bluuebunny/crossref_metadata_2025 huggingface dataset:
PARSIFAL: A randomized, multicenter, open-label, phase II trial to evaluate palbociclib in combination with fulvestrant or letrozole in endocrine-sensitive patients with estrogen receptor (ER)[+]/HER2[-] metastatic breast cancer.
Authors: Llombart-Cussac Antonio , Pérez-García José Manuel , Bellet Meritxell , Dalenc Florence , Gil Gil Miguel J. , Ruiz Borrego Manuel , Gavilá Joaquín , Sampayo-Cordero Miguel , Aguirre Elena , Schmid Peter , Marmé Frederik , Di Cosimo Serena , Gligorov Joseph , Schneeweiss Andreas , Albanell Joan , Zamora Pilar , Wheatley Duncan , Martínez-De Dueñas Eduardo , Amillano Kepa , Cortes Javier
Published: May 2020

1007

Background: The CDK4/6 inhibitor palbociclib (P) in combination with letrozole (L) has become a standard first-line treatment for patients (pts) with luminal metastatic breast cancer (MBC) (PALOMA-1 & 2 trials). Meanwhile, the anti-estrogen fulvestrant (F) showed to be superior to anastrozole in the same population (FALCON trial). We aimed to identify the best endocrine agent to combine with P in this first-line scenario. Methods: A total of 486 pts with ER[+]/HER2[-] MBC with no prior therapy in the advanced setting and endocrine sensitive criteria (relapse > 12 months [mo] after the end of adjuvant endocrine therapy or diagnosed with “de novo” metastatic disease) were randomly assigned (1:1 ratio) to receive P (oral 125 mg/day [d]; 3 wks on/1 wk off) plus F 500 mg/d (I.M Days 0, 14, 28, and then every 28 d) or PL (oral 2.5 mg/d). Pts were stratified by visceral involvement and type of disease presentation (“de novo”/recurrent). Primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), and safety. 254 events were needed with 80% power to detect a hazard ratio (HR) ≤0.7 in favor of PF (2-sided α = 0.05). Results: By March 9th, 2020, 256 PFS events occurred. Pts characteristics were well balanced. Median age was 62 years (range: 25–90), 56.6% were ECOG 0, 40.7% had “de novo” metastatic disease, 48% had visceral disease, and 43.6% with ≥3 organ sites involved. At median follow-up of 32 mo, median PFS was 27.9 mo (95% confidence interval [CI], 24.2-33.1) with PF and 32.8 mo (95% CI, 25.8-35.9) with PL (HR: 1.1; 95% CI, 0.9-1.5; P = 0.321). No differences were observed for pts with or without visceral involvement (HR: 1.3 and HR: 0.97 respectively, interaction P = 0.275), and for “de novo” or recurrent metastatic disease (HR: 1.1 and HR: 1.1 respectively, P = 0.979). The 4-year OS rate was 67.6% in PF and 67.5% in PL arm (HR: 1; 95% CI, 0.7-1.5; P = 0.986). No differences were observed in ORR or CBR between arms. Grade ≥3 adverse events were similar in both arms, being neutropenia and leukopenia the most frequent. No treatment-related deaths were reported. Conclusion: This study was not able to identify an improvement in PFS for PF over PL in patients with endocrine-sensitive ER[+]/HER2[-] MBC. As both arms demonstrated comparable 4 years-OS, PF is a reasonable alternative to PL in this setting. Clinical trial information: NCT02491983 .
Patient-reported outcomes (PROs) from the phase III IMspire150 trial of atezolizumab (A) + cobimetinib (C) + vemurafenib (V) in patients (pts) with BRAFV600+melanoma.
Authors: Lewis Karl D. , Robert Caroline , Ascierto Paolo Antonio , Stroyakovskiy Daniil , Gogas Helen , Protsenko Svetlana , Pereira Rodrigo Perez , Eigentler Thomas K. , Rutkowski Piotr , Demidov Lev V. , Manikhas Georgy Moiseevich , Tadesse-Bell Sara , Huang Kuan-Chieh , McNally V. , Mulla Sohail , McArthur Grant A. , Gutzmer Ralf
Published: May 2020

10073

Background: In IMspire150, A+C+V significantly improved investigator-assessed progression-free survival vs placebo (Pbo)+C+V in previously untreated pts with unresectable stage IIIc/IV BRAFV600+melanoma. PRO data from this trial are now reported. Methods: 514pts were randomized 1:1 to 28-day cycles of A+C+V or Pbo+C+V. Pts received C+V in cycle 1; A or Pbo was added on days 1 and 15 from cycle 2 onward. Pts completed the EORTC QLQ-C30 questionnaire on day 1 of cycle 1 (baseline), days 1 and 15 of cycle 2 and cycle 3, day 1 from cycle 4 onward, within 28-d of treatment discontinuation, and ≤6 months post-treatment. Prespecified secondary PRO endpoints were time to confirmed deterioration (TTCD; defined as time from randomization to first ≥10-point decrease from baseline held for 2 consecutive assessments, or 1 assessment followed by death on treatment) in quality of life (QoL) and physical functioning (PF). Prespecified exploratory endpoints were TTCD in role functioning (RF); mean change from baseline and percentage of pts with a clinically meaningful change (≥10 points from baseline) in QoL, PF, and RF. Results: Questionnaire completion rates were > 80% for most of the treatment period. At baseline, mean QoL, PF, and RF scores were moderate to high (Table). At week 6 (cycle 2), following initiation of A, QoL, PF, and RF scores declined, but returned to near-baseline levels at week 10 (cycle 3) and were largely maintained until week 36 (cycle 10), when < 50% of pts contributed data. In this time, ≥56% pts in both arms did not experience a clinically meaningful deterioration in QoL, PF, and RF. TTCD on QoL (hazard ratio [HR] 1.23; 95% CI 0.90-1.67), PF (HR 1.27; 95% CI 0.93-1.74), and RF (HR 1.15; 95% CI 0.86-1.55) favored Pbo, but only one-third of pts overall experienced a confirmed deterioration. Conclusions: PRO data showed that A+C+V did not worsen QoL, PF, and RF in pts with advanced BRAFV600+melanoma, thus supporting its use as a treatment option. Clinical trial information: NCT02908672. [Table: see text]
Safety and clinical activity of gene-engineered T-cell therapy targeting HPV-16 E7 for epithelial cancers.
Authors: Norberg Scott , Nagarsheth Nisha , Sinkoe Andrew , Adhikary Sabina , Meyer Thomas , Lack Justin , Kanakry Jennifer Ann , Bagheri Mohammadhadi , Schweitzer Colleen , Astrow Stephanie H. , Bot Adrian , Stroncek David , Gkitsas Nikolaos , Highfill Steven , Hinrichs Christian S.
Published: May 2020

101

Background: Genetically engineered T-cell therapy has shown remarkable clinical activity in hematologic malignancies. It is not known if this type of treatment can be applied effectively to epithelial cancers, which account for 80% to 90% of human malignancies. Methods: We conducted a phase I clinical trial with a 3 + 3 dose escalation in which patients with metastatic HPV-16+ epithelial cancers were treated with a one-time infusion of genetically engineered T cells expressing a T-cell receptor targeting an HLA-A*02:01-restricted epitope of HPV-16 E7 (E7 TCR-T cells). A lymphocyte-depleting conditioning regimen was administered before cell infusion, and high-dose systemic aldesleukin was administered after cell infusion. Results: Twelve patients, previously treated with a median of 4 (range, 3 to 7) anticancer agents, were treated. The cell dose was not limited by toxicity. Six patients demonstrated objective clinical responses, which included regression of bulky tumors and complete elimination of some tumors. Responses occurred in patients with vulvar, anal, head and neck, and cervical cancer. Four patients who previously received PD-1-based therapy responded. Response duration ranged from 3 to 9 months. Sustained, high-level engraftment of E7 TCR-T cells in peripheral blood was observed (median after approximately 6 weeks, 66% of total T cells, range 1% to 88%) and correlated with cell dose but not with clinical response. Infused T cell characteristics did not correlate strongly with response. Of the 4 resistant tumors that were studied, 3 demonstrated genetic defects in HLA-A*02:01 or B2M (necessary components of the target complex) and 1 demonstrated copy loss with decreased expression of antigen presentation and interferon response molecules (i.e. TAP1, TAP2, IFNGR1, IFNGR2). Of the 3 sensitive tumors studied, 0 showed genetic defects in these molecules. Conclusions: E7 TCR-T cells demonstrated safety and clinical activity in the treatment of highly refractory metastatic HPV-16+ cancers. Treatment resistance was linked to definitive genetic defects in the targeted peptide-HLA complex and to manifold defects in antigen processing and interferon response. Clinical trial information: NCT02858310.
Association of tumor mutational burden (TMB) and clinical outcomes with pembrolizumab (pembro) versus chemotherapy (chemo) in patients with metastatic triple-negative breast cancer (mTNBC) from KEYNOTE-119.
Authors: Winer Eric P. , Lipatov Oleg , Im Seock-Ah , Goncalves Anthony , Muñoz-Couselo Eva , Lee Keun Seok , Schmid Peter , Testa Laura , Witzel Isabell , Ohtani Shoichiro , Lunceford Jared , Karantza Vassiliki , Mejia Jaime Alberto , Cristescu Razvan , Aurora-Garg Deepti , Jelinic Petar , Huang Lingkang , Cortes Javier
Published: May 2020

1013

Background: In the randomized, open-label, phase 3 KEYNOTE-119 study (NCT02555657) , OS was not significantly different with pembro monotherapy versus chemo in second- or third-line settings for mTNBC; however, the pembro treatment effect increased with increasing PD-L1 enrichment. We evaluated the association of TMB with efficacy of pembro monotherapy versus chemo in patients with previously treated mTNBC. Methods: Patients with centrally confirmed TNBC and 1 or 2 prior systemic treatments for metastatic disease were enrolled. Patients were randomly assigned 1:1 to pembro 200 mg Q3W or single-agent chemo per investigator’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine. Association of TMB, as measured by FoundationOne CDx (Foundation Medicine), with response was an exploratory objective evaluated using receiver operator characteristic (ROC) analysis, logistic regression (ORR), and Cox regression (OS; PFS) within treatment arms; estimates of efficacy based on TMB cutpoint used a prespecified cutpoint of 10 mut/Mb. Results: TMB data were available for 253/601 (42.1%) treated patients (pembro, n = 132; chemo, n = 121); baseline characteristics were similar to that of the overall study population. One-sided P values for the association of TMB and clinical outcomes in pembro-treated patients were 0.154 for ORR, 0.014 for PFS, and 0.018 for OS; the area under the ROC curve ([AUROC] 95% CI) for predicting ORR was 0.58 (0.43-0.73). Two-sided P values for the association of TMB and clinical outcomes in chemo-treated patients were 0.114 for ORR, 0.478 for PFS, and 0.906 for OS; AUROC (95% CI) was 0.43 (0.27-0.59). Twenty-six patients had TMB ≥10 mut/Mb. Thus, the prevalence of TMB ≥10 mut/Mb was ~10%. Outcomes based on TMB cutpoint are reported in the Table. Conclusions: Data from this exploratory analysis from KEYNOTE-119 suggest a potential positive association between TMB and clinical benefit with pembro but not chemo in patients with mTNBC. Although precision is limited by sample size and the number of patients with TMB ≥10 mut/Mb, ORR and HRs for OS suggested a trend towards increased benefit with pembro versus chemo in patients with TMB ≥10 mut/Mb. Clinical trial information: NCT02555657 . [Table: see text]
A first in-human study of A166 in patients with locally advanced/metastatic solid tumors which are HER2-positive or HER2-amplified who did not respond or stopped responding to approved therapies.
Authors: Liu Yongheng , Lian Wei , Zhao Xi , Qi Wei , Xu Jian , Xiao Liang , Qing Yan , Xue Tongtong , Wang Jingyi
Published: May 2020

1049

Background: HER2 is an effective therapeutic target for breast and gastric cancer. A166 is an antibody-drug conjugate composed of a novel cytotoxic drug site-specifically conjugated to transtuzumab sequence via a stable protease-cleavable valine citrulline linker. Methods: This was a single arm, open-label, multicenter, dose escalating Phase 1 first-in-human study of A166 as monotherapy in solid tumor patients. Dose escalation and MTD identification was directed using a Bayesian logistic regression model with overdose control. The following dose levels were evaluated in this study: 0.3, 1.2, 3.6, 4.8 mg/kg. (ClinicalTrials.gov NCT03602079) Results: As of November 1, 2019 35 pts have completed the DLT evaluation period across 4 dose levels. Overall, A166 had an acceptable toxicity profile with no unexpected toxicities related to the study drug. No adverse events recorded met the protocol specified definition of a dose limiting toxicity at any studied dose level. Most frequently (≥10%) occurring TEAEs include were Keratitis, Decreased appetite, Dry eye, Vision blurred etc. Overall incidence of ophthalmic toxicities in the 3.6 mg/kg cohort was 80% and in the 4.8 mg/kg cohort it was 83%. Among the 27 patients evaluable for efficacy, best response was progression of disease in 11 patients (41%), stable disease in 9 patients (33%) and partial response in 7 patients (26%), for the total disease control rate of 59%.Responses were seen only at the dose levels of 3.6 mg/kg and 4.8 mg/kg. Conclusions: A166 demonstrated clinically meaningful efficacy in heavily pretreated patients with relapsed or refractory advanced solid cancers. The achievement of an ORR of 36% at efficacious dose levels and up to 100% in HER2 positive patients regardless of histology (2 CRC, 1 BC and 1 NSCLC) at the highest studied dose level exceed Clinical trial information: NCT03602079 .
Randomized comparisons of bevacizumab (B) and irinotecan (I), added to temozolomide (T), in children with relapsed or refractory high-risk neuroblastoma (RR-HRNB): First survival results of the ITCC-SIOPEN BEACON-Neuroblastoma phase II trial.
Authors: Wheatley Keith , Holt Grace , Owens Cormac , Laidler Jennifer , Valteau-Couanet Dominique , Gambart Marion , Castel Victoria , van Eijkelenburg Natasha , Castellano Aurora , Nysom Karsten , Gerber Nicolas U. , Laureys Genevieve , Ladenstein Ruth Lydia , Makin Guy , Vaidya Sucheta , Thebaud Estelle , Kearns Pamela , Pearson Andrew DJ , Moreno Lucas
Published: May 2020

10501

Background: BEACON is a randomized phase 2 trial assessing whether inhibiting angiogenesis with bevacizumab adds to the activity of chemotherapy and evaluating chemotherapy regimens for children with RR-HRNB. Methods: Patients with RR-HRNB were eligible. There were randomizations (rand), in a 3x2 factorial design, to: T, IT or topotecan (To)-T, +/- B. Toxicity and response were reported in 2019 (ASCO, ESMO). Survival outcomes – progression-free (PFS) and overall (OS) – for the I and B rands are reported here (To rand is still open). The B rand used a relaxed alpha (1-sided p=0.2) for PFS as its phase 2 success criterion; the I rand was Bayesian. Cox model hazard ratios (HR) <1.0 indicate benefit for I or B. Heterogeneity tests (HT) assessed interactions between B and I. Analysis was intention-to-treat. Results: From 2013-19, 160 patients were randomized to B v. no B, including 121 to I v. no I, with: median age 5.8 years; 113 and 47 measurable and evaluable disease; 67 and 93 refractory and relapsed disease; 35 had MYCN amplification. Median follow-up was 15.4 months. PFS and OS are shown in the table. In the main comparisons (I v. no I, B v. no B), I improved PFS and OS (98% probability that true HR<1.0 for both) and B just met its success criterion (PFS: 1p=0.20; OS: 1p=0.19). However, there was some, but not conclusive, evidence of a positive interaction between B and I for both PFS (HT: p=0.06) and OS (HT: p=0.12). If real, this would suggest that adding either I (IT) or B (BT) to T does not improve outcome, but adding both (BIT) does. Twice as many patients had serious adverse events with BIT (57%) than with T (26%) or IT (27%), with BT at 40%. Conclusions: The BEACON results show that single agent T is suboptimal. Statistical uncertainty about an interaction between I and B means two further interpretations are possible: 1) IT and possibly BT are better than T; 2) IT and BT are not better than T, but I and B together (BIT) are better. Hence, a definitive conclusion on the best combination(s) to take forward is not currently possible and further randomized evaluation is needed. Clinical trial information: ISRCTN40708286. [Table: see text]
Dabrafenib + trametinib combination therapy in pediatric patients with BRAF V600-mutant low-grade glioma: Safety and efficacy results.
Authors: Geoerger Birgit , Bouffet Eric , Whitlock James A. , Moertel Christopher L. , Hargrave Darren R. , Aerts Isabelle , Cohen Kenneth J. , Kilburn Lindsay Baker , Wright Karen D. , Choi Jeea , Gasal Eduard , Russo Mark W. , Fox Elizabeth
Published: May 2020

10506

Background: Low-grade gliomas (LGGs) are the most common brain tumors among children. Pediatric LGGs are often not surgically resectable and tend to demonstrate relapsed/remitting courses with current standard chemotherapy regimens. Moreover, radiation is often avoided due to its associated neurocognitive and endocrinologic sequelae. However, in pediatric patients (pts) with BRAF V600-mutant LGG, dabrafenib monotherapy has demonstrated meaningful clinical activity and acceptable tolerability (Hargrave et al, Clin Cancer Res. 2019; NCT01677741). Here we report the efficacy and safety of dabrafenib + trametinib (D+T) combination therapy in pediatric pts with previously treated BRAF V600-mutant LGG. Methods: This is a 4-part, open-label, multicenter, phase I/II study (NCT02124772). The limited dose-escalation (ESC) portion evaluated the D+T combination in pediatric pts ( < 18 y) with recurrent/refractory BRAF V600-mutated solid tumors that were naive to MAPK pathway–targeted therapy. This was followed by a tumor cohort expansion (EXP), and the D+T combination was evaluated in BRAF V600-mutant LGG pts at recommended dose levels. Efficacy was determined by both investigator and independent review using the RANO criteria (for gliomas). Adverse events (AEs) were assessed per NCI-CTCAE v4.03. Results: Overall, 36 pediatric pts with LGG received D+T combination therapy (ESC, n = 16; EXP, n = 20); pooled efficacy data were available for both ESC and EXP, while LGG-specific safety data were available for EXP. At interim analysis (Aug 2019), 17 of the 20 pts in EXP remained on protocol therapy. Three pts withdrew/discontinued treatment because of AEs. Skin toxicity (95%) and pyrexia (75%) were the frequent AEs reported. No on-treatment deaths were reported. Across both ESC and EXP, the objective response rate (ORR) was 25% (95% CI, 12%–42%) per independent review (1 complete response [CR], 8 partial response [PR], 24 stable disease [SD], 2 progressive disease [PD], 1 unknown [UNK]) and 50% (95% CI, 33%–67%) per investigator review (2 CR, 16 PR, 17 SD, 1 UNK). However, ORR + SD was similar, with 92% and 97% of pts having SD or better per independent and investigator review, respectively. Conclusions: In pediatric pts with pretreated BRAF V600-mutant LGG, D+T combination therapy demonstrated clinical activity, with 92% of pts having SD or better by independent review using the RANO criteria. Pyrexia and skin toxicity were the common AEs; majority of these were low-grade and manageable. Clinical trial information: NCT02124772.
Outcomes with reduced intensity therapy in a low-risk subset of children with National Cancer Institute (NCI) standard-risk (SR) B-lymphoblastic leukemia (B-ALL): A report from Children’s Oncology Group (COG) AALL0932.
Authors: Schore Reuven J. , Angiolillo Anne J. , Kairalla John A , Devidas Meenakshi , Rabin Karen R. , Zweidler-McKay Patrick A , Borowitz Michael J. , Wood Brent L. , Carroll Andrew J , Heerema Nyla A. , Relling Mary V. , Hitzler Johann , Lane Ashley R. , Maloney Kelly W. , Wang Cindy , Carroll William L. , Winick Naomi J. , Raetz Elizabeth A. , Loh Mignon L. , Hunger Stephen
Published: May 2020

10509

Background: Post-hoc analysis of COG P9904 identified a low risk (LR) group of SR B-ALL patients aged 1-9.99 years with WBC < 50,000/µL, no CNS3, and either ETV6/RUNX1 or double trisomies (DT) of chromosomes 4 and 10 with day 8 peripheral blood (PB) and day 29 marrow (BM) minimal residual disease (MRD) < 0.01% who had a 5-year event-free survival (EFS) of 97±2% and overall survival (OS) 98.8±0.8%. Outstanding results were also obtained for LR patients on COG AALL0331 using CCG-based ALL therapy. AALL0932 tested prospectively whether LR B-ALL patients could attain a 5-year EFS ≥95% with these regimens. Methods: Following a 3-drug induction, eligible AALL0932 LR patients had NCI SR B-ALL (no testicular leukemia, unfavorable genetics or Down syndrome) with DT or ETV6/RUNX1 fusion, CNS1, no steroid pre-treatment, with Day 8 PB and Day 29 BM MRD < 0.01%. Between 2010-16, 603 LR patients were randomized to P9904-based regimen LR-M (n = 301) or CCG 1991/COG AALL0331-based regimen LR-C (n = 302). LR-M included 6 24-hour infusions of 1 gm/m2 of methotrexate (MTX) with leucovorin rescue, but no anthracyclines or alkylating agents. Maintenance followed with daily 6-mercaptopurine (6-MP) and weekly oral MTX, and every 16 week 7-day pulses of dexamethasone (DEX) with vincristine (VCR) on days 1 and 8. Boys and girls were treated for 2.5 years from diagnosis. LR-C had no 24-hour MTX infusions, but included 2 Interim Maintenance (IM) phases with VCR and escalating IV MTX without leucovorin rescue given every 10 days for 5 doses, flanking an 8-week Delayed Intensification (DI) phase that included DEX, VCR, pegasparagase, doxorubicin (75 mg/m2), cyclophosphamide (1 gm/m2) and 8 doses of low-dose cytarabine (75 mg/m2/dose). LR-C Maintenance included daily 6-MP and weekly oral MTX with 5-day pulses of DEX and 1 dose of VCR given every 12 weeks. Girls received 2 years and boys 3 years of therapy from the start of IM I. Results: Both regimens achieved outstanding outcomes: 5-yr disease-free survival (±SE) 98.8%±0.8% for LR-M and 98.5%±0.9% for LR-C (p = 0.67). Both had 5-yr OS 100%. Therapies were well tolerated with higher rates of mucositis (12.9 vs 6.3%; p = 0.008) and allergic reactions (2.3% vs 0%; p = 0.02) on LR-C. Conclusions: AALL0932 demonstrated that application of stringent risk criteria can identify a favorable B-ALL subgroup almost certain to be cured with either LR-M or LR-C, allowing physicians and families to select the optimal treatment approach in the future. Clinical trial information: NCT01190930.
Outcomes in children with Down syndrome (DS) and B-lymphoblastic leukemia (B-ALL): A Children’s Oncology Group (COG) report.
Authors: Rabin Karen R. , Chen Zhiguo , Devidas Meenakshi , Hitzler Johann , Larsen Eric , Burke Michael , Salzer Wanda L. , Schore Reuven J. , Carroll Andrew J , Heerema Nyla A. , Borowitz Michael J. , Wood Brent L. , Carroll William L. , Winick Naomi J. , Raetz Elizabeth A. , Hunger Stephen , Loh Mignon L. , Maloney Kelly W. , Angiolillo Anne L.
Published: May 2020

10510

Background: Patients with DS and B-ALL experience increased rates of relapse and toxicities. Here, we report results from 4 COG trials (2003-2018). Methods: We analyzed clinical, and outcome data for DS (n = 743) and non-DS (n = 21,703) patients age 1-30 enrolled on standard-risk (SR) trials AALL0331 and AALL0932 and high-risk (HR) trials AALL0232 and AALL1131. Initially, DS-ALL patients on AALL0232/AALL0331 experienced excess mortality, prompting enhanced supportive care and omission of induction anthracycline except for slow responders on AALL1131. Other modifications included: non-random assignment to treatment strata without investigational agents; leucovorin rescue after intrathecal methotrexate (MTX); equal maintenance length for boys and girls; every 12-week maintenance vincristine/steroid pulses; and reduced anthracycline and intravenous MTX for HR patients. Results: Across all 4 trials, DS and non-DS patients did not differ significantly in age, sex, initial WBC, or CNS status. DS-ALL patients had significantly higher end of induction (EOI) minimal residual disease (MRD) vs non-DS patients on both AALL0932 and AALL1131, but the difference persisted at end of consolidation (EOC) only on AALL1131, with fewer EOI MRD+ DS patients achieving EOC MRD < 0.01% (76.1 vs 88.0%, p = 0.001). 5-year EFS and OS were significantly poorer for DS vs non-DS across all trials (EFS 79.6+2.1% vs 86.3+0.3%, p < 0.0001; OS 86.5+1.8% vs 93.1+0.2%, p < 0.0001), as well as on each individual trial. In Cox regression analysis for all DS patients, inferior EFS was associated with several known risk factors (age > 10, EOI MRD >0.01%) but not with cytogenetics or CRLF2 status Induction death was more frequent in DS patients (3.4% vs 0.8%, p < 0.0001) as was death in remission (4.8+0.8% vs 1.8+0.1%, p < 0.0001). For death in remission, the increased frequency occurred pre-maintenance and in patients taken off protocol therapy, but not during maintenance, in contrast to prior reports. Grade >3 mucositis, infections, and hyperglycemia were significantly more frequent in DS patients on all trials. Grade >3 seizures were significantly more frequent in DS patients on HR but not SR trials (4.1% vs 1.7%. p = 0.001) and occurred in all phases pre-maintenance. Conclusions: Patients with DS and B-ALL continue to have inferior outcomes compared to non-DS, with increased relapse and toxicities. Less toxic approaches such as immunotherapies and targeted therapies hold promise to improve outcomes in both these areas.
Temsirolimus combined with etoposide and cyclophosphamide for relapsed/refractory acute lymphoblastic leukemia: Therapeutic advances in Childhood Leukemia Consortium (TACL 2014-001) trial.
Authors: Rheingold Susan R. , Silverman Lewis B. , Whitlock James A. , Sposto Richard , Schafer Eric S. , Schultz Kirk R. , Hutchinson Raymond J. , Gaynon Paul S. , Bateman Caroline , Cooper Todd Michael , Laetsch Theodore Willis , Sulis Maria Luisa , Wayne Alan S. , Tasian Sarah K.
Published: May 2020

10512

Background: PI3K/mTOR signaling, a critical pathway in cell proliferation, metabolism, and apoptosis, is often dysregulated in acute lymphoblastic leukemia (ALL). A phase 1 trial of the mTOR inhibitor temsirolimus combined with etoposide and cyclophosphamide was performed in children with relapsed/refractory (r/r) ALL. Methods: Temsirolimus was administered intravenously (IV) on days 1 and 8 with cyclophosphamide 440 mg/m2 and etoposide 100 mg/m2 IV daily days 1-5. The starting dose level (DL) of temsirolimus was 7.5 mg/m2 (DL1) with escalation to 10 mg/m2 (DL2), 15 mg/m2 (DL3), and 25 mg/m2 (DL4). MRD was performed centrally. PI3K pathway inhibition was measured by phosphoflow cytometry (PFC) analysis of peripheral blood (PB) from treated patients (pts). Results: Sixteen heavily pretreated r/r ALL pts ages 2-19 years with marrow blasts > 25% were enrolled; 15 were evaluable [10 B-ALL/5 T-ALL]. One dose-limiting toxicity (DLT) of grade (Gr) 4 pleural and pericardial effusions with pneumonitis/lung infection leading to Gr 5 cardiorespiratory arrest occurred in a pt treated at DL3. No further DLTs were seen in the DL3 expansion and DL4 cohorts. Gr 3/4 non-hematologic toxicities occurring in ≥ 3 pts included febrile neutropenia, elevated ALT, hypokalemia, mucositis, and tumor lysis syndrome and were independent of dose. Of 15 evaluable pts, 4 (27%; 2 B-ALL/2 T-ALL) had a complete response (CR) after cycle 1, comprised of 1 pt at each DL. Three had MRD < 0.01%. Three pts (20%; 2 B-ALL/1 T-ALL) had partial response (PR). Overall response rate (CR+PR = ORR) was 47%. Pharmacodynamic PFC studies compared phosphoprotein levels pre (day 0) and post treatment (days 3-5) in 9 consenting pts with available PB. All tested pts showed basal activation of PI3K pathway signaling. Dose-dependent inhibition of mTOR targets phosphorylated (p) S6 and/or p4EBP1 was observed in 9/9 and 6/9 pts, respectively, following temsirolimus and chemotherapy treatment. Various patterns of compensatory upregulation of pPI3K, pmTOR, pAkt, and/or pERK was observed. Conclusions: Temsirolimus at 25 mg/m2 combined with salvage etoposide and cyclophosphamide has an acceptable safety profile in high-risk pediatric patients with r/r ALL. Responses were observed at all DLs. mTOR target inhibition was achieved and appeared to correlate with dose level. Future testing of other PI3K/mTOR pathway inhibitors in combination with chemotherapy may be warranted with a goal of further increasing response in r/r ALL. Clinical trial information: NCT01614197.
Dexrazoxane and heart function among long-term childhood cancer survivors: A Children’s Oncology Group study.
Authors: Chow Eric Jessen , Aggarwal Sanjeev , Doody David R , Aplenc Richard , Armenian Saro , Baker Kevin Scott , Bhatia Smita , Blythe Nancy , Colan Steven , Constine Louis S. , Freyer David Robert , Kopp Lisa M. , Laverdiere Caroline , Leisenring Wendy M. , Sasaki Nao , Vrooman Lynda M. , Asselin Barbara , Schwartz Cindy L. , Lipshultz Steven E.
Published: May 2020

10513

Background: Dexrazoxane (DRZ) has cardioprotective effects among doxorubicin (DOX) treated childhood cancer survivors up to 5 years after therapy. However, longer-term data are lacking. Methods: P9404, P9425, P9426, and DFCI 95-01 were randomized trials of acute lymphoblastic leukemia and Hodgkin lymphoma, where patients were randomly assigned to DOX±DRZ. P9754 enrolled osteosarcoma patients who all received DOX+DRZ. In all studies, DRZ was given as an intravenous bolus before DOX (10:1mg ratio). DOX doses ranged from 100-600 mg/m2 across these 5 trials. A subset of COG institutions prospectively assessed cardiac function in long-term survivors from these trials, plus a matched group of osteosarcoma survivors treated with DOX alone. Echocardiograms (left ventricular [LV] Biplane ejection fraction [EF], shortening fraction [SF]) and blood biomarkers (b-type natriuretic peptides [BNP], N-terminal [NT] proBNP) were all analyzed centrally, with DRZ status masked. Lower LV function was defined as EF<50% or SF<30%. T-test, rank-sum, and multivariate regression adjusted for sex, cancer diagnosis age, current age, DOX dose, and chest radiotherapy were used to examine differences and associations by DRZ status. Results: Among 173 participants assessed (52% DRZ+; 54% male; mean DOX 294±96 mg/m2) 17.6±2.4y since cancer diagnosis, DRZ+ participants were slightly younger (27.8 vs 29.6y, p=0.02), but baseline characteristics otherwise did not differ significantly by DRZ status. DRZ status was associated with higher FS (34.7±3.6% vs 33.4±4.3%, p=0.04) and EF (63.4±5.4% vs 61.4±5.5%, p=0.01), and lower BNP (median 10.4 pg/mL [IQR 6.0-18.0] vs 13.0 [IQR 6.0-28.2], p=0.03) and NT-proBNP (median 30.8 pg/mL [IQR 18.9-58.2] vs 47.1 [IQR 23.0-83.1], p<0.01). In stratified analyses, the cardioprotective effects associated with DRZ tended to be more pronounced in females (vs males) and those who received DOX ≥300 mg/m2 (vs <300mg/m2). Results from multivariate models were similar: DRZ was associated with higher SF (1.4% [95% CI 0.2, 2.6]) and EF (2.7% [95% CI 0.8, 4.6]), and reduced BNP (-4.0 pg/mL [95% CI -7.6, -0.4]) and NT-proBNP (-20.7 pg/mL [95% CI -33.5, -7.9]). Overall, DRZ was associated with a reduced risk of having lower LV function (odds ratio 0.27 [95% CI 0.08-0.96]). Conclusions: After >17y, childhood cancer survivors treated with DOX+DRZ had better LV systolic function and less myocardial wall stress compared with those treated with DOX alone. DRZ may preferentially benefit females and those treated with greater DOX doses.
Individual prediction of non-adherence to oral mercaptopurine (6MP) in children with acute lymphoblastic leukemia (ALL): Results from COG AALL03N1 study.
Authors: Hoppmann Anna Lynn , Chen Yanjun , Landier Wendy , Hageman Lindsey , Relling Mary V. , Wong F. Lennie , Bhatia Smita
Published: May 2020

10530

Background: Poor adherence to 6MP (measured electronically [MEMS]) increases relapse risk in children with ALL (Bhatia et al. JAMA Oncol 2015). Adherence is difficult to assess clinically and non-adherers are more likely to over-report 6MP intake (Landier et al. Blood 2017). Key sociodemographic/clinical factors (Bhatia et al. JCO 2012) and red cell methyl-mercaptopurine (MMP, a 6MP metabolite) levels (Hoppmann et al. ASCO 2017) are associated with non-adherence and could potentially identify non-adherers. Methods: We developed a prediction model for 6MP non-adherence (MEMS adherence rate < 90%), using receiver operating characteristic (ROC) analyses in 407 children with ALL receiving 6MP (mean age 7.7±4.4y; 68% males; 35% Caucasians, 34% Hispanics, 16% African Americans, 15% Asians). The cohort was divided into a training set (n = 250) and test set (n = 157) using stratified random sampling (stratified by race/ethnicity, gender, age and 6MP non-adherence). We used logistic regression with backward variable elimination, guided by change in area under ROC (AUC), to create a prediction model in the training set, using only clinical and sociodemographic variables (Clinical Model). We then generated a model that added 6MP dose-intensity (6MPDI)-adjusted red cell MMP levels to the Clinical Model (Final Model). All models were validated in the test set. Results: Predictors retained in the Training Clinical Model included: age, race/ethnicity, absolute neutrophil count, 6MPDI, family structure, and taking 6MP at the same vs varied time of day (AUC = 0.79; 95%CI 0.72-0.85). The Training Final Model (adding 6MPDI-adjusted MMP to the Clinical Model) yielded an AUC = 0.79 (95%CI 0.72-0.86). The Test Final Model (AUC = 0.79, 95%CI 0.69-0.88) showed significantly superior discrimination compared to the Test Clinical Model (AUC = 0.74, 95%CI 0.63-0.85; P = 0.002). Using a binary classifier with predicted probability of non-adherence ≥0.5, the Test Final Model had an accuracy of 79%, and positive and negative predictive values of 71% and 80%, respectively. Conclusions: We created, validated, and compared 2 risk-prediction models for 6MP non-adherence in children undergoing maintenance chemotherapy. While inclusion of red cell MMP levels provided superior discrimination in identifying non-adherent patients, the Clinical Model (without MMP levels) performed adequately well, and could be used in the clinical setting.
A phase I/II study of eribulin mesilate (ERI) plus irinotecan (IRI) in children with refractory or recurrent solid tumors.
Authors: Casanova Michela , Kramm Christof , Reinhardt Dirk , Locatelli Franco , D'Adamo David R. , Scott Rachael , Jia Yan , Aluri Jagadeesh , Favre Claudio , Bautista Francisco , Hladun Alvaro Raquel , Sastre Urgelles Ana , Kontny Udo
Published: May 2020

10535

Background: ERI is an inhibitor of microtubule dynamics. IRI is used to treat pediatric sarcomas. In the pediatric preclinical testing program, ERI was well tolerated and had promising activity compared with vincristine (a common chemotherapeutic for pediatric cancers) for various solid tumors ( in vivo xenograft panels). Methods: Children with relapsed/refractory solid tumors (excluding active central nervous system tumors) were enrolled. Prior treatment with IRI was allowed. Dose escalation was conducted for 2 schedules with the primary objective (phase 1) of determining the maximum tolerated dose and the recommended phase 2 dose: (A) ERI 1.4 mg/m2 IV infusion (Days 1 + 8 of 21-day cycle) + IRI 20 or 40 mg/m2 IV infusion (Days 1–5 of 21-day cycle); (B) ERI 1.4 mg/m2 IV infusion (Days 1 + 8 of 21-day cycle) + IRI 100 or 125 mg/m2 IV infusion (Days 1 + 8 of 21-day cycle). Safety and pharmacokinetic parameters were assessed. Results: 13 patients (pts) were enrolled (median age: 9 years [range: 3–17]); 4 pts had rhabdomyosarcoma (RMS), 2 had non-RMS soft tissue sarcoma, 2 had Ewing sarcoma, 2 had hepatoblastoma, 2 had nephroblastoma, and 1 had neuroblastoma. Overall, 7 pts previously received IRI. No dose-limiting toxicities (DLTs) were reported for either schedule. At data cut-off (July 14, 2019), 4 pts (with Ewing sarcoma, neuroblastoma, RMS, or hepatoblastoma) continued treatment (A, n = 2; B, n = 2) and 9 pts discontinued treatment (primarily for radiographic progression, n = 7 [A, n = 4; B, n = 3]). All pts experienced ≥1 treatment-emergent adverse event (TEAE); the most common any grade TEAE was neutropenia (n = 10; A, n = 5; B, n = 5). 11 pts had grade ≥3 TEAEs (A, n = 6; B, n = 5); the most frequent grade ≥3 TEAE was neutropenia (n = 9; A, n = 5; B, n = 4). No pt withdrew ERI or IRI due to an AE; 3 pts had dose reductions for ERI (A, n = 1; B, n = 2) and 3 pts had dose interruption of ERI (A, n = 2; B, n = 1) due to AEs. No pt had dose reductions for IRI, and 3 pts had dose interruption of IRI (A, n = 2; B, n = 1) due to AEs. 3 deaths occurred; 2 deaths were the result of tumor progression (A, n = 1; B, n = 1), and the cause of 1 was unknown (B). 1 pt with neuroblastoma treated according to schedule A had a partial response. Systemic exposures of ERI, IRI, and SN-38 (IRI active metabolite) were similar between schedules and doses. Conclusions: No DLTs were observed. Toxicity was manageable. Administration of IRI treatment on Days 1–5 is widely used in pediatric cancers; enrollment for phase 2 is ongoing with treatment Schedule A (ERI 1.4 mg/m2 Days 1 + 8 of 21-day cycle; IRI 40 mg/m2 Days 1–5 of 21-day cycle). Clinical trial information: NCT03245450.
Deep learning for improved prediction of late-onset cardiomyopathy among childhood cancer survivors: A report from the St. Jude Lifetime Cohort (SJLIFE).
Authors: Gunturkun Fatma , Davis Robert L , Armstrong Gregory T. , Jefferies John L. , Ness Kirsten K. , Green Daniel M. , Lucas John Thomas , Srivastava Deokumar , Hudson Melissa M. , Robison Leslie L. , Mulrooney Daniel A. , Soliman Elsayed Z , Karabayir Ibrahim , Akbilgic Oguz
Published: May 2020

10545

Background: Early identification of survivors at high risk for treatment-induced cardiomyopathy may allow for prevention and/or early intervention. We utilized deep learning methods using COG guideline-recommended baseline electrocardiography (ECG) to improve prediction of future cardiomyopathy. Methods: SJLIFE is a cohort of 5-year clinically assessed childhood cancer survivors including baseline ECG measurements. Development of cardiomyopathy was identified from clinical and echocardiographic measurement using CTCAE criteria (grade 3-4). We applied deep learning approaches to ECG, treatment exposure and demographic data obtained at baseline SJLIFE assessment. We trained a cascaded model combining a 12-layer 1D convolutional neural network to extract features from waveform ECG signals with a 2-layer dense neural network to embed features from other phenotypic data in tabular format to determine if use of deep learning with ECG data could improve prediction of cardiomyopathy. Results: Among 1,218 subjects (median age 31.7 years, range 18.4-66.4) without cardiomyopathy at baseline evaluation, 616 (51%) were male, 1,041 (85%) white, 157 (13%) African American and 792 (65%) were survivors of lymphoma/leukemia. Follow-up averaged 5 (0.5 to 9) years from baseline examination. Mean chest radiation dose was 1350 cGy (range 0 to 6,200 cGy) and mean cumulative anthracycline dose was 191 mg/m2 (range o to 734 mg/m2). A total of 114 (9.4%) survivors developed cardiomyopathy after baseline. A cascaded deep learning model built on a training set (N = 974 participants) classified cardiomyopathy in the test set (N = 244 participants) using both clinical and ECG data with a sensitivity of 70%, specificity of 73%, and AUC of 0.74 (95% CI 0.63-0.85), compared to a model using clinical data alone (sensitivity 61%, specificity 62%, and AUC 0.67, 95% CI 0.56-0.79). In subgroup analyses, models predicting cardiomyopathy within 0-4 years following baseline had a sensitivity, specificity, and AUC of 77%, 78%, and 0.78 (0.65-0.91), respectively. When predicting cardiomyopathy 5-9 years following baseline, model performance dropped to a sensitivity, specificity, and AUC of 70%, 70%, and 0.68 (0.50-0.87), respectively. Conclusions: Deep learning using ECG at baseline evaluation significantly improved prediction of cardiomyopathy in childhood cancer survivors at high risk for cardiomyopathy. Future directions will incorporate deep learning approaches to echocardiography to further improve prediction.
HAGHL genetic variants increase first fracture risk (FFR) in female childhood cancer survivors: A report from the Childhood Cancer Survivor Study (CCSS) and St. Jude Lifetime Cohort Study (SJLIFE).
Authors: Im Cindy , Li Nan , Moon Wonjong , Morton Lindsay M. , Leisenring Wendy M. , Howell Rebecca M. , Oeffinger Kevin C. , Sklar Charles A. , Wilson Carmen Louise , Sapkota Yadav , Ness Kirsten K. , Hudson Melissa M. , Robison Leslie L. , Bhatia Smita , Armstrong Gregory T. , Yasui Yutaka
Published: May 2020

10554

Background: Recent genome-wide association studies (GWAS) have reported substantial sex differences in the genetic architectures of bone-related phenotypes. We investigated sex-specific genetic determinants of FFR in survivors of childhood cancer. Methods: We performed sex-combined and sex-stratified GWAS for FFR using Cox regression models fitted on follow-up age in 2,453 long-term (≥5 years) survivors in CCSS with ~5.4 million imputed SNPs (minor allele frequency, MAF≥5%), with self-reported FFR defined by first fracture at any site after diagnosis. Replication analyses were conducted in an independent sample of 1,417 SJLIFE survivors with whole-genome sequencing and clinician-assessed FFR. All models were adjusted for relevant genetic (e.g., ancestry) and clinical (e.g., height, weight, treatment) factors. Results: Sex-combined and male-specific analyses yielded no associations with P < 10−7. Among female CCSS survivors (N = 1,289, 33% ≥1 fractures), we discovered 7 genome-wide significant (P < 5x10−8) SNP-FFR associations with strong evidence of sex effect heterogeneity (P < 7x10−6) across 2 independent loci with no known associations with bone phenotypes. We replicated these associations in SJLIFE (P≤0.05) for 3 coding SNPs in the HAGHL gene (16p13.3), among which rs1406815 showed the strongest association (MAF = 20%, meta-analysis HR = 1.43, P = 8.2x10−9; N = 1,935 women, 35% ≥1 fractures). We observed increased HAGHL SNP effects on FFR that corresponded with increasing head/neck (HN) radiation therapy (RT) dose (Table). Public omics data show replicated SNPs are associated with differential HAGHL expression in sex gland and musculoskeletal tissues (GTEx) and in osteoblasts treated with dexamethasone or prostaglandins (GRASP), suggesting sex-/therapy-specific biological pathways involving HAGHL SNPs for fracture are plausible. Conclusions: Novel associations between HAGHL genetic variants and FFR potentially reveal new sex- and therapy-specific biological mechanisms underlying bone-related health conditions in survivors of childhood cancer. [Table: see text]
Is it safe and worthwhile? A multi-site randomized clinical trial of FAmily CEntered (FACE) pediatric advance care planning for adolescents with cancer and their families.
Authors: Baker Justin N. , Thompkins Jessica , Needle Jennifer , Cheng Yao , Friebert Sarah , Lyon Maureen E
Published: May 2020

10557

Background: Many clinicians express concern that pediatric ACP (pACP) is too distressful for families. We describe the effect of FAmily CEntered pACP for Teens with Cancer (FACE-TC) on families’ self-reported experience. Methods: A 4-site, intent-to-treat, longitudinal, randomized clinical trial recruited adolescent/family dyads from hospital-based cancer-specialty clinics from 2016-2019. Adolescent/family dyads were screened/assented/consented/enrolled and randomized at a 2:1 ratio to either FACE-TC or Treatment as Usual control. FACE-TC is three weekly, 60-minute sessions with a certified facilitator (ACP survey; Next Steps: Respecting Choices Interview; Five Wishes advance directive). Satisfaction Questionnaire measured 7 positive (useful, helpful, load off my mind, satisfied, something I needed to do, courageous, worthwhile) and 6 emotional reactions (scared, hurtful, harmful, too much to handle, angry, sad). It was administered by a trained/blinded research assistant immediately following the Respecting Choices interview or 3 weeks post-baseline for controls. Results: Family participants were: primarily mothers (75%); mean age 46 years; 83% female; 82% white. Household income was ≤100% Federal poverty level for 26%; 58% had less than a Bachelor’s degree. Attendance was 92% for three FACE sessions. FACE families (N = 116) compared to controls were more likely to report the study was “worthwhile” (97% vs. 86%, 0 = 0.0245); “useful” (97% vs. 83%, p = 0.0102); “helpful” (96% vs. 79%, p = 0.0079); and “something I needed to do” (84% vs. 55%, p = 0.0006). FACE families (Mean 28.1, SD 3.3) reported higher positive subscale scores than control families (Mean 24.9, SD 4.4) (β = 2.98, p = 0.0001). No significant differences were found for age, gender, race, household income, or adolescent on active treatment. There were no differences between FACE or control dyads on the 6 emotional reactions subscale score. Conclusions: Among a geographically, economically diverse families, FACE pACP was safe and worthwhile. Clinicians can be assured that a structured facilitated pACP intervention, although emotionally intense, did not unduly distress families who found the experience overwhelmingly worthwhile. Results fill the gap about how to successfully engage families in pACP with their adolescent child. Clinical trial information: NCT02693665.
NivoCUP: An open-label phase II study on the efficacy of nivolumab in cancer of unknown primary.
Authors: Tanizaki Junko , Yonemori Kan , Akiyoshi Kohei , Minami Hironobu , Ueda Hiroki , Takiguchi Yuichi , Kondoh Chihiro Nakayama , Segawa Yoshihiko , Takahashi Shin , Iwamoto Yasuo , Kidera Yasuhiro , Fukuoka Kazuya , Nakamura Yasushi , Chiba Yasutaka , Nishio Kazuto , Nakagawa Kazuhiko , Hayashi Hidetoshi
Published: May 2020

106

Background: CUP has a poor prognosis with a median survival of less than 12 months. Given the recent approval of immune checkpoint inhibitors in several cancer types, we performed a multicenter phase II study of nivolumab in CUP patients (pts). Methods: The main population of this study is CUP pts who were previously treated with more than one line of systemic chemotherapy. Previously untreated CUP pts were also enrolled for exploratory analysis. Pathological examination (including IHC), CT, FDG-PET, gastroscopy and colonoscopy and medical examination were mandatory for diagnosis of CUP before enrollment. CUP pts belonging to favorable prognosis groups were excluded from the trial. Nivolumab (240 mg/body) was delivered as an intravenous infusion every 2 weeks for up to 52 cycles until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) according to RECIST 1.1 by an Independent Endpoint Review Committee in previously treated pts. The secondary objectives include investigator-assessed ORR, progression-free survival (PFS), overall survival (OS), safety and the association between the efficacy of nivolumab and PD-L1 expression. Results: A total of 56 CUP pts, 45 previously treated and 11 previously untreated pts, were enrolled in this trial. The median age was 65.5 years, 22 pts were male. Median follow-up was 8.05 mo (range, 0.1 to 20.7 mo). Of 45 previously treated pts, 2 and 9 had an investigator-assessed complete response and partial response (ORR 24.4%, 95% CI: 12.9-39.5%), with a median PFS (mPFS) and OS (mOS) of 5.4 mo (95% CI: 2.6-6.9) and 15.1 mo (95% CI: 8.3-NR), respectively. Among 11 previously untreated pts, 1 pt had partial response (ORR 9.1%, 95% CI: 0.2-41.3%). The mPFS was 3.9 mo and the mOS was not reached in untreated pts (95% CI: 1.1-5.6, and 95% CI: 2.6-NR, respectively). Nivolumab demonstrated a mPFS of 5.1mo (95% CI: 2.7-5.6) and a mOS of 15.9 mo (95% CI: 8.4-NR) in an overall population. Immune-related adverse events occurred in 57% of overall pts with 5% of grade 3 or higher, and the most common were rash (27%), hypothyroidism (16%), and diarrhea/colitis (16%). No treatment related death was observed. Conclusions: In pts with previously treated and untreated CUP, nivolumab demonstrated durable antitumor activity with a manageable safety. Clinical trial information: UMIN000030649.