tbuckley/cabot-search huggingface dataset:
Peripheral blood biomarkers in immune checkpoint inhibition therapy in metastatic melanoma.
Authors: Ghanshyam H. Ghelani, Anupa Mandava, Maroun Bou Zerdan, Radhika Mehta, Abirami Sivapiragasam
Journal: Journal of Clinical Oncology (2024)

e21543 Background: Immune checkpoint inhibitors are extensively employed in the management of various solid cancers. Our study aims to assess the potential prognostic and predictive value of peripheral blood biomarkers, as well as their correlation with adverse events. Methods: In this study, we conducted a retrospective analysis of data retrieved from a cohort of 23 patients diagnosed with metastatic melanoma at a single institution between 2015 and 2019. Specifically, we focused on analyzing the neutrophil-to-lymphocyte ratio (NLR), absolute neutrophil+monocyte-to-absolute lymphocyte+eosinophil ratio (ANMC/ALEC) from complete blood count (CBC), and lactate dehydrogenase (LDH) level from peripheral blood to assess their correlation with progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs). Results: Our findings revealed that NLR values less than 0.34 and ANMC/ALEC ratio less than 3.45 were associated with improved PFS and OS, as well as a lower incidence of immune-related adverse events, which supports our initial hypothesis. However, these results were not statistically significant due to the low power of our study. On the other hand, high NLR values were significantly associated with higher pre-treatment LDH levels (P-value = 0.037), which is a well-established adverse prognostic factor in melanoma. Additionally, high ANMC/ALEC ratios were also found to be associated with high LDH levels, although this relationship was not statistically significant (P-value = 0.133). Conclusions: The results of our study suggest that patients with lower pre-treatment NLR and ANMC/ALEC ratios have better PFS and OS, as well as lower incidence of irAEs. Conversely, those with high NLR and high ANMC/ALEC ratios exhibited lower PFS and OS, as well as higher incidence of irAEs. High NLR and ANMC/ALEC ratios were also found to be associated with higher pre-treatment LDH levels, which have previously been demonstrated to be an adverse prognostic factor in melanoma. [Table: see text]
Responses to immune checkpoint inhibitor therapy in NF1 mutated cutaneous melanoma.
Authors: Matthew Robert Kroll, Anthony N Snow, Bradley T. Loeffler, Mohammed M. Milhem, Asad Javed
Journal: Journal of Clinical Oncology (2024)

e21535 Background: NF1 mutations occur in 14% of cutaneous melanoma. Less than 20% of advanced melanoma patients on Immune Checkpoint Inhibitor (ICI) therapy achieve radiographic Complete Response (CR). We present data on radiographic responses to ICI therapy in advanced melanoma patients with tumors harboring NF1 (Neurofibromatosis 1) mutations. Methods: Patients with metastatic or unresectable NF1 mutated melanoma were included in the analysis. Mutation status was identified via NGS and mutation pathogenic status was determined using Genome Oncology Software. All patients received ICI therapy. RECIST 1.1 was used to assess treatment responses with CT scans. CR on PET was defined as disappearance of all metabolically active lesions. Results: 26 metastatic or unresectable melanoma patients met criteria for inclusion. Of these, eight (30.8%) had CNS metastasis. ICI therapy included Ipilimumab-Nivolumab, Pembrolizumab, Nivolumab, or Relatlimab-Nivolumab (24/26 in front-line setting). The 12- and 24-month estimated cumulative incidence of CR were 43.9% and 60.6%, respectively. Altogether, 16 patients achieved CR as their best overall response. Four patients that achieved CR subsequently progressed. Four patients progressed without achieving CR. Six patients achieved a partial response by last follow-up without achieving CR or disease progression. Of the 8 patients with CNS metastasis, five (62.5%) had intra-cranial radiographic responses to ICI therapy, including 1 (12.5%) complete response. Five (62.5%) had multifocal ( &gt; 2 sites of intracranial metastasis) intracranial disease. Five (62.5%) of these patients with intracranial disease received radiation, 2/8 (25.0%) received radiation and surgical resection, and one (12.5%) received neither radiation nor surgery. Three (37.5%) patients with CNS metastasis experienced disease progression while on ICI therapy. Conclusions: NF1 mutated melanoma appears to have high rates of radiographic responses to ICI therapy. Prospective validation of this finding, particularly in patients with CNS metastasis, is warranted.
Options for enhancing specific antitumor immunity in patients with melanoma.
Authors: Alexander Valerievich Sultanbaev, Irina Vladimirovna Kolyadina, Mikhail Sultanbaev, Shamil Musin, Konstantin Menshikov, Nadezda Sultanbaeva, Dmitry Kudlay, Irina Tuzankina
Journal: Journal of Clinical Oncology (2024)

e21547 Background: The special interest in oncology is the research of the immune status of patients. Quantification of T-cell receptor excision rings (TREC) and B-cell receptor κ deletion elements (KREC) allows to evaluate a humoral and a cellular immunity. In melanoma, the effectiveness of the use of drugs to control immune points depends on the formation of specific antitumor immunity. Quantitative indicators of excision recombination rings reflect the formation of a different repertoire of T-cell receptors, which are an integral component in the formation of specific immunity. The understanding of changes in TREC levels in patients with melanoma during therapy with various drugs can improve the selection of patients for immunotherapy. The purpose of this study is to assess the dynamics of changes in quantitative indicators of the T-cell receptor during adjuvant therapy for melanoma. Methods: The study included 82 patients with melanoma. Among patients with melanoma, the proportion of male patients was 36.5% (30/82), female - 63.5% (52/82). The median age in the group of patients with cancer was 63 years [Q1-Q3: 52.8-75]. Results: From the results obtained, it follows that in cancer patients, a decrease in the number of TREC in the blood indicates the presence of immunodeficiency. The data obtained indicate significant changes in TREC in melanoma. Targeted therapy (dabrafenib + trametinib) and interferon therapy are accompanied by a significantly significant increase in the level of TREC, which indicates an increase in the formation of specific antitumor immunity. Conclusions: The results obtained demonstrate a significant decrease in TREC content in patients with melanoma compared to healthy individuals. Determination of TREC levels during adjuvant therapy demonstrated the effectiveness of dabrafenib in combination with trametinib and interferon α-2β, which is reflected in a significant increase in the T-cell receptor repertoire. The presented data indicate the possibility of using the method for determining the TREC level to predict the risk of cancer progression and the effectiveness of prescribed therapy.
Impact of race and gender on outcomes from patients with stage IV non-small cell lung cancer receiving immunotherapy: A retrospective study performed at Mitchell Cancer Institute, Mobile, AL.
Authors: Daisy E. Escobar, Krithika Muthyala, Muhammmad Areeb Ashfaq, Brian Edward Persing, Madhuri S. Mulekar, Pranitha Prodduturvar
Journal: Journal of Clinical Oncology (2024)

e20562 Background: The use of immunotherapy is associated with improved survival among patients with Non-Small Cell Lung Cancer (NSCLC). The impact of race and gender on survival with immunotherapy is limited and conflicting. Our study sought to examine the influence of race and gender on the outcomes of patients with stage IV NSCLC treated with first line immunotherapy. Methods: A retrospective review of 91 patients with stage IV NSCLC was performed. Patients with confirmed NSCLC who received first line immunotherapy between January 2018 to December 2022 identified from Mitchell Cancer Institute (MCI) Cancer Registry were analyzed for clinical outcomes. Disease-specific survival was evaluated and compared among patients across racial/ethnic categories using mean, standard deviation, median, and interquartile range. Mean outcomes for numerical factors were compared using a t-test, while median outcomes were compared using a median test. The association between categorical factors was assessed using Fisher’s test, with a significance level of 0.05. Results: A total of 91 patients (45 [49.5%] male) were included in the analysis, with 61 White (67.0%; mean [SD] age, 70.2 [10.1] years) and 30 African American [AA] (32.9%; mean [SD] age, 65.9 [9.2] years). Based on histological analysis 71(77.8%) were adenocarcinoma, 18 (19.8%) squamous cell carcinoma, and 2 (2.2%) adenosquamous carcinoma. Mean progression free survival (PFS) was greater in Whites (315 vs 178 days; p = 0.041). Mean overall survival (OS) was longest in Whites (397 vs 218 days; p = 0.016). No significant differences were observed in age at diagnosis (p = 0.096), mean cycles given (p = 0.406) and PD-L1 status (p = 0.077) between Whites and AA’s. No significant differences were observed in age at diagnosis (p = 0.184), mean cycles given (p = 0.729) and time to progression (p = 0.769) or death (p = 0.938) between genders. PD-L1 distribution differed between males and females (p = 0.021) with a higher percentage of females having PD-L1 ≥1% (63% vs 38%). Conclusions: Our study showed longer PFS and OS in White patients receiving first line immunotherapy in stage IV NSCLC regardless of age at diagnosis or PD-L1 status. No differences in PFS or OS were seen between genders irrespective of age at diagnosis, mean cycles of treatment or PD-L1 status. These findings demonstrate the importance of integrating race, ethnicity, and gender as prognostic variables in the evaluation of patients with NSCLC in the incorporation of social determinants of health. This inclusion is crucial to obtain a more comprehensive understanding of how these factors influence patient outcomes.
Overall survival and efficacy subgroup analysis of tunlametinib in patients with advanced NRAS-mutant melanoma: A multicenter, open-label, single-arm, phase 2 study.
Authors: Xiaoting Wei, Zhengyun Zou, Weizhen Zhang, Meiyu Fang, Xiaoshi Zhang, Zhiguo Luo, Jing Chen, Gang Huang, Peng Zhang, Ying Cheng, Jiwei Liu, Jiyan Liu, Junping Zhang, Di Wu, Yu Chen, Xiaobiao Ma, Hongqi Tian, Zhongwei Jia, Jun Guo, Lu Si
Journal: Journal of Clinical Oncology (2024)

9545 Background: NRAS-mutant melanoma is an aggressive subtype with worse prognosis. However, no targeted therapy has been approved to date worldwide. Tunlametinib (HL-085) has showed an encouraging efficacy (confirmed ORR:34.8%, mPFS:4.2 months) with a manageable safety profile in phase II pivotal registrational study, which was published in ASCO 2023 annal meeting (NO.:9510). Here, we report the updated efficacy results. Methods: This is a multicenter, single-arm, phase II, pivotal registrational study. Patients (pts) with NRAS-mutant unresectable stage III or IV melanoma were enrolled and received tunlametinib 12 mg orally twice daily. The primary endpoint was confirmed objective response rate (ORR) per Response Evaluation Criteria In Solid Tumors, version 1.1 assessed by independent radiology review committee (IRRC). Results: A total of 100 pts were enrolled and 95 pts were included in the full analysis set (FAS) for efficacy analysis. At cut-off date (October 31, 2023), median follow-up was 24.4 months (95% CI: 21.9, 27.9). The confirmed ORR was 35.8% (95%CI: 26.3%, 46.3%). Median progression-free survival (mPFS) was 4.2 months (95%CI: 3.5, 5.6). The median overall survival (mOS) was immature during last year's ASCO annual meeting, and the present mOS was 13.7 months (95% CI of 10.3–18.0). The IRRC-assessed ORRs by melanoma subtype were 42.9% (95% CI of 29.7–56.8) in acral melanoma, 25.0% (95% CI of 7.3–52.4) in mucosal melanoma. ORRs by NRASmutation site were 41.3% (95% CI of 30.1–53.3), 13.3% (95% CI of 1.7–40.5) and 20.0% (95% CI of 0.5–71.6) for Q61, G12, and G13, respectively. ORR in patients who had been treated with immunotherapy was 40.6% (95% CI of 28.5–53.6), while in those without immunotherapy, ORR was 25.8% (95% CI of 11.9–44.6). The difference in PFS was not statistically significant across subgroups, regardless of melanoma type, NRAS mutation site, line of previous treatment, type of previous treatment and previous treatment with immunotherapy. The safety profile is similar with last year's ASCO annual meeting. The most frequent treatment related adverse events (TRAEs) were increased blood creatine phosphokinase (CK), diarrhea, facial oedema, peripheral oedema, and increased aspartate aminotransferase. No treatment-related death was reported. Conclusions: Tunlametinib demonstrated an encouraging treatment response rate in patients with advanced NRAS-mutant melanoma with a manageable safety profile. These results suggest that tunlametinib could be a promising treatment option for NRAS-mutant melanoma, even for those who had previously received immunotherapy. Clinical trial information: NCT05217303 .
Effect of first-line bevacizumab on prognosis of second or later-line immunotherapy in patients with advanced non-squamous non-small cell lung cancer: A retrospective analysis.
Authors: Qian Chen, Shumin Yuan, Ni Liu, Huimin Wang, Xiaoling Shang, Xinchun Ma, Ying Sun, Chenxi Wei, Lian Liu, Xiuwen Wang, Yanguo Liu
Journal: Journal of Clinical Oncology (2024)

e20570 Background: Previous studies have demonstrated that anti-angiogenic agents have the capacity to regulate tumor microenvironment and may affect the clinical effect of immune checkpoint inhibitors (ICIs). However, the impact of previous anti-angiogenic agents on clinical outcomes of non-squamous non-small cell lung cancer (nsqNSCLC) patients treated with ICIs remains unclear. Methods: In the present study, we incorporated POPLAR, OAK, and BIRCH trials with a total of 912 non-squamous NSCLC patients. Using Vivli data-sharing platform, we have obtained specific clinical information about individual patients. The progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier analysis with a log-rank test, and the corresponding hazard ratio (HR) and 95% confidence interval (CI) were estimated using the Cox proportional regression model. Chi-squared test was used to compare proportions between different groups. All statistical analysis and plotting were done in R version 4.1.1 and SPSS R26.0.0.2. P less than 0.05 was considered statistically significant. Results: In the overall cohort, PFS (2.77 months vs. 2.83 months; hazard ratio [HR],1.1; 95% confidence interval [CI], 0.9 to 1.3; p = 0.43) and OS (15.1 months vs. 14.3 months; HR,1.0; 95% CI, 0.8 to 1.3; p = 0.86) in patients treated with bevacizumab before atezolizumab (pre-bevacizumab group) and patients treated without bevacizumab before atezolizumab (no pre-bevacizumab group) were not statistically different. Merely in patients with KRAS mutation, no pre-bevacizumab group had an improved PFS (4.04 months vs. 1.64 months; HR,1.7; 95% CI, 1.0 to 2.7; p = 0.04) as compared to the pre-bevacizumab group. Longer use of bevacizumab (≥1.43 months) before atezolizumab suggested a longer PFS compared with shorter use of bevacizumab ( &lt; 1.43 months) (20.07 months vs. 2.75 months; HR,0.40; 95% CI, 0.17 to 0.95; p = 0.03). Conclusions: In conclusion, our study demonstrated that whether or not first-line bevacizumab is given has no effect on PFS or OS of second-line or later-line immunotherapies. Patients with longer duration of first-line bevacizumab use have a longer PFS on later immunotherapy. The more appropriate timing and sequence of administration of anti-angiogenic agents and ICIs will help us achieve a better therapeutic effect in the clinical practice of patients with advanced NSCLC.
A multicenter, single-arm, open-label phase II study to evaluate the efficacy and safety of YH003 in combination with pembrolizumab and nab-paclitaxel in the first-line treatment of patients with unresectable/metastatic mucosal melanoma.
Authors: Yu Chen, Xiaoshi Zhang, Ya Ding, Yu Jiang, Jing Chen, Xingxiang Pu, Xiubao Ren, Weizhen Zhang
Journal: Journal of Clinical Oncology (2024)

e21520 Background: Mucosal melanoma therapy remains a formidable challenge especially in Asia. Although several therapies are available for skin type of melanoma, the efficacy of mucosal melanoma is not satisfactory. YH003, a humanized agonistic anti-CD40 monoclonal antibody specifically recognizes and agonizes CD40 to enhance immune responses, has demonstrated good safety and promising antitumor activity in Phase I clinical studies in patient with ocular melanoma. Here, we report the results of the phase II study of YH003 in combination with pembrolizumab and nab-paclitaxel in the first-line treatment of patients with unresectable/metastatic mucosal melanoma. Methods: Patients with unresectable/metastatic mucosal melanoma were enrolled and received 0.3 mg/kg YH003, 200 mg pembrolizumab and 200 mg/m 2 of nab-paclitaxel iv, every 21 days. The treatment continued for 12 months if subject was deriving an ongoing clinic benefit. The primary endpoint was overall Response Rate (ORR) by investigator’s assessment per RECIST 1.1. Results: A total of 20 patients were enrolled and had at least 1 evaluable post-treatment tumor assessment, the unconfirmed ORR was observed in 7 patients (35.0%), with 7 partial responses (PR). 7 patients (35.0%) had stable disease (SD), and the Disease Control Rate (DCR) was 70.0%. The mOS was not reached, mPFS was 4.11 months. The grade 3 or above TEAE that occurred in the 20 patients were 30.0% (6/20). There is no significant safety signal from the study. Conclusions: The results of the phase II study have shown that YH003 in combination with pembrolizumab and nab-paclitaxel, as 1L treatment in patients with unresectable/metastatic mucosal melanoma have promising antitumor activity and response durability and well tolerated. Clinical trial information: NCT05420324 .
Atezolizumab (A), cobimetinib (C), and vemurafenib (V) in patients (pts) with <i>BRAF</i><sup>V600</sup> mutation–positive melanoma with central nervous system (CNS) metastases (mets): Final results and exploratory biomarker analysis from the phase 2 TRICOTEL study.
Authors: Reinhard Dummer, Mitchell Levesque, Elisa Bellini, Marissa Chen, Youyou Hu, Tiffany Wong, Katja Stassen, Pauline Duhard, Yibing Yan, Hussein A. Tawbi
Journal: Journal of Clinical Oncology (2024)

9550 Background: Primary analysis results from the phase 2 TRICOTEL study showed intracranial activity with the triplet combination of A + C + V in pts with BRAF V600 -mutated melanoma with CNS mets (1). Here, we report final analysis results and exploratory biomarker analyses for pts with BRAF V600 -mutated melanoma in the triplet combination cohort from TRICOTEL. Methods: Eligible pts were aged ≥18 y and had melanoma, MRI-confirmed CNS mets ≥5 mm in ≥1 dimension, and no prior systemic treatment for metastatic disease. Pts received A (840 mg on days 1 and 15 of each 28-d cycle) + C (60 mg once daily for 21 d on, 7 d off) + V (720 mg twice daily) except in cycle 1, during which A was withheld. Tumor tissue and circulating tumor DNA (ctDNA) samples collected at baseline (cycle 1, day 1) and ctDNA at the time of progressive disease (PD) were profiled for mutations using next-generation sequencing. Tumor tissue was profiled using a pipeline programmed for MelArray, and ctDNA was measured based on the tissue genetic profile. Results: A total of65 pts were enrolled in the triplet combination cohort. At final analysis, median follow-up was 12.4 mo. Per independent review committee (IRC) assessment, intracranial ORR (confirmed by assessments ≥4 wk apart) was 38% (95% CI, 27–51) and median intracranial PFS was 5.1 mo (95% CI, 3.7–6.9) (Table). Median OS was 13.4 mo (95% CI, 10.7–16.9). No new safety signals were observed since primary analysis. Mutations were detected in baseline ctDNA samples of 60 pts (5 pts not reported) and showed high prevalence of NF1, NRAS, and GNAI2 mutations; relative to tumor tissue, 11 additional BRAF mutations were detected in ctDNA at baseline. Acquired mutations in AKT1 were detected in ctDNA at PD. Median OS shortened in pts with &gt;2 versus ≤2 mutated MAPK pathway genes in ctDNA at baseline (9.1 vs 14.5 mo; hazard ratio, 2.0 [95% CI, 1.0–3.7]; p&lt;0.05). In tumor tissue, baseline mutations in PIK3C2A and PLEKHG4 were enriched in nonresponders, while RAD51B mutations were enriched in responders. Conclusions: Combination A + C + V had clinical intracranial activity in pts with BRAF V600 -mutated melanoma with CNS mets. Exploratory biomarker analyses in this small cohort demonstrate the presence of ctDNA in pts with melanoma and CNS mets and provide insight into mutations associated with response and resistance to the triplet combination. 1. Dummer R et al, Lancet Oncol 2023. Clinical trial information: NCT03625141 . [Table: see text]
Immune phenotype profiling based on anatomic origin of melanoma and impact on clinical outcomes of immune checkpoint inhibitor treatment.
Authors: Soohyun Hwang, Hyang Joo Ryu, Youhyun Kim, Soo Ick Cho, Chiyoon Oum, Aaron Valero Puche, Jinhee Lee, Kyoo Hyun Kim, Kee Yang Chung, Sang Joon Shin, Chan-Young Ock, Minkyu Jung, Jeanne Shen
Journal: Journal of Clinical Oncology (2024)

9569 Background: The inflamed immune phenotype is associated with a favorable response to immunotherapy in metastatic malignant melanoma. Although variations in molecular features across melanoma subtypes and differing ethnic distributions have been well reported, studies investigating immune phenotypes across multiple institutions within the context of different melanoma subtypes are scarce. We examined the association of immune phenotypes with outcomes after immunotherapy, based on subtypes of malignant melanoma. Methods: Two institutional advanced melanoma cohortsrepresenting Asian and Western populations (YUHS, n = 123; Stanford University, n = 102) were included. H&amp;E-stained tumor slides were assessed using Lunit SCOPE IO, an AI-powered whole slide image analyzer, to define the inflamed score (IS, % of inflamed area) and the inflamed phenotype (&gt;33.3% IS). Clinical outcomes after immune checkpoint inhibitor (anti-PD-1/PD-L1) treatment, including progression-free survival (PFS) and overall-survival (OS), were assessed. Results: In the overall cohort (n = 225), the inflamed phenotype was associated with prolonged PFS (HR = 0.634, 95% CI: 0.453 – 0.887, p = 0.007) and OS (HR = 0.655, 95% CI: 0.432 – 0.992, p = 0.044). On analysis of melanoma subtypes, we identified non-acral cutaneous melanomas (CM, n = 94), acral melanomas (AM, n = 52), mucosal melanomas (n = 43), uveal melanomas (n = 16), and melanomas of unknown primary site (n = 20), with a disproportionate enrichment of AM (37.4%) and mucosal (29.3%) melanoma cases in the YUHS cohort and CM cases (68.6%) in the Stanford cohort. The IS varied across different melanoma subtypes, with the highest IS observed in CM (median, [IQR]; 34.0, [5.8–52.2]), and significantly lower scores in AM (22.3, [7.7–36.9]), mucosal (13.6, [0–31.4]), and uveal melanoma (5.5, [0–13.6]). Among CM patients, the inflamed phenotype was significantly associated with better post-immunotherapy PFS (HR = 0.476, 95% CI: 0.274 – 0.826, p = 0.007). In contrast, the inflamed phenotype did not correlate with survival in AM patients (p = 0.58), who exhibited universally poorer PFS compared to non-AM patients (HR = 2.124, 95% CI: 1.486 - 3.005). Conclusions: AI-powered immune phenotype assessment highlights a heterogeneity of immune phenotypes across specific melanoma subtypes, as well as differential association with outcomes after immune checkpoint inhibitor treatment. While CM patients were well-stratified by immune phenotype, the predictive value of immune phenotyping was less pronounced in acral melanomas, which demonstrated poorer outcomes following immunotherapy.