bluuebunny/crossref_metadata_2025_split huggingface dataset:
Triplet therapy (continuous ribociclib, everolimus, exemestane) in HR+/HER2− advanced breast cancer postprogression on a CDK4/6 inhibitor (TRINITI-1): Efficacy, safety, and biomarker results.
Authors: Bardia Aditya , Hurvitz Sara A. , DeMichele Angela , Clark Amy Sanders , Zelnak Amelia Bruce , Yardley Denise A. , Karuturi Meghan Sri , Sanft Tara B. , Blau Sibel , Hart Lowell L. , Ma Cynthia X. , Caria Nicola , Purkayastha D. Das , Mistry Alomi , Moulder Stacy L. 
Published: May 2019

1016 Background: The combination of CDK4/6 inhibitor (CDK4/6i) + endocrine therapy (ET) provides consistent improvement in PFS and response rates compared with single-agent ET as first- or subsequent-line therapy in HR+, HER2− advanced breast cancer (ABC), but the optimal regimen postCDK4/6i progression, including the role of continued CDK 4/6 blockade, is unclear. Methods: TRINITI-1 is a Phase I/II, open-label trial (NCT02732119) of triplet therapy: ribociclib (RIB; CDK4/6i) + everolimus (EVE; mTORi) + exemestane (EXE; ET) in men or postmenopausal women with HR+, HER2− ABC that progressed on prior CDK4/6i and up to 3 lines of therapy (≥ 1 ET and ≤ 1 chemotherapy regimen). Phase I determined RP2D; Phase II assessed efficacy/safety of RIB 300 or 200 mg + EVE 2.5 or 5 mg + EXE 25 mg/day. Here we present the first results in the entire patient population who received this triplet regimen and the correlation of biomarkers with outcomes. Results: As of October 24, 2018, 95 patients were evaluable (ET refractory and postCDK4/6i) in Phases I (n = 17) and II (n = 78). Continuous RIB + EVE + EXE demonstrated clinical benefit at week 24 in 39 patients (41.1%), exceeding the predefined primary end point threshold (> 10%). ORR was 8.4% by investigator assessment, median PFS was 5.7 months, and 1-year PFS was 33%. AEs were consistent with known safety profile of RIB, EVE, and EXE. Most common AEs were neutropenia (all grades, 41.7%; grade 3/4, 31.3%), stomatitis (41.7%; 3.1%), and fatigue (35.4%; 1.0%). No grade 3/4 QTc prolongation was noted. ctDNA genotyping revealed patients with certain tumor alterations, eg ESR1, had shorter median PFS vs wild-type: 3.5 vs 6.9 mo (HR 1.76, 95% CI 1.01–3.05). Additional genomic results, including PIK3CA, will be presented. Conclusions: TRINITI-1 met its primary efficacy end point and is the first trial to demonstrate clinical benefit and tolerability of continuous triplet therapy with ET + mTORi + CDK4/6i in patients with ET-refractory HR+, HER2− ABC postCDK4/6i progression. Tumor genomic profile might impact the clinical outcome with triplet therapy and warrants additional research to guide rational therapy selection. Clinical trial information: NCT02732119.
Association of STK11/LKB1 genomic alterations with lack of benefit from the addition of pembrolizumab to platinum doublet chemotherapy in non-squamous non-small cell lung cancer.
Authors: Skoulidis Ferdinandos , Arbour Kathryn Cecilia , Hellmann Matthew David , Patil Pradnya Dinkar , Marmarelis Melina Elpi , Awad Mark M. , Murray Joseph Christopher , Hellyer Jessica , Gainor Justin F. , Dimou Anastasios , Bestvina Christine M. , Shu Catherine A. , Riess Jonathan W. , Blakely Collin Michael , Pecot Chad Victor , Mezquita Laura , Tabbò Fabrizio , Scheffler Matthias , Papadimitrakopoulou Vassiliki , Heymach John 
Published: May 2019

102 Background: Addition of pembrolizumab (P) to platinum-doublet chemotherapy [carboplatin (or cisplatin) and pemetrexed (CP)] prolongs overall survival and is a standard of care (SOC) for the 1st line treatment of metastatic EGFR/ALK wild-type (wt) non-squamous non-small cell lung cancer (mnsNSCLC). Despite widespread adoption of the CPP regimen, molecular determinants of clinical benefit from the addition of P to CP remain poorly defined. We previously identified genomic alterations in STK11/LKB1 as a major driver of primary resistance to PD-1/PD-L1 blockade in mnsNSCLC. Here, we examine the impact of STK11/LKB1 alterations on clinical outcomes with CPP chemo-immunotherapy. Methods: 497 pts with mnsNSCLC and tumor genomic profiling encompassing STK11/LKB1 from 17 academic institutions in the US and Europe were included in this study. Clinical outcomes were collected for two distinct patient cohorts: a) 377 pts treated with first-line CPP (or > 1st line following FDA-approved TKIs) that were alive for 14 days thereafter and b) 120 STK11/LKB1-mt pts that received CP prior to regulatory approval of CPP. Results: Among 377 CPP-treated pts, STK11/LKB1 genomic alterations (N = 102) were associated with significantly shorter PFS (mPFS 4.8m vs 7.2m, HR 1.5, 95% CI 1.1 to 2.0; P = 0.0063) and shorter OS (mOS 10.6m vs 16.7m, HR 1.58, 95% CI 1.09 to 2.27; P = 0.0083) compared with STK11/LKB1-wt tumors (N = 275). ORR also differed significantly between the two groups (32.6% vs 44.7%, P = 0.049). Similar results were obtained when limiting the analysis to EGFR and ALK-wt tumors (N = 333). Importantly, in pts with STK11/LKB1-mt mnsNSCLC, addition of pembrolizumab to CP did not improve PFS (mPFS 4.8m vs 4.3m, HR 1.13, 95% CI 0.83 to 1.54, P = 0.75) or OS (mOS 10.6m vs 10.3m, HR 1.03, 95% CI 0.71 to 1.49, P = 0.79) compared to CP alone. Conclusions: In mnsNSCLC, STK11/LKB1 alterations define a subgroup of pts with inferior clinical outcomes with CPP and lack of benefit from the addition of pembrolizumab to CP chemotherapy. Novel therapeutic strategies are required to establish effective antitumor immunity in STK11/LKB1-mutant NSCLC.
Biosimilar trastuzumab-dkst monotherapy versus trastuzumab monotherapy after combination therapy: Final overall survival (OS) from the phase III HERITAGE Trial.
Authors: Waller Cornelius F. , Manikhas Aleksei , Pennella Eduardo J. , Bondarenko Igor , Mukhametshina Guzel , Tiambeng Maria Luisa Abesanis , Akewanlop Charuwan , Vynnychenko Ihor , Sriuranpong Virote , Ray Sirshendu , Hernandez-Bronchud Miguel , Herson Jay , Parra Joseph D. , Parra Joseph D. , Nemsadze Gia , Gopalakrishnan Unmesh , Loganathan Subramanian , Muniz Rafael , Barve Abhijit , Rugo Hope S. 
Published: May 2019

1021 Background: The multicenter, double-blind, randomized, parallel-group, phase 3 Heritage trial (NCT02472964) evaluated efficacy and safety of trastuzumab-dkst (Ogivri), a trastuzumab biosimilar, vs trastuzumab, plus taxane as first-line therapy for patients with HER2+ metastatic breast cancer. Overall response at week (wk) 24 and progression-free survival (PFS) at wk 48 have been reported (Rugo et al, JAMA 2017; ASCO 2018). Methods: Eligible patients were randomized 1:1 to trastuzumab-dkst or trastuzumab, plus taxane. After 24 wks, patients with responding/stable disease continued monotherapy per randomization. Safety and OS during maintenance, cumulative through 36 months of follow-up from last patient on study, are described. Results: 500 patients were randomized; 343 received monotherapy after 24 wks (trastuzumab-dkst, n = 179; trastuzumab, n = 164). 128 patients discontinued monotherapy (trastuzumab-dkst, n = 63; trastuzumab, n = 65); mean time to discontinuation was 19 months in both groups. Treatment-emergent adverse events (TEAEs) during monotherapy were similar for trastuzumab-dkst (69%) and trastuzumab (73%); most were low grade and serious TEAE rates were 6% in both groups. Cumulative rates of TEAEs of special interest were similar for hypersensitivity, pulmonary, and cardiac events (trastuzumab-dkst, 23%, 16%, and 5%; trastuzumab, 24%, 13%, and 5%). Incidences of left ventricular ejection fraction (LVEF) < 50% ≥1 time postbaseline (trastuzumab-dkst, 5%; trastuzumab, 3%) and LVEF < 50% postbaseline and ≥10% reduction (trastuzumab-dkst, 4%; trastuzumab, 3%) were low. At 36 months, 169 patients had received further lines of therapy, with similar distribution of HER2 treatments, endocrine therapies, and chemotherapies. Final median PFS was 11.1 months in both groups. Median duration of response was 9.9 and 9.8 months and median OS was 35.0 and 30.2 months for trastuzumab-dkst and trastuzumab, respectively: unstratified hazard ratio, 0.9 (95% CI, 0.70-1.17). Conclusions: Long-term safety data with similar median OS compared with originator trastuzumab further support the safety and efficacy profile of trastuzumab-dkst. Clinical trial information: NCT02472964.
mTORC1 activation assessed in metastatic sample to predict outcome in patients with metastatic breast cancer treated with everolimus-exemestan: Results from the SAFIRTOR study.
Authors: Bachelot Thomas Denis , Treilleux Isabelle , Schiffler Camille , Bieche Ivan , Campone Mario , Patsouris Anne , Arnedos Monica , Cottu Paul H. , Jacquin Jean-Philippe , Dalenc Florence , Attignon Valéry , Rouleau Etienne , Morel Alain , Legrand François , Jimenez Marta , Andre Fabrice 
Published: May 2019

1024 Background: Using samples from TAMRAD study (Treilleux, Ann Oncol, 2015), we previously reported that p4EBP1, a downstream protein of mTOR, was associated with higher benefit to everolimus (eve). SAFIRTOR study was designed to validate clinical utility of this biomarker. Methods: Patients (pts) with ER+, HER2 negative, AI resistant MBC were prospectively included (NCT02444390). All pts had a biopsy of a metastatic site and were then treated with standard eve + exemestane (exe) combination. The primary end point was to validate that p4EBP1 expression is associated with longer PFS in patients treated with eve. 120 evaluable pts were needed for the pre planed statistical analysis. All samples were collected and processed in a standardized procedure in order to allow phophoproteins IHC staining. In addition to p4EBP1, we explored prognostic value of pS6K, pAkt, PTEN and LKB1, together with genomic alterations assessed by NGS and CGH arrays. Results: 150 pts were included, 30 pts had no adequate sample, and further 13 had missing clinical data, 107 were evaluable for primary objective. Median age was 62, they had previously progressed on AI treatment, either in the adjuvant (22 pts) or the metastatic setting (83 pts). 20 were considered as primary hormone resistant, 87 as secondary resistant. The median Allread score for p4EBP1 was 5.5 (range: 0-6.5). Analysis of the primary endpoint showed that p4EBP1 staining above the median is associated with a longer PFS on eve+exe. (median PFS: 9.3 months, 95CI 6.3-13.1 for high p4EBP1 versus 5.8 months, 95CI 3.7-7.8 for low p4EBP1, p = 0.02). Prognostic value of high pEBP1 remained significant when assessed in a multivariate analysis along classical clinico-biological prognostic factors for MBC (HR 0.57, 95%CI 0.38-0.88, p = 0.01). In this AI resistant population, the tumor of 42 (46%), 33 (35%) and 5 (5.3%) pts carried an activating mutation for ESR1, PIK3CA and AKT1, respectively. None of these mutational statuses were correlated to outcome. Conclusions: This prospective study validates p4EBP1 expression analysis to select patients most likely to benefit from everolimus + exemestane. Clinical trial information: NCT02444390.
A phase III, randomized, double-blind, placebo (Pla)-controlled study of pertuzumab (P) + trastuzumab (H) + docetaxel (D) versus Pla + H+ D in previously untreated HER2-positive locally recurrent/metastatic breast cancer (LR/MBC) (PUFFIN).
Authors: Xu Binghe , Li Wei , Zhang Qingyuan , Zhimin Shao , Jia Wang Xiao , Li Huiping , Sun Tao , Yin Yongmei , Zheng Hong , Zhang Hong , Chan Tiffanie , Lei Guiyuan , Restuccia Eleonora 
Published: May 2019

1026 Background: In CLEOPATRA (NCT00567190), adding P to H + D significantly improved progression-free and overall survival (PFS/OS) v Pla + H + D in patients (pts) with previously untreated HER2-positive LR/MBC. PUFFIN (NCT02896855) is a China bridging study; the objective being to assess consistency of efficacy with CLEOPATRA. Methods: Pts with previously untreated HER2-positive LR/MBC were randomized 1:1 to P + H + D or Pla + H + D, stratified by visceral v non-visceral disease and hormone receptor status. The primary endpoint was investigator-assessed PFS. Secondary endpoints included objective response rate (ORR in pts with measurable baseline disease), OS, and safety. The target sample size (240) was determined based on the consistency threshold for PFS, defined as hazard ratio (HR) < 0.81, which maintains ≥ 50% of the risk reduction determined in CLEOPATRA (HR 0.62). Results: Two hundred forty-three pts were randomized. Baseline/disease characteristics and prior therapies were generally balanced between arms. For PFS, the HR was 0.69 (95% CI 0.49, 0.99) in the ITT population. No cases of heart failure or symptomatic left ventricular ejection fraction decline were reported. Efficacy/safety are shown in the table. Conclusions: PUFFIN met its primary endpoint. Overall, efficacy data were consistent with CLEOPATRA (ITT population and Asian subgroup). Safety was also consistent and in line with the known P safety profile, with no new or unexpected signals reported. PUFFIN adds to the totality of data with P in previously untreated HER2-positive LR/MBC, and supports the favorable benefit–risk profile of P in Chinese pts. Clinical trial information: NCT02896855. [Table: see text]
Association of polybromo-associated BAF (PBAF) complex mutations with overall survival (OS) in cancer patients (pts) treated with checkpoint inhibitors (ICIs).
Authors: Abou Alaiwi Sarah , Nassar Amin , El Bakouny Ziad , Berchuck Jacob E , Nuzzo Pier , Flippot Ronan , Flaifel Abdallah , Steinharter John A. , Baca Sylvan , Margolis Claire , Vokes Natalie , Du Heng , Shukla Sachet A , Braun David A. , Signoretti Sabina , Sonpavde Guru , Kwiatkowski David J. , Van Allen Eliezer Mendel , Choueiri Toni K. 
Published: May 2019

103 Background: ICIs have shown benefit across several metastatic carcinomas, yet predictive biomarkers are still lacking. 20% of malignancies harbor alterations in ≥1gene that is part of PBAF complex. With recent data suggesting an association between PBRM1 mutations (mts) and outcomes in renal cell carcinoma (RCC) pts treated with ICIs (Miao, Science, 2018), we examined the association between PBAF mts and OS in ICI-treated patients across several solid cancer (ca) types. Methods: Of 6007 pts with different ca histologies and targeted exome sequencing (Oncopanel) at Dana Farber Cancer institute (DFCI), 138 pts had truncating mts in any PBAF gene (SMARCA4, PBRM1, and ARID2) or oncogenic missense mts in SMARCA4 and were treated with ICIs. 138 histology-matched DFCI pts had none. A publicly-available cohort (2:1 histology matched) from Memorial Sloan Kettering (MSKCC) (Samstein et al., Nature Genetics, 2019) of 621 ca pts (PBAF mutant [MT] = 207, PBAF wild type [WT] = 414) treated with ICIs was analyzed for association between PBAF mts and OS. OS was defined from time from ICI initiation. OS was compared by Cox regression between PBAF MT and PBAF WT. Hazard ratio (HR) was derived using univariable and multivariable analysis (MVA) adjusted for ICI regimen (single vs combination) and age. Results: Median (Md) follow-up for the combined cohort (n = 897) was 27 months (m). Major histologies were non-small cell lung ca (268; 29.9%), melanoma (220; 24.5%), RCC (181; 20.2%), and bladder ca (65; 7.2%). Results on univariable and MVA analyses from individual and combined cohorts are presented below. Conclusions: PBAF mts are associated with survival in ICI-treated ca pts. Work in progress with non-ICI treated pts will determine if this is prognostic or predictive of response. [Table: see text]
Clinical characteristics of patients with no evidence of disease (NED) versus residual disease (RES) to anti-HER2 therapy in metastatic breast cancer (MBC): A multi-institutional analysis.
Authors: Veitch Zachary William Neil , Bedard Philippe L. , Tang Patricia A. , Conway Jessica L. , Ribnikar Domen , Albaba Hamzeh , King Karen M. , Lupichuk Sasha M. , Cescon David W. 
Published: May 2019

1034 Background: Anti-HER2 therapy has improved survival in HER2+ MBC. Yet, large patient cohorts with no evidence of disease (NED) with long-term follow up are incompletely described in the literature. We evaluated the clinical characteristics of patients with HER2+ MBC and prolonged response to anti-HER2 therapy, exhibiting NED vs Residual disease (RES). Methods: Patients treated with chemotherapy plus trastuzumab (CT) from 2005-2013, or taxane plus trastuzumab-pertuzumab (TTP), or trastuzumab-emtansine (TDM1) from 2012-2016 for HER2+ MBC at Princess Margaret Cancer Centre in Toronto, Ontario or in Alberta, Canada were included. Duration on anti-HER2 therapy (without switch) was collected. Patients with median duration of response (MDR; months) 2x higher than phase II/III trials for each regimen (CT = 18.2; TTP = 40.4; TDM1 = 25.2) were included to select for prolonged response. Clinical features (ie: stage at diagnosis, survival, etc) and oncologist/radiologist reported best response were collected. Responses were grouped as NED (including sclerotic bone metastases) or RES. Clinical variables were evaluated by Chi-square and survival by Kaplan-Meier (log-rank). Results: 2403 patients (CT = 1830; TTP = 394; TDM1 = 179) were evaluated. After cut-off, 119 patients (5%) were included, with NED in 41% (49/119) and RES in 59% (70/119). More women aged < 50 vs ≥50 (p = 0.015) had NED (61%) than RES (39%). No breast surgery (curative or metastatic) showed higher (p = 0.015) rates of NED (49%) relative to RES (27%). More women having NED (92%) than RES (37%) were still alive (p < 0.0001) at data cut-off, with improved mPFS (years; p < 0.0001) for NED (11.2, 95%CI: 11.2-NR) vs RES (3.0, 2.7-3.6), and mOS (years; p < 0.0001) for NED (NR) vs RES (3.4, 95%CI: 2.8-4.2). Significance persisted with TDM1 patients excluded. Treatment type (p = 0.053) and number of organs with metastases (p = 0.067) were of borderline significance. Conclusions: Patients with NED have improved survival compared to RES. Younger age and avoiding breast surgery correlates with NED. Evaluation of genomic factors influencing NED are planned.
Safety, efficacy, and biomarker analysis of pyrotinib in combination with capecitabine in HER2-positive metastatic breast cancer patients: A phase I clinical trial.
Authors: Ma Fei , Li Qiao , Guan Xiuwen , Chen Shanshan , Yi Zongbi , Lan Bo , Xing Puyuan , Fan Ying , Wang Jiayu , Luo Yang , Yuan Peng , Cai Ruigang , Zhang Pin , Li Qing , Xu Binghe 
Published: May 2019

1035 Background: Cross-signaling in the ErbB family is an important mechanism in Trastuzumab resistance. Pyrotinib is an irreversible pan-ErbB inhibitor targeting EGFR/HER1, HER2 and HER4, which may offer the potential for improved efficacy to block HER2 signaling in trastuzumab-resistant breast cancer. This phase I study assessed the safety, tolerability, maximum-tolerated dose (MTD), pharmacokinetics, antitumor activity and predictive biomarkers of pyrotinib in combination with capecitabine in patients with HER2-positive metastatic breast cancer (MBC). Methods: Patients received oral pyrotinib 160 mg, 240 mg, 320 mg, or 400 mg once daily continually plus capecitabine 1000mg/m2 twice daily on days 1 to 14 of a 21-day cycle. Pharmacokinetic blood samples were collected predose on day 1 and day 14 of treatment. Next-generation sequencing (NGS) was performed on circulating tumor DNA (ctDNA) to probe for predictive biomarkers of this combination. Results: A total of 28 patients were enrolled. All 28 (100%) patients experienced at least one treatment-related Adverse Events (AE), which were predominantly grade 1 or 2. Grade 3 treatment-related AE occurred in 12 (42.9%) patients; anemia (14.3%) and diarrhea (10.7%) were the most common grade 3 AEs. Three (10.7%) patients discontinued capecitabine administration due to AEs. The overall response rate (ORR) was 78.6% (95% CI: 59.0% to 91.7%), and the disease control rate (complete response+ partial response+ stable disease) was 96.4% (95% CI: 81.7% to 99.9%). The median progression-free survival (PFS) was 22.1 months (95% CI: 9.0 to 26.2 months). ORR was 70.6% (12/17) in trastuzumab-pretreated patients and 90.9% (10/11) in trastuzumab-naive patients. NGS analysis of all genetic alterations of HER2 bypass signaling pathway, PI3K/Akt/mTOR pathway and TP53 in baseline blood samples suggested that concomitant (two or more) genetic alterations were significantly associated with poorer PFS compared to none or one genetic alteration (median, 15.8 vs. 26.2 months, p = 0.006). Conclusions: Pyrotinib in combination with capecitabine are well-tolerated and demonstrate promising antitumor activity in HER2-positive MBC patients. Clinical trial information: NCT02361112.
Association of HER2 alterations and ESR1 mutations in cell-free DNA (cfDNA) with circulating tumor cells (CTCs), multiple metastasis, and prognosis in stage III/IV breast cancer (BCa).
Authors: Zhang Qiang , Gerratana Lorenzo , Shah Ami N. , Davis Andrew A. , Flaum Lisa E. , Zhang Youbin , Qiang Wenan , Behdad Amir , Gradishar William John , Platanias Leonidas C. , Cristofanilli Massimo 
Published: May 2019

1036 Background: The monitoring of CTCs and cfDNA in metastatic BCa showed ability to predict treatment resistance and survival. Here we report a highly significant correlation between HER2 alterations and ESR1 mutations of cfDNA with CTCs and prognosis of BCa, which may help to predict disease recurrence and treatment benefit. Methods: A total of 85 blood samples (7.5ml/each) were collected from 85 patients with stage III/IV BCa who received treatments at Northwestern RHLCCC. CTC enumeration was performed in FDA approved CELLTRACKS ANALYZERII System (Menarini). Plasma cfDNA was analyzed using Guardant360 NGS-based assay including a 73-gene panel for genomic alterations or mutations. We previously reported cut-off of 5.7% (2018 ASCO) was used to dichotomize the prognostic value of cfDNA percentage. Kruskal-Wallis test was used for statistics. Results: Of the 85 whole samples analyzed, there were 72 samples and 67 samples without ESR1 mutations (ESR1-) and HER2 alterations ( HER2-) respectively, and there are 13 samples and 18 samples that had ESR1 mutations ( ESR1+) and HER2 alterations ( HER2+, 10 amplified, 7 mutated, 1 for both) respectively. CTC positive (≥5) were detected in 13/57 ESR1-HER2- samples (Group 1) and 5/15 ESR1- HER2+ samples (Group 2), 7 /10 ESR1+ HER2- samples (Group 3), 3/3 ESR1+ HER2+ samples (Group 4). The median CTCs number/sample in Group 3 (15 CTCs) and Group 4 (12 CTCs) were significantly higher than Group 1 (0 CTC) and Group 2 (2 CTCs) (P = 0.0020). There were a significant higher average metastasis sites in Group 3 (3 sites) and Group 4 (3 sites) in compared to Group 1 (2 sites) and Group 2 (1 site) (P = 0.0035). Furthermore, patients in Group 4 ( ESR1+ HER2+) has the worst prognosis in compared to other groups (P = 0.0151) on overall survival. Conclusions: Both ESR1 mutations and HER2 alterations in cfDNA contribute to CTCs detection and disease metastasis sites independently, when ESR1 mutations plays a major role. The synergy of ESR1 mutation and HER2 alteration expands the predictive role of liquid biopsy tests monitoring the metastatic prognosis and endocrine resistance for clinical decision-making.