bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of tunlametinib in patients with advanced NRAS-mutant melanoma: A multicenter, open-label, single-arm, phase 2 study.
Authors: Si Lu , Zou Zhengyun , Zhang Weizhen , Fang Meiyu , Zhang Xiaoshi , Luo Zhiguo , Chen Jing , Huang Gang , Zhang Peng , Cheng Ying , Liu Jiwei , Liu Jiyan , Zhang Junping , Wu Di , Chen Yu , Ma Xiaobiao , Wei Xiaoting , Sun Peng , Jia Zhongwei , Guo Jun 
Published: June 2023

9510 Background: NRAS-mutant melanoma is an aggressive subtype with worse prognosis. However, no targeted therapy has been approved to date worldwide. Tunlametinib (HL-085), a novel, potent, selective, oral small-molecule MEK1/2 inhibitor, has showed a favorable pharmacokinetics profile, acceptable tolerability and encouraging antitumor activity in the phase 1 study (BMC Med. 2023 Jan 4;21(1):2). Methods: This is an ongoing, multicenter, open-label, single-arm, phase 2 pivotal registration study. Patients (pts) with NRAS-mutant unresectable stage III or IV melanoma were enrolled and received tunlametinib 12 mg orally twice daily. A historical control of objective response rate (ORR) of 10% was predefined for sample size estimation (100 pts, assuming loss to follow-up rate of 5%) and efficacy evaluation. The primary endpoint was the confirmed ORR per RECIST v1.1 assessed by independent radiology review committee. Results: A total of 100 pts were enrolled. All pts were included in the safety analysis set and 95 pts were included in the full analysis set (FAS) for efficacy analysis. At cut-off date (August 17, 2022), median follow-up was 7.9 months (95% CI: 6.6, 9.8). In the FAS, the median age was 58.0 years (range: 24 to 84). Sixty-four pts (67.4%) had received prior immunotherapy (PD-1/PD-L1 inhibitor). Fifty-six pts (58.9%) were acral melanoma, 16 (16.8%) mucosal melanoma and 12 (12.6%) skin melanoma. Fourteen pts (14.7%) were stage III and 81 (85.3%) stage IV. The most frequent NRAS mutation types were Q61R (40.0%), Q61K (29.5%) and G12D (9.5%). Confirmed ORR was 34.7% (95%CI: 25.3%, 45.2%). Median progression-free survival was 4.2 months (95%CI: 3.5, 5.6), overall survival was immature, and 1-year survival rates was 57.2% (95% CI, 44.7%, 67.8%). Subgroup analysis showed that, in pts who had previously received immunotherapy, the confirmed ORR was 39.1% (95% CI: 27.1%, 52.1%). The most frequent treatment related adverse events (TRAEs) were increased blood creatine phosphokinase (CK), diarrhea, peripheral oedema, facial oedema and increased aspartate aminotransferase. Grade ≥3 TRAEs occurred in 68 pts (68.0%), of which 38.0% (38/100) were increased blood CK. Most of pts with CK elevation are asymptomatic and can be managed by dose interruption or reduction without permanent treatment discontinuation. No treatment-related death was reported. Conclusions: Tunlametinib was well tolerated and demonstrated encouraging treatment response rate in pts with advanced NRAS-mutant melanoma. These results indicate that tunlametinib could be a promising treatment option for NRAS-mutant melanoma, even for those immunotherapy failed pts. Clinical trial information: NCT05217303 .
Revisiting the optimal neoadjuvant immunotherapy regimen in resectable stage III melanoma based on the interferon gamma signature: A pooled analysis.
Authors: Lucas Minke W. , Dimitriadis Petros , Reijers Irene L.M. , Menzies Alexander M. , Rozeman Elisa A. , Versluis Judith M. , Huang Alexander Chan Chi , Cornelissen Sten , Broeks Annegien , Scolyer Richard A. , Mitchell Tara C. , Long Georgina V. , Blank Christian U. 
Published: June 2023

9516 Background: Neoadjuvant anti-PD1 has been shown to be superior to adjuvant administration. Combination of neoadjuvant ipilimumab (IPI) + nivolumab (NIVO) induces even higher pathologic response rates (pRR) and event-free survival (EFS), but at the cost of higher toxicity. We previously showed that the interferon gamma (IFN-γ) signature is associated with a higher pRR after neoadjuvant IPI+NIVO. We hypothesized that IFN-γ high patients (pts) might benefit from less toxic anti-PD1 monotherapy (mono), while IFN-γ low pts might need an escalated regimen with IPI 3mg/kg + NIVO 1mg/kg. Methods: In this pooled analysis, pts with macroscopic nodal melanoma who received neoadjuvant NIVO 1mg/kg + IPI 3mg/kg (IPI3/NIVO1), IPI 1mg/kg + NIVO 3mg/kg (IPI1/NIVO3), sequential IPI 3mg/kg and NIVO 3mg/kg (IPI3>NIVO3), or NIVO mono (240mg; IFN-γ high pts only) from the OpACIN-neo, PRADO and DONIMI trials, were analyzed according to their baseline IFN-γ signature. RNA gene expression from baseline tumor biopsies was analyzed using the Nanostring nCounter platform. The IFN-γ scores were calculated using an algorithm and cut-off previously developed at the NKI and prospectively tested in the DONIMI trial. Results: Baseline tumor material was available from 151 pts (Table). Median follow-up was 42 months for the entire cohort and 19 months for NIVO mono pts. Combined IPI+NIVO in IFN-γ high pts induced similar major pathologic response (MPR) rates compared to NIVO mono in IFN-γ high pts (71% vs 80%, p=0.715), and significantly higher MPR rates compared to IPI+NIVO in IFN-γ low pts (71% vs 45%, p=0.003). At 18-months, EFS rates were 87%, 100% and 73% respectively, and overall survival (OS) rates were 98%, 100% and 96%. Notably, IPI3/NIVO1 seemed to induce a higher MPR rate than IPI1/NIVO3 in IFN-γ low pts (64% vs 41%), which was not statistically significant due to small subgroups. At 36 months, EFS was 91% vs 62% and OS was 91% vs 82%. Conclusions: Neoadjuvant NIVO mono seems to have equal outcomes as IPI+NIVO in IFN-γ high pts. IFN-γ low pts may benefit from IPI+NIVO with higher doses of IPI. Incorporating baseline biomarkers like the IFN-γ signature algorithm in neoadjuvant treatment decisions will optimize the risk-benefit ratio for these pts. [Table: see text]
Efficacy of adjuvant therapy in patients (pts) with AJCC v8 stage IIIA cutaneous melanoma.
Authors: Grover Piyush , Li Isabel , Kuijpers Anke , Kreidieh Firas Y. , Williamson Andrew , Amaral Teresa Maria Santos , Dimitriou Florentia , Placzke Joanna , Olino Kelly , Vitale Maria Grazia , Saiag Philippe , Gutzmer Ralf , Allayous Clara , Olofsson Bagge Roger , Asher Nethanel , Meniawy Tarek , Lawless Aleigha , Warburton Lydia , Menzies Alexander M. , Long Georgina V. 
Published: June 2023

9518 Background: Pts with resected AJCC v8 stage IIIA melanoma have been under-represented in clinical trials of adjuvant drug therapy. The benefit of adjuvant targeted and immunotherapy in this population is unclear. Methods: In this multicenter, retrospective study, pts with stage IIIA melanoma (AJCC v8) who received adjuvant pembrolizumab or nivolumab (PD1), BRAF/MEK-targeted therapy dabrafenib + trametinib (TT), or no adjuvant treatment (OBS) were included. Recurrence free survival (RFS), distant metastasis free survival (DMFS), and toxicity rates were examined. Results: 613 pts from 34 centers across Australia, Europe and USA were included. The median follow-up was 2.6 yrs (IQR, 1.6-3.4 yrs). Pt characteristics and follow-up were similar across the cohorts (Table). Completion rates of 12-month PD1 and TT therapy were 57.0% and 69.2% respectively. 1-yr RFS was 93.3% (95% CI, 90.3-96.4) in PD1, 100% in TT and 91.3% (95% CI, 88.1-94.7) in OBS cohorts. 2-yr RFS was 79.3% (95% CI, 74.1-84.8) for PD1, 100% for TT and 84.3% (95% CI, 79.9-89.0) in OBS cohorts. 2-yr DMFS was 88.4% (95% CI, 84.3-92.8) in PD1, 100% in TT and 91.1% (95% CI, 87.7-94.7) in OBS cohorts. Risk of recurrence was associated with higher breslow thickness (HR 1.73, 95% CI 1.36-2.20), higher mitotic rate (HR 1.07, 95% CI 1.02-1.12) and neck as the site of nodal metastases (HR 2.71, 95% CI 1.45-5.06) in the overall cohort (p<0.05). Neck nodal metastases were associated with higher risk of recurrence in OBS cohort (HR 3.82, 95% CI 1.91-7.66; p<0.05) but not in the PD1 cohort. Rates of ≥ Grade 3 toxicities were 10.9% with PD1 and 20.0% with TT; discontinuation due to toxicity occurred in 25.0% and 30.0%, respectively. No new safety signals were observed. Rates of unresolved toxicity at last follow-up were 26.9% in PD1 and 7.7% in TT cohorts. Conclusions: In this large international study, adjuvant PD1 or TT did not significantly improve RFS or DMFS compared to OBS in pts with resected stage IIIA melanoma. Prognosis in stage IIIA melanoma is favourable and outcomes after adjuvant therapy in this population needs further study in prospective randomised trials. [Table: see text]
Identification of RPTOR mutation as a novel predictor of efficacious immunotherapy in melanoma.
Authors: Li Yongzhao , Zhang Qin , Tan Yuan , Duan Qianqian , Sun Tingting , Qi Chuang 
Published: June 2023

9524 Background: mTOR pathway is known to influence cancer immunity by metabolism reprogramming. RPTOR (Regulatory Associated Protein of MTOR Complex 1), one of mTOR pathway genes, which is involving in control of mammalian target of mTORC1 activity for regulating cell growth and survival. Whether mutations of RPTOR are associated with clinical efficacy of immune checkpoint inhibitors (ICIs) in melanoma is still ambiguous. Methods: In discovery cohort, we retrospective analyzed the genomic data of 418 melanoma samples which derived from seven immunotherapy studies ( http://www.cbioportal.org/ ) to evaluate the relationship between RPTOR mutation status and efficacy of immunotherapy. Then in validation cohort, the predictive value of RPTOR mutation was confirmed in 320 melanomas from MSKCC cohort (http://www.cbioportal.org/). TMB was calculated as the total count of nonsynonymous mutations in coding sequence. We used the CIBERSORT to evaluate the 22 types immune cell infiltration status in TCGA melanoma cohort. Results: The TMB level of RPTOR-mutant patients was higher than RPTOR-wildtype patients in both discovery (Median [IQR]: 43.11[23.76-140.15] vs. 6.13[2.07-13.66], P < 0.001) and validation (Median [IQR]: 37.38[20.17-84.95] vs. 8.85[3.35-21.07], P < 0.001) cohort. In discovery cohort, compared to RPTOR-wildtype patients, the RPTOR-mutant patients achieved prolonged OS (median OS: not reach, NR vs 22.7 months, HR (95%CI): 0.47(0.22-0.99), P = 0.043). This result was confirmed in validation cohort (median OS: NR vs. 42; HR (95%CI): 0.34 (0.11-1.0); P = 0.049). According to analysis of immune cell infiltration status, the mechanism of the predictive values of RPTOR mutations to ICI efficacy may be activated CD4 memory T cell more abundant in RPTOR-mutant tumors. Conclusions: RPTOR mutation is associated with higher TMB in ICI-treated melanoma patients. Survival analysis shows RPTOR mutation have a good link with longer OS after immunotherapy. These findings indicate that RPTOR mutation may serve as a potential predictive biomarker for ICIs in melanoma.
Encorafenib (enco) + binimetinib (bini) + pembrolizumab (pembro) for unresectable locally advanced or metastatic BRAF V600-mutant melanoma: Results from STARBOARD safety lead-in (SLI).
Authors: Schadendorf Dirk , Dummer Reinhard , Robert Caroline , Ribas Antoni , Sullivan Ryan J. , Panella Timothy J. , McKean Meredith , Santos Edgardo S. , Clancy Jill S. , Thakur Mahgull Nazar , Polli Anna , Di Pietro Alessandra , Ascierto Paolo Antonio 
Published: June 2023

9531 Background: BRAF inhibitors (BRAFi) + MEK inhibitors (MEKi) (eg, enco + bini) and immune checkpoint inhibitors (CPIs) (eg, pembro) are approved for patients (pts) with BRAF V600-mutant metastatic melanoma. Combinations of BRAFi + MEKi with CPIs further improve outcomes and may offer additional treatment strategies. STARBOARD (NCT04657991) is an ongoing randomized, double-blinded, placebo-controlled, phase 3 study of enco + bini + pembro vs pembro in pts with unresectable locally advanced or metastatic BRAF V600-mutant cutaneous melanoma. Here we present the SLI results. Methods: Key inclusion criteria were histologically confirmed unresectable/metastatic BRAF V600E/K-mutant cutaneous melanoma and ≤1 prior systemic therapy for unresectable/metastatic disease. Pts received enco 450 mg QD + bini 45 mg BID + pembro 200 mg IV Q3W (COMBO450+P) or enco 300 mg QD + bini 45 mg BID + pembro 200 mg IV Q3W (COMBO300+P). The primary objective was to identify the recommended phase 3 dose (RP3D). The primary endpoint was dose-limiting toxicity (DLT) incidence; secondary endpoints included safety, objective response rate (ORR), time to response (TTR), and PFS (post hoc). Results: 20 pts received COMBO450+P and 17 COMBO300+P (cutoff: Dec 2, 2022). See table for baseline characteristics. 1 pt had a DLT with COMBO450+P: Grade (G) 3 drug-induced liver injury with concurrent G4 ALT increase and G3 bilirubin increase that resolved. 2 pts had DLTs with COMBO300+P: 1 with G3 rheumatoid arthritis flare and 1 with inability to receive drug due to G4 arthralgia, G4 back pain, G4 pyrexia, G3 chills, G3 headache, G3 paranesthesia, and G3 maculopapular rash. Drug-related AEs led to permanent discontinuation in 4, 5, and 6 pts for enco, bini, and pembro, respectively. 1 pt in the COMBO300+P arm died <28 days after discontinuing all study treatments due to disease progression. See table for antitumor activity data. Conclusions: Safety across cohorts was comparable and consistent with the known safety profile of each agent. Both regimens were generally tolerable; COMBO450+P was chosen as the RP3D based on the totality of the safety data. The phase 3 portion of STARBOARD is ongoing. Clinical trial information: NCT04657991 . [Table: see text]
Determinants of racial disparities in immune-related adverse events (irAE) with checkpoint inhibition (ICI) in melanoma.
Authors: Ibrahim Milad , Angulo Paola , Fa'ak Faisal , Abdel-Wahab Noha , Diab Adi , Mehnert Janice M. , Weber Jeffrey S. , Lund Amanda , Schober Markus , Zhong Judy , Osman Iman 
Published: June 2023

9549 Background: We recently reported that a pretreatment autoantibody (AutoAb) signature predicts immune-related adverse events (irAE) with an AUC of ~0.80 in melanoma patients enrolled in two phase III clinical trials of adjuvant ICI (Johannet et al. CCR 2022). The vast majority of those patients were non-Hispanic whites (NHW). We hypothesized that underrepresented minority (URM) melanoma patients might have a different baseline autoAb profile compared to NHW patients, as their site-specific irAEs differ ( Xue Bai et al. Br J of Derm 2022) and autoimmune disease is generally more common in underrepresented minorities (Roberts MH, Erdei E. Autoimmune Review 2020). We also explored the possibility that differences in the immuno-biology of acral melanoma (AM) and cutaneous melanoma (CM) – most commonly detected in URM and NHW patients, respectively – might inform our understanding of the racial differences in irAEs. Methods: We compared pre-treatment sera autoAb from URM melanoma patients (n=35) to NHW patients (n= 185) enrolled in Checkmate-238 (NCT02388906), Checkmate-915 (NCT03068455) or the NYU melanoma program database using the CDI and Sengenics proteomic platforms, and analyzed their association(s) with the development of grade 3-4 irAEs. We carried out single cell RNA-seq in AM versus CM tumor tissues to test whether expression of genes whose proteins were associated with irAE were preferentially expressed in AM tissue. We also compared RNA-seq of an immunoregulatory gene panel in AM versus CM tumors. Results: We identified autoAbs that were only detected in sera from URM patients with grade 3-4 irAEs (e.g. ALDOA, BANK1, LDHB and RNF7) and autoAbs that were only detected in NHW patients with grade 3-4 irAEs (e.g. GMEB2, YWHAE and ANKRD45). A subset of these autoAb targets was preferentially expressed in AM or CM tissues, while other targets were undetected in these melanoma subtypes. Cytokine signaling pathways were enriched in sera from URM but not NHW patients, and expression of genes known to modulate irAEs and response to ICI were significantly more expressed in AM than CM tumors, e.g. FOXP3 ( P=0.01), IL2 ( P=0.00547), IL4 ( P=0.0221) and IL10 ( P=0.0126). Conclusions: Our data suggest that URM patients have an altered tumor immune microenvironment that defines their response to ICI and risk of developing irAE. An integrative analysis of both the tumor and systemic immune environments is needed to better understand molecular links between response to ICI and irAEs in URM and NHW melanoma patients. A multi-center study is planned to address these questions.
Efficacy and safety of first-line (1L) nivolumab plus relatlimab (NIVO + RELA) versus NIVO plus ipilimumab (NIVO + IPI) in advanced melanoma: An indirect treatment comparison (ITC) using patient-level data (PLD).
Authors: Schadendorf Dirk , Tawbi Hussein A. , Lipson Evan J. , Hodi F. Stephen , Ascierto Paolo Antonio , Larkin James , Lao Christopher D. , Grob Jean-Jacques , Ejzykowicz Flavia , Moshyk Andriy , Horton Viviana Garcia , Zhou Jenny , Xin Yiqiao , Palaia Jennell , McDonald Laura , Keidel Sarah , Salvatore Anthony , Sakkal Leon A. , Long Georgina V. 
Published: June 2023

9552 Background: NIVO + RELA and NIVO + IPI are approved as dual checkpoint inhibitor, 1L treatment options for patients (pts) with advanced melanoma based on results from the RELATIVITY-047 (NIVO + RELA vs NIVO; enrollment, 2018–2020) and CheckMate 067 (NIVO + IPI or NIVO vs IPI; enrollment, 2013–2014) trials, respectively. However, there is no head-to-head trial comparing the combinations; therefore, this ITC was conducted using PLD. Methods: To adjust for cross-trial imbalances in baseline characteristics, inverse probability of treatment weighting (IPTW) was used. Database locks were selected to best align follow-ups in RELATIVITY-047 (min., 21 mo; median, 25 mo) and CheckMate 067 (min., 28 mo; median, 29 mo). Efficacy and safety outcomes were selected based on data availability, including progression-free survival (PFS) per investigator, confirmed objective response rates (ORRs) per investigator, overall survival (OS), treatment-related adverse events (TRAEs), and TRAEs leading to discontinuation (DC). Efficacy was also evaluated in key subgroups. PFS and OS were compared for NIVO + RELA vs NIVO + IPI using Kaplan–Meier curves and hazard ratios (HRs); ORRs were compared using odds ratio (OR). As an internal validation of the ITC and matched assessments, the weighted NIVO cohorts from both trials were compared. Results: After IPTW, key baseline characteristics were balanced for NIVO + RELA (n = 340) and NIVO + IPI (n = 298). PFS, confirmed ORR, and OS after IPTW were similar between the treatments (table). Efficacy outcomes appeared to be similar between the treatments across subgroups, although trends favoring NIVO + IPI were observed for certain subgroups, such as pts with BRAF mutant disease or lactate dehydrogenase more than twice the upper limit of normal. Grade 3/4 TRAEs occurred in 23% and 61% of pts receiving NIVO + RELA and NIVO + IPI, respectively; any-grade TRAEs leading to DC occurred in 17% and 40% of pts. Efficacy outcomes were similar between the NIVO cohorts (table). Conclusions: In the absence of head-to-head trials, this ITC suggests that 1L treatment with NIVO + RELA may have comparable efficacy to, and better tolerability than, NIVO + IPI in pts with advanced melanoma. Similar outcomes between the NIVO cohorts support the ITC methodology. Results should be interpreted with caution given differences in study design and changes in treatment landscape over time. [Table: see text]
Melanomas lacking HLA class I expression and response to checkpoint inhibitor.
Authors: Chapman Paul B. , Jayaprakasam Vetri Sudar , Callahan Margaret K. , Shoushtari Alexander Noor , Postow Michael A. , Lezcano Cecilia , Wolchok Jedd D. , Nandakumar Subhiksha , Chatila Walid Khaled 
Published: June 2023

9553 Background: The current paradigm of how checkpoint inhibitors (CPIs) mediate anti-tumor effects relies on αβ T cells as the effector cells. However, HLA class I allele expression loss is common in melanoma, and in some cases, both β2-microglobulin (β2m) alleles are silenced, which results in complete loss of HLA I expression. We reasoned that if CPI therapy requires αβ T cells as the effector cells, melanoma tumors with biallelic loss of β2m could not present antigen to αβ T cells and should never respond to CPI. Methods: We screened the 2754 melanoma patients (pts) whose tumors had been genotypically analyzed using MSK-IMPACT, a hybridization capture-based next-generation assay for targeted deep sequencing of all exons and selected introns of up to 505 genes, including β2m. We identified 13 pts who had been treated with CPI, were evaluable for response and progression-free survival, and whose pre-treatment melanoma was found to have biallelic loss of β2m. In 1 pt, only a post-treatment tumor was available for genetic testing for β2m loss but lack of β2m expression in a pre-treatment tumor was confirmed by immunohistochemistry (IHC). Pts were assessed for clinical responses using RECIST 1.1. We recorded best overall response, duration of response, and overall survival. When available, pre-treatment tumor tissue was assessed by IHC for β2m and HLA class I expression, and for lymphocytic infiltrates expressing CD3, CD4, CD8, and CD56. Results: Anti-tumor responses were observed in 3/13 patients (23%); 2 PRs, 1 metabolic CR lasting for 24, 9.4, and 6.4 months, respectively. Responses were to ipilimumab (ipi) (N=2) and ipi/nivolumab (N=1). One pt responding to ipi had progressed on pembrolizumab; the other 2 responders were treatment-naïve. One pt died 11.5 months after starting treatment; the other 2 pts remain alive 5.5 and 8.9 years after starting treatment. IHC confirmed the lack of cell surface expression of β2m and HLA class I in all 5 tumors available for IHC staining. IHC evaluations of lymphocyte infiltrates in tumors from 1 responder and 4 non-responders showed variable degrees of CD3+ tumor infiltrating lymphocytes (TIL) with CD4+ T cell predominance. Interestingly, the 1 responder had the least dense pretreatment TIL among the 5 cases. In all 5 tumors, CD56+ lymphocytes, indicating NK cells, were rare-to-absent. Conclusions: Melanomas lacking HLA class I expression can respond to CPI therapy. Although all patients ultimately progressed, some responses were long-lived and 2 of 3 patients remain alive >5yrs. It seems unlikely that traditional CD8+ T cells are mediating these responses but more work needs to be done to identify the effector cells in these cases.