bluuebunny/crossref_metadata_2025 huggingface dataset:
Improvement in incident resolution time with implementation of an electronic patient management solution at a community oncology practice.
Authors: Wilfong Lalan S. , Patel Amila , Ortega Lance , Boren Rhonda , Pearson Ben , Jensen Terry Lynn , Books Holly , Hudson Kathryn Elizabeth , Patt Debra A.
Published: June 2021

1578

Background: Value-based care models such as the Oncology Care Model incentivize practices to reduce hospitalizations and emergency department (ED) visits. Texas Oncology found that most ED visits occurred during regular business hours. Prolonged patient call back times were consistently rated poorly on satisfaction surveys and often led to ED visits for symptoms that could be managed in our offices. We partnered with Navigating Cancer (NC) to implement an electronic patient management technology solution. Methods: For each of our 200 locations, call volume was estimated based on clinic volume. We then reallocated or hired dedicated triage nurses and operators. Incoming calls were entered into the NC dashboard by operators as incidents which were routed based on symptom priority following system generated prompts. Incident volumes and resolution times were tracked. We instituted PDSA cycles at all locations with a goal of less than 90-minute resolution of symptom-related incidents Utilizing the electronic dashboard allowed us to continue this initiative during the COVID-19 public health emergency as our staff could work remotely. Nurses were able to document if a potential ED visit was avoided. These data points allowed our practice to establish comprehensive and strategic actions plans for quality improvement. Results: We finalized implementation of the system in February of 2020. Total incidents for 2020 were over 1 million, averaging over 5000 per location. Resolution time for all incidents started at 3.2 hours pre-implementation and improved to 2.2 hours in December of 2020. Resolution times for symptom-related incidents started at 2.3 hours pre-implementation and ended at 1.5 hours in December of 2020 with over 60% resolved under one hour. 8% of symptom-related incidents resulted in definite or probable ED avoidances by nursing assessment. Shortness of breath, vomiting, chills, and weakness were the top symptom types addressed for ED avoidances. Conclusions: An electronic patient management solution with PDSA cycles of quality improvement can markedly reduce call back times, especially for symptom related calls. We believe managing symptoms in a timely fashion will lower ED visits and hospitalizations as well as improve patient satisfaction. We will report on these outcomes once available.[Table: see text]
Profiling of immune checkpoint biomarkers by multiplex immunofluorescence in breast cancer brain metastases.
Authors: Griguolo Gaia , Tosi Anna , Guarneri Valentina , Dieci Maria Vittoria , Fineberg Susan , Ventura Annavera , Bauchet Luc , Jacob Jack , Rigau Valerie , Jacot William , Rosato Antonio , Darlix Amelie , Conte Pierfranco
Published: June 2021

2021

Background: Despite potential clinical implications, the complexity of immune microenvironment in breast cancer (BC) brain metastases (BM) is still poorly understood. Multiplex immunofluorescence (mIF) allows simultaneous visualization of several IF labeled proteins while maintaining spatial information. This novel technique can be used to comprehensively describe BCBM immune microenvironment, potentially providing useful information to guide novel therapeutic approaches. Methods: Clinical data and archival BM samples from 60 BC patients undergoing neurosurgery (2003-2018) at three institutions were collected. BCBMs were characterized using a custom mIF panel, including immune checkpoint and co-inhibitory molecules (CD3, PD1, PD-L1, TIM3, LAG3, CD163) and localization (keratin for tumor recognition) markers. Mean marker density was determined by digital image analysis (positive cells/mm2) and classified in tumor and stroma areas. Associations between immune marker densities, BC subtype and overall survival from BM diagnosis (OS) were studied. Results: Sixty BCBM samples were analyzed; 32% HR+/HER2-, 38% HER2+, 30% HR-/HER2-. At a median follow-up of 43 months, the only clinical variable associated with OS was BC subtype (shortest for HR-/HER2- and longest for HER2+, p=0.02). In the total sample area and tumor area, no significant difference in marker density was observed according to BC subtype. In the stroma area, a significant difference in TIM3+ cell density was observed according to BC subtype (highest density in HR+/HER2- and lowest density in HER2+ tumors, Kruskal-Wallis p=0.017). Higher CD163 density (a marker of M2 macrophage polarization), both in the tumor and in the stroma area, was significantly associated with worse OS, even after correction by BC subtype. In the subgroup of patients with HR+/HER2- BCBM, high TIM3+ cell density in the stroma area was significantly associated with longer OS (median OS 54.1 versus 23 months respectively for TIM3+ density above and below median value; p=0.01). Conclusions: In BCBM, stromal TIM3+ immune infiltrate differs according to BC subtype. M2 macrophage polarization is consistently associated with worse OS across all BC subtypes and might represent a potential therapeutic target for these patients.[Table: see text]
A phase II trial combining nivolumab and stereotactic brain radiosurgery for treatment of brain metastases in patients with NSCLC.
Authors: Wong Philip , Florescu Marie , Plourde Marc-Emile , Panet-Raymond Valerie , Pavic Michel , Owen Scott Peter , Masson-Cote Laurence , Menard Cynthia , Routy Bertrand , Tehfe Mustapha , Blais Normand , Roberge David , Masucci Laura
Published: June 2021

2023

Background: Previous studies suggested activity of anti-PD-1 in brain metastases from non-small cell lung cancer (NSCLC) and renal cell cancer (RCC). This investigator initiated phase 2 trial examined the safety and efficacy of combining nivolumab with radiosurgery (SRS) in the treatment of patients with brain metastases from NSCLC and RCC. Methods: This is a multicentre open-label trial (NCT02978404) in which patients diagnosed with NSCLC or RCC, having ≤ 10 cc of un-irradiated brain metastases, no whole brain radiotherapy and no prior immunotherapy were eligible. Study treatment commenced with a dose of nivolumab (240mg or 480mg IV), which was continued for up to 2 years at bi-weekly or monthly intervals until progression. SRS (15-21Gy) to all visible un-irradiated brain lesions was administered within 14 days after the first dose of nivolumab (cycle 1). Patients were followed by brain MRI, CT scan of the chest, abdomen and pelvis, neurocognitive and quality of life questionnaires (FACT-Br) every 3 months. The primary endpoint was intracranial progression free survival (icPFS), with death and disease progression within the brain as events. Results from NSCLC patients are presented here. Results: Of the 26 study patients, 22 NSCLC patients were enrolled between Aug 2017 and January 2020. Patients had a median of 2 (1-9) brain metastases. The median diagnosis-specific graded prognostic score was 2 (1-3). Median treatment and follow-up durations were 4.3 months (0-24.8 months) and 11 months (0-24.8 months), respectively. Forty-two percent of the patients had received prior cytotoxic chemotherapy, and 1 patient had received prior brain SRS. PD-L1 status was known for 21 of the 22 NSCLC (12 with ≥50% PD-L1 expression (DAKO 22C3). Median icPFS was 5.0 months (3 intracranial progression and 8 deaths without progression in the brain). Accounting for death as a competing risk, the 1-year cumulative incidence of intracranial relapse was 17.4%. Median extracranial PFS and overall survival were 2.9 months and 14 months, respectively. Four grade 3 adverse events in 2 patients were related to nivolumab or SRS. The rate of survival free of neurocognitive decline (Hopkins Verbal Learning Test total recall) was estimated to be 89% by 4 months. Mean FACT-Br total scores were 89.4 at baseline and improved (p = 0.01) to 139.3 within 2-4 months. Conclusions: Neurocognitive and quality of life assessments suggest that upfront SRS during nivolumab is well tolerated. High intracranial control was observed, but deaths from extracranial disease progression resulted in short icPFS. Studies evaluating the strategic addition of SRS combined with more efficacious systemic treatments are needed. Clinical trial information: 02978404.
Palliative care service utilization and advance care planning issues for adult glioblastoma patients: A systematic review.
Authors: Wu Adela , Colon Gabriela Ruiz , Aslakson Rebecca , Pollom Erqi L. , Patel Chirag B
Published: June 2021

2036

Background: Glioblastoma (GBM) is a devastating disease with a median survival under 2 years and a 10-year survival rate of 0.71%. As patients with GBM suffer simultaneously from both a terminal cancer and a neurodegenerative disease, proactive provision of advance care planning (ACP) and palliative care (PC) seem appropriate. We conducted a systematic review exploring the published literature on the prevalence of ACP, healthcare services utilization at the end of life (EOL, including PC services), and location of death among adults with GBM, and the experiences of their caregivers. Methods: We systematically searched PubMed, Embase, Scopus, and Cochrane Library from database inception until 12/20/2020, using search terms including ‘glioblastoma’, ‘end of life’, ‘advance care planning’, and ‘advance directive’. Preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines were followed. Inclusion criteria were quantitative and qualitative studies written in English of adults with GBM and their caregivers, with at least 20 subjects. Included studies were assessed for quality using the Newcastle-Ottawa Scale. Results: We screened 344 article abstracts and 39 full text articles to yield a final cohort of 16 articles that fit inclusion criteria. These studies reported the experiences of 10,706 GBM patients and 123 caregivers. All were nonrandomized studies conducted in six countries with all but two published in 2014 or later. Across studies, ACP documentation varied from 4-55%, PC referral was pursued in 39-40% of cases, and hospice referrals were made for 66-76% of adult GBM patients. Hospitalizations frequently occurred at the EOL, 20-56% of patients spent over 25% of their overall survival time hospitalized, and 39-64 % of deaths occurred in the home setting. Caregivers commonly reported restrictions on their ability to work (60%), financial barriers to care (29%), and feeling unprepared (29%). Conclusions: Despite having both a terminal disease and neurocognitive decline, a majority of adults with GBM do not pursue ACP or have access to PC. There is a dearth of focused and high-quality studies on ACP, PC, and hospice use among adults with GBM. Prospective studies that address these and additional aspects related to end-of-life care in this population, such as healthcare costs and inpatient supportive care needs, are needed.
A phase II study of anlotinib combined with STUPP regimen in the treatment of patients with newly diagnosed glioblastoma (GBM).
Authors: Li Peijing , Chen Yuan yuan Yuan , Lai Shuzhen , Jiang Fagui , Liu Xiaohui , Tao Changjuan , Wang Lei , Liu Guihong , Huang Jing , Tang Yiqiang , Liu Zhigang , Shen Guoping , Li Chaoming , Xie Tieming , Lu Fangxiao
Published: June 2021

2039

Background: STUPP regimen is now the standard treatment for newly diagnosed GBM, while the effectiveness is limited. This study assessed the efficacy and safety of anlotinib, a multitarget tyrosine kinase inhibitor, combined with the STUPP regimen in treating these patients. Methods: This is a phase II, multicenter, open-label, single-arm trial (NCT04119674). Thirty-three patients (17 males and 16 females) were enrolled from 8 hospitals in China between January 2019 and February 2021. Inclusion criterion included 1) newly diagnosed histologically confirmed glioblastoma (WHO grade IV), 2) 2-6 weeks (wks) after surgery with healed incision, 3) 18-70 years old, 4) KPS≥60, 5) at least one measurable lesion according to RANO criteria, 6) radiotherapy (RT), chemotherapy, immunotherapy or biotherapy naïve. All patients received 54-60 Gy radiation (1.8-2.0 Gy per fraction, five days per week) concurrently with temozolomide (TMZ, 75mg/m2, orally, QD) and anlotinib (8mg, orally, QD, d1-14/3wks). Adjuvant therapy started four weeks after RT completion, including six cycles of TMZ (150-200mg/m², orally, d1-5/4wks) and eight cycles of anlotinib (8mg, orally, QD, d1-14/3wks). Patients who completed adjuvant therapy were administrated anlotinib continuously until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Safety assessment was done in patients who received at least one dose of study agent. Results: The median age is 52 (range 32-69) years. Analyses included data collected through February 6, 2021. The median treatment duration was 6.5 months. The median PFS was not reached, and the median overall survival (OS) was 17.4 months [95%CI 11.6-23.2]. The 1-year PFS and OS rate was 84.0% and 100.0%, respectively. Tumor response occurred in 21 patients, 63.6% (21/33) objective response (CR/PR), and 24.2% (8/33) patients had stable disease (SD).The clinical benefit rate (CBR), defined as the proportion of patients who achieved durable disease control (CR/PR/SD) more than six months, was 57.6% (19/33). Hypertension (6.1%) was the most common ≥grade 3 adverse event. No treatment related death occurred in this study through the last follow-up. Overall, toxicities are mild and manageable. Conclusions: Anlotinib combined with the STUPP regimen is efficacious and well-tolerated in newly diagnosed GBM patients. Clinical trial information: NCT04119674.
A phase II, open-label, single-arm trial of pembrolizumab for refractory atypical and anaplastic meningioma and hemangiopericytoma.
Authors: Yust-Katz Shlomit , Amiel Alexandera , Siegal Tali , Limon Dror
Published: June 2021

2064

Background: Grade II and III meningiomas are invasive tumors which tend to recur following initial treatment and are associated with shorter survival (relative to grade I). Hemangiopericytoma (HPC) is a dural based tumor that originates in the pericytes in the walls of capillaries. Treatment options for these tumors include surgical resection and radiation. There are no defined standard treatments after failure of these modalities, and efficient systemic treatments are lacking. This trial concept was formed following previous reports of high PD-L1 levels in anaplastic meningioma. We currently report our initial experience with pembrolizumab for refractory atypical/anaplastic meningioma (RAM) and HPC patients. Methods: This is a single arm, single institute, phase 2 trial. Inclusion criteria included patients with RAM or HPC whose all previous lines of treatment were exhausted. All patients were treated with pembrolizumab (200mg every 3 weeks) until disease progression. Primary endpoint was 6- and 12-months progression free survival (PFS). The study was planned for 25 patients and we report here preliminary results. Results: Through February 2021, 12 patients were enrolled to this study (two with HPC, 10 with RAM). After a median follow up of 18.5 months, the 6 and 12 months PFS were 25% and 16.7% respectively, with a median PFS of 2.75 months. Two patients had a partial response while all others progressed, making the overall response rate 16.7%. One of the responders had HPC and has been stable for 30 months, while the second had atypical meningioma and was stable for 13 months. Median survival has not been yet reached; 1 year survival rate was 82.5%. Grade 3 toxicities included hyperglycemia, elevated liver enzymes and fatigue (that did not cause treatment discontinuation), with no grade 4 or 5 toxicities. PD-L1, mutation burden, MSI and other genomic analyses are still pending. Conclusions: Pembrolizumab induced a low response rate for RAM and HPC. However, a subset of patients might benefit from this treatment with a prolonged response period. To define this subpopulation further molecular studies are needed. Clinical trial information: NCT03016091.
ARTISTRY-1: Nemvaleukin alfa monotherapy and in combination with pembrolizumab in patients (pts) with advanced solid tumors.
Authors: Boni Valentina , Winer Ira Seth , Gilbert Lucy , Vaishampayan Ulka N. , Rosen Seth David , Muzaffar Jameel , Spreafico Anna , McDermott David F. , Chu Quincy S. , Dumas Olivier , Chauhan Aman , Chaudhry Arvind , Tomczak, MD Piotr , Bruno Debora S. , Du Yangchun , Bidollari Ilda , Rege Jessicca Martin , Ernstoff Marc S. , Strauss James F. , Velcheti Vamsidhar
Published: June 2021

2513

Background: Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel, engineered cytokine that selectively binds the intermediate-affinity interleukin-2 (IL-2) receptor complex to preferentially activate CD8+ T cells and natural killer cells with minimal expansion of regulatory T cells, designed to leverage antitumor effects of the IL-2 pathwaywhile mitigating potential toxicity that would limit use. Methods: ARTISTRY-1 (NCT02799095) is a phase 1/2 study. Parts A (dose escalation 0.1-10 µg/kg) and B (6 µg/kg [recommended phase 2 dose]) are monotherapy; pts receive intravenous nemvaleukin for 5 days every 14 or 21 days. In Part C, pts receive nemvaleukin (3 or 6 µg/kg) every 21 days in combination with pembrolizumab (200 mg on day 1). We present safety and antitumor activity (RECIST v1.1, iRECIST) data as of 12/02/2020. Results: In Part A, 39 pts received nemvaleukin. No dose-limiting toxicities were observed; maximum tolerated dose was not reached. Part B enrolled immune checkpoint inhibitor–pretreated pts into melanoma or renal cell carcinoma (RCC) cohorts. 18 pts with melanoma enrolled; 10 were evaluable, 2 (both with metastatic mucosal melanoma) achieved a partial response (PR; 1 unconfirmed). 24 pts with RCC enrolled; 1 of 16 evaluable pts achieved a PR (awaiting confirmation). 12 pts in each cohort continue on study. In Parts A and B, treatment-related adverse events in ≥40% included chills (74.4% and 52.4%, respectively) and pyrexia (74.4% and 47.6%, respectively). In Part C (83 evaluable pts), 12 objective responses (OR) were observed; an additional 5 pts had stable disease (SD) >6 months (1 pt with breast cancer, 2 with ovarian cancer, and 2 with non-small-cell lung cancer). Nemvaleukin did not demonstrate any additive toxicity to that already established with pembrolizumab alone. OR data are summarized in the table. Conclusions: Nemvaleukin was generally well tolerated and demonstrated antitumor activity as monotherapy and in combination with pembrolizumab. Pharmacodynamic studies to identify biomarkers are ongoing. Future research of monotherapy and combination therapy with nemvaleukin is warranted. Clinical trial information: NCT02799095. [Table: see text]
Preliminary results of a phase 1b study of fruquintinib plus sintilimab in advanced colorectal cancer.
Authors: Guo Ye , Zhang Weijie , Ying Jieer , Zhang Yanqiao , Pan Yueyin , Qiu Wensheng , Su Weiguo , Tan Panfeng , Yin Hongyan , Wang Yan , Luo Yang , Zhou Hui , Li Jin
Published: June 2021

2514

Background: To explore the safety and synergistic anti-tumor effect of fruquintinib (a VEGFR inhibitor) in combination with sintilimab (an anti-PD-1 Ab) in patients (pts) with advanced colorectal cancer (CRC) and other solid tumors. Methods: This is an ongoing phase Ib/II, multicenter, two-stage study. Pts with variety cancer types, including CRC, were enrolled and is continuously enrolling in the study. For this interim analysis, all pts were analyzed for safety whereas only CRC pts were analyzed for efficacy. MMR status were analyzed for all enrolled CRC pts. Stage 1 was classical “3+3” dose escalation with pts assigned to one of the following 4 cohorts, fruquintinib taken orally at 3mg (Cohort A, 3 weeks on/ 1 week off), 4mg (Cohort B, 3 weeks on/ 1 week off), 5mg-intermittent (Cohort C, 2 weeks on/ 1 week off) or 3mg-continuous (Cohort E, once daily), while sintilimab was given at 200mg intravenously with Q4W in Cohort A and Cohort B whereas Q3W in Cohort C and Cohort E. DLT was observed for 28 days. Stage 2 was dose expansion with pts receiving 5mg-intermittent or 3mg-continuous fruquintinib plus sintilimab (200mg, Q3W). The primary endpoints were safety and tolerability and secondary endpoint was objective response rate (ORR). Results: As of Jan 5, 2021, 44 CRC pts which failed to at least 2 previous lines of therapy containing fluoropyrimidine, oxaliplatin or irinotecan were enrolled. They received either 5mg-intermittent or 3mg-continous dosage (n = 22, each), the ORR was 22.7% (10/44, 95% CI: 11.5-37.8%) with 27.3% (6/22, 95% CI: 10.7-50.2%) in 5mg-intermittent group and 18.2% (4/22, 95% CI: 5.2-40.3%) in 3mg-continuous group. With a median follow-up time of 8.3 (range: 0-9.6) months, the K-M estimated median PFS was 6.8 (95% CI:5.6-NA) months and 4.3 (95% CI:3.5-NA) months for 5mg-intermittent group and 3mg-continuous group, respectively. Overall, 60 pts were enrolled for safety analysis, including 23 in stage1 and 37 (only CRC) in stage 2. In stage 1, all pts experienced TEAEs, 52.2% of which were ≥ grade 3. The most frequently reported TEAEs were TSH increasing (73.9%), fecal occult blood positive (56.5%), and Palmar-plantar erythrodysaesthesia syndrome (PPES) (56.5%). SAEs occurred in 8 (34.8%) pts and no treatment-related death was reported. One patient in Cohort B reported manageable DLT. In stage 2, all pts experienced TEAEs, 18 (48.6%) pts experienced ≥ grade 3 TEAEs with 6 (31.6%) in 5mg-intermittent group and 12 (66.7%) in 3mg-continuous group. The most common TEAEs were proteinuria (45.9%) and TSH increasing (37.8%). TEAEs leading to either fruquintinib or sintilimab discontinuation occurred in 3 (5%) pts each. Conclusions: Fruquintinib plus sintilimab showed promising efficacy and favorable safety profile in advanced CRC. Clinical trial information: NCT03903705.
Phase 1 trial of the adenosine A2A receptor antagonist inupadenant (EOS-850): Update on tolerability, and antitumor activity potentially associated with the expression of the A2A receptor within the tumor.
Authors: Buisseret Laurence , Rottey Sylvie , De Bono Johann S. , Migeotte Ariane , Delafontaine Brant , Manickavasagar Thubeena , Martinoli Chiara , Wald Noémie , Rossetti Maura , Gangolli Esha A. , Wiegert Erol , McIntyre Nicola , Lager Joanne J. , Machiels Jean-Pascal H.
Published: June 2021

2562

Background: Tumors produce high levels of extracellular adenosine which suppress anti-tumor immune responses. Blocking A2A receptors, predominantly expressed on tumor-infiltrating immune cells, can reverse the immunosuppressive effect of adenosine. Inupadenant is a non brain-penetrant, potent and highly selective small molecule antagonist of the A2A receptor that remains active even at the high adenosine concentrations found in tumors. Methods: This is the phase I portion of an ongoing first-in-human, clinical trial (NCT02740985) to evaluate safety/tolerability, pharmacokinetic, pharmacodynamic and anti-tumor activity of inupadenant in adult patients with solid tumors who have exhausted standard treatment options. In addition, tumor biomarkers, including adenosine-pathway markers by immunohistochemistry (IHC), are being evaluated. We present updated results of the dose escalation, new results from the monotherapy expansion and new analysis of tumor biomarkers. Results: Overall, 42 patients (21 patients in the dose escalation and an additional 21 patients in a monotherapy expansion) with a median of 3 prior regimens were treated as of the data cut off (DCO, 30Nov20).The dose levels investigated, along with the most frequent (>20%) treatment-emergent adverse events (TEAEs) across all dose levels are presented in the table. 7 AEs led to discontinuation; 2 (atrial fibrillation and myocardial infarction) were considered possibly study drug-related by the investigator. No dose reductions were required. Two partial responses (PRs) were reported: melanoma (NRAS-mutant; received prior immunotherapy), and prostate cancer (received antiandrogen and chemotherapy). At the DCO, both PRs were ongoing with a duration of response >230 days. 12 patients had stable disease (SD) as best response and SD >6 months was observed in 3 patients. Response and stable disease were associated with a higher number of cells expressing the A2A receptor within the tumor at baseline, as measured by IHC. Conclusions: Inupadenant monotherapy was generally well-tolerated as of the DCO at a dose of 80 mg twice daily with initial evidence of clinical benefit, including 2 durable PRs in patients who have exhausted standard treatment options. Analysis of pre-treatment tumor biopsies has identified the A2A receptor as a biomarker which may be associated with clinical benefit. Clinical trial information: NCT03873883. [Table: see text]
Antitumor activity of dostarlimab in patients with mismatch repair-deficient/microsatellite instability–high tumors: A combined analysis of two cohorts in the GARNET study.
Authors: Berton Dominique , Banerjee Susana N. , Curigliano Giuseppe , Cresta Sara , Arkenau Hendrik-Tobias , Abdeddaim Cyril , Kristeleit Rebecca Sophie , Redondo Andrés , Leath Charles A. , Antón Torres Antonio , Guo Wei , Im Ellie , Andre Thierry
Published: June 2021

2564

Background: Dostarlimab is an investigational, humanized programmed death 1 (PD-1) receptor monoclonal antibody that blocks interaction with the PD-1 ligands, PD-L1 and PD-L2. GARNET (NCT02715284) is a phase 1 study assessing the antitumor activity and safety of dostarlimab monotherapy in patients with solid tumors. Methods: This multicenter, open-label, single-arm study is being conducted in 2 parts: dose escalation and expansion. Here we report on the 2 expansion cohorts that enrolled mismatch repairdeficient/microsatellite instabilityhigh (dMMR/MSI-H) patients. Cohort A1 enrolled patients with advanced or recurrent dMMR/MSI-H endometrial cancer (EC), and cohort F enrolled patients with advanced or recurrent dMMR/MSI-H or POLε-hypermutated non-EC solid tumors, mainly gastrointestinal (GI) tumors (99 [93.4%] had GI tumors, including 69 [65.1%] with colorectal cancer). Patients received 500 mg IV of dostarlimab every 3 weeks for 4 cycles, then 1000 mg IV every 6 weeks until disease progression or discontinuation. The primary endpoints were objective response rate (ORR) and duration of response (DOR) by RECIST v1.1. Here we report ORR and DOR, by individual cohort and as an overall population, in patients with dMMR tumors identified by immunohistochemistry testing. Results: For this interim analysis, an efficacy analysis was performed for the patients who had baseline measurable disease and ≥6 months of follow-up in the study (N = 209). The ORR was 41.6% (95% CI, 34.9%48.6%) for the combined A1+F dMMR cohorts (Table). Responses were durable, and median DOR has not been reached in either cohort (median follow-up: cohort A1, 16.3 months; cohort F, 12.4 months). A total of 267 patients were included in the safety population (all patients who received ≥1 dose; cohort A1, N = 126; cohort F, N = 141). Treatment-related adverse events (TRAEs) were consistent across tumor types. Overall, the most frequently reported any-grade TRAEs were asthenia (13.9%), diarrhea (13.5%), and fatigue (11.2%). The most common grade ≥3 TRAEs were anemia (2.2%), lipase increased (1.9%), alanine aminotransferase increased (1.1%), and diarrhea (1.1%). No deaths were attributed to dostarlimab. Conclusions: Dostarlimab demonstrated durable antitumor activity in patients with dMMR solid tumors, with consistent antitumor activity seen across endometrial and nonendometrial tumor types. The safety profile was manageable, with no new safety signals detected. Most TRAEs were low grade and were similar across cohorts. Clinical trial information: NCT02715284. [Table: see text]
Anlotinib enhanced penpulimab efficacy through remodeling of tumor vascular architecture and immune microenvironment in hPD-L1/hPD-1 humanized mouse model.
Authors: Shan Yunlong , Zhong Chongjin , Ni Qi , Zhang Mengying , Wang Guangji , Zhou Fang
Published: June 2021

2581

Background: Even though immune checkpoint inhibitor (ICI) such as anti-PD-1 mAb has emerged as effective treatment for tumor regression, the response rate of ICI monotherapy in solid tumor is low. Many studies have demonstrated that the efficacy of combination therapy of ICI and anti-angiogenesis was superior to monotherapy. Penpulimab (AK105), a humanized IgG1 mAb that blocks PD-1 binding to PD-L1, engineered to eliminate FcγR binding and ADCC/ADCP completely. Here, we explore a new combined therapy of penpulimab and anlotinib, an oral multi-targeted tyrosine kinase receptor inhibitor. Methods: MC38-hPD-L1 tumor-bearing B-hPD-1 humanized mouse model were conducted to investigate the effects of anlotinib (1 mg/kg, every day, p.o) or penpulimab (5 mg/kg, twice a week, i.p) alone or in combination. Immunofluorescence was applied to elucidate tumor vessel normalization. In vivo imaging was conducted to detect the distribution of AF647-labelled penpulimab after anlotinib treatment. Flow cytometry and other techniques were performed to investigate intratumoral immune cells. Results: After 3-week treatment, immunotherapeutic administration of anlotinib or penpulimab showed moderate inhibition of tumor growth (tumor volume: 66.5% and 58.4% of control group, respectively), while combined treatment of anlotinib with penpulimab significantly decreased tumor volume to 36.5% of control group. Tissue pathological and blood biochemical results showed no significant toxic and side effects. Immunohistochemistry revealed that anlotinib induced tumor vascular normalization, indicated by decreased CD31+ area, increased α-SMA around tumor vessels and reduced GLUT1+ area. Furthermore, anlotinib markedly enhanced the delivery of AF647-penpulimab into tumors. Combining anlotinib with penpulimab also promoted infiltration and activity of anti-tumoral immune cells by reducing the level of immune checkpoint TIM3 and increasing the IFNγ secretion from T cells. Conclusions: Our work provides a strong scientific rationale for the combination therapy of anlotinib and penpulimab to improve tumor microenvironment and immunotherapy, which highlights the clinical potential for this new combined therapy.
Preliminary data from QUILT 3.055: A phase 2 multi-cohort study of N803 (IL-15 superagonist) in combination with checkpoint inhibitors (CPI).
Authors: Wrangle John M. , Awad Mark M. , Badin Firas Benyamine , Rubinstein Mark P , Bhar Paul , Garner Chad , Reddy Sandeep K. , Soon-Shiong Patrick
Published: June 2021

2596

Background: There is currently a paucity of treatment options for checkpoint relapsed patients who have had an initial response but subsequently progress. N803, a novel IgG1 Fc-engineered IL-15-complexed protein may rescue checkpoint activity in a checkpoint independent manner via its selective enhancement of natural killer cell (NK) and CD8+ T cell number and function, without stimulation of T regs and MDSCs. Methods: QUILT 3.055, (NCT03228667) a phase 2b study of N803 plus investigator choice CPI in 11 tumor types: NSCLC, SCLC, Urothelial carcinoma, HNSCC, Merkel cell carcinoma, Melanoma (single PD-1/PD-L1 CPI or w/ ipilimumab), Renal cell carcinoma (RCC), Gastric cancer, Cervical cancer, Hepatocellular carcinoma, Microsatellite instability-high (MSI-H)/ mismatch repair deficient (dMMR) solid tumors, with a heterogeneous mix of prior therapies. We present interim data for 135 patients treated with CPI alone or in combination with chemotherapy as their most recent prior therapy. Trial inclusion required investigator assessed progression on last line of therapy, patients had either CR with relapse or partial response or stable disease for 6 months with progression as their most recent result of checkpoint therapy. Patients with hyperprogression or best initial response of progression were excluded. Subjects received N803 15mck/kg SC q 3 weeks in combination with the same checkpoint inhibitor on which they had their most recent progression. Results: Preliminary data from 135 patients (60% NSCLC) with treatment with checkpoint and N-803 following progression on the same checkpoint show CR 0%, PR 8%, Stable Disease 51%, Progression 29%, response unevaluable 12% to date. A PR or SD was seen in all subgroups. Median PFS 3.9 months (95% CI: 2.6,5.0). Median OS 13.8 months (95% CI: 11.8, 16.3) N-803 is well tolerated with grade 1-2 common N-803 treatment related adverse events (TRAE) were injection site reaction (68%), chills (32%) fatigue (26%), pyrexia (26%), flu-like illness (14%), nausea (12%) and no other individual AE > 10%. Grade 3 N-803 TRAE were 12% but no individual grade 3 AEs were greater than 5%. Conclusions: N803 demonstrates low toxicity in patients previously treated with CPI and promising efficacy of cessation of progression and induction of response and durable stable disease in patients who had previously progressed on a CPI containing regimen in multiple tumor types and different CPIs. Clinical trial information: NCT03228667.
Therapeutic effect of DDR pathway with different functional annotations for immune checkpoint inhibitor.
Authors: Nie Wei , Zhong Hua , Wen Fengcai , Zhang Ding , Chen Shiqing , Han Baohui
Published: June 2021

2611

Background: DNA damage response and repair (DDR) pathway-related gene mutations have been reported to predict the efficacy of immune checkpoint inhibitor (ICI). However, therapeutic effect of DDR pathway with different functional annotations is not fully studied. Here we explore the relationship of DDR pathway with different functional annotations and clinical outcomes in public cohorts of immunotherapy and chemotherapy. Methods: Genetic testing and clinical outcomes data were obtained from the public clinical cohorts across 10 tumor types. 232 DDR pathway-related gene were assigned to eight pathway according to the literature. Nine predictive models for the mutation pathogenicity were included in the analysis, of which at least five returned positive results were defined as deleterious mutations. All annotations were according to the American College of Medical Genetics (ACMG) standards and guidelines. To explore the association between DDR pathways and ICI, DDR pathway mutation is grouped. Patients, who harbored mutations in two or more DDR pathways and meanwhile had deleterious mutation in at least one DDR pathway, were enrolled in group A. Patients, who harbored deleterious mutations in only one DDR pathway or had only uncertain significance mutations, were enrolled in group B. Patients with no DDR gene mutations were enrolled in Group C. We analyzed relation of the group and survival outcomes in four public cohorts. Results: Of 4 clinical cohort analyzed, the group A treated with ICI has the best PFS or OS outcomes. However, the comparison of group B and group C is not coincide across different cohorts. Treatment is the key factor that influents the relation of DDR pathway mutations and clinical outcomes. As shown in POPLAR/OAK cohort, patients in group C has the best PFS (p=0.0381) or OS (p=0.0350) outcome when treated with chemotherapy, but patients in group A has the best PFS (p=0.0083) or OS (p=0.0222) outcome when treated with ICI. Conclusions: When treated with ICI, patients with at least one deleterious mutation and another deleterious or uncertain significance mutation has the best PFS or OS outcomes, but not for chemotherapy. Our study suggested that DDR pathway with deleterious mutations might be a potential predictive factor for immunotherapy.[Table: see text]
Association and prevalence of venous thromboembolism in cancer patients with COVID-19: A single healthcare system experience.
Authors: Ananthula Aneesha , Tran Dat , Thomas Katharine , McQueen Amaker Katie Lauren McLemore , Nguyen Anh , Mahato Soham , Thrash Brandon T , Chapple Andrew G , Subbiah Suki
Published: June 2021

2627

Background: There are increasing reports of thromboembolic complications in patients with COVID-19 infection. According to a meta-analysis of 28,173 patients, the prevalence of venous thromboembolism (VTE) in hospitalized COVID-19 patients ranges from 7.9% to 22.7% based on the severity of COVID-19. Cancer and anti-cancer therapies are known risk factors for thrombosis. Another study based on registry data reported the overall prevalence of VTE in hospitalized COVID-19 patients with cancer to be 14.5%. Our study aimed to assess the prevalence of VTE in cancer patients diagnosed with COVID-19 as well as the association between VTE and cancer in the setting of COVID-19 infection in a large predominantly urban healthcare system. Methods: We utilized a cohort data query tool in the electronic medical record at University Medical Center in New Orleans, Louisiana to identify patients >17 years of age with a hospital or clinic visit in the LCMC Health system between March 1, 2020 and December 31, 2020 which were considered the base population for the study. Cancer patients were identified via the cancer registry tool. Patients with COVID-19 were identified using the abnormal COVID-19 PCR test result search field. An encounter diagnosis of deep venous thrombosis (DVT) or pulmonary embolism (PE) was used to identify patients with VTE. Odds ratios, p-values, and corresponding confidence intervals (CI) were calculated using 2x2 contingency tables. Results: In our database, we identified 3,807 patients with a diagnosis of COVID-19 and 9,560 with a cancer diagnosis. 158,812 patients had neither COVID-19 nor cancer. There were statistically significant greater odds of developing VTE in all subgroups compared: COVID-19 alone vs neither (OR 2.43), cancer alone vs neither (OR 3.8), and COVID-19 and cancer vs neither (OR 10.65). Conclusions: COVID-19 and cancer are both risk factors for VTE. Based on our study, appears that cancer has the greater effect on VTE compared with COVID-19 infection. Also, there is possibly a synergistic effect between COVID-19 and cancer, which further increases the likelihood of VTE. This study is a preliminary analysis. Further investigation is warranted in the form of either variable adjusted analysis of the same data, individual chart review, or a prospective study.[Table: see text]
Priming immunotherapy with radiotherapy (RT) in advanced non-small cell lung cancer (NSCLC) and head and neck squamous cell cancer (HNSCC): Interim analysis of phase II clinical trial.
Authors: Jacob Aasems , Kreimer Alexander , Wei Jing , Wu Jianrong , Corum Lauren , Reusch Ellen , Woodward Jerold , Cohen Donald , Bondada Subbarao , Adams Val R. , Morgan Rachael , McGarry Ronald C. , St Clair William H. , Kudrimoti Mahesh R. , Myint Zin , Arnold Susanne M. , Villano John L.
Published: June 2021

2628

Background: Preclinical models demonstrate that combined RT with immune checkpoint inhibitor (ICI) results in specific CD8+ T-cell phenotype associated with a tumor-reactive population resulting in significant tumor response. Sequential treatment could allow radiation to release tumor antigens from immune inaccessible areas and provide robust anti-tumor immune response with ICI. We report an interim analysis of the phase II clinical trial evaluating the efficacy and safety of the combination. Methods: Advanced NSCLC and HNSCC patients who had initiated on FDA approved single-agent ICI were eligible. Patients were given SBRT (BED>100Gy) or 30 Gy fractionated RT delivered as a 3-dimensional dose to a single metastatic site within 14 days of the first ICI dose. Primary objective was 6-month PFS and secondary objectives were safety and tolerability, 1Y PFS and OS. This interim analysis was done after enrollment of 43 patients. Results: Between 10/2017 to 1/2021, 43 patients were enrolled, and 38 included in this analysis. Median age was 62 years; 26 patients were male. 9 patients received ICI for NSCLC as first-line, 7 for NSCLC second-line and 22 for HNSCC second-line. 24 patients received pembrolizumab and 14 nivolumab; 21 had SBRT and 17 fractionated RT. Median follow up duration was 11.8m (range: 2.7 - 31.4m) for patients without progressive disease (PD). 10 patients were off-study, 7 continuing treatment. 15 died and 26 had PD. 14 patients died of malignancy and cause of death for one patient was unknown. 6-month PFS was 49.19% with median PFS of 5.5 months. (table) Fifty-two grade-3-5 adverse events (AEs) were reported among 21 subjects. Most common were transaminitis (n=15), lymphopenia (n=8), and GI side effects (n=4). Treatment related AEs included 19 grade-3 events, and none were grade 4/5. Two grade-5 AEs were from PD (oral bleeding and unspecified). There were 20 grade-1/2 and 3 grade-3 immune related adverse events (IRAEs). No grade-4/5 IRAEs were reported. Two patients discontinued treatment due to grade 3 transaminitis. Conclusions: Interim analysis shows that 6m PFS was acceptable with majority of patients being second-line metastatic HNSCC who historically had mPFS of 2.1-2.3 months and mOS 7.7-8.4 months in Checkmate-141/KEYNOTE-040 trials. Hence, the combination is of further interest and accrual will continue to reach the goal. The combination therapy was tolerable without unexpected AEs. Majority of deaths were from disease progression. No treatment related grade 4/5 adverse events were reported. Two patients discontinued treatment due to grade-3 IRAE. Clinical trial information: NCT03313804. [Table: see text]
Phase 1 dose escalation study of MGC018, an anti-B7-H3 antibody-drug conjugate (ADC), in patients with advanced solid tumors.
Authors: Jang Sekwon , Powderly John D. , Spira Alexander I. , Bakkacha Ouiam , Loo Deryk , Bohac Gerry C. , Sharma Manish
Published: June 2021

2631

Background: MGC018 is an investigational ADC with a duocarmycin payload linked to an anti-B7-H3 monoclonal antibody (mAb). B7-H3 is expressed on multiple solid tumors with limited normal tissue expression. It is hypothesized that MGC018 may exert activity against B7-H3-expressing tumors with an acceptable safety profile. Studies demonstrate that B7-H3 is a significant factor in progression and events of metastasis of multiple tumor types, including melanoma. Methods: This phase 1 study characterizes safety, maximum tolerated or maximum administered dose, pharmacokinetics, immunogenicity, and tumor response per RECIST v1.1 of MGC018 in a 3+3+3 dose escalation design in patients with advanced solid tumors. MGC018 was administered intravenously (IV) every 3 weeks. Results: The study enrolled 29 patients of multiple tumor types, which included 3 melanoma patients refractory to ≥2 prior lines of checkpoint therapy. The study completed 5 of 6 planned dose cohorts (0.5 mg/kg - 4 mg/kg) as of the data cutoff of 21 January 2021. The final cohort of 4 mg/kg has 3 patients with ongoing treatment and follow-up at the date of submission. Dosing MGC018 IV every 3 weeks resulted in minimal serum accumulation. At least 1 treatment emergent adverse event occurred in 29 patients (100.0%); most common (≥25%) were anemia, neutropenia, fatigue, hyperpigmentation, infusion related reaction, nausea, and palmar plantar erythrodysesthesia. Two dose-limiting toxicities occurred; one grade 4 neutropenia (2 mg/kg) and one grade 3 fatigue lasting 7 days (4 mg/kg). No febrile neutropenia was reported. The 3 melanoma patients had reductions in target lesion sum of 24.4%, 27.5%, and 35% (unconfirmed partial response) and remain on treatment as of the data cutoff. The recommended phase 2 dose was determined to be 3 mg/kg. Conclusions: Results to date demonstrate a manageable safety profile, with early evidence of clinical activity in pretreated metastatic melanoma. Cohort expansion is ongoing using a recommended phase 2 dose of 3 mg/kg IV every 3 weeks. The planned enrollment includes advanced metastatic castrate-resistant prostate cancer, melanoma, triple-negative breast cancer, and non-small cell lung cancer. Clinical trial information: NCT03729596.
Maintenance immunosuppressive therapy with resumption of immune checkpoint inhibitor treatment to reduce recurrence of immune-mediated colitis.
Authors: Abu-Sbeih Hamzah , Zou Fangwen , Dutra Barbara , Altan Mehmet , McQuade Jennifer Leigh , Thompson John A. , Thomas Anusha , Wang Yinghong
Published: June 2021

2642

Background: Immune-mediated colitis (IMC) may limit immune checkpoint inhibitors (ICI) treatment. Current guidelines recommend consideration of resuming ICI when IMC symptoms subside to ≤ grade 1. We aimed to investigate the effect of maintenance immunosuppressive therapy (IST) on the outcome of IMC in patients who resume ICI therapy. Methods: We retrospectively studied patients who resumed ICI therapy after adequate treatment of IMC from March 2015 to June 2020 at MD Anderson Cancer Center. Relevant demographic, oncologic, and ICI data were collected and analyzed. Univariate logistic regression analysis was conducted to assess risk factors of IMC recurrence. Results: We included 102 patients with a median age of 61 years. 66% were males and 97% were Caucasians. 48 patients (47%) received IST maintenance in conjunction with ICI resumption and 54 patients did not. Symptoms of IMC recurred in 28 patients, 8 (17%) in the concurrent IST group and 20 (37%) in the other group. Compared to no concurrent IST group, patients on concurrent IST were more likely to have received combined ICI regimen (60% vs 41%, p = 0.003) and more initial ICI doses (9 vs 5 doses, p = 0.030). Concurrent IST group had significantly longer ICI treatment duration on resumption (72 vs 62 days, p = 0.023), more ICI resumed doses (5 vs 4 doses, p = 0.038), and lower IMC recurrence (17% vs 37%, p = 0.027). Patient who received more IST doses, both therapeutic and prophylactic, had lower rate of IMC recurrence (OR 0.72, p = 0.012; table). IST maintenance treatment (OR 0.34, p = 0.024) was associated with lower IMC recurrence rate after ICI resumption. Vedolizumab was the predominant IST used. Overall survival was comparable among the two groups (p = 0.934). Conclusions: Concurrent IST treatment with ICI resumption after IMC was associated with significantly lower IMC recurrence and more extended ICI treatment while reserving similar overall survival to patients without IST maintenance therapy. Future prospective randomized trial of concurrent IST is still merited for further clarification.[Table: see text]