most common biologic subtype of breast cancer (BC). We examined treatment patterns and outcomes associated with adjuvant or neoadjuvant therapy among elderly patients (pts) in the US. Methods: The analysis included 18,470 first primary HR+HER2- BC pts from the linked SEER-Medicare database. Pts were diagnosed with Stage I-III disease between 1/1/2007-12/31/2011, ≥66 years, continuously enrolled in Medicare Parts A/B in the year prior to diagnosis, enrolled in Part D in the year after diagnosis, and underwent BC surgery ≤6 months after diagnosis. Time-varying Cox proportional hazards regression assessed overall survival adjusting for pt characteristics. Date of last follow-up was 12/31/2013. Results: There were 13,670 (74%) pts treated with hormonal therapy +/- chemotherapy and 4,800 (26%) untreated. Compared to treated pts, untreated pts were older, had earlier stage, lower grade, smaller tumors, poorer performance, higher comorbidity, and less genomic testing for risk of recurrence (p<0.0001). In a multivariate analysis, increasing age, stage, tumor size, tumor grade, comorbidity score and poor performance were significantly associated with higher mortality risks, while use of genomic testing was associated with a lower risk of death. The Cox model showed a 48% higher risk of death in untreated compared to treated pts (HR=1.48; 95% CI=1.35-1.61). Even in a subset of 8,967 pts with stage I disease, tumor size <2.0cm and grade 1/2; untreated pts had a 22% higher risk of death compared to treated pts (HR=1.22; 95% CI=1.05-1.41). Conclusions: Patients who are older with favorable disease characteristics (earlier stage, smaller tumor, lower grade) are less likely to be treated and have a higher risk of death compared to pts who received adjuvant or neoadjuvant therapy. The unmet need among elderly BC pts remains, suggesting that age should not deter guideline-based therapy. [Table: see text]
A randomized phase III trial of docetaxel plus cisplatin or paclitaxel plus carboplatin compared with doxorubicin plus cisplatin as adjuvant chemotherapy for endometrial cancer at high risk of recurrence: Japanese Gynecologic Oncology Group study (JGOG2043).
Authors: Nomura Hiroyuki , Aoki Daisuke , Michimae Hirofumi , Mizuno Mika , Nakai Hidekatsu , Arai Masahide , Sasagawa Motoi , Ushijima Kimio , Sugiyama Toru , Saito Motoaki , Tokunaga Hideki , Omatsu Kohei , Nakanishi Toru , Watanabe Yoh , Saito Toshiaki , Yaegashi Nobuo
Published: September 2018

5503

Background: The superiority of chemotherapy regimens employing a taxane plus a platinum agent over standard therapy with doxorubicin plus cisplatin (AP) was recently demonstrated for advanced or recurrent endometrial cancer. This multicenter phase III trial evaluated the clinical benefit of taxane plus platinum agent regimens as adjuvant chemotherapy compared with AP for endometrial cancer patients at high risk of recurrence after surgery. Methods: Endometrial cancer patients having a high risk of recurrence and postoperative residual disease < 2 cm were randomly assigned (1:1:1) with stratification by FIGO stage and histologic grade to receive 6 cycles of doxorubicin (60 mg/m2) plus cisplatin (50 mg/m2) on day 1 (AP), docetaxel (70 mg/m2) plus cisplatin (60 mg/m2) on day 1 (DP) or paclitaxel (180 mg/m2) plus carboplatin (AUC 6.0 mg/mL x minute) on day 1 (TC) every 3 weeks as adjuvant chemotherapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), adverse events, and tolerability. Results: From November 2006 to January 2011, 788 patients were enrolled from 118 institutions in Japan and were eligible for evaluation. The proportion of patients receiving 6 cycles was 80% for AP, 83% for DP, and 76% for TC, and tolerability of the regimens showed no significant difference. After a median follow-up period of 7.0 years, there was no statistical difference of PFS (P=0.1246) or OS (P=0.6734) among the 3 groups. The 5-year PFS rate was 74.9% for AP, 80.9% for DP, and 74.7% for TC, while the 5-year OS rates were 84.3%, 89.3%, and 88.4%, respectively. Conclusions: There was no significant difference of survival among patients receiving AP, DP, or TC as adjuvant chemotherapy for endometrial cancer. Since each regimen showed adequate tolerability, taxane plus platinum agent regimens may be a reasonable alternative to AP. Clinical trial information: UMIN000000522.
Phase II randomized trial of neoadjuvant (NA) chemotherapy (CT) with or without bevacizumab (Bev) in advanced epithelial ovarian cancer (EOC)‏ (GEICO 1205/NOVA TRIAL).
Authors: Garcia Garcia Yolanda , De Juan Ana , Mendiola Cesar , Barretina-Ginesta Maria Pilar , Prat Aleix , Santaballa Ana , Bover Isabel , Gil-Martin Marta , Manzano Aránzazu , Rubio M Jesus , Romeo Margarita , Arqueros Cristina , Garcia Martinez Elena , Gonzalez Martin Antonio
Published: September 2018

5508

Background: First line carboplatin(C)-paclitaxel(P) and Bev has proved to be an active combination after primary debulking surgery and improve overall survival in sub-optimal resected advanced EOC patients (pts). However, the role of Bev in the NA setting has not been well defined yet. Methods: We performed a phase II randomized open label multicentric study in pts with high grade serous or endometrioid EOC, FIGO stage III-IV, ECOG 0-2, considered unresectable in whom NA CT and interval debulking surgery (IDS) were planned. Main exclusion criteria were intestinal occlusion and contraindication for Bev. Pts were randomized to 4 courses of triweekly C AUC 6 and P 175 mg/m2 iv alone or with at least 3 courses of Bev 15 mg/kg i.v. every 3w in experimental arm. The primary endpoint was complete macroscopic response (CMR) rate at IDS. Secondary objectives were safety, surgical feasibility, optimal surgery rate (OSR), RECIST 1.1 and CA-125 GCIG response rate. Sample collection for translational research was taken at diagnosis and IDS. After surgery pts in both arms completed 3 additional cycles of CT and Bev, followed by maintenance Bev up to 15 mo. Results: Sixty-eight out of seventy-one evaluable pts. Clinical pts characteristics were well balanced, median age 60.0 y.o and a 33.8% stage IV. No differences in CMR were found at IDS (2/33 Control and 2/35 Bev). Bev arm was favoured in rate of surgical feasibility (66.7 vs 88.6%, p = 0.029), while no differences were found in OSR (63.6 vs 65.7%, p = 0.858) and in number of pts considered unresectable at time of IDS (2 vs 0). Median time from IDS to restarting Bev was 7.1 w. Median PFS was 20.3 mo in both arms, 20.13 mo in control arm and 20.36 mo in Bev arm, HR: 1.14 (IC 95%, 0.656 - 1.994). There were lower rates of serious adverse events (grade 3-4) in Bev arm (69.7 vs 42.9%, p = 0.026). 8 pts presented AE of special interest in Bev arm (3G2 proteinuria, 1G2/1G3 hypertension, 1G3 entero-vaginal fistulae, 1G3 entero-cutaneous fistulae, 1G3 deep venous thrombosis, 1G2 bleeding, 1G1 surgical dehiscence). Conclusions: NACT with Bevacizumab was feasible and improved the surgical outcomes at IDS in pts initially considered unresectable. Clinical trial information: 2012-003883-31.
Evaluation of BRCA1/2 and homologous recombination defects in ovarian cancer and impact on clinical outcomes.
Authors: Yates Melinda S. , Timms Kirsten , Daniels Molly S , Oakley Holly D. , Munsell Mark F. , Lanchbury Jerry S. , Lu Karen H.
Published: September 2018

5511

Background: Recent studies show that germline or somatic BRCA1/2 mutations and homologous recombination (HR) defects can be used to predict response to PARP inhibitors in recurrent ovarian cancer. However, the impact of defects in BRCA1/2 and HR genes on overall clinical outcomes are not yet defined for patients undergoing neoadjuvant chemotherapy (NACT) versus upfront surgical debulking (USD). Methods: Previously untreated ovarian cancer patients were prospectively enrolled under approved IRB protocol. Germline and tumor BRCA1/2 mutation testing and methylation were analyzed when sufficient tumor and blood was available. Mutation in 21 additional hereditary cancer genes (including HR genes) was also evaluated. Tumor HR defects were scored on LOH, telomeric allelic imbalance, and large-scale state transitions (as previously described). Presence of germline or somatic BRCA1/2 mutations, BRCA1 methylation, HR score ≥42, or germline mutation in other HR genes were defined together as HRD positive. Results: Of 299 enrolled patients, 129 (43%) received USD and 170 (57%) received NACT. Patients receiving USD had better outcomes compared to NACT, including overall survival (OS, 65.8 vs 45.2 months, p = 0.0003) and event free survival (EFS, 24.8 vs 15.6 months, p < 0.0001). In the overall cohort, EFS was significantly longer for HRD positive patients vs HRD negative (20.5 vs 16.3 months, p = 0.0268). Patients with somatic and germline BRCA1/2 mutations had longer OS vs BRCA1/2 negative (65.3 vs 46.1 months, p = 0.0403). Overall outcomes were worse in NACT compared to USD, but impact of BRCA1/2 mutations and HR defects was stronger in this group. NACT patients with any HR defect had longer EFS (19.7 vs 14.5 months, p = 0.0247). NACT patients with BRCA1/2 germline mutations had longer OS (65.3 vs 38.3 months, p = 0.0230). NACT patients with BRCA1/2 germline mutation had longer EFS (22.6 vs 14.6 months, p = 0.0047). OS and EFS in USD patients were significantly changed based on only debulking status; mutation or HR status did not have a statistically significant effect. Conclusions: While HR defects and BRCA1/2 mutations influence overall outcomes for ovarian cancer patients, the impact is stronger in NACT compared to USD.
Effect of adoption of neoadjuvant chemotherapy for advanced ovarian cancer on all-cause mortality.
Authors: Melamed Alexander , Fink Günther , Wright Alexi A. , Keating Nancy Lynn , Gockley Allison Ann , del Carmen Marcela G. , Schorge John O. , Rauh-Hain Jose Alejandro
Published: September 2018

5537

Background: Use of neoadjuvant chemotherapy followed by surgery for advanced epithelial ovarian cancer is controversial in the United States. Methods: Use of neoadjuvant chemotherapy for stage IIIC and IV ovarian cancer has increased gradually in the United States since 2007, but rates of adoption vary by region. Between 2011 and 2012, use of neoadjuvant chemotherapy increased by 27% in the New England and East South Central regions, but remained unchanged in three control regions (South Atlantic, West North Central, and East North Central regions). Employing prospectively collected data from Commission on Cancer-accredited cancer programs in the United States, we used this discontinuity in treatment approach to assess the causal impact of neoadjuvant chemotherapy on all-cause mortality in a quasi-experimental fuzzy regression discontinuity design. Kaplan-Meier curves and proportional hazard models were estimated to compare mortality differences between rapidly-adopting regions and controls. We also conducted a cross-sectional analysis of the relationship between regional use of neoadjuvant chemotherapy and survival. Results: We identified 1,156 women treated for advanced epithelial ovarian cancer during 2011 and 2012 in the two rapidly-adopting regions and 4,878 women in the three control regions. In the rapidly-adopting regions, patients treated in 2012 compared with 2011 had a mortality hazard ratio (HR) of 0.81 (95%CI=0.71-0.94) after adjusting for mortality time trends, while no difference was observed in control regions (HR=1.02, 95%CI=0.93-1.12). Compared with control regions, we observed larger declines in 90-day surgical mortality (7.0% to 4.0% versus 5.0 to 4.3%, p=0.01) and in the proportion of women not receiving surgery and chemotherapy (20.0% to 17.4% versus 19.0 to 19.5%, p=0.04) in rapidly adopting regions. Cross-sectional analysis confirmed that treatment in regions with greater use of neoadjuvant chemotherapy was associated was lower mortality (p=0.001). Conclusions: Adoption of neoadjuvant chemotherapy for advanced epithelial ovarian cancer in New England and East South Central regions led to a sizable reduction in mortality within three years after diagnosis.
Efficacy and long-term safety with bevacizumab included in neoadjuvant and adjuvant therapies in patients with advanced ovarian cancer: Results of the ANTHALYA trial.
Authors: Joly Florence , Cottu Paul H. , Gouy Sebastien , Lambaudie Eric , Selle Frédéric , Leblanc Eric , Floquet Anne , Pomel Christophe , Chereau Elisabeth , Zohar Sarah , Dupin Julien , Balouet Sabine , Ferri Rose-Marie , Urbieta Marisol , Kockler Leila , Rouzier Romain
Published: September 2018

5538

Background: ANTHALYA showed that neoadjuvant Bevacizumab (B) added to Carboplatin and Paclitaxel (CP) was well tolerated and achieved encouraging complete resection rates at IDS (58.6%) in unresectable FIGO stage IIIC/IV ovarian, tubal or peritoneal adenocarcinoma (EJC 2017;70:133–42). We report response rates, PFS and long-term safety. Methods: Patients (pts) in ANTHALYA were randomized 2:1 to 4 cycles (c) of neoadjuvant CP ±3 c of B (15 mg/kg), IDS for eligible patients, then 1 c of CP + 3 c CPB + 21 c of B. Response and progression were evaluated by RECIST 1.1 using CT scan and CA-125. Circulating tumor cell counts (CTC) were evaluated at baseline, c2 and IDS. Results: 95 pts were treated in CP (n=37) or BCP (n=58) groups (mean study duration were 16.1 months [mo] and 16.9 mo, respectively). 80 pts (CP: 81% / BCP: 88%) had a CA-125 response (50% reduction in CA-125 level) before IDS. Objective response rates were 65% (62% CP / 67% BCP) before IDS (28 days after c4), 46% at c8 (46% CP/ 47% BCP) and 19% at c26 (19% CP/ 19% BCP). 24 (64.9%) CP pts and 26 (44.8%) BCP pts progressed during follow up (median PFS 21.2 mo [95%CI: 14.5, 26.7] and 23.5 mo [18.5, 30.6], respectively). Median PFS was respectively: 25.8 mo (21.0, 30.0) and 17.1 mo (13.5, 22.2) for pts with/without complete resection at IDS; 21.0 mo (15.0, 25.4) and 25.8 mo (18.5, 27.2) for pts with/without baseline CTCs (n=29 / 59); 21.8 mo (17.5, 27.1) and 22.2 mo (15.3, 38.0) for pts with FIGO IIIC and IV tumors. 36 pts did not receive adjuvant therapy within the study (21 were unresectable for IDS), 59 pts (57% CP / 66% BCP) received it. Of those, 34 pts (52% CP / 61% BCP) had Grade ≥3 adverse events including neutropenia (29% CP / 34% BCP), HBP (10% CP / 8% BCP), proteinuria (10% CP / 0% BCP), deep venous thrombosis (5% CP / 3% BCP), pulmonary embolism (0% CP / 8% BCP). Conclusions: Neoadjuvant BCP followed by IDS and adjuvant BCP achieves high response rates and extended PFS with an acceptable toxicity in this specific population of pts with FIGO stage IIIC/IV ovarian, tubal or peritoneal adenocarcinoma not eligible for primary debulking surgery. IDS outcome and CTC counts should be further explored as long term prognostic factors. Clinical trial information: NCT01739218.
Safety findings from FORWARD II: A Phase 1b study evaluating the folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC) mirvetuximab soravtansine (IMGN853) in combination with bevacizumab, carboplatin, pegylated liposomal doxorubicin (PLD), or pembrolizumab in patients (pts) with ovarian cancer.
Authors: O'Malley David M. , Moore Kathleen N. , Vergote Ignace , Martin Lainie P. , Gilbert Lucy , Gonzalez Martin Antonio , Nepert Dale L. , Ruiz-Soto Rodrigo , Birrer Michael J. , Matulonis Ursula A.
Published: September 2018

5553

Background: FORWARD II is a phase 1b study of the FRα-targeting ADC, mirvetuximab soravtansine (IMGN853), in combination with bevacizumab (BEV), carboplatin, PLD, or pembrolizumab in adults with FRα-positive EOC, primary peritoneal, or fallopian tube tumors (NCT02606305). Methods: The escalation stage of this trial evaluated the safety and tolerability of IMGN853 as part of 4 combination regimens: IMGN853 + BEV; + carboplatin; + PLD; and + pembrolizumab. IMGN853 was administered in combination on Day 1 of a 21 (BEV or carboplatin) or 28-day cycle (PLD). Pembrolizumab escalation is continuing. The starting dose of IMGN853 was 5 mg/kg (adjusted ideal body weight, AIBW), one level lower than the recommended single agent phase 2 dose (RP2D; 6 mg/kg AIBW) defined in a first-in-human study (NCT01609556). Adverse events (AEs) were evaluated by CTCAE v4.0. Results: 46 pts enrolled in the first 3 cohorts. IMGN853 was escalated from 5 to 6 mg/kg. Carboplatin and PLD dosing were escalated from AUC4 to AUC5 and 30 to 40 mg/m2, respectively; BEV dosing remained constant at 15 mg/kg. Diarrhea, nausea, and fatigue were common across cohorts (all grades; 33-57%) and mostly low grade (i.e. ≤ 2), consistent with the IMGN853 safety profile from the earlier phase I monotherapy study. AEs of interest related to the combination agents were seen in each arm. For example, grade 1/2 proteinuria (36%) and grade 3 hypertension (21%) were only observed in the BEV combination. Thrombocytopenia (44%) and neutropenia (39%), grades 1-3, occurred most frequently in the carboplatin arm. Grade 3 anemia and vomiting (each 14%), as well as low grade (≤ 2) constipation (43%), were seen in the PLD cohort. Conclusions: The RP2D dose of IMGN853 was readily combined with the highest doses (as per protocol) of BEV, carboplatin, and PLD. The AE profiles for these combinations were manageable and as expected based on known profiles of each agent; importantly, no new safety signals were identified. Updated data from all 4 combination regimens will be presented. Clinical trial information: NCT02606305.