bluuebunny/crossref_metadata_2025 huggingface dataset:
Mortality within 30 days of immunotherapy (checkpoint inhibitors) in metastatic cancer patients treated at Australian tertiary cancer center.
Authors: Mandaliya Hiren A. , Kim Sang , Quah Gaik Tin , Tun Min Sandy , Carlton James , Faulkner Jack , Oldmeadow Christopher , Mallesara Girish
Published: May 2019

6600

Background: Cancer treatment has evolved rapidly since the advent of immunotherapy (checkpoint inhibitors). As compared to chemotherapy, immunotherapy is associated with a more favourable but distinct side effect profile. Mortality within 30 days of chemotherapy in cancer patients has been accepted as a clinical indicator of preventable harm and used as an auditing tool for clinical practice and improving quality of life. This should be investigated in the current era of immunotherapy, as it has been the standard treatment for advanced melanoma, lung cancer, renal cell cancer and others. Methods: We conducted a retrospective study on patients with advanced cancer treated with immunotherapy and died within 30 days of treatment. Clinical data on patients treated with immunotherapy at Calvary Mater Newcastle between 2006 and 2018 was collected. Data were compared with 30-day mortality statistics of chemotherapy. Results: A total of 601 metastatic cancer patients received immunotherapy agents (Pembrolizumab, Nivolumab, Ipilimumab, Atezolizumab, Tislelizumab and MSB0011359C) on 5022 occasions. Seventy-six (12.6%) patients died within 30 days of receiving immunotherapy. Median age was 68 years (35-90). Melanoma was the most prevalent cancer type (63%) followed by lung (20%). Forty-seven (47%) of patients received immunotherapy as first-line treatment and 39% as second-line. Patients died within 30 days received an average 2 (1-16) immunotherapy doses. A quarter of patients had ECOG 3 and ECOG 4 before last dose. Majority of deaths were related to disease (86%). Nearly 80% of patients died in hospital. One patient died due to treatment-related pneumonitis. In univariate analysis, there was no association between mortality and patients’ demographic variables such as age, sex, BMI, cancer type, ECOG performance status, immunotherapy agent and prior treatment. Conclusions: To our knowledge, this is the first ever real-world data on 30-day mortality after immunotherapy in advanced cancer. Thirty-day mortality rates were comparable to published data on patients treated with chemotherapy. Results emphasise significance of careful selection of advanced cancer patient for immunotherapy. Due to small sample size, the power to detect a significant association between patients demographics and survival is reduced.
Does the innovative 4R Cancer Care Delivery Model improve patient self-management in safety net and non-safety net centers?
Authors: Trosman Julia Rachel , Weldon Christine B. , Makower Della F. , Rapkin Bruce D. , Bozier Moreen , Knightly Eileen , Schaeffer Cathleen M. , Hoskins Kent , Gallagher Christopher , Lo Shelly S. , Grace-Louthen Cathy , Throckmorton Alyssa , Vanderwalde Lindi , Krueger Editha A. , Van Horn Jennifer , Schapira Lidia , Santa-Maria Cesar Augusto , Ravelo Arliene , Benson Al Bowen , Gradishar William John
Published: May 2019

6601

Background: Under the NCI ASCO Teams Project, we proposed a 4R Model of teamwork and patient self-management (pSM) (Trosman JOP ’16). 4R (Right Info / Care / Patient / Time) enables patient (pt) and care team to manage complex care continuum with an innovative multimodality 4R Care Project Plan. 4R includes a novel “project” feature – a graphical description of care interdependencies. 4R was previously piloted at 3 Chicago centers (Trosman ASCO ‘18). Methods: In this new study, we improved and tested 4R for impact on pSM at 4 safety net and 3 non safety net centers across the US. 4R Plans were provided to stage 0-III breast cancer pts Jan - Nov’18 (4R cohort). We surveyed the 4R cohort and a historical control cohort of pts who received care at same centers pre-4R, Jan - Dec ’17. Results: Survey response rates: 65%, 105/162 (4R cohort); 44%, 190/432 (control). 4R markedly improved 4 of 5 pSM metrics vs control (Table). Additional analyses showed that safety net pts had a significant increase in 4R vs control cohort in “seldom overwhelmed” (84%, 49/58 vs 64%, 67/104 respectively, p = .007), while non safety net pts had nonsignificant increase. Other metrics improved to a similar extent for safety net vs non safety net pts. Within the 4R cohort, 85% found 4R useful in organizing their care and 73% found 4R’s novel “project” feature useful in understanding care interdependencies. Safety net pts reported similar usefulness of 4R in organizing their care as non safety net pts (88%, 51/58 vs 81%, 38/47, NS) and similar usefulness of the “project’ feature in understanding care interdependencies as non safety net pts (74% vs. 72%, NS). Conclusions: 4R significantly improved patient self-management, but further efforts are needed to expand the benefit to as close to a 100% of pts as feasible. Safety net pts benefited from 4R at similar or higher rates than non safety net pts, indicating that 4R may reduce care disparities. An expansion of 4R across the US continues this work. [Table: see text]
The impact of NCI-sponsored network group clinical trials on guideline care and new drug indications.
Authors: Unger Joseph M. , Nghiem Van T. , Hershman Dawn L. , Vaidya Riha , LeBlanc Michael Leo , Blanke Charles David
Published: May 2019

6604

Background: National Cancer Institute Clinical Trial Network (NCTN) groups serve a vital role in identifying new antineoplastic regimens. However, the clinical impact of their trials has not been systematically examined. We analyzed the influence of network group cancer clinical trials on clinical guidelines and new drug approvals. Methods: We evaluated Phase III cancer clinical trials which the SWOG Cancer Research Network coordinated or participated in (1980-2017). Included trials were completed and its results published. A documented practice influential (DPI) trial was one with verified influence on National Comprehensive Cancer Network (NCCN) clinical guidelines (available starting in 1996) or on U.S. Food and Drug Administration (FDA)-approved package inserts. We estimated the rate of DPI trials overall and over time. The total federal investment supporting the set of trials was also determined based on public data. Results: In total, 182 trials comprising 148,028 patients were studied. We identified 79 DPI studies (43.4%); 73 influenced NCCN guidelines, 12 influenced new drug approvals, and 6 influenced both. The rate of DPI trials was 72.3% (47/65) among formally positive trials (i.e., achieved their protocol specified endpoint) and 27.4% (32/117) among negative trials. Thus 40.5% (32/79) of DPI trials were based on negative studies, half of which (16/32 = 50.0%) reaffirmed standard of care over experimental therapy. There were no differences between DPI and non-DPI trials in key study design characteristics. Total federal investment for the programs conducting the trials was $1.36 billion (USD2017), a rate of $7.5 million per trial, or $17.2 million per DPI trial. Conclusions: Nearly half of all phase III trials by one of the NCTN’s largest groups had documented practice influence on clinical care guidelines or new drug approvals. Even many negative trials impacted guideline recommendations. Compared to the costs of a new drug approval in pharmaceutical companies – typically estimated at > $1 billion – the amount invested by federal funders to provide this valuable evidence was modest. These findings highlight the major role of the NCTN’s clinical trial program in advancing oncology practice.
Survivorship care: Improving delivery of care plans for hematology patients at the Washington Cancer Institute (WCI).
Authors: Latif Hira , Beplat Maya , Singh Prabhjyot , Dilawari Asma Ali
Published: May 2019

6605

Background: Cancer and long-term sequalae of its treatment impact the future health and psychosocial wellness of these survivors. ASCO guidelines recommend providing survivorship care to cancer patients who have completed treatment with curative intent. The Commission on Cancer (COC) recommends that survivorship care including treatment summaries be delivered to 50% of eligible patients. In our ASCO Quality Training Program project, we aimed to achieve this COC goal of 50% for the year 2018. Methods: Baseline data collected from Jan 1, 2016 to June 30, 2018 indicated that 33% of hematologic malignancy survivors at WCI received treatment summaries and survivorship care. For the year 2018, there were 11 survivors of hematologic malignancy, and 4 of them (36%) had received survivorship care prior to initiation of the project. We surveyed 12 providers to obtain data for perceived challenges to deliver survivorship care. Large volume of patients, lack of resources, no standardized process and high no-show rates were identified as the most important barriers. A bi-monthly survivorship clinic run by hematology/oncology fellows was initiated in September 2018 to address some of these barriers. Patient referral forms were mounted in the clinic work rooms to assist providers with identifying patients that qualify for survivorship; a pathway for referrals to the survivorship clinic was created and providers were informed about the clinic. Information flyers regarding survivorship care and the clinic were placed in the waiting room to increase awareness amongst patients. Results: By November 30, 2018, 63% of hematological cancer survivors received survivorship care and treatment summaries. Compared to the average from the preceding two years, survivorship care delivery increased by 30%. Conclusions: Our institution was able to meet the COC requirement by delivering survivorship care to 63% of survivors of hematological malignancies through the intervention from this quality improvement study. We intend to extend this process to other tumor types to increase the delivery of consolidated survivorship care at the WCI.
Impact of specialist palliative care delivered over three months prior to death on a colorectal cancer patient’s risk of experiencing aggressive end-of-life care.
Authors: Sinnarajah Aynharan , Earp Madalene , Cai Pin , Fong Andrew , Blacklaws Kelly , Karim Safiya , Cheung Winson Y. , Kerba Marc
Published: May 2019

6614

Background: More patients are experiencing aggressive end-of-life (EOL) care. This is concerning as aggressive EOL care, on a population level, is associated with poor quality care. Specialist palliative care (PC) has been shown to help relieve EOL symptoms, improve patient quality of life, and reduce aggressive EOL care. This study aimed to estimate the impact of the timing of specialist PC, specifically PC delivered at least 3 months prior to death, on a colorectal cancer (CRC) patient’s risk experiencing aggressive care in the last 30 days of life. Methods: A population-based retrospective cohort study of adult patients who died from CRC in Alberta, Canada from 2011-2015. The Alberta Cancer Registry was used to identify the cohort, which was linked to healthcare resource use data in local, provincial, and national databases. Individuals who died < 30 days from CRC diagnosis were excluded. Patients who accessed any of the provinces specialist PC services were deemed exposed to specialist PC (includes PC consult team, intensive PC unit, palliative home care, hospice). Aggressive EOL care was defined as having experienced at least one of: hospital death, > 1 emergency department visit, > 1 hospital admission, > 14 days of hospitalization, ≥1 intensive care unit admission, ≥1 new chemotherapy program (or any treatment in the last 14 days of life). Logistic regression was used to model factors (specialist PC timing and clinical characteristics) associated with aggressive EOL care. Results: The cohort comprised 2979 patients. Most patients received specialist PC before death (58%); 60% had ≥1 indicator of aggressive EOL care. Relative to patients who received specialist PC > 3 months before death, patients who received specialist PC < 3 months before death were 1.5 times more likely to experience aggressive EOL care (CI: 1.2-1.9). Patients who received no specialist PC were 2.1 times more likely to experience aggressive EOL care (CI: 1.7-2.8). Short disease duration ( < 1 year from diagnosis to death), younger age at death, living in a rural area, and male sex, were also associated with higher odds of experiencing aggressive EOL care. Conclusions: Specialist PC delivered > 3 months before death reduces a CRC patient’s risk of experiencing aggressive EOL care over PC delivered < 3 months before death.
Evaluating the impact of telephonic nurse care management during high toxicity chemotherapy treatment.
Authors: Hunter Craig A , Krueger Andrew C , Soliman Omar A , Inman Angela S , Glenn Erika R , Johnson Kjel Andrew
Published: May 2019

6623

Background: Care management is aimed at improving quality and cost of cancer care. To measure this we evaluated inpatient (IP) and emergency room (ER) admissions and costs of chemotherapy patients receiving versus not receiving telephonic nurse care management. Methods: 1,609 patients were studied over a 35 month period, of which 802 enrolled in a voluntary holistic telephonic nurse care management program. Patients were identified based on having been prescribed or initiating treatment with a high toxicity chemotherapy agent within the previous 60 days, following which notification was received from an oncology pathways intermediary. Nurse care managers engaged patients one or more times per month based on patient need, educating on side effects, pain management, where to seek care, and general well-being. IP and ER were measured during the 14 days following chemotherapy administration (Risk-Period) and compared to a baseline of all remaining patient claims history, excluding 28 days following chemotherapy administration (14 day Risk Period and 14 day washout period). Results: IP rates per 1,000 Risk Period Days for managed patients decreased during the 14 days following chemotherapy by 44% as compared to their baseline (3.02 v 5.39, p≤0.001), while non-managed patients increased by 29% (2.33 v 1.81, p=0.003). ER rates per 1,000 Risk Period Days were not significantly different for managed patients (2.72 v 2.35, p=0.188) and significantly increased by 117% for non-managed patients (2.34 v 1.08, p≤0.001). Baseline utilization for managed patients was more than twice the rate of non-managed patients, suggesting that a greater need for support may influence voluntary participation in care management. Conclusions: Telephonic nurse care management meaningfully reduced IP and ER admissions and their associated costs. [Table: see text]
Cost disparities with age in the treatment of advanced non-small cell lung cancer (NSCLC) in Ontario, Canada.
Authors: Wang Ying , Ellis Peter Michael , Pond Gregory Russell , Seow Hsien , Gafni Amiram
Published: May 2019

6629

Background: Previous studies noted an association between age and cost of care in NSCLC. The drivers of these cost disparities have not yet been fully examined. We conducted a cost analysis study examining the differences in, and drivers of, costs of NSCLC care across age groups in Ontario, Canada. Methods: We conducted a retrospective cohort study of patients diagnosed in Ontario from Apr 1, 2007 to Mar 30, 2014, who received palliative chemotherapy for stage IV NSCLC. Variables of interest were extracted from registry data linked by the Institute for Clinical Evaluative Sciences (ICES). The mean total cost of care including systemic therapy and supportive care, was calculated in 2015 CAD dollars by fiscal year of diagnosis. Results: Of all NSCLC cases diagnosed in Ontario (n = 37,786), 17,203 (45.5%) were de novo stage IV, of which 29.7% of patients received any chemotherapy for their disease (n = 5,113), and 281 patients are presumed alive. In this population, median age was 65 to 69 years, 51.9% were male, 43.5% were adenocarcinomas, and 25.1% received second line chemotherapy. After adjusting for comorbidities, income, gender, year of diagnosis, and rural versus urban living, the average lifetime costs per patient remains significantly inversely related to age (p < 0.001). Belonging to the highest income quintile (p = 0.006) and being diagnosed in more recent years (p < 0.001) contributes significantly to increasing overall healthcare costs. Elderly patients (80+) cost less (71%) and have shorter survival time (HR of death 1.28, 95% C.I. 1.10 to 1.50) compared to younger patients (≤45 years old). Accounting for longer survival in younger patients, the youngest group still incur a higher cost per day alive than other age groups ($471/day in ≤45 group, $301/day in > 85 group). Hospitalization accounts for ~30% of total cost in both age groups. Chemotherapy accounts for 1% of total health care costs amongst the elderly (80+) age group and 10% of costs in ≤45 group. Conclusions: Our study shows that, despite everyone receiving systemic therapy in this patient population, younger patients incur significantly higher costs than elderly patients with advanced NSCLC, both before and after adjusting for survival. While hospitalization accounts for the biggest component of total costs, patients with high income and more recent years of diagnosis drive the higher costs of care, and chemotherapy remains a driver of higher costs amongst younger patients.
Clinical outcomes of patients with stage IV cancer receiving immune checkpoint inhibitors in the inpatient setting.
Authors: Durbin Sienna , Zubiri Leyre , Niemierko Andrzej , Petrillo Laura A , Bardia Aditya , Sullivan Ryan J. , McEwan Corey , Mulvey Therese Marie , Allen Ian Matthew , Lawrence Donald P. , Cohen Justine Vanessa , Hochberg Ephraim P. , Ryan David P. , Reynolds Kerry Lynn
Published: May 2019

6634

Background: Immune checkpoint inhibitors (ICI) represent a major leap in the treatment of many cancers. Use has rapidly expanded in recent years, yet it is unknown whether hospitalized patients, who are often sicker than those who were studied in clinical trials, derive benefit from ICI. The primary objectives of this study were to characterize the clinical features and outcomes of inpatients receiving ICI at a single institution, and to identify predictors of survival. Methods: After IRB approval, we conducted a retrospective chart review of inpatients with Stage IV solid tumors receiving ICI between 2015 – 2018 at a tertiary care referral hospital. Patients receiving ICI on clinical trial were excluded. We examined the clinical characteristics, readmission rate, and post-discharge survival. We then conducted a Cox multivariable regression analysis to identify predictors of post-discharge survival. Results: A total of 103 patients with Stage IV solid tumors were treated with ICI as inpatients between 2015 – 2018. Average age was 57 years (range = 26 to 85); 57% were male; 27% had ECOG performance status (PS) 3-4; average Charlson Comorbidity Index score was 8.3. Most common tumor types were melanoma (35%) and lung (22%). Seventy-six percent began ICI as an inpatient and 24% received ICI as continuation of outpatient therapy. Seventeen percent experienced an immunotherapy related adverse event, most commonly colitis and pneumonitis. The 30 day readmission rate was 41%. The median post-discharge survival was 31 days; 47% of patients died during admission or within 30 days of discharge; 14% survived more than 6 months. Factors predictive of shorter post-discharge survival were PS of 3-4 relative to PS 0-2 (HR 2.0, p < 0.004), and lung cancer (HR 2.0, p < 0.024) and other tumor types (HR 2.1, p < 0.004) relative to melanoma. Conclusions: While the majority of inpatients receiving ICI died during admission or within 30 days of discharge, a subset of patients with stage IV disease were alive at 6 months. Tumor type and ECOG PS predict post-discharge survival and may be used to identify inpatients more likely to benefit from ICI. These novel findings, which are unique to a single institution, require additional validation.
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.
Predictable early onset high-dose-glucocorticoid-associated-irAE and its predictive role in anti-PD-1 monotherapy treated advanced melanoma patients.
Authors: Bai Xue , Kim Michelle S. , Kasumova Gyulnara , Chen Tianqi , Cohen Justine Vanessa , Lawrence Donald P. , Freedman Christine , Fadden Riley , Rubin Krista M. , Sharova Tatyana , Frederick Dennie T. , Flaherty Keith , Sullivan Ryan J. , Boland Genevieve Marie
Published: May 2019

9544

Background: Though uncommon, a subgroup of patients with melanoma develop early-onset severe immune-related adverse effects (irAEs) that require immunosuppressive treatment with high-dose glucocorticoids (HD-GCCs). We aimed to examine the impact of early onset HD-GCC-associated-irAE (EO-HGA-irAE) in the setting of anti-PD-1 monotherapy initiation on prognosis and to develop a predictive scoring system. Methods: Clinical data was collected retrospectively from advanced melanoma patients treated with anti-PD-1 monotherapy at Massachusetts General Hospital from Sept 2009 to Dec 2017. The relationship between EO-HGA-irAE and PFS (defined as time from anti-PD-1 monotherapy initiation to PD) was assessed using 8-week conditional landmark analysis (Kaplan-Meier curves, log-rank test) and time-dependent COX regression model (multivariate analysis). Demographic characteristics and baseline routine laboratory variables were collected and correlated with occurrence of EO-HGA-irAE using logistic regression modeling. Best cutoff values were identified using ROC curve (Youden index) to dichotomize continuous variables. Results: Among 146 patients, 13 (8.9%) developed EO-HGA-irAE. In 8-week landmark analysis, median PFS was 2.9 (95% CI, 2.8-3.0) and 17.5 (95% CI, 10.8-24.2) months (P = .001) for patients with and without EO-HGA-irAE, respectively. Multivariate analysis revealed that EO-HGA-irAE was independently correlated with significantly higher risk of disease progression with hazard ratio of 2.4 (95% CI 1.4-4.0) (P = .001). Potential predictive variables (P < .25 for continuous variables, P < .1 for dichotomous variables) in favor of the occurrence of EO-HGA-irAE included age, baseline glucose, and neutrophil, eosinophil, and WBC count. After dichotomization and further validation using a logistic regression model, a scoring system (score range 0-3) composed of 3 dichotomized predictors, including age, baseline glucose, and baseline neutrophil count was developed with odds ratio of 3.4 (95% CI, 1.6-8.8) (P = .001). The probabilities of patients scoring 0,1,2,3 of developing EO-HGA-irAE were 1.1%, 3.5%, 11.1%, and 29.9%, respectively. Conclusions: Development of EO-HGA-irAE is correlated with shorter PFS in advanced melanoma patients treated with anti-PD-1 monotherapy. A scoring system based on age and simple, easily accessible, routinely tested biomarkers can be used to help predict the risk of EO-HGA-irAE occurrence. Validation with a larger sample size is required.
Phase I-II open label multicenter study of PD0332991 in BRAFV600mut metastatic melanoma patients harboring CDKN2A loss and RB1 expression and treated with vemurafenib.
Authors: Louveau Baptiste , Resche-Rigon Matthieu , Lesimple Thierry , Pracht Marc , Baroudjian Barouyr , Delyon Julie , Jouenne Fanelie , Amini-Adle Mona , Dutriaux Caroline , Da Meda Laetitia , Ghrieb Zineb , Bouton Didier , Tibi Annick , Huguet Samuel , Rezai Keyvan , Battistella Maxime , Mourah Samia , Lebbe Celeste
Published: May 2019

9545

Background: Among mechanisms of resistance to BRAF inhibitors (BRAFi), cell cycle effectors including CDK4 have been involved in ERK reactivation. In this phase I-II open label study, we aimed to establish the Maximum Tolerated Dose (MTD) of PD0332991, an inhibitor of CDK4/6, when added to vemurafenib (VM) in metastatic melanoma patients. Methods: Patients with BRAFV600E/K mutated metastatic melanoma harbouring CDKN2A loss and RB1 expression were included. Patients were treated with a 14 days followed by 7 days rest daily dosing schedule of PD0332991 + continuous BID dosing of VM, and stratified into 2 groups according to previous BRAFi treatment (no group 1, yes group 2). Dose levels (PD0332991 (mg/QD)/VM (mg/BID) ranged from 25/720 to 200/960. The primary endpoint was the occurrence of a DLT within the first 2 cycles of therapy. Secondary endpoints included best response (RECIST), OS, PFS, pharmacokinetics parameters, tumour molecular profiling on baseline lesions using transcriptomic and NGS analysis. Results: Nineteen patients were enrolled, among them 16 (84%) in group 2, with 18.5 months median follow-up. Characteristics at baseline were: male 11 (58%), median age 54.4 years, unresectable stage IIIC 2 (11%), stage IV 17 (89%), M1C 12 (67%), high LDH 9 (47%), median time from advanced melanoma diagnosis to inclusion 26.8 months, ≥ 2 lines therapy 13 (68%). A DLT was observed for 1 and 5 patients in group 1 and 2 respectively, defining the MTD at PD0332991 25mg and VM 960mg in group 2. No significant evidence for drug-drug interaction between PD0332991 and VM was highlighted. In group 2, ORR was estimated to 4 (25%), SD to 8 (50%), median PFS to 9.3 months and median OS to 13.2 months. Baseline transcriptomic analysis revealed high alteration rate associated with clinical response and enrichment in genes related to MAPK, cell cycle and apoptosis pathways. Conclusions: While combination of fixed dose of PD0332991 + VM did not allow us to increase PD0332991 dosage above 25mg, significant clinical benefit was achieved in heavily pretreated patients; baseline molecular analysis revealed an association between transcriptomic data and clinical response. Clinical trial information: NCT02202200.