bluuebunny/crossref_metadata_2025 huggingface dataset:
Blood mRNA signature to predict survival in patients with metastatic melanoma treated with tremelimumab.
Authors: Saenger Yvonne M. , Magidson Jay , Liaw Bobby Chi-Hung , Wassmann Karl , Barker William , Harcharik Sara , Fisher David , Oh William K. , Friedlander Philip
Published: March 2020

9080

Background: Tremelimumab (Ticilimumumab, Pfizer), a monoclonal antibody targeting CTLA-4, a T cell inhibitory molecule, has shown activity in metastatic melanoma. Ipilimumab (Yervoy, BMS), another antibody targettingCTLA-4, improves survival relative to a peptide vaccine and is now FDA approved. A minority of patients will achieve durable tumor control with CTLA-4 blockade and biomarkers are urgently needed to identify those patients. Methods: 170 inflammatory, melanoma-specific and CTLA4-pathway related mRNA transcripts were measured using RT-PCR in pre-treatment peripheral blood samples from 218 patients with refractory melanoma receiving tremelimumab in a multi-center phase II study. A 2-class latent model yielded a risk score based on 4-genes that was highly predictive of survival (p<0.001), and was used to categorize patients into low, medium and high-risk groups. An independent cohort of 260 treatment naïve melanoma patients receiving tremelimumab as part of a multi-center phase III study was then used to validate the risk score as well as the 3 risk groups defined using the pre-specified cut-points. Results: There was no significant difference between the two cohorts in terms of age, gender, stage of disease or ECOG status. Median time of follow up was 297 days for the training cohort and 386 days for the validation cohort. 67% of patients in the training cohort and 70% of patients in the validation died during time of follow-up. Collectively, the ability of the 170 genes to predict survival exhibited a high degree of consistency across the cohorts (p < 0.001). A 4-gene model including cathepsin D (CTSD), Phopholipase A2 group VII (PLA2G7), Thioredoxin reductase 1 (TXNRD-1) and Interleukin 1 receptor associated kinase 3 (IRAK3) predicted survival in the validation cohort (p=0.001 by log rank test). Multivariable cox analysis showed that the 4-gene model added to the predictive value of clinical predictors (p<0.0001). Conclusions: Expression levels of CTSD, PLA2G7, TXNRD1, and IRAK3 in peripheral blood are predictive of survival in melanoma patients treated with ticilimumab (αCTLA-4). Blood mRNA signatures should be further explored to define patient subsets likely to benefit from immunotherapy.
Cetuximab with or without chemotherapy for recurrent, unresectable squamous cell carcinoma of the skin (SCCS).
Authors: Nadiminti Kalyan , Shao Ryan , Clamon Gerald H. , Wehbe Ahmad Mouhamad
Published: March 2020

9090

Background: With an increasing aging population and a growing number of people with organ transplant on immune suppression, patients presenting with locally advanced, unresectable and metastatic SCCS are on the rise. Options of therapy are limited to platinum or taxane doublets but the tolerability of these regimens is poor. Data regarding use of cetuximab in advanced SCCS is scarce and consists of a few case series and one phase II trial. The purpose of this study is to evaluate the use of cetuximab alone or in combination with chemotherapy in patients with SCCS treated at the University of Iowa Hospitals (UIHC). Methods: Patient data was compiled through medical record review of all patients diagnosed with locally recurrent, unresectable or metastatic SCCS seen at UIHC and treated with cetuximab alone or in combination with chemotherapy. Pathology was centrally reviewed. Results: A total of nine patients with SCCS received cetuximab as part of a definitive or palliative therapy with a loading dose of 400 mg/m2 followed by weekly 250mg /m2.Median age of patients is 64. Four patients had locally recurrent or unresectable disease, and five had distant metastases. Three patients had prior history of organ transplant. Chemotherapy included carboplatin AUC 5 with 5 fluorouracil 1000mg/m2/day for four days in two patients and weekly paclitaxel 80mg/m2 in four patients. One patient received concurrent definitive radiation with 6600 cGy. In total, six patients completed at least 6 weeks of cetuximab. All these patients showed clinical improvement in pain, tumor ulcer and bleeding as compared to pretreatment. Median time to disease progression after stopping treatment was 3 months. Three patients could not complete 6 weeks of cetuximab due to disease progression. The most common side effect was skin rash and hypomagnesemia. Conclusions: Cetuximab alone or in combination with chemotherapy is well tolerated and does show promise in treatment of patients with unresectable or metastatic SCCS. Most common side effect was skin rash. A larger trial with longer follow up is warranted to establish the role of cetuximab and an optimal combination therapy in improving quality of life in this patient population.
Targeting BET proteins in melanoma: A novel treatment approach.
Authors: Paoluzzi Luca , Segura Miguel F. , Fontanals-Cirera Barbara , Gaziel-Sovran Avital , Guijarro Maria V , Hanniford Douglas , Gonzales-Gomez Pilar , Zhang Weijia , Zhang Guantao , Darvishian Farbod , Ohlmeyer Michael , Osman Iman , Zhou Ming-Ming , Hernando Eva
Published: March 2020

9091

Background: Manipulation of key epigenetic regulators in melanoma proliferation is emerging as a new therapeutic strategy. Bromodomain-containing proteins such as the extraterminal domain (BET) family are components of transcription factor complexes and determinants of epigenetic memory. We investigated the expression of BRD4, a BET family member in melanoma cell lines and tissues, and the effects of its inhibition with the small molecule compounds MS436 and MS417 in in vitro and in vivo models of melanoma. Methods: BRD2 and BRD4 expression were analyzed by immunohistochemistry. We tested the effects of pharmacological or RNAi-mediated inhibition of BRD4 in melanoma cells using crystal violet-based assays for proliferation/colony formation and flow-cytometry for cell cycle analysis. The molecular effects of BRD4 suppression were examined using RNA sequencing, Real-Time quantitative PCR and western blots for p27, p21, MYC, ERK1 and SKP2. In the in vivo xenograft experiments NOD/SCID/IL2γR-/-mice were injected with melanoma cells and treated with MS417. Statistical significance was determined by unpaired t-test (GraphPad). Results: BRD4 was found significantly upregulated in primary and metastatic melanoma tissues compared to melanocytes and nevi (p<0.001). Treatment with BET inhibitors impaired melanoma cell proliferation in vitro and tumor growth and metastatic behavior in vivo, effects that were mostly recapitulated by individual silencing of BRD4. Rapidly after BET displacement, key cell cycle genes (SKP2, ERK1 and c-MYC) were downregulated concomitantly with the accumulation of CDK inhibitors (p21, p27), followed by melanoma cell cycle arrest. BET inhibitor efficacy was not influenced by BRAF or NRAS mutational status. Conclusions: Our results demonstrate for the first time a role for BRD4 in melanoma maintenance and support the role of BET proteins as novel targets in melanoma. Further investigation in the clinical setting is warranted.
Assessment of absolute lymphocyte count (ALC) as a predictor of progression-free survival (PFS) and overall response rate (ORR) in metastatic melanoma (MM) patients (pts) treated with high-dose interleukin-2 (HD IL-2).
Authors: Yorio Jeffrey Thomas , Fox Patricia S , Joseph Richard Wayne , Bassett Roland , Davies Michael A.
Published: March 2020

9096

Background: HD IL-2 is an approved immunotherapy that can achieve durable cures in MM pts. Due to toxicity and low ORR, identification of predictors of clinical benefit would enhance pt selection and outcomes with HD IL-2. Recent research identified a positive correlation for ALC ≥ 1000 (either at baseline or at dose 3) with OS among MM pts treated with the immunotherapy agent ipilimumab. We tested the hypothesis that ALC (≥ 1000) or other hematological parameters correlates with clinical benefit from HD IL2. Methods: Results of hematologic testing in patients (n=98) treated with HD IL2 at MD Anderson Cancer Center were collected, including absolute levels of neutrophils (ANC), lymphocytes (ALC), monocytes (AMC), eosinophils (AEC), and platelets (APC) at baseline, after cycle 1 (C1), and after cycle 2 (C2) of HD IL-2; changes in each parameter for each interval were also calculated. Hematologic values were assessed as categorical (for ALC, ≥ 1000 Yes/No; other parameters, above upper limit of normal [ULN] Yes/No) and continuous variables. Associations between these parameters and PFS and ORR were analyzed. Results: ALC was≥ 1000 in 75 pts (76%) at baseline, in 81 (83%) after C1, and in 80 of 86 pts (93%) after completion of C2 of HD IL-2. PFS was not significantly associated with ALC ≥ 1000 at baseline (HR 0.69, p=0.13), after C1 (HR 1.32, p=0.33), or after C2 (HR 1.01, p=0.98). ALC ≥ 1000 at each timepoint was not significantly associated with ORR or OS. There was no significant difference in the change in ALC with HD IL2 treatment among responders versus non-responders. Among baseline hematological factors, APC > ULN was significantly associated with PFS (p=0.001), but it was rare (2/98 patients). Exploratory analyses identified significantly shorter PFS for patients with baseline APC > 300 (11%, HR 2.75, p=0.002). Analysis of hematologic factors as continuous values identified significant associations with PFS for AMC (HR 2.42, p=0.03) and AEC (HR 1.73, p=0.009) after C2. Conclusions: ALC ≥ 1000 did not correlate with PFS, ORR, or OS with HD IL-2 therapy in this cohort of metastatic melanoma pts.
Analysis of stage of melanoma diagnosis in relation to insurance type and income as indicator of early/late diagnosis.
Authors: Lamie Peter Makram
Published: March 2020

9099

Background: This study compares the average stage of diagnosis for melanoma by insurance status and household income. This is the largest such study for melanoma to date. Methods: Using the National Cancer Database we examined 299K patients with melanoma between 2000 and 2009 at 1,408 hospitals. The relationship of average stage of diagnosis is compared across insurance types and by income for 293K patients. Results: The VA patients had the lowest average stage of diagnosis 0.8 with the Medicaid population exhibiting the highest 1.8. The VA was lower than Tricare which had an average diagnosis of 1.1, private insurance 1.2, Medicare 1.3, and uninsured 1.7. The lowest rate of stage IV was private insurance 3.3%, Tricare 3.6%, VAH 4.4%, Medicare 5.7%, uninsured 10%, and the highest rate was among Medicaid 14.3%. The highest income category ≥$49K had the lowest average stage at diagnosis of 1.1 compared to $39K to $48K 1.2, $33K to $38K 1.3, $28K to $32K 1.4, and <$28K had the highest average stage of diagnosis 1.4. Stage IV rate increased from the highest income 3.6%, $39K to $48K 4.6%, $33K to $38K 5.1%, $28K to $32K 5.8%, and <$28K 6.9%. Data available. Conclusions: VA, higher income and private insurance had earlier stage of melanoma compared to uninsured and Medicaid who had higher frequency of stage IV disease. [Table: see text]
Survival and long-term follow-up of safety and response in patients (pts) with advanced melanoma (MEL) in a phase I trial of nivolumab (anti-PD-1; BMS-936558; ONO-4538).
Authors: Sznol Mario , Kluger Harriet M. , Hodi F. Stephen , McDermott David F. , Carvajal Richard D. , Lawrence Donald P. , Topalian Suzanne Louise , Atkins Michael B. , Powderly John D. , Sharfman William Howard , Puzanov Igor , Smith David C. , Wigginton Jon M. , Kollia Georgia , Gupta Ashok Kumar , Sosman Jeffrey Alan
Published: March 2020

CRA9006^

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Saturday, June, 1, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
Multicenter, randomized phase II trial of GM-CSF (GM) plus ipilimumab (Ipi) versus ipi alone in metastatic melanoma: E1608.
Authors: Hodi F. Stephen , Lee Sandra J. , McDermott David F. , Rao Uma N. M. , Butterfield Lisa H. , Tarhini Ahmad A. , Leming Philip D. , Puzanov Igor , Kirkwood John M. ,   Eastern Cooperative Oncology Group
Published: March 2020

CRA9007

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Saturday, June, 1, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
Concurrent bevacizumab (BEV) with biochemotherapy (BC) followed by ipilimumab for advanced melanoma: A phase I-II trial.
Authors: Minor David R. , Wang Wei , Kashani-Sabet Mohammed
Published: March 2020

e20001

Background: Decrescendo biochemotherapy (BC) has become a common regimen for advanced melanoma; however only a minority of patients are long term survivors, and 6 cycles of BC may be complicated by severe neuropathy, asthenia, and other toxicities. The BEAM trial (JCO 30: 34-41, 2012) suggested that BEV added to chemotherapy improved response rate and survival. We felt BEV might improve the efficacy of biochemotherapy, and wanted to explore the feasibility of sequential ipilimumab to improve duration of response. Methods: 24 patients with advanced metastatic melanoma (79% stage M1C) were treated with temozolomide 150mg/m2,cisplatin 20mg/m2, vinblastine1.2mg/m2 all days1-4, IL-2 36miu day1, 18miu day2, 9miu days 3-4, and interferon 5miu/m2 d1-5 with BEV 15mg/kg q21d patients1-6 and BEV 7.5mg/kg patients 7-24 After 4 cycles of BC patients received ipilimumab at 3mg/kg. Results: 6 patients received BEV at 15mg/kg. Two had dose-limiting toxicities: one with brain metastases had CNS hemorrhage and one (thrombocytopenic) had gastrointestinal hemorrhage. Per protocol the next 18 patients received BEV at 7.5 mg/kg q 21d. One patient had posterior reversible encephalopathy syndrome but no other unusual toxicities were seen either with the BEV-biochemotherapy or the ipilimumab phase. Responses (3CR, 6 PR) were seen in 45% of 20 evaluable patients with cutaneous melanoma. Median PFS was 7 months and overall survival 12 months; these results are similar to BC alone. (Oncologist, Oct. 14 (10) 995-1002, 2009). Conclusions: Bevacizumab at 7.5mg/kg q 21days can be safely added to 4 cycles of decrescendo biochemotherapy. Further study of this combination is justified. Clinical trial information: NCT01743157.
A phase I/I b study of GSK1120212 (trametinib) alone and in combination with gemcitabine in Japanese patients with advanced solid tumors.
Authors: Kurata Takayasu , Furuse Junji , Okamoto Isamu , Kasuga Akiyoshi , Fujisaka Yasuhito , Kitamura Hiroshi , Shimizu Toshio , Takasu Atsuko , Okamoto Wataru , Naruge Daisuke , Nagashima Fumio , Katsura Koichi , Mukaiyama Akihira , Matsushita Hideki , Nakagawa Kazuhiko
Published: March 2020

e20004

Background: Trametinib is a potent and selective allosteric MEK1/2 inhibitor. In Western countries, trametinib was investigated as monotherapy and in combination with various agents including gemcitabine in the studies with pancreatic cancer, melanoma and other types of cancer. According to these studies, the recommended dose (RD) and maximum tolerated dose (MTD) were determined as 2.0 mg QD and 3.0 mg QD respectively as monotherapy, and as 2.0 mg QD for both in combination with gemcitabine. The objectives of this study are to assess its tolerability and safety, and to evaluate the RD and the MTD in Japanese patients (pts). Methods: This open-label, dose-escalation study evaluated the tolerability/safety, pharmacokinetics (PK), and preliminary efficacy (RECIST) of trametinib alone (part 1) and in combination with gemcitabine (1000 mg/m2on Days 1, 8, and 15 of each 28-day cycle) (part 2) in Japanese pts with advanced solid tumors (NCT01324258). After confirming the tolerability and safety in part 1, part 2 was investigated. Results: (Part 1) Thirteen pts received trametinib at doses of 1.0 mg (n=4), 2.0 mg (n=6), and 3.0 mg (n=3). Various cancer types including melanoma were enrolled. One DLT (Grade 3 infectious pneumonia) was observed in part 1 in a subject at the 2.0 mg dose. The most common AE was Grade 1/2 rash (n=12). One PR (salivary gland cancer) and 3 long SDs (appendix cancer (n=1) and melanoma (n=2)) were observed. Preliminary PK results showed no obvious ethnic difference. (Part 2) Five pts with pancreatic cancer received trametinib (2.0 mg QD) in combination with gemcitabine. Although there was no DLT in the first 28 days (DLT observation period), interstitial lung disease (ILD) was observed in 3 pts after DLT observation period. Best responses were 3 PRs and 2 SDs. Conclusions: The RD (2.0 mg QD) and the MTD (3 mg QD) of trametinib that were determined in Western countries were tolerated in Japanese patients as monotherapy. In combination with gemcitabine, although trametinib was tolerated in the short term and showed promising antitumor efficacy, it is required to closely monitor patients for ILD while the combination is administered to patients. Clinical trial information: NCT01324258.
Spanish Melanoma Multidisciplinary Group (GEM): Long-term survivors treated with ipilimumab (IPI) in the expanded access programme (EAP).
Authors: Hernando Cristina , Soriano Virtudes , Berros Jose Pablo , Arance Ana Maria , Mujika Karmele , Rodriguez Abreu Delvys , Alonso Lorenzo , Alonso Martina , Yapur Lorena , Berrocal Alfonso ,   Grupo Español Multidisciplinar de Melanoma
Published: March 2020

e20007

Background: Advances in metastatic melanoma treatment have demonstrated improvement in survival. After 5 year follow-up of clinical trials with IPI, LTS have been reported. Current follow-up of patients treated within IPI EAP in Spain is 2 years. Methods: we performed a retrospective subgroup analysis of 138 treated patients (pts) within the IPI not randomized EAP (48% of the total EAP population). LTS were defined as pts with ≥ 12 months overall survival (OS). Pts were treated with IPI at 3 mg/kg q 3 w x 4. Data was registered using a socio-demographic and therapeutic questionnaire, collecting overall response (RR), survival (OS) and toxicity (T). Results: In our analysis of138 treated pts 39 were LTS (28.2%), 14 pts were alive at 12 months (M), 12 pts between 13-19 m and 7 pts 20-24m, for all this patients the follow up continues. Median age was: 56.5 (30-81). Gender: Male 48.7%. Stage: IVa 25.6%, IVb 17.9%, IVc 56.8%. Primary tumor site: skin 56.4%; accral 12.8%; mucosal 10.3%; ocular 10.3%; rest unknown. Metastases (mts): soft tissue 38.5%, lung 33.3%, visceral 28.2%. Median number of prior treatments: 1 (1-5), 20.5% received more than one chemotherapy (chx) line. 92.3% of total pts population have completed the induction schema (4 IPI doses). Response assessment: CR 15.4%; PR 38.5%; SD 33.3%; P 12.8%. Mean duration of response: 10.6m. Mean survival: 16.6m. 56.4% received thx after IPI, in those pts 41% received chx; 17.9% radiotherapy; 12.9% B-RAF inhibitor. 18 pts (46.2%) presented T: 12.8% Grades (G) 3-4 were reported; 23.1% G2; 7.7% G1. The most frequent T was cutaneous (17.9%). When compared with the overall EAP pts population LTS have less visceral disease, lower median LDH, more objective responses and completion of the four induction ipilimumab doses. Conclusions: Ipilimumabin the Spanish EAP experience in pretreated patients has shown to improve long term survival similar to that seen in studies in patients with advanced melanoma. Further research and analysis are needed to identify the patient population most likely to achieve a long term survival benefit with ipilimumab treatment.
Ocular melanoma liver metastases treated by percutaneous hepatic perfusion with melphalan followed by ipilimumab: A case report.
Authors: Idris Ahmad Fitri , Martin Michael John , Davidson Ian R , O'Sullivan Gerard J , Jamaludin Ahmad A , Donnellan Paul P.
Published: March 2020

e20008

Background: Patients with unresectable liver metastases from ocular melanoma have a poor prognosis with just 10% surviving 1 year with standard treatments. High-dose melphalan via percutaneous hepatic perfusion (PHP) and filtration system (ChemoSat, Delcath Inc.) is licensed in Europe for treatment of liver-only metastases from ocular melanoma and neuroendocrine tumours. Ipilimumab (Ipi), anti-CTLA4 immunotherapy is licensed in US and Europe for treatment of metastatic malignant melanoma. A 32-year-old man was referred to our unit with unresectable liver metastases from primary ocular melanoma treated 8 years earlier. Here we describe the first report of sequential ChemoSat and Ipi in this setting. Methods: With assistance of an international proctoring team, and following on-site training, we treated this patient with ChemoSat according to manufacturer’s instructions (details at meeting). There were no immediate complications or subsequent hematological or other systemic chemotherapy side-effects. On day 4, the patient developed acute epigastric pain, pyrexia, ST elevation, and elevated troponin. Cardiac ECHO, coronary angiogram, CT pulmonary angiogram, abdominal USS and gastroscopy were normal. Blood cultures were repeatedly negative. He developed acute kidney injury secondary to intravenous contrast and NSAIDs. Repeat abdominal USS showed a thickened wall of gall bladder. A diagnosis of acute chemical cholecystitis was made. His symptoms settled, kidney function improved and he was discharged on day 23 of procedure. 10 weeks post ChemoSat the patient underwent treatment with Ipi 3mg/kg i.v. day 1, q 3/52 x 4 cycles which he received without significant side-effects. Results: MRI scan of liver 8 weeks post-ChemoSat (pre-Ipi) showed the liver lesions to be unchanged. CT scan 6 weeks post-Ipi treatment showed significant improvement. Conclusions: ChemoSat treatment is feasible and safe but can cause unexpected gall-bladder toxicity. Subsequent treatment with ipilimumab seems to be effective in this single case with short-term follow up.
BKM120 combined with vemurafenib in vemurafenib-refractory BRAF mutant metastatic melanoma: Two cases.
Authors: Algazi Alain Patrick , Posch Christian , Ortiz-Urda Susana , Cockerill Alyson , Munster Pamela N. , Daud Adil
Published: March 2020

e20010

Background: PTEN loss and PI3K activation are common in BRAF mutant metastatic melanoma, and PI3K activation has been implicated as a cause of acquired resistance to BRAF inhibitors. Two vemurafenib refractory were treated with the potent BRAF inhibitor, vemurafenib, and the pan-class I PI3K inhibitor BKM120. Methods: The study enrolled BRAF-V600E/K mutant metastatic melanoma patients with an ECOG PS ≥ 2 and adequate organ function. Vemurafenib refractory BRAF-V600E/K mutant melanoma patients started both vemurafenib twice daily and BKM120 daily on cycle 1, day 1 after a vemurafenib washout of at least 14 days. Serial biopsies prior to treatment, on cycle 1 day 15, and at progression were obtained for pharmacodynamics analysis in patients with visible or palpable tumors. Results: 3 BRAF inhibitor refractory patients were treated on study with vemurafenib 720 mg PO bid and BKM120 60 mg PO daily. One patient was inevaluable due to non-compliance and had minimal exposure to study drug. Pre-treatment biopsy specimens were available in the remaining 2 vemurafenib-refractory patients. Both patient expressed PTEN at baseline and had demonstrable pAKT and pS6 staining. One patient had a mixed response to treatment with a 35.9% reduction in target lesions and two new small subcutaneous lesions. This patient also developed dose limiting febrile neutropenia on trial. The second patient tolerated treatment well but had widespread disease progression at 8 weeks. Conclusions: Combination therapy with vemurafenib and BKM120 in BRAF-V600E/K mutant melanoma led to substantial regression of several tumors in a PTEN+ patient with prior disease progression on vemurafenib alone. A phase I dose escalation trial in ongoing. Clinical trial information: NCT01512251.
Effect of Melan-Α/Μart-1-peptide vaccination plus IMP321 on antitumor immunity and clinical benefit in patients receiving autologous PBMCs after lymphodepletion.
Authors: Romano Emanuela , Bichat Helene , Stravodimou Athina , Romero Pedro , Daniel Speiser E , Triebel Frederic , Michielin Olivier , Harari Alexander , Leyvraz Serge
Published: March 2020

e20011

Background: Immunotherapy offers great promise for cancer treatmet. Strong evidence supports adoptive cell transfer (ACT) and immunemodulation for regression of advanced melanoma. Few studies assessed the potential synergy between these two strategies. Methods: Twelve patients with metastatic melanoma received multiple Melan-A/Mart-1-peptide vaccinations with (n=6) or without (n=6) IMP321 (LAG-3Ig fusion protein) as an adjuvant in combination with lymphodepleting chemotherapy and ACT. All patients were selected on the basis of ex vivo detectable Melan-A-specific CD8 T cell responses and were immunized at day (D) 0, 8, 15, 22, 28, 52, and 74 post-reinfusion. Results: One-week after reinfusion of bulk autologous PBMCs, a significant expansion of Melan-A-specific CD8 T cells was measured in >83% (n=5) and <17% (n=1) of patients from the IMP321 and control groups, respectively (p=0.02). Compared to the control group, the mean fold increase of Melan-A-specific CD8 T cells was respectively >2-, >4-, and >6-fold higher in the IMP321 group at D15, D30, and D60 (p=0.02). A long-lasting Melan-A-specific CD8 T-cell response was significantly associated with IMP321 (p<0.001). A higher proportion of Melan-A-specific CD8 TEMRA (i.e., CD45RA+CCR7-CD127-) cells was observed in the IMP321 group at the peak of the response (p <0.002), whereas no significant difference was observed in the expression of co-inhibitory receptors (i.e., PD-1, 2B4, TIM3, CD160). IMP321 was associated with a significantly (p<0.04) reduced expansion of regulatory T cells (TREGS); we observed a negative correlation between the fold increase of Melan-A-specific CD8 T cells and the relative expansion of TREGS. Clinical benefit (assessed as CR, PR, and SD) was observed in none of the control patients vs 67% (4/6) of patients from the IMP321 group, (p=0.02). Conclusions: Vaccination with IMP321 as an adjuvant in combination with lymphodepleting chemotherapy and ACT provided clinical benefit and this was associated with a more robust and durable cellular antitumor immune response, supporting further development of IMP321 for future immunotherapeutic strategies. Clinical trial information: NCT00324623.
Familial melanoma in Spain: Preliminary report of the FAM-GEM-1 study.
Authors: Martin-Gonzalez Manuel , Cerezuela Pablo , Martin-Carnicero Alfonso , Puertolas Teresa , Martin-Algarra Salvador , Gil-Arnaiz Irene , Maldonado-Seral Cayetana , Gonzalez Cao Maria , Belon Joaquin , Aviles Izquierdo Jose Antonio , Marquez-Rodas Ivan ,   Grupo Español Multidisciplinar de Melanoma
Published: March 2020

e20015

Background: In addition to environmental factors and phenotype, melanoma risk is determined by familial background. It is estimated that 5-10% of melanoma cases occur in a familial setting. High susceptibility genes like CDKN2A and intermediate risk like M1CR are the most known, but explain less than 1/3 of the cases, most of them cases with 2 or more first degree relatives involved, the classical definition for familial melanoma (FM). In Spain there are several local studies about epidemiology and characteristics of FM, but there are no studies that cover all the territory. Methods: FAM-GEM-1 is a national, observational, 2 years-registry study (2011-2013), conducted by the Spanish Multidisciplinary Melanoma Group (GEM), whose principal objective is to assess the rate of melanoma patients with family history of melanoma in Spain. Secondary objectives are to analyze whether patients with family history are different from sporadic melanoma in terms of clinical, pathological and molecular features; and to constitute a registry of FM in order to deeper characterise these patients in further studies. We present the exploratory results of the first 219 patients registered Results: See Table. Conclusions: We have found that almost 9% of patients have family history of melanoma. Of them, almost 3/4 fulfils familial melanoma criteria. It seems that there are not relevant differences among sporadic and familial melanoma in our registry, except for sex, although the preliminary nature of the results makes necessary more patients in order to determine if there are clinical and/or pathological differences between both groups. [Table: see text]
Comparison of mucosal and cutaneous melanoma in the head and neck region: Different clinical features and similar outcomes.
Authors: Ciftci Rumeysa , Keskin Serkan , Karabulut Senem , Yildiz Ibrahim , Kilic Leyla , Sen Fatma , Tastekin Didem , Tas Faruk
Published: March 2020

e20016

Background: Mucosal melanoma (MM) of head and neck (H&N) is a relatively rare and different disease from cutaneous melanoma (CM). We aimed to define clinical features and outcomes of patients with MM of H&N and to emphasize its differences from CM. Methods: The medical records of patients (n= 41 for MM, n=94 for CM) between 2000 and 2010 were assesed. Results: In MM group, 21 patients had primary oral cavity (OCM) and 20 had sinonasal melanoma (SNM). The median age was 60 years and gender distribution was similar. Thirty-two (78%) of patients had stage I, 4 (10%) had stage II, and 5 (12%) patients had stage III disease. One and 5-year overall survival (OS) rates were 81% and 58%, and similar for SNM and OCM (p=0.67). Among CM patients, primary sites were face (53%), scalp (28%) and ear region (19%). Facial melanoma (FM) patients were older (p=0.001) than scalp (SM) or ear melanoma (EM). Male gender was more frequent among SM patients (81%) than FM (42%, p=0.001) and EM (50%, p=0.03). Most of FM patients had localized disease (84%), while most of EM (72%) and SM (46%) patients had advanced disease. One and 5-year OS rates of CM were 86% and 43%, respectively. Five-year OS rates were 72% for FM, 27% for EM and 17% for SM (FM v SM, p<0.001; FM v EM, p=0,012; EM v SM, p=0.40). Advanced disease (stage III and IV) had significant impact on OS (p=0.001) for only SM patients. In addition, male patients with CM had poorer prognosis than female patients (p=0.034). However, age of patient did not affect OS. MM group was older (median 60 v 54 years, p= 0.008) and had a higher rate of localized disease than CM (78% v 65%, p=0.06). Advanced disease had a significant impact on OS for both MM and CM (p= 0.03). OS rates of CM and MM were similar (p=0.53). Conclusions: Melanoma of H&N region is a very heterogeneous disease. MM has different clinicopathologic features from CM. Primary site of melanoma in this region is also important for prognosis and biological behaviour of tumour. Therefore, approaches to these melanomas should be different.
A phase III trial of nab-paclitaxel versus dacarbazine in chemotherapy-naive patients (pts) with metastatic melanoma: Analysis of peripheral neuropathy.
Authors: Del Vecchio Michele , Hersh Evan , Brown Michael Paul , Clements Arthur , Loquai Carmen , Ferrucci Pier Francesco , Robert Caroline , Li Mingyu , Elias Ilena , Renschler Markus F. , Hauschild Axel
Published: March 2020

e20025

Background: Peripheral neuropathy (PN) is a common side effect associated with taxane treatment. In a phase III trial, nab-paclitaxel vs dacarbazine demonstrated a significant improvement in progression-free survival (4.8 vs 2.5 months; P = 0.044) and at the interim survival analysis, a trend toward prolonged overall survival (12.8 vs 10.7 months; P = 0.094) for the treatment of chemotherapy-naive patients with metastatic melanoma. Here we report on the PN profile of nab-paclitaxel in this phase III trial. Methods: Pts (median age, 63 years) with chemotherapy-naive stage IV melanoma (M1c stage, 65%; elevated LDH, 28%) and an ECOG performance status 0-1 were randomized to nab-paclitaxel 150 mg/m2 on days 1, 8, and 15 of a 28-day cycle (n = 264) or dacarbazine 1000 mg/m2on day 1 of each 21-day cycle (n = 265). PN events were defined based on the Standardized MedDRA Query (V 12.1, broad scope). Results: As expected, a higher proportion of pts receiving nab-paclitaxel vs dacarbazine had ≥ 1 treatment-related PN event (68% vs 8%; P < 0.001). Treatment-related grade ≥ 3 PN was more frequent with nab-paclitaxel vs dacarbazine (25% vs 0%; P < 0.001); 2 grade 4 events were reported in the nab-paclitaxel arm. Treatment-related grade ≥ 3 PN was 15% in pts who received up to the median of 3 cycles of nab-paclitaxel. PN led to dose reduction in 13% or discontinuation in 15% of nab-paclitaxel–treated pts. The median time to onset of grade ≥ 3 PN was 101 days (95% CI, 85 - 113). Most early-onset PN events, occurring within the first 3 cycles, were grade 1. Grade ≥ 2 PN events peaked by cycle 4 and subsided by cycle 9. Forty-one of the 64 (64%) pts with a grade ≥ 3 PN event had an improvement of ≥ 1 grade, with a median time to improvement of 28 days (95% CI, 17 - 64), and 33 of 64 (52%) pts had improved to grade 1 or better by a median of 67 days from onset (95% CI, 22- upper limit not estimable); 30 of 64 (47%) pts resumed treatment with nab-paclitaxel. Conclusions: In this phase III trial, grade ≥ 3 PN was the main treatment-related toxicity with nab-paclitaxel as observed in other studies. However, PN was rapidly reversible; a majority of pts had improvement of PN symptoms within 1 month and resumed treatment. Clinical trial information: NCT00864253.
Combination therapy with ipilimumab and electrochemotherapy: Preliminary efficacy results and correlation with immunologic parameters.
Authors: Simeone Ester , Benedetto Lucia , Gentilcore Giusy , Caraco Corrado , Di Monta Gianluca , Grimaldi Antonio M , Esposito Assunta , Capone Marilena , Marone Ugo Di , Curvietto Marcello , Madonna Gabriele Di , Di Cecilia Marialuisa , Mori Stefano Di , Mozzillo Nicola , Ascierto Paolo Antonio
Published: March 2020

e20031

Background: Ipilimumab is the first agent approved for the treatment of advanced melanoma that showed a survival benefit in randomized phase 3 trials. Despite the survival benefit, due to its mechanism of action it is associated with a slow onset and low rate of responses and, in many cases, responses occur after other therapies, like chemotherapy, targeted therapy and radiotherapy. Electrochemotherapy (ECT) has been shown to be effective and well tolerated for local control of metastatic melanoma with superficial lesions. The current challenge is to improve ipilimumab efficacy by combination/sequence with other therapies. We performed a pilot study of combination with ipilimumab and ECT in order to verify the possible increase of response rate. Furthermore, due to the lack of predictive markers, we evaluated the possible predictive role of circulating T-regulatory cells (T-Reg) variations in peripheral blood mononuclear cells (PBMC) of treated patients. Methods: We collected data from 10 patients (pts) with advanced melanoma (6 stage IIIc and 4 stage IV M1c) treated with ipilimumab at 3 mg/kg every 3 weeks for 4 cycles (day 1) and ECT with bleomycine at 15 mg/m2 (day 2) on superficial lesions. Blood draws were collected on day 0, 1 and 2, then on day 15 and 30 from ECT, at each cycle of ipilimumab and at every tumor evaluation (every 12 weeks). PBMC were thawed and labeled with anti-CD4-Pe-Cy-5, CD25-Pe and anti-FoxP3-AlexaFlour488 for T-Reg. Results: 10/10 (100%) pts showed local objective responses (4 CR and 6 PR). 7/10 (70%) pts showed local response (6 PR and 1 CR) after the second ipilimumab dose and 3/10 showed response (3 CR) at week 12. Two pts with PR (28%) out of the group of 7 showed response on distant lesions at week 24 (abscopal effect). All pts are still alive with a median follow up of 11 months (range 6-18). We found in all pts a decrease of T-Reg of 0.10% (range 0.50-2.6%) per cycle and no variation of CD4+ and CD25+ lymphocytes. Conclusions: Our preliminary results show that a combination approach with ipilimumab and ECT may increase responses to ipilimumab. T-Reg decrease in PBMC could be associated with response to treatment. Further studies about this combination are warranted.
Clinical characteristics of melanoma patients with non-V600E/K BRAF mutations.
Authors: Nowroozi Sasan , Zuo Zhuang , Patel Keyur , Patel Sapna Pradyuman , Luthra Rajyalakshmi , Routbort Mark , Lazar Alexander J. F. , Davies Michael A. , Hasanein Hassan , Papadopoulos Nicholas E. , Hwu Wen-Jen , Bedikian Agop Y. , Woodman Scott , Hwu Patrick , Kim Kevin
Published: March 2020

e20036

Background: BRAF mutations are found in ~50% of melanoma. V600E/K substitutions are the most common and well-characterized. We analyzed the clinical characteristics of patients with non-V600E/K BRAF mutations. Methods: We identified 38 melanoma patients whose tumor contained a non-V600E/K BRAF mutation and reviewed the clinical characteristics. The sequencing analysis was performed with either pyrosequencing or next generation sequencing assay. Results: 38 patients were identified with non-V600E/K BRAF mutations. Mutations detected in more than 1 patient included V600R (n=14, 37%), K601E (5, 13%), G469E (3, 8%); L597S (3, 7%), D594G (2, 5%); 11 other mutations were identified in single patients. Median age was 57 yrs; 82% were men; 95% were white. The common primary subtypes were nodular (26%), superficial spreading (24%), unknown primary (21%); no one were acral, mucosal or uveal melanomas. Ten (26%) of 27 with known ulceration status had ulceration, and 3 (7%) of 22 with known mitosis status had < 1 mitosis /mm2. The sites of primary melanoma were located mostly in the head/neck and the trunk (63%), extremities (16%) and unknown primary (21%). The stage at diagnosis was I /II (29%), III (40%), IV (18%) and unknown (13%). Among 33 (87%) patients who ultimately developed distant metastases, 23(67%) had metastasis in the soft tissue/nodes, 21 (63%) in the lung, 9 (24%) in the brain, 7 (21%) in the liver, 6 (16%) in the bone, and 5 (15%) in the adrenal gland. Among patients (n=25) with initial stage I-III melanoma who later developed distant metastasis, the median duration between the time of initial diagnosis and distant metastases was 36 months. Among the 32 (84%) of the patients who developed stage IV melanoma, the median survival from the time of stage IV diagnosis was 18 months. Five patients received vemurafenib treatment, and 2 patients (K601E; T599_V600ins2) had stable disease and 2 patients (L597Q; G466E) had disease progression and 1 lost to follow up. Conclusions: Unexpectedly higher proportion of the patients with non-V600E/K mutant-melanoma had unknown primary melanoma and higher mitotic rate. In a small number of patients who received vemurafenib, the clinical response appears to be low.
Ipilimumab for advanced, refractory melanoma: A report of the Israeli cohort of expanded access program.
Authors: Shapira-Frommer Ronnie , Stephen Frank , Ben-Ami Eytan , Hamburger Tamar , Markel Gal , Ospovat Inna , Zippel Douglas , Merims Sharon , Apter Sara , Steinberg Hani , Silman-Steiberg Yael , Peretz Tamar , Lotem Michal , Schachter Jacob
Published: March 2020

e20039

Background: As the first agent to show survival advantage in metastatic melanoma, Ipilimumab (Yervoy, BMS) is being gradually introduced into health services worldwide. It's unique immune mediated side effects requires the incorporation of follow-up guidelines to prevent toxic sequella. We report on safety and efficacy results of refractory melanoma patients (pts) treated on an international expanded access program of Ipilimumab. Methods: Between 4/2010 and 12/2011 183 pts were treated. Pts received Ipilimumab 3 mg/kg q3w for 4 doses. Pts with evidence of clinical benefit at week 12 (CR, PR or SD), were eligible for re-induction upon progression. Results: All pts were pretreated for metastatic disease (median:1 line,range 1-5). 140 pts(77%) had M1c disease, 63 pts(34%) had brain metastasis and 84 (46%) had LDH above ULN, reflecting poor prognostic characteristics of this cohort. Patients received 3.6 doses of Ipilimumab on average. 11% received less than 4 cycles due to toxicity. Grade 3/4 immune-related adverse events were noted in 19.6% with the most common all grades toxicity being diarrhea (17.5%), pruritus (14%) rash (13%) and fatigue (8.7%). Grade 5 toxicity was noted in 4 patients (2%). Five pts were treated with anti TNF antibodies (Infliximab) for steroid resistant toxicity. Objective responses were noted in 16 pts (8.7%;4 CR, 12 PR), 26 pts(14.2%) had stable disease, overall yielding clinical benefit in 23%. Patients with stage IIIc, M1a and M1b were more likely to benefit (52% Vs 23% of the group, p<0.001) as well as patients previously treated by immunotherapy (p=0.026). Median OS was 9.2 months with 1 year survival of 42%. 34 pts (18.6%) are alive beyond 20 months, the majority of them received no further treatment. Factors favoring survival included stage IIIc, M1a and M1b, LDH below ULN and lymphocyte count at week 6 above 1000/ml (p values: <0.001,<0.001, 0.03 respectively). None of the 14 ocular melanoma pts exhibited clinical benefit. Conclusions: Our cohort reflects rapid adoption of this new modality. Ipilimumab had significant clinical benefit, comparable with previous reports, in a heterogenous group of patients, including those with poor prognostic factors.
Outcome and prognostic factors in BRAF mutation positive metastatic melanoma treated with a BRAF inhibitor: A population-based study in British Columbia.
Authors: Vergidis Joanna , Klasa Richard John , Zhou Youwen , Moon Elena , Jepson Debbie , Savage Kerry J.
Published: March 2020

e20045

Background: BRAF mutations are present in approximately 40-60% of cutaneous melanomas. The BRAF inhibitor vemurafenib has demonstrated dramatic anti-tumour activity in phase III trials in BRAF mutation positive (BRAFm) metastatic/unresectable melanoma; however, there is limited data outside of clinical trials. Methods: All patients > 18 years of age, PS 0-2, with metastatic/unresectable melanoma considered for treatment with vemurafenib in British Columbia between March 2011 to December 2012 were identified. CNS disease, if present, had to be radiographically stable/asymptomatic and treated with radiation and/or surgery. The BRAF V600E mutation status was evaluated centrally on primary or metastatic biopsies using a real-time PCR assay (Cobas 4800 BRAF Mutation Test, Roche Molecular Systems). Vemurafenib was initially provided through an Expanded Access Program/Roche patient assistance program and subsequently through provincial funding. Results: In total, 84 patients were identified that had undergone BRAF mutation screening, 49(58%) were BRAFm, 35(42%) were BRAFwt. For the BRAFm patients 33 have received 1 cycle of vemurafenib and are included in the present analysis (n=21 (64%) 1st line therapy; 12(36%) > 1st line therapy). BRAFm patients: median age 53 y; 64% male; PS 0/1 76%; LDH elevated 51.5%; M1c 91%; 27% history CNS metastases. With a median follow-up of 4.9 m the median PFS, measured from the 1st dose of vemurafenib, was 9 m and the median OS was 12.4 m. The 1 year PFS and OS were 47% and 50%, respectively. The median OS of patients who progressed following vemurafenib was only 2 months. There was an inferior PFS in patients with an elevated LDH (median PFS 5 m vs not reached, p=0.024) prior to receiving vemurafenib. Conclusions: The efficacy of vemurafenibin BRAF + melanoma in this population-based analysis compares favorably to estimates in the clinical trial setting. The survival of patients who progress on vemurafenib is short, highlighting the need to explore combination therapies. An updated analysis will be presented.
A prospective evaluation of vascular endothelial growth factor (VEGF) and the immune system in stage III/IV melanoma.
Authors: Agostino Nicole Marie , Weiss Michael , Shi Wenjing , Nevala Wendy Kay , Hemperly Stephen , Markovic Svetomir , Nair Suresh G
Published: March 2020

e20046

Background: The immune system and VEGF may play a role in melanoma behavior. We prospectively collected data in 10 stage III and 22 stage IV melanoma patients to observe factors influencing outcomes. Methods: We assessed median survival (MS), LDH, BRAF, VEGF, Th1/Th2 ratio, regulatory T cells (Tregs) and CD4/CD8 ratio, which were measured upon enrollment. LDH and BRAF were measured in standard commercial labs; VEGF via ELISA at LVHN; Th1/Th2 ratio and CD4/CD8 ratio via flow cytometry at Mayo Clinic. Stage III patients were treated with resection and interferon or observation. Stage IV patients were treated with some or all of the following: resection +/- GM-CSF, IL-2, ipilimumab, vemurafenib, carboplatin/paclitaxel/bevacizumab and temazolamide. Results: MS for stage IV patients was 48 months using a Kaplan-Meier survival curve. The only variable associated with survival was LDH, (HR=1.0017, 95%CI: 1.0003-1.0032, p=0.02). In stage IV patients, there was a positive correlation between VEGF and Tregs (r=.485, n=22 p=0.022) and a negative correlation between Tregs and Th1/Th2 (r=-.470, n=22, p=0.027). In stage III/IV patients who were alive at study completion, there was a positive correlation between CD4/CD8 and VEGF (r=.792, n=10, p=0.006). In patients who died, there was a negative correlation between Tregs and Th1/Th2 (r=-.660, n=12, p=0.02). 7 of the stage IV patients are currently disease free, including 5 of the 10 who received IL-2 +/- metastectomy. Conclusions: While a median survival of 48 months was provocative for stage IV patients, it may reflect referral selection at an IL-2 center. Recent advances such as ipilimumab (which lowers Tregs), BRAF inhibitors, and immunotherapy/aggressive resection as initial therapy may have impacted survival. The literature suggests that an elevated CD4/CD8 ratio predicts better outcomes. Higher VEGF levels have also been associated with lower overall survival in patients treated with IL-2. We found an association between higher VEGF levels and increased Tregs in deceased patients but not in living patients. In patients still alive, higher VEGF was balanced by a higher CD4/CD8 ratio. We did not find a correlation between baseline VEGF and survival.