bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of BRAF and NRAS mutation status in advanced melanoma patients treated with anti-CTLA-4 antibodies: Association with overall survival?
Authors: Mangana Joanna , Goldinger Simone M. , Schindler Katja , Rozati Sima , Frauchiger Anna L. , Rechsteiner Markus , Moch Holger , Romano Emanuela , Kaehler Katharina C. , Michielin Olivier , Hauschild Axel , Hoeller Christoph , Dummer Reinhard
Published: March 2020

9025

Background: Ipilimumab and tremelimumab are human monoclonal antibodies against cytotoxic T-lymphocyte antigen-4 (CTLA-4). Ipilimumab was the first agent to show a statistically significant benefit in overall survival with durable-long-term responses for advanced melanoma patients both in first-and second-line setting. Up to date, there is no proven association between the BRAF-V600E mutation and the disease control rate (DCR) in response to Ipilimumab. Moreover, significantly shorter survival rates have been reported in patients harboring an NRAS mutation than in those without. This retrospective analysis was carried out to assess if BRAF (V600) and NRAS mutation status affects the clinical outcome of Ipilimumab-treated melanoma patients. Methods: This is a retrospective multi-center analysisof 71 patients, with confirmed BRAF and NRAS mutation status, treated with anti-CTLA-4 antibodies from December 2006 until August 2012. The cut-off for the estimation of overall survival was end of November 2012. Results: The median overall survival of BRAFV600/NRAS mutant patients (n=44) was 1,41 years compared with 2.67 years in BRAF/NRAS wild-type patients (n=27). Although this difference was not statistically significant there was a trend for improved survival in wild-type patients. Of the 71 patients analyzed, 56 received chemotherapy prior to Ipilimumab. In the BRAF/NRAS mutant cohort, 12 patients received Ipilimumab following either a BRAF- or a MEK- inhibitor. Of those 12 patients, 8 progressed and were unable to complete Ipilimumab. Of the 4 patients who completed 4 cycles of Ipilimumab, 2 were subsequently treated with a BRAF inhibitor. Furthermore out of the 71 patients, 8 patients received a BRAF or a MEK inhibitor after progression; 5 of them are still alive. Conclusions: This is the first retrospective study to evaluate the association of both BRAF and NRAS mutational status with the overall survival of Ipilimumab-treated patients. There was a trend towards an improved survival in the BRAF/NRAS wild-type subpopulation. Additional patients will be examined to foster these preliminary results.
Initial results from a phase I, open-label, dose escalation study of the oral BRAF inhibitor LGX818 in patients with BRAF V600 mutant advanced or metastatic melanoma.
Authors: Dummer Reinhard , Robert Caroline , Nyakas Marta , McArthur Grant A. , Kudchadkar Ragini Reiney , Gomez-Roca Carlos , Sullivan Ryan J. , Flaherty Keith , Murer Carla , Michel Daniela , Tang Zhongwen , De Parseval Laure A. , Delord Jean-Pierre
Published: March 2020

9028

Background: LGX818, a potent and selective BRAF inhibitor (BRAFi) being investigated in BRAF V600 mutant melanoma, has unique biochemical properties with a dissociation half-time > 10 times longer than other BRAF inhibitors. Methods: A phase I trial of LGX818 administered orally once (qd) or twice (bid) daily in BRAF V600 tumors was initiated to define the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) and to assess pharmacokinetics and clinical activity in BRAFi–naive or pretreated patients with BRAF V600 mutant advanced melanoma. Baseline assessment of biomarkers from MAPK/PI3K pathways and pharmacodynamics were also evaluated. Results: Fifty-four patients have been enrolled in the dose-escalation phase (dose levels [DLs], 50-700 mg qd [n=42] and 75-150 mg bid [n=12]). LGX818 plasma concentrations increased proportionally by dose with a mean t1/2 of 4 hours and steady state in ≈ 15 days. The MTD/RP2D (450 mg qd) was well tolerated. Seven patients had a dose limiting toxicity (DLT): 5 at qd (1 each with hand-foot skin reaction [HFSR], foot pain, fatigue, diarrhea/rash, insomnia/asthenia) and 2 at bid (1 facial paresis/confusion, 1 musculoskeletal pain/neuralgia). All DLTs were grade 3 and reversible. The most common adverse events (≥ 20%) suspected to be treatment related were cutaneous (rash, dry skin, HFSR, pruritus, keratosis pilaris, alopecia), pain in extremity, arthralgia, and fatigue. Squamous cell carcinoma was observed in 2 patients (1 naive and 1 pretreated). As of 30 Sept 2012, the preliminary efficacy (all DLs) in patients with at least 1 postbaseline tumor assessment was 16 partial responses [PRs] (67%; 12 confirmed) out of 24 BRAFi–naive patients and 2 PRs (8.3%; 1 confirmed) among 24 BRAFi–pretreated patients. Responses were seen at all DLs from 50 to 550 mg qd. Updated safety and efficacy including time to event endpoints will be reported. Conclusions: Initial results from this study identified the MTD/RP2D as 450 mg/day and provided an early sign of promising activity in advanced melanoma. Expansion cohorts are ongoing in BRAFi–naive and BRAFi–pretreated melanoma and colorectal cancer. Clinical trial information: NCT01436656.
Preliminary results from a phase Ib/II, open-label, dose-escalation study of the oral BRAF inhibitor LGX818 in combination with the oral MEK1/2 inhibitor MEK162 in BRAF V600-dependent advanced solid tumors.
Authors: Kefford Richard , Miller Wilson H , Tan Daniel Shao-Weng , Sullivan Ryan J. , Long Georgina , Dienstmann Rodrigo , Tai Wai Meng David , Flaherty Keith , Stutvoet Simone , Schumacher Karl Maria , Wandel Simon , De Parseval Laure A. , Tabernero Josep
Published: March 2020

9029

Background: Clinical data indicate that combining a BRAF and a MEK inhibitor (BRAFi, MEKi) may be more effective than BRAFi monotherapy in BRAF-mutant metastatic melanoma and that a MEKi may overcome or delay resistance to a BRAFi. Methods: This ongoing phase 1b/2 study is evaluating the combination of LGX818, a potent, selective BRAF inhibitor, and MEK162, a selective MEK1/2 inhibitor, in BRAFi-naive and -pretreated patients with BRAF-mutant tumors. The objective of the phase 1b part is to determine the maximum tolerated dose and/or recommended phase 2 dose (RP2D) for oral, daily LGX818 + MEK162 in BRAF V600–mutant advanced solid tumors. A Bayesian logistic regression model with overdose control guides the treatment dose escalation. Results: As of January 8, 2013, 20 patients (7 BRAFi-naive melanoma; 9 BRAFi-pretreated melanoma; 2 BRAFi-naive thyroid cancer; 1 BRAFi-naive metastatic colorectal cancer; 1 BRAFi-pretreated colorectal cancer) were treated with LGX818 qd + MEK162 bid at the following dose levels (DLs): 50 mg + 45 mg, 100 mg + 45 mg, 200 mg + 45 mg, and 400 mg + 45 mg. No dose-limiting toxicity has been observed at these DLs. The next DL of 600 mg + 45 mg is under investigation. The single agent RP2Ds for LGX818 and MEK162 are 450 mg and 45 mg, respectively. The most common adverse events (≥ 20%, all grades) suspected to be treatment related were nausea, abdominal pain, and headache. No events of fever, hand-foot-skin reactions, hyperkeratosis, or squamous cell carcinoma were observed. In patients with at least 1 post-baseline CT scan available for investigator-determined response, a complete response was observed in 1/7 (14%) BRAFi-naïve melanoma patients and partial responses were observed in 5/7 (71%) BRAFi-naive melanoma patients, 2/9 (22%) BRAFi-pretreated melanoma patients (starting at 50 mg + 45 mg DL), and 1/2 thyroid cancer patients. Conclusions: Preliminary data from this study indicate that LGX818 + MEK162 can be safely combined with promising clinical benefit. No febrile events or photosensitivity were reported suggesting a distinct safety profile for this BRAFi/MEKi combination vs others. Clinical trial information: NCT01543698.
Sunitinib versus dacarbazine as first-line treatment in patients with metastatic uveal melanoma.
Authors: Sacco Joseph J , Nathan Paul D. , Danson Sarah , Lorigan Paul , Nicholson Steve , Ottensmeier Christian , Corrie Philippa , Steven Neil , Goodman Andrew , Larkin James M. G. , Evans T. R. Jeffry , Kumar Satish , Coupland Sarah E , Silcocks Paul , Marshall Ernie
Published: March 2020

9031

Background: Uveal melanoma (UM) is a rare cancer with a propensity for metastasis. There are no effective systemic therapies for metastatic UM, although dacarbazine is commonly used in practice. Sunitinib is a tyrosine kinase inhibitor with activity against several targets including c-Kit and VEGF receptors, both of which have been implicated in the pathogenesis of UM. Methods: In this randomized multicentre, phase II study (SUAVE), patients (pts) with metastatic UM, ECOG PS 0-2, and no prior systemic therapy for advanced disease, were randomized 1:1 to sunitinib (50mg daily for 28 days, followed by a 14 day break), or dacarbazine (1000 mg/m2once every 21 days). Crossover was permitted on progression. The primary endpoint was PFS; secondary endpoints included response rate and OS. A sample size of 124 was planned, with a power of 0.9 to detect an increase in 3 month PFS from 0.2 to 0.4 (HR: 0.563) and a one-sided alpha of 0.05. A preplanned futility analysis was performed after 50% of events, and recruitment stopped early, due to low conditional power (0.17% under current trend). Presentation of results was approved by DMC. Results: 74 pts from 12 centres were randomized over 24 months. Overall response rates of 0% and 8% were observed in the sunitinib and dacarbazine arms; while stable disease was observed in 24% of pts on sunitinib, and 11% on dacarbazine. PFS and OS were not improved with sunitinib (see Table). 11 pts in the sunitinib arm and 23 in the dacarbazine arm underwent crossover on progression. No unexpected AEs were observed, and no deaths due to toxicity occurred. Conclusions: In these preliminary results sunitinib did not have significant clinical activity in metastatic UM. This trial is one of the largest undertaken in metastatic UM and demonstrates that timely recruitment to collaborative multicentre randomized trials is achievable in this rare disease. Clinical trial information: 75033520. [Table: see text]
Final efficacy results of NCIC CTG IND.202: A randomized phase II study of recombinant interleukin-21 (rIL21) in patients with recurrent or metastatic melanoma (MM).
Authors: Petrella Teresa M. , Mihalcioiu Catalin Liviu Dragos , McWhirter Elaine , Belanger Karl , Savage Kerry J. , Song Xinni , Hamid Omid , Cheng Tina , Davis Mary L. , Lee Christopher W , Spatz Alan , Monzon Jose Gerard , Hagerman Linda , Chen Bingshu E , Dancey Janet
Published: March 2020

9032

Background: rIL21 is a T-cell derived cytokine with antitumor activity dependent on NK cells or CD8+ T cells through induction of central and effector memory cells. A previous phase II study demonstrated an ORR of 22.5% in previously untreated patients with MM. We conducted a multicentre randomized phase II study of MM evaluating the efficacy, toxicity, pharmacokinetics, immunogenicity, and biomarkers of rIL21 versus dacarbazine (DTIC). Methods: Eligible patients: Recurrent or MM, with either maximum tumour lesion size of < 50 mm or LDH < 2.5 x ULN and prior therapy with BRAF/MEK inhibitors allowed. Patients were treated with either rIL-21, 30 µg /kg/day dose IV daily x 5 days weeks 1, 3, 5 q 8 weeks or dacarbazine (DTIC) 1000 mg/m2 IV q 3 weeks. The primary objective was to compare progression free survival (PFS). The trial was designed to detect a hazard ratio of 1.75 with one-sided alpha of 0.1; 58 progression events were required to provide 80% power. Results: 64 patients were randomized, 32 in the rIL-21 arm and 32 in the DTIC arm. The Table summarizes key demographic and efficacy endpoints. Common rIl21 related adverse events were fatigue, rash, diarrhea, nausea, myalgia and elevated liver enzymes. At least one dose reduction/ interruption or discontinuation occurred in 32 (100%) and 27 (96.4%) of rIL21 and DTIC patients. Conclusions: Despite encouraging efficacy in prior phase I/II studies, the results suggest that rIL-21 is comparable to DTIC in this patient population. Additional biomarker analysis from this study is pending and combination studies are currently ongoing. Clinical trial information: NCT00514085. [Table: see text]
Vismodegib, a Hedgehog pathway inhibitor (HPI), in advanced basal cell carcinoma (aBCC): STEVIE study interim analysis in 300 patients.
Authors: Grob Jean Jacques , Kunstfeld Rainer , Dreno Brigitte , Jouary Thomas , Mortier Laurent , Basset-Seguin Nicole , Ascierto Paolo Antonio , Hansson Johan , Mitchell Lada , Starnawski Michal , Hauschild Axel
Published: March 2020

9036

Background: Therapy options are limited for locally advanced (la) and metastatic (m) BCC. Aberrant Hedgehog (Hh) signaling is the key driver in BCC pathogenesis. Vismodegib, a first-in-class HPI, is approved in the US for use in adults with aBCC. STEVIE is an ongoing study focusing on safety of vismodegib therapy in patients with aBCC. We present data from the third interim analysis (data cutoff: 19 October 2012), which also permits a preliminary assessment of efficacy of vismodegib in the largest study ever conducted in patients with aBCC. Methods: Adult patients with laBCC or mBCC received oral vismodegib 150 mg QD until progressive disease, unacceptable toxicity, or withdrawal. Safety is the primary objective of STEVIE (Common Terminology Criteria for Adverse Events 4.0). Secondary endpoints include efficacy variables. Recruitment is ongoing. Results: This analysis included 300 patients with locally advanced (n=278) or metastatic (n=22) BCC from 11 countries with potential for ≥3-month follow-up. Median treatment duration, including vismodegib interruption, was 176.5 days (range 1-455 days). Common treatment-emergent AEs (TEAEs), typically ≤ grade 2, included muscle spasm (59.3%), alopecia (49.3%), and dysgeusia (41.0%) and were comparable to prior analysis. Serious TEAEs occurred in 53 patients (17.7%). 131 (43.7%) discontinued from the study, mainly due to patient or investigator request (n=41), AEs (n=35), disease progression (n=18) or death (n=13; 7 due to AEs assessed by the investigator as unrelated to study drug, 3 due to AEs not possible to be assessed, 3 due to disease progression). Preliminary best overall response in patients with available tumor assessments (n=251) included complete response (17.5%), partial response (39.8%), stable disease (39.0%) and progressive disease (2.8%). Patient recruitment and monitoring is ongoing. Conclusions: This third interim analysis of STEVIE confirms the previously observed vismodegib safety profile but can also provide further information about the high rate of tumor control with vismodegib in a large series of patients with aBCC. Clinical trial information: 2011-000195-34.
Toward an miRNA signature for predicting outcome in patients with melanoma.
Authors: Pameijer Colette R
Published: March 2020

9039

Background: Melanoma remains a clinical challenge, as an aggressive and often unpredictable tumor. The incidence continues to increase, but treatment options are limited. One significant challenge is predicting which patients with stage I or II disease will have a poor outcome. We sought to develop a tool to assist in risk stratifying patients with melanoma. Methods: This is a prospective trial in which patients with melanoma at least 0.5mm deep were enrolled between 2007-2011. Tissue was collected from primary tumors, bulky nodes and metastatic deposits. RNA was extracted, labeled and hybridized to a miRNA microarray (Affymetrix). Hierarchical cluster method was used to find similarities among samples. A clinical patient database was maintained. Results: This study looks at 58 intermediate and high risk subjects. The median depth of melanoma was 3mm. The median age was 69 (range 26-95) and most patients (48/58, 83%) were treated with surgery alone, with ten receiving adjuvant therapy. All patients underwent wide excision, and 43 patients had sentinel node biopsy. Twenty-seven patients developed a recurrence (47%), and 19 (33%) patients have died, 14 from melanoma. The median length of follow-up is 21 months (range 1-76 months). A total of 112 probes are differentially expressed at a p value of 0.005. The largest number of differentially expressed probes relate to location of the tumor. Other significant differences are origin of the specimen (primary versus node), mitotic rate and subject age. High expression of miR-193b was correlated with death from melanoma, p=0.05. Parameters with no differential expression include gender, tumor depth and subtype, and ulceration. Conclusions: Microarray analysis of miRNAs is a reliable platform to obtain prognostic information about melanoma. The miRNA signatures found in this patient population reinforce some well described differences among patients with melanoma, and fail to find a difference between other groups thought to be clinically important. Tumor genetic profiling may provide better risk stratification of patients with melanoma than clinical parameters alone.
Adjusting for treatment crossover in the BREAK-3 metastatic melanoma trial for dabrafenib: Preliminary analysis.
Authors: Latimer Nicholas , Abrams Keith R. , Amonkar Mayur , Stapelkamp Ceilidh , Swann R. Suzanne
Published: March 2020

9044

Background: In BREAK-3, dabrafenib improved PFS (hazard ratio [HR]=0.30 [95% CI 0.18–0.51; p<0.0001] as of Dec 19, 2011) vs dacarbazine (DTIC) in patients (pts) with previously untreated BRAF V600E+unresectable or metastatic melanoma. In an updated analysis (data as of June 25, 2012), PFS HR=0.37 (95% CI 0.24–0.58; p<0.0001). Overall survival (OS) results may underestimate the effect of dabrafenib as DTIC pts could cross over to dabrafenib at progression. This analysis attempts to adjust for confounding effects of crossover on OS using BREAK-3 results from June 2012 data. Methods: Randomization-based crossover adjustment methods – Rank Preserving Structural Failure Time Models (RPSFTM) and the Iterative Parameter Estimation (IPE) algorithm – were used. We conducted 2 sets of analyses testing different assumptions regarding the durability of the treatment (trt) effect. “Trt group” analyses adjusted for crossover under the assumption that the trt effect is maintained until death regardless of trt duration; “On trt – observed” analyses adjusted for crossover under the assumption that the trt effect disappears upon trt discontinuation. Results are presented as HRs. Results: 187 and 63 pts were randomized to dabrafenib and DTIC, respectively. At the time of this analysis, 55.6% of DTIC pts crossed over to dabrafenib. Median duration of follow-up was 10.5 months and 76 (30.4%) pts died. Median OS has not yet been reached. Crossover adjustment results are presented in the Table. Conclusions: All RPSFTM and IPE analyses resulted in point estimates for the OS HR that represented a substantial increase in trt effect compared with the unadjusted HR of 0.75. Results are exploratory, as the OS data are not mature. Analyses will be updated when further data are available. [Table: see text]
Prognostic implication of KIT mutations in melanoma.
Authors: Roth Katherine G. , Zabor Emily C. , Colgan Marta N. , Wolchok Jedd D. , Chapman Paul B. , Schwartz Gary K. , Panageas Katherine S. , Carvajal Richard D.
Published: March 2020

9049

Background: The natural history of BRAF and NRAS mutant (mut) melanoma (mel) has been described, but prognostic implications of KIT mut mel have not. Methods: We performed a single-center retrospective review of 180 patients (pts) enriched for mucosal, acral or chronic sun-damaged skin (CSD) mel and screened for KIT, BRAF, and NRAS mut from 4/07 - 4/10 as a part of a phase II imatinib study. Pt/disease characteristics were compared using the Kruskal-Wallis or Chi-square tests. Factors associated with outcomes were assessed by Kaplan-Meier methods and multivariable Cox regression. Results: Median age, 63.7 years; 54.4% male. Primary site: 40% mucosal, 29% acral, 22% CSD, 9% others. Mut rate: 18% KIT, 16% BRAF, 14% NRAS, 52% wild-type (wt). Pathologic subtype differed by genetic subgroup (p<.001) while age, gender, and stage did not (all p>0.05). 18/26 (69%) KIT mut pts received imatinib in the metastatic (met) setting; 6/18 received > 1 other KIT inhibitor. 3/25 (12%) BRAF mut pts received vemurafenib. 8/27 (30%) KIT mut, 4/27 (15%) BRAF mut, 6/20 (30%) NRAS mut, and 6/20 (30%) wt pts received ipilimumab. 149/180 (83%) pts developed mets at a median of 2.15 years (95% CI: 1.72, 2.72). Median follow-up (FU) of pts not developing mets was 3.91 yrs (range: 0.25, 14.34). Older age (HR: 1.02, 95% CI: 1.00, 1.03) and pathologic subtype (mucosal vs CSD HR: 1.70, 95% CI: 1.02, 2.84; non-CSD/unknown vs CSD HR: 2.05, 95% CI: 1.00, 4.21) were associated with increased risk of mets but not with time from mets to death. Of 149 pts who progressed, 123 (83%) died during FU. Median time from met to death was 1.21 years (95% CI: 0.91, 1.67). Median FU from time of mets among those alive at last FU was 2.53 yrs (range: 0.06, 6.85). Mut status including KIT mut was not associated with time to first met or time from met to death. Pts who received ipilimumab from time of first distant met had reduced risk of death (HR: 0.55, 95% CI: 0.36, 0.87) independent of mut status. No impact was observed with KIT inhibition. Conclusions: KIT mut status is not an independent predictor of time to mets or survival in pts with mets. Ipilimumab improved pt outcomes regardless of mut status. The lack of impact of KIT inhibitors is likely due to the heterogeneity of KIT mut in mel but does not preclude efficacy in appropriately selected pts.
Long-term survival in patients with metastatic melanoma who received ipilimumab in four phase II trials.
Authors: Lebbé Celeste , Weber Jeffrey S. , Maio Michele , Neyns Bart , Harmankaya Kaan , Hamid Omid , O'Day Steven , Chin Kevin M. , McDowell Diane Opatt , Cykowski Lori , McHenry Brent , Wolchok Jedd D.
Published: March 2020

9053

Background: Ipilimumab (Ipi) has shown improved overall survival (OS) in two phase III trials of patients (pts) with metastatic melanoma (MM), with survival follow-up of >4 years in one trial. The present analyses provide survival follow-up of >5 years in four phase II trials of Ipi in MM. Methods: Pts with MM were enrolled in one of four phase II trials: (1) CA184-004, a biomarker study with Ipi at 3 or 10 mg/kg in treatment-naive (TN) and previously treated (PT) pts; (2) CA184-007, with Ipi at 10 mg/kg +/- prophylactic budesonide in TN and PT pts; (3) CA184-008, a single-arm study with Ipi at 10 mg/kg in PT pts; and (4) CA184-022, a dose-ranging study of Ipi at 0.3, 3, or 10 mg/kg in PT pts (crossover from lower dose groups to 10 mg/kg was allowed upon disease progression). Ipi was administered q3 wk x4 (induction), followed by maintenance (q12 wk from week 24) in eligible pts. Some pts were retreated with Ipi at 10 mg/kg upon disease progression. Along with survival data collected through March 2012 for studies 007, 008, and 022, we report updated 5-year OS data for study 004 collected through September 2012. Results: Five-year OS rates for TN and PT pts are reported in studies 007, 008, and 022, with combined analyses for TN and PT pts within each dose group in study 004 (Table). The results show that survival rates reach a plateau beginning at year 3. Conclusions: In pts who received Ipi at 3 or 10 mg/kg in phase II studies, regardless of prior treatment, a proportion (12.3–49.5%) remained alive 5 years after the start of treatment. These results demonstrate long-term survival with Ipi therapy in MM. An ongoing phase III trial will compare OS for Ipi at 3 vs 10 mg/kg in pts with MM. Clinical trial information: NCT00162123. [Table: see text]
Safety and efficacy of adjuvant anti-PD1 therapy (nivolumab) in combination with vaccine in resected high-risk metastatic melanoma.
Authors: Gibney Geoffrey Thomas , Weber Jeffrey S. , Kudchadkar Ragini Reiney , De Conti Ronald C. , Tetteh Leticia , Eysmans Cabell , Yu Bin , Martinez Alberto J , Younos Ibrahim
Published: March 2020

9056^

Background: Nivolumab (BMS-936558), a fully human monoclonal antibody targeting the programmed death-1 (PD-1) receptor, has demonstrated clinical activity in advanced metastatic melanoma patients (pts). In this phase I study, the safety and activity of nivolumab plus a multipeptide vaccine was investigated as adjuvant therapy in resected stage IIIC and IV melanoma pts. Methods: HLA-A*0201 positive pts with HMB-45, NY-ESO-1, and/or MART-1 positive tumors received nivolumab (1mg/kg, 3mg/kg, or 10mg/kg IV) with a multipeptide vaccine (gp100, MART-1, NY-ESO-1, Montanide ISA 51 VG) every 2 weeks for 12 doses followed by nivolumab maintenance every 3 months (8 doses) or until disease recurrence. The primary objective was safety and determination of maximum tolerated dose (MTD). Secondary objectives were immunologic response and relapse free survival. Results: 33 pts were enrolled: 12 pts at 1mg/kg, 10 pts at 3mg/kg, and 11 pts at 10mg/kg nivolumab. Median age was 47 yrs; 55% male and 52% M1c disease (2 IIIc, 7 M1a, 7 M1b, and 17 M1c pts). As of January 16, 2012, median follow up time was 14 months and median number of doses was 12 (20 pts still receiving therapy). A MTD was not reached. Grade 2-3 related adverse events (AEs) occurred in 27 pts with the most common AEs being fatigue, rash/pruritis, and endocrinopathies. 4 pts experienced grade 3 AEs: (colitis/diarrhea (3), rash (1)). No drug related grade 4 or higher AEs occurred. 7/33 pts have relapsed to date. One pt with biopsy-proven relapse on trial had spontaneous disease regression. Non-relapsing pts had higher pre-treatment PD-1 expression on Treg and TCD4+ cells (p=0.053) and a greater increase in Treg cells after 12 weeks on treatment (p=0.027). Among all pts, treatment led to a rise in Treg cells (p=0.015) and decreased PD-1 expression on TCD4+ and TCD8+cells (p=0.014 and p<0.001, respectively). Conclusions: Nivolumab is well tolerated in combination with vaccine and preliminary data demonstrates immunologic and clinical activity as adjuvant therapy, justifying a randomized phase III study in resected high risk melanoma pts. Clinical trial information: NCT01176474.
BEVATEM: Phase II study of bevacizumab (B) in combination with temozolomide (T) in patients (pts) with first-line metastatic uveal melanoma (MUM): Final results.
Authors: Piperno-Neumann Sophie , Servois Vincent , Bidard Francois-Clement , Mariani Pascale , Plancher Corine , Diallo Alhassane , Vago-Ady Nora , Desjardins Laurence
Published: March 2020

9057

Background: Overall survival (OS) of MUM pts remains poor (median 12 months), stressing the lack of effective therapies in this rare cancer. Targeting angiogenesis seems to be promising in uveal melanoma (UM). Antiangiogenic agents are used to treat neovascular ocular diseases such as age-related macular degeneration or proliferative diabetic retinopathy. B suppressed in vitro growth and in vivo hepatic establishment of micrometastases in experimental UM. Preclinical data suggest a potential clinical benefit of the combination of dacarbazine and B. Methods: Two-stage phase II trial; expected 6-month progression-free rate (PFR) of 40% with BEVATEM versus 15% with chemotherapy (power 94%, α risk 3%). Primary endpoint: 6-month PFR according to RECIST. Secondary objectives: response and survival rates, safety; liver perfusion CT for functional imaging of response; impact of VEGF-A gene polymorphisms on B pharmacodynamics. Treatment schedule: T 150mg/m2 d1-d7 and d15-d21 oral route, B 10 mg/kg d8 d22 IV infusion, 6 cycles (d1=d28) then B maintenance until toxicity or progression. Results: 35 evaluable pts have been enrolled from May 2010 to May 2012. First step analysis showed 3/17 first patients with disease control at 6 months and good tolerance. The final population consisted of 19 men and 16 women, median age 55 (29-72). PS was 0 in 28 and 1 in 7 pts, and the median time to metastasis was 38 months (17-62). Liver was the sole metastatic site in 29 pts.With an administered dose-intensity similar to the planned schedule, 7 and 9 pts experienced grade 3 (neutropenia 4, thrombocytopenia 1, constipation 1, pruritis 1) or grade 4 toxicities (neutropenia 3, thrombocytopenia 4, thrombosis 1) respectively. Despite no objective response, 9/35 pts showed stable disease, and the 6-month PFR was 26% [95%CI 13-41]. With a median follow-up of 18 months, 5 pts (14%) had long lasting non progressive disease with B maintenance (10+ to 29+ months). Finally, the median PFS and OS were 3 and 12 months respectively. Conclusions: BEVATEM regimen in first line MUM patients showed safety and 6-month PFR of 26% including 14% of pts with durable clinical benefit. Clinical trial information: 2009-011751-46.
Ipilimumab (Ipi) retreatment at 10 mg/kg in patients with metastatic melanoma previously treated in phase II trials.
Authors: Neyns Bart , Weber Jeffrey S. , Lebbé Celeste , Maio Michele , Harmankaya Kaan , Hamid Omid , O'Day Steven , Chin Kevin M. , McDowell Diane Opatt , Cykowski Lori , McHenry Brent , Wolchok Jedd D.
Published: March 2020

9059

Background: Ipi is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte antigen-4 to augment antitumor immune responses. In phase III study MDX010-20, where patients (pts) could be retreated if they met safety criteria and achieved an objective response or stable disease ≥3 months from the end of the induction period (q3 weeks for 4 doses), 21 of 31 pts (68%) retreated with Ipi reestablished disease control. CA184-025 is a roll-over study of extended Ipi treatment or survival follow-up in pts who received Ipi in phase II trials, with the primary objective of evaluating safety during extended treatment. We report the safety profile in pts retreated with Ipi in study 025. Methods: Eligible pts in phase II trials CA184-004, -007, -008, -022, MDX010-08, or -015 were enrolled in study 025 (N=248) to receive retreatment (at the time of progression), extended maintenance (if no prior progression), or survival follow-up only. Pts were ineligible for retreatment if they had experienced a grade 3-4 non-skin toxicity during prior Ipi therapy. Ipi was administered at 10 mg/kg, q3 weeks for 4 doses, to 111 pts who initially received Ipi induction at 0.3, 3, or 10 mg/kg in a parent study. Results: In this selected population of eligible pts, the nature and frequency of immune-related adverse events (irAEs) during retreatment were similar to those reported in previous studies, which most commonly affected the GI tract and skin (Table). There were no new types of drug-related irAEs and no grade 5 irAEs upon retreatment. Conclusions: Retreatment with Ipi at 10 mg/kg in these pts was generally well tolerated and the safety profile was similar to that during induction dosing in the parent studies. The higher frequencies of irAEs at lower doses should be interpreted with caution given the small sample sizes. An ongoing, randomized phase II trial will evaluate the clinical benefit of Ipi retreatment. Clinical trial information: NCT00162123. [Table: see text]
Evaluating the safety of anti-CTLA-4 therapy in the elderly with unresectable melanoma.
Authors: Chandra Sunandana , Madden Kathleen M. , Kannan Rajni , Pavlick Anna C.
Published: March 2020

9063

Background: Anti-CTLA-4 monoclonal antibodies demonstrated an improvement in overall survival in patients with metastatic melanoma and ipilimumab (ipi) was FDA approved in 2011. We performed a retrospective analysis of 74 elderly (age ≥ 65) patients (pts) who were treated with anti-CTLA-4 therapy (tx) and evaluated their treatment related adverse events (AEs) as well as clinical response. Methods: 65 pts were treated with ipi 3 mg/kg x 4, among whom 8 pts were re-treated with ipi 3 mg/kg x 4; 3 pts were treated with ipi 10 mg/kg x 4 with 2 pts who went on to receive maintenance tx; 2 pts were treated with tremelimumab (treme) 15 mg/kg q 3 months; 4 pts are currently undergoing tx with ipi 3 mg/kg x 4. There were 17 treatment naïve pts, and 57 pts were previously treated with 1-4 prior therapies. Thirty-nine pts received all 4 doses of ipi. There were 46 males and 28 females. Ages ranged from 65 to 90, median age 74. Melanoma subtypes included: 55 cutaneous, 8 mucosal, 7 ocular, 3 acral, and 1 unknown primary. Ten pts had M1a, 18 M1b, and 45 M1c disease. One pt had unresectable stage IIIC disease. Results: The most common tx related AEs included rash (33 AEs ≤ grade 3), diarrhea/colitis (21 AEs ≤ grade 3, with 1 grade 4 AE), fatigue (17 AEs ≤ grade 2), and pain at tumor site (17 AEs ≤ grade 2). There were 3 hepatotoxicity-related AEs, including 1 grade 5 AE; and 3 endocrinopathy-related AEs, including 1 grade 4 hypopituitarism. Toxicities were managed with corticosteroids, anti-histamines, anti-motility agents, analgesics, thyroid and cortisol supplementation. Of the 69 pts evaluable for response, 16 pts (23%) had complete response (CR) or partial response (PR), and 9 pts (13%) had stable disease (SD) as measured radiographically using mWHO criteria at least 12 weeks post completion of treatment. When analyzed within melanoma subtypes, 17 cutaneous pts (31%) had tumor response (CR, PR, SD), 6 mucosal (75%), and 2 ocular (29%). Conclusions: Anti-CTLA-4 tx, including ipi and treme, was safe and well tolerated by the elderly population. Reported adverse events and response rates were consistent with published data in younger cohorts.
Gender differences in survival from cutaneous melanoma: Analysis of United States SEER data, 1992 to 2009.
Authors: Dronca Roxana Stefania , Weaver Amy , Brewer Jerry D. , Shuster Lynne T , Kottschade Lisa A. , Morita Shane Young , Markovic Svetomir
Published: March 2020

9073

Background: An accumulating body of evidence suggests that the outcome of early-stage melanoma is influenced by endocrine and menopausal status. However, it remains controversial as to whether the superior female melanoma-specific survival (MSS) is restricted to early stage disease or if it also pertains to patients with metastatic melanoma (MM). Methods: We analyzed data from the 13 registries that participate in the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program. We identified all cases of primary invasive melanoma diagnosed between 1992 and 2009; none of the patients had a prior history of another cancer. MSS was compared between males and females, stratified by stage of disease. Age groups were defined as 18-45y, 46-54y, 55-64y, 65+y as a proxy of female menopausal status. Results: The study population included 87,165primary invasive melanoma cases (unstaged n=2834). MSS was significantly poorer for males compared to females for localized (n=72,456) and regional (n=8,945) disease for all age groups (Hazard ratio (HR) ranging from 1.21 to 2.09, all p<0.001). MSS was not significantly different between males and females for patients with distant disease at diagnosis (n= 2930; HR 0.99, 0.92, 1.11, 1.07 for each age group) and remained non-significant after adjusting for Breslow thickness, histologic subtype, anatomic site, and age group (adjusted HR 1.04 males vs. females; 95% CI 0.95-1.14; p=0.41). Conclusions: While our results were consistent with earlier reports that women have higher MSS rates compared to men for early (stage I-III) melanoma, the intriguing finding of this study was that the female survival advantage does not vary with age or menopausal status as compared to men, which is contrary to previously published reports. Furthermore, we found that the difference in survival was no longer significant for patients with MM, suggesting that sex may influence local and regional, but not distant cancer progression.
Treatment patterns in patients with early and advanced malignant melanoma.
Authors: Gastanaga Victor M. , Lethen Jan E. , Vanderwalde Ari M. , Cyprien Lori A. , Kelsh Michael A. , Kallich Joel D.
Published: March 2020

9083

Background: We seek to characterize tx patterns for patients (pts) with early stage (ES) and advanced stage (AS) malignant melanoma (MM). MarketScan is a large insurance claims database with complete diagnosis (dx) and tx information. Methods: Using MarketScan data, pts were identified between Jan 2001 and Jun 2011 using ≥1 inpatient or ≥2 outpatient MM ICD9 codes ≥6 weeks apart. Pts with a history of other malignancies or lacking records at least 1 year prior to diagnosis were excluded. Pts were considered AS if they received chemotherapy, interferon, ≥2 days of MM surgery, or a code of secondary metastases. All other pts were classified as ES. Radiotherapy, immunotherapy, chemotherapy, and surgery type were identified with HCPCS, CPT, and ICD9 procedure codes. Pts were categorized by type of progression (ToP): AS at time of dx (AS-D), ES at dx with progression to AS during follow-up (ES-P), and ES at dx with no progression during follow up (ES-NP). Results: Of 30,678 eligible pts, 55% were male, median age was 59 yrs, and median follow-up was 31 months. Initial disease locations were head and neck (21%), torso (27%), upper extremities (17%), and lower extremities (14%). Twenty-five percent (7607 pts) were identified as having AS MM during follow-up. Of these, 2,445 (8%) were AS-D, while 5162 (17%) were ES-P. The remaining 23,071 pts (75%) were ES-NP. Frequency of most extensive surgery type after diagnosis date are shown by ToP (table). No ES-NP pts received systemic tx during follow-up, but 21% of ES-P and 64% of AS-D pts received either chemotherapy, immunotherapy, or both. Agents most commonly prescribed in AS pts were interferon and temozolomide. Conclusions: The tx burden in MM pts is extensive and appears to increase with disease severity. Claims data can be a valuable tool in elucidating MM tx patterns by disease stage. [Table: see text]
Changes in the quality of life of advanced melanoma patients after 12 weeks of treatment with ipilimumab compared to gp100 in a phase III clinical trial.
Authors: Harvey Becca , Lee Dawn , Gaudin Anne-Francoise , Gueron Beatrice , Bregman Bruno , Lebbé Céleste , Borget Isabelle
Published: March 2020

9084

Background: This study analyses health-related quality of life (HRQL) outcomes for ipilimumab (ipi) with and without gp100 and gp100 alone during the 12 week treatment (T) induction period compared to baseline. The aim of this study was to express the HRQL as proportions of patients experiencing changes during the induction period, when most of the immune-related adverse events (ir-AE) on ipi occur. Methods: Data from the MDX010-20 trial, including 676 previously treated patients (pts) with unresectable stage III or IV melanoma, was analysed. Differences between ipi with/without gp100 and gp100 alone in terms of HRQL 12 weeks after randomisation according to the EORTC QLQ-C30 were searched for. The sample consisted of 388 pts (ipi: 83; ipi + gp100: 227; gp100: 78) completing both baseline and week (W)12 questionnaires. Ordinal regression was performed for these pts to determine a T effect on W12 scores (in ordered categories) whilst adjusting for key covariates. Fisher’s Exact Test was used to detect differences between Ts for each EORTC domain when considering mean change in scores, categorised as “clinically worse” (≤-10 on functional domains, ≥10 on symptoms), “stable” (>-10 to <10) and “clinically improved” (≥10 on functional domains, ≤-10 on symptoms). Results: There were no significant differences for any domain score between the 3 T arms at W12. The odds of attaining high HRQL scores at W12 were heavily dependent on the baseline scores; baseline scores explained most of the variability as per regression analysis. There was no significant difference between the 3 T arms in terms of pts showing a clinically significant reduction or improvement in HRQL. HRQL remained globally stable from baseline to W12, in > 50% of pts for most domains. Conclusions: Ipi with/without gp100 does not have a significant negative HRQL impact in stage III-IV melanoma during the T induction phase relative to gp100 alone after adjustment for differences in baseline scores. The lower rate of pts showing HQRL reduction and the absence of difference with gp100 suggest that ir-AE have little impact on HRQL. Further HRQL studies are needed, as efficacy benefits of ipi continue after W12.
Use of tumor exome analysis to reveal neo-antigen-specific T-cell reactivity in ipilimumab-responsive melanoma.
Authors: van Rooij Nienke , Haanen John B. A. G. , van Buren Marit , Philips Daisy , Toebes Mireille , Heemskerk Bianca , van Dijk Laura , Behjati Sam , Stratton Michael R. , Kerkhoven Ron M , Kesmir Can , Kvistborg Pia , Schumacher Ton
Published: March 2020

9085

Background: Evidence for T cell mediated regression of human cancer in particular melanoma following immunotherapy is strong. Anti-CTLA4 treatment has been approved for treatment of metastatic melanoma and blockade of PD-1 has shown encouraging results. However, it is unknown which T cell reactivities are involved in cancer regression. Reactivity against non-mutated tumor self-antigens has been analyzed in patients treated with Ipilimumab or with autologous TILs, but the size of these responses are modest. Therefore, T cell recognition of patient-specific mutant epitopes may be a potentially important component. Animal model data recently suggested that analysis of T cell reactivity against patient-specific neo-antigens may be feasible through exploitation of cancer genome data. However, human data have thus far been lacking. Methods: To address this we have used MHC class I peptide exchange technology allowing production of very large collections of pMHC complexes, together with a pMHC "combinatorial coding" strategy for parallel detection of dozens of different T cell populations within a single sample. Results: From a melanoma patient responding to ipilimumab treatment, we identified tumor specific mutations via exome sequencing of tumor material. The exome contained 1,075 non-synonymous mutations. Possible MHC epitopes covering these mutations were predicted based on; 1) predicted to bind the patient’s MHC; 2) predicted to be cleaved by the proteasome; 3) genes of which the mutated peptides arose had evidence of RNA expression. The analysis yielded 1,952 epitopes restricted to the HLA-A and HLA-B. To screen for T cell reactivity against these epitopes we used the pMHC combinatorial coding approach. We found T cell reactivity against 2 neo-antigens, including a dominant T cell response against a mutant epitope of the ATR gene product. Analysis of PBMC samples collected before and during Ipilimumab therapy showed that this particular response increased strongly after treatment from 0.06% to 0.28% of CD8 T cells after being stable in magnitude for 10 months. Conclusions: These data provide the first demonstration of cancer exome-guided analysis to dissect the effects of melanoma immunotherapy.
Gamma knife stereotactic radio-surgery and BRAF inhibition in metastatic melanoma.
Authors: Wilson Melissa , Lee John Y , Alonso-Basanta Michelle , Xu Wei , McGettigan Suzanne , Schuchter Lynn Mara , Amaravadi Ravi K. , Gangadhar Tara C.
Published: March 2020

9088

Background: Gamma knife radio-surgery (GK) is an effective approach to treating brain metastases in patients with metastatic melanoma. BRAF inhibition with vemurafenib produces a median progression free survival (PFS) of 7 months, but low central spinal fluid penetration may limit its effectiveness in patients who develop brain metastases. We report long term follow-up of patients with BRAF mutant melanoma treated with vemurafenib and GK. Methods: Demographics and clinical outcomes were characterized for 18 BRAF mutant melanoma patients with brain metastases treated between 2007 and 2012 with GK and with vemurafenib (vem) for >1 month. Results: The median age at starting vem was 51 yrs (range 34-76). 61% of the patients were women. Patients were treated with a median of 1 prior therapy (range 0-3). 7/18 patients (39%) had brain involvement prior to starting vem. 16/18 patients (89%) had stage M1c disease at the time of starting vem. Patients were treated with vem for a median of 8.4 months (range 2.1 to 27 months), had a median survival of 15.7 months after starting vem (range 4.2-29.4), and a median survival after GK of 7.8 months (range 1.2-21.1). Patients underwent GK to a median of 3 lesions (range 1-6). In total, 8/18 patients (44%) were treated with WBRT. 7/18 patients underwent craniotomies, 2 of which were for progression in lesions treated with GK, and 4 of which were also among the patients treated with WBRT. In 7/18 patients treated with GK for new brain progression after starting vem, vem was continued after GK for a median duration of 4.1 months (range 1.3 to 15.8). In these 7 patients that had vem and GK and continued vem, the median overall survival after starting vem was 19.9 months (range 6.7 to 29.3). Of these 7 patients, 4 required whole brain radiation therapy (WBRT); 3 have not required any additional brain directed therapy, including 2 patients who continue on vemurafenib at the time of analysis. 5/18 patients were treated with more than 1 round of GK, 3 of which were subsequently treated with WBRT. Conclusions: Despite the brain being a common site of progression on vemurafenib therapy, long term survival can be achieved in some cases by continuing vem after GK therapy.
Activity of cabozantinib in metastatic uveal melanoma: Updated results from a phase II randomized discontinuation trial (RDT).
Authors: Daud Adil , Kluger Harriet M. , Edelman Gerald , Gordon Michael S. , Schimmoller Frauke , Weitzman Aaron , Samuel Thomas A. , Moussa Ali H. , Flaherty Keith , Shapiro Geoffrey
Published: March 2020

9094

Background: MET and VEGF signaling are implicated in angiogenesis, invasion, and metastasis, and upregulation of MET as a consequence of GNAQ/GNA11 mutation has been implicated in uveal melanoma. Historical rates of median overall survival (OS) in patients (pts) with metastatic uveal melanoma range from 6-9 months (mos). A RDT evaluated activity and safety of cabozantinib, a MET and VEGFR2 inhibitor, in 9 tumor types including a metastatic melanoma cohort where 55% and 5% of pts experienced objective tumor regression and confirmed partial response, respectively (J. Clin. Oncol. 30, 2012 (suppl; abstr. 8531)). Here we report on the longer term followup of metastatic uveal melanoma pts enrolled to this cohort. Methods: Eligible pts were required to have progressive measurable disease per RECIST. Pts received cabozantinib at 100 mg po qd over a 12 wk Lead-in stage. Tumor response (mRECIST) was assessed q6 wks. Treatment ≥ wk 12 was based on response: pts with PR continued open-label cabozantinib, pts with SD were randomized to cabozantinib vs placebo, and pts with PD discontinued. Pts were followed for overall survival. Results: 23 of 77 pts enrolled in the melanoma cohort had the uveal subtype. Median age was 65 yrs; median prior regimens was 1 (range 0-5). Tumor mutation status was determined for 10/23 pts. 9/10 harbored either a GNAQ or GNA11 mutation, while GNA11 status was unknown for one pt. Pts had substantial tumor burden; median sum of the longest diameter of target lesions was 11.9 cm (range, 2-37.2). Median follow-up was 26.5 mos. (range 21.7-33.8). Median PFS from Study Day 1 was 4.8 mos. The estimate of PFS at month 6 (PFS6) was 41% and median OS was 12.6 mos. Most common Grade 3/4 AEs were HTN (13%), abdominal pain (9%), hypokalaemia (9%), hyperbilirubinaemia (9%) and increased lipase (9%). Conclusions: Cabozantinib is active in pts with metastatic uveal melanoma. Treatment with cabozantinib is associated with encouraging progression-free and overall survival. The safety profile of cabozantinib was comparable to that of other VEGFR TKIs. A randomized Phase 2 study is planned comparing cabozantinib to temozolomide plus dacarbazine in pts with uveal melanoma. Clinical trial information: NCT00940225.