bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and clinical activity of atezolizumab (atezo) + radium-223 dichloride (r-223) in 2L metastatic castration-resistant prostate cancer (mCRPC): Results from a phase Ib clinical trial.
Authors: Morris Michael J. , Fong Lawrence , Petrylak Daniel Peter , Sartor A. Oliver , Higano Celestia S. , Pagliaro Lance C. , Alva Ajjai Shivaram , Appleman Leonard Joseph , Tan Winston , Vaishampayan Ulka N. , Porcu Raphaelle , Tayama Darren , Kadel Edward Ernest , Yuen Kobe Chi Yung , Datye Asim , Armstrong Andrew J.
Published: May 2020

5565

Background: mCRPC patients (pts) tend to have a poor prognosis and limited treatment (tx) options, especially those with concomitant bone metastases (mets). We explored the ability of combination tx with atezo (anti–PD-L1) and r-223 (α-particle emitter) to stimulate anti-tumor immunity in mCRPC pts. Methods: This Phase Ib study evaluated the safety and tolerability of atezo + r-223 in pts with mCRPC and multiple bone mets, visceral mets and/or lymphadenopathy who progressed after androgen pathway inhibitor tx. The initial cohort phase evaluated the safety and tolerability of a concurrent dosing schedule (CDS), in which atezo and r-223 were administered on the same day. Following assessment of CDS, pts were randomized 1:1:1 to CDS or 1 of 2 staggered dosing schedules (atezo or r-223 introduced a full cycle before the other). This was followed by an expansion of enrollment (randomized 1:1:1). Pts got atezo 840 mg IV q2w and r-223 at 55 kBq/kg IV 6 times at 4-wk intervals until unacceptable toxicity or loss of clinical benefit. Exploratory measures of efficacy included investigator-assessed ORR (RECIST 1.1), PSA response rate, time to PSA progression, radiographic PFS (rPFS; PCWG2 criteria) and OS. Biopsy samples were collected at baseline and prior to cycle 2 to evaluate changes in the tumor microenvironment during tx. Results: As of Oct 4, 2019, 45 pts were enrolled and 44 had evaluable data. Baseline characteristics were generally similar across groups. All 44 evaluable pts had ≥ 1 all-cause AE; 23 (52.3%) had Gr 3-4 AE. Eight pts (18.2%) had Gr 5 AE as per protocol reporting of deaths; 4 (9.1%) were from disease progression. Median follow-up was 13.9 mo (range, 1.7–34.2). Confirmed ORR was 6.8% (95% CI: 1.43, 18.66). Confirmed PSA response rate was 4.5% and median time to PSA progression was 3.0 mo (95% CI: 2.8, 3.3). Median rPFS was 3.0 mo (95% CI: 2.8, 4.6) and median OS was 16.3 mo (95% CI: 10.9, 22.3). Changes in PD-L1 and CD8 IHC were consistent with the known mechanism of action of atezo, as were changes in alkaline phosphatase with radium. Conclusions: No dose-limiting toxicities, safety signals, or changes in serum biomarkers were observed beyond the known safety profiles of atezo and r-223. This Phase 1b study did not seem to show clinical benefit from combination tx. Ongoing subgroup and biomarker analyses may provide additional insights. Studies of PD-1/PD-L1 targeted therapies in combination with tumor-directed radiation in molecularly selected mCRPC pts are planned or underway. Clinical trial information: NCT02814669 .
CARD: Overall survival (OS) analysis of patients with metastatic castration-resistant prostate cancer (mCRPC) receiving cabazitaxel versus abiraterone or enzalutamide.
Authors: Tombal Bertrand F. , Castellano Daniel , Kramer Gero , Eymard Jean-Christophe , De Bono Johann S. , Sternberg Cora N. , Fizazi Karim , Wulfing Christian , Bamias Aristotelis , Carles Joan , Iacovelli Roberto , Melichar Bohuslav , Sverrisdottir Asgerdur , Theodore Christine , Feyerabend Susan , Helissey Carole , Poole Elizabeth , Ozatilgan Ayse , Geffriaud-Ricouard Christine , De Wit Ronald
Published: May 2020

5569

Background: The CARD trial (NCT02485691) compared cabazitaxel vs. an androgen receptor targeted agent (ART; abiraterone/enzalutamide) in mCRPC previously treated with docetaxel and the alternative ART (abiraterone/enzalutamide), in any order. These post hoc analyses assessed OS from various time points and the impact of prognostic factors. Methods: Patients with mCRPC previously treated with docetaxel and progressing ≤ 12 months on prior abiraterone/enzalutamide were randomized 1:1 to cabazitaxel (25 mg/m2 IV Q3W + daily prednisone + prophylactic G-CSF) vs. abiraterone (1000 mg PO + daily prednisone) or enzalutamide (160 mg PO). OS was calculated from date of diagnosis of metastatic disease, date of mCRPC, and start of 1st, 2nd or 3rd life-extending therapy (LET). A stratified multivariate Cox regression analysis assessed the impact of 14 prognostic factors on OS using a stepwise model selection approach with a significance level of 0.10 for entry into the model and 0.05 for removal. Results: In the CARD study (N = 255), median OS was longer with cabazitaxel vs. abiraterone/enzalutamide (13.6 vs 11.0 months; HR 0.64, 95% CI 0.46–0.89; p = 0.008). OS was numerically improved for cabazitaxel vs. abiraterone/enzalutamide when assessed from the time of diagnosis of metastatic disease or mCRPC, or from start of 1st or 2nd LET (Table). In the multivariate analysis, low hemoglobin, high baseline neutrophil to lymphocyte ratio, and high PSA values at baseline were associated with worse OS. In presence of these factors, the OS benefit observed with cabazitaxel versus abiraterone/enzalutamide remained significant (HR 0.63, 95% CI 0.42–0.94, p = 0.022). Conclusions: Cabazitaxel numerically improved OS vs. abiraterone/enzalutamide in patients with mCRPC previously treated with docetaxel and the alternative ART (abiraterone/enzalutamide), whatever the time point considered. The robustness of this OS benefit was confirmed by stratified multivariate analysis. Sanofi funded. Clinical trial information: NCT02485691 . [Table: see text]
Survival outcome in patients with metastatic castration-resistant prostate cancer according to first-line treatment.
Authors: Gross-Goupil Marine , Thurin Nicolas H. , Rouyer Magali , Jové Jérémy , Haaser Thibaud , Rebillard Xavier , Soulie Michel , de Pouvourville Gérard , Pierrès Marie , Capone Camille , Lamarque Stéphanie , Bignon Emmanuelle , Droz-Perroteau Cécile , Moore Nicholas , Blin Patrick
Published: May 2020

5570

Background: Therapeutic strategy in metastatic castration-resistant prostate cancer (mCRPC) has evolved significantly with the introduction of abiraterone acetate in association with prednisone/prednisolone in first-line treatment in December 2012. This work aimed to compare the effectiveness of abiraterone acetate and docetaxel as first-line treatments for mCRPC, in real-life setting. Methods: Patients with mCRPC were identified in the main scheme of the National Healthcare System database (SNDS), which covers about 86% of the French population, and capturing all reimbursed healthcare expenditures and hospital discharge summaries. Those initiating docetaxel or abiraterone acetate in 1st line in 2014 were included and 1:1 matched on the previous prostate cancer stage before mCRPC status, the delay from the date of initial diagnosis and a high-dimensional propensity score. The 36-month overall survival and the 36-month discontinuation-free survival (i.e. survival time until treatment switch or death) were compared using Cox proportional hazards risk model. Results: In 2014, out of the 12,951 patients with prevalent mCRPC, 1,214 initiated docetaxel in 1st line and 2 444 initiated abiraterone. A total of 716 patients per group were matched with good comparability (C-statistic = 0.6). The median duration of docetaxel–defined as the time between the first and the last infusion–was 7.3 months with a median of 6 infusions. The median duration of abiraterone acetate–corresponding to the period covered by the dispensed drug–was 9.1 months. Near 70% of the docetaxel and 62% of the abiraterone acetate patients received a 2nd line of treatment. Results related to the main survival outcomes are presented in the table below. Conclusions: First-line treatment with abiraterone acetate in mCRPC patients results in a better 36-month overall survival and discontinuation-free survival compared to docetaxel in real-life setting. [Table: see text]
Quality of life (QOL) for the treatment sequence of abiraterone acetate plus prednisone (AAP) followed by enzalutamide (ENZ) versus the opposite sequence for metastatic castration-resistant prostate cancer (mCRPC): Results from a phase II randomized clinical trial.
Authors: Khalaf Daniel J , Sunderland Katherine , Eigl Bernhard J. , Finch Daygen L. , Oja Conrad D. , Vergidis Joanna , Zulfiqar Muhammad , Kollmannsberger Christian K. , Gleave Martin , Chi Kim N.
Published: May 2020

5578

Background: A randomized cross-over phase II trial (Lancet Oncol 20(12):1730, 2019) showed the sequence of AAP followed by ENZ is associated with a better time to PSA progression compared with the opposite sequence and superior 2nd line activity of ENZ. It is unknown whether one treatment sequence is associated with better QOL than the other. Methods: 202 Patients were randomized (1:1) to receive either AAP followed by ENZ at PSA progression (arm A) or the opposite sequence of ENZ followed by AAP (arm B). FACT-P questionnaires were completed at baseline, cross-over and every 4 weeks on treatment. Time to QOL deterioration (TTQOLD) for the treatment sequence was determined from start of 1st line treatment to first questionnaire with a clinically meaningful decrease from baseline and compared between arms using the log-rank test. TTQOLD was also determined for 1st line and 2nd line separately. The proportion of patients with QOL deterioration for total FACT-P score and FACT-P subscores from baseline to week 12 of 1st and 2nd line treatment was compared between arms using X2 test. Results: Median follow-up for 1st and 2nd line and whole sequence were 9.3, 6.6 and 22.0 months (mos) respectively and questionnaire completion rate was 81%. TTQOLD for total FACT-P score for the whole sequence for arm A vs B was 10.5 mo (95% CI 5.0-15.5) vs 10.8 mo (5.5-13.1), p = 0.74. For 1st-line AAP vs ENZ, median TTQOLD was 15.5 mo (5.5-21.2) vs 11.0 (5.5-13.3) respectively (p = 0.23). For 2nd line ENZ vs ABI, median TTQOLD was 3.7 mo (2.0-5.4) vs 5.8 (2.8-12.1), p = 0.13. There was a higher rate of deterioration in physical well-being (PWB) for 1st line ENZ (arm B) and 2nd line ENZ (arm A) (Table). Conclusions: There was no difference in TTQOLD between the two treatment sequences of AAP and ENZ. Although treatment with second line ENZ has been associated with greater anti-cancer effects, ENZ was associated worse PWB QOL scores. Clinical trial information: NCT02125357 . [Table: see text]
Obesity and metabolic syndrome correlate with a higher risk of biochemical recurrence in high risk and intermediate risk prostate cancer patients who underwent robotic-assisted laparoscopic prostatectomy.
Authors: Mao Shifeng , Miller Ralph , Lyne John , Cohen Jeffrey , Samiei Arash
Published: May 2020

5580

Background: Obesity and metabolic syndrome (MS) is prevalent in our society, and have been linked to a higher incidence of prostate cancer (PCa). The relationship of obesity or MS and cancer control has yielded mixed results in previous studies. We examined the correlation between the incidence of biochemical recurrence (BCR) with MS and BMI in a cohort of patients with PCa who underwent robotic-assisted laparoscopic prostatectomy (RALP). Methods: A retrospective study of patients who underwent RALP at a single center from 2007 to 2015 was conducted. Parameters including preoperative BMI, fasting glucose, lipid profile, blood pressure, PSA, Gleason score, pathologic stage, time to BCR, and surgical margin status were analyzed. Patients were categorized in high (HR), intermediate (IR), and low-risk (LR) groups based on the National Comprehensive Cancer Network (NCCN) guidelines. WHO classification was used for MS criteria, and BCR was defined as two consecutive postoperative PSA volume of ≥ 0.2 ng/mL. Obesity is defined as BMI ≥30 kg/m2. Results: A total of 726 patients with 189 in HR, 471 in IR and 66 patients in LR groups were included in this study with the median age of 59 (interquartile range [IQR] 55-64) years old. The median follow-up from surgery was 38 (IQR 22-46) months. More obese patients were found in the HR group compared to IR/LR group (46.5% vs. 33.1%, p<0.01). There were also more patients with MS in the HR group compared to IR/LR group (36.5% vs. 12.0%, p<0.01). Obese patients had a higher rate of BCR across risk groups in comparison to non-obese patients 32.1% vs. 15.4% (P<0.001), specifically 68% vs. 40%(p<0.01) in HR group and 21.3% vs. 12.7% (p=0.035) in the IR group. Similarly, patients with MS had a higher rate of BCR in HR and IR groups in comparison to the patients without MS, 39.1% vs. 18.7% (P<0.01); specifically, 67.7% vs. 42.2% (p<0.01) in HR and 29% vs. 11.6% (p<0.01) in the IR group. No correlation between MS or obesity and BCR was observed in LR group. There was no statistically significant difference in the positive surgical margin rate between obese and non-obese cohorts in each risk group. Conclusions: Among HR and IR-PCa patietns who underwent RALP, both obesity and MS correlate with increased risk of BCR. There were significantly more obesity and MS in HR-PCa patients, suggesting a potential pathophysiologic interplay between obesity or MS and cancer progression.
Cost-effectiveness of novel antiandrogens (AAs) for treatment of nonmetastatic castrate-resistant prostate cancer (nmCRPC).
Authors: Riaz Irbaz Bin , Almutairi Abdulaali , Lang Daenielle K. , Asghar Noureen , Riaz Anum , Yao Yuan , Sipra Qurat Ul Ain Riaz , Ryu Alexander J. , Alkhatib Nimer S , Oh Mok , Abraham Ivo , Murad M. Hassan , Kohli Manish
Published: May 2020

5583

Background: FDA has approved three novel AAs [Apalutamide(A), Darolutamide(D) and Enzalutamide(E)] in combination with Androgen deprivation therapy ( ADT) for treatment of (nmCRPC) patients (pts). We report the cost-effectiveness of these drugs from the US perspective to help facilitate the choice of these agents for clinical practice. Methods: A life time Markov state-transition model was constructed with three health states (Metastasis-Free Survival[MFS], Metastatic disease, and Death) to compare cost-effectiveness of AA therapies for treatment of nmCRPC based on US healthcare payer perspective. A network meta-analysis of MFS and OS was conducted due to the lack of head to head trials. An approximation of the original individual-level patient time-to-event data were derived from digitized Kaplan-Meier curves for OS and MFS. Weibull distributions was selected as the best fitted model fitted and extrapolated as per the NICE decision support unit recommendations. Medication costs were based on wholesale acquisition cost. Adverse event (AE) grades 3/4 management costs were incorporated in the model. Discount rate of 3% per year was applied to costs and effects. Life years (LYs) and quality adjusted life years (QALYs) for each treatment as well as the incremental cost effectiveness (ICER) and cost utility (ICUR) ratios were estimated. Base case analyses (BCA) and probabilistic sensitivity analyses (PSA) were estimated. Results: The table summarizes the results form BCA analyses. A+ADT offers best gain in LYs (8.37yrs) and QALYs (5.30 yrs) but at higher cost. Conclusions: Apalutamide was associated with gains in LYs and QALYs traded off with higher lifetime cost relative to other AA alternatives. ADT was associated with lower gains in LYs and QALYs traded off with lower lifetime cost relative to other alternatives. Based on a $150,000/QALY threshold pay off, A+ADT is likely more cost effective compared to E+ADT or ADT alone; while E+ ADT may be more cost effective compared to D+ ADT. [Table: see text]
Short-term adjuvant versus neoadjuvant hormone therapy in localized prostate cancer: A pooled individual patient analysis of two phase III trials.
Authors: Spratt Daniel Eidelberg , Malone Shawn , Roy Soumyajit , Grimes Scott , Eapen Libni , Morgan Scott Carlyle , Malone Julia , Craig Julia , Dess Robert Timothy , Jackson William , Schipper Matthew J , Michalski Jeff M. , Lee W. Robert , Pisansky Thomas Michael , Feng Felix Y , Shipley William U. , Sandler Howard M. , Roach Mack , Sun Yilun , Lawton Colleen Anne
Published: May 2020

5584

Background: The timing of systemic therapy in relation to radiotherapy (RT) is important in most malignancies. In contrast, androgen deprivation therapy (ADT) has largely been investigated in relation to its duration rather than its sequencing with RT. Herein, we conduct the first combined individual patient analysis of two phase III randomized trials to determine the optimal timing of ADT with RT in localized prostate cancer (PCa). Methods: Individual patient data was obtained from the Malone et al trial (JCO 2019), which randomized patients to receive neoadjuvant/concurrent or concurrent/adjuvant ADT for 6 months with prostate only RT. This was combined with the prostate only RT arms of RTOG 9413 that randomized patients to 4 months of neoadjuvant/concurrent or adjuvant ADT. The neoadjuvant/concurrent arms of both trials were combined into the “neoadjuvant” group, and the concurrent/adjuvant (Malone) and adjuvant arm (RTOG 9413) were combined in the “adjuvant” group. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Cumulative incidence of distant metastasis (DM), PCa-specific mortality (PCSM) and biochemical failure (BF) were calculated using the Fine-Gray method with non-PCa deaths as competing events. Late genitourinary (GU) and gastrointestinal (GI) toxicity are also reported. Results: The median follow-up was 14.9 years (yrs) and 1065 patients were included (n=531 neoadjuvant, 534 adjuvant). Groups were well balanced for all baseline characteristics. Adjuvant ADT was superior to neoadjuvant ADT in terms of BF (15yr: 33% vs 43%, HR: 1.37 (95%CI: 1.12-1.68), p=0.002), DM (15yr: 12% vs 18%, HR: 1.40 (95%CI: 1.00-1.95), p=0.04), and PFS (15yr: 36% vs 29%, HR: 1.25 (95%CI: 1.07-1.47), p=0.01). Adjuvant ADT yielded lower PCSM (15yr: 15% vs 20%, HR: 1.29 (95%CI: 0.95-1.75), p=0.10), but did not reach statistical significance. This approached statistical significance in high risk PCa (HR 1.39 (95%CI 1.00-1.93), p=0.053). OS was not significantly different between arms (15yr: 39% vs 34%, HR: 1.11 (95%CI: 0.95-1.30), p=0.20). There was no significant difference in either late grade ≥3 GI (p=0.21) or GU (p=0.98) toxicity. Conclusions: We demonstrate for the first time that sequencing of ADT with RT significantly impacts long-term oncologic outcomes in localized PCa, favoring an adjuvant rather than neoadjuvant approach, without increasing late toxicity. This data has important implications to ongoing and future clinical trial design. Clinical trial information: NCT00769548 .
Novel estrogen receptor beta agonist S-equol decreases tumor proliferation in patients with triple negative breast cancer (TNBC).
Authors: Lathrop Kate Ida , Kaklamani Virginia G. , Brenner Andrew Jacob , Li Rong , Nazarullah Alia , Hackman Sarah , Thomas Courtney , Gelfond Jonathan , Rodriguez Marisa , Elledge Richard
Published: May 2020

560

Background: Patients with TNBC breast cancer have inferior treatment outcomes compared to other breast cancer subtypes and targeted therapies are lacking. S-equol is a novel oral Estrogen Receptor (ER) Beta agonist with preclinical data showing suppression of TNBC cellular proliferation. We therefore conducted an early phase window of opportunity trial to evaluate the impact of S-equol on Ki-67 change in patients with TNBC. Methods: This neoadjuvant window trial enrolled 39 patients with confirmed TNBC on diagnostic core needle biopsy. Cohort A (20 patients) received a daily dose of 50 mg daily and Cohort B (19 patients) received a higher dose of 150 mg daily. Paired biopsies were evaluable for 36 patients. Both cohorts were treated for a duration of 10-21 days. Primary outcome was change from pre- to post-treatment Ki-67 evaluated by paired t-test. All tests were 2-sided with a significance level of 0.05. Statistics were conducted within an accountable data analysis process in R (ADAPR). Secondary outcomes included toxicity and correlative biomarkers. Results: The mean (SD) pre-treatment was 68% (21.99) and post-treatment 59% (20.62). The average decrease in Ki-67 was 8% (P = 0.00206, 95% CI -13.46 to -3.26). A Ki-67 decrease of at least 20% from baseline was observed in 28% of the patients. S-equol was well tolerated with the most common toxicities being nausea, constipation, diarrhea, and headache. All toxicities were grade one. Treatment compliance was greater than 95%. Planned correlative studies included RNA-seq. A total of 161 genes are differentially expressed with fold change > = 2 and p value < 0.05. The top genes of the differential expression list include BMP5, S100A7, FABP7, SCGB2A2, CH507-338C24.1, and DUSP1. Gene Set Enrichment Analysis (GSEA) indicates that top enriched gene modules are related to interferon function and immune response, most of which are downregulated in the post-treatment group. Conclusions: S-equol is a novel well tolerated oral ER-Beta agonist with inhibition of proliferation in patients with TNBC as measured by a decrease in Ki-67. RNA-seq data supports potential immune activation during this short period of drug exposure. Future studies aim to evaluate S-equol as an immune activating agent for combination with immunotherapies such as checkpoint inhibitors in TNBC. Clinical trial information: NCT02352025 .
Can sentinel node biopsy after neoadjuvant systemic chemotherapy (NAC) be safely omitted in selected patient with early breast cancer?
Authors: Yoshida Atsushi , Kojima Yasuyuki , Tazo Mizuho , Matsuda Naoko , Tsugawa Koichiro , Yamauchi Hideko , Nakamura Seigo , Hayashi Naoki
Published: May 2020

564

Background: There is a recent trend of performing minimum axillary surgery considering the prognostic value and fewer complications for primary breast cancer patients since the results of ACOSOG Z011. Nodal status after NAC is not be useful for postoperative treatment in most of cN0 patients. Therefore, sentinel node biopsy (SNB) may be omitted if ypN0 after NAC can be predicted in cN0 patients. We assessed clinicopathological factors associated with ypN0 after NAC in cN0 primary breast cancer patients. Methods: Two-institutional retrospective cohort study of clinically N0 breast cancer patients before NAC and who underwent breast surgery was conducted, including 419 consecutive patients between 2009 and 2016 in St. Luke's International Hospital and St. Marianna University School of Medicine hospital. Each institutional review board approved this study. In the patients with or without nodal metastasis on SNB after NAC, we compared clinicopathological factors including Estrogen Receptor (ER), Progesterone Receptor (PgR), human epidermal growth factor receptor 2 (HER2), Ki-67 on needle biopsy specimens, and tumor size before and after NAC on MRI findings. Results: Of the 419 patients, 380 patients (90.7%) were ypN0 and 39 patients (9.3%) were ypN+ after NAC. In univariate analysis, clinical complete response of primary tumor on MRI findings (MRI-CR) (p<0.01), ER-negative (p<0.01), PgR-negative (p<0.01), and high-Ki-67 >30% (p<0.01) were significantly associated with ypN0 on SNB after NAC. In multivariate analysis, MRI-CR (HR 5.12, p<0.01) and high-Ki-67 (HR 2.86, p<0.01) were independent predictive factors of ypN0 after NAC.According to breast cancer subtype, only one of 72 ER-negative and HER2-positive had significantly low risk of ypN+ (1.3%) comparing other subtypes (p<0.01). Conclusions: Achieving cCR of primary tumor after NAC and high-Ki67 in cN0 patients, especially in HER2 type breast cancer, might have ypN0. We are conducting prospective study to omit SNB for these populations based on these results,
Establishing analytical and clinical similarity between HD201 and herceptin.
Authors: Hii Jocelyn , Pivot Xavier , Mclendon Kristi , Chan Kuo Wei , Feyaerts Peggy , Lee Jeong-Hyeon , Ang Felicia , Demarchi Martin , Coliat Pierre , Deforce Filip , Derde Marie_Paule , Kim Michael J , Park Lisa Soyeon
Published: May 2020

579

Background: Trastuzumab, an approved prescription drug by EMA and FDA under the name Herceptin has become the key treatment in patients with HER2−positive breast cancer. HD201, developed by Prestige Biopharma Pte Ltd is a biosimilar candidate to Herceptin. The biosimilarity of HD201 was established based on systematic stepwise comparisons between HD201 and reference product, Herceptin. In order to confirm clinical similarity of HD201 to Trastuzumab, two clinical studies were undertaken. Methods: First, in a double-blind, randomised and parallel group study, 101 randomised healthy human subjects were subjected to a single 6 mg/kg IV dose by body weight over 90-min infusion of either HD201, EU- and US-Herceptin group by assessing pharmacokinetic (PK) and safety (TROIKA-I). The second study was a randomised, double-blind, parallel group, equivalence, multicentre clinical phase III trial (TROIKA) designed to compare the efficacy based on total pathological complete response rate (tpCR), safety, and pharmacokinetics of HD201 to EU-Herceptin in patients with HER2 positive early breast cancer. Each group of ~250 subjects were administered with either HD201 or EU-Herceptin in combination with chemotherapy in neoadjuvant followed by the antibody alone in the adjuvant phase. Results: TROIKA-I study demonstrated that HD201 was safe and well tolerated with comparable PK as EU- and US-Herceptin. Based on the neoadjuvant data from TROIKA study, the tpCR rate in the HD201 and Herceptin treatment groups was comparable and the 95% CI was included within the pre-defined margins of equivalence (Table). The incidence and severity of reported TEAEs did not imply any significant safety concerns and were comparable between both groups. In addition, the comparison of steady-state Ctrough between both arms in TROIKA study has established equivalence. Conclusions: The overall comparison exercise demonstrated the equivalence of HD201 to Herceptin. Clinical trial information: 2016-0040019-11 . [Table: see text]
The impact of pattern of tumor response and other post-treatment histologic features on local recurrence in patients treated with neoadjuvant chemotherapy and breast conservation.
Authors: Laws Alison , Pastorello Ricardo G. , Choi Jungeon , Kantor Olga , Grossmith Samantha , Schnitt Stuart J. , Golshan Mehra , Mittendorf Elizabeth A. , King Tari A.
Published: May 2020

581

Background: Residual disease after neoadjuvant chemotherapy (NAC) is a poor prognostic factor. The relationship between the pattern of tumor response and other post-treatment histologic features on local recurrence (LR) is not well studied. Methods: We identified 380 patients (pts) treated with NAC, breast-conserving surgery and radiation from 2002-2014. Pts with available surgical slides underwent detailed pathology review. Pathologic complete response (pCR) was defined as no invasive or in situ disease in the breast or axilla. Pattern of tumor response was defined as: none, scattered, or concentric. The degree of treatment effect was categorized as: absent, mild or marked. Univariate (UVA) and multivariate analyses (MVA) were performed to identify factors associated with LR. Results: 243 (64%) cases had complete slides available and formed the study cohort. 76 (31%) were ER+/HER2-, 90 (38%) ER-/HER2- and 77 (31%) HER2+. 98% of HER2+ pts received neoadjuvant trastuzumab; 89% of ER+ pts received adjuvant endocrine therapy. At median follow-up of 75 months, 10/243 (4.1%) pts had LR and 5-yr LR-free survival was 95.7%. LR occurred in 1/76 (1.3%) pts with breast pCR, 1/19 (5.2%) with residual DCIS, and 8/148 (5.4%) with residual invasive disease; including 6/78 (7.7%) with scattered tumor response, 2/46 (4.3%) with concentric response and 0/24 with no response. On UVA, age (OR < 50 vs ≥50 5.9, p = 0.03) and residual DCIS with comedonecrosis (OR 8.2, p < 0.01) were significantly associated with LR. Presence of tumor bed at the margin (OR 4.6, p = 0.06) approached significance. The odds of LR were higher with scattered regression (OR 1.83 vs. concentric, p = 0.47) and lower with breast pCR (OR 0.23, p = 0.17), but these results were not statistically significant. Multicentric disease, receptor status, ypT, ypN, RCB score, degree of treatment effect, high-grade residual invasive disease, margin status of residual disease and lymphovascular invasion were not associated with LR (all p > 0.05). Age (OR < 50 vs ≥50 7.4, p = 0.04) and residual DCIS with comedonecrosis (OR 7.5, p = 0.02) remained significant on MVA. Conclusions: With modern systemic therapy, LR rates after NAC, breast-conserving surgery and radiation are low, with less than 5% of patients experiencing a LR after a median follow-up of over 6 years. Young age and residual DCIS with comedonecrosis were associated with LR, but not pattern of tumor response.
Neoadjuvant TCH (docetaxel/darboplatin/trastuzumab) versus EC-TH (epirubicin/cyclophosphamide followed by docetaxel/ trastuzumab ) in patients with HER2-positive breast cancer (neoCARH): A randomised, open-label, multicenter, phase II trial.
Authors: Gao Hong-Fei , Wu Zhiyong , Lin Ying , Song Xiangyang , Cao Yin , Liu Zhenzhen , Chen Qian-Jun , Zhang Liulu , Yang Ci-Qiu , Yang Mei , Zhu Teng , Li Jieqing , Ji Fei , Cheng Min-Yi , Wang Kun
Published: May 2020

585

Background: The optimal neoadjuvant treatment for HER2-positive breast cancer is unknown. We wanted to compare the efficacy and safety of the anthracycline regimen EC-TH versus nonanthracycline regimen TCH in neoadjuvant setting for HER2-positive breast cancer. Methods: Patients with stage II or III HER2-positive breast cancer were randomly assigned to either four cycles of epirubicin/cyclophosphamide followed by four cycles of docetaxel and trastuzumab (EC-TH) every 3 weeks during all chemotherapy cycles, or six cycles of docetaxel and carboplatin plus trastuzumab (TCH) every 3 weeks. The primary endpoint was pathological complete response (defined as the absence of invasive tumour cells in breast and axilla, ypT0/is ypN0). This trial is registered with ClinicalTrials.gov, number NCT03140553. Results: From September 2016 to November 2019, 140 patients were randomly assigned, and 131 were evaluable for the primary end-point. The pathological complete response was recorded in 25 (38.5%, 95% confidence interval [CI] 26.6–50.2) of 65 patients in the EC-TH group and in 37 (56.1%, 44.1–68.0) of 66 in the TCH group (p=0.044). In the EC-TH group, 15 (23.1%) of 65 patients underwent breast-conserving surgery. In the TCH group, 21 (31.8%) of 66 patients underwent breast-conserving surgery. There was no difference in the proportions of patients undergoing breast-conserving surgery between the two treatment groups (p=0·262). The most common adverse events were neutropenia (in 23 [35.4%] of 65 patients in the EC-TH group vs 27 [40.9%] of 66 in the TCH group), anemia(in 33 [50.8%] of 65 patients in the EC-TH group vs 34 [51.5%] of 66 in the TCH group) and thrombocytopenia (in 5 [7.7%] of 65 patient in the EC-TH group vs 17 [25.8%] of 66 in the TCH group). Conclusion: This is the first multicenter prospective randomised phase II trial compare EC-TH with TCH for neoadjuvant therapy in HER2-positive breast cancer. There was a similar incidence of AEs but a higher pCR rate in TCH arm compared with the EC-TH arm. TCH regimen might be a preferred approach in patients with HER2-positive breast cancer. Long-term follow-up is required to confirm these results. Clinical trial information: NCT03140553 .
Neoadjuvant docetaxel + carboplatin versus epirubicin+cyclophosphamide followed by docetaxel in triple-negative, early-stage breast cancer (NeoCART): Results from a multicenter, randomized controlled, open-label, phase II trial.
Authors: Zhang Liulu , Wu Zhiyong , Lin Ying , li jie , Liu Zhenzhen , Cao Yin , Zhang Gangling , Gao Hong-Fei , Yang Mei , Yang Ci-Qiu , Zhu Teng , Cheng Min-Yi , Ji Fei , Li Jieqing , Wang Kun
Published: May 2020

586

Background: Taxane- and anthracycline-based neoadjuvant regimens have become a standard treatment for triple-negative breast cancer (TNBC). Previous studies have shown that adding carboplatin to neoadjuvant chemotherapy regimens significantly improved pCR rate in TNBC patients. The NeoCART study was designed to compare the efficacy and safety of docetaxel plus carboplatin with standard neoadjuvant chemotherapy in TNBC. Methods: NeoCART was designed as a multicenter, randomized controlled, open-label, phase 2 trial. The patients enrolled were at least 18 years old with previously untreated stage II-III (T1cN1-2 or T2-4N0-2) invasive TNBC who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. All eligible patients were randomly assigned, in a 1:1 ratio, to the experimental arm (docetaxel (75 mg/m2) plus carboplatin (AUC 6) for six cycles) or the standard treatment arm (epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 four cycles, followed by docetaxel 100 mg/m2 for four cycles). The primary end point was the pCR rate (ypT0/is and ypN0). Secondary endpoints included event-free survival, frequency of breast-conserving surgery, and safety. Results: Between September 1, 2016, and December 31, 2019, 88 patients from 6 participating centers were included and randomized (44 patients to the DCb arm and 44 to the EC-D arm). In the primary end point analysis, 27 patients (61.4%, 95% CI 47.0 - 75.8) in the DCb group achieved a pCR compared with 17 patients (38·6%, 95% CI 24.3 - 53.0) in the EC-D group (odds ratio 2.52, 95% CI 2.4 - 43.1; p = 0.033). In different stage disease, the pCR rates of the DCb and the EC-D groups were 73.3% (22/30) vs 48.4% (15/31) in stage II (p = 0.046), and 35.7% (5/14) vs 15.4% (2/13) in stage III (p = 0.384). In patients with axillary lymph node involvement, the pCR rates were 45.8% (11/24) vs 30.8% (8/26) (p = 0.273); and 80.0% (16/20) vs 50.0% (9/18) with lymph node negative disease (p = 0.052). The frequency of breast-conserving surgery in the DCb and EC-D groups was 36.4% and 37.2%, respectively (p = 0·935). The grade 3/4 adverse events include anemia (4.5%), thrombocytopenia (2.3%), neutropenia (2.3%) and ALT/AST increased (2.3%) in the DCb group. Conclusions: Compared with the standard neoadjuvant regimen, docetaxel combined with carboplatin showed a higher pCR rate in TNBC. The higher pCR rate was more significant in patients with earlier disease stage and negative lymph node. Clinical trial information: NCT03154749 .
12-chemokine gene expression score in breast cancer patients treated with neoadjuvant chemotherapy.
Authors: Soliman Hatem Hussein , Prabhakaran Sangeetha , Rosa Marilin , Cox Charles E. , Whitworth Pat W. , Uygun Sahra , Kling Heather M. , Yoder Erin , Audeh William
Published: May 2020

591

Background: Although advances in immunotherapy for the treatment of breast cancer have been minimal compared with other cancers, studies demonstrating tumor-infiltrating lymphocytes and immunomodulatory gene activation in the tumor microenvironment suggest the importance of antitumor immune responses in clinical outcomes. A 12-chemokine gene score has been shown to predict the presence of ectopic lymph node-like structures (ELN) in the tumor microenvironment and improved survival in melanoma, colon cancer, and breast cancer patients (Prabhakaran, 2017). Here, we evaluated this signature in an independent dataset of breast cancer patients treated with neoadjuvant chemotherapy. Methods: Tumor specimens used in this retrospective analysis (n = 92) were from breast cancer patients enrolled in either MINT (NCT0151487) or NBRST (NCT01479101) neoadjuvant registry trials from 2011 to 2016. Clinical data were captured with informed consent, and 70-gene signature (70-GS), 80-gene signature (80-GS), and full transcriptome data were generated by Agendia, Inc. Gene expression data were quantile normalized using R limma package. Principal component analysis (PCA) was performed on the normalized dataset using R princomp package. Chemokine score (CS) was defined as the first principal component values resulting from PCA. 70-GS/80-GS and clinical data were evaluated in relation to CS. CS were compared using Mann-Whitney test. Results: Of 92 breast tumors available for analysis, 84% were 70-GS High Risk (HR). Tumors were 39% Luminal-type, 24% HER2-type, and 32% Basal-type by 80-GS. HR tumors had higher CS than 70-GS Low Risk (LR) tumors (p < 0.001). 80-GS Basal-type, HER2-type, and Luminal B tumors had higher CS than Luminal A tumors (p < 0.01 for each comparison). High grade and ER-negative tumors seemed to have a high CS, although not significantly. Tumors from patients who achieved a pathological complete response (pCR) following neoadjuvant chemotherapy had higher CS than patients with residual cancer burden (p = 0.048). Conclusions: The current study demonstrated a significantly higher CS in 70-GS HR tumors and those which achieved pCR following neoadjuvant chemotherapy. Although further study is needed to evaluate the association of high CS with tumor-associated ELN, these results support previous work demonstrating that, although high CS is associated with aggressive clinical features, it also predicts superior clinical outcomes. The current study suggests validation of the 12-chemokine gene score in an independent dataset of breast cancer patients.
Randomized phase III study to evaluate the impact of secondary cytoreductive surgery in recurrent ovarian cancer: Final analysis of AGO DESKTOP III/ENGOT-ov20.
Authors: Du Bois Andreas , Sehouli Jalid , Vergote Ignace , Ferron Gwenael , Reuss Alexander , Meier Werner , Greggi Stefano , Jensen Pernille Tina , Selle Frederic , Guyon Frederic , Pomel Christophe , Lecuru Fabrice , Zang Rongyu , Avall-Lundqvist Elisabeth , Kim Jae-Weon , Ponce Jordi , Raspagliesi Francesco , Ghaem-Maghami Sadaf , Reinthaller Alexander , Harter Philipp
Published: May 2020

6000

Background: The role of secondary cytoreductive surgery in recurrent ovarian cancer (ROC) has been under debate for decades. A recent trial in unselected patients (pts) failed to show an OS benefit. Methods: Pts with ROC and 1st relapse after 6+ months (mos) platinum-free interval (TFIp) were eligible if they presented with a positive AGO-score (PS ECOG 0, ascites ≤500 ml, and complete resection at initial surgery) and were prospectively randomized to second-line chemotherapy alone vs. cytoreductive surgery followed by the same chemotherapy; platinum combination therapy was recommended. OS was primary endpoint in this superiority trial. Results: 407pts were randomized 2010-2014. The TFIp exceeded 12 mos in 75% of pts. 206 pts were allocated to the surgery arm of whom finally 187 (91%) were operated. A complete resection was achieved in 75%; almost 90% in both arms received a platinum-containing second-line chemo. Primary endpoint analysis showed median OS of 53.7 mos with and 46.2 mos without surgery (HR 0.76, 95%CI 0.59-0.97, p=0.03); median PFS was 18.4 and 14 mos (HR: 0.66, 95%CI 0.54-0.82, p<0.001), median time to start of first subsequent therapy (TFST) was 17.9 vs. 13.7 mos in favor of the surgery arm (HR 0.65, 95%CI 0.52-0.81, p<0.001). An analysis according to treatment showed an OS benefit exceeding 12 mos for pts with complete resection (CR) compared to pts without surgery (median 60.7 vs. 46.2 mos); pts with surgery and incomplete resection even did worse (median 28.8 mos). 60 d mortality rates were 0 and 0.5% in the surgery and no-surgery arm. Re-laparotomies were performed in 3.7% of operated pts. Further grade 3/4 adverse events did not differ significantly between arms. Conclusions: This is the first surgical study demonstrating a meaningful survival benefit in OC: Surgery in pts with first relapse and TFIp of 6+ mos and selected by a positive AGO-Score resulted in a significant increase of OS, PFS and TFST with acceptable morbidity and, therefore, should be offered to suitable pts. The benefit was exclusively seen in pts with CR indicating the importance of both the optimal selection of pts (eg. by AGO score) and of centres with expertise and a high chance of achieving a CR. Clinical trial information: NCT01166737.
Final results from the KEYNOTE-100 trial of pembrolizumab in patients with advanced recurrent ovarian cancer.
Authors: Matulonis Ursula A. , Shapira Roni , Santin Alessandro , Lisyanskaya Alla Sergeevna , Pignata Sandro , Vergote Ignace , Raspagliesi Francesco , Sonke Gabe S. , Birrer Michael , Sehouli Jalid , Colombo Nicoletta , González-Martín Antonio , Oaknin Ana , Ottevanger P. B. , Rudaitis Vilius , Wu Haiyan , Keefe Stephen Michael , Stein Karen , Ledermann Jonathan A.
Published: May 2020

6005

Background: Pembrolizumab (pembro) showed modest clinical activity in patients (pts) with recurrent advanced ovarian cancer (AOC) after a median follow-up of 16.9 mo in an interim analysis of KEYNOTE-100 (NCT02674061). We present the protocol-specified final analysis based on a data cutoff of 18-SEP-2019. Methods: Key eligibility criteria included epithelial ovarian, fallopian tube, or primary peritoneal cancer, confirmed recurrence following front-line platinum-based therapy, ECOG PS 0-1, and provision of a tumor sample for biomarker analysis. Pts in cohort A received ≤2 prior chemotherapy lines for recurrent AOC and had a platinum-free or treatment-free interval (PFI/TFI) of ≥3 to 12 mo. Pts in cohort B received 3-5 prior chemotherapy lines and had a PFI/TFI of ≥3 mo. Pts received pembro 200 mg Q3W for 2 yr or until progression, death, or unacceptable toxicity. Tumor imaging was performed every 9 wk for 1 yr and every 12 wk thereafter. Primary study endpoint was ORR per RECIST v1.1 by independent central review in both cohorts and by tumor PD-L1 expression using the combined positive score (CPS). Secondary endpoints included DOR, DCR (CR+PR+SD≥24 wk), PFS, OS, and safety. Results: 376 pts were enrolled and treated, 285 in cohort A and 91 in cohort B. Median age (range) was 61 (25 to 89) yr, 64.4% had ECOG PS 0, and 75.3% had high grade serous disease. In cohorts A and B, ORR (95% CI) was 8.1% (5.2, 11.9) and 9.9% (4.6, 17.9) in the total population, 6.9% (2.8, 13.8) and 10.2% (3.4, 22.2) in pts with CPS ≥1, and 11.6% (3.9, 25.1) and 18.2% (5.2, 40.3) in pts with CPS ≥10. Median DOR (range) was 8.3 (3.9 to 35.4+) mo in cohort A and 23.6 (3.3+ to 32.8+) mo in cohort B. DCR (95% CI) was 22.1% (17.4, 27.4) and 22.0% (14.0, 31.9). Median PFS was 2.1 mo in both cohorts. In cohorts A and B, median OS was 18.7 mo (17.0, 22.5) and 17.6 mo (13.3, 24.4) in the total population, 20.6 mo (15.2, 23.2) and 20.7 mo (13.6, 27.4) in pts with CPS ≥1, and 21.9 mo (12.9, 26.8) and 24.0 mo (14.5, NR) in pts with CPS ≥10. 73.7% of pts had treatment-related AEs and 20.2% were grades 3-4. There were 2 treatment-related deaths (Stevens-Johnson syndrome and hypoaldosteronism). Immune-mediated AEs occurred in 23.7% of pts. Conclusions: Pembro monotherapy was associated with modest antitumor activity in pts with recurrent AOC. There appeared to be a trend toward increased ORR with higher PD-L1 expression in both cohorts. Responses were durable and typically lasted ≥6 months. Median OS was 18.7 months overall, with a trend toward a longer OS with increasing PD-L1 expression in both cohorts. No new safety signals were identified. Clinical trial information: NCT02674061.
Long-term oncological safety of sentinel lymph node biopsy in early-stage cervical cancer.
Authors: Balaya Vincent , Guani Benedetta , Magaud Laurent , Hélène Bonsang-Kitzis , Ngo Charlotte , Mathevet Patrice , Lecuru Fabrice ,   SENTICOL
Published: May 2020

6006

Background: The goal of this study was to assess disease-free survival (DFS) and disease-specific survival (DSS) in patients with early-stage cervical cancer who underwent bilateral sentinel lymph node (BSLN) biopsy alone versus bilateral pelvic lymphadenectomy (BPL). Methods: An ancillary analysis of two prospective multicentric trials on SLN biopsy for cervical cancer (SENTICOL I and II) was performed. All patients with early stage cervical cancer (IA to IIB FIGO stage), negative SLN after ultrastaging and negative non-SLN after final pathologic examination were included. Risk-factors of recurrency and disease-specific deaths were determined by Cox proportional hazard models. Kaplan-Meier survival curves were compared by applying log-rank test. Results: Between January 2005 and July 2012, 259 patients met the inclusion criteria: 85 patients underwent only bilateral SLN biopsy whereas 174 patients underwent BPL. None had positive SLN at ultrastaging or positive non-SLN at final pathologic examination. Between the both groups, there was no differences in histology, final FIGO stage and type of surgical approach. In the BPL group, patients had more frequently tumor size larger than 20 mm (22.9% vs 10.7%, p = 0.02) and postoperative radiochemotherapy (10.7% vs 1.6%, p = 0.01). The median follow-up was 47 months (4-127). During the follow-up, 21 patients (8.1%) experienced reccurencies, including 4 nodal recurrences (1.9%), and 9 patients (3.5%) died of cervical cancer. The 5-year DFS and the DSS were similar between BSLN and BPL groups, 94.1% vs 97.7%, p = 0.14 and 88.2% vs 93.7%, p = 0.14 respectively. After controlling for final FIGO stage and margin status, BSLN compared to BPL was not associated with DFS (HR = 1.76, 95%CI = [0.69 – 4.53], p = 0.24) and DSS (HR = 2.5, 95%CI = [0.64 – 9.83], p = 0.19). Only final FIGO stage was independent predictor of DSS. Conclusions: SLN biopsy alone is oncologically safe in early-stage cervical cancer. Full lymphadenectomy could be omitted in case of bilateral negative SLN. Worse prognosis was associated with higher FIGO stage disease.