bluuebunny/crossref_metadata_2025_split huggingface dataset:
A first-in-human phase I/II study of HL-085, a MEK Inhibitor, in Chinese patients with NRASm advanced melanoma.
Authors: Wang Xuan , Si Lu , Mao Lili , Cui Chuanliang , Chi Zhihong , Sheng Xinan , Bai Xue , Zhou Li , LIAN BIN , Tang Bixia , Yan Xieqiao , Li Siming , Kong Yan , Guo Jun 
Published: May 2020

10047 Background: MEK inhibitors have confirmed effects on malignant tumors, especially for those induced by RAS/RAF dysfunction. There is no effective drug in clinic for NRASm advanced melanoma. HL-085 is a selective MEK inhibitor, showing good safety and efficacy in preclinical studies. This study is a phase I/II study to evaluate the safety, tolerability, pharmacokinetic and preliminary anti-cancer activity of HL-085 in patients(pts) with NRASm advanced Melanoma. Methods: The phase I/II study is conducted using a “3+3” regimen for dose escalation. The pts are treated with HL-085 at a starting dose of 0.5mg BID to 18mg BID. Adverse events (AEs) are reported per NCI CTCAE version 5.0. Preliminary anti-cancer activity is evaluated by ORR, DCR, PFS and DoR. Results: Total 33 pts were enrolled in the study. The histologic types were acral (51.4%), mucosal (27.2%) and other (21.2%). The NRAS mutation types were Q61 (72.7%), G12 (18.2%) with half for G12D, and G13 (9.1% ). Most AEs were G1 or G2, and the most common drug-related AEs were rash, increased creatine phosphokinase, peripheral edema, increased alanine aminotransferase and aspartate aminotransferase. No dose-limited toxicity was observed. PK analysis was shown linear PK profile with no obvious accumulation. Among 12 evaluable pts over 9 mg, 4 pts were at the stage of M1c with 1 liver metastasis. Average targeted tumor size was 74.6mm with the largest 184 mm. 10 pts achieved tumor shrinkage [ 60% with Q61, 20% with G12D, 10% each with G12S and G13R]. 4 pts ( 2 acral, 1 mucosal and 1 other, each pt has mutaiton type of Q61R,Q61L, Q61K and G12S respectively ) had confirmed partial response(PR) [median treatment duration 26.6 weeks (wks) with longest 47.6 wks]). 6 pts achieved stable disease (SD) (median treatment duration 15.72 wks with longest 24 wks), and 66.7% were over 14 wks . The median PFS was 17.4 wks, and confirmed best ORR was 33.3% with DCR 83.3% . Conclusions: Our data demonstrated that HL-085 is well tolerated, with manageable side-effects and promising anti-cancer activity in pts with NRASm advanced melanoma. Clinical trial information: NCT 03973151.
Preclinical and clinical studies of a class I/IV HDAC inhibitor, mocetinostat, in melanoma.
Authors: Weber Jeffrey S. , Laino Andressa S , Vassallo Melinda , Pavlick Anna , Malatyali Saundra , Krishnarajapet Swathi , DeLeon Gabriel , Chen Isan , Hallin Max , Woods David 
Published: May 2020

10052 Background: Mocetinostat is a class I/IV HDAC inhibitor with HDAC1/2/3/11 activity. Preclinical murine data suggest that HDAC inhibition has immune activity and may augment the clinical benefit of checkpoint inhibition. Several trials are assessing the effects of adding HDAC inhibition to PD-1 blockade. Methods: Patients with therapy-naive metastatic melanoma were treated in a pilot phase Ib trial with nivolumab at 3 mg/kg/ipilimumab at 1 mg/kg every three weeks four times and a starting dose of mocetinostat at 70 mg orally three times a week in a 12-week induction cycle followed by 12-week maintenance cycles of nivolumab 240 mg every 2 weeks and mocetinostat at the same dose and schedule as induction. Endpoints were toxicity, definition of a recommended phase 2 dose and preliminary assessment of response as well as correlative marker determination. Peripheral blood mononuclear blood cells from patients were tested in vitro at varying concentrations of mocetinostat, and its impact on T, regulatory T and myeloid-derived suppressor cell phenotypes were assessed by flow cytometry, as well as cytokine production by Luminex. Results: In the mocetinostat, nivolumab and ipilimumab phase I trial, 10 patients were treated, including 5 males and 5 females with a median age of 59. There were 2 complete and 5 partial responses confirmed; 6 of 7 are maintained at a median of 16 months of follow up. Three patients had progressive disease. Seven patients had grade 3-4 immune related adverse events; in 3 they were multiple. No patients died. In vitro, mocetinostat at doses from 125 to 500 nM increased relative percentage of CD4/CD8 central memory T cells, and decreased IL-6 levels while increasing interferon-gamma production (p = 0.005). Percentages of regulatory T and monocytic myeloid-derived suppressor cells were decreased by mocetinostat (p = 0.005), which also down-modulated regulatory T cell function by reducing FOXP3, HELIOS and GARP (p = 0.001). Conclusions: In vitro, mocetinostat promoted accumulation of central memory CD8 and CD4 T cells from melanoma patients, and decreased percentages and suppressive activity of T regulatory cells and myeloid-derived suppressor cells. In a pilot clinical trial, mocetinostat combined with nivolumab and ipilimumab in treatment-naïve metastatic melanoma patients exhibited a response rate of 70% with long duration of response but all ten patients treated had at least one grade 3 or 4 immune-related toxicity. De-escalation of the mocetinostat dose to 50 mg three times a week was felt to be indicated due to the toxicity of the triple regimen. Clinical trial information: NCT03565406.
Risk of disease progression (PD) following discontinuation of BRAF±MEK targeted therapies for reasons other than PD in patients (pts) with metastatic or unresectable melanoma.
Authors: Corti Francesca , Randon Giovanni , Bini Marta , Raimondi Alessandra , Manglaviti Sara , Zattarin Emma , Bisogno Ilaria , Vetrano Irene , Cimminiello Carolina , De Braud Filippo G. , Del Vecchio Michele , Di Guardo Lorenza 
Published: May 2020

10053 Background: In pts with metastatic melanoma bearing BRAF V600E/K mutations BRAF V600±MEK inhibitors are administered until PD/unacceptable toxicity. In patients achieving durable responses, outcomes following discontinuation for reasons other than PD are largely unknown. Methods: We identified all patients who interrupted BRAF±MEK inhibitors for reasons other than PD after complete (CR) or partial response (PR) from a clinical dataset of patients with BRAF mutated metastatic/unresectable melanoma treated with targeted therapy at a single Institution. Results: We included 24 pts. Fifteen (62.5%) and 9 (37.5%) pts were treated respectively with BRAF inhibitor monotherapy and BRAF+MEK inhibitor combination. All pts had normal baseline LDH and ECOG PS0, 2 (8%) pts had brain metastases and 15 (62.5%) had multi-organ metastatic involvement. Dose reduction was required for 12 (50%) pts. Median treatment duration was 59 (12-88) months. Causes of discontinuation were unacceptable toxicity (19 pts-79%) and consent withdrawal (5 pts-21%). At the time of discontinuation, 17 (71%) and 7 (29%) pts had achieved respectively CR and PR. At a median follow up of 31 (8-59) months after treatment discontinuation, 9 (37.5%) pts had experienced PD. Median time to PD after treatment discontinuation was 9 (3-16) months. At time of PD, 2 (22%) pts displayed involvement of new organ sites. Risk of PD following discontinuation was respectively 31% and 45% at 12 and 24 months. Neither baseline characteristics nor treatment duration and time to best response influenced risk of PD; we found a non-significant trend towards higher risk of relapse for patients interrupting treatment with residual disease compared to those who interrupted treatment after achieving CR [HR 3.3; 95%CI (0.8–14.1); log-rank p = 0.081]. After PD, 6 pts received BRAF+MEK inhibitors with a response rate of 100% and 3/6 pts achieving CR. Conclusions: In a subset of patients with favorable prognostic characteristics and retained sensitivity to BRAF±MEK inhibitors, treatment discontinuation was associated with relevant risk of relapse with about one third of pts experiencing PD within one year. Biomarker studies are needed to identify pts who might safely discontinue therapy due to sustained toxicity, especially after achieving CR.
Landmark analysis of immunotherapy duration and disease free survival in advanced melanoma patients with a complete response.
Authors: Selig Grayce N. , Huang Alexander Chan Chi , Karakousis Giorgos C. , Xu Wei , Zheng Cathy , Carberry Mary , Giles Lydia , Kreider Kristin , McGettigan Suzanne , Lukens John Nicholas , Schuchter Lynn Mara , Amaravadi Ravi K. , Mitchell Tara C. 
Published: May 2020

10054 Background: Checkpoint blockade improves survival in patients with melanoma, with durable complete responses (CR) after stopping therapy. Based on data from KEYNOTE-001, immunotherapy is often continued for 24 months in patients with confirmed CR. Outcomes with treatment of less than 24 months hav not been adequately evaluated and reported. If equally efficacious, shorter courses would potentially reduce health care costs and toxicity. Methods: 45 patients with locally advanced stage III and IV melanoma who received immunotherapy (pembrolizumab, nivolumab or ipilimumab/nivolumab) as 1st line or subsequent therapy, achieved a CR, and stopped therapy were identified under an IRB approved protocol at Penn. Disease Free Survival (DFS) was defined as time from declaration of CR until recurrence or date of analysis (1/15/20). Landmark DFS from time of CR was analyzed based on duration of therapy (less than or greater than 7 months, based on early trial requirements to treat patients with confirmed CR for at least 6 months). Rationale for stopping (toxicity or CR) was also analyzed. Results: Of 45 patients with CR, 27 (60%) were treated less then 7 months (median 4.8, range 1 day to 6.7 months) and 18 (40%) were treated for greater than 7 months (median 12.4, range 7.5 to 24.2 months). Patients who were treated for less than 7 months had a median DFS from time of CR of 30.4 months (95% CI 23.7 to 37.2, range 2.9 to 65.7 months). Patients treated for greater than 7 months had a median DFS of 28.0 months (95% CI 18.9 to 37, range 8.5 to 73.7 months). Patients who stopped due to toxicity (N = 17, 40%) had a median treatment duration of 3.7 months. Their median DFS from time of CR was 30.4 months (95% CI 20.7 to 40.1, range of 2.9 to 65.7 months). Patients who stopped due to CR (N = 28, 60%) had a median treatment duration of 8.5 months. Their median DFS was 27.6 months (95% CI 21.2 to 34 range 7.2 to 73.7 months). Two of 27 (7.4%) patients treated for less then 7 months and 3 out of 18 (16%) patients treated greater than 7 months recurred after stopping. One out of 17 (5.8%) recurred after stopping for toxicity vs. 4/28 (14.3%) who stopped after CR. Conclusions: Patients who stop therapy at less than 7 months have CRs that are equally durable as those treated longer than 7 months, without reduction in landmark DFS. Patients who stopped therapy due to toxicity and then achieved a CR had no difference in DFS compared to patients treated until CR. There was no significant difference in recurrence after achieving a complete response in patients treated for a longer vs shorter treatment course.
Long-term immune-related adverse events under PD-1 inhibitors: a multicenter prospective cohort study (MELBASE).
Authors: Nardin Charlee , Dalle Stéphane , Leccia Marie Thérèse , Mortier Laurent , Dalac-Rat Sophie , Dutriaux Caroline , Legoupil Delphine , Montaudie Henri , Dereure Olivier , De Quatrebarbes Julie , Granel-Brocard Florence , Le-Bouar Myrtille , Charles Julie , Brunet-Possenti Florence , Dreno Brigitte , Lefevre Wendy , Allayous Clara , Lebbe Celeste , Aubin Francois 
Published: May 2020

10057 Background: PD-1 inhibitors (anti-PD1) are frequently associated with immune-related adverse events (IRAE). Since melanoma patients included in clinical trials were frequently treated during two years, data on IRAE occurring after 2 years of treatment are lacking. This study aimed to describe IRAE in melanoma patients treated with anti-PD1 for longer than 2 years in a real-life setting. Methods: Patients were screened from MelBase, a French multicentric biobank dedicated to the prospective follow-up of unresectable stage III or IV melanoma. All patients who received anti-PD1 for at least 2 years between January 2013 and November 2019 were included. Among them, patients who experienced IRAE and long-term IRAE defined as IRAE occurring after 2 years of anti-PD1 were identified. Results: Among 1849 patients with advanced melanoma included in Melbase, 119 patients received anti-PD1 monotherapy during at least 2 years, from January 2013 to November 2019, with a median follow-up of 41.7 months (25.2-57.5). Patients characteristics at treatment initiation were: male gender (61%), mean age of 63 years old, past history of autoimmune disease (11%), BRAF WT (72%), AJCC stage IV (84%), brain metastases (22%), ECOG 0-1 (88%) and normal LDH (56%). Patients were treated with Nivolumab (n = 53) or Pembrolizumab (n = 66). IRAE occurred in 99 patients (83%) with a median time of 13.3 months (0-53.9), including severe IRAE (grade 3 or 4) in 30 patients (30%). Long-term IRAE, mostly grades 1-2, occurred in 52 patients (43%). Long-term IRAE led to 5 hospitalizations (4%) of which 4 were grades 3-4. Among patients with long-term IRAE, 45 patients (87%) previously experienced IRAE within the first 2 years of anti-PD1 and 29 patients (56%) experienced multiple IRAE. Conclusions: Our data demonstrate that long-term IRAE are frequent especially in patients who already experienced IRAE within the first two years of treatment. These data should be taken into account to establish formal recommendations on the duration of anti-PD1 therapy.
Clinical outcomes in patients with BRAFV600 mutant melanoma and undetectable circulating tumor DNA treated with dabrafenib and trametinib.
Authors: Algazi Alain Patrick , Othus Megan , Voorhies Benjamin Newell , Kendra Kari Lynn , Dakhil Shaker R. , Harker-Murray Amy K. , Lao Christopher D. , Chmielowski Bartosz , Lo Roger , Grossmann Kenneth F. , Ribas Antoni 
Published: May 2020

10059 Background: Circulating tumor DNA (ctDNA) analysis has been promoted as a less-invasive surrogate assay for tumor-tissue based tumor oncogene analysis. Here, we associate detection of BRAF mutant ctDNA with PFS and OS in patients with tissue-confirmed BRAFV600 mutant melanoma enrolled in S1320, a randomized phase 2 clinical trial of continuous versus intermittent dosing of dabrafenib and trametinib. Methods: Patients with BRAFV600 melanoma received continuous therapy with dabrafenib and trametinib for 8 weeks after which patients were randomized 1:1 to proceed with intermittent treatment on a 3-week-off, 5-week-on schedule or to continue with continuous therapy. Pre-treatment blood samples were interrogated using the Guardant 360 ctDNA assay for all exons of 30 known oncogenes including BRAF and for all exons with known oncogenic mutations in the COSMIC database in 40 additional oncogenes. Clinical responses were assessed at 8-week intervals by RECIST v1.1 and PFS and OS estimates were compared using log-rank test in patients with detectable versus undetectable BRAFV600 mutant ctDNA,. Results: Somatic BRAFV600E or BRAFV600K ctDNA was detected in 34 of 50 patients with baseline (before lead-in cycle 1) blood samples available for analysis including 16 of 23 (70%) patients randomized to continuous dosing, 15 of 21 (71%) randomized to intermittent dosing, and 3 of 6 (50%) who were not randomized due to disease progression at 8 weeks or other factors. Four additional patients had other detectable somatic mutations but no detectable BRAFV600 ctDNA at baseline, and 12 patients had no detectable somatic ctDNA mutations at baseline. Detection of BRAFV600 ctDNA was associated with baseline disease stage (p = 0.008). There was no difference in the overall response rate based on baseline ctDNA detection. Detection of ctDNA at baseline was associated with worse PFS (median BRAFV600 ctDNA positive = 5.8; 95% CI: 4.2-9.6 months, BRAFV600 ctDNA negative = 21.4 mos; 95% CI 10.4-NA; measured from registration to lead-in cycle 1, p = 0.001) and OS (BRAFV600 ctDNA positive = 17.8 mos; 95% CI 9.76-NA, BRAFV600 ctDNA negative = not reached; 95% CI NA-NA, p = 0.0021). Conclusions: The absence of detectable BRAFV600 ctDNA at baseline is associated with improved PFS and OS in patients receiving treatment with dabrafenib and trametinib. Clinical trial information: NCT02196181.
Alpelisib (ALP) + fulvestrant (FUL) in patients (pts) with PIK3CA-mutated (mut) hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDKi) + aromatase inhibitor (AI): BYLieve study results.
Authors: Rugo Hope S. , Lerebours Florence , Ciruelos Eva , Drullinsky Pamela , Ruiz Borrego Manuel , Neven Patrick , Park Yeon Hee , Prat Aleix , Bachelot Thomas , Juric Dejan , Turner Nicholas C. , Sophos Nickolas , Zarate Juan Pablo , Arce Christina , Shen Yu-Ming , Chia Stephen K. L. 
Published: May 2020

1006 Background: PIK3CA mutations (mut) occur in ~40% of pts with HR+, HER2– ABC and are associated with poor prognosis and resistance to treatment (tx). ALP, a PI3Kα inhibitor, plus FUL demonstrated efficacy in the phase 3 SOLAR-1 trial of HR+, HER2– PIK3CA-mut ABC. Little clinical data and few prospective studies are available to inform tx decisions for pts with HR+, HER2– PIK3CA-mut ABC in the post-CDKi setting. BYLieve is the first trial evaluating ALP + endocrine therapy (ET; FUL or letrozole) in pts with HR+, HER2– PIK3CA-mut ABC who progressed on/after prior therapy, including CDKi. In this ongoing phase 2, open-label, noncomparative study, 112 pts with centrally confirmed PIK3CA mut in tumor tissue are enrolled in each cohort per immediate prior tx of CDKi + AI, CDKi + FUL, or systemic chemo or ET. Enrollment is complete in prior CDKi + AI and CDKi + FUL cohorts and ongoing in prior systemic chemo or ET cohort. We report on the cohort of pts with CDKi + AI as immediate prior tx. Methods: Pts received ALP 300 mg/day + FUL 500 mg Q28D + C1D15. Primary endpoint was proportion of pts alive without disease progression at 6 mo per local assessment; 2-sided 95% confidence intervals (CI) were calculated using Clopper and Pearson (1934) exact method. Evidence of clinically meaningful tx effect was defined as the lower bound of the 95% CI > 30%. Safety was assessed in all patients; AEs presented by preferred term. Results: 127 pts whose immediate prior tx was CDKi + AI were enrolled, of whom 121 had centrally confirmed PIK3CA mut; median follow-up was 11.7 mo. Primary endpoint was met: proportion of pts without disease progression at 6 mo was 50.4% (95% CI, 41.2-59.6). Most frequent all-grade AEs were diarrhea (60%), hyperglycemia (58%), nausea (46%), fatigue (29%), decreased appetite (28%), and rash (28%). Most frequent grade ≥3 AEs included hyperglycemia (28%), rash (9%), and rash maculopapular (9%). Incidence of AEs leading to discontinuation was low; most frequent AEs leading to discontinuation were rash (5 pts, 3.9%), colitis, hyperglycemia, urticaria, and vomiting (2 pts, 1.6% each). Conclusions: With follow-up still ongoing, BYLieve shows in a large number of pts that ALP + FUL demonstrates clinically meaningful efficacy and manageable toxicity post CDKi tx. Building on findings from SOLAR-1, BYLieve further supports use of ALP + FUL for HR+, HER2– PIK3CA-mut ABC. Clinical trial information: NCT03056755 .
PARSIFAL: A randomized, multicenter, open-label, phase II trial to evaluate palbociclib in combination with fulvestrant or letrozole in endocrine-sensitive patients with estrogen receptor (ER)[+]/HER2[-] metastatic breast cancer.
Authors: Llombart-Cussac Antonio , Pérez-García José Manuel , Bellet Meritxell , Dalenc Florence , Gil Gil Miguel J. , Ruiz Borrego Manuel , Gavilá Joaquín , Sampayo-Cordero Miguel , Aguirre Elena , Schmid Peter , Marmé Frederik , Di Cosimo Serena , Gligorov Joseph , Schneeweiss Andreas , Albanell Joan , Zamora Pilar , Wheatley Duncan , Martínez-De Dueñas Eduardo , Amillano Kepa , Cortes Javier 
Published: May 2020

1007 Background: The CDK4/6 inhibitor palbociclib (P) in combination with letrozole (L) has become a standard first-line treatment for patients (pts) with luminal metastatic breast cancer (MBC) (PALOMA-1 & 2 trials). Meanwhile, the anti-estrogen fulvestrant (F) showed to be superior to anastrozole in the same population (FALCON trial). We aimed to identify the best endocrine agent to combine with P in this first-line scenario. Methods: A total of 486 pts with ER[+]/HER2[-] MBC with no prior therapy in the advanced setting and endocrine sensitive criteria (relapse > 12 months [mo] after the end of adjuvant endocrine therapy or diagnosed with “de novo” metastatic disease) were randomly assigned (1:1 ratio) to receive P (oral 125 mg/day [d]; 3 wks on/1 wk off) plus F 500 mg/d (I.M Days 0, 14, 28, and then every 28 d) or PL (oral 2.5 mg/d). Pts were stratified by visceral involvement and type of disease presentation (“de novo”/recurrent). Primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), and safety. 254 events were needed with 80% power to detect a hazard ratio (HR) ≤0.7 in favor of PF (2-sided α = 0.05). Results: By March 9th, 2020, 256 PFS events occurred. Pts characteristics were well balanced. Median age was 62 years (range: 25–90), 56.6% were ECOG 0, 40.7% had “de novo” metastatic disease, 48% had visceral disease, and 43.6% with ≥3 organ sites involved. At median follow-up of 32 mo, median PFS was 27.9 mo (95% confidence interval [CI], 24.2-33.1) with PF and 32.8 mo (95% CI, 25.8-35.9) with PL (HR: 1.1; 95% CI, 0.9-1.5; P = 0.321). No differences were observed for pts with or without visceral involvement (HR: 1.3 and HR: 0.97 respectively, interaction P = 0.275), and for “de novo” or recurrent metastatic disease (HR: 1.1 and HR: 1.1 respectively, P = 0.979). The 4-year OS rate was 67.6% in PF and 67.5% in PL arm (HR: 1; 95% CI, 0.7-1.5; P = 0.986). No differences were observed in ORR or CBR between arms. Grade ≥3 adverse events were similar in both arms, being neutropenia and leukopenia the most frequent. No treatment-related deaths were reported. Conclusion: This study was not able to identify an improvement in PFS for PF over PL in patients with endocrine-sensitive ER[+]/HER2[-] MBC. As both arms demonstrated comparable 4 years-OS, PF is a reasonable alternative to PL in this setting. Clinical trial information: NCT02491983 .