Immune Checkpoint Inhibitors In Melanoma Research Articles

Abstract PO5-25-04: Predictive value of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in patients with triple negative breast cancer treated with pembrolizumab

Abstract Background: Immune checkpoint inhibitors (ICIs) offer new treatment possibilities for women with triple-negative breast cancer (TNBC) – one of the most challenging breast cancer subtypes. The PD-1 inhibitor pembrolizumab (pembro; Keytruda®) is approved in metastatic TNBC (mTNBC) patients with PD-L1(+) tumors, and for neoadjuvant treatment (NAT) in stage II/III TNBC [1, 2]. Residual cancer burden (RCB) after NAT is highly prognostic, with pathologic complete response (pCR, RCB 0) anticipating long-term survival [3]. In mTNBC, pembro plus chemotherapy in the 1st-line improves progression free survival (PFS), but durable responses are rare. Optimizing ICI use in TNBC thus remains an unmet need, and defining easily assessable markers of response is crucial. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are peripheral blood surrogates of tumor inflammation and have prognostic and predictive value in TNBC [4-8]. Elevated NLR (≥ 5) and PLR (≥ 200) correlate with worse outcomes upon ICIs in melanoma and non-small-cell lung cancer [9, 11-14]; however, this has not been studied in breast cancer [9, 10]. We evaluated the relationship of baseline NLR and PLR with pembro responses in TNBC patients. Methods: We retrospectively reviewed data from TNBC patients who completed pembro between 10/2/20 - 6/1/23 at Weill Cornell. Patients on NAT who did not complete treatment were excluded. RCB score (pCR/0, 1, 2, 3) was calculated from surgical resection pathology reports using the MD Anderson RCB Calculator [15, 16]. Baseline laboratory data were obtained from clinical records. Associations between NLR and PLR with RCB levels were examined using the non-parametric Kruskal-Wallis test (if >2 levels), the Wilcoxon rank sum test (if 2 levels), or the Spearman’s rank correlation. NLR and PLR were also correlated with PFS (measured from pembro start date to date of progression) in metastatic patients. PFS data for metastatic patients without interval imaging since pembro initiation were censored at the date of data analysis, and PFS was not calculated for patients who received only 1 cycle of pembro. Results: We identified 63 eligible patients: 24 were excluded due to lack of TNBC diagnosis (n=20), or because they only received adjuvant pembro (n=4). Of the 39 remaining patients, 5 did not complete NAT and 2 had missing data, leaving 32 evaluable patients (17 in the NAT cohort and 15 in the mTNBC cohort). Overall, the median age was 51 years, and 16% were Hispanic, 11% Asian, 57% non-Hispanic, 24% Black, and 65% Non-Black. Neoadjuvant cohort: The pCR rate was 30%. Patients with both NLR ≥ 5 and PLR ≥ 200, had a pCR rate of 0%; in patients with NLR < 5 or PLR < 200, pCR rate was 43%. Median NLR in pCR vs. non-pCR groups was 1.91 [IQR: 1.72- 2.73] vs. 2.44 [IQR: 1.97- 5.24] (p=0.3), with trends towards significance when NLR was compared between RCB levels >1 (2.67; IQR: 2.05, 6.49) vs. RCB levels ≤1 (1.91; IQR: 1.63, 2.58) (p=0.14). Mean PLR was higher in patients with RCB 2-3 (409) compared to those with pCR or RCB 1 (167) (p=0.146). Metastatic cohort: The overall mean PFS was 7.8 months. Visceral metastases were seen in 80% of patients (17% liver, 33% brain). In patients with brain mets, baseline NLR and PLR were higher than in the overall cohort (NLR, 4.86 vs. 2.78; PLR, 429 vs. 186). Conclusions: Our study is the first to evaluate NLR and PLR as response biomarkers in TNBC patients receiving pembro and is the first report of our real-world data of TNBC patients on pembro. In our neoadjuvant cohort, higher baseline NLR and PLR correlated with higher RCB levels, with a trend towards statistical significance. Further investigation and correlation of NLR and PLR with tumor microenvironment features will help to clarify these relationships. Citation Format: Ashley Schreier, Roberta Zappasodi, Inna Serganova, Laura Munoz Arcos, Xi Kathy Zhou, Massimo Cristofanilli, Eleni Andreopolu. Predictive value of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in patients with triple negative breast cancer treated with pembrolizumab [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-25-04.

Huang Lian Jie Du Decoction enhances the anti-tumor efficacy of immune checkpoint inhibitors by activating TLR7/8 signalling in melanoma

BackgroundThe clinical application of immune checkpoint inhibitors (ICIs) is limited by their drug resistance, necessitating the development of ICI sensitizers to improve cancer immunotherapy outcomes. Huang Lian Jie Du Decoction (HLJD, Oren-gedoku-to in Japanese, Hwangryunhaedok-tang in Korean), a famous traditional Chinese medicinal prescription, has exhibited potential in the field of cancer treatment. This study aims to investigate the impact of HLJD on the efficacy of ICIs in melanoma and elucidate the underlying mechanisms.MethodsThe potential synergistic effects of HLJD and ICIs were investigated on the tumor-bearing mice model of B16F10 melanoma, and the tumor infiltration of immune cells was tested by flow cytometry. The differential gene expression in tumors between HLJD and ICIs group and ICIs alone group were analyzed by RNA-seq. The effects of HLJD on oxidative stress, TLR7/8, and type I interferons (IFN-Is) signaling were further validated by immunofluorescence, PCR array, and immunochemistry in tumor tissue.ResultsHLJD enhanced the anti-tumor effect of ICIs, significantly inhibited tumor growth, and prolonged the survival duration in melanoma. HLJD increased the tumor infiltration of anti-tumor immune cells, especially DCs, CD4+ T cells and CD8+T cells. Mechanically, HLJD activated the oxidative stress and TLR7/8 signaling pathway and IFN-Is-related genes in tumors.ConclusionsHLJD enhanced the therapeutic benefits of ICIs in melanoma, through increasing reactive oxygen species (ROS), promoting the TLR7/8 pathway, and activating IFN-Is signaling, which in turn activated DCs and T cells.

Identification of the transcriptomic alterations of resistance to immune checkpoint inhibitors in melanoma

Although immunotherapeutics like immune checkpoint inhibitor (ICI) therapy have greatly improved survival rates, death rates of melanoma still remain high. One of the reasons for this is that the solid tumor microenvironment creates obstacles for the effectiveness of anti-PD1 immunotherapy in patients. Therefore, it is crucial to identify potential biomarkers that could be used in combination therapy with anti-PD1 to modify the tumor microenvironment and enhance response to treatment. In this study, we examined clinical and tumor transcriptional sequencing data from 91 patients who received anti-PD1/anti-CTLA4 therapy. Through both bulk RNA sequencing analysis and single-cell RNA-sequencing (scRNA-seq), we discovered that 8 key pathways were upregulated in patients who responded well to the therapy. Interestingly, these pathways were found in myeloid and T cell populations, indicating their significant role in response to anti-PD1/anti-CTLA4 therapy. Among these pathways, genes such as IRF1, IRF2, C1, and C3 emerged as potential biomarkers that could potentially enhance the effectiveness of ICIs therapy. Further clinical research is required to validate the impact of these genes. The novelty of this study lies in the combination of bulk RNA sequencing and single RNA sequencing methods, which allowed us to uncover distinct differences in the transcriptomic landscape of solid tumors, particularly melanoma.

A real-world study on the safety profile of extended-interval dosing of immune checkpoint inhibitors for melanoma: a single-center analysis in Japan.

Anti-programmed death-1 (PD-1) antibodies are the mainstay for the treatment of unresectable or high-risk melanoma. However, real-world data on the safety profile of their extended-interval doses (EDs) are limited, particularly in Asian patients with melanoma. In this single-center retrospective study, we analyzed the risks of immune-related adverse events (irAEs) among 71 Japanese patients (36 males; mean age, 65.0 years) who received anti-PD-1 monotherapy for melanoma at our institute. Patients who were administered ipilimumab prior to anti-PD-1 monotherapy were excluded. Patients were divided into three groups: canonical-interval dose (CD) group (n = 50, body weight-based dosing or 240 mg Q2W for nivolumab and body weight-based dosing or 200 mg Q3W for pembrolizumab), ED group (n = 14, 480 mg Q4W for nivolumab and 400 mg Q6W for pembrolizumab), and dose-switch (DS) group (n = 7, upfront CD followed by ED). The CD group received nivolumab more frequently in the metastatic setting. There were no significant differences in baseline characteristics among the three groups, including in sex, age, primary tumor site, tumor subtype, and follow-up period. irAEs occurred in 36.6% (26 patients) of all patients (32.0% of the CD group, 35.7% of the ED group, and 71.4% of the DS group), while severe (grade ≥ 3) irAEs occurred in only two patients, both of whom were in the CD group. Most of the irAEs occurred during the first 6 months of anti-PD-1 therapy and, interestingly, all of the irAEs in the DS group occurred before the switch (during the CD). There was no significant difference among the three groups in the probability of irAE estimated by the Kaplan-Meier method. These findings may highlight the safety of ED of anti-PD-1 monotherapy in the treatment of Asian patients with melanoma.

Association between immune-related adverse events and prognosis in patients treated with immune checkpoint inhibitors in melanoma: A surrogacy analysis.

Immune checkpoint inhibitors (ICI) represent a breakthrough in oncology in terms of prognosis and safety. They now constitute a cornerstone in the management of metastatic melanoma. However, a new kind of adverse event called immune-related adverse events (irAE) has emerged. These irAE could be conceptually considered as an indicator of the antitumoral immune response, but the association between irAE and prognosis is still a matter of debate. The purpose of this study was to investigate the association between the overall survival (OS) and the prevalence of irAE in melanoma. MEDLINE/PubMed, WebofScience, ClinicalTrials, and WHOTrials databases were searched to identify phase 3 randomized controlled trials (RCT) assessing ICI in melanoma and published up to April 2021. A weighted regression was performed to estimate this association according to standard method of surrogacy analysis. A total of 14 RCT including 7646 patients (median age: 59.3years) with melanoma were included. All types of ICI were represented (ipilimumab, tremelimumab, pembrolizumab, nivolumab, atezolizumab, as well as ipilimumab and nivolumab combination). irAE were frequent but rarely fatal. The combination of ICI caused more irAE than anti-PD1 (or PDL1) and anti-CTLA4 monotherapies. No relationship was found between the occurrence of irAE and OS (beta coefficient 0.078, R2 3%, p = 0.52), nor between cutaneous irAE and OS (beta coefficient 0.080, R2 6%, p = 0.33). Although limited by the heterogeneity of ICI included in the regression and the low number of included RCT, the present study suggests an absence of association between irAE and prognosis in melanoma.

MODL-06. THE GUT MICROBIOTA OF BRAIN TUMOR PATIENTS CAN IMPACT IMMUNOTHERAPY EFFICACY IN A PRECLINICAL MODEL OF GLIOMA

Abstract Combination immune checkpoint inhibitors (ICI) can affect durable response in melanoma brain metastases (MBM) but have largely been ineffective for the treatment of glioblastoma (GBM), a primary brain tumor. Recent studies in animal models and humans have suggested that the microbe composition of the gut can influence the effectiveness of ICI in melanoma and other cancers. Our central hypothesis is that the gut microbiome can influence immunotherapy responsiveness for GBM patients. We obtained microbiome (stool) samples from GBM and MBM patients prior to beginning any treatment or surgical interventions. We then transplanted these microbiome samples into gnotobiotic mice to create humanized microbiome mice. We transplanted two GBM patients and two MBM patients microbiome samples to create 4 unique patient-derived humanized microbiome mouse lines (GBM1, GBM2, MBM1, and MBM2). Using 16s ribosomal RNA microbiome sequencing, we found that each patient-derived microbiome mouse line had a unique microbiome composition as measured by relative abundance and diversity of species. Mice from each line were then intracranially injected with GL261 murine glioma cells and treated with the ICI anti-PD-1 or isotype control. We found that MBM1 and GBM2 mice were resistant to anti-PD-1 and did not display prolonged survival with anti-PD-1 treatment. However, GBM1 and MBM2 mice were positive responders to anti-PD-1 and displayed significantly prolonged survival compared to isotype control. Additional microbiome sequencing analyses are ongoing that will reveal positive microbiome profiles among these patient-derived lines, and additional GBM and MBM patient-derived microbiome lines are being created and tested for immunotherapy efficacy. Ultimately, understanding how certain microbial communities can enhance the effectiveness of immunotherapy may lead to the development of new approaches that include modification or transplantation of microbe communities in GBM patients for increased therapeutic impact.

Learning about and living with toxicity: A qualitative study of patients receiving immune checkpoint inhibitors for melanoma or lung cancer and their caregivers.

297 Background: Immune checkpoint inhibitors (ICIs) have revolutionized treatment for melanoma and lung cancer and are in widespread use. This study aims to describe how patients and caregivers learn about ICI toxicities and their lived experiences of receiving an ICI. Methods: We conducted a qualitative study of patients with advanced cancer receiving ICIs from a single academic center and their caregivers. We purposively sampled patients with stage IV non-small cell lung cancer (n=16) or stage III (n=9) or IV (n=17) melanoma who were initiating or discontinuing an ICI. We conducted semi-structured interviews to explore patients' and caregivers' experiences learning about and living with ICI toxicity. We used a framework approach to analyze interview transcripts, which included developing a codebook, double-coding transcripts, and synthesizing codes into themes with a multidisciplinary research team. Results: The median age of patients was 68 years, 31% were female and 49% had at least a college degree. We identified the following themes: i) Patients initiating ICIs received exhaustive counseling about side effects (“everything from rash to death,” “like a drug ad on television”), yet some patients lost details in the deluge of information (“I'm sure I was told of the risk, I just can't specifically recall what”); ii) Patients and caregivers identified several factors that helped them feel comfortable to proceed with treatment, namely that the oncology team emphasized the infrequency of serious side effects and that the team was ready to manage whatever toxicity occurred. In addition, patients perceived that ICI benefits outweighed the risks or felt that they had no alternative; iii) Among patients who discontinued ICIs, the association between ICI toxicity and efficacy was a source of hope (“I hope every day to find vitiligo... that might say that the immunotherapy is working”); iv) Patients’ and caregivers’ impressions of ICIs depended on patients’ outcomes. Patients tolerating ICIs well and their caregivers were surprised at how easy their treatment was, whereas patients who discontinued ICIs after experiencing severe side effects felt frustrated and surprised by toxicity, or worried their cancer would progress. Conclusions: Patients receiving ICIs for advanced cancer and their caregivers felt they received comprehensive education about ICI toxicity. They appreciated when their oncology team provided reassurance that side effects were rare and manageable, as well as messages that framed toxicity as a sign of efficacy once they occurred. Even with excellent preparation for the possibility of toxicity, patients who experienced severe toxicity were still surprised and disappointed. These perspectives highlight patient and caregiver preferences for learning about ICIs and opportunities to support patients in coping with advanced cancer.

LB1643 Novel insights into vitiligo-like depigmentation under immune checkpoint inhibitors in melanoma compared to classical vitiligo and healthy skin biopsies

LB1643 Novel insights into vitiligo-like depigmentation under immune checkpoint inhibitors in melanoma compared to classical vitiligo and healthy skin biopsies

Immunotherapy around the Clock: Impact of Infusion Timing on Stage IV Melanoma Outcomes.

Although the impact of circadian timing on immunotherapy has yet to be integrated into clinical practice, chronoimmunotherapy is an emerging and promising field as circadian oscillations are observed in immune cell numbers as well as the expression of immunotherapy targets, e.g., programmed cell death protein-1 and its ligand programmed death ligand 1. Concurrent retrospective studies suggest that morning infusions may lead to higher effectiveness of immune checkpoint inhibitors in melanoma, non-small cell lung cancer, and kidney cancer. This paper discusses the results of a retrospective study (2016-2022) exploring the impact of infusion timing on the outcomes of all 73 patients with stage IV melanoma receiving immunotherapy at a particular medical center. While the median overall survival (OS) was 24.2 months (95% confidence interval [CI] 9.04-39.8), for a median follow-up of 15.3 months, our results show that having more than 75% of infusions in the afternoon results in shorter median OS (14.9 vs. 38.1 months; hazard ratio 0.45 [CI 0.23-0.86]; p < 0.01) with more expressive impacts on particular subgroups: women, older patients, and patients with a lower tumor burden at the outset of immunotherapy. Our findings highlight the potential benefits of follow-up validation in prospective and translational randomized studies.

SETBP1 mutation determines sensitivity to immune checkpoint inhibitors in melanoma and NSCLC.

SET binding protein 1 (SETBP1) plays crucial roles in various biological processes; however, its involvement in cancer immune checkpoint inhibitor (ICI) treatments has never been studied. In this study, we collected a total of 631 melanoma and 109 non-small cell lung cancer (NSCLC) samples treated with ICI agents (i.e., anti-CTLA-4, anti-PD-1/PD-L1, or combination therapy). Additionally, we obtained their corresponding somatic mutational profiles. We observed that SETBP1 mutated (SETBP1-MUT) melanoma patients exhibited significantly prolonged ICI survival outcomes compared to wild-type patients (HR: 0.56, 95% CI: 0.38-0.81, P = 0.002). Consistently, an elevated ICI response rate was also noticed in the SETBP1-MUT group (42.9% vs. 29.1%, P = 0.016). The Association of SETBP1 mutations with favorable immunotherapeutic prognosis and response was further supported by an independent NSCLC cohort (both P < 0.05). Additional immunological analyses revealed that favorable immune infiltration, tumor immunogenicity, and immune response circuits were enriched in SETBP1-MUT patients. Overall, our findings suggest that SETBP1 mutations may serve as a new biomarker for stratifying beneficiaries of ICI treatments in melanoma and NSCLC, which provides possible evidence for tailoring clinical immunotherapeutic strategies.

Subcutaneous Fat Abundance and Density Are Associated with an Enhanced Response to Immunotherapy in Metastatic Melanoma: A Retrospective Cohort Study

Despite the impressive efficacy of immune checkpoint inhibitors (ICIs) in the treatment of metastatic melanoma, not all patients respond to therapy. In addition, ICI harbors the risk for serious adverse events (AEs), highlighting the need for novel biomarkers predicting treatment response and occurrence of AEs. Recently, the identification of enhanced response to ICI in obese patients has indicated that body composition might influence treatment efficacy. The aim of the current study is to assess radiologic measurements of body composition as biomarkers for treatment response and AEs to ICI in melanoma. In the current work, we analyze adipose tissue abundance and density, as well as muscle mass via computed tomography scans in a retrospective cohort of 100 patients with non-resectable stage III/IV melanoma receiving first-line treatment with ICI in our department. From these, we investigate the impact of the subcutaneous adipose tissue gauge index (SATGI) and other parameters of body composition on treatment efficacy and occurrence of AEs. Low SATGI was associated with prolonged progression-free survival (PFS) in univariate and multivariate analyses (hazard ratio 2.56 [95% CI 1.18-5.55], P = .02), as well as an enhanced objective response rate (50.0% vs 27.1%; P = .02). Further analysis with a random forest survival model highlighted a nonlinear relationship between SATGI and PFS with a clear separation into high- and low-risk cohorts separated by the median. Finally, a significant enrichment of cases with vitiligo, but no other AEs, was observed in the SATGI-low cohort (11.5% vs 0%; P=.03). We identify SATGI as a biomarker predicting treatment response to ICI without increased risk for severe AEs in melanoma.

Identification of RPTOR mutation as a novel predictor of efficacious immunotherapy in melanoma.

9524 Background: mTOR pathway is known to influence cancer immunity by metabolism reprogramming. RPTOR (Regulatory Associated Protein of MTOR Complex 1), one of mTOR pathway genes, which is involving in control of mammalian target of mTORC1 activity for regulating cell growth and survival. Whether mutations of RPTOR are associated with clinical efficacy of immune checkpoint inhibitors (ICIs) in melanoma is still ambiguous. Methods: In discovery cohort, we retrospective analyzed the genomic data of 418 melanoma samples which derived from seven immunotherapy studies ( http://www.cbioportal.org/ ) to evaluate the relationship between RPTOR mutation status and efficacy of immunotherapy. Then in validation cohort, the predictive value of RPTOR mutation was confirmed in 320 melanomas from MSKCC cohort (http://www.cbioportal.org/). TMB was calculated as the total count of nonsynonymous mutations in coding sequence. We used the CIBERSORT to evaluate the 22 types immune cell infiltration status in TCGA melanoma cohort. Results: The TMB level of RPTOR-mutant patients was higher than RPTOR-wildtype patients in both discovery (Median [IQR]: 43.11[23.76-140.15] vs. 6.13[2.07-13.66], P &lt; 0.001) and validation (Median [IQR]: 37.38[20.17-84.95] vs. 8.85[3.35-21.07], P &lt; 0.001) cohort. In discovery cohort, compared to RPTOR-wildtype patients, the RPTOR-mutant patients achieved prolonged OS (median OS: not reach, NR vs 22.7 months, HR (95%CI): 0.47(0.22-0.99), P = 0.043). This result was confirmed in validation cohort (median OS: NR vs. 42; HR (95%CI): 0.34 (0.11-1.0); P = 0.049). According to analysis of immune cell infiltration status, the mechanism of the predictive values of RPTOR mutations to ICI efficacy may be activated CD4 memory T cell more abundant in RPTOR-mutant tumors. Conclusions: RPTOR mutation is associated with higher TMB in ICI-treated melanoma patients. Survival analysis shows RPTOR mutation have a good link with longer OS after immunotherapy. These findings indicate that RPTOR mutation may serve as a potential predictive biomarker for ICIs in melanoma.

The association between body mass index and immune checkpoint inhibitors outcomes in melanoma: Results from real-world data.

e14604 Background: The “obesity paradox” refers to increase cancer risk in obesity with paradoxical improved outcomes. This phenomenon was previously reported in melanoma patients on immunotherapy; however, results are uncertain. Immune checkpoint inhibitors (ICI) are the mainstay of melanoma treatment. There is a lack of real-world data on the impact of body mass index (BMI) on overall survival (OS) and immunotherapy-related adverse events (irAEs) in melanoma patients on ICI. Methods: Data were retrospectively collected from an electronic health record database (TriNetX) which includes over 89 million patients from 56 healthcare systems in the United States. We identified adults with melanoma who received ICI; pembrolizumab, nivolumab, or a combination of ipilimumab and nivolumab between 2012 and 2022. Patients were stratified based on the WHO body mass index (BMI) classification. Overweight and obese patients were 1:1 propensity score-matched for age, sex, race, and use of ICI, with patients with normal BMI. Results: Ourcohort included 11,656 melanoma patients on ICI. 62% were males, 91% were white, and 86% were non-Hispanics. OS was significantly improved in overweight and obese compared to normal BMI patients (HR 0.72, 95% CI, 0.60-0.86; P &lt; 0.001, and HR 0.53, 95% CI, 0.43-0.65); P &lt; 0.001, respectively). Nearly one-third of all weight categories had an irAE. Skin toxicity was the most common, 16.5%-18.2%, while pneumonitis was the least common, 1.0% -2.0%. There was no statistically significant difference between the groups in all included irAE; skin toxicities, thyroid dysfunction, colitis, pneumonitis, or hepatitis. Conclusions: This is the largest real-world data study describing the association between weight status and the outcomes of ICI in melanoma. Our study showed that overweight and obese melanoma patients treated with single or combination ICI had a significantly improved OS compared to patients with normal BMI, in keeping with the “obesity paradox” phenomenon. Intriguingly, high BMI wasn’t associated with an increased risk of irAE. Studies to clarify the underlying mechanisms in melanoma and other malignancies are needed. [Table: see text]

The validity of a machine learning algorithm in predicting response to immune checkpoint inhibitors in melanoma.

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 &lt;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.

Cardiovascular Immunotoxicity Associated with Immune Checkpoint Inhibitors in Metastatic Melanoma

Checkpoint inhibitors, such as PD-1 inhibitors (nivolumab, pembrolizumab) and anti-CTLA-4 (CD152) (ipilimumab), are widely used in metastatic melanoma, and most immune-related adverse events are known. Several cardiovascular AEs (CVAEs) associated with immune checkpoint inhibitor exposure have been reported in post-marketing surveillance studies and represent major issues for patients with melanoma during and after cancer treatment. Data on CVAES induced by immune checkpoint inhibitors in melanoma, especially incidence and risk factors, are lacking. A systematic review of the literature up to 31 August 2020 was performed in Medline, the Cochrane Central Register of Controlled Trials (CENTRAL), and the ClinicalTrials.gov register according to prespecified selection criteria from inception to 7 April 2020. Statistics were performed on 3289 patients from five randomized clinical trials on melanoma. Patients with melanoma treated with immune checkpoint inhibitors had a significant risk of presenting dyslipidemia (Peto OR: 4.74, 95% CI: 2.16-10.41, p < 0.01, I2 = 0%, p = 0.94). The Peto OR was numerically significant for pericarditis, myocarditis, heart failure, myocardial infarction, cerebral ischemia, high pulmonary pressure, blood high pressure, arrhythmias, endocarditis, and conduction disturbances, but the confidence interval was not significant. The risk of CVAEs was not statistically different between melanoma treated with immune checkpoint inhibitors and other tumors treated with immune checkpoint inhibitors (range of p-value from 0.13 to 0.95). No interaction between follow-up length and CVAE reporting was found. Our study underlines that checkpoint inhibitors used for melanoma increase CVAEs, especially dyslipidemia, which could pave the way to chronic inflammatory processes, atherosclerosis, and, finally, ischemic cardiopathy. These cardiovascular adverse events could be acute or delayed, justifying the monitoring of lipidic biology and a baseline cardiology consultation.

A novel Cuprotosis-related signature predicts the prognosis and selects personal treatments for melanoma based on bioinformatics analysis.

Melanoma is a common and aggressive cutaneous malignancy characterized by poor prognosis and a high fatality rate. Recently, due to the application of Immune-checkpoint inhibitors (ICI) in melanoma treatment, melanoma patients' prognosis has been tremendously improved. However, the treatment effect varies quite differently from patient to patient. In this study, we aim to construct and validate a Cuproptosis-related risk model to improve outcome prediction of ICIs in melanoma and divide patients into subtypes with different Cuproptosis-related genes. Here, according to differentially expressed genes from four melanoma datasets in GEO (Gene Expression Omnibus), and one in TCGA (The Cancer Genome Atlas) database, a novel signature was developed through LASSO and Cox regression analysis. We used 781 melanoma samples to examine the molecular subtypes associated with Cuproptosis-related genes and studied the related gene mutation and TME cell infiltration. Patients with melanoma can be divided into at least three subtypes based on gene expression profile. Survival pan-cancer analysis was also conducted for melanoma patients. The Cuproptosis risk score can predict tumor immunity, subtype, survival, and drug sensitivity for melanoma. And Cuproptosis-associated subtypes can help predict therapeutic outcomes. Cuproptosis risk score is a promising potential biomarker in cancer diagnosis, molecular subtypes determination, TME cell infiltration characteristics, and therapy response prediction in melanoma patients.

100P Immunotherapy around the clock: Impact on stage IV melanoma

Immunotherapy is currently the standard of care in the treatment of metastatic melanoma. Immune cells in the tumor microenvironment play a decisive role in tumor growth and response to therapy. NK and dendritic cells, monocytes, T and B lymphocytes exhibit circadian oscillations in the peripheral blood, as well as PD-L1 expression. Recent data from MEMOIR study suggests the effectiveness of immune checkpoint inhibitors in melanoma is lower when more than 20% of infusions are in the late afternoon.

Fibroblast growth factor receptor family mutations as a predictive biomarker for immune checkpoint inhibitors and its correlation with tumor immune microenvironment in melanoma.

The emergence of immune checkpoint inhibitors (ICIs) has significantly improved the clinical outcomes of patients with metastatic melanoma. However, survival benefits are only observed in a subset of patients. The fibroblast growth factor receptor (FGFR) family genes are frequently mutated in melanoma, yet their impacts on the efficacy of ICIs remain unclear. Our study aimed to explore the association of FGFR mutations with ICIs efficacy in metastatic melanoma. The Cancer Genome Atlas (TCGA) data (PanCancer Atlas, skin cutaneous melanoma (SKCM), n = 448) in cBioPortal were collected as a TCGA cohort to investigate the association between FGFR mutations and prognosis of melanoma patients. To explore the impact of FGFR mutations on the efficacy of ICIs in melanoma, clinical and tumor whole-exome sequencing (WES) data of four ICI-treated studies from cBioPortal were consolidated as an ICIs-treated cohort. Moreover, the relationship between FGFR mutations and immunogenicity (tumor mutation burden (TMB), neo-antigen load (NAL), mismatch repair (MMR)-related genes and DNA damage repair (DDR)-related genes) of melanoma was evaluated utilizing data from the ICIs-treated cohort. The influence of FGFR mutations on the tumor immune microenvironment (TIME) of melanoma was also analyzed using the TCGA cohort. In the TCGA cohort, survival in melanoma patients with or without FGFR mutations was nearly equivalent. In the ICIs-treated cohort, patients with FGFR mutations had better survival than those without (median overall survival: 60.00 vs. 31.00 months; hazard ratio: 0.58, 95% CI: 0.42-0.80; P = 0.0051). Besides, the objective response rate was higher for patients harboring FGFR mutations (55.56%) compared to wild-type patients (22.40%) (P = 0.0076). Mechanistically, it was revealed that FGFR mutations correlated with increased immunogenicity (e.g., TMB, NAL, MMR-related gene mutations and DDR-related gene mutations). Meanwhile, FGFR mutant melanoma tended to exhibit an enhanced antitumor TIME compared with its wild-type counterparts. Our study demonstrated that FGFR mutations is a promising biomarker in stratifying patients with advanced melanoma who might benefit from ICIs therapy.

Effect of Cancer Stage on Adverse Kidney Outcomes in Patients Receiving Immune Checkpoint Inhibitors for Melanoma

Immune checkpoint inhibitors (ICIs) have transformed the treatment of melanoma. Since the approval of ipilimumab, a humanized cytotoxic T-lymphocyte associated antigen 4 antibody (anti-CTLA-4) in 2011, pembrolizumab and nivolumab (both targeting programmed cell death protein 1 [anti-PD-1]), as well as combination therapy (ipilimumab/nivolumab) have been shown to prolong progression-free survival and were approved for treatment of stage 4 melanoma. 1,S1,S2 Most recently, ICIs have been approved as adjuvant therapy for surgically resected stage 3 melanoma.

Abstract 5251: GRIN2A mutations as potential positive predictor for response of immune checkpoint inhibitors in melanoma

Abstract Background: Melanoma is a serious skin cancer. Immune checkpoint inhibitors (ICIs) including atezolizumab, pembrolizumab, nivolumab, ipilimumab have shown durable responses and have been approved by FDA. However, ICIs demonstrate antitumor effects only in a fraction of patients, and research exploring the association between gene mutation and clinical benefit is limited. Studies have shown that Tumor Mutation Burden (TMB) was significantly (p &amp;lt; 0.001) associated with mutations in genes like GRIN2A in Non-Small Cell Lung Cancer (NSCLC), which means that the mutation of GRIN2A gene may be related to the efficacy of immunotherapy in patients with NSCLC, but the association between GRIN2A mutation and TMB or survival in melanoma is unknown. Methods: The association between GRIN2A mutation with TMB and survival data was analyzed in melanoma patients from the public immunotherapy-treated cohort called Miao2018.Pancancer.249.WES, which worked as training cohort while the validation cohort was retrieved from Melanoma.Allen2015.WES.110. Wilcoxon test was used for the comparison of TMB and Tumor Neoantigen Burden (TNB). Progress Free Survival (PFS):Overall survival (OS) analyses were conducted in the public cohort using Kaplan-Meier curves and log-rank tests. Statistical significance was set at p=0.05. Results: In the training cohort, 33.8% (51/151) melanoma patients harbored GRIN2A mutation. GRIN2A mutation is associated with higher TMB (p&amp;lt;0.001) and higher TNB (p&amp;lt;0.001). Survival analysis demonstrated that GRIN2A mutation resulted in significantly longer PFS (5.6 vs 3.3months; HR, 0.58; p=0.027) and longer OS (22.5 vs 12.8 months; HR, 0.61; p=0.039) in melanoma patients treated with ICIs. While validation cohort1 showed that 22.7% (25/110) melanoma patients harbored GRIN2A mutation and GRIN2A mutation resulted in an increasing trend on TMB with strongly significant difference (p&amp;lt;0.001) and significantly longer OS (22.5 vs 8.3months; HR, 0.53; p=0.025). Conclusions: This study shows that GRIN2A mutation is correlated with higher TMB and TNB in melanoma and serve as a predictive biomarker of ICI benefit in melanoma. Citation Format: Ling Ye, Dandan Fan, Yaoxu Chen, Mengli Huang. GRIN2A mutations as potential positive predictor for response of immune checkpoint inhibitors in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5251.