bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term survival of de novo stage IV human epidermal growth factor receptor 2 (HER2)-positive breast cancers treated with HER2 targeted therapy.
Authors: Wong Yao , Raghavendra Akshara Singareeka , Hatzis Christos , Irizarry Javier Perez , Vega Teresita , Barcenas Carlos Hernando , Chavez-Mac Gregor Mariana , Valero Vicente , Tripathy Debu , Pusztai Lajos , Murthy Rashmi Krishna
Published: September 2018

1021

Background: An increasing number of metastatic HER2 positive cancers represent de novo stage IV disease as fewer early stage patients relapse. We hypothesize that a subset of these has long progression free survival (PFS) after initial combined modality HER2-targeted therapies. Methods: 483 patients with de novo stage IV HER2 positive breast cancer diagnosed between 1998-2015 were identified through the medical records at Yale and MD Anderson Cancer Centers, respectively. Treatment, clinical variables and survival were extracted and compared between those who achieved “no evidence of disease” (NED) status with initial therapy and those who did not. Results: All patients received trastuzumab and 94 (20%) also received pertuzumab as first line therapy.The median OS was 5.5 years (95% Cl: 4.8-6.2); OS rates at 5 and 10 years were 54% (95% CI: 48%-60.4%) and 18% (95% Cl: 11.4%-28.3%), respectively and PFS were 41% (95% CI: 35%-48%) and 41% (95% CI: 35%-48%). Sixty-three patients (13.0%; 95% CI: 10.2% -16.4%) achieved NED. The PFS and OS at 5 and 10 years were the same 100% and 98% (95% CI: 94.6%-100%), respectively. For patients with no-NED (n = 420), the median OS was 4.7 years (95% Cl: 4.2-5.3), the PFS and OS rates at 5 and 10 years were 12% (95% CI: 4.5%-30.4%) and 0% and 45% (95% CI: 38.4%-52.0%) and 4% (95% CI: 1.3%-13.2%), respectively. NED patients had significantly longer progression free survival (log-rank test p≤0.001) and overall survival (log-rank test p≤0.001), more frequently had single organ site metastasis (76% vs 57%, p = 0.005), and more frequently had surgery for primary tumor (59% vs. 25%, p ≤0.001) than no-NED patients, but there was no significant difference in age, grade, race, year of diagnosis, ER status, treatment distribution, or radiation between the groups. Conclusions: About 13% of de novo, stage IV, HER-2 positive MBC patients achieved NED with HER-2 targeted therapies, all of these patients were progression free at 5 years and overall survival at 10-years was 98% compared to 4% among those with no-NED in our data sets. These results suggest that aggressive multimodality therapy of newly diagnosed stage IV HER2 positive cancers to render them NED may be warranted.
The effect of pembrolizumab in combination with CD19-targeted chimeric antigen receptor (CAR) T cells in relapsed acute lymphoblastic leukemia (ALL).
Authors: Maude Shannon L. , Hucks George E , Seif Alix Eden , Talekar Mala Kiran , Teachey David T. , Baniewicz Diane , Callahan Colleen , Gonzalez Vanessa , Nazimuddin Farzana , Gupta Minnal , Frey Noelle V. , Porter David L. , Levine Bruce L , Melenhorst Jan J. , Lacey Simon F. , June Carl H. , Grupp Stephan A.
Published: September 2018

103

Background: CD19-targeted CAR T cells show CR rates of 70-95% in B-ALL. Yet a subset of patients do not respond or relapse due to poor CAR T cell expansion and persistence. We hypothesized that PD-1 checkpoint pathway inhibition may improve CAR T cell expansion, function and persistence. Methods: Four children with relapsed B-ALL treated with murine (CTL019) or humanized (CTL119) anti-CD19 CAR T cells received 1-3 doses of the PD-1 inhibitor pembrolizumab (PEM) for partial/no response or prior history of poor CAR T cell persistence starting 14d-2mo post CAR T cell infusion. Results: PEM increased and/or prolonged detection of circulating CAR T cells in all 4 children, with objective responses in 2/4. It was well tolerated, with fever in 2 pts and no autoimmune toxicity. Pts 1-3 received CTL119 for CD19+ relapse after prior murine CD19 CAR T cells. Pt 1 had 1.2% CD19+ residual disease despite expansion with detectable CTL119 by D28 and received PEM at 2mo for progressive disease with decreasing circulating CTL119. CTL119 became detectable at 0.2% of CD3+ cells by flow cytometry, but disease progressed. Pt 2 had no response after initial CTL119 expansion with a rapid disappearance by D28. After CTL119 reinfusion with PEM added 14d later, circulating CAR T cells remained detectable at 4.4% by D28, but disease progressed with decreased CD19 expression. In Pt 3, prior treatment with both CTL019 and CTL119 produced CR with poor CAR T cell persistence followed by CD19+ relapse. CTL119 reinfusion combined with PEM at D14 resulted in CR with prolonged CTL119 persistence (detectable at D50 compared to loss by D36 after 1st CTL119 infusion). Pt 4 received PEM for widespread extramedullary (EM) involvement at D28 post CTL019 infusion despite marrow remission. Initial CTL019 expansion peaked at 63% at D10 and fell to 20% at D28. Resurgence of CTL019 expansion, with a 2nd peak of 70% 11d after PEM, was associated with dramatic reduction in PET-avid disease by 3mo post CTL019. Conclusions: PEM was safely combined with CAR T cells and increased or prolonged CAR T cell detection, with objective responses seen. Immune checkpoint pathways may impact response to CAR T cell treatments and warrant further investigation. Clinical trial information: NCT02374333, NCT02906371.
A phase II, randomized, open-label 3-arm clinical trial of fulvestrant (F) plus goserelin (G) versus anastrozole (A) plus goserelin (G) versus goserelin (G) alone for hormone receptor (HR) positive, tamoxifen (T) pretreated premenopausal women with recurrent or metastatic breast cance r(MBC) (KCSG BR10-04).
Authors: Kim Ji-Yeon , Im Seock-Ah , Jung Kyung Hae , Ro Jungsil , Sohn Joohyuk , Kim Jee Hyun , Park Yeon Hee , Kim Tae Yong , Kim Sung-Bae , Lee Keun-Seok , Kim Gun Min , Kim Se Hyun , Ahn Jin Seok , Lee Kyung-Hun , Ahn Jin-Hee , Park In Hae , Im Young-Hyuck
Published: September 2018

1041

Background: Endocrine therapy(ET) is the preferred treatment for HR(+) MBC. For premenopausal patients who were pretreated with T, ovarian function suppression with G ± aromatase inhibitor(A.I.) is a reasonable option. Fulvestrant yields favorable outcomes in postmenopausal women with MBC. We investigated the efficacy and safety of F+G and A+G in comparison with G alone in premenopausal women with HR(+), T-pretreated MBC. Methods: In this multicenter, open-label, randomized phase 2 study, women > 18 years with HR(+), T-pretreated MBC were stratified by presence of visceral metastasis and recurrence within or after 1 year of completion of adjuvant T. Premenopausal women with T-pretreated MBC eligible for ET were randomly assigned (1:1:1) to F+G (F 500 mg IM + G 3.6 mg SC Q 4 wks), or A +G (A 1 mg P.O. qd + G 3.6 mg SC Q 4 wks) or G (G 3.6 mg SC Q 4 wks). The primary endpoint was time to progression(TTP), analyzed by intention to treat with log-rank test. Secondary endpoints included overall survival, overall response rate, clinical benefit rate and toxicities according to NCI CTCAE v3.0 (ClinicalTrials.gov, No. NCT01266213). Results: Of 138 eligible pts, 44 were randomly assigned to F+G, 47 to A+G, 47 to G. The median duration of follow-up was 28.8 months(mo) and median age was 43 (range; 23.0-55.0). The median TTP was 16.3 mo(95% C.I. 7.5-25.1) for F+G, 14.5 mo(95% C.I. 11.0-18.0) for A+G, and 13.5 mo(95% C.I. 10.3-16.8) for G alone, respectively. For the comparison of each experimental arm to control arm, 24-mo TTP were analyzed: F+G vs G(%±SE): 40.5±7.5 vs. 25.3±7.0, one-sided P = 0.048, A+G vs G(%±SE): 23.9±7.2 vs. 25.3±7.0, one-sided P = 0.304. Grade 3/4 toxicities were rarely observed. Most common adverse events were grade 1 joint stiffness and arthralgia which were more frequently observed in F+G compared to A+G and G (P = 0.018 and 0.015, respectively). Conclusions: The combination of F+G as well as G ±A.I. might be a valid option for HR(+) premenopausal women with T-pretreated MBC and further investigation is warranted. Clinical trial information: NCT01266213.
First-line ribociclib plus letrozole for postmenopausal women with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC): MONALEESA-2 safety results.
Authors: Janni Wolfgang , Burris Howard A. , Blackwell Kimberly L. , Hart Lowell L. , Chan Arlene , Nusch Arnd , Burdaeva Olga Nikolaevna , Alba Emilio , Yardley Denise A. , Bachelot Thomas Denis , Gil Gil Miguel J. , Richards Donald A. , Sparano Joseph A. , Kattan Joseph Gergi , Bourgeois Hugues Pierre , El Karak Fadi Rafic , Ramaswamy Bhuvaneswari , Sutradhar Santosh C. , Miller Michelle Kristine , Conte Pier Franco
Published: September 2018

1047

Background: In the randomized, phase III MONALEESA-2 study (NCT01958021), first-line therapy with ribociclib (RIB; cyclin-dependent kinase 4/6 inhibitor; 600 mg/day; 3-weeks-on/1-week-off) + letrozole (LET; 2.5 mg/day) in postmenopausal women with HR+, HER2– ABC significantly prolonged progression-free survival vs placebo (PBO) + LET (hazard ratio: 0.556; p = 0.00000329; Hortobagyi GN et al. N Engl J Med 2016;375:1738–48). Here we present further safety analyses from MONALEESA-2. Methods: Adverse events (AEs) were characterized per CTCAE v4.03. Analyses of key AEs included time to first event, duration (time to AE resolution), and the rate of associated dose interruptions or reductions. Results: Safety analysis included 664 patients (pts; RIB + LET: 334; PBO + LET: 330). Neutropenia was the most common all-grade (G) and G3/4 AE in the RIB + LET arm (Table); febrile neutropenia rates were low (RIB + LET arm: 1.5%) with no associated deaths. Median time to first event for G ≥2 neutropenia in the RIB + LET arm (based on neutrophil counts) was 16 days. Other common G3/4 AEs (increased by ≥5% in the RIB + LET vs PBO + LET arm) were leukopenia (21% vs 1%), elevated alanine aminotransferase (ALT; 9% vs 1%), lymphopenia (7% vs 1%), and elevated aspartate aminotransferase (AST; 6% vs 1%). Neutropenia was the most common AE leading to dose interruptions/reductions; G3/4 neutropenia led to dose interruptions in 48% vs < 1% and reductions in 30% vs 0% of pts in the RIB + LET vs PBO + LET arm. 7.5% vs 2.1% of pts (RIB + LET vs PBO + LET) discontinued due to AEs; common AEs leading to discontinuation ( > 1% pts) were elevated ALT (5% vs < 1%), elevated AST (3% vs 1%), and vomiting (2% vs 0%). Conclusions: First-line RIB + LET had a manageable safety profile in postmenopausal women with HR+, HER2– ABC. Neutropenia was the most common AE in the RIB arm, and was transient and reversible with dose modifications. Additional AE analyses will be presented. Clinical trial information: NCT01958021. [Table: see text]
A phase I trial of pomalidomide for children with recurrent, progressive/refractory central nervous system (CNS) tumors: A Pediatric Brain Tumor Consortium (PBTC) study.
Authors: Fangusaro Jason R. , Mitchell Duane Anthony , Kocak Mehmet , Onar-Thomas Arzu , Sadighi Zsila Sousan , Baxter Patricia Ann , Hwang Eugene I. , Huang Jianping , Dunkel Ira J. , Fouladi Maryam , Warren Katherine E.
Published: September 2018

10543

Background: CNS malignancies are the most common solid tumors among children. Novel therapies are needed to help improve the survival outcomes in children with recurrent disease. Pomalidomide is an immunomodulatory agent thought to also function through a combination of anti-angiogenic, anti-inflammatory and cytotoixic activity making it a good candidate to explore in pediatric CNS tumors. Methods: A Phase I trial of pomalidomide was conducted among children ≥ 3 to < 21 years old with recurrent, progressive/refractory CNS tumors using the “rolling 6” dose escalation design. The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) when given orally once daily for 21 consecutive days of a 28-day course. Once the MTD was established, 12 additional patients were enrolled on expansion cohorts based on age and steroid use. Results: 29 children were enrolled and 25 were evaluable for dose limiting toxicity (DLT) evaluation. The MTD was 2.6 mg/m2 (Dose level 2). DLTs observed at dose level 3 (3.4 mg/m2) included diarrhea (n = 1), thrombocytopenia (n = 1) and lung infection (n = 1), all grade 3. The most common toxicities were grade 1 lymphopenia (55%), leukopenia (62%) and thrombocytopenia (38%). There were no obvious differences in tolerability based on age or steroid use. Pharmacokinetics were similar to those observed in adults and increased in a dose-dependent manner. At the RP2D of 2.6 mg/m2, the Cmax was 97.4 ng/mL and the t½ was 4.1 hours. The median number of treatment cycles was 1.6 (0.2-12.3). Two patients, one with an oligodendroglioma and one with anaplastic pleomorphic xanthoastrocytoma, had long term stable disease for 9 and 18+ cycles. No objective responses were observed. Twelve month progression-free and overall-survivals were 5.2+/-3.6% and 12.8+/-8.5%, respectively. Immunologic correlate analyses are ongoing. Conclusions: The RP2D of pomalidomide is 2.6 mg/m2 in children with recurrent brain tumors. Further prospective evaluation of this agent alone or in combination will be necessary to better understand its efficacy in specific pediatric CNS tumor populations. Clinical trial information: NCT02415153.
Phase I study of pexidartinib (PLX3397) in children with refractory leukemias and solid tumors including neurofibromatosis type I (NF1) related plexiform neurofibromas (PN).
Authors: Hittson Lauren , Glod John , Amaya Melissa , Derdak Joanne , Widemann Brigitte C. , Kaplan Rosandra N.
Published: September 2018

10546

Background: Refractory tumors remain a significant treatment challenge, and novel approaches targeting the tumor microenvironment may hold promise. Pexidartinib, an oral inhibitor of tyrosine kinases including CSF1R, KIT and FLT3, has activity in adults with tenosynovial giant cell tumor. Methods: We are conducting a phase 1 trial (NCT02390752) to determine the maximum tolerated dose (MTD) and plasma pharmacokinetics (PK) of pexidartinib in patients (pts) 3-21 years old with refractory leukemias and solid tumors including NF1 PN. The MTD is based on cycle (C) 1 toxicities. Pexidartinib is given once daily continuously (1C = 28 days) at DL 1: 400 mg/m2/dose, 2: 600mg/m2/dose, or 3: 800 mg/ m2/dose. Response is assessed after C1 and then every other C, and for NF1 PN with volumetric MRI analysis after every 4 C. Results: Fourteen pts (8 M:6 F, median age 16 years, (range 4-21) with CNS tumors (n = 2), sarcomas (n = 7), peritoneal mesothelioma (n = 1), leukemia (n = 1), NF1 PN (n = 3) have enrolled at DL1 (n = 4), DL2 (n = 4) and DL3 (n = 6). No dose-limiting toxicities have been observed and 11 pts are evaluable for MTD determination (received ≥ 85% of pexidartinib doses in C1). Common non-DLT toxicities are fatigue, decrease in WBC, increase in creatinine kinase and serum amylase, headache, anorexia, vomiting, diarrhea, and hair hypopigmentation. Mean (SD) pexidartinib C1 day 1 PK parameters at [DL1 (n = 4), DL2 (n = 4), and DL3 (n = 4)] were: Cmax DL1 2,813 ng/mL (1,483), DL2 6,065 ng/mL (1,308), DL3 10,323 ng/mL (2,129); AUC0-24h DL1 44,492 ng·h/mL (12,904), DL2 76,569 ng·h/mL (25,790), DL3 132,903ng·h/mL (40,482). The mean (SD) accumulation ratio (C1 D15 AUC0-24h : C1 D1 AUC0-24h ) was 3.9 (0.7) for DL1, 2.4 (0.3) for DL2, and 1.4 (0.6) for DL3. Pts received a median of 1 C (range (1-21+). Pts with NF1 PN received 1, 4, and 6 C of pexidartinib and had stable disease. One pt with peritoneal mesothelioma is receiving C 21. Conclusions: In children, pexidartinib was tolerated at all dose levels, and the recommended phase II dose (RP2D) is 800 mg/m2/dose once daily. This dose exceeds the adult RP2D of 1000 mg/day. Enrollment on the expansion cohort is ongoing. Clinical trial information: NCT02390752.
Long-term outcomes after irradiation (RT) for pediatric low-grade glioma.
Authors: Tsang Derek S. , Murphy Erin Sennett , Merchant Thomas E.
Published: September 2018

10549

Background: Treatment for pediatric low-grade glioma (LGG) is variable, depending on age and tumor location. Systemic therapy (ST) is often used to delay RT, but ST does not result in durable local control. The goal of this study was to evaluate event-free survival (EFS) and toxicities for pediatric LGG treated with RT over a 30-year period. Methods: All patients age ≤21 with intracranial pediatric LGG (WHO grade I-II) treated with RT at a single institution since May 1986 were included in this retrospective review. Patients with metastatic disease (M+) received craniospinal irradiation (CSI); otherwise, RT was conformal. EFS and overall survival (OS) were measured from the first day of RT. Events included death, progression, or secondary high-grade glioma. Results: 221 patients were eligible. Median follow-up was 11.3 yrs (range, 0.1-30.5). Median RT dose was 54 Gy. 10-yr EFS and OS were 67.9% (95% CI 60.4-74.3) and 91.1% (95% CI 85.8-94.5) for non-metastatic patients, respectively. For 12 M+ patients treated with CSI, 10-yr EFS and OS were 58.9% (95% CI 23.4-82.5) and 70.0% (32.9-89.2), respectively. 28.6% developed pseudoprogression (PP) with median time to onset and resolution of 6.1 months (IQR 3.6-14.6) and 6.4 months (IQR 3.5-11.7), respectively. Patients with PP had improved 10-yr EFS (83.4% vs. 61.0%, HR 0.40, p = .006). Patients with grade II tumors and who received pre-RT ST had lower EFS (Table). Sex, NF-1, tumor location, extent of surgery and CSI were not independently associated with EFS. 10-yr cumulative incidence of grade ≥2 vasculopathy was 7.5% (95% CI 4.9-11.4). There were 12 cases of secondary high-grade glioma, with a 20-yr cumulative incidence of 5.5% (95% CI 2.6-11.4). Conclusions: Irradiation provides long-term control of pediatric LGG in a majority of patients. Receipt of pre-RT systemic therapy was associated with reduced EFS; this association requires further investigation. [Table: see text]
Genome-wide discovery of novel susceptibility loci for treatment-associated hypothyroidism among survivors of pediatric medulloblastoma.
Authors: Brown Austin L , Biclamowicz Kevin J. , Sonabend Rona , Scheurer Michael E. , Lupo Philip , Paulino Arnold , Dreyer ZoAnn Eckert , Mahajan Anita , Chintagumpala Murali M. , Okcu M. Fatih
Published: September 2018

10571

Background: Pediatric medulloblastoma patients exposed to craniospinal radiation (CSI) are at high risk of developing endocrinopathies, including hypothyroidism. We sought to evaluate the role of genetic variation on hypothyroidism susceptibility among survivors of pediatric medullobastoma. Methods: Records from 61 medulloblastoma survivors treated at Texas Children’s Hospital between 1997 and 2013 were reviewed. All patients completed baseline and yearly follow-up thyroid assessments. Genome-wide genotyping was performed on Illumina HumanOmni1 and HumanOmni2.5 BeadChip single nucleotide polymorphism (SNP) arrays. Following standard quality control measures and exclusion of rare variants (minor allele frequency [MAF] < 5%), 572,562 autosomal SNPs were included in our analyses. The association between each SNP and hypothyroidism was tested using Fisher’s exact test and logistic regression, assuming additive allelic effects. Results: A total of 25 patients (41%) developed hypothyroidism with median follow-up of 8.3 years from diagnosis (range: 1.8-17.2 years). Primary hypothyroidism was identified in 9 (36%) cases, while the remaining 16 (64%) developed central hypothyroidism. Hypothyroidism was detected in 13 of 40 (33%) individuals exposed to < 30 Gy CSI and 12 of 21 (57%) individuals exposed to ≥30 Gy CSI (p = 0.06). Genome-wide association analysis identified several risk loci, including 3 variants associated with hypothyroidism (p-value < 1x10-5) at chromosome 2q11.2 ( NPAS2 gene). The top overall SNP (MAF = 27.5%, p-value = 6.5x10-7) remained strongly associated with hypothyroidism after accounting for possible confounders, including CSI dose, CSI type (proton/photon), age, sex, and genetic ancestry. Conclusions: Our findings suggest susceptibility to treatment-related hypothyroidism is strongly influenced by common genetic variation in NPAS2. The NPAS2 gene, a central component of the circadian rhythm network, is a transcriptional activator and regulator of DNA damage response and DNA repair genes.
Predictors of specialized pediatric palliative care involvement and impact on patterns of end-of-life care in children with cancer: A population-based study.
Authors: Gupta Sumit , Sutradhar Rinku , Rapoport Adam , Nelson Katherine , Liu Ying , Vadeboncouer Christina , Zelcer Shayna M. , Kassam Alisha , Pole Jason D , Earle Craig , Wolfe Joanne , Widger Kimberley
Published: September 2018

10573

Background: Children with cancer are at risk of receiving high-intensity (HI) care at the end-of-life (EOL) and associated high symptom burden. The impact of palliative care (PC) delivered by generalists or of specialized pediatric palliative care (SPPC) on patterns of EOL care is unknown, with previous studies limited by small sample sizes or low response rates. Methods: Using a provincial registry, we assembled a retrospective cohort of Ontario children with cancer who died between 2000-2012 and who received care through a pediatric institution with a SPPC team and a clinical PC database. Patients were linked to population-based healthcare data capturing inpatient, outpatient, and emergency visits. Clinical PC databases were used to identify patients receiving SPPC. Remaining patients were categorized as having received either general PC (GPC) or no PC depending on the presence of PC associated physician billing or inpatient codes. We determined predictors of SPPC involvement, and whether either SPPC or GPC was associated with HI-EOL outcomes: ICU admission < 30 days from death, mechanical ventilation < 14 days from death, or in hospital death. Sensitivity analyses excluded treatment-related mortality (TRM) cases. Results: 572 patients met inclusion criteria. Children less likely to receive SPPC services included those with hematologic cancers [odds ratio (OR) 0.33, 95th confidence interval (CI) 0.30-0.37; p < 0.001)], in the lowest income quintile (OR 0.44, 95CI 0.23-0.81; p = 0.009), and living at increased distance from the treatment center (OR 0.46, 95CI 0.40-0.52; p < 0.0001). In multivariate analysis, SPPC was associated with a 3-fold decrease in the odds of an EOL ICU admission (OR 0.32, 95CI 0.18-0.57), while GPC had no impact. Similar associations were seen with all other HI-EOL indicators. Excluding TRM had little impact. Conclusions: SPPC, but not GPC, is associated with lower intensity care at EOL. Access to such care however remains uneven. In the absence of randomized trials, these results provide the strongest evidence to date supporting the creation of SPPC teams. These results can be used to support PC advocacy and policy efforts.
A phase I study of enfortumab vedotin (ASG-22CE; ASG-22ME): Updated analysis of patients with metastatic urothelial cancer.
Authors: Petrylak Daniel Peter , Perez Raymond P. , Zhang Jingsong , Smith David C. , Ruether Joseph D. , Sridhar Srikala S. , Sangha Randeep S. , Lang Joshua Michael , Heath Elisabeth I. , Merchan Jaime R. , Gartner Elaina M. , Chu Rong , Anand Banmeet , Doñate Fernando , Jackson Lynnae , Adams Jeffrey , Melhem-Bertrandt Amal , Rosenberg Jonathan E.
Published: September 2018

106

Background: Enfortumab vedotin, an antibody–drug conjugate, delivers monomethyl auristatin E to tumors expressing Nectin-4, which is overexpressed in metastatic urothelial cancer (mUC). Methods: This Phase I study (NCT02091999) enrolled patients (pts) with solid tumors, including pts with mUC, treated with ≥1 prior chemotherapy regimen. All pts received different dose levels of IV enfortumab vedotin (0.5, 0.75, 1, 1.25 mg/kg) once weekly for 3 out of 4 wks. Nectin-4 expression was determined by IHC on archival tumor specimens and quantified by histochemical scoring (H-score). Primary endpoint was tolerability; secondary endpoint was antitumor activity assessed every 8 wks per RECIST v1.1. Results: As of 3 Jan 2017, 68 pts with mUC (46 M/22 F; median age, 67 yr [range: 41–84]) had been treated. Of these, 62% received ≥2 prior therapies in the metastatic setting and 40% had prior immune checkpoint inhibitor (CPI) therapy. In these pts, Nectin-4 expression was high and prevalent (median H-score, 280 [range: 32–300]). Treatment-related adverse events (TRAEs) were reported in 58 pts (85%); diarrhea, fatigue, nausea, and pruritus were TRAEs reported in ≥25% of pts. Most TRAEs were grade ≤2 in severity; 19 pts (28%) experienced a TRAE of grade ≥3. The most common grade ≥3 AEs (occurring in ≥5 pts), regardless of attribution to treatment, were urinary tract infection (10%) and hypophosphatemia (9%). No treatment-related deaths have occurred. Sixty pts had ≥1 post-baseline assessment. Antitumor activity was observed across the dose range; overall response rate (ORR) was 40% (95% CI: 27.6–53.5) for all evaluable pts (n = 60), 46% (95% CI: 25.6–67.2) in pts with prior CPI exposure (n = 24), and 44% (95% CI: 19.8–70.1) in pts with metastasis to the liver (n = 16). Complete responses were noted in 3 pts at doses ≥1 mg/kg. Median treatment duration was 26 wks (range: 5.1–64.6), median duration of response was 18 wks (95% CI: 8.4–40.1), and median progression-free survival was 17 wks (95% CI: 15.1–23.3). Study enrollment is ongoing. Conclusions: Enfortumab vedotin demonstrated a favorable tolerability profile with encouraging antitumor activity in heavily pretreated mUC, including pts for whom CPIs have failed. Clinical trial information: NCT02091999.
Combination of paclitaxel and LAG3-Ig (IMP321), a novel MHC class II agonist, as a first-line chemoimmunotherapy in patients with metastatic breast carcinoma (MBC): Interim results from the run-in phase of a placebo controlled randomized phase II.
Authors: Duhoux Francois P. , Jager Agnes , Dirix Luc , Huizing Manon Thirza , Jerusalem Guy Heinrich Maria , Vuylsteke Peter , De Cuypere Eveline , Breiner Doris , Mueller Christian , Brignone Chrystelle , Triebel Frederic
Published: September 2018

1062

Background: IMP321 is a recombinant soluble LAG3-Ig fusion protein that binds to MHC class II molecules and mediates antigen-presenting cell (APC) activation followed by CD8 T-cell activation. The activation of the dendritic cell network with IMP321 the day after a low dose injection of a single agent chemotherapy may lead to stronger anti-tumor CD8 T-cell responses. We report initial results of the safety run-in of a randomized, placebo-controlled phase IIb trial in patients (pts) with hormone receptor positive (HR+) MBC receiving first-line weekly paclitaxel. Methods: In the safety run-in phase 15 pts with MBC received weekly paclitaxel (80 mg/m2; D1, D8, D15) in a four week cycle in conjunction with either 6 mg (n = 6; cohort 1) or 30 mg (n = 9, cohort 2) IMP321 injections s.c. (D2 and D16) for 6 cycles. Patients without progressive disease could continue with a maintenance phase of 12 additional injections of IMP321 every 4 weeks. Blood samples for pharmacokinetics and immuno-monitoring were taken in cycle 1 and 4 just before and after IMP321 injection. Results: In total 15 pts (median age 53 years) were enrolled between Jan 2016 and Oct 2016. No dose limiting toxicities have been reported. Cytokine release syndrome grade 1 was the only serious adverse event (SAE) related to IMP321 and occurred twice in the same patient. Grade 1 and 2 injection site reactions were the most common related AEs and occurred in 14 pts (93 %). A dose-dependent increase in serum IMP321 concentration was observed among the two dose levels with a Cmaxbetween 4 and 24 hours. Increased number of circulating monocytes, dendritic cells and increased activation were observed at both dose levels of IMP321, supporting the working hypothesis. Conclusions: The 30 mg s.c. IMP321 given every two weeks in combination with weekly paclitaxel is the recommended phase 2 dose which is used in the ongoing randomized placebo controlled phase II part of the study. Clinical trial information: NCT02614833.
Overall survival (OS) of men and women with breast cancer according to tumor subtype: A population-based study.
Authors: Leone Julieta , Zwenger Ariel Osvaldo , Leone Bernardo Amadeo , Vallejo Carlos Teodoro , Leone Jose Pablo
Published: September 2018

1069

Background: The outcomes of male breast cancer (MBC) and female breast cancer (FBC) according to tumor subtype are poorly known. Our group previously reported the prognostic significance of tumor subtypes in MBC. The aim of this study was to analyze differences in OS between MBC and FBC according to tumor subtype compared with other factors. Methods: We evaluated men and women with microscopically confirmed invasive breast cancer between 2010 and 2013 with known estrogen receptor (ER) and progesterone receptor (PR) (together hormone receptor [HR]) status and human epidermal growth factor receptor 2 (HER2) status reported to the SEER program. Patients (pts) with other primary either before or after breast cancer were excluded. Pt characteristics were compared between MBC and FBC. Univariate and multivariate analyses were performed to determine the effect of each variable on OS. Results: We included 1,187 MBC and 166,054 FBC pts. Median age for MBC was 65 years (range 26-97) and for FBC was 60 years (range 18-108). Median follow-up was 21 months (range 1-48) for both groups. OS at 3 years for MBC and FBC was 85.6% and 90.4%, respectively (p = 0.0002). MBC pts were more frequently ductal, had higher grade, presented with more advanced stage and were more often HR+/HER2- (all p < 0.0001). MBC had worse OS than FBC in HR+/HER2- (Hazard ratio [HaR] 1.5; p = 0.0005), HR+/HER2+ (HaR 2.8; p < 0.0001) and triple negative (TN) (HaR 4.3; p < 0.0001) (p for interaction < 0.02). MBC had significantly worse OS than FBC in stage I and II, but similar OS in stage III and IV (p for interaction < 0.01). In multivariate analysis adjusted for age, race, grade, stage, surgery, radiation and marital status; HR+/HER2+ was the only subtype with significant differences in OS between MBC and FBC (HaR 2.0; p = 0.002). Conclusions: In this cohort, we observed significant differences in the distribution of tumor subtypes between MBC and FBC. OS was significantly different in both groups. Men had worse OS in stage I and II while similar OS in stage III and IV. There were significant differences in OS according to tumor subtype; compared with women, men with HR+/HER2+ tumors had twice the risk of death.
Trop2 gene expression (Trop2e) in primary breast cancer (BC): Correlations with clinical and tumor characteristics.
Authors: Vidula Neelima , Yau Christina , Rugo Hope S.
Published: September 2018

1075

Background: Trophoblast antigen 2 (Trop2) is a glycoprotein expressed by many cancers. A phase I study of the trop2 antibody drug conjugate (ADC) IMMU-132 has shown promising activity in triple negative (TN) BC. We studied associations of primary BC trop2e with clinical characteristics, outcomes, and selected genes in publically available databases. Methods: Trop2e was evaluated with microarray data from the neoadjuvant I-SPY 1 (n=149), METABRIC (n=1992) & TCGA (n=817) databases. Associations with clinical features were assessed with the Kruskal-Wallis test (all). Correlations with chemotherapy response were evaluated with the Wilcoxon rank sum test (I-SPY 1) & with recurrence free survival (RFS) by the Cox proportional hazard model (I-SPY 1 & METABRIC). Pearson correlations were used to study associations between trop2e & selected genes (all). Results: In all 3 datasets, trop2 was detectable and had a wide range of expression in all BC subtypes. In I-SPY 1, trop2e did not vary by hormone receptor (HR) & HER2 or intrinsic subtype; in METABRIC & TCGA trop2e was lower in HER2+ than HR+/HER2- & TNBC (METABRIC p=0.03, TCGA p=0.007) & in HER2+ enriched and luminal B BC (p < 0.001, METABRIC & TCGA). Trop2e was higher in grade I vs. II/III BC in METABRIC (p < 0.001). No association with chemotherapy response was seen (I-SPY 1) or with RFS (I-SPY 1 & METABRIC). The table below shows significant (p<0.05) gene correlations with trop2e in ≥2 datasets. Conclusions: Trop2e is seen in all BC subtypes, particularly luminal A and TNBC. Trop2e correlates with the expression of genes involved in cell epithelial transformation, adhesion, and proliferation and inversely with immune genes, which may contribute to tumor growth. These findings support the use of trop 2 directed ADC in all BC subtypes. [Table: see text]
The Metastatic Breast Cancer (MBC) project: Accelerating translational research through direct patient engagement.
Authors: Wagle Nikhil , Painter Corrie , Anastasio Elana , Dunphy Michael , McGillicuddy Mary , Kim Dewey , Jain Esha , Buendia-Buendia Jorge , Cohen Ofir , Knelson Erik , Holloway Jamie , Johnson Shawn , Larkin Katie , Adalsteinsson Viktor , Ha Gavin , Freeman Samuel , Gydush Greg , Reed Sarah , Lander Eric , Golub Todd
Published: September 2018

1076

Background: The Metastatic Breast Cancer Project is a nationwide research study, launched in Oct 2015 in collaboration with patients (pts) and advocacy groups, that directly engages pts through social media and seeks to empower them to share their experiences, clinical information, and samples to accelerate research. Methods: MBC pts enroll by providing their information at mbcproject.org. Pts are sent a saliva kit and asked to mail back a sample which is used to extract germline DNA. We contact pts medical providers and obtain medical records (MRs) and stored tumor samples. Pts may also submit a blood sample, used to extract cell free DNA (cfDNA). Whole exome sequencing (WES) is performed on tumor, germline, and cfDNA; transcriptome sequencing is performed on tumor. Clinical and genomic data are used to generate genomic landscapes in pt subgroups and to identify mechanisms of response and resistance to therapies. Data are shared widely through public databases. Pts receive regular study updates. Results: In 12 months, 2908 MBC pts from 50 states enrolled. 95% completed the 16-question survey about their cancer, treatments, and demographics. 1730 (60%) completed the online consent form. 100-200 pts continue to enroll monthly. To date, 1539 saliva kits were mailed and 1120 samples were received (73%). 992 unique treating institutions were reported by pts, including 733 institutions reported by only 1 pt each and 5 institutions reported by more than 40 pts each. We have obtained MRs from 253 patients (67% yield) and tumor samples from 85 pts (67% yield). WES was successfully completed for 79 tumors of 88 attempted (90%). WES has been performed on initial cfDNA samples. Conclusions: A direct-to-patient approach enabled rapid identification of thousands of MBC pts willing to share MRs, saliva, and tumor samples, including many with rare phenotypes. Remote acquisition of MRs, saliva, tumor, and blood for pts located throughout the US is feasible. We estimate that for ~33% of consenting patients, we can obtain medical records, saliva, and tumor tissue. Genomic analysis of tumor and cfDNA from subgroups including young pts, pts with extraordinary responses, and pts with de novo MBC will be presented.
The role of high-dose chemotherapy (CT) and stem-cell support in high-risk stage II, locally advanced, and responding stage IV breast cancer (BC): The Israeli experience with 20 years median follow-up.
Authors: Peretz Idit , Rizel Shulamith , Hardan Izhar , Stemmer Salomon M.
Published: September 2018

1077

Background: Lately, updated data led the medical community to reconsider the use of intensive CT with stem-cell support for selected groups of BC patients (pts). Herein, we provide an update on a study investigating the efficacy, feasibility, and toxicity of high-dose CT with stem-cell support in pts with high-risk stage II, chemosensitive stage III and IV BC. Methods: The protocol offered adjuvant/neoadjuvant/induction doxorubicin-based CT, 75-90 mg/m2 X 4 courses followed by high-dose CT (cyclophosphamide 6000 mg/m2, carboplatin 800 mg/m2, and thiotepa 500 mg/m2) and autologous stem cell support with growth factors. Post-transplant local radiotherapy was delivered. Pts who were hormone receptor (HR) positive received Tamoxifen. Results: From 2/1994 to 11/1998, 292 BC pts were referred to the study from all Israeli oncology centers. Median follow-up from transplant was 20 (range, 18-22) years; 119 had stage 2 disease (42 with 4-9 positive nodes, 77 with ≥10 positive nodes); 87 had stage 3 disease, of whom 50 had locally advanced/inflammatory BC treated with neoadjuvant CT; and 86 had chemosensitive stage IV BC. Two acute transplant-related deaths and one death due to late transplant-related toxicity were reported. Median age at transplant was 45 (range, 24-63) years. Overall survival (OS) by HR status is presented in the table. In total, 167 of the 292 pts died (based on death status data retrieved from the Registry of the Ministry of the Interior), representing OS of 42%. The OS rates for stage II, III, and IV were 55%, 45%, and 23%, respectively. Conclusions: Long-term accurate follow-up of pts receiving well-defined treatments remains an important tool in cancer research. High-dose CT with stem-cell support could represent a therapeutic/curative option in select BC patients in all disease stages. Reintroduction of this approach should be re-examined. [Table: see text]
Single agent activity of DS-8201a, a HER2-targeting antibody-drug conjugate, in heavily pretreated HER2 expressing solid tumors.
Authors: Doi Toshihiko , Iwata Hiroji , Tsurutani Junji , Takahashi Shunji , Park Haeseong , Redfern Charles H. , Shitara Kohei , Shimizu Chikako , Taniguchi Hiroya , Iwasa Tsutomu , Taira Shinichiro , Lockhart Albert C. , Fisher Jennifer M. , Jikoh Takahiro , Fujisaki Yoshihiko , Lee Caleb C. , Yver Antoine , Tamura Kenji
Published: September 2018

108

Background: Human epidermal growth factor 2 (HER2) is a potential strong tumor driver for breast (BC) and gastric cancer (GC) as well as other HER2 expressing tumors. Antibody-drug conjugates (ADC) provide wider therapeutic window by more efficient and specific drug delivery. DS-8201a is a HER2 targeting ADC of high drug to antibody ratio (7 to 8) with a novel topoisomerase I inhibitor. In preclinical studies, DS-8201a showed a broader antitumor spectrum than T-DM1, including efficacy against low HER2 expressing tumors. Current trial includes dose escalation (Part 1) and expansion (Part 2) focusing on HER2 expressing solid tumors (NCT02564900). Methods: Part 1 used a modified continuous reassessment method to identify the expansion dose in patients (pts) with BC or GC. Part 2 was designed to evaluate the safety and efficacy in 4 expansion cohorts: T-DM1 treated HER2+ BC, trastuzumab treated HER2+ GC, BC with low HER2 expressing and other HER2 expressing solid tumors. Adverse events (AEs), objective response rate (ORR) and durability of responses were assessed. Results: 89 pts were administered in total: 24 pts in Part 1 and 65 pts (BC, GC, colorectal, salivary and non-small cell lung cancer) in Part 2 with median prior therapies of 4. DS-8201a was administered up to 8.0 mg/kg in Part 1, and dose levels of 6.4 and 5.4 mg/kg IV every 3 weeks were chosen for Part 2. There was no dose limiting toxicity, and maximum tolerated dose was not reached in Part 1. The most common AEs in Part 1 and Part 2 were nausea (62%), anorexia (56%) and platelet count decreased (28%). 29% pts experienced ≥ Gr3 AEs (Gr3: 25% Gr4: 4%). The ORR and disease control rate (DCR: CR + PR + SD) are shown in the table. ORR and DCR were 40% and 90%, respectively in evaluable 73 pts including 14 low HER2 expression. One T-DM1 treated BC pt achieved CR. 4 PRs were achieved in pts with low HER2 expression. 63 pts in total are currently being treated. Median duration of treatment was ≥27 weeks in Part 1 and not reached in Part 2. Conclusions: DS-8201a was well tolerated and is remarkably active in heavily pretreated HER2 expressing cancers. Clinical trial information: NCT02564900. [Table: see text]
Whole exome sequencing of metaplastic breast cancer (MpBC): Effect of mutation status on survival.
Authors: Baez Vallecillo Luis , Chang Jeffrey T , Chen Ken , Moss Tyler J. , Shaw Kenna Rael , Meric-Bernstam Funda , Eterovic Agda Karina , Mills Gordon B. , Mani Sendurai , Li Xiaoxian (Bill) , Gilcrease Michael , Moulder Stacy L.
Published: September 2018

1090

Background: Metaplastic Breast Cancer (MpBC) is considered a chemo-refractory, aggressive subtype that is characterized by squamous and/or mesenchymal differentiation and associated with a high rate of molecular aberrations that activate the PI3K pathway. The goal of this study was to correlate outcomes data with underlying genomic aberrations in MpBC. Methods: A cohort of 52 archived samples of MpBC collected from 1986 and 2016 that had clinical outcomes data available for central review underwent hybrid capture sequencing of 202 cancer-related genes (n = 52) and, when sufficient material was available, whole exome sequencing (n = 21). Relapse free (RFS) and overall (OS) survival analyses at 5 years were compared between patients having mutation vs. wild-type (WT) in the whole genome using Kaplan-Meier statistics. Results: The variant allele frequency (VAF) was relatively low with most mutations having a VAF of < 50%. TP53 mutation was found in 33 tumors (63%) and was associated with improved RFS (HR = 2.4; p = 0.03) and OS (HR = 3.7; p = 0.006) compared to WT. Aberrations in the PI3K/AKT/mTOR pathway were present in 29% of tumors and associated with diminished OS (HR = 0.27; p = 0.02) but not RFS (HR = 0.67; p = 0.32). Though uncommon, the presence of an AKT1 (6%) mutation was associated with worse RFS (HR = 0.006; p = 0.006) and OS (HR = 0.0005; p < 0.0001). Conclusions: Surprisingly, TP53 mutation was associated with better prognosis in MpBC with increased RFS and OS. Mutations in AKT1 were uncommon but associated with a significantly worse RFS and OS. Notably, all patients harboring an AKT1 mutation died within a year of diagnosis. Mutations activating the PI3K/AKT/mTOR pathway were associated with worse OS.
Validity of 1% hormonal positivity cutoff by American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines at Georgia Cancer Center.
Authors: Abdul Sater Houssein Talal , Sadek Ramses F. , Zhang Li fang , Gopal Aaron , Blaize Jean-Pierre , Yashar David , Patel Reena , Aribindi Swetha , Patel Hiral S , Tang Shou-Ching
Published: September 2018

1094

Background: Hormone Receptor Status (HS) in breast cancer (BC) is a universally accepted biomarker. ASCO/CAP 2010 guidelines set the threshold of Estrogen and Progesterone Receptor positivity to 1 %. BC with 1-9% HS expression remains controversial with recent data disputing these guidelines. The objective of this retrospective study was to validate these guidelines at Georgia Cancer Center (GCC) with high percentage of black race. Methods: All female patients with invasive BC diagnosed between 2005-2010 at GCC (11y follow-up) were chart reviewed. We used Cox proportional hazards model to explore survival among three HS groups ( < 1%, 1-9%, ≥10%) adjusting for standard prognostic factors. Hazard ratios (HR) and 95% confidence intervals (CI) were also reported. 1-9 %, and ≥10% groups were further explored using same method to test survival difference with or without hormone therapy (HT). Fischer’s Exact test was used to evaluate response to HT in these groups. Results: 400 patients (all stages) with mean age of 59, were 24.75% HS < 1%, 17.5% HS1-9%, and 57.75% HS≥10%. Race was 43.75% Black, and 54% White. Disease stages were 84.4% early (I-IIIA) and 15.56% late (IIIB-IV). Grades were 51.42% low (1-2) and 48.58% high (3). The 2 groups (1-9%, ≥10%) received chemotherapy (42.86%, 39.83%), and HT (58.57%, 80.52%) respectively while 70.71% of < 1% HS group had chemotherapy. Mortality in HS < 1% was significantly higher than HS ≥10% (HR 1.8, 95% CI 1.07-3.02), while mortality between HS 1-9% and HS ≥10% was not different (HR 1.05, 95% CI 0.48-2.30). Treated (HT) subjects had lower mortality than untreated subjects in the 1-9% group (HR 0.10, 95% CI 0.01-0.85). 100% of HT group had no evidence of tumor at last follow up compared to 87.5% in non-treatment group (p = 0.048). There was no significant difference in mortality between treated (HT) 1-9% and ≥10% groups. Conclusions: Hormone receptor expression as low as 1-9% was found to be equi-prognostic to ≥10% expression. It also predicted response to hormonal therapy. Whether other factors as lympho-vascular invasion, grade, and other parameters change the behavior of the 1-9% HS group remain to be explored.
Immune response, safety, and survival impact from CMB305 in NY-ESO-1+ recurrent soft tissue sarcomas (STS).
Authors: Somaiah Neeta , Chawla Sant P. , Block Matthew Stephen , Morris John Charles , Do Khanh Tu , Kim Joseph W. , Druta Mihaela , Sankhala Kamalesh Kumar , Hwu Patrick , Gnjatic Sacha , Lu Hailing , Kenney Richard T. , Bohac Gerry C. , Pollack Seth
Published: September 2018

11006

Background: CMB305 is an active immunotherapy regimen designed to generate and expand anti-NY-ESO-1 T cells. It consists of LV305, a dendritic cell targeting lentiviral vector encoding NY-ESO-1, and a boost with G305, an NY-ESO-1 recombinant protein plus GLA-SE, a TLR-4 agonist. An LV305 phase 1 study demonstrated a 1-yr survival of 81% and induction of anti-NY-ESO-1 T cells in sarcoma patients (pts). This first-in-human study of CMB305 examined safety, immunogenicity, and efficacy in pts with NY-ESO-1 positive (+) solid tumors. Methods: Adults with previously treated NY-ESO-1+ sarcomas, NSCLC, ovarian cancer were enrolled in a 3+3 dose-escalation with an expansion phase 1 study. The CMB305 regimen included 4 intradermal injections of LV305 at 109 or 1010 vector genomes, alternating with 3 intramuscular G305 injections at 250 µg for 3 months, then bimonthly G305 injections up to 1 yr. Results: As of 31Dec2016, 25 pts with STS (15 synovial (SS), 8 myxoid/round cell liposarcoma (MRCL), 2 other) were evaluable for safety; 23 SS/MRCL pts were evaluable for immune response (IR) and efficacy. All SS and MRCL pts received prior therapy for locally advanced/metastatic disease, 67% > = 2 prior chemo regimens. No DLTs were observed; treatment related AEs were grade 1 and 2, except 1 pt with grade 3 SAE (prostatic pain). Of 11 SS/MRCL pts tested, 64% pts developed NY-ESO-1 specific T cells and 72% pts anti-NY-ESO-1 antibodies. T cell receptor sequencing indicated increased clonality, and antigen spreading after CMB305. Best response by immune related response criteria was stable disease in 8/15 (53%) SS pts and 6/8 (75%) MRCL pts. The 3 month PFS rate was 74% and 75% for SS and MRCL pts. Median survival has not been reached with 1-yr survival rate of 86% and 100% for SS and MRCL pts. Conclusions: CMB305 is safe, well tolerated, and demonstrates a survival rate that is favorable when compared with approved agents for recurrent STS. CMB305 resulted in a stronger and broader integrated IR than LV305, including antigen spreading. These data warrant further investigation of CMB305 as a monotherapy in a randomized clinical study in STS. A randomized study of CMB305 in combination with atezolizumab in SS/MRCL pts is ongoing. Clinical trial information: NCT02387125.