bluuebunny/crossref_metadata_2025_split huggingface dataset:
Towards organ preservation and cure via 2 infusions of immunotherapy only, in patients normally undergoing extensive and mutilating curative surgery for cutaneous squamous cell carcinoma: An investigator-initiated randomized phase II trial—The MATISSE trial.
Authors: Zuur Charlotte L. , Breukers Sabine , Machuca-Ostos Mercedes , Boere Thomas , Smit Laura , De Boer J.P. , Cornelissen Sten , Navran Arash , van Houdt Winan J. , Westerink Bram , Wondergem Maurits , de Bree Remco , Devriese Lot A. , Thommen Daniela , Traets Joleen , Haanen John B. A. G. 
Published: June 2023

9507 Background: Standard of care for locally advanced cutaneous SCC (CSCC) consists of extensive and mutilating surgery often with adjuvant radiotherapy (RT). To improve clinical prospects of these patients (pts), we tested efficacy of neoadjuvant nivolumab (NIVO) and nivolumab plus ipilimumab (COMBO) in pts with CSCC with an indication for extensive surgery with or without adjuvant RT. Methods: 40 pts with T1-4N0-3M0 or TxN1-3M0 CSCC and an indication for extensive and/or mutilating surgery were needed to reach the primary objective of this trial. Pts were randomized for ARM A: NIVO (3 mg/kg, weeks 0&2, N = 26) or ARM B: NIVO (3 mg/kg, weeks 0&2) + IPI (1mg/kg, week 0, N = 24) prior to surgery (week 4). Primary objective was pathological response at time of surgery. A major pathological response (MPR) was defined as ≤10% residual viable cancer cells in the surgical resection specimen. Secondary endpoints were tolerability (CTCAE v.5.0), survival, and quality of life (QOL). Key exploratory aim for the trial was the serial collection of pre- and on-treatment tumor samples to investigate immunogenomic features correlating with immunotherapy response. Preliminary results: 50 pts were enrolled at median age 76, of whom 32% with TxN1-3M0 disease. Grade 3-4 irAEs occurred in 6 (12%) pts and were well manageable. 40 pts underwent standard of care surgery w/wo adjuvant RT, of whom 40% and 53% reached an MPR upon NIVO and COMBO, respectively. However, 10 pts withdrew consent to undergo surgery and RT, of whom nine pts declined because of self-reported substantial clinical remission upon neoadjuvant immunotherapy. These clinical responses were confirmed via FDG-PET evaluation in week 4. All these 9 pts are currently cancer free at median FU of 12 months (range 4 to 27) with superior QOL compared to MATISSE pts undergoing standard of care. Overall, we found deep clinical responses in 13/26 (50%) and 14/23 (61%) of pts upon NIVO and COMBO, respectively, being either a MPR at time of surgery or a clinical CR in patients declining surgery. Preliminary conclusions: The MATISSE trial shows deep responses of 50% and 61% upon neoadjuvant NIVO and COMBO, respectively, with well manageable toxicity in this elderly CSCC population. Nine MATISSE patients have proven the concept that organ preservation and durable complete remissions can be achieved after two infusions of neoadjuvant immunotherapy only, without extensive or mutilating curative surgery and/or RT. Clinical trial information: NCT04620200 .
Temozolomide plus cisplatin versus toripalimab (anti-PD-1) as adjuvant therapy in resected mucosal melanoma.
Authors: Lian Bin , Tian Hui , Si Lu , Chi Zhihong , Sheng Xinan , Wang Xuan , Mao Lili , Bai Xue , Tang Bixia , Yan Xieqiao , Li Siming , Zhou Li , Wei Xiaoting , Li Juan , Li Caili , Cui Chuanliang , Guo Jun 
Published: June 2023

9508 Background: Chemotherapy (temozolomide plus cisplatin) has been demonstrated to be a better adjuvant regimen compared to high-dose interferon alpha-2b in resected Mucosal Melanoma (MuM) in the pre-immunotherapy era. Yet in the present immunotherapy era, PD-1 inhibitor was recommended as a standard adjuvant therapy for resected Melanoma. No adjuvant trial comparing chemotherapy with PD-1 inhibitor in resected MuM had been reported. we conducted this study to determine the efficacies of adjuvant chemotherapy versus PD-1 inhibitor in resected MuM. Methods: All patients (pts) with resected MuM received chemotherapy (temozolomide 200 mg/m2/day orally on days 1 to 5 plus cisplatin 75 mg/m2 i.v. on days 1-3, repeated every 3 weeks for six cycles) or Toripalimab (anti-PD-1, 3 mg/kg every 2 weeks via intravenous infusion) as adjuvant therapy from 2013 to 2019 were included retrospectively. Demographic and clinical characteristics between the two groups were matched with 1:1 by propensity score matching (PSM) to reduce the bias. After PSM, the efficacies of the two groups were compared, and subgroup analysis was performed according to the baseline characteristics. The endpoints were relapse-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). Kaplan-Meier methods and Cox regressions were used to estimate median RFS, DMFS, OS and HR. Results: A total of 247 pts were included, of which 78 were in the Toripalimab group and 169 were in the Chemo group. PSM matched 65 pts from each of the two groups. The baseline characteristics were similar. At a median follow-up of 52.6 months (95%CI, 44.6-60.6 months), patients receiving chemo had a longer median RFS (28.2 vs. 12.0 months; HR=0.64, 95% CI, 0.42 to 0.98; P=0.04), DMFS (42.0 vs. 19.0 months; HR=0.58, 95% CI, 0.36 to 0.92; P=0.02) and OS (93.4 vs. 39.3 months; HR=0.56, 95% CI, 0.33 to 0.94; P=0.03) versus the toripalimab group (Table). Conclusions: Adjuvant chemotherapy (temozolomide plus cisplatin) shows remarkable longer RFS, DMFS, and OS than Toripalimab (anti-PD-1). It suggested that adjuvant chemotherapy may be a better option for patients with resected mucosal melanoma even in the present immunotherapy era. [Table: see text]
Initial efficacy and safety of RP1 + nivolumab in patients with anti–PD-1–failed melanoma from the ongoing phase 1/2 IGNYTE study.
Authors: Chmielowski Bartosz , Milhem Mohammed M. , Sacco Joseph J. , Bowles Tawnya Lynn , Tsai Katy K. , In Gino Kim , Muñoz-Couselo Eva , Vanderwalde Ari M. , Chesney Jason Alan , Michels Judith , Samson Adel , Beasley Georgia , Schadendorf Dirk , Mahmoud Fade , Wong Michael K.K. , Wise-Draper Trisha Michel , Zhu Junhong , Bommareddy Praveen , Hou Jeannie W. , Middleton Mark R. 
Published: June 2023

9509 Background: Patients (pts) with melanoma who progress on anti–PD-1 therapy (anti–PD-1–failed) have limited treatment options. RP1 is an HSV-1–based oncolytic immunotherapy expressing human GM-CSF and a fusogenic protein (GALV-GP-R−). Here, we present data from the first 75 pts enrolled into the registration-directed (R-D) cohort in anti–PD-1–failed melanoma (target enrollment N = 125) from the phase 1/2 IGNYTE study (NCT03767348). Methods: Pts must have locally advanced or metastatic cutaneous melanoma with ≥1 measurable and injectable tumor (≥1 cm) and confirmed progressive disease (PD) on 2 assessments ≥28 days apart while on ≥8 consecutive weeks of anti–PD-1 ± anti–CTLA-4 therapy, with anti–PD-1 being the last treatment received. Pts on prior adjuvant anti–PD-1 therapy must have had PD confirmed by biopsy while on adjuvant therapy. RP1 is initially given intratumorally at 106 PFU/mL and then every 2 weeks (Q2W) at 107 PFU/mL for ≤8 total cycles (≤10 mL/dose) combined with nivolumab (nivo; cycles 2–8, 240 mg IV); pts then receive nivo alone (240 mg Q2W or 480 mg Q4W IV) for ≤2 years, with the option to reinitiate RP1 if specified criteria are met. Results: A total of 91 pts are included in this analysis (initial melanoma cohort, 16 pts; R-D cohort, 75 pts; data cut: Dec 30, 2022). The overall objective response rate (ORR) was 37.4% (initial cohort, 37.5%; R-D cohort, 37.3%) and 18.7% of pts achieved complete response (CR; Table). The response rates seen were also encouraging when evaluated by prior anti–PD-1 therapy setting and disease stage (Table). Responses were seen in uninjected lesions in most responding patients, including in pts with bulky and visceral disease. The majority of responses were observed in pts with PD-L1–negative tumors at baseline (17 of 52 pts with PD-L1–negative tumors responded, compared to 15 of 26 pts with PD-L1–positive tumors, and 2 of 13 pts for whom PD-L1 status was unknown). 85.3% of responses were ongoing 3.7–36.6 months from initiating therapy. Most treatment-related adverse events (TRAEs) were Grade 1–2 with the most common (>20%) being fatigue, chills, pyrexia, and nausea. Conclusions: The initial data from this expanded cohort show that RP1 + nivo provides durable and clinically meaningful antitumor activity in pts with anti–PD-1–failed melanoma. Responses were observed in both injected and uninjected lesions, including visceral lesions. The combination continues to be well tolerated, with mostly on-target TRAEs. Additional and updated data will be presented. Clinical trial information: NCT03767348 . [Table: see text]
NeoPlus: A phase II study of neoadjuvant lenvatinib and pembrolizumab in resectable mucosal melanoma.
Authors: Mao Lili , Si Lu , Dai Jie , Bai Xue , Li Caili , Wei Xiaoting , Cui Chuanliang , Chi Zhihong , Sheng Xinan , Tang Bixia , Lian Bin , Wang Xuan , Yan Xieqiao , Zhou Li , Kong Yan , Wu Xiaowen , Li Siming , Li Juan , Guo Jun 
Published: June 2023

9514 Background: Combination therapy of anti-PD1 agent with VEGFR inhibitor is a promising therapeutic approach in unresectable or metastatic mucosal melanoma. We conducted this study evaluating neoadjuvant lenvatinib and pembrolizumab in pts with resectable mucosal melanoma. Methods: This was a single-arm, open-label, single-center, ongoing phase 2 study conducted from Sep 2021. Eligible pts were adults (18-75 yr) with histologically confirmed, resectable mucosal melanoma. Pts received lenvatinib 20mg qd and pembrolizumab 200mg q3w for 2 cycles, followed by surgery. Pembrolizumab (200mg q3w) continued post operatively for further 15 cycles. The primary endpoint was complete pathologic response (pCR). Secondary endpoints were Event free survival (EFS), Overall survival (OS) and safety. Results: As of Dec 2022, 19 pts were enrolled with a median follow-up of 49 wks (95%CI, 38 -60). Median age was 57 yrs, 14 were female. Primary sites included: 8 female genital, 6 ano-rectal, 4 head & neck (1 nasal, 3 oral),1 esophageal. 12 pts were localized disease,7(37%) were regional lymphatic disease. KIT or NRAS mutations were presented in 2 and 3 pts, respectively. 15 pts underwent surgery, 2 pts had a pCR (13.3 %), 1 MPR, 3 pPR, with a pathologic response rate of 40%(6/15,95%CI 16-67%). 4 pts did not proceed with planned surgery for pts preference. Median EFS has not been reached. IHC data of the resected tumor showed higher CD8+ T cells density in responders (R=pCR+ MPR + pPR) than non-responders (NR=pNR) (p = 0.04). In 6 pts(one pPR and 5pNR) with paired pre and post treatment samples, CD3+ and CD8+ T cells were significantly increased following treatment (p =0.03). Most common AEs were proteinuria (6, 32%), hypothyroidism (6, 32%), dysphonia (5, 26%). One pt(5%, 1/19) had grade 3 ALT elevation. No grade 4-5 toxicities were observed. Conclusions: The combination of pembrolizumab plus lenvatinib as neoadjuvant therapy in resectable MM is safe. The preliminary data has shown promising pathologic response with increased CD8+ T cell infiltration, supporting further investigation of neoadjuvant treatment in MM. Acknowledgement: Investigational funding and products are granted from Merck Sharp & Dohme LLC. Clinical trial information: NCT04622566 .
The validity of a machine learning algorithm in predicting response to immune checkpoint inhibitors in melanoma.
Authors: Fa'ak Faisal , Coudray Nicolas , Jour George , Goldberg Clara , Johannet Paul , Huang Alexander Chan Chi , Mitchell Tara , Xu Xiaowei , Tsirigos Aristotelis , Weber Jeffrey S. , Osman Iman 
Published: June 2023

9523 Background: We previously reported the development of a machine learning algorithm to predict immunotherapy response in patients with advanced melanoma using retrospectively collected pretreatment histologic slides (Johannet et al, CCR 2021). In this study, we tested the validity of the same algorithm in two independent cohorts of melanoma patients enrolled in phase III clinical trials of immune checkpoint inhibitors (ICI), one metastatic, and one adjuvant. Methods: We examined 336 patients enrolled in CheckMate 067(NCT01844505) and CheckMate 238 (NCT02388906). We used deep convolutional neural networks (DCNN) to automatically segment images into three regions of interest: tumor, lymphocytes, and stroma. The algorithm was previously trained and tested to predict the complete and partial response (CR/PR) versus progression of disease (POD) and to predict the probability of progression-free survival (PFS) while on ICI. We tested the performance in the two cohorts; the first (CheckMate 067) included 164 patients with stage III/IV unresectable melanoma who received ipilimumab (n= 49), nivolumab (n = 59), or combination (n= 56) therapy as a first line, then tested whether the algorithm could perform as well in the second cohort (CheckMate 238) which included 172 patients with stage III/IV resectable melanoma who received adjuvant ipilimumab (n = 87) or nivolumab (n = 85) therapy as first line. Results: The segmentation classifier identified tumor within slides with an area under the curve (AUC) of 0.99. A combined model of DCCN and treatment predicted POD with an AUC of 0.72 in metastatic melanoma patients enrolled in Checkmate 067. The DCCN classified patients into high and low risk based on their likelihood of PFS (P <0.0001). However, the same algorithm is not effective in predicting recurrence in patients treated in the adjuvant setting in Checkmate 238 (AUC 0.52). Retraining and testing using only patients treated in the adjuvant setting improved the AUC average to 0.65-0.70. Conclusions: Our results show the reproducibility of our previously developed algorithm in predicting response in patients with advanced metastatic melanoma. The inability of the model to predict recurrence in patients treated in the adjuvant setting might reflect the difference in the endpoint tested (response versus recurrence), which requires further training on larger datasets for this particular endpoint prediction, and/or the limited tumor volume in resected disease below a threshold that machine learning can predict a difference.
Economic evaluation for the US of relatlimab and nivolumab (RELA+NIVO) versus nivolumab (NIVO) monotherapy in untreated advanced melanoma.
Authors: Aqel Osama , Alfayoumi Ibrahim , Shen Yunrong , Aliu Oiza , Zaidi Syeda Hina , Moreno-Rodriguez Valeria , Ayoade Oluwayemisi O , Alzahir Hassan , Kopecky Jan Marco , Khattab Salma , Snyder Mattie , Abraham Ivo 
Published: June 2023

9539 Background: The RELATIVITY-047 trial demonstrated longer median progression-free survival (PFS) with the combination of RELA+NIVO (10.1 months, 95% CI = 6.4 to 15.7) over NIVO (4.6 months, 95%CI = 3.4 to 5.6) in patients with untreated advanced melanoma (hazard ratio for progression or death = 0.75, 95%CI = 0.62 to 0.92). This economic evaluation aimed to estimate the cost-effectiveness/utility of RELA+NIVO vs. NIVO monotherapy in this setting. Methods: A two state partitioned survival model (PFS, progressed/death) was developed to compare costs and PFS outcome associated with both treatments. PFS curves were digitized and parametric functions fitted. A 5-year time horizon from a US payer perspective with a 3% discount rate/year was considered. Costs of treatment (average sales price), administration and monitoring parameters were derived from Centers for Medicare & Medicaid Services databases; cost of adverse events (grade 3/4 with rate >5%) were derived from prior advanced melanoma economic evaluations. Incremental costs, PFS life years (PFSLY), and PFS quality adjusted life years (PFSQALY) gained (g) were estimated in base case (BCA) and probabilistic sensitivity analyses (PSA). A cost-effectiveness acceptability curve (CEAC) was plotted to determine the probability of either treatment to be cost-effective over the other at different willingness to pay (WTP) thresholds. Results: Exponential regression was used to extrapolate RELA+NIVO and NIVO survival curves. According to the result table shown below, the BCA (PSA) shows an incremental cost of RELA+NIVO over NIVO of $405,663 ($402,936), incremental PFSLY of 0.326 (0.325), and incremental PFSQALY of 0.260 (0.256). The BCA (PSA) ICERs indicated an additional $1,244,365 ($1,239,803) per PFSLY gained (g) and an additional $1,560,242 ($1,573,969) per PFSQALYg. The CEAC curve shows that RELA+NIVO treatment had a 50% probability of being cost-effective regimen at a WTP threshold value of $1,525,000 and 100% probability at a threshold of $3,050,000 or above. Conclusions: In the setting of advanced melanoma, this economic evaluation showed that RELA+NIVO is associated with improvement in LY and QALY, however, at a marked incremental cost, requiring a very high WTP threshold. [Table: see text]
Updated safety and efficacy results from the phase I study of either LBL-007 (an anti-LAG-3 antibody) in combination with toripalimab (an anti-PD-1 antibody) or LBL-007 in combination with toripalimab and axitinib in patients with advanced melanoma.
Authors: Bai Xue , Li Mei , Chen Yu , Si Lu , Chen Jing , Pu Xingxiang , Cheng Ying , Zou Zhengyun , Zhao Shiwei , Li Tao , Cai Shengli , Guo Jun 
Published: June 2023

9541 Background: Initial safety and efficacy data of LBL-007 plus toripalimab in patients with advanced melanoma (Part A) have been reported in 2022 ASCO (Abstract 9538). Here we present the updated results of part A and the preliminary results of part B (LBL-007 plus toripalimab with axitinib). Median follow-up was 9.7 months at cut-off data (January 11, 2023). Methods: Patients with advanced melanoma with or without prior therapy were enrolled during Jan 2021 - Aug 2022. This trial comprised 2 parts: Part A, patients received LBL-007 (0.25 - 10 mg/kg for dose escalation; 3 or 6 mg/kg for dose expansion) plus toripalimab at 3 mg/kg (both i.v. Q2W); and Part B, patients received LBL-007 at 3 or 6 mg/kg plus toripalimab at 3 mg/kg (both i.v. Q2W) and axitinib at 5 mg BID. The primary objective was safety, the second objectives were pharmacokinetics, pharmacodynamics and efficacy (per RECIST v.1.1). Results: In part A, 68 patients in total (57 treatment-naïve) were enrolled including 20 patients in dose escalation and 48 patients in dose expansion, and among which, 31 additional patients have been enrolled since 2022 ASCO report. Nineteen (27.9%) patients occurred grade ≥3 TEAEs, the common grade ≥3 TEAEs was anaemia (11.8%). No new safety signals were detected. Among 55 efficacy evaluable treatment-naïve patients (41 with acral, 7 mucosal, 7 others), ORR was 23.6%, DCR was 58.2%, and mPFS was 5.7 months (95% CI: 3.7, 9.5). In part B, 11 patients (10 mucosal, 1 acral) were enrolled. No DLT was observed. Five patients (45.5%) occurred grade ≥3 TEAEs, the common grade ≥3 TEAEs included blood pressure increased (18.2%) and transaminases increased (18.2%). One (9.1%) patient discontinued treatment due to TEAEs. ORR was 45.4% (including 4 mucosal and 1 acral), DCR was 72.7%, and mPFS was 5.5 months (95% CI: 1.8, 9.1). Conclusions: LBL-007 plus toripalimab continued to show promising antitumor activity and manageable safety profile in patients with treatment-naïve melanoma, which support further development in this indication. LBL-007/toripalimab/axitinib combination demonstrated acceptable safety profile and encouraging antitumor activity in patients with mucosal melanoma. Acknowledgements: Junshi Biosciences. Clinical trial information: NCT04640545 .
Durable clinical outcomes in patients (pts) with advanced melanoma and progression-free survival (PFS) ≥3y on nivolumab (NIVO) ± ipilimumab (IPI) or IPI in checkmate 067.
Authors: Hodi F. Stephen , Chiarion-Sileni Vanna , Gonzalez Rene , Grob Jean-Jacques , Rutkowski Piotr , Lao Christopher D. , Cowey Charles Lance , Schadendorf Dirk , Wagstaff John , Dummer Reinhard , Queirolo Paola , Smylie Michael , Butler Marcus O. , Hill Andrew Graham , Marquez-Rodas Ivan , Ritchings Corey , Sakkal Leon A. , Wang Peter , Wolchok Jedd D. , Larkin James 
Published: June 2023

9542 Background: NIVO + IPI has demonstrated durable clinical benefit at 7.5 y in pts with advanced melanoma in the phase 3 CheckMate 067 study. PFS curves plateaued at ~3 y in this study, suggesting that being alive and progression-free for ≥ 3 y (PFS ≥ 3y) may be a good surrogate for long-term clinical benefit. We conducted analyses to quantify this association. Methods: Pts with treatment (tx)-naive, unresectable stage III/IV melanoma (stratified by PD-L1 expression, BRAF mutation status, and metastasis stage) received NIVO 1 mg/kg + IPI 3 mg/kg for 4 doses Q3W, followed by NIVO 3 mg/kg Q2W (n = 314); NIVO 3 mg/kg Q2W + placebo (n = 316); or IPI 3 mg/kg Q3W for 4 doses + placebo (n = 315) until progression or unacceptable toxicity. Exploratory post hoc analysis was performed in pts with PFS ≥ 3y. Results: In the NIVO + IPI, NIVO, and IPI arms, respectively, 99 (32%), 78 (25%), and 21 (7%) pts had PFS ≥ 3y. Objective response rates (ORRs) in these pts were ≥ 95% (table). The majority of responses were complete responses (CRs; table); in almost all pts with partial responses (PRs) on NIVO + IPI or NIVO, target-lesion size decreased by ≥ 50%. At 7.5 y of follow-up among pts alive and progression-free at 3 y, PFS rates were ≥ 68%, overall survival (OS) rates were ≥ 85%, and melanoma-specific survival (MSS) rates were ≥ 95% in the 3 tx groups (table). Among pts in this group who died after 3 y on study, the majority of deaths were unrelated to disease (table). The majority of pts with PFS ≥ 3y who were alive and in follow-up were tx-free at the 7.5-y data cutoff (77/84, 57/64, and 13/16). Pts who received NIVO + IPI were off tx (median) for 75.5 mo (NIVO, 55.7 mo; IPI, 59.2 mo). Among pts with PFS ≥ 3y in the 3 tx groups, 4%, 5%, and 19% received subsequent systemic tx (table). No new safety signals were observed in pts with PFS ≥ 3y. Conclusions: This exploratory post hoc analysis suggested that PFS ≥ 3y may be a good surrogate for long-term MSS with NIVO + IPI or NIVO, with very few occurrences of progression or death due to melanoma in this population through 7.5 y. Most pts were tx-free without having received subsequent systemic tx after demonstrating PFS ≥ 3y. Further study of pts with PFS ≥ 3y may allow the burden of imaging and follow-up visits to be reduced in this group. Clinical trial information: NCT01844505 . [Table: see text]