bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II study of capecitabine (Cape) or 5-fluorouracil (5-FU) with pegylated interferon alpha-2b (Peg-IFNA-2b) in unresectable/metastatic cutaneous squamous cell carcinoma (CSCC).
Authors: Muzaffar Jameel , Khushalani Nikhil I. , Russell Jeffery Scott , Parameswaran Janaki , Kirtane Kedar , De La Iglesia Janis , Slebos Robbert , Chung Christine H. 
Published: May 2019

e21020 Background: Patients (pts) with unresectable/metastatic CSCC have a poor prognosis, and until recently had limited treatment options. Based on encouraging efficacy in case report series, we conducted a phase 2 trial to evaluate the efficacy of CAP or 5-FU in combination with Peg-IFNA-2b in advanced CSCC. Methods: Eligible pts with measurable unresectable/metastatic CSCC were treated with CAP (1000mg/m2 PO twice daily days 1-14) or 5-FU (800 mg/m2 IV days 1-4), and Peg-IFNA-2b (subcutaneously at 3ug/kg weekly) in a 21-day cycle for up to 9 cycles, intolerable toxicity or progression. The primary objective was to assess overall response rate (ORR) while secondary objectives were safety and survival. Exploratory correlative tissue immune markers were studied using multiplex immunohistochemistry (mIHC) on pre- and post-treatment optional tumor biopsies. Results: Poor accrual led to early study closure after enrolling 8 pts. All pts were male, median age was 73.5 yrs. The ORR was 25% (1 CR, 1 PR); 4 pts had SD, 1 with PD and 1 withdrew consent prior to first restaging. The pt with CR had previously progressed on anti-PD1 therapy; tissue mIHC from this pt showed an increase in CD8+ cells prior to starting trial therapy. Due to the low sample size the 6 and 12-month survival estimates for OS and PFS are the same, 87.5% and 50% for 6 and 12 months respectively. Grade ≥ 3 or higher toxicities included decreased WBC (n = 3), fatigue, failure to thrive, anemia (all n = 2), and neutropenia, dehydration, hand-foot syndrome (all n = 1). Dose reductions were frequently encountered. Conclusions: Combination CAP/5-FU plus Peg-IFNA-2b has activity in advanced CSCC but with considerable toxicity at studied doses. The small sample size precludes meaningful conclusions on efficacy, though the CR observed post-PD1 progression might warrant further investigation of this combination as a therapeutic strategy given the recent approval of cemiplimab in CSCC. Clinical trial information: NCT02218164.
Dendritic cell vaccination in metastatic uveal melanoma as compassionate treatment: Immunological and clinical responses.
Authors: Moreira Alvaro , Gross Stefanie , Uslu Ugur , Doerrie Jan , Kummer Mirko , Schliep Stefan , Sponagl Felix , Lischer Christopher , Erdmann Michael , Heinzerling Lucie , Schuler Gerold , Schuler-Thurner Beatrice 
Published: May 2019

e21024 Background: Other than cutaneous melanoma, metastatic uveal melanoma (UM) is minimally responsive to checkpoint inhibitors. The prognosis remains very poor with mortality rates nearly unchanged over the last decades. The recently growing insight that immunotherapy significantly improves outcomes for cancer patients led to a re-emergence of vaccines including dendritic cell (DC) vaccines. Methods: We vaccinated an UM patient in a compassionate use setting and assessed the immunological and clinical responses. Based on this experience we performed individual compassionate treatments in other UM patients using DC loaded by peptide pulsing and/or mRNA transfection (autologous tumor RNA or RNA coding for tumor antigens). Results: The first patient was vaccinated in 2013 after a liver metastasis was resected and checkpoint blockade with ipilimumab was started. In 2014 the patient showed progression in the liver. We continued DC vaccination in shorter intervals and adapted antigen loading (with mRNA coding for an individual GNAQ driver mutation) accompanied by a further cycle of ipilimumab. Therapy resulted in complete remission of liver metastases, but the patient developed new skin metastases. Again the loading of DC was adapted (peptides of passenger mutations predicted after Next-Generation Sequencing) and infusions with pembrolizumab were started. Pathology from some regressing lesions showed a massive T cell infiltration and in parallel GNAQ mutation-specific T cells could be found in the patient’s blood. Skin metastases regressed and the patient is now free of detectable tumor after 65 months. Immune monitoring in the patient’s blood showed a vaccine-induced functional T cell response against the QNAQ-driver mutation. Three of other four patients are also still alive, one in complete remission under DC vaccination in combination with pembrolizumab, two of them showing measurable disease, and one deceased disease related after 28 months, resulting in a median OS of the five patients of 36.4 months. Immune monitoring in one of those patients showed a CD4+ and CD8+ INF-gamma T cell response against the autologous tumor RNA vaccine. No grade 3 or 4 toxicity occurred. Conclusions: The observed prolonged median OS and the fact that 2/5 patients remain disease-free is definitely encouraging. Vaccination immunotherapy with antigen-laden DC is a potential therapeutic option for patients with metastatic uveal melanoma. Combinations with checkpoint inhibitors proved promising, and should be further evaluated in clinical trials.
Clinical efficacy of vaccination with the autologous tumor lysate particle loaded dendritic cell (TLPLDC) vaccine in metastatic melanoma.
Authors: Hickerson Annelies , Clifton Guy T. , Brown Tommy A , Campf Jessica , Myers John William , Vreeland Timothy J. , Hale Diane F. , Peace Kaitlin M. , Jackson Doreen O , Yu Xianzhong , Wagner Thomas , Peoples George Earl 
Published: May 2019

e21025 Background: The treatment of melanoma has changed drastically with the advent of immunotherapy. The autologous tumor lysate, particle loaded, dendritic cell (TLPLDC) vaccine stimulates T-cells and may work synergistically with other immunotherapies. Here, we describe results in patients (pts) with metastatic melanoma (MM) treated with the TLPLDC vaccine together with other approved therapies. Methods: The TLPLDC vaccine is created using autologous tumor lysate loaded yeast cell wall particles to prime autologous dendritic cells ex-vivo. 1-1.5x106 TLPLDCs are given via intradermal injection monthly x 4 followed by boosters at six and nine months (mo). Pts who recurred while enrolled in our adjuvant phase IIb trial of the TLPLDC vaccine and pts with MM with measurable disease enrolled in a separate phase I/IIa trial were offered vaccination of TLPLDC vaccine in an open-label fashion in addition to other approved therapies as determined by their treating physician. Tumor response is measured by RECIST 1.1 criteria. Results: To date, 50 pts have been enrolled in the two trials (25 pts in each). Of the 42 pts with measureable disease, 30 pts received at least one dose of the vaccine, 11 progressed prior to vaccine administration, and 1 is pending. 2 pts withdrew at 2 and 7 mo. Of the remaining 28 evaluable pts, 13 pts had progressive disease with a median follow-up (f/u) of 3 (range 0-12) mo, 12 pts had stable disease with a median f/u of 7.5 (range 1-23) mo, 2 pts had a partial response with f/u of 7 and 13 mo, and one pt had a complete response with 18 mo of f/u. Overall, in pts with measureable disease, the disease control rate was 54% (15/28) and objective response rate was 11% (3/28). 8 pts were without measurable disease at enrollment, 3 recurred at a median f/u of 8 mo and 5 remain disease-free at a median of 26 mo f/u. No grade ≥ 3 toxicities were observed with combination TLPLDC vaccination and approved systemic therapies. Conclusions: Vaccination with the TLPLDC vaccine in combination with systemic approved therapies in MM pts is well tolerated and may provide clinical benefit in patients with and without measurable disease. Clinical trial information: NCT02678741.
Targeting MAP2K1 mutation with trametinib in a triple wild-type melanoma patient.
Authors: Homicsko Krisztian Gyuta , Aedo Veronica , Missiaglia Edoardo , Bisig Bettina , Michielin Olivier 
Published: May 2019

e21027 Background: MAP2K1 inhibitors combined with BRAF inhibitors provide a prolonged progression-free survival for BRAF mutant patients. However, the impact of MEK inhibition of MAP2K1 mutant and BRAF/NRAS/NF1 wild type melanoma patients remains elusive. Methods: We performed next-generation sequencing using an in-house developed 400 full exon panel for one of our triple wild type (BRAF/NRAS/NF1) melanoma patient. The patient received off-label, trametinib at a dose of 2 mg o.d. We performed additional sequencing at progression. After progression, the patient was treated off-label with combined trametinib and palbociclib therapy. Furthermore, we screened the TCGA melanoma and MSK-IMPAKT databases for patients with similar mutation profiles. Results: Our patient presented with dual somatic MAP2K1 mutations at Cys121Ser and Pro124Arg with a 68% allele frequency. The tumor also harbored a minor EGFR mutant clone (11% allele frequency) and a complete loss of the CDKN2A locus. The patient received trametinib and after two months presented a partial response as per RECIST1.1. However, after two additional months, the patient progressed. A new biopsy was performed, and the treatment was modified to combine trametinib and palbociclib to co-target MAP2K1 and the loss of the CKDN2A locus. The patient progressed under dual trametinib/palbociclib therapy without any objective benefit. The on-progression biopsy showed the absence of a gatekeeper mutation of MAP2K1 and the persistence of the loss of the CDKN2A locus. We detected a large number of novel copy number variations, most notable amplification of MITF (9x), FGFR1 (10X) and of MDM2 (16x). We also detected a loss of the minor, EGFR mutant clone. The analysis of large-scale state transitions (LSTs) for deficiency in homolog recombination (HRDness) was negative in pre and post-treatment biopsies. Conclusions: Our patient provides unique evidence to target solitary MAP2K1 mutations in triple wild melanoma by MEK1 inhibitors. Resistance to MEK1 inhibition developed rapidly and likely involved FGFR1 and MDM2, which have not been previously associated with resistance to MEK inhibitor monotherapy. The addition of palbociclib could not rescue these potential resistance mechanisms.
Treatment patterns and outcomes among patients with advanced cutaneous squamous cell carcinoma (CSCC) in a US community oncology setting.
Authors: Cowey C. Lance , Robert Nicholas J. , Davies Kalatu , Espirito Janet L. , Frytak Jennifer R. , Lowy Israel , Fury Matthew G. 
Published: May 2019

e21033 Background: Advanced CSCC is a term that encompasses the locally advanced (laCSCC) and metastatic (mCSCC) condition. For advanced CSCC patients who receive conventional anticancer systemic treatment, there are limited data regarding treatment patterns and clinical outcomes. Methods: This was a retrospective, observational study of adult patients with laCSCC and mCSCC who initiated first-line (1L) systemic treatment from 1/1/2008 to 12/31/2015, with follow-up to 9/30/2017. Data were abstracted from the US Oncology Network’s iKnowMedSM electronic health record database, supplemented by chart review. ECOG performance status (PS) of 0 or 1 was required for inclusion. Exclusion criteria included tumor of unknown primary site, treatment with an anti-PD-1/anti-PD-L1 agent, participation in clinical trial, and concurrent primary cancer. Duration of therapy (DOT) and overall survival (OS) were analyzed by Kaplan-Meier method. Response rate was calculated as the proportion of patients who achieved physician assessed-response. Results: 82 patients met inclusion criteria (17 laCSCC and 65 mCSCC). Median age at start of 1L treatment was 75y; 85% were male, 79% Caucasian, 88% of patients had an ECOG PS of 1, 90% had prior surgery, 84% prior radiotherapy, and 8.5% had prior organ transplant. The most common 1L regimens were carboplatin + paclitaxel (27% of patients) and cetuximab monotherapy (24%). Median 1L DOT was 2.4 mo for the overall population; 4.1 mo for laCSCC, 2.3 mo for mCSCC. Physician-assessed response rate for 1L therapy was 18.3% overall; 17.6% for laCSCC, and 18.5% for mCSCC. Median OS from the start of 1L treatment was 15.3 mo (95% CI, 10.4-21.0) overall; 16.2 mo for laCSCC, and 15.3 mo for mCSCC. Only 24 patients (29%) received 2L therapy. Conclusions: This is the largest retrospective data set regarding advanced CSCC patients treated with conventional chemotherapy. Efficacy was low in both laCSCC and mCSCC. These data provide historic benchmarks for outcomes in advanced CSCC patients prior to the FDA approval of cemiplimab-rwlc.
What impact do the proton pump inhibitors have on the efficacy of immune check point inhibitors in metastatic malignant melanoma?
Authors: Afzal Muhammad Zubair , Shirai Keisuke 
Published: May 2019

e21040 Background: Acidic microenvironment facilitates the proliferation, progression, and metastasis of the tumors. Mouse models have shown that the proton pump inhibitors (PPI) cause neutralization of the acidic tumor microenvironment (TME) and inhibit the tumor growth. PPI also sensitize the resistant tumors to chemotherapeutic and immunotherapeutic effects. Moreover, PPI’s modify the gut microbiota, that impact the efficacy of immune checkpoint inhibitors (ICI). Clinical studies have shown variable impact of PPI on efficacy of ICI, ranging from no benefit at all to a negative impact. Since, PPI are one of the most commonly used medications, it is important to evaluate its impact on the efficacy of ICI. Methods: We conducted a retrospective analysis on 120 metastatic malignant melanoma patients treated with anti- CTLA-4 (ipilimumab), anti PD-1(pembrolizumab) alone or in combination. Cohort A included patients who were taking PPI at the time of ICI initiation. Cohort B included non-PPI users. Objective response rate (ORR), disease control rate (DCR), overall survival (OS), and progression free survival (PFS) were calculated. ORR and PFS were the primary outcomes. Cox regression univariate and multivariate analyses were performed. The proportions of grade 3 or 4 immune related adverse events (IrAE) were compared between PPI users and nonusers using the Fisher’s exact test. Results: Cohort A included 29 (24.2%) patients, of which 68.7% patients were male. Median age was 65 years. Majority of the patients were taking omeprazole (58.6%). Proportion of the patients taking ipilimumab and pembrolizumab or nivolumab were almost similar (48.3% vs. 44.8%, respectively). Significantly higher proportion of patients achieved ORR and DCR in cohort A [76%, OR = 3.8(1.39 – 10.5), P = 0.009) and 84%, OR = 4.3(1.37 – 13.7), P = 0.013, respectively). The median PFS was significantly higher in cohort A [A = 27.6 vs. B = 4.4 months, HR = 0.3, P = 0.005(0.1 – 0.7)]. Although, median OS was considerably higher in cohort A, the difference was not statistically significant [A = 39.3 vs. B = 28.0 months, HR = 1.01, P = 0.9(0.4-2.0). PPI did not significantly increase the Odds of having grade 3 or 4 IrAE. Conclusions: In this retrospective review, we have observed favorable outcomes in patients receiving PPI when starting on ICI contrary to some of the studies suggesting negative impact of PPI on ICI efficacy. As PPI is one of the commonly used chronic medications, prospective studies are needed to evaluate the real impact of PPI on ICI when taking concomitantly.
Utility of concurrent immunoradiation for locally advanced and/or medically inoperable melanoma and Merkel cell carcinoma.
Authors: Poulose Joyson , Wheelden Megan , Mackley Heath B. , Schmeck Carla , Zhu Junjia , Pameijer Colette , Neves Rogerio Izar , Schell Todd , Mallon Carol , Drabick Joseph J. 
Published: May 2019

e21053 Background: Melanoma and Merkel Cell Carcinoma (MCC) are aggressive cutaneous malignancies with poor responses to cytotoxic chemotherapy. The use of immune checkpoint inhibitors (ICI) has substantially improved outcomes in metastatic disease and in the neoadjuvant setting. Addition of concurrent radiation therapy (RT) can augment the response of ICI, however there are little data on this combined approach as a neoadjuvant or non-operative strategy. Methods: We retrospectively analyzed outcomes of patients who received RT combined with an ICI against PD1, PD-L1, CTLA-4, or dual targets as neoadjuvant or definitive non-operative management for non-polymetastatic disease at our center from 2012 to 2018. Results: This study analyzed 14 patients, 7 males and 7 females, with a median age of 75 years. There were 10 patients with melanoma and 4 patients with MCC. Among them, 9 patients had stage III disease and 5 patients had oligometastatic disease. Prior treatments included surgery (71%), radiation (21%), and immunotherapy (21%) comprising interferon alpha (1), intralesional BCG (1), and Nivolumab (1). The ICI used were Pembrolizumab (5), Nivolumab (2), Avelumab (2), Ipilumumab (4) and Ipilumumab + Nivolumab (1). Immune related adverse events were seen in 8 patients and included endocrine (5), skin (4), and gastrointestinal (2) toxicity, majority of which were grade 1. Both grade 3 dermatitis and colitis were seen in 2 patients, and 1 patient had grade 3 colitis. There was 1 patient with grade 1 radiation dermatitis. Following concurrent ICI + RT, 4 patients who did not achieve a complete response (CR) at the irradiated site underwent surgical resection with no postoperative complications. An objective response at the irradiated site was seen in 13 (93%) patients, and 12 (86%) patients achieved a CR outside the radiated field. At the time of last follow up, 10 patients remain alive, of which 8 patients are in sustained complete remission. Conclusions: Concurrent use of ICI + RT was a safe approach in patients with locally advanced or medically inoperable melanoma and MCC with potential for durable complete remissions in the majority. Prospective studies are warranted to further validate this approach.
A phase III study comparing trastuzumab emtansine with trastuzumab, pertuzumab, and docetaxel in elderly patients with advanced stage HER2-positive breast cancer: (JCOG1607 HERB TEA study).
Authors: Shimomura Akihiko , Tamura Kenji , Mizutani Tomonori , Shibata Taro , Hara Fumikata , Fujisawa Tomomi , Niikura Naoki , Hojo Takashi , Kanbayashi Chizuko , Saji Shigehira , Masuda Norikazu , Sawaki Masataka , Yamamoto Naohito , Nagashima Fumio , Shien Tadahiko , Iwata Hiroji 
Published: May 2019

TPS1100 Background: Systemic chemotherapy with anti-HER2 therapy is the standard of care for HER2-positive advanced breast cancer. Patient outcomes have improved remarkably with the use of novel anti-HER2 drugs, including trastuzumab (H), pertuzumab (P), and trastuzumab emtansine (T-DM1). The combination treatment comprising H, P, and docetaxel (D) (HPD) is highly recommended as the 1st-line treatment for patients with HER2-positive advanced breast cancer. In contrast, for elderly patients over 65 years of age, this regimen seems to be intolerable mentally and physically, and impairs their quality of life. A new standard treatment with less toxicity and non-inferior efficacy for elderly patients is needed. Methods: We have planned a randomized, multicenter, open-label, phase III trial to confirm the non-inferiority of T-DM1 compared to HPD in terms of overall survival (OS) in elderly patients with HER2-positive advanced breast cancer. The eligibility criteria are as follows: 1) histologically proven metastatic breast cancer, 2) age 65-74 years with a performance status (PS) score 0-2, or 75-79 years with a PS score 0-1, 3) HER2 overexpression or amplification confirmed in primary or metastatic tissues, and 4) no anti-HER2 therapy with chemotherapy for breast cancer, excluding (neo) adjuvant therapy. Patients are randomized to receive either HPD (H 6 mg/kg, P 420 mg/body, and D 60 mg/m2) or T-DM1 3.6 mg/kg every 3 weeks. The dose up of D (75 mg/m2) after the second cycle is defined based on the data regarding safety during the first cycle. The primary endpoint is OS. The secondary endpoints are progression-free survival, response rate, adverse events, breast cancer-related death, and deterioration of activities of daily living. The trial is designed to achieve 70% power to confirm non-inferiority of T-DM1 to HPD at a one-sided alpha of 5% with a non-inferiority margin of 1.3 in terms of hazard ratio. With a median OS of 30 months in both arms, 6 years of accrual, and 5 years of follow up, the planned sample size is 330. The trial began in January 2018 and nineteen patients have been enrolled as of January 2019. Clinical trial information: UMIN000030783.
A phase II study of dual immune checkpoint blockade (ICB) plus androgen receptor (AR) blockade to enhance thymic T-cell production and immunotherapy response in metastatic breast cancer (MBC).
Authors: Page David B. , Kim Isaac K , Chun Brie , Redmond William L , Martel Maritza , Mori Motomi , Wadell Dottie , Moxon Nicole , Mellinger Staci L. , Urba Walter John , Gucalp Ayca , Traina Tiffany A. 
Published: May 2019

TPS1106 Background: ICB (atezolizumab, anti-PD-L1) is known to improve survival when added to chemo, however only in PD-L1-positive, triple-negative MBC. ICB is less effective in hormone receptor positive (HR+) MBC, or when administered following palliative chemo. Novel approaches are required to broaden clinical benefit of ICB, particularly in PD-L1-negative, HR+, or chemo-experienced MBC. Dual ICB with anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab) is associated with enhanced activity in melanoma other malignancies, but has not been explored extensively in MBC. Androgen receptor (AR) blockade, in addition to known direct cytostatic effects in AR-expressing MBCs (50% of TNBC, > 75% of HR+ MBC), may also modulate immune response. AR blockade has been shown experimentally to stimulate thymic production of naïve T-cell clones, which in turn can facilitate de novo anti-tumor immune responses. Concurrent ICB can enhance the activity of these T-cell clones by interfering with PD-1-mediated peripheral tolerance. This combination approach is promising in MBC in light of known AR positivity, and the routine use of lymphodepleting chemo regimens in the curative-intent setting. Methods: This is a phase II trial of dual immune checkpoint blockade (nivolumab 240mg IV q2w; ipilimumab 1mg/kg IV q6w) plus AR blockade (bicalutamide, 150mg PO daily, dose reduction allowed) in triple-negative MBC (cohort A: AR-positive [ > 1% by IHC]; cohort B: AR-negative) or HR+ MBC (cohort C) in subjects who received 0/1 prior chemotherapies in the non-curative setting. Objectives include 24-week clinical benefit rate by iRECIST (primary), safety (CTCAE v4.0), and other response measures (RECIST1.1, PFS, OS). Efficacy for each cohort is defined as > 20% improvement in response over historical control (30% per EMBRACE clinical trial) employing a Simon 2-stage design to minimize futility (n = 46/cohort, stage I n = 15). Thymic generation of T-cells will be measured via quantitative deep sequencing of T-cell receptors (TcR, ImmunoSEQ assay) and TcR excision circles (TRECs), as well as real-time flow cytometry using surrogate cell surface markers of recent thymic emigration. Enrollment has commenced, sites: Earle A. Chiles Research Institute (Portland, OR), Memorial Sloan Kettering Cancer Center (New York, NY). Clinical trial information: NCT03650894.