bluuebunny/crossref_metadata_2025 huggingface dataset:
Elucidating the role of RBM10 in brain metastasis of EGFR19del lung adenocarcinoma.
Authors: Yu Yan , Xu Gang , Jia Dexin
Published: July 2024

e20501

Background: The EGFR mutation was detected in 66.3% of Asian patients with lung adenocarcinoma. Among these mutations, EGFR 19del exhibited the highest sensitivity and best response. However, it is worth noting that patients with EGFR 19del have a high cumulative incidence of brain metastases, which contributes significantly to treatment failure. Based on previous WES analysis of primary lung cancer cases and their corresponding brain metastases, RBM10 co-mutation was observed in four out of ten cases with EGFR 19del mutation, leading to decreased expression levels of RBM10. These findings suggest a potential role for RBM10 in modulating the development of brain metastases in patients with EGFR 19del lung cancer. Methods: To investigate the role of RBM10 in brain metastasis, we performed RNA-seq on the PC9 cell line to identify metabolic pathways and genes associated with RBM10 and brain metastasis. Additionally, the brain metastasis model was established by injecting PC9 cells into the left ventricle of nude mice, and the ability of PC9 cells to form brain metastases after knocking down RBM10 was confirmed through two rounds of in vivo screening using the PC9 cell line. Lipidomics analysis further validated that RBM10 affects key metabolite production. Clip-seq and RNA-seq were employed to analyze how RBM10 regulates sphingolipid metabolism. Finally, we identified key targets affecting blood-brain barrier function within the sphingolipid metabolism pathway and verified their ability to inhibit brain metastasis using both in vitro and in vivo models. Results: RNA-seq results demonstrated the regulatory role of RBM10 in the sphingolipid metabolism pathway, specifically in GALC regulation. In vitro and in vivo models revealed an enhanced brain metastasis ability of the PC9shRBM10 group. Lipidomics analysis revealed that the knockdown of RBM10 resulted in a reduction in ceramide and an elevation in SPH. Integrated RNA-seq and Clip-seq analyses demonstrated that the splicing regulation on GALC was attenuated upon RBM10 knockdown, leading to an increase in GALC expression. Furthermore, this perturbation enhanced the downstream sphingosine-1-phosphate signalling axis (SPH-SK1/2-S1P), consequently promoting increased S1P production and elevated blood-brain barrier permeability. Finally, fingolimod, an S1P inhibitor, was employed to validate its efficacy in inhibiting brain metastasis; moreover, a combination therapy comprising osimertinib and fingolimod exhibited superior capacity for suppressing brain metastasis. Conclusions: This study aims to elucidate the regulatory mechanism underlying the impact of RBM10 on sphingolipid metabolism in brain metastasis of EGFR 19del lung adenocarcinoma, to identify novel therapeutic targets for preventing brain metastasis in patients exhibiting EGFR 19del lung adenocarcinoma with low RBM10 expression.
The efficacy and safety of a novel PD-1/CTLA-4 bispecific antibody cadonilimab (AK104) in advanced non-small cell lung cancer: A multicenter retrospective observational study in China.
Authors: Li Jisheng , Yu Shuwen , Zhao Wen , Li Hongxin , Li Chengming , Shen Hongchang , Li Meiying , Wang Chengjun , Wang Jian , Yi Cuihua , Han Chunyan , Meng Xue , Wang Jun , Wang Xiuwen , Liu Lian
Published: July 2024

e20518

Background: Treatment choice for advanced non-small cell lung cancer (NSCLC) after front-line immuno-chemotherapy therapy is limited. As the first approved dual programmed cell death-1(PD-1) / cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) bispecific antibody worldwide, cadonilimab combined with anlotinib, a vascular epidermal growth factor tyrosine kinase inhibitor, showed potential anti-tumor activity in advanced NSCLC patients resistant to anti-PD-1/ programmed cell death ligand-1(PD-L1) antibodies in a phase Ib/II clinical trial. Methods: We retrospectively collectedthe efficacy and safety data in advanced NSCLC patients treated with cadonilimab in later therapy lines. The primary endpoints were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and safety results. The secondary endpoints were overall survival (OS). Results: Totally, 41 advanced NSCLC patients who were refractory to previous chemotherapy and anti-PD-1/PD-L1 therapy and treated with later line cadonilimab-based regimens were enrolled. More than half of patients received cadonilimab as a fourth or later line of treatment. Until the data cut-off date (August 29, 2023), the treatment efficacy of 23 patients could be evaluated. One (4.3%) patient had partial response, 8 (34.8%) patients had stable disease, and 14 (60.9%) patients progressed. The ORR and DCR were 4.3% and 39.1%, respectively. The median PFS of all evaluated patients was 108.0 days (95% confidence interval: 62.3-153.7). Due to the short follow-up, median OS has not been reached yet. Treatment-related adverse events (TRAEs) and immune-related adverse events (irAEs) occurred in 26(63.4%) and 9(22%) patients, respectively. The most common AEs included gamma-glutamyl transferase elevation (17.1%), coughing (14.6%), and fatigue (12.2%). Five patients (12.2%) experienced grade≥3 AEs. Two patients temporarily paused medication due to Grade 2 rash. One patient and 2 patients permanently discontinued medication due to Grade 3 myocarditis and Grade 2 infusion reactions, respectively. Metabolomics results showed that lipids and lipid-like molecules were rich in stools of patients responsive to cadonilimab treatment. Conclusions: In this heavily treated advanced NSCLC patient cohort, cadonilimab-based regimens only showed moderate anti-tumor efficacy with a generally tolerable and manageable safety profile. More evidence supporting administration of cadonilimab is needed in NSCLC patients refractory to previous anti-PD-1/PD-L1 therapy.
Population pharmacokinetics of trastuzumab deruxtecan (T-DXd) in subjects with HER2-mutant and HER2-overexpressing non-small cell lung cancer (NSCLC).
Authors: Khatri Amit , Cobbina Enoch , Cheng Shen , Abutarif Malaz , Garimella Tushar
Published: July 2024

e20537

Background: T-DXd is a novel human epidermal growth factor receptor 2 (HER2) targeting antibody drug conjugate, approved globally at the dose of 5.4 mg/kg in HER2-positive or HER2-low breast cancer (BC) and HER2-mutant (HER2m) NSCLC1,2. The aim of the analysis was to characterize the populaton pharmacokinetics (PopPK) of T-DXd and its released payload, deruxtecan (DXd), in HER2m or HER2-overexpressing (HER2-OE) NSCLC subjects using data across tumor types (BC, NSCLC and others) from 12 Phase 1 to 3 studies with T-DXd doses ranging from 0.8-8.0 mg/kg. Methods: Analysis wasperformed using nonlinear mixed-effects modeling methods in NONMEM (version 7.4.3), similar to the previous analysis in HER2-positive BC1. Covariate effects were explored on the PK parameters of T-DXd and DXd. Results: Analysis included data across 1822 subjects, including 346, 1128, and 348 subjects with NSCLC, BC, and other cancers, respectively. The PK of T-DXd and DXd were adequately described by a PopPK model, judging by standard model diagnostics3. Covariate effects on T-DXd and DXd steady-state area under the concentration-time curve (AUC) were not clinically meaningful (within 0.8 to 1.25 AUC ratio interval for tested covariate level versus reference), except for subjects with high body weight (e.g., 90 kg; 95th percentile) showing a 31% and 37% higher T-DXd and DXd AUC, respectively, relative to typical subject with 58 kg body weight (median).The T-DXd and DXd AUC were also similar across subjects with BC, HER2m or HER2-OE NSCLC, with the same T-DXd dose. T-DXd and DXd AUC in NSCLC subjects were similar across subjects with mild hepatic or mild or moderate renal impairment (vs. normal counterparts), region (Asia, North America, Europe, and rest of the world), and race-country (Asian-Japan, Asian-Non-Japan, and Non-Asian) groups. Conclusions: T-DXd and DXd exposures were similar across subjects with BC and HER2m or HER2-OE NSCLC, as well as across hepatic function, renal function, region, and race-country groups within NSCLC supporting the use of 5.4 mg/kg dose (approved dose in BC) in HER2m or HER2-OE NSCLC from PK perspective. Reference: Enhertu [package insert]. Basking Ridge, NJ: Daiichi Sankyo, Inc.; 2022. Enhertu [summary of product characteristics]. Daiichi Sankyo Europe GmbH, Munich; 2022 Yin O et al. Clin Pharmacol Ther. 2021;109(5):1314-1325. Clinical trial information: NCT04644237 , NCT03505710 .
Sugemalimab in locally advanced and advanced Chinese NSCLC: A real-world retrospective study.
Authors: Liu Jiayu , Wang Yan , Wang Qi , Yang Ke , Xie Tongji , Sun Dantong , Wu Lige , Junling Li , Xing Puyuan
Published: July 2024

e20575

Background: Lung cancer is a major cause of cancer deaths in China. Immunotherapy has emerged as a promising treatment approach for advanced NSCLC without sensitive mutations. Sugemalimab, a fully human immunoglobulin G4 monoclonal antibody, retains its Fc function, inducing antibody-dependent cellular phagocytosis. This study aims to evaluate the real-world effectiveness and safety of Sugemalimab in various treatment patterns, particularly with radiotherapy, in Chinese NSCLC patients with locally advanced or metastatic disease. Methods: We retrospectively evaluated locally advanced (LA-) and metastatic (m-) NSCLC patients (pts) treated with Sugemalimab in Cancer Hospital, Chinese Academy of Medical Sciences from Feb. 2022 to Sep. 2023. Demographic characteristics, clinical features, genetic landscape and therapy patterns were collected. We employed descriptive statistics to determine the Objective Response Rate (ORR) and Disease Control Rate (DCR), and used the Kaplan-Meier method for estimating Progression-Free Survival (PFS) and Overall Survival (OS). Safety profiles, including adverse events and immune-related pneumonitis, were similarly analyzed. Results: 76 pts with LA-NSCLC and mNSCLC were enrolled. Majority were male (92.1%) and smokers (84.2%) and ECOG PS 0-1 (78.9%). Median age was 66. Squamous-cell carcinoma was found in 44 pts (57.9%). The main metastatic sites were bone, brain, liver, lung and lymph node for mNSCLC pts. Genetic profiling in 39 pts revealed TP53 mutations in 19 (48.7%) and KRAS mutations in 10 (25.6%). A total of 38 pts (51.3%) received 1L Sugemalimab therapy, while 21 pts (27.6%) receiving 2L. Main treatment pattern was Sugemalimab plus platinum-based chemo. Radiotherapy (RT) was main local therapy approach, concurrent with Sugemalimab in 18 pts. Majority of pts received either volumetric modulated arc therapy or intensity-modulated radiation therapy to thoracic lesions. Tomotherapy was administered to brain metastases in 2 pts. The median follow-up time was 9.18m at this cut-off date. 16 pts receiving Sugemalimab plus chemo achieved objective response (ORR 44.4%) and DCR was 91.5% in 1L therapy. Median PFS (mPFS) has not been reached. PFS rate at 6m, 12m was 75.6%, 62.1% respectively. 1L OS was immature. For pts receiving additional thoracic RT concurrent with 1L systematic therapy, mPFS was still not mature. PFS rate was 82.4% at 6m and 74.9% at 12 m. Common RT-related side effects were radiation pneumonitis, radiation esophagitis and skin injury. None immune-related pneumonitis was found in this population. Only one case of immune-related pneumonitis was observed in a pts without RT. Conclusions: Our study demonstrated Sugemalimab-based therapy provide clinical benefits to LA-NSCLC and mNSCLC with good safety in real-world setting. The combination treatment of Sugemalimab with radiotherapy illustrates low pulmonary toxicity and superior tolerability.
Prognostic factors and long-term survivors in EGFR-mutated lung cancer: A multi-institutional retrospective analysis.
Authors: Kuan Feng-Che , Yang Yao Ren , Yuying Wu , Lin Meng-Hung , Shi Chung-Sheng
Published: July 2024

e20594

Background: Evolution of tyrosine kinase inhibitors (TKIs) shapes the treatment paradigm of EGFR-mutated lung cancer, but resistance eventually develops. It is important to dissect the prognostic factors and to know the differences between long-term responders (LTR) and non-responders (NR). Methods: Electronic medical records were retrieved from Chang-Gung Medical Foundation from 2011 to 2020. Kaplan-Meier method was used to estimate survival, such as progression-free survival (PFS), and overall survival (OS). Multivariate Cox proportional hazard models was adopted to estimate adjusted hazard ratios and 95% confidence intervals. P < 0.05 was set to be statistical significance. Results: Totally, there are 3,551 patients receiving frontline TKIs, of which 825 (23.2%) are LTR with OS > 36 months, and 1,036 (29.2%) are NR with OS < 12 months. Besides, there are 1,200 (33.8%) LTRs with PFS > 18 months and 882 (24.8%) NR with PFS < 6 months. LTR tend to be younger, female, non-smoker, clinical stage 3b, no baseline brain metastasis, exon 19 deletions subtype, subsequent T790M development, bevacizumab usage, and osimertinib exposure (p all < 0.05). The median PFS of all enrolled patients is 12.3 months and median OS is 22.3 months. By multivariate analysis, age older than 65 years (Hazard ratio, [HR]:1.25 [1.15-1.36]), male (HR: 1.24 [1.13-1.36]), clinical stage 4 (2.19 [1.78-2.69]), baseline brain metastasis (1.25 [1.12-1.37]) are poor prognostic factors (p < 0.05). Also, T790M is not only predictive to osimertinib but also prognostic factor to OS (p < 0.05), and patients who developed subsequent T790M tend to have better PFS (18.1 v.s. 11.8 months). In patients without detected T790M along their disease course, exposure to osimertinib is related to better OS (33.1 v.s. 18.3 month, log-rank p < 0.05). Conclusions: LTR and NR are of distinctive characteristics, and T790M is prognostic and predictive to osimertinib. Further study is warranted for choosing the optimal treatment by clinical factors and T790M status.
First-line immunotherapy in patients with mNSCLC with rare molecular alterations.
Authors: Rossi Sabrina , Finocchiaro Giovanna , Lorenzi Elena , Masini Silvia , D'Argento Ettore , Toschi Luca
Published: July 2024

e20604

Background: Oncogene-addicted non-small cell lung cancer (NSCLC) is an heterogeneous group including different molecular alterations. Most single agent (IO) and combination immunotherapy (CT-IO) trials excluded specific oncogene-addicted NSCLCs such as ALK and EGFR; however, it is likely that other oncogene driven tumours were not tested for but included in these trials and could be actually treated with IO in clinical practice. Methods: Among 428 patients treated with IO or CT-IO as first-line treatment, 30 patients were identified to harbour rare molecular alterations (37% non-smokers, 63% former or current smokers): METex14 skipping mutation (n = 10), MET amplifications (n = 4), BRAF other than V600E mutations (n = 7), HER2 exon 20 insertions (n = 5), RET fusions (n = 2), EGFR exon 20 insertions (n = 2). We analyzed progression-free survival (PFS) and overall survival (OS) in patients harbouring these mutations who underwent first-line IO (if PD-L1≥50%; n = 23) or CT-IO (if PD-L1 < 1-49% n = 2 or < 1% n = 5). Results: In whole population median PFS was 5,1 months (95%CI: 2,39-11,29) and median OS 25,5 months (95%CI: 8,80-60,98); 13 patients experienced progressive disease as best response, the disease control rate (DCR) was 56,7%. Patients treated with IO (n = 22) had a mPFS of 4,7 m (95%CI: 2,13-23,48) and a mOS of 29,8 months (95%CI: 10,08-60,98); those treated with CT-IO (n = 8) had a mPFS of 5,1 m (95%CI: 2,29-6,01) and a mOS of 8,5 m (95%CI: 7,68-12,51). Among the most represented molecular alterations, MET alterations (n = 14, 3 treated with CT-IO and 11 with IO) had a mPFS of 5,1 m (95%CI: 1,67-23,90) and a mOS of 25,5 m (95%CI: 8,80-60,72). In particular METex14 skipping mutations had a mPFS of 5,1 m and a mOS of 25,5 m, while MET amplifications had a mPFS of 2,4 m and mOS of 10,3 m. BRAF nonV600E mutations (n = 7, 2 treated with CT-IO and 5 with IO) had a mPFS 5,3 m and mOS not reached. HER2 exon 20 insertions (n = 5, 2 treated with CT-IO and 3 with IO) had a similar mPFS (6,0 m) but a poorer OS outcome (8,5 m). ( Table 1) Conclusions: Our results show a limited effectiveness of both IO alone and CT-IO as first-line treatment in oncogene addicted mNSCLC, even taking into account survival outcomes of upfront CT compared to targeted agents in pivotal trials. [Table: see text]
Safety and efficacy of osimertinib plus bevacizumab as first-line treatment in EGFR-mutant NSCLC with brain metastases: A dynamic ctDNA-guided study.
Authors: Wei Fang , An Juan , Hua Yichun , Ding Xiaosheng , Sun Shibin , Li Xiaoyan
Published: July 2024

e20606

Background: Non-small cell lung cancer (NSCLC) patients with positive driver genes had a higher incidence of brain metastasis. This study evaluates the efficacy and safety of Osimertinib combined with Bevacizumab as first line treatment in EGFR-mutant NSCLC with brain metastases, utilizing liquid biopsy and dynamic molecular detection to guide treatment strategies. This approach is anticipated to bring progression-free survival (PFS) benefits and shows different resistant mechanisms. Methods: We enrolled EGFR-mutant NSCLC patients with brain metastases receiving Osimertinib and Bevacizumab as first-line therapy. Paired plasma and cerebrospinal fluid (CSF) samples were collected at baseline, during stable disease, and at disease progression for Next-Generation Sequencing (NGS) analysis. The study's primary endpoints were central nervous system (CNS) PFS and objective response rate (ORR). Secondary endpoints included overall PFS, ORR, disease control rate (DCR), and safety. We also investigated resistance mechanisms to the combination therapy. Results: A total of 28 patients from Beijing TianTan Hospital (May 2020 - July 2023) were retrospectively enrolled. The average Bevacizumab treatment duration was 8.21 months (range: 1-27 months). CNS PFS was 26.73 months (95% CI, not reached), and overall PFS was 21.93 months (95% CI, 18.84-25.02 months). The CNS PFS for patients with 19del and L858R mutations were not reached and 26.73 months (95% CI, 15.11-38.35 months), respectively (p = 0.25). Patients undergoing intracranial local treatment showed a CNS PFS not reached, compared to 23.33 months (95% CI, 16.21-30.45 months) for those who did not (p = 0.417). The CNS ORR was 88%, ORR was 76%, and DCR was 100%. At the time of data cutoff (Dec 15th, 2023), 1 patient progressed in both lung and CNS metastases, 8 patients only progressed in lung, 8 patients only progressed in CNS metastases .EGFR C797S mutation was detected in 2 plasma sample, Met amplification in 1 tumor tissue, EGFR C719S mutation in 1 paired plasma-tumor tissue and PIK3CA in 2 plasma sample. Increasing abundance in TP53 and CDKN2A were detected in 2 paired plasma-tumor tissue. Adverse events of grade 3 or higher included one case (3.6%) of severe ulcerative colitis leading to Osimertinib discontinuation and two cases (7.1%) of bevacizumab discontinuation due to bleeding events. Conclusions: Osimertinib combined with Bevacizumab as a first-line treatment significantly prolonged CNS PFS in EGFR-mutant NSCLC patients with brain metastases, offering superior control over intracranial lesions compared to Osimertinib monotherapy (15.2 months, FLAURA study). This study underscores the potential of dynamic ctDNA monitoring in guiding effective treatment strategies for this patient population. Further research is warranted to explore the broader clinical implications of these findings.
Unveiling disparities: Metastatic lung cancer incidence across income strata in metropolitan residencies.
Authors: Kenmoe Jerry , Akanbi Maxwell Oluwole , Amadi Nwonukwuru I , Olafimihan Ayobami Gbenga , Mikhail Elizabeth , Hrinczenko Borys
Published: July 2024

e20616

Background: Over recent years, there has been growing interest in the field of lung cancer. Great efforts have been invested in recent years to improve screening and mortality outcomes with respect to lung cancer, particularly metastatic lung cancer (mLC). In the dynamic landscape of metropolitan residencies (MR), this study delves into the impact of household income (HI) on the occurrence of mLC. Unraveling the intricacies of these disparities is crucial for advancing our understanding of healthcare access and outcomes in urban settings. Methods: Appropriating data from the Surveillance, Epidemiology, and End Results (SEER) database, we looked at the incidence rates of mLC among adults aged 55-80 years by HI levels ( < $35,000, $45,000-49,999, $55,000-$59,999, $65,000-69,999 and $75,000+) in MR from 2004 to 2017. Age-adjusted rates were calculated, and joinpoint regression models were used to estimate the average annual percentage change (AAPC) in incidence across different subgroups. Results: The study population included a total of 321,281 individuals diagnosed with mLC. The incidence of mLC declined rapidly from 2004 to 2017 across all HI groups in metropolitan residence; the AAPC for HIs $45,000-49,999 was -0.70%, $55,000-59,999 was -2.11%, $65,000-69,999 was -4.32% and $75,000+ was -3.72%. Of note, there was not enough data to characterize the trend for HIs < $35,000. Conclusions: Our study revealed an overall decline in the incidence of mLC since 2004 across all HI groups in MRs. Although the trend is one of diminution across all groups, there is however, still some differences in incidence rates amongst different HI groups. This study elucidates the vital role HI plays in influencing the landscape of mLC in metropolitan areas. Recognizing and addressing these disparities is crucial for developing comprehensive public health strategies aimed at reducing the burden of advanced lung cancer and promoting equal access to quality healthcare.
Fostering collaborative care in multiple myeloma: The impact of holistic education on decision-making with antibody and CAR-T platforms.
Authors: Deluca Carmine , Beyer Michael , Ahlstrom Jennifer M. , Orlowski Robert Z. , Faiman Beth , Ghobrial Irene M. , Brugger Abigail , Drew Heather
Published: July 2024

e21008

Background: The management of multiple myeloma (MM) continues to be transformed by evidence supporting the use of CD38 antibodies and B-cell maturation antigen (BCMA) immunotherapy (chimeric antigen receptor (CAR-T) and bispecific antibodies) in newly diagnosed and relapsed/refractory MM (NDMM and RRMM), respectively. However, real-world evidence and survey data show that these approaches are under-utilized across lines of therapy and that educational outreach to patients on their use is inadequate (Puig N et al. ASH 2022. Abstract 1859; Pink S et al. ISPOR 2022. Abstract HSD44; Terpos E et al. Blood Cancer J. 2021;11:40; Adu Y et al. ASH 2023. Abstract 2418). Methods: To address these gaps, PeerView partnered with HealthTree Foundation for Multiple Myeloma to develop 4 live events and 5 online enduring activities from 06/2022 to 06/2023, to educate clinicians on the evidence and principles for integrating CD38 and BCMA antibody platforms into patient care. The activities’ core objectives focused on improving knowledge and skills for integrating CD38 antibodies and BCMA immunotherapy platforms into sequential MM treatment. Furthermore, through the partnership with HealthTree Foundation, the initiatives featured patient perspectives as well as tools and resources to foster clinician–patient communication on use of antibody and CAR-T therapy. Pre- and post-activity multiple choice questions measured changes in knowledge and skills. Responses from enduring activity learners were compared with those from a matched sample of nonparticipants. In a meta-analysis of outcomes from the 9 activities, learning objectives were grouped by key themes, with changes in knowledge and skills averaged across them. Results: Total learners: 12,248 (hematologist-oncologists/oncologists: 7,345; oncology nurses: 1,247) In all activities, learners’ knowledge and skills improved, with increases of: 35 percentage points (ppt) in knowledge of new evidence and changing practice guidelines supporting BCMA antibody platforms in RRMM (44% to 79%); 36 ppt in skills in treatment planning and evidence-based integration of CD38 and BCMA-targeting antibodies in the management of MM (52% to 88%); 46 ppt in ability to address safety considerations related to the use of antibody therapy and BCMA immunotherapy (39% to 85%); 58 ppt in patient interaction skills (eg, counseling, shared decision-making) when using antibody-based and CAR-T platforms (28% to 86%). Conclusions: Improvements in knowledge and skills, combined with a greater focus on patient-centricity, suggest that learners are poised to more effectively integrate CD38 antibodies and BCMA immunotherapy into guideline-recommended MM care that improves the overall well-being and outcomes of patients with MM.
Temozolomide and nivolumab in patients with refractory metastatic melanoma (MM).
Authors: Quintos Jessica , Schellhammer Sophie , Ancell Kristin Kathleen , Johnson Douglas Buckner
Published: July 2024

e21521

Background: Immune checkpoint inhibitors (ICI) are the standard treatment for patients (pts) with MM. However, only a subset of pts respond to ICIs. Temozolomide (TEM) is used in refractory settings but with low objective response rates and no clear overall survival benefit. The efficacy of combined ICI + TEM is not well described. Methods: This was a single center, retrospective study of pts with MM who received treatment with nivolumab (NIVO) and TEM or TEM alone between 11/6/2013 and 11/6/2023. Demographic information, disease characteristics, LDH, treatment, toxicity, objective response, and outcomes were collected. Results: 34 patients were included. 16 were treated with NIVO + TEM and 18 were treated with TEM alone. In the NIVO + TEM group, 81% were male (n = 13) with median age of 59.5 years (range 20-79), and in the TEM group, 56% were male with median age 61 (range 35-81). For NIVO + TEM, 31% had partial response (PR; n = 5), 6% had stable disease (SD, n = 1), and 63% had progressive disease (PD; n = 10). For TEM, 11% had PR (n = 2), 22% had SD (n = 4), and 67% had PD (n = 12) (p = 0.37). For NIVO + TEM, 2 PRs were durable, ongoing at 442 and 741 days; 3 PRs were transient (85-179 days); 1 pt had durable SD ongoing at 201 days. For TEM, PR durations were 173 and 504 days, and SD durations between 213-435 days. Five pts with PD treated with NIVO + TEM had mixed responses (31%) compared with 1 pt treated with TEM (6%). Median progression free survival (PFS) was 80 days (range 11-748) for NIVO + TEM and 55.5 days (7-415) for TEM (p = 0.31). Median overall survival (OS) was 160 days (43-363) for NIVO + TEM and 118 days (7-1938) for TEM (p = 0.15). There were 26 adverse events (AEs) for NIVO + TEM (27% grade 1, 42% grade 2, 19% grade 3, and 12% grade 4; thrombocytopenia and pneumonitis), and 25 AEs for TEM (40% grade 1, 40% grade 2, 12% grade 3, and 8% grade 4; thrombocytopenia) [p = 0.64]. Conclusions: NIVO + TEM occasionally produced durable responses, although outcome metrics were not clearly superior to TEM alone in this small study. Further studies should quantify the benefit of ICI + chemotherapy regimens in refractory MM. [Table: see text]
Treatment-free survival after immunotherapy discontinuation in advanced melanoma: A systematic review and meta-analysis of real-world studies.
Authors: Lu Ziyao Eric , Abbasi Muhammad Shahmir , Ephraim Adam , Hemphill Colton , Lapp Caroline , Kuznia Heidi , Afzal Muhammad Zubair , Shirai Keisuke
Published: July 2024

e21523

Background: Immune checkpoint inhibitors (ICIs) have altered the treatment landscape of advanced melanoma with remarkable improvements in progression-free survival (PFS). Durable responses to ICI cessation have been shown in early clinical trials for ICI usage in melanoma, although the optimal duration of immunotherapy remains unclear. Treatment-free survival (TFS) after immunotherapy cessation for patients with complete response (CR), partial response (PR), and stable disease (SD) has been reported in real-world studies and may help to guide discontinuation of ICI therapy. Methods: A systematic search was conducted using PubMed, Embase, and the Cochrane Library to identify real-world studies reporting TFS after immunotherapy in advanced cutaneous melanoma patients with CR, PR, and SD at 12 and 24 months. Discontinuation due to iRAEs were included. Effect sizes were pooled using a random-effects model using the meta and metafor packages in R after logit transformation. Inter-study heterogeneity was quantified using I2 statistic. Results: Systematic review yielded 34 studies investigating TFS in prospective and retrospective studies. Of these, three retrospective cohort studies reported real-world TFS at 12 and 24 months. Overall, 738 patients with advanced melanoma were included in this meta-analysis, with 384 patients in CR, 278 patients in PR, and 76 patients in SD at time of ICI discontinuation. Mean patient age was 66.4 and 61.9% of patients were male. Pooled 12 and 24-month TFS proportions were higher for patients with CR than PR and for patients with PR than SD. Pooled 24-month TFS was statistically significantly greater in patients with CR compared to SD. I2 statistics showed considerable heterogeneity between studies ( > 80% in CR and PR subgroups). Conclusions: 12 and 24-month TFS after ICI discontinuation was significant for patients with CR and PR to therapy, suggesting the feasibility of ICI discontinuation in patients after therapy response. Pooled 12-month TFS for patients with SD was 66%, although with decline to 36% at 24 months. Limitations of this meta-analysis include a limited number of included studies. Further research is needed to determine the optimal duration of ICI therapy for patients with advanced melanoma depending on best overall therapy response. [Table: see text]
Characteristics of patients with metastatic malignant melanoma in Colombia: Results of the Epidemiologic Registry of Malignant Melanoma REMMEC ACHO.
Authors: Ospina Serrano Aylen Vanessa , Ortiz Diaz Juan David , Contreras Fernando , Munevar Isabel , Jimenez Paola , Mantilla William Armando , Idrobo Henry , Ramos Pedro , Manneh Kopp Ray , Arango Acevedo Natalia , Santa Daniel Andres , Rivas Tafurt Giovanna Patricia , Quiroga Alicia , Vargas Claudia , Yepes Andres , Alcala Castro Carmen Marcela , Lema Mauricio , Chinchia Isabel , Russi Noguera July Andrea , Triana Ivan Camilo
Published: July 2024

e21530

Background: The features and prognostic factors of patients with metastatic malignant melanoma are not well established in our country. Our objective is to collect and analyze the characteristics of a cohort of Colombian patients. Methods: Analytical cohort study based on the Epidemiologic Registry of Malignant Melanoma in Colombia (REMMEC). Data were collected between January 2011 and December 2023. Patients older than 18 years with a confirmed diagnosis of advanced melanoma were included. Descriptive analysis of demographic and clinical characteristics and survival analysis using Cox regression and Kaplan-Meier models were performed. Results: 322 patients were included. Median age was 66.5 years (range 55-76), 56% (180) of patients were men, 87% (280) had advanced disease at diagnosis, most (82%) with non-brain metastases and 51% (164) with multiple organ involvement. Table 1. For first-line treatment, patients received single-agent immunotherapy (37.26%), doublet immunotherapy (10.25%), targeted therapy (9%), and chemotherapy (7.14%), while 29% received best supportive care BSC. In the second line, single agent immunotherapy 9.32%, targeted therapy (4.34%), doublet immunotherapy 3.42%, chemotherapy (5%) and 77% received BSC. In the third line, only 9% (29) of patients were able to receive any therapy. Median follow-up was 16 months (IQR 7-32), median progression-free survival (PFS) was 8 months (IQR 4-35) and median overall survival (OS) was 23 months (IQR 9-66). OS in the first-line setting with immunotherapy as monotherapy was 23 months (IQR 12-40) HR 0.40 P 0.035 and with doublet immunotherapy 16 months (IQR 8-28) HR 0.16 P 0.005 Clinical characteristics associated with lower median OS were brain metastasis (HR 1,95 P 0.001), ECOG 3-4 (HR 5,49 P 0.001) and multiple metastatic disease (HR 2,15 P 0.001). According to acral vs. non-acral histologic type, the median OS was 26 vs. 44 months, respectively (HR 1.30 P 0.26). Conclusions: In our cohort of patients with metastatic melanoma, we found clinical outcomes similar to those reported in the worldwide literature. It is necessary to continue the registry and follow-up of patients to identify specific prognostic factors. [Table: see text]
NRAS mutation in melanoma: Association of codon-specific changes on patient outcomes.
Authors: Mathew Thomas Vinay , Adeyelu Tolulope Tosin , Abdulla Farah R. , VanderWalde Ari , Park Soo J. , Russell Jeffery Scott
Published: July 2024

e21545

Background: NRAS mutant melanoma is an aggressive subtype making up 20-30% of cutaneous melanoma cases without specific treatment options beyond immune checkpoint inhibition (ICI). Previous studies have suggested specific NRAS codon mutations are associated with unique signaling pathways. To test the hypothesis that NRAS codon mutations in cutaneous melanoma may drive a preferential response to ICI, we evaluated specific genetic subsets of NRAS mutant melanoma based on the Q61 and G12/G13 codons. Methods: Cutaneous melanoma samples (n = 4091) were analyzed by NGS at Caris Life Sciences. Samples were stratified by NRAS status and subdivided into NRASQ61, NRASG12/13, and NRAS-wildtype. PD-L1 expression was assessed using IHC (positive ≥ 1%). TMB-high was defined as ≥ 10 mutations/Mb. Transcriptomic signatures of MAPK pathway activation and T-cell signatures were calculated. Real-world overall survival (rwOS) information was obtained from insurance claims data, with Kaplan-Meier estimates calculated from time on ICI until last date of contact. Mann-Whitney U, Chi-square, and Fisher exact tests were applied as appropriate, with p-values adjusted for multiple comparisons. Results: Cutaneous melanoma samples were comprised of 22% NRASQ61 (n = 902), 3.1% NRASG12/13 (n = 125) and 74.8% NRASWT (n = 3064), with the most common NRAS mutation being Q61R. Patients harboring NRASG12/13 codon changes were associated with concurrent mutations in BRAF (21.0 vs 6.4%, p< 0.0001), NF1 (50.5% vs 8.7%, p< 0.0001), KIT (3.2% vs 0.2%, p< 0.001), ARID2 (22.1% vs 11.3%, p< 0.01), MAP2K1 (7.2% vs 2.6%, p = 0.022) compared to NRASQ61. NRASG12/13 tumors were more frequently TMB-high compared to NRASQ61 or NRASWT (83.1% vs 62.1% vs 55.1%, p = 0.0001), but no difference was observed in the prevalence of dMMR/MSI-H or PD-L1 expression. Transcriptomic analysis showed that NRASQ61 mutants had a significantly higher MPAS compared to NRASG12/13 or NRASWT cohorts (Median: 1.16 vs 0.67 vs 0.46, p = 0.0147), while T-cell-inflamed scores were significantly higher in NRASWT compared to NRASQ61 (Median: 4 vs -40, p = 0.00492) but not to NRASG12/13 (Median: 4 vs -13.5, p = 0.674). No difference in rwOS was identified in NRASG12/13 and NRASQ61 melanoma treated with ICI (HR: 0.753, [95% CI: 0.43 – 1.31], p = 0.316). Conclusions: Patients with NRAS-mutated cutaneous melanoma exhibit codon-specific ( NRASQ61 vs NRASG12/13) signaling and prevalence of immunotherapy-related biomarkers. Our findings indicate that melanoma samples with NRASG12/13 mutation tend to exhibit immune richness suggesting they could be viewed as a distinct group that might potentially benefit from immune therapies. This observation offers valuable insight into codon-specific tumor subsets, differential response to therapy, resistance mechanisms, and the potential development of combination therapies to enhance survival outcomes of patients with NRAS mutant melanoma.
RNA expression-based risk stratification of stage III cutaneous melanoma.
Authors: Kim Donghyun , Yu Yeonhwa
Published: July 2024

e21551

Background: Prognostication of locally advanced cutaneous melanoma (CM) relies on accurate assessment of primary tumor invasion depth and extent of lymph node involvement. However, precision is often limited by detection limits of positron emission computed tomography and sentinel lymph node biopsy, and the estimated disease-specific survival (DSS) can vary widely. In this study, we explored tumor gene expression-based risk stratification strategies and found that CDH1 (E-cadherin) and BRAF transcript level profiles can predict DSS in stage III CM. Methods: The Cancer Genome Atlas Skin Cutaneous Melanoma (TCGA-SKCM) project’s normalized RNA-Seq transcriptome profile (n = 288) was analyzed with MATLAB software. TCGA-SKCM adopted AJCC 7th edition staging. "High” or “low” level of each gene was determined by the median FPKM of the cohort used as cutoff. P-values were obtained from Cox proportional hazards regression model. Results: In stage III (n = 96), 3-year DSS for high- and low-CDH1 groups were 45% and 75%, respectively (p = 1.5x10-5). High-BRAF group was weakly associated with superior 3-year DSS compared to low-BRAF group (75% vs. 55%; p = 0.06), although high-BRAF group was composed of more BRAF hotspot mutants compared to low-BRAF group (56% vs. 30%). The 3-year DSS for high-CDH1/low-BRAF and low-CDH1/high-BRAF groups were 28% and 84%, respectively (p = 4.4x10-5). Composition of stages [IIIA, IIIB, IIIC, IIINOS] in high-CDH1/low-BRAF and low-CDH1/high-BRAF groups were [5%, 18%, 45%, 32%] and [23%, 13%, 37%, 27%], respectively. For high-CDH1/high-BRAF group, 3-year DSS was 54% with stage composition [6%, 33%, 39%, 22%]. DSS was not associated with CDH1/BRAF levels in stage I and II. Stage IV was not analyzed due to the small sample size. Conclusions: We demonstrate CDH1/BRAF transcript level-based prognostication of CM cases with regional metastasis (metastatic node, in-transit or satellite metastasis) defined as stage III. Our findings are contrary to the notion that CDH1 is a tumor/invasion suppressor gene, although we note the emerging evidence that CDH1 expression boosts establishment of cancer at a secondary site once they escape from the primary site1). The association between high BRAF level and superior survival may also seem counterintuitive given the well-accepted oncogenicity of activating BRAF mutations in variety of malignancies. However, we speculate that wild-type and oncogenic BRAF, which RNA-Seq cannot easily differentiate, may play independent roles in tumorigenesis similar to what has been previously reported in wild-type and oncogenic RAS2). References: 1) Padmanaban, et al. E-cadherin is required for metastasis in multiple models of breast cancer. Nature. 2019 Sep;573(7774):439-444 2) Young, et al. Oncogenic and wild-type Ras play divergent roles in the regulation of mitogen-activated protein kinase signaling. Cancer Discov. 2013 Jan;3(1):112-23.
Geospatial analysis of the distribution of uveal melanoma patients at a referral center in the United States.
Authors: Seedor Rino S. , Vader Daniel T. , Moore Renee H. , Motta Alexandre J. , Lally Sara E. , Shields Carol L. , Sato Takami , Orloff Marlana M.
Published: July 2024

e21566

Background: Approximately 2500 new uveal melanoma (UM) cases (5.2 cases per million population) are diagnosed yearly in the United States. We previously identified three unique geospatial accumulations of UM in North Carolina, Alabama, and New York based on our clinical experience. Such unexpected findings prompted us to conduct a more systematic evaluation of geospatial accumulations of UM patients at our institution. Methods: Through the electronic medical record system, we identified patients seen at our institution with a diagnosis of UM. Identified living patients and family of deceased patients were either sent an e-mail or paper letter with an internet link to a survey. The survey asked for the patient’s name, date of birth, sex, date of primary UM diagnosis, address at time of UM diagnosis and number of years at that address, and all previous addresses and dates of residence prior to the UM diagnosis. Using these addresses, ArcGIS and R software was used to analyze the geospatial distribution of our UM patients. The data was supplemented with 2020 American Community Survey census estimates at the state, county, and census tract level to estimate population-based rates of UM. Results: We identified 2718 UM patients in our clinical database, and a total of 726 participants completed the survey with a total of 2939 US addresses. The majority of addresses were precise to the street address level (77.9%). At the time of UM diagnosis, patients had lived at their current address for a median of 16 years. Pennsylvania and the neighboring states expectedly made up the majority (63.6%) of our patients, but about 1/3 of our patients resided in other states at the time of their UM diagnosis (total of 42 different states). Several counties presented elevated rates of UM with ≥5 case per 100,000 persons. We observed a group of counties in central Pennsylvania, at the border of Pennsylvania and New York, and in upper New York by the Finger Lakes with notably elevated rates of UM, which was consistent with our clinical observations at our institution. Several neighboring counties in Kentucky and Virginia also presented elevated rates. Conclusions: Through this pilot project, we have demonstrated that it is possible to collect lifetime residency information from UM patients in order to map their geospatial distribution in the US. Furthermore, although institutional bias toward referring physicians should be considered, our geospatial analysis identified accumulations of UM in areas similar to our clinical concerns. The results of our study warrant further investigations into environmental influences on UM development. Our future goal is to extend our approach through national and international collaborations to increase the number of participants in the analysis and to minimize institutional bias.
Clinical significance of HER2 expression between primary tumors and metastatic lymph nodes in patients with extramammary Paget's disease.
Authors: Liu Zhicheng , Tan Xingliang , Tang Yi , Zhou Qianghua , Yuan Gangjun , Wei Wensu , Yao Kai
Published: July 2024

e21568

Background: HER2 has been reported to be a potential oncogene and therapeutic target in extramammary Paget's disease (EMPD). However, the expression of HER2 in EMPD, especially in matched metastatic lymph nodes (LNs), is limited. Here, we investigated the heterogeneity of HER2 expression between primary tumors and positive nodes and its clinical significance in advanced EMPD patients and detected the efficacy of HER2-targeted antibody drug conjugates (ADCs) in EMPD. Methods: A total of 170 patients with pathologically confirmed EMPD of the scrotum and/or penis treated at SYSUCC from 2003 to 2023 were included. HER2 IHC staining (anti-HER2/neu (4B5), Ventana) and scoring were performed according to the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2023 guidelines. Outcome relationships were explored using Cohen's kappa coefficient, multivariate Cox regression and log-rank analysis. Results: A total of 102 primary tumor and 32 metastatic specimens were ultimately subjected to HER2 IHC staining. HER2 high-expression (IHC: 2/3+) was detected in 71.6% (0: 9.8%, 1+: 18.6%, 2+: 40.2% and 3+: 31.4%) and 68.8% (0: 21.9%, 1+: 9.4%, 2+: 28.1% and 3+: 40.6%) of the primary tumors and metastatic LNs, respectively. HER2-high EMPD patients experienced poorer outcomes, with a 5-year OS of 56.5%, than did HER2-low patients (P = 0.032). A multivariate Cox regression model showed that a positive lymph node (HR 15.39, 95% CI 3.79~62.43; P < 0.001) and HER2 high-expression in primary tumors (HR 3.68, 95% CI 1.49~9.09; P = 0.005) were independent poor prognostic factors. Notably, in 31 paired samples, 35.5% (n = 11) of patients had inconsistent HER2 expression between primary tumors and corresponding lymph node metastases. Six (19.4%) patients exhibited a shift from high expression of HER2 in primary tumors to low expression of HER2 in the lymph nodes, and 5 (16.1%) patients exhibited the reverse change. Advanced EMPD patients with HER2 high-expression were treated with Disitamab Vedotin (RC48), for which the ORR was 80% and the DCR was 100% (n = 5). No adverse events (AEs) above grade 3-4 were observed. Conclusions: HER2 was highly expressed in both primary and metastatic LNs in EMPD patients. However, there was some heterogeneity in HER2 expression between paired primary and corresponding metastatic LNs. The expression status of HER2 should be evaluated in both primary tumors and corresponding lymph node metastases. A positive lymph node and HER2 high-expression are poor prognostic factors in patients with EMPD. RC48 demonstrated significant efficacy in treating patients with HER2-high advanced EMPD and has promising potential that requires further validation.
Establishing a protocol to increase racial/ethnic minority enrollment on an active radiation oncology randomized clinical trial.
Authors: Gardner Ulysses Grant , Brawley Otis W. , Obi Elizabeth E , Redmond Kristin Janson , McClelland Shearwood
Published: July 2024

TPS1638

Background: In the United States (US), underrepresented racial/ethnic groups lack ample enrollment in clinical trials, yielding ungeneralizable trial results. Barriers to increasing minority enrollment include decreased awareness of clinical trials, lack of access, financial burden and toxicity, medical system mistrust, and discordant physician-patient demographics. The ongoing Spine Patient Optimal Radiosurgery Treatment for Symptomatic Metastatic Neoplasms (SPORTSMEN) clinical trial (NCT05617716) has a study design to actively accrue minority patients. We present our protocol addressing key targets to increase minority enrollment on this randomized, phase II clinical trial. Methods: Adults with evidence of symptomatic spine metastases are eligible. Baseline demographics (including race/ethnicity) are reported for statistical analysis. Our protocol seeks to minimize barriers to minority enrollment and targets four key areas. Access to care: SPORTSMEN involves institutions located in zip codes with diverse ethnic populations, presently located in regions 46% and 70% African American. Clinical trial design: SPORTSMEN has a prespecified goal of accruing patients to mirror US census representation. The rate of minority enrollment will be reviewed periodically at the discretion of the Data Safety and Monitoring Board. Community outreach and engagement: The trial team will engage with local health care systems to create an alliance within different oncology specialties to provide the basis and benefit for SPORTSMEN and patient-centered education on eligibility criteria, rationale, and intended outcomes. Our principal focus will be providers in prostate, breast, and lung cancers as minorities with these primary site malignancies have a higher propensity to be trial-eligible. Furthermore, we understand the historical mistrust of minorities for the medical community. Therefore, we will engage local grassroot organizations such as churches, community outreach centers, and social clubs to increase awareness of clinical trials and to help foster trust. Financial burden and toxicity: SPORTSMEN does not have direct enrollment costs. A short-course treatment regimen is used to minimize the number of treatment visits required allowing for decreased resources for travel, time lost at work, and additional childcare or eldercare needs. Financial toxicity will be objectively quantified using the validated COST-Functional Assessment of Chronic Illness Therapy survey. Increasing clinical trial diversity is a challenge that must be addressed with meaningful intent to present robust Level 1 data that broadens the understanding of treatment response in all demographics. Our protocol takes a patient-centered approach to achieve the objective of concordant racial/ethnic representation in a randomized clinical trial. Clinical trial information: NCT05617716 .