bluuebunny/crossref_metadata_2025 huggingface dataset:
Implications of rapidity of response to initial therapy in multiple myeloma.
Authors: Ghimire Krishna Bilas , Rajkumar Vincent , Dispenzieri Angela , Lacy Martha , Gertz Morie , Buadi Francis , Dingli David , Hayman Suzanne R. , Leung Nelson , Russell Stephen , Lust John Anthony , Zeldenrust Steven R. , Lin Yi , Kapoor Prashant , McCurdy Arleigh Robertson , Kyle Robert A. , Kumar Shaji
Published: March 2020

8606

Background: The rapidity of response to initial therapy in multiple myeloma (MM) depends on a variety of factors. There is limited data on its implications on long term outcomes in patients (pts) with newly diagnosed MM. Methods: We retrospectively examined the outcomes in a cohort of 454 pts with newly diagnosed MM between Jan 2000- Dec 2011 undergoing induction therapy. Results: The median age at diagnosis was 66 yrs (29-92). Pts had measurable serum M-spike (>= 1 g/dL), dFLC (>=10 mg/dl) or 24 hour urinary M protein excretion (UrM; >=200 mg) in 70, 63 and 39% respectively. We first examined the relationship between the response to first cycle of therapy and overall survival (OS). We divided pts into quartiles based on their % reduction in the serum M spike, dFLC or UrM. The median OS (Table) was poorest for pts with the least reduction of serum M protein (P<0.001) and of dFLC. The cutoffs for Q1 was 25, 40and 40% decrease for serum M spike, dFLC and 24 hr UrM respectively. Among various baseline characteristics only higher age was predictive of a poor (Q1) response. Given the trend toward worse OS among the Q 4 group (maximum decrease in serum M spike), we examined the relationship to cytogenetic risk. Among 232 pts with FISH data available, proportion of pts with high-risk disease was 27, 12, 22 and 31% respectively in quartiles 1 - 4). In a multivariate analysis, quartile 1 and 4 of serum M-protein response and the high-risk FISH were independent risk factors associated inferior OS. Conclusions: Both shallow and very deep response to therapy in cycle 1 is a strong indicator of eventual disease outcome and should be considered as marker of high-risk disease, likely through different mechanisms. For the shallow responders, prospective trials should assess if a change in therapeutic management will alter the outcome of these pts. The rapid deep responders also appear represent a different high-risk biology, emphasizing the fact that pts with high-risk disease often have excellent initial responses, but poor long term outcomes. [Table: see text]
BRAF inhibitor (BRAFi) dabrafenib in combination with the MEK1/2 inhibitor (MEKi) trametinib in BRAFi-naive and BRAFi-resistant patients (pts) with BRAF mutation-positive metastatic melanoma (MM).
Authors: Sosman Jeffrey Alan , Daud Adil , Weber Jeffrey S. , Kim Kevin , Kefford Richard , Flaherty Keith , Infante Jeffrey R. , Hamid Omid , Cebon Jonathan S. , Schuchter Lynn Mara , McWilliams Robert R. , Sznol Mario , Sharfman William Howard , Algazi Alain Patrick , Lewis Karl D. , Little Shonda M , Sun Peng , Long Georgina , Patel Kiran , Gonzalez Rene
Published: March 2020

9005

Background: Dual inhibition of the MAP kinase (MAPK) pathway with dabrafenib (D) and trametinib (T) in combination has demonstrated clinical benefit compared to D alone in a randomized Phase II trial in V600 BRAF-mutant MM pts, thus delaying the development of BRAFi resistance. Little is known about the efficacy of D + T after BRAFi resistance has been acquired. This analysis evaluates the ability of D + T combination to treat acquired resistance compared to the D + T combination as first-line treatment. Methods: These data from a phase I/II study include 1. BRAFi-resistant group: pts who received 150/2 D+T in Part B (n=26) and Part C (n=43) following progression on BRAFi monotherapy (mono); 2. BRAFi-naïve group: pts who received initial 150/2 D+T in Part B (n=24) and Part C (n=54). Results: Baseline characteristics (ECOG PS, M staging, LDH) were similar across all groups.In the Part B BRAFi-resistant group, 93% of pts previously received D or vemurafenib and all pts received D prior to D+T in Part C. In BRAFi-resistant group, prior best response of CR/PR (38%, 56%), SD (35%, 27%), PD (27%, 7%) was observed in Parts B and C respectively. In BRAFi-resistant group, the ORR and PFS with D+T was lower than initial D+T in BRAFi-naive group. Median duration of response (DoR) in BRAFi-resistant group cannot be calculated due to small no. of pts responding. Median DoR for BRAFi-naïve pts was 11.3 mo and 10.5 mo in Parts B and C respectively. In Part C, the 12-mo overall survival rates in BRAFi-naïve (150/2) pts was 79% vs 70% for pts initially on D mono, despite 80% pts crossing over to D+T combination. Conclusions: The clinical activity for 150/2 D+T combination is consistently superior in BRAFi-naive group vs BRAFi-resistant group in both Parts B and C. Dual MAPK blockade can delay clinical resistance to BRAF inhibition. However, once BRAFi resistance has occurred, the combination of BRAFi + MEKi is far less effective. Clinical trial information: NCT01072175. [Table: see text]
Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic melanoma (mM).
Authors: Hamid Omid , Sosman Jeffrey Alan , Lawrence Donald P. , Sullivan Ryan J. , Ibrahim Nageatte , Kluger Harriet M. , Boasberg Peter D. , Flaherty Keith , Hwu Patrick , Ballinger Marcus , Mokatrin Ahmad , Kowanetz Marcin , Chen Daniel S. , Hodi F. Stephen
Published: March 2020

9010

Background: mM is an immunotherapy responsive disease where PD-L1 overexpression is prevalent. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, targets PD-L1, blocking PD-L1 from binding its receptors, including PD-1 and B7.1. Initial antitumor activity observed during dose escalation supported further expansion in mM with MPDL3280A as monotherapy and in combination with targeted therapy. Methods: Pts with mM of any histologic subtype received MPDL3280A administered IV q3w for up to 1 y. Objective response rate (ORR) was assessed by RECIST v1.1. Reported ORR includes u/cCR and u/cPR. In addition, a separate Ph 1b was initiated to evaluate the safety and efficacy of MPDL3280A with vemurafenib (vem) in pts with BRAF-V600 mutated mM. Results: As of Jan 10, 2013, 45 mM pts were treated at ≤1 (n=4), 10 (n=10), 25 (n=20) and 20 mg/kg (n=11) and evaluable for safety. Median pt age was 63 y (range 21-83 y), 100% were PS 0-1, 91% had prior surgery and 64% received prior systemic therapy. Pts received MPDL3280A treatment for a median duration of 127 days (range 1-282). The incidence of all G3/4 AEs, regardless of attribution, was 33%, including hyperglycemia (7%), elevated ALT (7%) and elevated AST (4%). No G3-5 pneumonitis was reported. No treatment-related deaths occurred on study. 35 mM pts who initiated treatment at doses of 1-20 mg/kg and enrolled prior to Jul 1, 2012, were evaluable for efficacy. An ORR of 26% (9/35) was observed, with all RECIST responses ongoing or improving. Further, some responding pts experienced tumor shrinkage within days of initial treatment. The 24-week PFS was 35%. Several additional pts had delayed antitumor activity after apparent radiographic progression and were counted as PD for the above analyses. Analysis of mandatory archival tumors showed a correlation between PD-L1 status and efficacy. Further, of three initial pts treated with MPDL3280A and vem, 2 experienced tumor shrinkage, including 1 CR. Conclusions: MPDL3280A was well tolerated as monotherapy, and durable ORs were observed. Therefore, further assessment of MPDL3280A as monotherapy and combination therapy is warranted. Clinical trial information: NCT01375842.
Phase I/II trial of PD-1 antibody nivolumab with peptide vaccine in patients naive to or that failed ipilimumab.
Authors: Weber Jeffrey S. , Kudchadkar Ragini Reiney , Gibney Geoffrey Thomas , De Conti Ronald C. , Yu Bin , Wang Wenshi , Sarnaik Amod , Martinez Alberto J , Kroeger Jodi , Eysmans Cabell , Gallenstein Donna , Zhao Xiuhua , Chen Ann
Published: March 2020

9011

Background: Nivolumab, an IgG4 fully human monoclonal antibody against checkpoint protein PD-1, is active in metastatic melanoma, renal cell and non-small cell lung cancer. It was administered with a multi-peptide vaccine to patients (pts) with unresectable melanoma who failed at least one regimen for metastatic disease and were ipilimumab naïve, or failed ipilimumab, to assess the toxicity and tolerability of the combination and perform correlative immune assays. Methods: Three cohorts of 10 HLA A0201 positive ipilimumab-naïve pts received nivolumab at 1, 3 or 10 mg/kg, then three additional cohorts of pts who had failed prior ipilimumab received nivolumab at 3 mg/kg: two cohorts of 10 pts each who were A0201 positive and had either grade 2 or less ipilimumab toxicity, or grade 3 dose limiting ipilimumab toxicity; finally 40 pts were treated with antibody who had grade 2 or less ipilimumab toxicity and were not HLA restricted. Pre-treatment archived tumor tissue as well as pre- and post-treatment peripheral blood cells were collected. Results: Median age for all pts was 59;76% were M1c. Response rates by RECIST were 28% in 34 pts naïve to, and 32% for 46 pts who failed prior ipilimumab. Nivolumab did not induce the same irAEs in pts with prior ipilimumab induced toxicity. No cohort had more than one dose limiting toxicity. 2 pts had grade 3 pneumonitis. Three of ten pts who failed nivolumb had stable disease or a partial response to subsequent ipilimumab. Biomarker studies showed that elevated NY-ESO 1 and MART-1 specific CD8 T cells pre-treatment were associated with non-response (p<0.005 and <0.001), and that CTLA-4 positive CD4 T cells and T regulatory cells were elevated after treatment in non-responders (p<0.01). Immunohistochemical analysis of pre-treatment tumors indicated that PD-L1 staining was associated with response, but responses were also observed in pts whose tumors did not stain. Conclusions: Objective responses to nivolumab were observed after failing ipilimumab, and to ipilimumab after failing nivolumab. Elevation of CTLA-4 after nivolumab in non-responders suggest that sequential therapy with the combination should be tested. Tumor PD-L1 was associated with but not predictive of response. Clinical trial information: NCT01176461.
An update on BREAK-3, a phase III, randomized trial: Dabrafenib (DAB) versus dacarbazine (DTIC) in patients with BRAF V600E-positive mutation metastatic melanoma (MM).
Authors: Hauschild Axel , Grob Jean Jacques , Demidov Lev V. , Jouary Thomas , Gutzmer Ralf , Millward Michael , Rutkowski Piotr , Blank Christian U. , Miller Wilson H. , Kaempgen Eckhart , Martin-Algarra Salvador , Karaszewska Boguslawa , Mauch Cornelia , Chiarion-Sileni Vanna , Mirakhur Beloo , Guckert Mary E. , Swann R. Suzanne , Haney Patricia , Goodman Vicki L. , Chapman Paul B.
Published: March 2020

9013

Background: Dabrafenib is a selective BRAF inhibitor with demonstrated efficacy in BRAF V600E-positive mutation in MM. The primary analysis of BREAK-3 (NCT01227889) compared progression-free survival (PFS) in patients (pts) with BRAF V600E-positive mutation MM treated with dabrafenib or DTIC. Methods: Median PFS for dabrafenib of 5.1 months (mo) and study methods were previously described (Hauschild A, et al. Lancet. 2012,380:358–365). Independent review ended at the primary analysis. PFS was updated in Jun 2012 at median follow-up of 10.5 mo for dabrafenib (67% of PFS events), and 9.9 mo for DTIC. Median overall survival (OS) was not reached, so another analysis of OS and safety was performed with data as of Dec 2012, at which time the median follow-up was 15.2 (dabrafenib) and 12.7 (DTIC) mo. PFS of subjects who crossed over was also evaluated at that time. Results: PFS hazard ratio was 0.37 [95% CI; 0.23, 0.57]; median PFS was 6.9 mo dabrafenib and 2.7 mo DTIC. In Dec 2012, 36/63 DTIC pts crossed over; median PFS was 4.3 [95% CI; 4.1, 6.1] mos. OS is presented in the Table.The four most common adverse events (AE) on the dabrafenib arm were hyperkeratosis (39%), headache (35%), arthralgia (35%), and pyrexia (32%). Serious AEs ≥ 5% on the dabrafenib arm included cutaneous squamous cell carcinoma/keratoacanthoma (10%) and pyrexia (5%). Conclusions: Longer follow-up confirms the benefits of dabrafenib on PFS and response rate. Median OS in the dabrafenib arm was over 18 mo and over 15 mo in the DTIC arm. OS results are confounded by crossover of DTIC pts to dabrafenib and likely by subsequent therapy after progression. The effects of subsequent therapy results will be investigated. The safety profile had no significant changes. Clinical trial information: NCT01227889. [Table: see text]
NRAS mutation: A potential biomarker of clinical response to immune-based therapies in metastatic melanoma (MM).
Authors: Johnson Douglas Buckner , Lovly Christine Marie , Flavin Marisa , Ayers Gregory Dan , Zhao Zhiguo , Iams Wade Thomas , Iafrate Anthony John , Berry Elizabeth Gates , Terry Charles R , Sullivan Ryan J. , Carvajal Richard D. , Sosman Jeffrey Alan
Published: March 2020

9019

Background: NRAS mutant (mut) MM comprises a distinct, molecularly defined cohort of this disease that appears to have a poor prognosis compared to other genetic subsets. In contrast to BRAF mut MM, there are no effective small molecule inhibitors specifically targeting NRAS. Immune based therapy (IT) has become a mainstay in MM treatment, especially in BRAF wild type (WT) patients (pts). Biomarkers to predict which pts will benefit from IT have not been validated. The goal of this study was to evaluate whether genetic subtype (specifically NRAS) has a role in predicting benefit from IT in BRAF WT MM. Methods: We identified 173 pts from 3 institutions who underwent clinical genotyping (exome or PCR based) for NRAS and BRAF mutation from 1/09 – 8/12 and were treated with IT (defined as IL-2, ipilimumab (ipi), or anti-PD-1 (nivolumab, MK3475)/ PD-L1 (MPDL3280A)). Only BRAF WT pts were included. Primary endpoints were response rate (RR) and clinical benefit rate (CBR), defined as RR + stable disease lasting >24 wks to IT (best response as assessed by treating clinicians in any line of IT). Secondary endpoints were overall survival (OS) and progression-free survival (PFS) from first line IT. Results: Of the 173 pts, 59 had NRAS mut MM compared to 114 WT/WT (no mutation in NRAS or BRAF). Improved clinical outcomes were seen in the NRAS mut compared to WT/WT cohort in terms of RR (32% vs. 18%, p=0.042), and CBR (49% vs. 30%, p=0.012). Improvements in PFS and OS did not reach statistical significance. By specific IT, NRAS mutation predicted benefit compared to WT/WT for anti-PD-1/PD-L1 (RR 78% vs. 19%, p=0.002; CBR 78% vs. 29%, p=0.013, n=30) and ipi (RR 18% vs. 12%, p=0.315; CBR 41% vs. 22%, p=0.018, n=137). No significant differences were observed with IL-2 (RR 33% vs. 28%, p=0.730; CBR 33% vs. 39%, p=0.741, n=33). Conclusions: This study demonstrates that pts with NRAS mut MM achieve increased clinical benefit from IT compared to pts with BRAF/NRAS WT MM. A larger, prospective analysis is necessary to validate and expand on these results, including those with BRAF mut and KIT mut MM. However, our data suggest that NRAS mutation status may be a biomarker of response to IT in MM and that molecularly targeted immunotherapy may be feasible.
Tumor-specific circulating cell-free DNA (cfDNA) to predict clinical outcome in BRAF V600 mutation-positive melanoma patients (pts) treated with the MEK inhibitor trametinib (T) or chemotherapy (C).
Authors: Schadendorf Dirk , Flaherty Keith , Hersey Peter , Nathan Paul D. , Garbe Claus , Milhem Mohammed M. , Demidov Lev V. , Hassel Jessica Cecile , Rutkowski Piotr , Mohr Peter , Dummer Reinhard , Trefzer Uwe , Larkin James M. G. , Utikal Jochen , Casey Michelle , Santiago-Walker Ademi , Sherman Laurie Jill , Martin Anne-Marie , Wu Frank S. , Robert Caroline
Published: March 2020

9020

Background: Tumor-derived cfDNA in the blood is a potential alternative source to derive tumor mutation (mut) status and could be a useful biomarker of therapeutic response. Data from METRIC (NCT01245062), an open-label randomized Phase III study evaluating the efficacy and safety of T vs C, were used to assess: correlation between baseline tumor and cfDNA BRAF muts; correlation between baseline cfDNA levels and tumor burden (i.e., the sum of target lesion diameters); and efficacy based on baseline cfDNA BRAF mut status. Methods: BRAF mut status was established for 322 pts using an allele-specific PCR assay in tumor samples. Baseline plasma samples were available for 305/322 pts. cfDNA BRAF mut status was evaluated by Inostics GmBH using BEAMing technology. Spearman correlation coefficients were used to determine the association between cfDNA fraction (mut DNA molecules > 0.01%) and baseline tumor burden. A Cox proportional hazards model was used to assess the association between cfDNA mut status and progression-free survival (PFS). Results: The overall agreement between tumor and cfDNA BRAF V600E and V600K mut status was 77%, and 96% respectively. V600E or V600K cfDNA mut fraction did not correlate with baseline tumor burden (R=0.38 and 0.23, respectively). Benefit of T vs C was observed regardless of cfDNA BRAF mut status (HR= 0.42, 0.41, 0.47 for V600E, V600K, and not detectable (cfDNA ND) subgroups). Interestingly, cfDNA ND pts had longer PFS vs cfDNA V600E/K pts, independent of treatment (HR=0.37 for cfDNA ND vs V600E/K, p=<0.0001). For T cfDNA ND median PFS was not reached (n=52), however the first quartile was 4.5 months; for V600E (n=127) and V600K (n=21) median PFS was 3.5 and 4.4 months, respectively. For C median PFS was 3.5, 1.4, and 1.5 months for cfDNA ND (n=28), V600E (n=69), and V600K (n=7), respectively. Similarly, higher response rates were seen in cfDNA ND pts vs cfDNA V600E/K pts across both treatment arms. Conclusions: Free circulating DNA can be used to detect BRAF V600 muts. cfDNA mut fraction was not linked to tumor burden. The absence of circulating BRAF mut DNA in BRAF V600 pts may be a marker of a better outcome. Clinical trial information: NCT01245062.
A phase III trial of nab-paclitaxel versus dacarbazine in chemotherapy-naive patients with metastatic melanoma: A subanalysis based on BRAF status.
Authors: Hersh Evan , Del Vecchio Michele , Brown Michael Paul , Kefford Richard , Loquai Carmen , Testori Alessandro , Robert Caroline , Li Mingyu , Elias Ileana , Renschler Markus F. , Hauschild Axel
Published: March 2020

9030

Background: Activating mutations of BRAF V600 can be found in 40%-50% of melanomas and are related to poor prognosis. In a phase 3 trial for the treatment of metastatic melanoma (MM) in chemotherapy-naive patients, nab-paclitaxel (nab-P) vs dacarbazine (DTIC) demonstrated a significant improvement in the primary endpoint of progression-free survival (PFS), assessed by independent radiological review (IRR), and a trend toward prolonged overall survival (OS) at the interim survival analysis. The study also explored the effect of BRAF status on the efficacy parameters. Methods: Chemotherapy-naive patients with stage IV melanoma (M1c stage 65%; elevated LDH 28%) and ECOG performance status 0-1 were randomized to nab-P 150 mg/m2 on days 1, 8, and 15 of a 28-day cycle (n = 264) or DTIC 1000 mg/m2 on day 1 of each 21-day cycle (n = 265) independent of BRAF status. Prespecified subgroup analyses of final PFS and interim OS in subgroups by BRAF status (V600E mutant, wild-type, or unknown) were performed. Results: BRAF mutation status was balanced between the treatment arms, with 36% and 38% of patients with known BRAF mutation status in the nab-P and DTIC arms, respectively. Patient characteristics were also balanced within BRAF subgroups. As shown in the Table, advantage in the nab-P arm vs DTIC arm was observed for both PFS and interim OS regardless of BRAFmutation status. Poststudy BRAF inhibitor treatment was also balanced. Conclusions: In this phase III trial, treatment effect was independent of BRAF mutation status, benefiting all patients who received nab-P vs DTIC. Therefore nab-P should be considered in the armamentarium for all chemotherapy-naive patients with MM. Clinical trial information: NCT00864253. [Table: see text]
Observation after a positive sentinel lymph node biopsy in patients with melanoma.
Authors: Bamboat Zubin M. , Coit Daniel G. , Konstantinidis Ioannis , Kuk Deborah , Panageas Katherine S. , Ariyan Charlotte Eielson , Brady Mary Susan
Published: March 2020

9033

Background: The therapeutic benefit of completion lymph node dissection (CLND) in melanoma patients with a positive sentinel lymph node (SLN) remains unknown. This study describes the natural history of selected patients undergoing nodal observation (no-CLND) after a positive SLN biopsy and compares outcomes with those undergoing immediate CLND. Methods: A prospective database was used to identify melanoma patients with a positive SLN biopsy from 1994 to 2012. Patient and tumor characteristics, reasons for not undergoing CLND, patterns of initial recurrence, and melanoma-specific survival data were analyzed. Results: Of 4319 patients undergoing SLN biopsy, 505 (12%) had a positive SLN. 170 (34%) patients underwent nodal observation and 335 (66%) had an immediate CLND. Patients in the no-CLND group were older (65 vs. 56 years, p<0.001) and more likely to have lower extremity lesions (43% vs. 30%, p=0.004). There were no differences in tumor thickness, Clark level of invasion, presence of ulceration, or degree of SLN tumor between groups. In 89% of cases, the reason to forgo CLND was due to doctor and/or patient decision. Median follow up was 23.5 and 78.5 months for no-CLND and CLND groups and median time to first recurrence was similar at 9 and 12 months (p=NS) respectively. There was no difference in regional recurrence rates between groups (20%). Nodal disease as a site of first recurrence occurred in 16% of patients in the no-CLND group compared with 7% of CLND patients (p<0.001). In contrast, systemic disease as first site of recurrence occurred in 8% of no-CLND patients compared with 27% of CLND patients (p<0.001). While median relapse-free survival was better after CLND (34.5 vs. 20.9 months, p=0.02), melanoma-specific survival was similar (not reached, no-CLND vs. 110 months, CLND, p=0.14). Conclusions: Immediate CLND after a positive SLN biopsy is associated with fewer initial nodal basin recurrences but similar melanoma-specific survival. These results support ongoing equipoise in the two arms of MSLT-II.
Differential genomic profiles of tumor-involved and tumor-free sentinel lymph nodes in patients with melanoma.
Authors: Tarhini Ahmad A. , LaFramboise William A , Rao Uma N. M. , Edington Howard , Pingpank James F. , Holtzman Matthew Peter , Tawbi Hussein Abdul-Hassan , Geskin Albert , Rose Amy , Milburn Christy , Merriman Michelle , Sander Cindy , Sciulli Christin , Lin Yan , Kirkwood John M.
Published: March 2020

9043

Background: For clinical stage I and II node negative melanoma the histologic status of the sentinel lymph node (SLN) is the most significant predictor of survival. Molecular characterization of node positive and node negative SLNs through gene expression profiling may improve the understanding of the molecular mechanisms of metastasis and identify specific gene signatures for SLN+/SLN- that correlate with clinical outcome. Methods: We characterized 15 SLN+ and 15 SLN- melanoma patients (T3a/b, T4a/b) who underwent SLN dissection for routine staging using transcriptome profiling analysis on 5μ sections of fresh LN samples. The primary endpoint was mRNA expression profiling using the U133A 2.0 Affymetrix gene chips. Significance Analysis of Microarrays v.4 was used to perform non-parametric analysis and statistical comparison for each transcript corrected for false discovery rate (q value) to control for type 1 errors arising from multiple tests. Pathway analysis was performed using Ingenuity Pathway Analysis software. Results: Tumor size ranged from 1-2mm in size. Twenty-one genes were expressed at significantly (q value <0.056) higher levels in SLN+ vs SLN-. These included CCNA2, CEP55, DCT, FEN1, HMMR, MLANA, PAICS, PBK, POSTN, RAB27A, RRM2, SHCBP1, SILV, TYR, CENPE, CCL20, CHEK1, LINS, TPX2, TTK, TYRP1. Pathway analysis (39 genes >1.4 fold; q < 0.12) identified the top disease categories as “Cancer” (26 genes, p = 5.7x10-9) and “Dermatological” (14 genes, p = 3.9x10-6). The top functional categories included “Cell Cycle” (21 genes p= 2.3x10-12) and “Cell Growth and Proliferation” (26 genes p=9x10-9). The relevant canonical pathways were “Eumelanin Biosynthesis” (p=3x10-5) and “Cell Cycle: G2/M DNA Damage Checkpoint Regulation” (p=1.2x10-4). Conclusions: We identified a 21 gene signature that is consistent with metastatic melanoma and its microenvironment and is differentially expressed in SLNs that are tumor involved. These gene families provide a signature of nodal involvement that may assist in diagnosis, and may be further explored towards prediction of outcome and development of therapy. A validation study is ongoing with clinical outcome association analyses as follow up is mature.
Impact of BRAF mutation and effectiveness of BRAF inhibitor on the brain metastases in patients with metastatic melanoma.
Authors: Gummadi Tulasi , Dronca Roxana Stefania , Kim Chul , Kottschade Lisa A. , Mittapalli Rajendar K , Elmquist William F. , Dudek Arkadiusz
Published: March 2020

9048

Background: Brain metastases continue to be the major cause of morbidity and mortality in patients with metastatic melanoma. The impact of BRAF mutations and effectiveness of BRAF inhibitors on the brain metastases in these patients is lacking. Methods: Preclinical studies were conducted to assessthe steady-state brain and plasma distribution of vemurafenib, a BRAF inhibitor in FVB wild-type and Mdr1a/b-/-Bcrp1-/- mice deficient in the drug efflux transporters, p-glycoprotein (P-gp) and breast cancer resistant protein (BCRP). A retrospective analysis of patients with metastatic melanoma treated at University of Minnesota from August 2011 to December 2012 was conducted. A similar analysis of cases treated at Mayo Clinic is underway. Results: The preclinical studies in mice show that both P-gp and BCRP play a significant role in limiting the brain distribution of vemurafenib. Retrospective analysis was performed on 57 patients with Stage IIIc /IV cutaneous and mucosal melanoma. Patients with BRAF mutation had a higher incidence rate of brain metastases compared to patients without BRAF mutation, although it was not statistically significant (Incidence ratio=1.56; 95% CI=0.70-3.48; P=0.27). Vemurafenib neither reduced the incidence of brain metastases (Incidence ratio = 0.89; 95% CI: 0.30-2.60; P=0.83) nor made significant difference in overall survival. It was observed that treatment with BRAF inhibitor led to improvement in extracranial disease but did not affect progression of intracranial disease. Conclusions: In concordance with preclinical data which indicates that P-gp and BCRP play a significant role in limiting the brain distribution of vemurafenib, the retrospective analysis shows that there is improvement in extracranial disease but progression in intracranial disease with treatment with BRAF inhibitor in patients with metastatic malignant melanoma with BRAF mutation. Development of BRAF inhibitors that are not substrates for P-gp and BCRP or concomitant use of P-gp and BCRP inhibitors with vemurafenib, may be needed in order to control or prevent intracranial disease in these patients. Further analysis to improve statistical power of our observation is underway.
Impact of age on treatment of primary melanoma patients.
Authors: Fleming Nathaniel H. , Tian Jiaying , Vega-Saenz de Miera Eleazar , Gold Heidi L. , Darvishian Farbod , Pavlick Anna C. , Berman Russell S. , Shapiro Richard L. , Polsky David , Osman Iman
Published: March 2020

9054

Background: Although patient age at diagnosis is not currently included in guidelines for treatment of primary melanoma, several lines of evidence suggest that patient age is an important, yet understudied, factor when considering treatment options. Here, we attempt to address the limited knowledge of the impact of age on primary melanoma treatment. Methods: In a prospectively enrolled and followed-up cohort of melanoma patients at NYU, we used logistic regression models to evaluate the association between patient age at diagnosis, tumor baseline characteristics, including BRAF and NRAS mutation status, and likelihood of receiving and responding to adjuvant therapy. We examined adjuvant therapy effectiveness using recurrence and melanoma-specific survival as endpoints. Results: 444 primary melanoma patients were included in the study (median follow-up: 6.3 years; age range: 19-95 years). Age was categorized into three groups spanning the range of age at presentation: younger (19-45 years; 24%), middle (46-70 years; 50%), and older (71-95 years; 26%). Older patients were significantly more likely to have advanced stage, nodular subtype (P < 0.01, both variables), and BRAF wildtype tumors (P = 0.04). Controlling for these factors as well as gender, older patients experienced a higher risk of recurrence (HR older vs. younger 3.34, 95% CI 1.53-7.25; P < 0.01). Of the 128/444 (29%) patients who were eligible for adjuvant treatment (clinical stage ≥ IIB), only 67/128 (52%) received treatment. Using a propensity score that accounts for stage at presentation, patients in the middle age group were more likely to receive adjuvant therapy than those in the older group (OR 2.61, 95% CI 1.12-6.08; P = 0.03). In addition, a trend suggesting benefit from adjuvant therapy (defined as longer melanoma-specific survival) was observed only in the middle age group (P = 0.07). Conclusions: Our data suggest that older melanoma patients, despite having a significantly worse prognosis, are less likely to receive and benefit from adjuvant therapy. Further work is needed to understand the biological variables contributing to the limited response to treatment in elderly primary melanoma.
Vemurafenib (VEM) in patients (pts) with BRAF-mutant melanoma and brain metastases (mets).
Authors: Harding James J. , Catalanotti Federica , Yaqubie Amin , McDermott Gregory C. , Kersellius Romona , Merghoub Taha , Carvajal Richard D. , D'Angelo Sandra P. , Dickson Mark Andrew , Schwartz Gary K. , Wolchok Jedd D. , Berger Michael F. , Solit David B. , Chapman Paul B.
Published: March 2020

9060

Background: Emerging data suggest that RAF inhibitors are an effective therapy for pts with BRAF-mutant melanoma and brain mets. Although reported efficacy is encouraging, these data are derived from case reports or early stage trials enriched with physiologically fit pts. It is therefore of interest to assess the “real world” experience of VEM in this population. Methods: Records of all BRAF-mutant melanoma pts treated with RAF inhibitors at our center from 2007 to 2012 were reviewed retrospectively. We determined the best overall response rate (BORR) and, when applicable, the overrall intracranial response rate (OIRR) by RECIST v1.1, progression-free survival (PFS), and overall survival (OS) to RAF inhibition. Pretreatment formalin-fixed, paraffin-embedded tumor was assessed using an exon capture assay able to sequence coding exons of 279 cancer-associated genes. Results: 21 (18%) of 119 pts with BRAF-mutant melanoma treated with VEM had active brain mets (age range: 25-86, sex: 52% men, median ECOG PS: 1, proportion with extracranial mets: 90%, BRAF mutation: 86% V600E and 14% V600K). 10/21 pts had no prior intracranial (IC) therapy; 11/21 pts received whole brain radiotherapy (WBRT, 7/21), stereotactic radiosurgery (1/21), metastasectomy (2/21) or multimodality therapy (1/21) prior to VEM. 12/21 pts received ipilimumab sometime during their disease course. For radiographically evaluable pts (N=17), the BORR was 65% (95% CI: 43-88) and the OIRR was 40% (95% CI: 15-65). For 4 pts, the BORR and OIRR were discordant−3 pts had IC progression but visceral tumor shrinkage, 1 pt had IC disease control but visceral progression. VEM was effective in pts whether or not they had received prior local brain therapy. The estimated median PFS and OS for all brain mets pts (N=21) were 4 and 8 months, respectively. Pretreatment tumor is available for exon sequencing in approximately half of these patients. This analysis is ongoing. Conclusions: In routine clinical practice, the OIRR to VEM was 40% which is higher than historical response rates to WBRT. VEM may be preferable to WBRT as a first-line therapy for pts with BRAF-mutant melanoma and brain mets. Whether RAF inhibitor treatment improves OS in this population will require further study.
Survival patterns following brain metastases for patients with melanoma in the targeted therapy era.
Authors: Wattson Daniel A. , Shih Helen Alice , Niemierko Andrzej , Merritt Ryan M. , Lawrence Donald P. , Oh Kevin S. , Sullivan Ryan J. , Flaherty Keith
Published: March 2020

9064

Background: Survival from metastatic melanoma (MM) has been significantly prolonged with the introduction of molecularly targeted therapy, including BRAF inhibitors (BRAFi) for patients (pts) with the V600E mutation. Here, we present the first data describing patterns of survival after diagnosis of brain metastases (BM) in a large cohort of these pts with long follow-up. Methods: A retrospective review of 191 MM pts accrued on multiple prospective trials between 2008–2012 was conducted. These trials assessed novel immunologic and targeted therapies in pts with both BRAF mutant (n=70) and wild type/unknown (n=121) tumors. We evaluated pt characteristics and the impact of systemic and BM-directed treatments. Results: Of 98 pts who developed BM, median follow-up after first BM was 7.7 months (15.5 months for the 25 living pts), and 33 were treated with BRAFi. Median duration of BRAFi use was 5.9 months (range 0.7–27.1), which preceded BM in 30%, was concurrent with first BM in 18%, and followed first BM in 52%. Ipilimumab or anti–PD-1/PD-L1 immunotherapy was given to 58% of pts who received a BRAFi and 95% of those who did not. Limited intracranial disease on initial BM presentation (defined as ≤3 lesions) occurred in 70% of BRAFi-treated pts and 74% of non-BRAFi pts, and 70% of BRAFi pts received at least one focal BM treatment (stereotactic radiosurgery or resection) compared to 75% of non-BRAFi pts. As shown in the Table, actuarial survival after BM diagnosis was prolonged among pts treated with a BRAFi. This is due primarily to the nearly 2-year median survival of pts for whom a BRAFi was initiated after BM were diagnosed. Conclusions: Survival for pts with BM from BRAF mutant MM can significantly exceed the often anticipated 4–6 months, particularly if a BRAFi is initiated after BM arise. This supports BRAFi activity in intracranial disease, and helps to inform trials currently under way testing BRAFi use among MM pts with previously diagnosed BM. [Table: see text]
Correlation between efficacy and toxicity in pts with pretreated advanced melanoma treated within the Italian cohort of the ipilimumab expanded access programme (EAP).
Authors: Di Giacomo Anna Maria , Grimaldi Antonio M , Ascierto Paolo Antonio , Queirolo Paola , Del Vecchio Michele , Ridolfi Ruggero , De Rosa Francesco , De Galitiis Federica , Testori Alessandro , Cognetti Francesco , Bernengo Maria Grazia , Savoia Paola , Guida Michele , Strippoli Sabino , Galli Luca , Mandala Mario , Parmiani Giorgio , Rinaldi Gaetana , Aglietta Massimo , Chiarion-Sileni Vanna
Published: March 2020

9065

Background: Ipilimumab was the first agent approved for the treatment of unresectable or metastatic melanoma that showed an overall survival benefit in randomised phase III trials. Early clinical studies explored the potential relationship between immune-related adverse events (irAEs) associated with ipilimumab and antitumor activity but no definitive conclusion has been reached. Here, we evaluated the possible correlation between efficacy of ipilimumab treatment and irAEs in patients (pts) enrolled in the EAP in Italy. Methods: Ipilimumab was available upon physician request for pts aged ≥16 years with unresectable stage III/stage IV melanoma who had either failed systemic therapy or were intolerant to ≥1 systemic treatment and for whom no other therapeutic option was available. Ipilimumab 3 mg/kg was administered intravenously every 3 weeks for 4 doses. Tumour assessments were conducted at baseline and after completion of induction therapy using immune-related response criteria. Pts were monitored for adverse events (AEs), including immune-related AEs (irAEs), using Common Terminology Criteria for Adverse Events v.3.0. Results: In total, 855 Italian pts participated in the EAP from June 2010 to April 2012 across 55 centres. Among 833 evaluable pts, 278 pts (33.4%) reported an irAE and 555 (66.6%) did not. As of December 2012, the disease control rates among pts with or without irAEs were 35.3% and 33.9% respectively. We noted that there was a difference in the distribution of pts with or without irAEs among pts who experienced a fast progression, thus not being able to receive at least 3 cycles, and pts with slow progression. In fact, due to the mechanism of action of the drug and consequent delayed onset of irAEs, pts with irAEs among fast and slow progressors were 22% and 37% respectively. Therefore, median overall survival was evaluated by adjusting the 2 groups for this factor and results showed a comparable survival between pts who reported an irAE and pts who did not (10.0 vs 9.7 months respectively). Conclusions: This exploratory analysis of EAP data suggest that activity and efficacy of ipilimumab is not related with the occurrence of irAEs.
The clinical and biologic impact of PPP6C mutations in melanoma.
Authors: Gold Heidi L. , Wengrod Jordan , Tian Jiaying , Vega-Saenz de Miera Eleazar , Nadeem Zaineb , Fleming Nathaniel H. , Shapiro Richard , Hernando-Monge Eva , Gardner Lawrence , Osman Iman
Published: March 2020

9067

Background: PP6C binds to regulatory units to affect a number of important pathways including cell proliferation and DNA repair. Recently two independent groups reported for the first time the presence of somatic mutations in the PPP6C gene in ~10% of short term cultures and limited number of human melanoma tissues. However, the clinical or biological relevance of PPP6C mutations in melanoma patients is unknown. Our objectives were to examine the clinical relevance of PPP6C mutations in a well characterized cohort of melanoma specimens linked to extensive, prospectively-collected clinical information and to explore the functional consequence of different categories of mutations. Methods: Sanger dideoxy sequencing was performed on PCR-amplified DNA from macro-dissected FFPE tumors. Associations between PPP6C mutations and baseline characteristics, recurrence, survival, and BRAF/ NRAS mutational status were examined. The impact of mutations on binding PP6C regulatory units was assessed as well as the effect on additional downstream pathways. Results: 308 primary melanoma patients (118 Stage I, 92 Stage II, and 98 Stage III) were examined (median follow up: 5.3 years). 50 PPP6C mutations in 33 patients (10.7%) were identified with 11 tumors harboring more than one mutation. One mutation (R301C) was identified in 6 patients. PPP6C mutations occurred with similar frequencies across stages and showed no association with BRAF or NRAS mutations. Mutations were categorized into 3 groups: Mutations resulting in premature stop codon (n=9), those occurring in the active site (n=16) and others (n=8). 8/9 (89%) patients with stop mutations recurred and developed visceral metastases. Functional studies revealed that PPP6C mutants also behaved differently; some PPP6C mutations led to decreased binding to regulatory subunits, others, including the R301C mutation did not. Conclusions: Our data suggest that PPP6C mutation is an early event in melanoma progression and independent of BRAF or NRAS mutations. Data also suggest different biologic and clinical impact of PPP6C mutations, with stop mutations showing association with development of visceral metastases that requires further clinical and functional study.
Personal melanoma risk awareness versus intrinsic risk.
Authors: Robert Caroline , Lebbé Céleste , Ricard Sevrine , Saiag Philippe , Grange Florent , Mortier Laurent , Lhomel Christine , Sassolas Bruno
Published: March 2020

9069

Background: Intrinsic risk factors for melanoma include personal and family history of the condition, a high number of naevi and a light skin phototype (I or II). The objective of this study was to evaluate the correlation between personal awareness of melanoma risk and objective risk factors and to analyze the elements associated with under-or over-evaluation of the actual risk. Methods: EDIFICE melanoma, a nationwide French observational survey, was conducted through phone interviews on a representative sample of 1502 subjects aged ≥ 18 using typical quotas. The survey took place from 28th Sept 2011 to 20th Oct 2011. Results: 393 subjects (26%) had at least one melanoma risk factor: personal: 1%; family history: 11%; high number of naevi: 8% and phototype I-II: 11%. 1109 (74%) had no risk factor. 1029 (73%) had a correct perception of their risk level, 135 (10%) overestimated their risk and 241 (17%) underestimated it. Compared to the control group (correct perception), the population overestimating the melanoma risk is characterised by a higher percentage of individuals living alone (32% vs. 24%, p<0.05), socio-professional category + (38% vs. 28%, p<0.01) and greater alcohol consumption (45% vs. 34%, p<0.02). They are also more likely to expose themselves to the sun (89% vs. 78%, p<0.004) and less likely to use sunscreen protection (58% vs. 44%, p<0.003). A greater proportion of them participates in melanoma screening programmes (21% vs. 14%, p<0.04). The population that underestimates the risk is characterised by lower educational attainment (11% vs. 7%, p<0.05), greater use of high SPF sunscreen (41% vs. 29%, p<0.0004) and a more frequent use of UV sunbeds (9% vs. 6%, p<0.06). Conclusions: Overall, the French have a fair perception of their personal likelihood of developing melanoma. Interestingly, subjects overestimating their intrinsic risk do not behave appropriately with respect to sun protection measures (more sun exposure and less sunscreen protection). On the other hand, subjects underestimating their risk use UV sunbeds more extensively.
Italian cohort of ipilimumab expanded access programme (EAP): Efficacy, safety, and correlation with mutation status in metastatic melanoma patients.
Authors: Queirolo Paola , Spagnolo Francesco , Altomonte Maresa , Chiarion-Sileni Vanna , Pigozzo Jacopo , Del Vecchio Michele , Di Guardo Lorenza , Ridolfi Ruggero , Scoppola Alessandro , Ferrucci Pier Francesco , Ferraresi Virginia , Bernengo Maria Grazia , Guida Michele , Marconcini Riccardo , Mandalà Mario , Parmiani Giorgio , Rinaldi Gaetana , Aglietta Massimo , Simeone Ester , Ascierto Paolo Antonio
Published: March 2020

9070

Background: Ipilimumab was the first agent approved for the treatment of unresectable or metastatic melanoma to show a survival benefit in randomised phase III trials. Efficacy and safety of ipilimumab treatment outside of clinical trials and the correlation with BRAF and NRAS mutation status were evaluated. Methods: Ipilimumab was available upon physician request for patients (pts) aged ≥16 years with unresectable stage III/stage IV melanoma who had either failed systemic therapy or were intolerant to ≥1 systemic treatment and for whom no other therapeutic option was available. Ipilimumab 3 mg/kg was administered intravenously every 3 weeks for 4 doses. Tumour assessments were conducted at baseline and after completion of induction therapy using immune-related response criteria. BRAF and NRAS mutation status was retrospectively collected for all available pts. Patients were monitored for adverse events, including immune-related AEs, using Common Terminology Criteria for Adverse Events v.3.0. Results: In total, 855 Italian pts participated in the EAP from June 2010 to January 2012 across 55 centres. With a median follow-up of 6.5 months (range 0.5-30), the disease control rate among 833 pts evaluable for response was 34.3%: 28 pts (3.4%) with complete response, 83 (10.0%) with partial response and 175 (20.9%) with stable disease. As of December 2012, median progression-free survival and overall survival were 3.3 months and 7.2 months respectively, with 1-year survival rate of 36%. The Table shows mutation status for available patients. Disease control rates were comparable among pts with BRAF positive tumors and BRAF wild-type (37.5% vs 39.5%) and among pts with NRAS positive tumors and NRAS wild-type (57.1% vs 49.3%). Survival curves were also comparable between groups. 399 pts (46.7%) had a AEs of any grade, with 286 (33.5%) considered IrAEs. IrAEs were reversible with protocol specific guidelines. Conclusions: Based on EAP data, ipilimumab is an effective and safe treatment for pretreated pts with metastatic melanoma regardless BRAF and NRAS mutation status. [Table: see text]
Dissection of anti-CTLA4-induced cytotoxic T-cell responses in melanoma.
Authors: Haanen John B. A. G. , Kvistborg Pia , Philips Daisy , Kelderman Sander , Heemskerk Bianca , Ottensmeier Christian , Speiser Daniel E , Michielin Olivier Alain , Romano Emanuela , Blank Christian U. , Schumacher Ton
Published: March 2020

9078

Background: There is strong evidence that melanoma-reactive T cells induced by immunotherapeutic interventions such as anti-CTLA4 therapy can exert clinically effects. However, there is very little information on how these therapies influence tumor-specific T cell responses. Furthermore, as the number of potential melanoma-associated antigens to which these responses can be directed is very high, classical strategies to map cytotoxic T cell reactivity do not suffice. Knowledge of such reactivities would be useful to design targeted strategies, selectively aiming to induce immune reactivity against these antigens. Methods: We have addressed these issues by designing MHC class I molecules occupied with UV-sensitive ‘conditional’ ligands, thereby allowing the production of very large collections of pMHC complexes for T cell detection. Secondly, we have developed a ‘combinatorial coding’ strategy that allows parallel detection of dozens of different T cell populations within a single sample. The combined use of MHC ligand exchange and combinatorial coding allows the high-throughput dissection of disease- and therapy-induced CTL immunity. We have used this platform to monitor immune reactivity against a panel of 145 melanoma-associated epitopes in patients receiving Ipilimumab treatment. Results: Comparison of PBMC samples from 32 melanoma patients pre- and post-therapy indicated a significant increase in the number of detectable melanoma-associated T cell responses (p=0.004). Furthermore, kinetic data on T cell responses during therapy suggests that this broadening generally occurs within weeks after start of therapy. The magnitude of melanoma-specific T cell responses that was detectable prior to start of therapy was not significantly altered (p=0.8). Conclusions: These results establish the pattern of melanoma-specific T-cell reactivity induced by anti-CTLA4 treatment and form a benchmark for evaluation of other immunotherapeutic interventions, like anti-PD1 treatment, that are currently undergoing clinical evaluation. Furthermore, our data suggests that the clinical activity of Ipilimumab may be mostly due to epitope spreading, rather than through enhancement of pre-existing immune activity.