bluuebunny/crossref_metadata_2025_split huggingface dataset:
ENCORE 601: A phase II study of entinostat (ENT) in combination with pembrolizumab (PEMBRO) in patients with melanoma.
Authors: Johnson Melissa Lynne , Gonzalez Rene , Opyrchal Mateusz , Gabrilovich Dmitry , Ordentlich Peter , Brouwer Susan , Sankoh Serap , Schmidt Emmett V. , Meyers Michael L. , Agarwala Sanjiv S. 
Published: September 2018

9529 Background: Entinostat is an oral, class I selective histone deacetylase inhibitor shown preclinically to enhance immune checkpoint inhibitor activity by regulation of immune suppressor cells in the tumor microenvironment. ENCORE 601 is designed to evaluate safety and efficacy of ENT in combination with PEMBRO. Phase 1b identified ENT 5 mg PO weekly and PEMBRO 200 mg IV every 3 weeks as the recommended Phase 2 dose for further investigation. Methods: Phase 2 of ENCORE 601 employs a Simon 2-stage design to assess activity across 3 cohorts: 1) NSCLC not previously treated with a PD-1/L1 blocking antibody, 2&3) NSCLC & melanoma previously progressing on or after a PD-1/L1 blocking antibody. Patients were enrolled irrespective of PD-L1 expression levels. The primary endpoint is ORR as assessed by irRECIST. Results of the first stage of Cohort 3 are reported. Criteria for advancing to Stage 2 are ≥2 responses out of 13 evaluable patients. Results: Stage 1 enrollment has been completed (n = 13). All patients received a prior PD-1 inhibitor; in addition, 7 patients received prior ipilimumab and 2 patients received a prior BRAF inhibitor. 9 patients are still on treatment; 4 patients have discontinued due to progression. To date, 1 confirmed and 1 unconfirmed objective response have been observed. The confirmed response (PR) was in a patient who was previously treated with ipilimumab/nivolumab for 6 months (best response of SD with subsequent progression on therapy). Treatment-related AEs occurred in 5 patients (most common being nausea and fatigue occurring in 2 patients); one patient experienced Gr3/4 events (fatigue and rash). Blood samples and pre-treatment biopsies were obtained in all patients along with paired post-treatment biopsies in 8 patients. Evaluation of PD-L1 expression, gene expression, myeloid and lymphoid compartments in blood and tumor samples is in progress. Of note, the patient with a confirmed PR converted from a PD-L1 negative, non-inflamed gene signature to PD-L1 positive, inflamed after 2 weeks of treatment. Conclusions: ENT combined with PEMBRO demonstrates acceptable safety and encouraging preliminary activity in melanoma patients refractory to checkpoint inhibitors. Clinical trial information: NCT02437136.
Phase II multicenter, single arm, open label study of nivolumab (NIVO) in combination with ipilimumab (IPI) as first line in adult patients (pts) with metastatic uveal melanoma (MUM): GEM1402 NCT02626962.
Authors: Piulats Josep M. , De La Cruz-Merino Luis , Curiel Garcia Maria Teresa , Berrocal Alfonso , Alonso-Carrión Lorenzo , Espinosa Enrique , López Castro Rafael , Rodriguez-Abreu Delvys , Luna Fra Pablo , Martin-Algarra Salvador 
Published: September 2018

9533 Background: Uveal melanoma is the most common primary intraocular malignant tumor in adults. Overall Survival (OS) at 5 years(y) is 62% due high incidence of liver metastasis, fatal within 4-9 months(m) from diagnosis. No standard treatment exists for MUM. NIVO+IPI combination has shown efficacy in metastatic cutaneous melanoma. However, MUM pts were excluded in these trials. Methods: GEM1402 is a phase-2 trial evaluating NIVO+IPI in untreated adult pts with MUM; is being conducted in 10 centers in Spain, leading by the Spanish Melanoma Group. Eligible pts had histologically-confirmed MUM, ECOG-PS 0/1, and no prior systemic treatment for MUM. Treatment consisted in NIVO (1mg/kg, iv, q3 weeks [wk]) and 4 doses of IPI (3mg/kg iv q3wk) followed by NIVO (3mg/kg q2wk) until progressive disease (PD), toxicity or withdrawal. Primary endpoint is OS and secondary progression free survival (PFS), Overall Response Rate (ORR) (per RECIST 1.1) and safety. Radiologic evaluations q6wk. Interim analysis (n = 19) was planned per protocol to assess safety and ORR. Intention to treat analysis includes pts with PD at first radiological evaluation. Safety population includes all pts receiving at least one dose of study treatment. Results:19 pts enrolled from April to July 2016: Median age 62y (43y-82y), 63% male, liver M1 84% pts and extra-liver M1 42% pts, 31% elevated baseline LDH. 11 pts completed cycle 2 and 8 pts stopped after 1 dose (6 PD, 2 toxicity). Treatment-related adverse events were reported in 12 pts and lead to end of treatment in 2 pts. Grade ≥3 toxicities were seen in 7 pts (36.8%): diarrhea, transaminitis, dermatological events, anemia, acute thyroiditis. All G3/4 were resolved following the toxicity guideline. One G5 acute thyroiditis related to NIVO+IPI was reported. ORR was observed in 15.8% and disease stabilization in 47.4%. With a median follow-up of 4.6m, PFS was 4.99m. Median OS was not reached at time of this analysis. Conclusions: Combination of NIVO+IPI is feasible for MUM. In this INTERIM ANALYSIS, ORR did not reach yet 20%, but PFS seems promising. The clinical trial is ongoing. Final results will be updated. Clinical trial information: 2015-004429-15.
Efficacy and safety of single agent pan-HER inhibitor dacomitinib in locally advanced unresectable or metastatic skin squamous cell cancer (sSCC).
Authors: Bossi Paolo , Cavalieri Stefano , Perrone Federica , Miceli Rosalba , Ascierto Paolo Antonio , Locati Laura D. , Bergamini Cristiana , Granata Roberta , Alfieri Salvatore , Resteghini Carlo , Galbiati Donata , Busico Adele , Paielli Nicholas , Patuzzo Roberto , Maurichi Andrea , Gallino Gianfranco , Ruggeri Roberta , Mariani Luigi , Palla Marco , Licitra Lisa 
Published: September 2018

9543 Background: In recurrent/metastatic skin squamous cell cancer (sSCC) not amenable to radiotherapy (RT) or surgery, chemotherapy (CT) has a palliative intent and limited clinical responses. We investigated the role of pan-HER inhibitor dacomitinib within a phase II trial in this setting. Methods: Patients (pts) with diagnosis of sSCC not amenable to curative approaches were included. Oral dacomitinib was started at a dose of 30 mg daily for 15 days, followed by 45 mg daily. Primary endpoint was response rate (RR). Tumor samples were analyzed through Next Generation Sequencing methods (pgm, Ion torrent) using a custom panel targeting 36 genes associated with sSCC. Results: Forty-two pts (33 M, 9 F; median age 77 years, range 45-92) were treated. ECOG PS was 0 in 58%, 1 in 40% and 2 in 2%. One fifth of the pts had distant metastasis. Most pts (86%) received previous treatments consisting in surgery (86%), RT (50%) and CT (14%). Among evaluable pts, overall RR was 28% (complete response CR 2%, partial response PR 26%), disease control rate 86%. Median duration of response was 11 months (range 1-26+). Median treatment duration was 4 months (range 1-26+). Reason for discontinuation were disease progression in 69%, adverse events (AEs) in 19%, non drug-related death in 5%; 3 pts are still on treatment. Median PFS and OS were 6 and 12 months, respectively. Most pts (93%) had at least one AE, mainly consisting in diarrhea and skin rash (71% each), fatigue (36%) and stomatitis (31%). G3/G4 AEs occurred in 36% of pts (diarrhea and skin rash 17% each). Tumor material was available from 7 responding (R: 6 PR, 1 CR) and 15 non-responding (NR: 13SD, 2PD) pts. Frequent TP53 (60%), NOTCH1/2 (60%) and FAT1 (40%) mutations were observed. NR pts showed a higher occurrence of HRAS/BRAF/NRAS mutations (40%) than R ones (28%). Moreover, HER3 (27%) CASP8 (27%), KMT2C (33%) and DCLK1 (27%) mutations were restricted to NR pts. Conclusions: In sSCC dacomitinib showed activity, similar to what observed with anti-EGFR monoclonal antibody cetuximab and panitumumab (RR 28% and 31%); safety profile was comparable to previous experiences in other diseases. Molecular pt selection could improve therapeutic ratio. Clinical trial information: NCT02268747.
KEYNOTE-029: Efficacy and safety of pembrolizumab (pembro) plus ipilimumab (ipi) for advanced melanoma.
Authors: Carlino Matteo S. , Atkinson Victoria , Cebon Jonathan S. , Jameson Michael B. , Fitzharris Bernie M. , McNeil Catriona M. , Hill Andrew G , Ribas Antoni , Atkins Michael B. , Thompson John A. , Hwu Wen-Jen , Hodi F. Stephen , Menzies Alexander M. , Guminski Alexander David , Kefford Richard , Shu Xinxin , Ibrahim Nageatte , Homet Moreno Blanca , Long Georgina V. 
Published: September 2018

9545 Background: We previously showed that standard-dose pembro plus reduced-dose ipi has manageable safety and robust antitumor activity in patients (pts) with advanced melanoma. Here, we present more mature data, including 1-y landmark PFS and OS estimates. Methods: In the phase 1 KEYNOTE-029 expansion cohort (NCT02089685), pts with advanced melanoma, ECOG PS 0-1, no active brain metastases, and no prior immune checkpoint inhibitor therapy received pembro 2 mg/kg Q3W + ipi 1 mg/kg Q3W for 4 doses, then pembro alone for up to 2 y. Primary end point was safety. Efficacy end points were ORR, PFS, and DOR per RECIST v1.1 by independent central review and OS. Results: 153 pts were enrolled between Jan 13, 2015, and Sep 17, 2015. Median age was 60 y, 66% were male, 25% had elevated LDH, 56% had stage M1c disease, 36% were BRAFV600mutant, and 13% received ≥1 prior therapy. As of Oct 17, 2016, median follow-up was 17 mo, and 64 (42%) pts remained on pembro. 110 (72%) pts received all 4 ipi doses. There were no treatment-related (TR) deaths. TRAEs occurred in all pts, were grade 3/4 in 69 (45%), and led to discontinuation of pembro and ipi in 17 (11%), ipi alone in 11 (7%), and pembro alone after ipi completion or discontinuation in 19 (12%). PD occurred in 1/11 pts who discontinued ipi alone and 4/17 pts who discontinued ipi and pembro. Of the 11 pts who discontinued ipi alone for a TRAE, 0 experienced recurrence of the same TRAE during pembro monotherapy and 2 discontinued pembro for a different TRAE (both elevated lipase). Immune-mediated AEs occurred in 90 (59%) pts and were grade 3/4 in 39 (25%). With 7 mo additional follow-up, there were 6 additional responses for an ORR of 61% (95% CI, 53%-69%); the CR rate increased from 10% to 15%. Median DOR was not reached (range, 1.6+ to 18.1+ mo), with 86/93 responders (92%), including 23/23 (100%) with CR, alive and without subsequent PD at cutoff. Median PFS and OS were not reached; 1-y estimates were 69% for PFS and 89% for OS. Conclusions: Pembro 2 mg/kg plus 4 doses of ipi 1 mg/kg has a manageable toxicity profile and provides robust, durable antitumor activity in pts with advanced melanoma. Clinical trial information: NCT02089685.
A phase I trial of panobinostat with ipilimumab in advanced melanoma.
Authors: Khushalani Nikhil I. , Markowitz Joseph , Eroglu Zeynep , Giuroiu Iulia , Ladanova Viktoriya , Reiersen Pamela , Rich Jeani , Thapa Ram , Schell Michael J. , Sotomayor Eduardo M. , Weber Jeffrey S. 
Published: September 2018

9547 Background: Immune checkpoint blockade is standard therapy for advanced melanoma (MEL), yet not all patients (pts) benefit. Panobinostat (PAN), a pan inhibitor of class I, II, and IV histone deacetylases (HDAC) is immunomodulatory, decreases tumor associated inhibitory cytokines and inhibition of effector T-cells. This dose finding study aimed to determine the safety and efficacy of escalating doses of PAN combined with ipilimumab (IPI) in advanced MEL. Methods: Eligible pts with unresectable stage 3/4 MEL, up to 3 prior lines of therapy, and adequate laboratory values were treated with oral PAN 5mg thrice weekly (TIW) plus IPI at 3mg/kg IV every 3 weeks X 4 doses, followed by maintenance PAN until progression or intolerance. Using a modified Ji design, PAN dose escalation by 5mg was planned in 3-12 pt cohorts up to a maximum dose of 20mg TIW, without intra-pt dose escalation. Dose limiting toxicity (DLT) was assessed up to day 84 from start of therapy. Results: Seventeen pts (M/F: 13/4), median age 66 yrs (48, 80) were treated with a median of 4 cycles of IPI (1,4). Of 6 pts treated at PAN 5mg TIW, there was one DLT (G3 hydronephrosis). Eleven pts received PAN 10mg TIW; of 9 evaluable for DLT, there were 3 DLTs (G3 rash, G3 diarrhea, G4 thrombocytopenia) preventing further dose escalation. Other G3 toxicities included anemia, hypophysitis, diarrhea, fatigue (all n = 2); rash, colitis, nausea, dehydration, dizziness, hypotension, ↑ lipase, ↓ sodium, & ↑ glucose (all n = 1). Three pts had previous anti-PD1 therapy. The response rate was 12% (2 PRs) with 35% stable disease. One pt remains on PAN > 24m since start of therapy. Median progression free- and overall survival was 2.23m (95% CI,1.57, 5.8) and 20.97m (95% CI, 8.97, NR) respectively. Biomarker analysis from peripheral blood and limited tumor biopsies pre-and on treatment examining immunoregulatory markers, including EOMES promoter acetylation in T-cells from PAN are ongoing. Conclusions: At tolerated doses, PAN does not appear to increase response to standard IPI in advanced MEL. Biomarker analyses will inform if immunomodulation by PAM improves efficacy of IPI. Combinations with selective HDAC inhibitors may be more appropriate for future study. Supported by grant P50 CA168536, Moffitt Skin Cancer SPORE. Clinical trial information: NCT02032810.
Surveillance imaging with FDG-PET/CT in the post-operative follow-up of stage 3 melanoma.
Authors: Sayers Louise , Lewin Jeremy Howard , Kee Damien , Walpole Imogen , Sanelli Alexandra , Herschtal Alan , Spillane John , Gyorki David E. , Speakman David , Estall Vanessa , Donahoe Simon , Pohl Miklos , Pope Kathy , Chua Margaret , Sandhu Shahneen Kaur , McArthur Grant A. , McCormack Christopher , Henderson Michael A. , Hicks Rodney J , Shackleton Mark J. 
Published: September 2018

9563 Background: With the evolving treatment landscape in metastatic melanoma, approaches to disease surveillance post resection in stage 3 disease requires reconsideration. We previously reported the outcomes of sub-stage-specific schedules of combined fluorodeoxyglucose-positron emission and computerized tomography (PET/CT) surveillance at high risk of relapse following surgery. The aim of this study was to provide an update on our surveillance protocol with an extended sample size and longer duration of follow-up. Methods: From 2009, patients with AJCC stage 3 melanoma underwent PET/CT scans according to pre-specified schedules based on Bayesian probabilities of sub-stage-specific relapse. Schedules were stage 3A: 6, 18 mo; stage 3B: 6, 12, 18, 24, 36, 48, 60 months; stage 3C: 6, 12, 18, 24, 36 months. Contingency tables were used to evaluate the sensitivity, specificity and predictive values of these schedules. Results: In total, 171 patients (3A: 34; 3B: 93; 3C:44) underwent 553 PET/CT scans with a median follow up of 47 months. Relapses were identified in 65 (38%) patients of which (72%) were asymptomatic at the time of radiologically documented relapse. False positive results occurred in 8%. The positive predictive value (PPV) of an individual scan for diagnosing true recurrence was 77% (64-87%). Negative scans at 6 months had negative predictive values (NPV) between 57% in Stage 3A to 69% in Stage 3B for relapse. Sensitivity and specificity of the overall approach of sub-stage-specific PET/CT surveillance for detecting disease relapse were 70% and 89%, respectively. Evaluable predictive values for detecting disease relapse were: stage 3A: PPV:56%, NPV:76%; 3B: PPV 83%, NPV 86%; stage 3C: PPV 84%, NPV 84%. 32 of 65 patients (49%; 3A: 1; 3B: 7; 3C: 2) underwent resection of relapsed disease and 10 of these patients remained free of disease with a median follow-up of 24 months. Conclusions: Sub-stage-specific PET/CT is effective in detecting asymptomatic recurrence in stage 3 melanoma, and is associated with a high rate of disease resection at relapse.
Clinicopathologic features and survival in immunocompromised vs. immunocompetent patients with Merkel cell carcinoma: An exploratory analysis of a series of consecutive patients.
Authors: Del Rosario Michael , Anderson Eric , Lu Yani , Farrell Stephanie , Plaxe Steven C. , Dasanu Constantin 
Published: September 2018

9568 Background: Clinicopathologic characteristics and outcomes between immunocompromised and immunocompetent Merkel cell carcinoma (MCC) patients may differ. Methods: With approval of IRB, we conducted retrospective analysis in 40 consecutive patients with MCC treated at our institution in 2006-2016. 10 patients were immunocompromised and 30 immunocompetent. Immunosuppressed patients included patients with organ transplantation (n = 3), chronic lympocytic leukemia (n = 2), metastatic skin cancer post chemotherapy (n = 1), rheumatoid arthritis on azathioprine (n = 1), myasthenia gravis on mycophenolate mofetil (n = 1), follicular lymphoma post chemotherapy (n = 1) and human immunodeficiency virus infection (n = 1). Clinicopathologic features, therapy and survival were compared between two cohorts. Significance of associations was assessed via Fishers' exact test. Survival analysis was performed via Cox proportional model and 95% confidence intervals (CI). Results: Compared to immunocompetent MCC patients, the immunocompromised had an absolute male predominance (100% vs. 67%; p < 0.01), more TNM stage III disease (40% vs. 33%; p = 0.021) but less lymphovascular invasion (30% vs. 7%; p < 0.01). They received more chemotherapy (50% vs. 30%; p < 0.01) and radiation therapy (80% vs 57%; p < 0.01). Survival was worse in immunocompromised subjects (average time to death 290.13 days vs. 618.2 days (p < 0.001), and they were 5 times more likely to die (RR = 5.01, 95% CI = 1.49-16.86). Conclusions: Immunocompromised MCC patients displayed significantly shorter survival than their immunocompetent counterparts. They were all male, with more advanced disease but less lymphovascular invasion. They received more chemo- and radiotherapy presumably due to a more advanced stage. As our study is limited by sample size, larger studies are needed to confirm the significance of our findings.
Performance of a 31-gene expression profile (GEP) test for metastatic risk prediction in cutaneous melanomas (CM) of the head and neck.
Authors: Vetto John T. , Leachman Sancy Ann , Middlebrook Brooke , Covington Kyle R. , Wayne Jeffrey D. , Gerami Pedram , Zager Jonathan S. 
Published: September 2018

9576 Background: Accurate prognostication of distant metastatic risk using sentinel lymph node (SLN) biopsy for CM can be challenging in melanomas of the head and neck due to a higher false negative rate compared to other anatomical areas. A GEP signature that predicts metastatic risk based on primary tumor biology, providing a binary outcome of Class 1 (low risk of metastasis) or Class 2 (high risk), was previously described. The prognostic capabilities of the GEP independently and in combination with SLN status in a cohort of patients with primary head and neck CM are assessed here. Methods: All samples and clinical data were collected under an IRB-approved multicenter protocol. qPCR analysis was used to assess expression of the gene signature (Class 1 vs. Class 2). Distant metastasis-free survival (DMFS) and melanoma-specific survival (MSS) were assessed. Results: 157 subjects with primary CMs in the head and neck region were identified. 110 of 157 subjects had a SLN biopsy performed. Median age was 65 years (range 25-89) and median Breslow depth was 1.6 mm (range 0.2-15.0 mm). In 71 SLN-negative patients, 18 of 27 (67%) distant metastatic events were GEP Class 2. Overall, 73% (47 of 64) distant metastases, and 88% (22 of 25) deaths due to CM were called Class 2. By comparison, sensitivities for DMFS and MSS were 41% (26 of 64) and 52% (13 of 25), respectively, using SLN biopsy alone, and increased to 80% (51 of 64) and 88% (22 of 25), respectively, when combining the SLN status and GEP class. Kaplan-Meier 5-year DMFS and MSS rates based on SLN status alone or in combination with GEP are shown in the table. Conclusions: These data support the ability of the GEP test to accurately identify low- and high-risk cases of head and neck melanoma. The results strongly support the role of GEP testing to enhance current staging by better predicting the risk of distant metastasis and death for patients with melanoma in an anatomic region that is associated with a higher SLN biopsy false negative rate. [Table: see text]
Neoadjuvant ipilimumab + nivolumab (IPI+NIVO) in palpable stage III melanoma: Updated data from the OpACIN trial and first immunological analyses.
Authors: Rozeman Elisa A. , Blank Christian U. , Van Akkooi Alexander Christopher Jonathan , Kvistborg Pia , Fanchi Lorenzo , Van Thienen Johannes V. , Stegenga Bauke , Lamon Brian , Haanen John B. A. G. , Schumacher Ton 
Published: September 2018

9586 Background: The combination of IPI+NIVO induces high response rates and improved overall survival in late stage melanoma. T cell checkpoint inhibition is of greatest value at the moment of TCR triggering and therefore dependent on the amount of antigen present, indicating that adjuvant immunotherapy may work most efficiently, when initiated prior to surgery. Methods: Two-arm Phase 1b feasibility trial of 20 high risk AJCC stage IIIB and IIIC melanoma patients with palpable nodal disease receiving the combination of IPI 3mg/kg and NIVO 1mg/kg, either adjuvant four courses after surgery, or split two courses neo-adjuvant and two courses adjuvant. Results: In this update all 20 patients are evaluable. Neo-adjuvant application of IPI+NIVO was feasible and no surgery-associated adverse events were attributed to (neo-)adjuvant therapy. 18/20 patients had to stop early due to grade 3/4 toxicities. Neo-adjuvant IPI+NIVO reduced tumor load in 8/10 patients (3 pCR, 4 near-pCRs [minimal remaining micrometastases], 1 pPR [75% reduction], 1 SD and 1 PD). To date, after a median follow-up of 45 weeks (range 13-74), none of the responders in the neoadjuvant arm has relapsed. Relapse was observed for both non-responders within the neo-adjuvant arm and for 3 patients within the adjuvant arm. TCR sequencing and MHC tetramer-based analysis to compare the induction and expansion of tumor (neo-)antigen-specific T cell responses between both treatment arms are underway and will be presented. Conclusions: The combination of IPI+NIVO in the (neo-)adjuvant treatment setting for high risk stage III melanoma patients is feasible and induces very frequent responses. At the same time, severe grade 3/4 toxicity is more frequent than expected from stage IV melanoma patient study data. These results indicate that IPI+NIVO is a promising combination for neo-adjuvant treatment in stage III melanoma. Adjusted combination schemes are currently tested in the phase 2 OpACIN-neo trial, with the aim of reducing toxicity while preserving efficacy. Clinical trial information: NCT02437279.