Treatment Of Advanced Melanoma Research Articles

Cutaneous Toxicities of Advanced Treatment for Cutaneous Melanoma: A Prospective Study from a Single-Center Institution

Background/Objectives: The landscape of advanced melanoma treatments has shifted dramatically in recent years. Target therapy and immunotherapy have changed the management of patients with both metastatic (stage IV according to AJCC 8th ed.) and nodal (stage IIB/C and III) disease. As the use of novel agents has increased, so have the cutaneous toxicities associated with these medications. While most skin reactions are low-grade and can be managed conservatively with topical therapies, high-grade or life-threatening drug reactions can arise during therapy, requiring prompt dermatologic recognition and treatment. Given the survival benefit attributed to these new agents, treating skin toxicity and maintaining a patient’s quality of life is of paramount importance. Methods: We undertook a prospective, monocentric, and descriptive study in Bologna, Italy, including patients referred to the Oncologic Dermatology Unit of IRCCS AOU of Bologna who developed biopsy-proven cutaneous adverse events (AE) under treatment with immunotherapy for cutaneous melanoma with nodal (stage IIB/C, III) and metastatic (stage IV) disease from January 2016 to April 2024. Results: In 202 identified patients, 75 (37.5%) developed skin AEs. Ipilimumab was causal for 48.1% of skin AEs, followed by nivolumab (37%) and pembrolizumab (31.4%). Recorded types of skin AEs included erythematous rash, vitiligo, alopecia, lichenoid, maculopapular, acneiform, urticarial, psoriasiform, granulomatous, eczematous, and severe cutaneous AEs, such as Erythema multiforme/Stevens-Johnson syndrome and bullous autoimmune dermatoses. Most AEs were low-grade [CTCAE 1–2] (97%) and typically occurred after 10 weeks of treatment. Conclusions: This study comprehensively describes skin AEs occurring during systemic treatment with ICIs for cutaneous melanoma at a single center.

Caerin 1.1 and 1.9 peptides halt B16 melanoma metastatic tumours via expanding cDC1 and reprogramming tumour macrophages

BackgroundCancer immunotherapy, particularly immune checkpoint inhibitors (ICBs) such as anti-PD-1 antibodies, has revolutionised cancer treatment, although response rates vary among patients. Previous studies have demonstrated that caerin 1.1 and 1.9, host-defence peptides from the Australian tree frog, enhance the effectiveness of anti-PD-1 and therapeutic vaccines in a murine TC-1 model by activating tumour-associated macrophages intratumorally.MethodsWe employed a murine B16 melanoma model to investigate the therapeutic potential of caerin 1.1 and 1.9 in combination with anti-CD47 and a therapeutic vaccine (triple therapy, TT). Tumour growth of caerin-injected primary tumours and distant metastatic tumours was assessed, and survival analysis conducted. Single-cell RNA sequencing (scRNAseq) of CD45+ cells isolated from distant tumours was performed to elucidate changes in the tumour microenvironment induced by TT.ResultsThe TT treatment significantly reduced tumour volumes on the treated side compared to untreated and control groups, with notable effects observed by Day 21. Survival analysis indicated extended survival in mice receiving TT, both on the treated and distant sides. scRNAseq revealed a notable expansion of conventional type 1 dendritic cells (cDC1s) and CD4+CD8+ T cells in the TT group. Tumour-associated macrophages in the TT group shifted toward a more immune-responsive M1 phenotype, with enhanced communication observed between cDC1s and CD8+ and CD4+CD25+ T cells. Additionally, TT downregulated M2-like macrophage marker genes, particularly in MHCIIhi and tissue-resident macrophages, suppressing Cd68 and Arg1 expression across all macrophage types. Differential gene expression analysis highlighted pathway alterations, including upregulation of oxidative phosphorylation and MYC target V1 in Arg1hi macrophages, and activation of pro-inflammatory pathways in MHCIIhi and tissue-resident macrophages.ConclusionOur findings suggest that caerin 1.1 and 1.9, combined with immunotherapy, effectively modulate the tumour microenvironment in primary and secondary tumours, leading to reduced tumour growth and enhanced systemic immunity. Further investigation into these mechanisms could pave the way for improved combination therapies in advanced melanoma treatment.

Histopathological Characteristics and Distinction of Immune Checkpoint Inhibitor-Related Colitis

Abstract Introduction/Objective Immune checkpoint inhibitors (ICPIs) represent a groundbreaking class of cancer immunotherapy for patients with various advanced-stage solid cancers. ICPIs have been associated with immune- related adverse events, with ICPI-related colitis being a prominent concern due to its potential for life-threatening clinical complications. Recognizing the histopathologic characteristics specific to ICPI-related colitis is crucial for pathologists to provide an accurate diagnosis. Here we have collected and analyzed colon biopsies from patients with ICPI-related colitis following treatment of ICPIs to identify its distinctive histopathologic features and differentiate it from other colitis. Methods/Case Report Colon biopsies are collected from patients with ICPI-related colitis after receiving CTLA-4 and PD-L1 inhibitors as treatment for advanced melanoma. Histopathological features, including epithelial mucin depletion, enterocyte apoptosis, basal lymphoplasmacytosis, cryptitis, glandular architectural distortion, and granuloma, are compared with those in other colitis including ulcerative colitis, Crohn’s disease, microscopic colitis, ischemic and infectious colitis. Immunohistochemistry is employed to analyze inflammatory cell populations and specific enterocyte subtypes. Results (if a Case Study enter NA) ICPI-related colitis, following treatment with Ipilimumab and Nivolumab, commonly presents as active colitis, either with or without chronic colitis. Less frequently, it manifests as microscopic colitis, infectious or ischemic colitis. The acute active form of ICPI-related colitis resembles acute colitis in infectious or ischemic colitis; however, prominent enterocyte apoptosis and intraluminal apoptotic debris are relatively unique features to ICPI-related colitis. The chronic active form of ICPI-related colitis resembles inflammatory bowel diseases, particularly Crohn’s disease, but ICPI-related colitis exhibits an inflammatory injury more affecting surface mucosa and less basal lymphoplasmacytosis. Notably, the most distinctive feature of ICPI-related colitis is the depletion of specific mucinous epithelium observed in our cohort. Conclusion Recognizing specific histopathologic features of ICPI-related colitis, such as mucinous epithelial depletion, enterocyte apoptosis, and surface-dominant inflammation, are essential for pathologists in accurately diagnosing and distinguishing this disease to ensure proper clinical management for patients receiving ICPI treatment.

Weekly carboplatin plus paclitaxel chemotherapy in advanced melanoma patients resistant to anti-PD-1 inhibitors: a retrospective, monocentric experience

Immunotherapy with anti-PD-1 antibodies significantly improved the prognosis in advanced melanoma patients, but most of them develop primary or secondary resistance to the treatment. In this study, we evaluated efficacy and safety of a chemotherapy regimen with weekly carboplatin plus paclitaxel (wCP) in patients previously treated with anti-PD-1 antibodies. We retrospectively identified 30 patients with advanced melanoma treated at our Institute over the last eight years with wCP. The co-primary endpoints of the study were overall survival (OS) and progression-free survival (PFS). In addition, we evaluated treatment tolerability. For this patient cohort, median PFS and OS were 3.25 and 7.69 months, respectively. All included patients had previously received anti-PD-1 immunotherapy, most of them had ECOG PS 0–1, and only 5 patients had a BRAF V600 mutation. In univariable analysis, we observed shorter OS in patients with > 2 involved metastatic sites, superficial spreading histology, and serum lactate dehydrogenase (LDH) values above the median. Liver metastases were associated with worse outcomes, while radiotherapy treatment of brain metastases was associated with improved OS. However, in a multivariable Cox regression model, only LDH above the median, superficial spreading histology, and female sex were significantly associated with worse OS. We reported grade 3 and 4 treatment-related toxicities in 4 and 0 patients, respectively. In conclusion, chemotherapy with wCP is a valid palliative treatment in advanced melanoma who progressed with anti-PD-1 antibodies.

Evaluation of the efficacy of combined immune checkpoint inhibitors in advanced melanoma treatment - Long term outcomes and emerging therapeutic perspectives: a narrative review

Combination therapy with immune checkpoint inhibitors, specifically CTLA-4 and PD-1 blockade, has shown promise in treating advanced melanoma. However, this approach often results in increased toxicity, necessitating a careful evaluation of both efficacy and safety. This review explores clinical outcomes, survival rates, and adverse events associated with these therapies. A systematic review of PubMed, Scopus, and clinical trial databases was conducted for studies published from 2014 to 2024. Studies assessing the combined use of CTLA-4 and PD-1 inhibitors in melanoma patients were included, focusing on overall survival (OS), progression-free survival (PFS), and treatment-related adverse events (AEs). The combination of CTLA-4 and PD-1 inhibitors significantly improved clinical outcomes in advanced melanoma. In trials like CheckMate 067, the five-year overall survival rate reached 52%, with a notable improvement in progression-free survival. However, these benefits came with substantial toxicity, as approximately 55% of patients experienced grade 3 or 4 treatment-related adverse events, including colitis, hepatitis, and pneumonitis. Despite these challenges, combination therapy led to durable responses in a subset of patients, underscoring its efficacy. The review emphasizes the need for balancing efficacy with toxicity management in clinical practice. While CTLA-4 and PD-1 inhibitor combinations improve survival in advanced melanoma, increased toxicity presents challenges. Further research is needed to optimize treatment strategies and enhance patient selection to balance efficacy and safety.

Melanoma medicine: New drugs for melanoma and the role of the general practitioner.

Following major achievements seen with drug therapies for the treatment of advanced melanoma in the last decade, they now also have an ever-increasing role for the treatment of earlier stage disease. This review outlines the current drugs used to treat melanoma, and how general practitioners (GPs) can assist in the management of patients with melanoma and the associated toxicities with treatment. This review summarises the evolving status of melanoma care, emphasising when to refer patients to medical oncologists as part of the multidisciplinary team. It provides guidance into recognising and managing immune-related adverse events (irAEs) associated with immunotherapy, and provides insights into the future changes in clinical practice. Drug therapies are increasingly used for the treatment of many patients with melanoma. Early referral is crucial, and clinical trials remain the best choice for most patients. Recognition and prompt management of irAEs is vital, and collaboration between GPs and oncologists is essential for best care.

1083P KEYMAKER 02B: A randomized trial of pembrolizumab (pembro) alone or with investigational agents as first-line treatment for advanced melanoma

1083P KEYMAKER 02B: A randomized trial of pembrolizumab (pembro) alone or with investigational agents as first-line treatment for advanced melanoma

Evidence for Radiation Therapy in Stage III Locoregionally Advanced Cutaneous Melanoma in the Post-Immunotherapy Era: A Literature Review.

In the landscape of Stage III locoregionally advanced cutaneous melanoma treatment, the post-immunotherapy era has sparked a number of questions on the management of the nodal basin. However, much of the available literature is not focused on radiation therapy as an adjuvant therapy. This literature review aims to illuminate the evidence surrounding radiation therapy's potential to mitigate regional recurrences in the adjuvant setting for melanoma. Additionally, it seeks to identify adjunct systemic therapy options and explore the synergy between systemic therapy and radiation. Despite strides in surgical techniques and systemic therapies, controlling regional Stage III melanoma remains a formidable clinical hurdle. While historical data strongly suggest the efficacy of adjuvant radiation therapy in reducing regional recurrence risk, its evaluation predates the advent of MAPK pathway inhibitors and robust immunotherapy options. Notably, clinical trials have yet to definitively demonstrate a survival advantage with adjuvant radiation therapy. Additional research should focus on refining the definition of high risk for regional recurrence through gene expression profiling or tumor immune profiling scores and elucidate the optimal role of adjuvant radiation therapy in patients treated with neoadjuvant systemic therapy.

A targetable type III immune response with increase of IL-17A expressing CD4+ T cells is associated with immunotherapy-induced toxicity in melanoma.

Immune checkpoint inhibitors are standard-of-care for the treatment of advanced melanoma, but their use is limited by immune-related adverse events. Proteomic analyses and multiplex cytokine and chemokine assays from serum at baseline and at the adverse event onset indicated aberrant T cell activity with differential expression of type I and III immune signatures. This was in line with the finding of an increase in the proportion of CD4+ T cells with IL-17A expression at the adverse event onset in the peripheral blood using flow cytometry. Multiplex immunohistochemistry and spatial transcriptomics on immunotherapy-induced skin rash and colitis showed an increase in the proportion of CD4+ T cells with IL-17A expression. Anti-IL-17A was administered in two patients with mild myocarditis, colitis and skin rash with resolution of the adverse events. This study highlights the potential role of type III CD4+ T cells in adverse event development and provides proof-of-principle evidence for a clinical trial using anti-IL-17A for treating adverse events.

Photothermal therapy improves the efficacy of topical immunotherapy against melanoma

BackgroundMelanoma is an aggressive cancer with poor response to traditional therapies. A combination of photothermal therapy and topical immunotherapy may enhance elimination of melanoma.. Materials and methodsC57BL/6 mice with early stage and metastatic melanoma were treated with laser immunotherapy (LIT), combining near-infrared laser-based photothermal therapy (PTT) and topical imiquimod (IMQ)-based immunotherapy. The volume of primary and abscopal melanoma, animal survival, tissue temperature, transcriptome, and immune cell response were investigated to evaluate the effect of LIT. ResultsLIT could eliminate primary tumors, inhibite abscopal tumors, and prolong animal survival. The tumor tissues were selectively destroyed under a photothermal gradient between 38.2 ± 3.7 °C and 73.0 ± 2.3 °C. Gene expression analysis showed a significant increase in the expression of damage associated molecular patterns. Additionally, the population of mature dendritic cells, CD4+ T cells, and CD8+ T cells were increased, while myeloid-derived suppressor cells were downregulated after LIT. ConclusionThe study showed that LIT inhibited the growth of both primary and abscopal melanoma by activating systemic antitumor immune responses and reversing the immunosuppressive tumor microenvironment, making LIT a potential method for advanced melanoma treatment.

Encorafenib and binimetinib followed by radiotherapy for patients with BRAFV600-mutant melanoma and brain metastases (E-BRAIN/GEM1802 phase II study).

Encorafenib plus binimetinib (EB) is a standard of care treatment for advanced BRAFV600-mutant melanoma. We assessed efficacy and safety of encorafenib plus binimetinib in patients with BRAFV600-mutant melanoma and brain metastasis (BM) and explored if radiotherapy improves the duration of response. E-BRAIN/GEM1802 was a prospective, multicenter, single arm, phase II trial that enrolled patients with melanoma BRAFV600-mutant and BM. Patients received encorafenib 450mg once daily plus binimetinib 45mg BID, and those who achieved partial response or stable disease at first tumor assessment were offered radiotherapy. Treatment continued until progression.Primary endpoint was intracranial response rate (icRR) after 2 months of EB, establishing a futility threshold of 60%. The study included 25 patients with no BM symptoms and 23 patients with BM symptoms regardless of using corticosteroids. Among them, 31 patients (64.6%) received sequential radiotherapy. After two months, icRR was 70.8% (95% CI: 55.9-83.1); 10.4% complete response. Median intracranial PFS and OS were 8.5 (95% CI: 6.4-11.8) and 15.9 (95% CI: 10.7-21.4) months, respectively (8.3 months for icPFS and 13.9 months OS for patients receiving RDT). Most common grade 3-4 treatment-related adverse event was alanine aminotransferase (ALT) increased (10.4%). Encorafenib plus binimetinib showed promising clinical benefit in terms of icRR, and tolerable safety profile with low frequency of high grade TRAEs, in patients with BRAFV600-mutant melanoma and BM, including those with symptoms and need for steroids. Sequential radiotherapy is feasible but it does not seem to prolong response.

Factors associated with response to talimogene laherparepvec in the treatment of advanced melanoma

Talimogene laherparepvec (T-VEC) is currently the only United States Food and Drug Administration-approved intralesional therapy for advanced melanoma. Recent studies have assessed the integration of T-VEC with systemic immunotherapy, though the response remains variable. Therefore, we sought to identify factors associated with the response to T-VEC by conducting a retrospective, single-center analysis involving melanoma patients treated with T-VEC. In the present study, we recorded demographic and clinicopathological data, details of T-VEC treatments, prior and concurrent treatments, and clinical outcomes. The primary endpoint was the in-field overall response rate (ORR: complete + partial). Secondary endpoints included complete in-field response, defined as complete resolution of disease or a negative biopsy; disease failure-free survival (DFFS), defined from the initiation of treatment as the time to progression in patients who did not experience a disease-free interval and time to recurrence in those who did; and overall survival (OS). We used two-sample t-tests for continuous variables and Fisher’s exact test for categorical variables. DFFS and OS were further analyzed using the Kaplan–Meier method and log-rank tests for selected variables. Among the 18 patients who met the inclusion criteria, an in-field response was observed in 14 (78%) patients. Low disease burden (<5 lesions or a total diameter <5 cm) was associated with a higher in-field ORR compared to high-burden disease (100% vs. 43%, P = 0.01). There was a trend toward decreased in-field ORR for patients with >2 prior lines of systemic therapy (P = 0.18). With a median follow-up of 386 days, DFFS was associated with BRAF wild-type melanoma (P = 0.04), an in-field ORR (P = 0.007), and a measurable bystander response (P = 0.01). Two or more prior lines of immunotherapy were associated with poorer survival (P = 0.006) and worse DFFS (P = 0.02). In conclusion, despite a low sample size, we identified covariates associated with in-field ORR, DFFS, and OS, warranting further study.

Targeting Cancers with oHSV-Based Oncolytic Viral Immunotherapy.

The recent success of cancer immunotherapies, such as immune checkpoint inhibitor (ICIs), monoclonal antibodies (mAbs), cancer vaccines, and adoptive cellular therapies (ACTs), has revolutionized traditional cancer treatment. However, these immunotherapeutic modalities have variable efficacies, and many of them exhibit adverse effects. Oncolytic viral Immunotherapy (OViT), whereby viruses are used to directly or indirectly induce anti-cancer immune responses, is emerging as a novel immunotherapy for treating patients with different types of cancer. The herpes simplex virus type-1 (HSV-1) possesses many characteristics that inform its use as an effective OViT agents and remains a leading candidate. Its recent clinical success resulted in the Food and Drug Administration (FDA) approval of Talimogene laherparevec (T-VEC or Imlygic) in 2015 for the treatment of advanced melanoma. In this review, we discuss recent advances in the development of oncolytic HSV-1-based OViTs, their anti-tumor mechanism of action, and efficacy data from recent clinical trials. We envision this knowledge may be used to inform the rational design and application of future oHSV in cancer treatment.

Causes of death and patterns of metastatic disease at the end of life for patients with advanced melanoma in the immunotherapy era.

e21522 Background: Despite the drastic improvement in survival of patients with metastatic melanoma from immune checkpoint inhibitors (ICIs), almost half of patients still die from their disease. Factors surrounding death including mechanisms of death, sites of disease, and settings of death remain poorly described. A better understanding of these factors is paramount to optimize management for these patients. Methods: A retrospective observational cohort study was performed for patients age > 18 who died after treatment for advanced melanoma with anti-PD1 therapy or ipilimumab + nivolumab (Ipi/Nivo) at Yale Cancer Center (YCC) between 1/2009 and 6/2023. Primary outcome was cause of death. Statistical analyses were performed with Stata SE, version 15.0 (StataCorp, College Station, TX). This study was approved by the Yale Institutional Review Board (Protocol #2000034631). Results: Overall, 287 patients with melanoma who received ICIs were documented to be deceased; 183 met inclusion criteria. Median time from metastatic diagnosis to death was 16.1 mos (range 0.3 to 135.1 mos). Median age at death was 70 (range 22-101), 62.8% were male, and 90.2% were white. Most patients (52.5%) received Ipi/Nivo first line, and 79.8% of patients received both anti-PD1 and anti-CTLA4 treatment at some point. The median number of metastatic sites at death was 4 (range 0-13). The majority (90.1%) of patients with measurable disease had multi-system involvement of melanoma. Eleven patients had no evidence of disease at death and died due to non-melanoma causes. The most common sites of metastatic disease at death were distant lymph nodes (62.8%), lung (57.9%), liver (50.8%), brain (38.8%), and bone (37.7%). In total, 80.3% (147/183) experienced hospitalization within 3 months prior to death or hospice enrollment. Most died in the hospital (31.7%) or while enrolled in hospice (31.2% inpatient vs. 29.4% home). Overall, 10.9% of patients had survival > 5 years after metastatic diagnosis; 76.2% of long-term survivors died due to melanoma. Of 174 patients with evaluable causes of death, 87.9% of deaths were due to melanoma (Table 1). Patients with pleural metastases were more likely to die of respiratory failure (p = 0.036, OR 2.41 95% CI 1.06-5.50). Conclusions: The majority of deaths were a consequence of metastatic melanoma, with the most common causes including FTT, respiratory failure, and infection. [Table: see text]

Advanced stage melanoma during pregnancy: Real-world management.

9540 Background: Treatment (tx) of advanced melanoma during pregnancy represents a major challenge. While management of early-stage melanoma is similar to non-pregnant patients (pts), very little data is available on outcome or tx guidelines for pregnant pts with advanced stage. Therefore, we collected real world management data, to ultimately develop management guidelines for these pts. Methods: This retrospective, international, multicenter database, included pts who either were diagnosed with advanced melanoma (newly diagnosed or recurrent) during pregnancy (group 1) or conceived while on systemic tx for melanoma (group 2) between 01/2011–06/2023. Patient, primary tumor and advanced melanoma characteristics, intervention/tx during pregnancy, and outcomes of mother and fetus were collected using a standardized, de-identified form. Results: 68 pts from 7 countries were included, with a total of 72 pregnancies: 60 pregnancies in group 1 and 12 in group 2, including 5 twin pregnancies. Median age at time of pregnancy was 32 (19-42). In group 1, advanced melanoma diagnosis occurred during the 1st trimester in 38%, followed by 3rd (32%), 2nd (22%) and unknown (8%) trimester. 2% had stage II melanoma, 48% stage III, and 50% stage IV. 76% were cutaneous melanoma, 7% mucosal, and 17% other subtypes. BRAF mutations were seen in 70%. Pregnancy was terminated in 15% of cases, and miscarriage occurred in 1 case. Of the 50 live births, 68% were induced and 56% were preterm (38% vaginal, 54% C-section). Median gestational age (MGA) was 34 wks (27-40). Systemic tx was initiated during pregnancy in 8 pts (targeted therapy [TT, 63%], immunotherapy [IT, 37%]). 90% switched or initiated new systemic tx after pregnancy (median time to start of therapy: 28 days; IT 65%, TT 27%, chemo 8%). 5-year overall survival (OS) was 49% (95%CI 34-69), with a median follow-up (MFU) of 26m. In group 2, 82% had cutaneous melanoma and 18% an unknown primary. 91% had a BRAF mutation. 42% of pts received systemic tx for stage III melanoma and 58% for stage IV (IT 75%, TT 25%). 33% of pregnancies were terminated, 8% ended in miscarriage. Of the 8 live births, 43% were preterm, 29% were induced (43% vaginal, 29% C-section). MGA was 35 wks (32-39). Half the pts initiated new or continued tx after pregnancy (IT 50%, TT 50%). 5-year OS was 78% (95%CI 55-100), with MFU of 48m. Of the 57 live births, 1 child born at 26w died after 3 days. No children developed melanoma, despite 5 placentas with melanoma involvement. 4 unexposed children had congenital deficits: prematurity-related (n=3) and congenital hypothyroidism (n=1). 1 child with 3rd trimester Vemurafenib exposure had heart malformations, and 2 experienced toxicity after in uteroIT exposure. Conclusions: This is the largest contemporary dataset of pts diagnosed with advanced melanoma during pregnancy and pts who became pregnant on systemic melanoma therapy, and provides a basis for developing clinical guidelines for this challenging population.

First-line treatment preferences for advanced melanoma among oncologists and patients in the US: A discrete choice experiment.

9539 Background: NCCN guidelines recommend nivolumab + ipilimumab, nivolumab + relatlimab, and anti-PD-1 monotherapy as category 1 preferred first-line (1L) treatments (txs) for advanced melanoma. These immunotherapies (IOs) however differ in administration, efficacy, and safety. Given these differences, this study examines oncologists (oncs) and patients (pts) preferences when choosing 1L tx. Methods: Pts with self-reported unresectable or metastatic melanoma and oncs completed an online cross-sectional survey. A discrete choice experiment assessed preferences for three efficacy attributes, three safety attributes, and dosing schedule. Attributes (shown in table) were identified via literature and qualitative research. Each attribute had two or three levels based on clinical trial data of recommended IOs. Participants completed 12 tasks; each task showed two tx options with varying levels for each attribute. Hierarchical Bayesian modeling was used to estimate preference weights for each level and relative importance estimates, based on the range between levels, were computed. Results: 75 oncs (male 76%; mean age 46 years; community-based 51%) and 62 pts (male 68%; mean age 43 years) were analyzed (pt recruitment ongoing; target n = 75). For both oncs and pts, improvements in safety attributes was more important than improvements in efficacy attributes (pts: 50.3 vs. 33.9; oncs: 48.6 vs. 40.9). For safety, a decrease in risk of discontinuation due to treatment-related adverse events (TRAEs) was most important in oncs (24.7); while for pts, lower risk of grade 3/4 TRAEs was most important (22.6). For efficacy, an increase in overall survival (OS) was most influential for oncs (21.0); pts had similar estimates within efficacy. Dosing schedule was third most important for pts (15.8), while it was among the least important for oncs. Conclusions: Oncs and pts prioritize minimizing the risk of serious AEs when efficacy differences are minimal in 1L advanced melanoma tx choice. These findings highlight that oncs and pts value an IO with an efficacy benefit while ensuring a favorable risk-benefit profile. This information can inform tx counseling and selection discussions among oncs and pts. [Table: see text]

Efficacy and safety of lifileucel, an autologous tumor-infiltrating lymphocyte cell therapy, and pembrolizumab in patients with immune checkpoint inhibitor-naive unresectable or metastatic melanoma: Updated results from IOV-COM-202 cohort 1A.

9505 Background: Immune checkpoint inhibitors (ICI) are front-line standard-of-care treatment (tx) for advanced (unresectable or metastatic) melanoma. Despite recent advances in front-line tx, a majority of patients (pts) do not achieve long-term benefit. Lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, potentially induces durable responses in pts with advanced melanoma previously treated with ICI. This study evaluates lifileucel combined with anti-PD-1 therapy in front-line advanced melanoma. Methods: IOV-COM-202 (NCT03645928) Cohort 1A assesses the efficacy and safety of lifileucel and pembrolizumab (pembro) in pts with ICI-naive unresectable or metastatic melanoma. Pts may have received BRAF/MEK inhibitor tx if BRAF mutation-positive. Eligible pts must have ≥1 resectable lesion (≥1.5 cm diameter) for 22-day cryopreserved lifileucel manufacturing, and ≥1 measurable lesion for response assessment per RECIST v1.1. The tx regimen consists of pembro, nonmyeloablative lymphodepletion (cyclophosphamide and fludarabine), a single lifileucel infusion (1 × 109 – 150 × 109 cells), ≤6 doses of IL-2 (600,000 IU/kg IV), and continued pembro until disease progression, or unacceptable toxicity for ≤24 months. The endpoints are investigator-assessed objective response rate (ORR) and incidence of grade ≥3 treatment-emergent adverse events (TEAE). Results: As of 22-Dec-2023, 22 pts with a median (range) age of 48.5 (18–68) years received lifileucel and pembro. At baseline, the median (range) target lesion sum of diameters was 54.5 (14–355) mm; 7 (31.8%) pts had liver lesions. Metastatic staging at study entry was as follows: 4 (18.2%) had M1a, 2 (9.1%) had M1b, 10 (45.5%) had M1c, and 2 (9.1%) had M1d. Eight (36.4%) pts had V600 BRAF mutations; 3 (13.6%) pts had prior BRAF/MEK inhibitor tx. Confirmed ORR was 63.6% (14/22), including 22.7% (5/22) CR and 40.9% (9/22) PR; 6 pts (27.3%) had SD. Median time to initial response was 2.5 months. All response evaluable pts demonstrated regression of target lesions. At a median follow-up of 17.2 months, median duration of response was not reached. Responses deepened over time; 10/14 (71.4%) pts had ongoing response and 8/14 (36.4%) pts had response ≥12 months. TEAEs were consistent with the underlying disease and known safety profiles of pembro, nonmyeloablative lymphodepletion, and IL-2. Most common grade ≥3 TEAEs were thrombocytopenia (68.2%), neutropenia (50.0%), and anemia (45.5%). Conclusions: These results demonstrate encouraging efficacy and durability for the combination of lifileucel and pembro and support its further evaluation in pts with untreated advanced melanoma in the phase 3 study TILVANCE-301 (NCT05727904). Clinical trial information: NCT03645928 .

Camrelizumab plus apatinib and temozolomide as first-line therapy for advanced acral melanoma: 2-year survival results from CAP 03.

9547 Background: Acral melanoma is the predominant subtype in Asia, which presents with aggressive biological behavior. First-line immunotherapy yields modest efficacy in advanced acral melanoma, suggesting the need of combination therapy. Our CAP 03 study investigated the combination of anti-PD-1 antibody plus antiangiogenic agent and chemotherapy for the first-line treatment of advanced acral melanoma, and the primary analysis has been published on JAMA Oncology in June 2023 (objective response rate [ORR], 64%; median progression-free survival [PFS], 18.4 months). Here we updated the efficacy results with a median follow-up of 30.3 months (95% CI, 28.9-32.5; reverse Kaplan-Meier method) at data cutoff date on January 8, 2024. Methods: In this single-center phase 2 trial (NCT04397770), patients with pathologically confirmed unresectable stage III or IV acral melanoma and without prior systemic therapy for advanced disease were recruited. Patients received first-line intravenous camrelizumab (200 mg once every 2 weeks) plus oral apatinib (250 mg once a day) and intravenous temozolomide (200 mg/m2 once a day on days 1-5 every 4 weeks) until disease progression or intolerable toxicity. The primary endpoint was ORR per Response Evaluation Criteria In Solid Tumors, version 1.1. Imaging assessment was performed after 4 weeks, then every 8 weeks until one year, and every 3 months thereafter. Overall survival (OS) was followed every 3 months. Results: Between May 2020 and August 2021, a total of 50 patients were enrolled. The confirmed ORR was 66.0% (33 of 50; 95% CI, 51.2%-78.8%). The median PFS was 21.2 months (95% CI, 10.1-27.1). The median OS was not reached, and the 1-year and 2-year OS rates were 88.0% (95% CI, 75.2%-94.4%) and 64.8% (95% CI, 49.5%-76.5%), respectively. Further analyses indicated comparable PFS benefit in subgroups by age (<65 years vs ≥65 years), sex (male vs female), Eastern Cooperative Oncology Group performance status (0 vs 1), NRAS status (variant vs wild-type), stage, lactic dehydrogenase (LDH) level, and PD-L1 combined positive score (<5 vs ≥5). Regarding OS, similar trends were observed in these subgroups, except that patients with normal LDH had better median OS than those with elevated LDH (not reached vs 22.6 months, log-rank nominal P=0.033). Conclusions: This first-line triplet combination shows encouraging survival benefits in patients with advanced acral melanoma, regardless of NRAS status or PD-L1 expression level. Follow-up is still ongoing to obtain mature OS data. Clinical trial information: NCT04397770 .

Enhanced dacarbazine efficacy in advanced melanoma patients previously treated with immune checkpoint inhibitors in Korea.

e21528 Background: Immune checkpoint inhibitors (ICI) have revolutionized advanced malignant melanoma treatment. But the lack of effective options post-ICI failure presents a significant challenge. Despite its modest efficacy, chemotherapy with dacarbazine remains practical choice in metastatic melanoma patients after ICI failure. Researchers suggested an increased efficacy of chemotherapy in melanoma patients previously treated with ICI. In this study, we aimed to assess the efficacy of dacarbazine of patients with or without prior ICI treatment. Methods: 71 patients with histologically confirmed malignant melanoma, who diagnosed and underwent chemotherapy between 2011 and 2023 at the Kyungpook National University Chilgok Hospital (Daegu, Korea) were included in this retrospective study. We included patients who had received either dacarbazine single or CVD(Cisplatin, Vinblastine, Dacarbazine) regimen for an unresectable stage IIIC, IIID or IV acral, cutaneous, mucosal melanoma according to American Joint Committee on Cancer(AJCC) 8th edition. Results: Among a total of 71 individuals, there were 16 patients who had not previously received pembrolizumab treatment (DTI-only group). There were 55 patients in the pembrolizumab (pem-DTI group) experienced group. The median PFS was 2.3 months in the DTI-only group and 3.9 months in the pem-DTI group, reflecting a significant PFS difference of 1.6 months. And the median OS was 6.8 months in the DTI-only group and 19.0 months in the pem-DTI group, demonstrating a statistically significant difference. In the univariate and multivariate analysis for PFS, the use of pembrolizumab was advantageous compared to non-use (HR 0.246, 95% CI 0.106-0.576, p= 0.001). The only favorable condition in the univariate analysis for OS was the use of pembrolizumab compared to non-use (HR 0.198, 95% CI 0.068-0.574, p= 0.003). The mean duration of response for the DTI-only group was 4.64 months, while for the pem-DTI group, it was 8.11 months, indicating that the pem-DTI group exhibited a longer duration. Conclusions: We have demonstrated superior PFS and OS in the group of metastatic melanoma patients who received dacarbazine after prior treatment with pembrolizumab compared to those treated with dacarbazine alone. Dacarbazine may still be a valid option after failure of ICI +/- targeted treatment. Future studies should focus on the immunomodulatory effects of dacarbazine on the tumor microenvironment, which could be harnessed to potentially enhance sensitivity to immune checkpoint-based therapy.

A phase I/II study of KD6001, a novel fully human anti-CTLA4 IgG1 monoclonal antibody, in combination with toripalimab in patients with advanced melanoma.

9527 Background: Anti-CTLA4 and anti-PD-1 immunotherapies have changed the treatment landscape of patients (pts) with advanced or metastatic melanoma. However, there is still a need to develop an anti-CTLA-4 antibody with further improved safety and efficacy profile. KD6001, a novel fully human anti-CTLA4 IgG1 monoclonal antibody that exhibits immunomodulatory effects, enhances T-cell-mediated anti-tumor immune response, and shows preliminary anti-tumor activity as monotherapy in a FIH phase I trial in pts with advanced solid tumors. Here we report a new study result of KD6001 in combination with toripalimab, an anti-PD-1 monoclonal antibody, in pts with advanced melanoma (KD6001CT02). Methods: KD6001CT02 is a phase I/II study conducted in advanced melanoma. This study consists of dose escalation and dose expansion phases. The primary objective is to evaluate the safety and tolerability of KD6001 in combination with toripalimab and determine the MTD/RP2D. The secondary objectives are to measure antitumor activity, immunogenicity, and pharmacokinetics (PK). Results: As of 15 Dec 2023, 29 pts with melanoma were enrolled (dose escalation n=6 and dose expansion n=23), including 9 (31.0%) acral, 9 (31.0%) nonacral cutaneous, 8 (27.6%) mucosal, and 3 (10.3%) unknown primary subtypes. 18 of them had no brain metastases. The median age was 56 yrs (range 41-78 yrs). The majority of pts previously received anti-PD-1/L1 therapy (16/29, 55.2%) and 27.6% of them received ≥3 lines of therapy. No dose-limiting toxicity or ≥Gr 3 adverse events (AEs) were reported in the dose escalation phase. The study did not reach MTD. 26 (89.7%) pts had treatment-related adverse events (TRAEs), with ≥Gr 3 TRAEs occurring in 3 (10.3%) pts and were well manageable. All other TRAEs were Gr 1 or 2. There were no death events due to TRAEs. No novel safety signals were seen other than the previously reported safety profile of treatment with a combined inhibition of CTLA-4 and PD-1. At data cutoff, among 13 efficacy-evaluable pts without brain metastases, the unconfirmed and confirmed objective response rates (ORR) were 38.5% and 23.1%, respectively. The disease control rate (DCR) was 76.9%. Among 3 pts with confirmed partial response (PR) , 2 pts were mucosal melanoma and 1 patient was nonacral cutaneous melanoma. Among 7 pts who received KD6001 as the ≥2 line treatment and all failed anti-PD-1/L1 therapy, the unconfirmed and confirmed ORR were 57.1% and 42.9%, respectively. DCR was 85.7%. The median PFS and OS were not reached. Conclusions: KD6001 in combination with toripalimab for treatment of advanced melanoma was safe, well-tolerated and showed anti-tumor activity in pts with advanced melanoma. Preliminary analysis indicates that KD6001 combined with toripalimab is efficacious in pts who have progressed after previous anti-PD-1/L1 therapy and in pts with mucosal melanoma. Clinical trial information: NCT05723432 .