bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical outcomes after intensive VDT-PACE therapy for relapsed multiple myeloma.
Authors: Singh Preet Paul , Gonsalves Wilson I. , Gupta Vinay , Buadi Francis , Lacy Martha , Dispenzieri Angela , Gertz Morie , Hayman Suzanne R. , Dingli David , Russell Stephen J. , Lust John Anthony , Zeldenrust Steven R. , Kapoor Prashant , McCurdy Arleigh Robertson , Rajkumar S. Vincent , Kumar Shaji
Published: March 2020

8600

Background: The combination of bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide (VDTPACE) was developed as an intense regimen for disease control prior to tandem transplantation for multiple myeloma (MM) in total therapy protocols. The regimen is very effective in this setting, and since has also been used in the relapsed setting. We examined the outcomes of a set of patients undergoing VDTPACE therapy for relapsed MM at our institution. Methods: We identified 71 patients who received VDTPACE for relapsed MM, at Mayo Clinic from 7/2006 to 7/2012. Plasma cell leukemia was excluded. All data was extracted from clinical records. Results: The median age of patients was 59 years (range, 39-80); 48 (67.6%) were male. The median time from diagnosis to initiation of VDTPACE was 38.2 months (range, 2-125). The median number of cycles given was 1 (range, 1-9). The overall response rate after one cycle was 57.1% (14.3% VGPR, 22.2% PR and 20.6% MR) in the 63 patients in whom the response was evaluable. The median overall survival (OS) post-VDTPACE was 8.2 months (95% CI, 5.7-10.9). Eighteen (25.4%) patients went on to autologous stem cell transplantation (SCT), and 7 (9.9%) received matched allogeneic SCT following VDTPACE, and the median OS post-VDTPACE was significantly longer for these groups compared to those who were not transplanted (15.3 and 20.5 months, respectively vs 5 months, p-value <0.001). Thirty eight of 66 (57.6%) patients were rehospitalized after initial admission for infusion therapy for a median duration of 6 days (range, 1-26). The median platelet and red cell transfusions were 4 (range, 0-21) and 5 (range, 0-22) units, respectively. Renal toxicity was seen in 13/62 (21%) patients and 27/65 (41.5%) patients developed neutropenic fever. The median duration to absolute neutrophil and platelet count recovery was 18 (range 12-42) and 27 (range, 12-42) days, respectively. Three (4.2%) patients died within 30 days and 11 (15.5%) within 8 weeks of initiating VDTPACE. Conclusions: VDTPACE is an effective therapy in relapsed MM but is associated with significant morbidity and short-term mortality. It appears to be more effective when followed by an autologous or allogeneic SCT.
Factors that predict successful remobilization after autologous hematopoietic progenitor cell transplant (aHCT) for multiple myeloma.
Authors: Papanikolaou Xenofon Dimitrios , Rosenbaum Eric , Tyler Lisa , Barlogie Bart , Cottler-Fox Michele
Published: March 2020

8610

Background: aHCT is a proven therapeutic modality in treating relapsed multiple myeloma (MM). However, previously transplanted patients may have no hematopoietic progenitor cells (HPC) left in storage. Methods: Collection of HPC after aHCT was studied in 221 MM patients who underwent 333 mobilization attempts between 10/2000 and 06/2012. Results: The median number of CD34+ collected was 4.7 ×106/kg, with 74% of collections yielding at least 2.5×106/kg. Mobilization with chemotherapy and G-CSF was most efficient, yielding a median of 6.84×106/kg (p<0.001). Growth factor-only mobilization was least effective, with a median of 3.01×106/kg (p<0.001). The addition of plerixafor yielded a significant increase if there was a previous “poor” (<2.5×106/kg) collection (1.83 vs. 3.43×106/kg, p<0.001). In univariate statistical analysis female sex (p=0.048), platelets (PLT) ≤100×106/L (p<0.001), hemoglobin ≤11g/dL (p=0.032), and albumin ≤3.5 g/dL (p=0.003) prior to mobilization correlated with a “poor” collection. In multivariate analysis only PLT ≤100×106/L was significant (p<0.001). Of the 221 patients collected, 154 underwent subsequent aHCT. Infusion of HPC procured after previous aHCT did not yield a difference in treatment-related mortality (p=0.766). Use of only cells collected after aHCT was related to a delayed platelet engraftment ≥50×106/L (p<0.001). Conclusions: Remobilization and collection of an adequate number of HPC after previous aHCT is feasible. PLT ≤100×106/L suggest the need for plerixafor for a successful collection. Infusion of the graft procured is safe and effective, but use of only cells collected after aHCT is associated with delayed platelet engraftment >50×106/L.
Next-generation sequencing of genomic and cDNA to identify a high frequency of kinase fusions involving ROS1, ALK, RET, NTRK1, and BRAF in Spitz tumors.
Authors: Stephens Phil , Wiesner Thomas , He Jie , Yelensky Roman , Esteve-Puig Rosaura , Otto Geoff , Berger Michael F. , Lipson Doron , Brennan Kristina , Miller Vincent A. , Cronin Maureen T. , Bastian Boris C.
Published: March 2020

9002

Background: Spitz tumors are melanocytic neoplasms with characteristic morphologic features that can overlap with melanoma. Predicting biologic behavior, which can range from an indolent disease to metastasis confined to regional lymph nodes and infrequent incidences of widespread metastatic disease with lethal outcome, is unreliable based on histopathological criteria and the genetic underpinnings of the disease as a whole are poorly understood. Methods: Genomic DNA and total RNA was isolated from 40 microns of FFPE sections from 20 benign Spitz nevi and 8 atypical Spitz tumors (with morphological features inconsistent with HRAS or BRAF/BAP1 mutations) in a CLIA-certified lab (Foundation Medicine). DNA sequencing was performed for 3230 exons of 182 cancer-related genes plus 37 introns of 14 genes commonly fused on indexed hybridization-captured libraries to an average unique coverage of 997x, with 99.96% of exons being sequenced at ≥100x coverage. RNA sequencing was performed on indexed libraries captured using the cDNA Kinome hybridization kit (Agilent) generating >50,000,000 unique pairs per specimen. Results: Only a single case harbored a point mutation in a gene known to be recurrently mutated in melanocytic neoplasms, HRAS Q61L and no known alterations were found in BRAF, NRAS, KIT, GNAQ or GNA11. Remarkably, genomic rearrangements were observed in 19/28 (68%) of cases. The rearrangements fused the intact kinase domains of ROS1 (36%), ALK (14%), RET (7%), NTRK1 (7%) and BRAF (4%) to a wide range of predominantly novel 5’ partners including PWWP2A, PPFIBP1, ERC1, MYO5A, CLIP1, HLA-A, ZCCHC8, DCNT1, LMNA and CEP89. These gene rearrangements, which were all expressed, formed constitutively activated chimeric oncogenes. All fusions occurred in a mutually exclusive pattern and were more common in younger patients compared to patients whose tumors did not harbor fusions (median age 14 versus 24 years, p=0.02). Conclusions: Next generation sequencing identified gene fusions in two thirds of Spitz tumors which are likely to be useful as diagnostic markers that may also serve as therapeutic targets for the rare subset of these tumors that metastasize.
Safety and clinical activity of nivolumab (anti-PD-1, BMS-936558, ONO-4538) in combination with ipilimumab in patients (pts) with advanced melanoma (MEL).
Authors: Wolchok Jedd D. , Kluger Harriet M. , Callahan Margaret K. , Postow Michael Andrew , Gordon Ruth Ann , Segal Neil Howard , Rizvi Naiyer A. , Lesokhin Alexander M. , Reed Kathleen , Burke Matthew M. , Caldwell Anne , Kronenberg Stephanie Anne , Agunwamba Blessing , Feely William , Hong Quan , Horak Christine E. , Korman Alan J. , Wigginton Jon M. , Gupta Ashok Kumar , Sznol Mario
Published: March 2020

9012^

Background: CTLA-4 and PD-1 are critical immune checkpoint receptors. In MEL pts, ipilimumab (anti-CTLA-4) prolonged survival in two phase III trials, and nivolumab (anti-PD-1) produced an objective response rate (ORR) of 31% (n=106) in a phase I trial. PD-1 is induced by CTLA-4 blockade, and combined blockade of CTLA-4/PD-1 showed enhanced antitumor activity in murine models. Thus, we initiated the first phase 1 study to evaluate nivolumab/ipilimumab combination therapy. Methods: MEL pts with ≤3 prior therapies received IV nivolumab and ipilimumab concurrently, q3 wk × 4 doses, followed by nivolumab alone q3 wk × 4 (Table). At wk 24, combined treatment was continued q12 wk × 8 in pts with disease control and no DLT. In two sequenced-regimen cohorts, pts with prior standard ipilimumab therapy were treated with nivolumab (q2 wk × 48). Results: As of Dec. 6, 2012, 69 pts were treated. We report efficacy data on 37 pts with concurrent therapy in completed cohorts 1-3 (Table); ORR was 38% (95% CI: 23-55). In cohort 2 (MTD), ORR was 47% and 41% of pts had ≥80% tumor reduction at 12 wk (Table) with some pts showing rapid responses, prompt symptom resolution, and durable CRs. Related adverse events (rAEs) for concurrent therapy were similar in nature with some higher in frequency than those typically seen for the monotherapies and were generally manageable using immunosuppressants. Cohort 3 exceeded the MTD (DLT: gr 3-4 ↑ lipase). At the MTD, gr 3-4 rAEs occurred in 59% of pts and included uveitis/choroiditis, colitis, and reversible lab abnormalities. Conclusions: Nivolumab and ipilimumab can be combined with a manageable safety profile. Clinical activity for concurrent therapy appears to exceed that of published monotherapy data, with rapid and deep tumor responses (≥80% tumor reduction at 12 wk) in 30% (11/37) of pts. A phase III trial is planned to compare concurrent combination dosing with each monotherapy. Clinical trial information: NCT01024231. [Table: see text]
Analysis of plasma-based BRAF and NRAS mutation detection in patients with stage III and IV melanoma.
Authors: Polsky David , Tadepalli Jyothirmayee S. , Hafner Shria , Chang Gregory , Fleming Nathaniel H. , Shao Yongzhao , Darvishian Farbod , Pavlick Anna C. , Berman Russell S. , Shapiro Richard L. , Osman Iman , Spittle Cynthia
Published: March 2020

9023

Background: Patients with metastatic melanoma are eligible for BRAF inhibitor therapy if the BRAF V600E mutation can be identified in their tumor specimen. Patients lacking an available specimen for genotyping are unable to receive inhibitor therapy. We developed two mutation-specific genotyping platforms and tested their ability to detect BRAF and NRAS mutations in archived plasma and tumor samples to determine the potential utility of blood-based tumor genotyping in melanoma. Methods: We analyzed a group of 96 patients with stage III or IV melanoma, prospectively enrolled and followed in the NYU Melanoma Biorepository program. Each patient had a plasma sample and one or more tumor samples available for analysis. We used a combination of allele-specific PCR (Taqman) and SNaPshot assays to identify BRAF V600 and NRAS Q61 mutations in the tumor and plasma samples. Results: Among the 96 patients, 51 had stage III disease at the time of analysis; 45 had stage IV disease. Seventy-two patients had 2 or more tumor samples available for analysis, for a total of 204 tumors analyzed. In total, 52/96 (54%) patients had one or more BRAF or NRAS mutant tumors, including one patient with separate BRAF and NRAS mutant tumors (BRAF, n=35 (36%); NRAS, n=18 (19%)). We successfully amplified plasma DNA from 39/52 (75%) patients with tumor-associated mutations. Among those patients with amplifiable plasma DNA we detected mutations in 7 (18%) patients including 3 BRAF V600E, one V600K, 2 NRAS Q61K and one Q61L. Plasma-based mutations matched tumor-associated mutations in all 7 patients. All 7 patients had active disease at the time of blood draw. There were 32 patients with tumor-associated mutations in which a mutation could not be detected in the plasma. Only 15 of those 32 (47%) had active disease at the time of blood draw. There were no mutations detected in the plasma of the 44 patients whose tumors lacked BRAF or NRAS mutations. Conclusions: These data suggest that plasma-based detection of BRAF and NRAS mutations has a high specificity for tumor-associated mutations. It may prove to be a useful adjunct to tumor-based genotyping in patients with active disease, especially those lacking an available tumor specimen.
Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma (aBCC): 18-month update of the pivotal ERIVANCE BCC study.
Authors: Sekulic Aleksandar , Migden Michael R. , Basset-Seguin Nicole , Garbe Claus , Gesierich Anja , Lao Christopher D. , Miller Chris , Mortier Laurent , Murrell Dedee F. , Hamid Omid , Quevedo Fernando , Schadendorf Dirk , Hou Jeannie , Yue Huibin
Published: March 2020

9037

Background: Therapies for aBCC, which includes metastatic (m) and locally advanced (la) BCC, are limited. Abnormal Hedgehog pathway signaling is a key driver in BCC pathogenesis. Primary analysis of the pivotal ERIVANCE BCC trial of vismodegib, an oral hedgehog pathway inhibitor (HPI), demonstrated an objective response rate (ORR) of 30% and 43%, in mBCC and laBCC patients, respectively, with a median duration of response (DOR) of 7.6 months. We present safety and investigator (INV) assessed efficacy results 18 months (29 May 2012) after primary analysis (26 Nov 2010). Methods: Multicenter, international, nonrandomized study in patients (N=104) with radiographically measurable mBCC or laBCC (surgery inappropriate due to multiple recurrence, or substantial morbidity or deformity anticipated) receiving 150 mg oral vismodegib daily until disease progression or intolerable toxicity. Key secondary endpoints included INV-assessed ORR, progression-free survival (PFS), DOR, overall survival (OS), and safety. Results: At data cutoff, 21 patients continued to undergo protocol-specified assessments and 56 patients were in survival follow-up. The median dose intensity was comparable with primary analysis. ORR was 48.5%, mBCC; 60.3%, laBCC, comparable with primary analysis. However, median DOR improved (mBCC=14.7; laBCC=20.3 months). The median OS for mBCC was 30.9 months but not estimable in laBCC. Adverse events remained consistent, with muscle spasm, alopecia, dysgeusia, weight decrease, and fatigue most frequently reported. Eleven more deaths were reported in the update period after primary analysis; these occurred in survival follow-up and were not drug-related. Conclusions: Vismodegib is the first FDA-approved HPI; thus, long-term efficacy and safety data are particularly relevant. 18-month update data confirmed prolonged responses and consistent safety in vismodegib-treated aBCC patients. Clinical trial information: NCT00833417.
Investigation of the diagnostic precision and utility of sentinel lymph node biopsy in the treatment of patients with Merkel cell carcinoma (MCC).
Authors: Paulus Elena Mantas , Shaw Fawwaz Ridwan , Fleming Martin D.
Published: March 2020

9042

Background: Merkel cell carcinoma (MCC) is a relatively uncommon and aggressive cutaneous neuroendocrine neoplasm with a high incidence of local recurrence and regional and distant metastasis. The management and identification of prognostic factors remains of value in the treatment of these patients. Although the optimal multidisciplinary treatment of MCC has yet to be determined, the purpose of this study was to investigate whether sentinel lymph node biopsy confers a lower risk of recurrent disease in patients with Merkel cell carcinoma at our institution. Methods: After obtaining institutional review board approvals, all patients with a diagnosis of MCC from 2002-2012 were obtained from our tumor registries. Clinical features, pathologic characteristics, management modalities, and patient outcomes were retrospectively reviewed. Results: Of 20 patients with MCC, nine patients underwent sentinel lymph node biopsy, another four received therapeutic lymph node dissections, and seven patients did not have lymph node evaluation at the initial operation. The most common nodal basins involved were cervical and axillary. Recurrent disease was observed in seven patients (35%). Three patients underwent complete regional lymph node dissection after developing clinically positive nodal disease subsequent to only wide local excision at the index operation (15%). Three patients developed locoregional recurrence and the seventh patient developed metastatic disease to the liver. Of these seven patients with recurrent disease, only two (28.57%) had initial lymph node evaluation. Twelve patients (60%) received adjuvant therapy with chemotherapy (carboplatin/etoposide) and/ or radiation therapy. Conclusions: Merkel cell carcinoma continues to demonstrate its propensity for high rates of recurrence and metastatic disease. Of the seven patients with recurrent locoregional and/or nodal disease in our study, only two patients had initial lymph node evaluation, which was statistically significant with a p value of 0.01175. Further analysis focusing on additional prognostic factors is necessary to optimize our management algorithms and patient outcomes.
Current management of advanced melanoma: A European perspective.
Authors: Jones Clare Frances , Zhao Zhongyun , Barber Beth L. , Bagijn Marloes , Saltman Deborah
Published: March 2020

9045

Background: Melanoma is a rare but serious subtype of skin cancer that can infiltrate deep skin layers and commonly metastasizes. Although it makes up only a small proportion (<5%) of all skin cancer cases, it causes 75% of deaths from skin cancer. Melanoma affects all ages with 38% of patients less than 55 years old causing significant work productivity and life impact. Median survival of patients with advanced (unresectable or metastatic) melanoma is less than a year. Conventional chemotherapy provides no overall survival benefit. Within the last 2 years, the EMA approved two new drugs for advanced melanoma: ipilimumab for second-line and vemurafenib for patients with BRAF mutation-positive tumors; both drugs provide survival benefits. The objective of this study was to investigate physicians' perceptions of the unmet need in the treatment of advanced melanoma in the new treatment landscape. Methods: 150 oncologists and dermatologists from France, Germany, Italy, Spain, and the UK who had treated at least 12 patients with advanced melanoma in the last 12 months prior to September 2012 were asked by a web-based survey to describe their treatment of advanced melanoma and the current issues in treatment. Results: Overall, 76% of respondents had used ipilimumab and 79% had used vemurafenib in the 12 months prior to September 2012. Toxicity and tolerability of treatment was the most commonly mentioned issue (cited by 43% of respondents). Limited treatment effectiveness (29% respondents) was also highlighted by respondents in all countries. Limited treatment options were identified as a key issue by 30% of respondents in Germany, France, and the UK. Other commonly mentioned issues were low response rates and poor survival. Conclusions: The majority of physicians surveyed had experience using vemurafenib and ipilimumab. However, a number of issues remain in the treatment of advanced melanoma, suggesting that unmet need remains high.
Safety and efficacy of ipilimumab in melanoma patients who received prior immunotherapy on phase III study MDX010-020.
Authors: Kaufman Howard , Lutzky Jose , Clark Joseph , Margolin Kim Allyson , Lawson David H. , Amin Asim , Collichio Frances A. , Pecora Andrew , Urba Walter John , Bennett Kelly L. , McDermott David F.
Published: March 2020

9050

Background: MDX010-020 was a phase III comparison of ipilimumab (Ipi), gp100 vaccine or the combination for advanced melanoma. A subset of patients (pts) received other immunotherapy (IM) for advanced disease prior to receiving Ipi, providing the opportunity to evaluate safety and efficacy of Ipi following IM. A prior analysis has shown that pts receiving prior IL-2 had a similar overall survival (OS) to pts who had not received prior IL-2 [Hodi et al NEJM2010]; we now report expanded results for pts receiving any prior IM (interferons and/or interleukin). Methods: Eligible pts (n=676) had unresectable stage III/IV melanoma and were randomized 3:1:1 to q3 wks x 4 doses of Ipi + gp100 or Ipi + placebo or gp100 + placebo. All Ipi doses were 3 mg/kg i.v. OS was retrospectively analyzed for pts receiving any prior IM; immune-related adverse events (irAEs) during induction were evaluated for pts who received any prior IM (322 pts, 48%) and for pts who received prior IL-2 (154 pts, 23%). Results: Demography and OS are summarized below. irAEs of any grade were reported for 60% (Ipi) and 54% (Ipi + gp100) of pts receiving any prior IM. Those receiving prior IL-2 specifically had 73% (Ipi) and 58% (Ipi + gp100) incidence of any grade irAEs. Incidence was similar for those not receiving prior IM or prior IL-2. Diarrhea, rash, and pruritus were the most common events in all groups. Conclusions: Results for OS in this subgroup analysis were similar for both those receiving any prior IM and those who did not receive prior IM and to the overall 020 population. In addition, safety profiles were similar irrespective of prior immunotherapy. Clinical trial information: NCT00094653. [Table: see text]
Melanoma of ocular, mucosal, and genital sites: Epidemiology and survival outcomes.
Authors: Bishop Kenneth D. , Olszewski Adam J.
Published: March 2020

9051

Background: Melanomas arising from noncutaneous sites are rare entities with poorly defined staging, prognosis and no evidence-based treatment guidelines. Methods: We analyzed melanoma cases in the Surveillance, Epidemiology and End Results database between 1988 and 2007. Differences in clinical and pathologic features, treatment, and mortality were studied according to primary site of disease. The risk of melanoma-related death was calculated from life tables based on expected survival. Relative survival was compared in a multivariable parametric model using individual data. Results: We identified 209,861 cases of melanoma, of which 9,267 (4.4%) were noncutaneous. These were notable for older age, higher proportion of women, racial minorities, and advanced-stage disease. Mortality was high, even in subgroups with localized stage at diagnosis. Mucosal melanomas of the gastrointestinal and genitourinary tract had the highest excess mortality hazard ratios (HR) in the multivariate model. A substantial proportion of patients underwent organ-specific radical resection (32% eye enucleation, 40% radical head/neck surgery, 31% gastrectomy, 23% abdominoperineal resection). Conclusions: Melanoma arising from mucosal sites portends markedly worse prognosis than cutaneous melanoma. Prospective studies of systemic adjuvant treatment are needed for this disease, which is rarely curable even with aggressive local therapy. [Table: see text]
Analysis of serum biomarkers and tumor genetic alterations from a phase II study of lenvatinib in patients with advanced BRAF wild-type melanoma.
Authors: Sachdev Pallavi , Hamid Omid , Kim Kevin , Hauschild Axel , O'Day Steven , Andresen Corina , Funahashi Yasuhiro , Kadowaki Tadashi , O'Brien James P. , Flaherty Keith
Published: March 2020

9058

Background: Lenvatinib is an oral receptor tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT, and PDGFRβ. Phase I and II studies of lenvatinib demonstrate that a subset of advanced melanoma patients (pts) appears to derive benefit from lenvatinib treatment (tx), prompting a need to identify predictive biomarkers for response to lenvatinib. Methods: Serum and archival tumor samples were collected from 93 enrolled pts in the BRAF wild-type (wt) cohort of the lenvatinib phase II study of advanced melanoma. Concentrations of 50 factors were measured in pre- and post-tx serum samples; 58 archival tumor tissues were obtained and gene mutation (mut) (n=53) and gene expression profiling (GEP) (n=39) analyses were performed. For mut analysis, targeted resequencing was performed on a select panel of genes using the Ion PGM Sequencer and mut validation studies were performed. For GEP analysis, the nCounterAnalysis System was used to measure the expression level of 330 genes. Results: Clinical benefit rate (32%) and objective response rate (9%) by independent radiologic review were observed in the BRAF wt cohort. In serum biomarker analysis, lenvatinib tx resulted in a decrease in soluble VEGFR2 and increase in VEGF and PlGF levels consistent with target engagement. Correlation with clinical outcome demonstrated that baseline (BL) levels of Ang-2, IL8, PlGF, and PDGFBB associated with OS, but only pts with low BL Ang-2 levels also demonstrated improved response. High BL levels of FLT3LG and eotaxin associated with longer OS and improved response. In GEP analysis, expression levels of a set of genes including TARBP2, ZNF544, and NF1 (targets identified in phase I and preclinical studies) associated with OS. In gene mut analysis, NRAS mut showed a trend towards longer OS. Pts with NRAS mut along with wt PIK3CA status demonstrated longer OS. Conclusions: Lenvatinib demonstrated limited response in BRAF wt advanced melanoma pts. A subset of pts may derive extended clinical benefit. NRAS mut/PIK3CA wt status and low BL Ang-2 levels appear to associate with improved clinical outcome in this pt population and require further study to assess their predictive value. Clinical trial information: NCT01136967.
Clinical characteristics and survival of BRAF-mutant (BRAF+) metastatic melanoma patients (pts) treated with BRAF inhibitor (BRAFi) dabrafenib or vemurafenib beyond disease progression (PD).
Authors: Chan Matthew , Haydu Lauren , Menzies Alexander M. , Azer Mary W. F. , Klein Oliver , Guminski Alexander , Kefford Richard , Long Georgina
Published: March 2020

9062

Background: Accelerated tumor growth has been demonstrated on BRAFi cessation in BRAFi-resistant melanoma cell lines. In BRAFi-treated pts initial response rates are high but most have PD at 6+ months. The benefit of ongoing BRAFi after PD is unknown. We sought to describe the characteristics of pts treated beyond progression (TBP) vs those not TBP, and whether TBP prolongs survival. Methods: Clinicopathologic data were collected on 112 pts enrolled in phase I-IV clinical trials at Westmead Hospital and Melanoma Institute Australia from July 2009 to Sept 2012 with unresectable stage IIIC or IV BRAF+ melanoma treated with single agent dabrafenib or vemurafenib. TBP was defined as ongoing BRAFi >28 days beyond RECIST PD. Pt and disease characteristics at baseline and at PD were examined, as well as survival data. Results: 92/112 (82%) pts had RECIST PD. 36/92 (39%) pts were TBP (mean 144 days, median 93 days, range 29–572 days). Pts TBP were significantly more likely to have achieved a RECIST response (CR/PR) prior to PD, have a lower ECOG at PD, presence of brain metastases at PD, have PD treated locally and a smaller RECIST sum of diameters (SoD) at PD, compared with those not TBP (all p<0.05). Median OS from commencement of BRAFi in those TBP was longer than those not TBP (15.0 vs 6.5 months, p<0.001), as was OS from RECIST PD (7.4 vs 1.9 mo, p=0.001). In multivariate analysis of all pts, TBP improved OS from RECIST PD (HR 0.32, p=0.012) even after adjusting for other potential prognostic factors at PD (see table). Within the TBP cohort, RECIST SoD at PD was the only factor that influenced OS from PD (p=0.009), and presence of brain metastases did not. Conclusions: Treatment with BRAFi may be continued after RECIST PD in selected pts, and is associated with a prolonged OS compared with ceasing treatment at PD. [Table: see text]
Upstream MAPK pathway inhibition: MEK inhibitor followed by a BRAF inhibitor in advanced melanoma patients.
Authors: Goldinger Simone M. , Murer Carla , Stieger Pascale , Dummer Reinhard
Published: March 2020

9071

Background: The presence of activating BRAF mutations in about 60% of all metastatic melanomas (mM) has led to the development of inhibitors (i) targeting the RAF and MEK kinases. MEK is the downstream effector of BRAF. However, the blockage of the MAPK pathway is limited due to the development of resistance mechanisms. MEK resistance can confer cross-resistance to BRAF inhibition, whereas BRAF resistance is independent from the MAPK pathway. Hence, it seems reasonable to start a MAPK pathway inhibition by a BRAFi. An upstream inhibition beginning the treatment reversed with a MEKi followed by a BRAFi has not yet been clinically explored. Methods: Patients at the Dermatology Department of the University Hospital of Zurich with mM harboring a BRAF mutation formed the study cohort. Patients were divided into a group who was treated initially with a BRAFi (vemurafenib or LGX818) followed by a MEKi (AZD6244, trametinib, or MEK 162), and a group who first received a MEKi and was later treated with a BRAFi. Duration of disease control (DDC) was measured in time from the initiation of the treatment to discontinuation due to disease progression or toxicity. Results: A total of 16 patients (7 females, 9 males, age 30-73 years) with BRAF mutated mM were evaluated. The median DDC (mDDC) was similar in both groups. When patients were treated first with a BRAFi (n=7), the mDDC for BRAFi was 7.6 and for MEKi 1.7 months, respectively. In contrast, when the treatment sequence was inversed (n=9), the mDDC for MEKi was 3.9 and for BRAFi 4.7 months. We observed some benefit (partial response, stable disease) using chemotherapy after BRAFi/MEKi progression. Conclusions: This analysis indicates that the sequential MEK-RAF inhibition of the MAPK pathway is acceptable in BRAF mutant mM patients. The sum of the DDC of both groups (9.3 and 8.6 months) is comparable to the promising BRAFi/MEKi combination therapy (median PFS 9.4 months). Besides the sequenced administration analyzed here, an intermittent administration should be further studied.
Thrombocytopenia associated with ipilimumab therapy of advanced melanoma at a single institution.
Authors: Sajjad Monique Z. , George Timothy , Weber Jeffrey S. , Sokol Lubomir
Published: March 2020

9072

Background: Ipilimumab (IPi) is a monoclonal IgG1κ antibody targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4) that was approved for the treatment of metastatic melanoma (MM). IPi therapy is associated with immune-related adverse events (irAEs) (Weber et al. J Clin Oncol2012 Jul 20;30(21):2691-7). Hematologic toxicity has rarely been reported. Methods: We analyzed 172 pts with MM treated adjuvantly or for metastatic disease with IPi on 2 clinical studies and an expanded access program (protocols MCC15283, MCC15722 and MCC15977). Clinical characteristics and hematologic parameters related to therapy were recorded. Medications, infections, comorbidities, prior therapies, and pathology reports from bone marrow (BM) biopsies were reviewed. Results: Of 172 subjects, 10 (5.8%) pts with normal platelet counts prior to therapy, developed thrombocytopenia (TCP) following IPi. Median number of doses was 8.5 (range 1-19). Median age at development of TCP was 64 years (range 21-93). Median time to development of TCP was 16.5 months (range 0.25 – 39). Of ten pts, three developed grade (gr) 1 or 2 TCP, three developed gr 3 and four pts developed gr 4 thrombocytopenia. BM analysis in pts with gr 4 TCP showed normal hematopoiesis and no evidence of melanoma. Six of 10 (60%) pts required therapy and were initiated on prednisone, but were deemed steroid refractory. No sustained responses to subsequent treatments with IVIG, rituximab, danazol, and/or splenectomy were observed. Three pts with grade 4 TCP were treated with eltrombopag. One of them achieved a sustained complete response lasting > 20 months. The other 2 pts who received eltrombopag discontinued treatment due to vascular events. Three out of 10 (30%) pts with any gr of TCP experienced mild bleeding episodes in the form of epistaxis. One pt with gr 4 thrombocytopenia experienced severe gastrointestinal bleeding requiring hospitalization. No deaths related to bleeding occurred. Conclusions: This is the first case series of hematologic irAEs in pts treated with IPi on clinical trials, suggesting that steroid refractory TCP may occur with IPi treatment . The timing and severity of IPi associated TCP is highly variable so careful hematologic monitoring should be considered.
Relevance of MIA and S-100 to monitor BRAF inhibitor (iBRAF) therapy in metastatic melanoma patients.
Authors: Sanmamed Miguel F. , Fernandez-Landazuri Sara , Castanon Eduardo , Echeveste Jose , Lozano Maria D. , Idoate Miguel A. , Perez-Gracia Jose Luis , Gonzalez Alvaro , Martin-Algarra Salvador
Published: March 2020

9074

Background: MIA and S-100 have been proposed as tumor markers for patients with melanoma, but they are not widely accepted. BRAF V600E mutation has been reported in more than 50% of melanomas. Recently, selective BRAF inhibitors have proved to be more active than DTIC in first line treatment of BRAF V600E melanoma patients. The aim of the present work is to evaluate the utility of MIA and S-100 during iBRAF treatment. Methods: BRAF V600E mutation was analyzed in 77 patients with metastatic melanoma by automated direct sequencing in tumor DNA. Tumor markers (MIA, S-100 and LDH) were studied in serum from all patients. Sixteen of these patients received iBRAF therapy (11 Vemurafenib, 5 Dabrafenib) and tumor markers were analyzed sequentially: baseline, best response and progression. MIA and S-100 were determined by immunometric methods and LDH by a spectrophotometric assay. The cut-off points were MIA=9 ug/L, S-100=0.1 ug/L, and LDH=290 U/L. Non-parametric statistical analysis was performed. Results: Forty-three patients had BRAF V600E mutation and 34 were wild type (WT). The percentage of cases with MIA above the cut-off in patients with V600E mutation was significantly higher than in the WT group (76.3% vs. 52.9%; p<0.05), while the frequency of elevated S-100 and LDH was similar. Among patients treated with iBRAF, the response rate was 87.5% (5 CR, 9PR). In responding patients, MIA and S100 levels decreased dramatically, but not LDH (Table). At the time of this report, thirteen patients have progressed. Upon progression, MIA and S-100 increased significantly above levels achieved at best response (Table). Conclusions: Serum MIA and S-100 are potentially useful markers in the clinical and follow-up management of patients receiving iBRAF therapy. Validation in a larger series is needed. [Table: see text]
A phase I study of the combination of sorafenib (Sor) and bortezomib (Bor) in patients (pts) with metastatic melanoma (MM).
Authors: Sullivan Ryan J. , Ibrahim Nageatte , Lawrence Donald P. , Aldridge Julie , Hodi F. Stephen , Flaherty Keith , Conley Christine , DeNoble Sarah , Mier James Walter , Cho Daniel C. , Atkins Michael B. , McDermott David F.
Published: March 2020

9076

Background: Sor is a small molecule tyrosine kinase inhibitor that has many targets and previously was developed for the treatment of MM. Bor is a proteasome inhibitor widely used to treat multiple myeloma and other malignancies. In preclinical studies, the combination of Sor and Bor has been shown to modulate expression of BCL-family members and augment cytotoxicity in MM cell lines. Methods: Pts with MM were enrolled in cohorts of 3 during dose escalation to determine the maximum tolerated dose (MTD) of Sor twice daily (BID) in combination with Bor given days 1, 8, 15 of a 28 day cycle. The MTD was defined as the highest dose level at which less than 33% of pts exhibited a dose limiting toxicity (DLT). Efficacy, as measured by 6-month progression free survival (PFS) and response rate (RR) per RECIST, was documented. Results: Eleven pts were enrolled in 3 dose levels. DLTs (fatigue and rash respectively) were seen in 2 of 3 patients enrolled at the highest dose level (Sor 400 mg and Bor 1.3 mg/m2). The next lowest dose level (Sor 400 BID and Bor 1.0) enrolled 5 pts and none had DLTs. Thus, this dose level was defined as the MTD. Toxicities seen in >20% of pts included hypertension, pruritus, hand-foot syndrome, mucositis, nausea, vomiting, rash, constipation, abdominal pain, anorexia and fatigue. Of 9 response evaluable pts, none had radiographic evidence of tumor response. Two of 11 (18%) pts remained progression free for greater than 6 months. Conclusions: The combination of Sor and Bor is safe, but minimally active in pts with MM. In the absence of tumor response at or above the MTD, the study was closed with only 5 pts treated at the provisional MTD and enrollment to a planned dose expansion cohort will not occur. Clinical trial information: NCT01078961.
Melanoma recurrence risk stratification using Bayesian systems biology modeling.
Authors: Styrmisdottir Edda Lind , Scanlon Patrick , Hanniford Douglas , Eberhardt John , Jones Thomas , Hernando Eva , Osman Iman
Published: March 2020

9089

Background: Estimating the risk of recurrence in patients with melanoma is extremely challenging. Standard of care is AJCC staging system, but the accuracy and robustness of this method is still under development. We conducted a proof of concept study exploring the use of machine-learned Bayesian Belief Networks (ml-BBNs) using a miRNA profiled cohort of melanoma patients with extended follow up to create Bayesian Biological Systems Models (BBSMs). We sought to determine if ml-BBNs could describe the biological system and if we could use the model to identify new cases with higher risk of recurrence. Methods: Our study cohort consisted of 89 patients (42 of which recurred) with a median follow up time of 118 months, that were examined for 869 miRNAs. Prior to modeling we segmented the data into training data (72 cases/80%) and testing data (17 cases/20%) at random. We recursively trained ml-BBNs on the training set, using all miRNAs. We used the directed graph structure of the ml-BBNs to identify miRNAs that consistently had more connectivity and goodness of fit as determined by Bayesian Information Criteria (BIC) scoring. MiRNAs that were in the top 50 BIC-scoring nodes across all models were selected for use to train the recurrence BBSMs. To compensate for a small number, bootstrapping was used to increase the sample to 100 records. We then compared our test set cases to our recurrence model, and used a similarity scoring algorithm to evaluate the similarity of values in each test instance to our biological models. For comparison we also trained an ml-BBN using clinical data from the same cohort. We then evaluated the scores against known recurrence outcome using Receiver Operating Characteristic (ROC) curve analysis. Results: BIC-scoring analysis selected 35 miRNAs for use in BBSM modeling. Area Under the Curve (AUC) for detection of recurrence is 0.76 in the training set and 0.62 in the testing set, while the clinical data yielded an AUC of 0.5 in this cohort. Conclusions: Our data suggest that ml-BBNs can be used to describe a biological model of melanoma recurrence. Additional data and refinement need to be made using independent datasets to be of a level that is clinically useful.
Relationship of bleeding to pathologic ulceration in a primary melanoma lesion.
Authors: Kang Paul T , Baker Amy Louise , Warneke James , Curiel Clara N , Jeter Joanne M. , Hersh Evan , Cranmer Lee D.
Published: March 2020

9102

Background: Lesion bleeding (BL) is a catalyst symptom leading to melanoma (MEL) diagnosis and is associated with adverse outcomes. The pathophysiologic significance of BL has not been elucidated. We hypothesize that BL reflects pathologic ulceration (UL). Methods: This retrospective cohort study was conducted using data from 850 patients seen 2005-2009 at our center. Eligible patients reported the pre-diagnosis BL status of their primary lesion; determination of its UL status was also required. Demographic, clinical, pathologic and outcomes data were abstracted from records. Χ2 and independent t-tests were used for univariate comparisons. Predictors of UL were analyzed with multiple logistic regression. Survival indices were analyzed by the Kaplan-Meier, log-rank, and Cox proportional hazards. Results: 190 patients with 193 MEL lesions were eligible. Median follow-up was 5.3 yr. 67 lesions bled prior to diagnosis; 68 demonstrated UL. BL and UL were associated with each other and with Breslow depth in univariate analyses; UL was also associated with age at diagnosis. Neither was associated with gender, lesion site, use of BL-associated drugs or Clark’s level. A logistic model was developed using BL, gender, lesion site, use of BL-associated drugs, and age at diagnosis. Only BL and age at diagnosis were associated with UL probability (OR=10.6/p<0.001 and OR=1.04/p=0.006, respectively). BL was associated with worsened median relapse-free (RFS) and overall survival (OS) (median 1.16y vs. 1.96y, p=0.001 and 3.06 y vs. 3.41y, p=0.001), as was ulceration. When status of BL and UL were considered together, only UL predicted outcomes. A Cox model of clinical factors (BL, gender, age at diagnosis, lesion site) confirmed the association of BL with RFS and OS (HR 1.82/p=0.006 and HR 2.36/p=0.001). Addition of UL to the model abrogated BL’s predictive value. Conclusions: BL of primary MEL lesions is strongly associated with pathologic UL. When clinical parameters are considered, BL significantly predicts RFS and OS, although this value is lost once UL status is known. Our data are consistent with BL’s reflecting the ulceration status of a primary lesion. When UL status is unknown, BL may be able to serve as its surrogate marker.
Adoptive T-cell therapy combined with intra-lesional administrations of TG1042 (adenovirus expressing interferon-γ) in metastatic melanoma patients.
Authors: Khammari Amir , Limacher Jean-Marc , NGuyen Jean-Michel , Saint-Jean Melanie , Quereux Gaelle , Brocard Anabelle , Peuvrel Lucie , Knol Anne-Chantal , Saiagh Soraya , Bataille Vincent , Dreno Brigitte
Published: March 2020

e20022

Background: The purpose of this study was to evaluate the feasibility, safety and efficacy of adding intra-tumoral injections of TG1042 (Adenovirus 5 expressing Interferon-γ) to adoptive T cell therapy in patients with advanced stage melanoma. Methods: This was a monocentric phase I/II study. The main inclusion criteria were: stage IIIc/IV melanoma, age 18 to 75, at least one injectable metastasis. Tumor infiltrating lymphocytes (TILs) produced from a surgical biopsy of a lesion were infused on days 1 and 29 followed by IL2 injections (6M UI daily) for 10 days. TG1042 was injected at the dose of 5x1010 viral particles per lesion (in up to 6 lesions) every 2 weeks from day -15 to month 2 and then every month up to month 11 or progression. Primary objective was the safety of the procedure; secondary objectives included response according to RECIST and translational research. Results: Eighteen patients have been included. The TILs production was successful in 16 of them. Minor erythema at the TG1042 injection site as well as minor to moderate flu-like symptoms linked to IL2 injections were the most frequent adverse events observed. No grade 3 or 4 treatment related adverse events was recorded. Among the 13 patients evaluable for tumor response 4 patients (31%) had an overall objective response (2 complete, 2 partial), 1patient had a stable disease and 8 progressed. When considering only the injected lesions 6 (46%) had an objective response (3 complete, 3 partial), 3 had a stable disease and 4 progressed. Distant responses in non-injected lesions were observed for 2 patients. Translational research on cutaneous biopsies before and after injections (3 months) showed an increase of CD8 T lymphocytes, IFN-γ and STAT 1 expression in 3 patients. Conclusions: This study demonstrates that co-delivery of TILs and intra lesional TG1042 is feasible and safe. Stimulation of innate immunity by adenovirus expressing interferon-γ could contribute to reverse the immunotolerant profile of the tumour environment. These results support to further explore combined immunotherapies in the treatment of melanoma. Clinical trial information: NCT01082887.
Use of preoperative ultrasound (US)-guided fine needle aspiration cytology (FNAC) to identify positive sentinel nodes (SN) in melanoma.
Authors: Van Akkooi Alexander Christopher Jonathan , Siegel Petra , Gooskens Saskia , Schoengen Alfred , Sterry Wolfram , Eggermont Alexander M. , Voit Christiane A.
Published: March 2020

e20035

Background: The surgical Sentinel Node (SN) is standard of care worldwide for the staging of AJCC stage I/II melanoma patients. It remains unclear if SN followed by early lymph node dissection in case of metastasis can lead to a survival benefit. Unlike other cancers, US-guided-FNAC has not been proven effective in melanoma. Aim was to analyze sensitivity (sens), specificity (spec), positive (PPV) and Negative (NPV) predictive values with use of the Berlin Morphology criteria, a low threshold for performing repeated FNAC and overnight cytology reports. Methods: Between 2001 and 2010 over 1,000 stage I / II consecutive melanoma pts have undergone US-FNAC prior to SN. All patients underwent lymphoscintigraphy prior to US-FNAC. Peripheral Perfusion (PP), Loss of Central Echoes (LCE), Balloon Shaped (BS) are the Berlin Morphology Criteria, which were registered. FNAC was performed (3-4x) in case any of these factors were seen. SN tumor burden was measured according to the Rotterdam Criteria. All patients underwent SN or LND in case of positive FNAC. Results: Mean/med Breslow thickness 2.59/1.57 mm (0.2 – 44 mm). Mean/med follow-up 39 / 32 months (0 – 115). Ulceration (ulc) present in 24 %. SN pos rate was 20.8 % (208 / 1000). 34.2% underwent FNAC. 8.9% was FNAC positive; this was 26% of all FNAC. Sens was 51%. Spec, PPV and NPV were 99%, 95% and 89%. Sensitivity was highest for T4 (76%) and in ulc (63%) tumors. PP, LCE, BS had sens of 51%, 37%, 24%. Sens of US-FNAC increased with increasing SN tumor burden (12% in < 0.1 mm to 61% in > 1 mm). PP was an early sign of metastasis (58% in < 0.1 mm mets). Threshold for pos FNAC was 0.4 mm in maximum diameter. 5-yr survival correlated to US-FNAC status (93% in neg, 51% in pos). 5-yr survival of pts with PP was 82% vs. 46% in BS vs. 92% in neg pts (P=0.001). Conclusions: US-FNAC according to the Berlin Morphology criteria can correctly identify half of the positive SNs, prior to the surgical SN procedure. PP is an early sign of metastasis, BS is a late sign. US-FNAC can significantly reduce the amount of unnecessary surgical SN procedures. US-FNAC sensitivity correlated with increasing T-stage, increasing SN tumor burden and ulc. US-FNAC can accurately predict survival.