bluuebunny/crossref_metadata_2025_split huggingface dataset:
Progression free survival (PFS) benefits of immuno-oncology agents (IOs) and implications for market cost-sharing inefficiencies.
Authors: Ashraf Syed Muhammad Mushtaq , Pandita Shruti , Alimpertis Emmanouil , Khan Talal , Verghese Cherian 
Published: May 2019

6643 Background: Cancer care expense has high financial toxicity with 6 in 10 patients reporting distress about finances. System wide cost has also increased with new treatment approvals; from 2011 to 2016 FDA approved 52 cancer treatments. During this time, US healthcare spending increased from $26.8 billion to $42.1 billion. Lung cancer has high mortality- in 2018 American Cancer Society estimated 234,030 new cases with 50% likely to die from the disease. Hence new treatments are important societal need but costs are concerning. Methods: We selected Phase 3 trials of IO based regimens for non-small cell lung cancer (NSCLC) in first line setting, approved by FDA in 2018. Median PFS was compared between intervention and no-intervention group (NIG). Total costs were evaluated using 2018 Medicare reimbursements rates. Cost and PFS were converted to represent expenditures accrued for 12 months (mths) PFS gain. Results: Study 1 (NCT02125461) for stage 3 NSCLC; looked at maintenance Durvalumab after platinum doublet chemoradiation induction. Median PFS 17.2 vs 5.6 mths in NIG. 1 year PFS cost $155,391 vs $27,477. Study 2 (NCT02578680) for stage 4 NSCLC; looked at maintenance Pembrolizumab, Pemetrexed or Pemetrexed alone after platinum doublet induction. Median PFS 8.8 vs 4.9 mths in NIG. 1 year PFS cost $283,949 vs $116,159. Study 3 (NCT02775435) for stage 4 NSCLC (squamous); looked at maintenance Pembrolizumab after platinum doublet induction. Median PFS 6.4 vs 4.8 mths in NIG. 1 year PFS cost $195,820 vs $119,146. Study 4 (NCT02366143) for stage 4 NSCLC; looked at maintenance Atezolizumab, Bevacizumab or Bevacizumab alone after platinum doublet induction. Median PFS 8.3 vs 6.8 mths in NIG. 1 year PFS cost $316,499 vs $199,278. Conclusions: Median PFS doubled from IOs in NSCLC but costs accrued, more than doubled. The expense has to be quantified in relation to per capita GNP in US- $53,128 in 2017. Accepting even a higher threshold of $100,000 for 1 quality adjusted life year gained, costs appear economically unsustainable. But PFS gains are significant indicating need to enable IOs utilization, by making innovative cost sharing platforms.
Total cost of care for patients (pts) with stage II colon cancer (CC-II): A SEER-Medicare analysis.
Authors: Barzi Afsaneh , Jiao Xiayu , Hay Joel W , Sadeghi Sarmad 
Published: May 2019

6648 Background: Adjuvant chemotherapy (AC) for stage II colon cancer remains a controversial topic. We used Surveillance Epidemiology End Results (SEER) linkage with Medicare claims to explore the benefits of AC and cost of care in pts with CC-II diagnosed between 2004-2010. Methods: Colon cancer was identified using ICD-O-3 codes. TNM staging was used to classify pts as stage II. Cohort was restricted to pts who had surgery within 4months (mos) of the diagnosis and excluded pts who died within 3mos after the surgery as well as those who were enrolledon a health maintenance organization. We searched claims in the 4mos after surgery to identify pts who received AC using ICD-9 diagnosis and procedure codes, HCPCS, and revenue center codes. Kaplan-Meier method was used for survival analysis. Cost of care from payer’s perspective (Medicare) starting from surgery service to death or 3 years after surgery was captured from claims data. Results: A total of 16948 pts with CC-II diagnosed 2004-2010 were included in this analysis. Among those 14% received AC and 33% of them oxaliplatin. After adjusting for pts and tumor characteristics, probabilityof survival at 3years was 72.9% for pts who received AC and 74.2% for those who did not, HR=1.06 (95% CI, 0.96-1.17), with P-value: 0.229. The cost of care for the AC was significantly higher than the no-AC group (median $254,116 vs. $91,086). The biggest difference in between two groups was cost of outpatient and physician services. Costs for AC group was higher in years 1, 2, and 3 as seen in table. Conclusions: AC for CC-II is has a low value in elderly pts and should be avoided. [Table: see text]
Efficacy and safety of the combination of nivolumab (NIVO) plus ipilimumab (IPI) in patients with symptomatic melanoma brain metastases (CheckMate 204).
Authors: Tawbi Hussein Abdul-Hassan , Forsyth Peter A. J. , Hodi F. Stephen , Lao Christopher D. , Moschos Stergios J. , Hamid Omid , Atkins Michael B. , Lewis Karl D. , Thomas Reena Parada , Glaspy John A. , Jang Sekwon , Algazi Alain Patrick , Khushalani Nikhil I. , Postow Michael A. , Pavlick Anna C. , Ernstoff Marc S. , Reardon David A. , Balogh Agnes , Rizzo Jasmine I. , Margolin Kim Allyson 
Published: May 2019

9501 Background: We previously reported efficacy and safety of NIVO+IPI in patients (pts) with untreated, asymptomatic, melanoma brain metastases (MBM) from the CheckMate 204 study. Here, we provide the first report of NIVO+IPI in pts with symptomatic MBM, and report updated data in pts with asymptomatic MBM. Methods: In this phase II trial, pts with ≥1 measurable, nonirradiated MBM 0.5–3.0 cm were enrolled into two cohorts: (1) those with no neurologic symptoms or steroid Rx (asymptomatic; cohort A); and (2) those with neurologic symptoms, whether or not they were receiving steroid Rx (symptomatic; cohort B). In both cohorts, pts received NIVO 1 mg/kg + IPI 3 mg/kg Q3W × 4, then NIVO 3 mg/kg Q2W until progression or toxicity. The primary endpoint was intracranial clinical benefit rate (CBR; proportion of pts with complete response [CR] + partial response [PR] + stable disease [SD] ≥6 mo). As of the clinical cutoff date on May 1, 2018, all treated pts (101 in cohort A and 18 in cohort B) had been followed for ~6 mo or longer. Results: In this updated analysis of cohort A (median follow-up of 20.6 mo), the CBR was 58.4% (Table). In cohort B, pts received a median of 1 NIVO+IPI dose and 2 of 18 pts (11%) received all 4 doses. At a median follow-up of 5.2 months in cohort B, intracranial objective response rate was 16.7% and the CBR was 22.2%. Grade 3/4 adverse events occurred in 54.5% of pts in cohort A and in 55.6% of pts in cohort B (6.9% and 16.7% in the nervous system, respectively), with one death related to treatment in cohort A (immune-related myocarditis). Conclusions: In pts with asymptomatic MBM, our updated results show a high rate of durable intracranial responses, further supporting NIVO+IPI as a first-line treatment in this population. Intracranial antitumor activity was observed with NIVO+IPI in pts with symptomatic MBM, but further study is needed to understand the biologic mechanisms of resistance to immunotherapy and to improve treatments in this challenging population. Clinical trial information: NCT02320058. [Table: see text]
A multicenter analysis of melanoma recurrence following adjuvant anti-PD1 therapy.
Authors: Owen Carina N. , Larkin James M.G. , Shoushtari Alexander Noor , Carlino Matteo S. , Blank Christian U. , Lee Belinda , Mangana Joanna , Atkinson Victoria , Millward Michael , Zaman Farzana , Young Arissa , Khattak Muhammad Adnan , Patel Sapna Pradyuman , Hoeller Christoph , Hersey Peter , Chauhan Dharmisha , Palmieri David James , Lo Serigne , Menzies Alexander M. , Long Georgina V. 
Published: May 2019

9502 Background: Adjuvant anti-PD1 monoclonal antibodies (mAbs) prolong recurrence-free survival in high-risk resected melanoma, however patients (pts) recur during or after therapy. The patterns of recurrence and optimal management are unclear. Methods: Pts from 15 melanoma centres who recurred having received adjuvant anti-PD1 mAbs (adj-PD1) for resected stage III/IV cutaneous melanoma were included. Disease characteristics, adjuvant treatment, recurrence characteristics, subsequent management and outcomes were examined. Results: 137 pts had melanoma recurrence; 97 (71%) during adj-PD1 and 40 (29%) following treatment cessation (25 had stopped early for toxicity after a median 3 months, 14 after completing 12 months, 1 who withdrew consent after 1 month). Median time to recurrence from start of anti-PD1 was 4.6 months (IQR 2.7-8.5), and median follow up from recurrence was 7.7 months (IQR 3.8-12.3). At 1st recurrence, 78 (57%) pts had distant disease (including 22 with both locoregional and distant), 59 (43%) had locoregional disease only. Of those who recurred locally, 22/59 (37%) later developed distant disease. 26 (19%) pts have died. 81 (59%) pts had systemic therapy for distant recurrence (either 1st recurrence or subsequent). Of those who recurred during adj-PD1, no pts (0/20) subsequently responded to anti-PD1 alone (N = 8) or with any investigational agent (N = 12; anti-LAG3, IDOi, MEKi, TLR9 agonist); 9/27 evaluable pts (33%) responded to ipilimumab-based therapy (alone or in combination with anti-PD1), and 15/19 (79%) responded to BRAF/MEKi . Of those who recurred after ceasing adj-PD1, 2/5 (40%) responded to anti-PD1 monotherapy, 2/5 (40%) responded to ipilimumab-based therapy, 7/8 (88%) responded to BRAF/MEKi. Conclusions: These data suggest minimal activity of further anti-PD1 monotherapy in those who recur while on adj-PD1, but possible activity in those who recur off treatment. Anti-CTLA4 and BRAF/MEKi therapy appear active in those who recur on or following adj-PD1. Data on locoregional recurrence and its management will also be presented.
Pharmacodynamic effect of IMCgp100 (TCR–CD3 bispecific) on peripheral cytokines and association with overall survival in patients with advanced melanoma.
Authors: Middleton Mark R. , Steven Neil Matthew , Evans TR Jeffry , Infante Jeffrey R. , Hamid Omid , Shoushtari Alexander Noor , Corrie Philippa Gail , Anthoney Alan , Gupta Avinash , Woodcock Victoria K , McAlpine Cheryl , Sznol Mario 
Published: May 2019

9523 Background: ImmTAC molecules are unique TCR–anti-CD3 bispecifics that redirect T cells against intracellular antigens. IMCgp100, an ImmTAC targeting melanocyte-expressed gp100 antigen, has demonstrated monotherapy activity in advanced melanoma and can cause rash and cytokine-mediated AEs, hypothesized to be on-target (gp100) or effector (CD3) mediated. A preclinical MoA for T cell bispecifics suggests chemokine CXCL10 redirection of CXCR3+ T cells from blood into antigen-positive tissues; this has not been clinically validated. Methods: 84 HLA-A2+ pts with advanced melanoma (n = 61 cutaneous [CM], n = 19 uveal [UM], n = 4 other) received IMCgp100 (NCT01211262). Serum (n = 40) and PBMC (n = 22) samples were taken pre- and post-infusion to analyze changes in cytokines and circulating T cells. Pre- (n = 16) and post-treatment (n = 11) tumor biopsies were analyzed by IHC for CD3, PD-L1 and gp100 expression; tumor RNA (n = 12) was analyzed for gene expression. Results: IMCgp100 induced a transient increase in IFNg-inducible cytokines, most prominently CXCL10. A greater increase in serum CXCL10 was associated with longer OS (p = 0.0002), tumor shrinkage (p = 0.003), and greater transient reduction in peripheral CXCR3+CD8+ T cells (p = 0.001). Reduction in CXCR3+ CD8+ T cells also trended with longer OS (p = 0.02), and tumor shrinkage (p = 0.03). 3/16 pre-treatment biopsies had < 1% gp100 expression (all progressive disease). 8/11 biopsies post-IMCgp100 had increased CD3+ T cells compared with matched pre-treatment samples (associated with baseline gp100 but not PD-L1 expression). Based on tumor biopsy gene expression analysis, IMCgp100 increased T cell markers, IFNg-inducible and cytotoxicity-related genes. Conclusions: The association of clinical benefit with increased serum CXCL10 and decreased peripheral CXCR3+ T cells supports the MoA of IMCgp100-induced T cell redirection and activation. Tumor biopsy results support IMCgp100 redirection of T cells to antigen-positive tumor. A Phase II trial in CM (NCT02535078), a Phase I/II trial in UM (NCT02570308), and a Pivotal RCT in UM (NCT03070392) are ongoing. Clinical trial information: NCT01211262.
Progression-free survival (PFS) in unresectable melanoma patients (pts) treated with talimogene laherparepvec (T-VEC) versus granulocyte macrophage colony-stimulating factor (GM-CSF) in OPTiM.
Authors: Milhem Mohammed M. , Harrington Kevin J. , Collichio Frances A. , Amatruda Thomas , Chesney Jason Alan , Agarwala Sanjiv S. , Bhatta Sumita , Yi Min , Middleton Mark R. , Ross Merrick I. , Puzanov Igor 
Published: May 2019

9524 Background: T-VEC is a modified oncolytic herpes virus designed as an intralesional therapy for unresectable advanced melanoma. OPTiM was a randomized, phase 3 trial that showed improved durable response rate (DRR) with T-VEC vs GM-CSF in pts with unresectable melanoma with regional or distant metastases (16.3% vs 2.1%, p < 0.001). Treatment benefit of T-VEC on DRR and overall survival (OS) was greater in stage IIIB-IVM1a vs IVM1b-IVM1c melanoma. This is the first report of PFS for T-VEC vs GM-CSF. Methods: OPTiM included pts ≥18 yrs with unresectable stage IIIB-IV melanoma; ≥1 injectable cutaneous, subcutaneous (SC), or nodal lesion; ECOG ≤1; LDH ≤1.5 ULN; ≤3 visceral metastases (excluding lung) with none > 3 cm. Pts were randomized 2:1 to receive intralesional T-VEC or SC GM-CSF. The primary endpoint was DRR (partial or complete response continuously for ≥6 mo starting within 12 mo) and reported previously. In this post hoc analysis, PFS was evaluated overall and by disease stage. Results: This analysis included 436 pts: 295 (68%) T-VEC, 141 (32%) GM-CSF; 57% men; 63 yr median age; 57% stage IIIB-IVM1a, 43% stage IVM1b-IVM1c. In the intention to treat set, T-VEC significantly improved PFS (HR: 0.68, 95% CI: 0.54, 0.85, unstratified log-rank p < 0.001). In stage IIIB-IVM1a, PFS favored the T-VEC arm vs the GM-CSF arm (HR: 0.60, 95% CI: 0.44, 0.80, unstratified log-rank p < 0.001). No treatment difference was seen in stage IVM1b-IVM1c (HR: 0.81, 95% CI: 0.57, 1.15, unstratified log-rank p = 0.199). Overall, the 12 mo PFS rate for T-VEC was 14.4% (95% CI: 10.5, 18.8) and GM -CSF was 4.6% (95% CI: 1.6, 10.2). In stage IIIB-IVM1a, the 12 mo PFS rate for T-VEC was 19.9% (95% CI: 14.0, 26.6) and GM-CSF was 3.2% (95% CI: 0.6, 9.9). In stage IVM1b-IVM1c, the 12 mo PFS rate for T-VEC was 7.4% (95% CI: 3.5, 13.2) and GM-CSF was 8.0% (95% CI: 1.9, 20.1). Conclusions: T-VEC demonstrated an improvement in PFS vs GM-CSF, driven primarily by pts with stage IIIB-IVM1a melanoma. This is consistent with previous data showing more pronounced OS benefit with T-VEC and greater efficacy with other immunotherapies in early metastatic disease. Clinical trial information: NCT00769704.
Relationship between clinical efficacy and AEs of IMCgp100, a novel bispecific TCR–anti-CD3, in patients with advanced melanoma.
Authors: Middleton Mark R. , Steven Neil Matthew , Evans TR Jeffry , Infante Jeffrey R. , Sznol Mario , Hamid Omid , Shoushtari Alexander Noor , Anthoney Alan , Gupta Avinash , Woodcock Victoria K , Easton Rachael , Corrie Philippa Gail 
Published: May 2019

9530 Background: Bispecific antibodies have shown activity in hematologic (heme) but not solid tumors. ImmTAC molecules are unique TCR–anti-CD3 bispecifics that redirect T cells against intracellular antigens. IMCgp100, an ImmTAC targeted against melanocyte-associated lineage antigen gp100, has shown monotherapy responses in advanced melanoma with associated immune changes. IMCgp100 causes rash and cytokine-mediated AEs, hypothesized to be on-target (gp100) or effector (CD3) mediated. We explored clinical and biological characteristics of pts associated with treatment benefit. Methods: 84 HLA-A2 positive advanced melanoma pts received IMCgp100 on study IMCgp100-01 in 13 dose escalation cohorts. Efficacy was assessed by Kaplan–Meier survival and treatment related AEs (TRAE) reported by CTCAE v4.0. Serum samples evaluated changes in cytokines. A multivariate analysis investigated the relationship between efficacy and safety variables. Results: Demographics: 73% cutaneous (CM), 23% uveal (UM) primaries; 51% LDH > ULN; 25% received prior anti-PD(L)1. 83 (99%) pts had ≥1 TRAE; most commonly in skin (rash 82%, pruritus 69%) or cytokine-mediated (pyrexia 57%); the majority were Grade 1–2 and occurred and resolved within first 3 doses. The 2 most frequent Grade ≥3 TRAEs were rash (26%) and lymphopenia (13%). IMCgp100 induced transient increases in peripheral cytokines (peaking Day 1–2) that attenuated with subsequent doses; cytokine-mediated AE had similar kinetics.1-yr OS was 65% (95% CI: 48–78). In multivariate analysis, longer OS was associated with: LDH ≤ULN (p = 0.002) and any-grade rash occurring within 21 days (p = 0.003); melanoma primary site and prior anti-PD-(L)1 did not significantly affect outcome. In exploratory analyses, longer OS associated with lower baseline serum IL-6 (n = 43) or TNFα (n = 44). Conclusions: IMCgp100 is a first-in-class, TCR-based bispecific with monotherapy efficacy in advanced melanoma. AEs were manageable and consistent with MoA. Association between IMCgp100 efficacy and on-target TRAEs, previously reported for bispecifics to heme lineage antigens, is now recognized for solid tumor lineage antigens. Pivotal studies in UM are ongoing. Clinical trial information: NCT01211262.
Health care resource utilization in patients with advanced melanoma receiving immunotherapies in the real world.
Authors: Joseph Richard Wayne , Shillington Alicia C. , Lee Todd , Macahilig Cynthia , Diede Scott J. , Dave Vaidehi , Harshaw Qing , Taymor Emilie , Liu Frank Xiaoqing 
Published: May 2019

9532 Background: Both pembrolizumab (PEMBRO) and combination ipilimumab + nivolumab (IPI+NIVO) are FDA-approved immunotherapies for advanced melanoma (AM). These two treatment regimens have different toxicity profiles which may impact health care resource utilization (HCRU). Our aim was to compare real-world risk of hospitalization and emergency department (ED) visits within 12 months of starting the two treatment regimens. Methods: A retrospective cohort study was conducted in patients ≥18 years old with AM initiating PEMBRO or IPI+NIVO between Jan 1, 2016 – Dec 30, 2017. Patients were identified from 12 US academic medical centers and affiliated satellite clinics. Data were abstracted through chart review. All-cause hospitalizations or ED visits and the rates per patient per month (PPPM) through 12 months of follow-up were calculated. Utilization was compared between PEMRBO and IPI+NIVO using multivariate logistic regression analysis. Results: 400 patients were included, 200 each PEMBRO and IPI+NIVO with mean (SD) follow-up time of 10 (3) and 10 (4) months, respectively. The PEMBRO cohort had poorer Eastern Cooperative Group (ECOG) performance status at treatment start, 71% ECOG 0 or 1 vs 88% (p < .001); more diabetes, 21% vs 13% (p = .045); a trend towards more heart disease, 18% vs 12% (p = .067); were more likely to be PD-L1 expression positive, 77% vs 63% (p = .011); and less likely to harbor a BRAF mutation, 35% vs 50% (p = .003). The proportion with at least one hospitalization through 12 months was 17% PEMBRO vs 24% IPI+NIVO. Less than 2% of patients had more than one admission and none had more than two, regardless of cohort. Unadjusted mean (SD) PPPM hospitalizations were .016 (.037) for PEMBRO and .020 (.038) for IPI+NIVO. The adjusted odds ratio for any hospitalization with PEMBRO was 0.55 (95% CI .31, .97; p = .039) vs. IPI+NIVO. ED visits occurred in 18% vs 21% in PEMBRO and IPI+NIVO respectively, with no difference in covariate-adjusted analysis (p = .147). Conclusions: Patients receiving PEMBRO had a significantly lower probability of hospitalization and similar probability of ER visits compared with IPI+NIVO in the real world through 12 months.
Phase 1b/2, open label, multicenter, study of the combination of SD-101 and pembrolizumab in patients with advanced melanoma who are naïve to anti-PD-1 therapy.
Authors: Milhem Mohammed M. , Long Georgina V. , Hoimes Christopher J. , Amin Asim , Lao Christopher D. , Conry Robert Martin , Hunt Jason , Daniels Gregory A. , Almubarak Mohammed , Shaheen Montaser F. , Medina Theresa Michelle , Barve Minal A. , Bishnoi Sarwan K. , Abdi Ehtesham A. , Chisamore Michael Jon , Xing Biao , Candia Albert , Gamelin Erick , Janssen Robert , Ribas Antoni 
Published: May 2019

9534 Background: SD-101 is a synthetic CpG TLR9 agonist. Pembrolizumab is a PD-1 inhibitor. SYNERGY-001/KEYNOTE-184 assesses the safety and preliminary efficacy of the combination of SD-101 and pembrolizumab in patients naïve to anti-PD-1/L1 therapy with unresectable stage IIIC-IV melanoma. Methods: SD-101 was evaluated as 2 mg/lesion injected into 1 to 4 lesions and 8 mg/lesion in 1 lesion as 4 weekly doses followed by 7 doses Q3W. Pembrolizumab was administered as 200 mg IV Q3W. CT scans were performed every 9 weeks. Responses were assessed per investigator using RECIST v1.1. Responses and post-hoc Kaplan-Meier analyses of PFS in the ITT population were compared for patients who received 2 mg/lesion with 8 mg/lesion. Results: 86 patients (2 mg: N = 45; 8 mg: N = 41) have been enrolled with similar baseline characteristics: median age = 66 years; male = 67%; ECOG stage 0 = 67%; disease stage: IIIC = 21%; IVM1a/b = 50%; IVM1c = 28%; LDH ≤ ULN = 71%; treatment naïve = 73%. Median follow up to date is 8.1 months in 2 mg group and 8.3 months in 8 mg group. SD-101 safety profile comprises flu-like symptoms with most frequent grade ≥3 SD-101-related AEs of headache (7%), fatigue (7%), malaise (5%), myalgia (4%), and chills (4%). Immune-related AEs were reported in 19%. ORR in 2 mg group = 71% (95% CI: 57, 82) (CR: 13%) and in 8 mg group = 49% (95% CI: 33, 65) (CR: 7%) with responses in both injected and non-injected lesions, including visceral. DOR = not reached (NR) in either group. ORR by baseline PD-L1 expression in 62 patients, 53% of whom were PD-L1 positive: 2 mg = 80%/79% (PD-L1 positive/negative); 8 mg = 62%/40% (PD-L1 positive/negative). PFS was higher in 2 mg group with median PFS in 2 mg = NR (95% CI: Not estimable [NE], NE) and in 8 mg = 10.4 months (95% CI: 4.2, NE), HR = 0.45 (95% CI: 0.21, 0.98), p = 0.036. 6 month PFS rate in 2 mg = 81% and in 8 mg = 60%. 6 month OS rate in 2 mg = 98% and in 8 mg = 92%. Conclusions: The TLR9 innate immune stimulant, SD-101, in combination with pembrolizumab has been well-tolerated, and is showing promising high response rates and PFS, regardless of PD-L1 expression, particularly in patients who received 2 mg SD-101. Clinical trial information: NCT02521870.