Combination Of Nivolumab Research Articles

Treatment outcomes of vulvar and vaginal melanoma at an NCCN institution between 1993 and 2021

BackgroundVulvar melanoma and vaginal melanoma are rare and difficult to treat. We describe the last three decades in a cohort predominantly treated surgically with adjuvant therapy. MethodsAll new patients between 1993 and 2021 followed until 2024. Collection of demographic and oncologic data allowed comparisons and Kaplan-Meier method was used to evaluate overall survival (OS) and progression free survival (PFS) stratified by adjuvant therapy type, diagnosis before and after 2011, and between vulvar and vaginal melanomas. ResultsConsultation for 63/72 patients (87.5 %) were for primary treatment. Most patients had vulvar melanoma (50/72, 69.4 %), received surgery (65/72, 90.3 %), and adjuvant treatment (40/72, 55.6 %) with immunotherapy, chemotherapy, and/or targeted therapy. Median survival for 63 patients presenting for primary treatment was 54.2 months, and 9/13 patients who were disease free after five years later received adjuvant immunotherapy. Survival did not vary by adjuvant therapy type or diagnosis after 2011 but was significantly less for vaginal melanoma. Following recurrence seven patients experienced complete response including three patients receiving combined nivolumab with ipilimumab and two nivolumab alone experienced. ConclusionsSurvival was not significantly different by adjuvant therapy type or after 2011. Most patients who were disease-free five years after surgery had received adjuvant therapy. Seven patients experienced complete responses to therapy after recurrence of whom five received immune checkpoint inhibitors. Although survival is not improved as in cutaneous melanomas by immune checkpoint inhibitors, signal continues for the use of immune checkpoint inhibitors in gynecologic melanomas.

CVM-1118: An oral anti-vasculogenic mimicry (VM) agent in combination with nivolumab in patients with unresectable advanced hepatocellular carcinoma (HCC)—A phase IIa study.

92 Background: CVM-1118 is a potent anti-tumor new chemical entity with multiple mechanisms of action including induction of apoptosis, cell cycle arrest, and inhibition of VM network formation. This study evaluated the anti-tumor effect and safety profile of CVM-1118 plus nivolumab in patients with progressive unresectable advanced HCC following the first-line therapy with TKIs. Methods: Eligible pts had unresectable advanced HCC and were refractory to prior systemic therapy (e.g., sorafenib, lenvatinib, regorafenib, and/or ramucirumab), with the exception of prior immunotherapy. Patients received oral CVM-1118 at 200 mg BID (400 mg daily) in combination with intravenous nivolumab at 240 mg Q2W in 28-day cycles. The primary endpoint of objective response rate was evaluated using mRECIST. The secondary endpoints were overall response rate (ORR) (per RECIST 1.1), progression free survival (PFS), disease control rate (DCR), and duration of overall response (DoR). Results: A total of 31 evaluable pts were enrolled (25 M/6 F; median age 65 y, range 44–80 y). All patients were Child Pugh A, BCLC stage B (13%, n=4) or C (87%, n=27) at the start of treatment. The median number of prior lines of therapy was 1 (range 1–2). The duration of CVM-1118 and nivolumab treatment ranged from 1.5–17.7 mos (median 3.1 mos) with 5/31 (16%) pts remaining on treatment for ≥ 5.2 mos (range 5.2–17.7 mos). The best ORR was 19.4% (mRECIST) (2 CR (6%), 4 PR (13%)), with remaining responses including 11 SD (36%) and 14 PD (45%). The DCR was 54.8% (95% CI 37.3–72.3%), the median PFS was 3.53 mos (95% CI 1.9–5.4 mos) and the median DoR was 12.1 mos (95% CI 5.2–16.1 mos). The most common treatment-related AEs ³ grade 3 included AST increased (12.9%), neutrophil count decreased (9.7%), anemia (6.5%), and WBC decreased (6.5%). As opposed to therapy with atezolizumab plus bevacizumab, gastrointestinal hemorrhage and hypertension were not observed in this study. Pharmacokinetics data demonstrated that CVM-1118 was rapidly metabolized to CVM-1125 in all pts following administration. On Day 1, the mean drug exposure of CVM-1125 was Cmax 564 ng/mL and the AUC0-24 was 2154 ng·hr/mL. Intersubject variability of drug exposure appeared to be high; the T1/2 of CVM-1125 was ~1.7 hr. Conclusions: CVM-1118 combined with nivolumab demonstrated clinical activity in advanced HCC pts with a safety profile that appears favorable compared to atezolizumab plus bevacizumab. These data support further development of the combination of CVM-1118 and nivolumab in pts with unresectable advanced HCC. Clinical trial information: NCT05257590 .

Genomic and transcriptomic profiles associated with response to eribulin and nivolumab combination in HER-2-negative metastatic breast cancer

BackgroundBiomarkers for predicting response to the immunotherapy and chemotherapy combination in breast cancer patients are not established. In this study, we report exploratory genomic and transcriptomic analyses of pretreatment tumor tissues from patients enrolled in phase II clinical trial of a combination of eribulin and nivolumab for HER-2-negative metastatic breast cancer (MBC) (KORNELIA trial, NCT04061863).MethodsWe analyzed associations between tumor molecular profiles based on genomic (n = 76) and transcriptomic data (n = 58) and therapeutic efficacy. Patients who achieved progression-free survival (PFS) ≥ 6 months were defined as PFS6-responders and PFS6-nonresponders otherwise.FindingsAnalyses on tumor mutation burden (TMB) showed a tendency toward a favorable effect on efficacy, while several analyses related to homologous recombination deficiency (HRD) indicated a potentially negative impact on efficacy. Patients harboring TP53 mutations showed significantly poor PFS6 rate and PFS, which correlated with the enrichment of cell cycle-related signatures in PFS6-nonresponders. High antigen presentation gene set enrichment scores (≥ median) were significantly associated with longer PFS. Naïve B-cell and plasma cell proportions were considerably higher in long responders (≥ 18 months).InterpretationGenomic features including TMB, HRD, and TP53 mutations and transcriptomic features related to immune cell profiles and cell cycle may distinguish responders. Our findings provide insights for further exploring the combination regimen and its biomarkers in these tumors.

Cytokine release syndrome associated with immune checkpoint inhibitors: a pharmacovigilance study based on spontaneous reports in FAERS

ABSTRACT Objective To describe cytokine release syndrome (CRS) associated with immune checkpoint inhibitors (ICIs) reported in the FDA Adverse Event Reporting System (FAERS). Methods We obtained ICIs adverse event (AE) reports from January 2011 to September 2023 from the FAERS database. The preferred term (PT) ‘cytokine release syndrome’ from the Medical Dictionary for Regulatory Activities (MedDRA) 26.1 was used to identify cases with ICIs-related CRS. The reporting odds ratio (ROR) of the disproportionality method was performed to quantify the association between CRS and ICIs treatment strategy. Results Three hundred and ninety-five cases were gathered. 42.03% of the patients were aged 18 to 65. Male patients outnumbered female patients (53.67% vs. 34.94%). The prevalent potential cancer types were lung cancer (33.42%) and skin cancer (20.51%). Japanese were responsible for the majority of ICIs-related CRS cases (176 cases). The combination of nivolumab and ipilimumab resulted in the most CRS cases (138 cases), and the ICIs combination therapy had the highest ROR signal value (ROR = 11.95 [10.14–14.06]). ICIs-related CRS had a median time to onset of 14 days (interquartile range [IQR] 7–43.25). Conclusions ICIs-related CRS is an increasingly important immune-related AE. Our study provided helpful information to help medical professionals learn more about ICIs-related CRS.

Analytical quality by design (AQbD) based optimization of RP-UPLC method for determination of nivolumab and relatlimab in bulk and pharmaceutical dosage forms

BackgroundThe Analytical Quality by Design (AQbD) methodology extends the application of Quality by Design (QbD) principles to the management of the analytical procedure life cycle, encompassing method creation, optimization, validation, and continuous improvement. AQbD assists in creating analytical procedures that are robust, reliable, precise, and cost-efficient. Opdualag™ is a combination of Nivolumab and Relatlimab, which are antibodies that block programmed death receptor-1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) receptors, used to treat advanced melanoma. This work aims to develop and validate a reversed-phase ultra-performance liquid chromatography (RP-UPLC) method using AQbD principles to determine NLB and RTB in pharmaceutical products.ResultsA central composite design (CCD) comprising three factors arranged in five distinct levels was implemented via Design-expert® software to optimize the chromatographic conditions. A mathematical model was constructed and the effects of three independent factors namely flow rate (X1), percentage of methanol in the mobile phase (X2), and temperature (X3) on responses including retention time (Y1–2), resolution factor (Y3), theoretical plates (Y4–5), and tailing factor (Y6–7) were investigated. The software determined the optimal chromatographic conditions for the separation of NLB and RTB, which were as follows: 32.80% methanol in the mobile phase, 0.272 mL/min flow rate, 29.42 °C column temperature, and 260 nm UV detection. The retention time for NLB and RTB were 1.46 and 1.88 min, respectively. The method exhibited linearity across the concentration ranges of 4–24 µg/mL for RTB and 12–72 µg/mL for NLB. The limits of detection (LOD) and limit of quantification (LOQ) for NLB and RTB, respectively, were 0.89 µg/mL, 2.69 µg/mL and 0.15 µg/mL and 0.46 µg/mL. The percentage relative standard deviation (%RSD) of intraday and interday precision for NLB and RTB was below 2. The recovery percentages for NLB and RTB were determined to be 99.57–100.43% and 99.59–100.61%, respectively. Both drugs were found to be susceptible to oxidative and photolytic degradation in forced degradation studies.ConclusionsEmploying the AQbD-based methodology, a straightforward, fast, accurate, precise, specific, and stability-indicating RP-UPLC method has been established for the quantitative analysis of NLB and its RTB in pharmaceutical formulations.

FRACTION: protocol of a phase II study of Fedratinib and Nivolumab combination in patients with myelofibrosis and resistance or suboptimal response to JAK-inhibitor treatment of the German MPN study group (GSG-MPN)

Development of Janus-kinase (JAK) inhibitors has revolutionized the therapeutic landscape for patients with myeloproliferative neoplasia (MPN). Following approval of the first JAK1/2-inhibitor Ruxolitinib, symptoms of this inflammatory disease, characterized by splenomegaly, release of inflammatory cytokines and appearance of thrombosis, could be effectively reduced for the first time. However, JAK-inhibitor treatment is limited in several aspects: 1) duration of response: 3 years after initiation of therapy more than 50% of patients have discontinued JAK-inhibitor treatment due to lack of efficacy or resistance; 2) reduction of disease burden: while effective in reducing inflammation and constitutional symptoms, JAK-inhibitors fail to reduce the malignant clone in the majority of patients and therefore lack long-term efficacy. Early clinical trials for patients with myelofibrosis (MF) have tried to address these issues for patients with suboptimal response to Ruxolitinib therapy while combination therapies with Fedratinib are rare. Recent reports provided first evidence on how the JAK2-V617F mutated myeloid cells may influence T-cell responses. JAK2-V617F promoted the synthesis of PD-L1 in MPN cells leading to limited anti-neoplastic T-cell responses, metabolic changes in T-cells and eventually JAK2-V617F-driven immune-escape of MPN cells. These findings may facilitate the use of immunotherapeutic approaches for JAK-mutated clones. Immune checkpoints refer to a variety of inhibitory pathways that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. The FRACTION study is a single arm, open label Phase II trial investigating the combination of Fedratinib with the PD-1 inhibitor Nivolumab in patients with myelofibrosis and suboptimal or lack of response to JAK-inhibitor therapy. Over a 12 months period the trial assesses longer term outcomes, particularly the effects on clinical outcomes, such as induction of clinical remissions, quality of life and improvement of anemia. No prospective clinical trial data exist for combinations of JAK- and immune-checkpoint-inhibitors in the planned MF study population and this study will provide new findings that may contribute to advancing the treatment landscape for MF patients with suboptimal responses and limited alternatives.

The role of cytoreductive nephrectomy in metastatic renal cell carcinoma in immune-oncology era (SEVURO-CN): study protocol for a multi-center, prospective, randomized trial

BackgroundThe role of cytoreductive nephrectomy (CN) in the treatment of metastatic renal cell carcinoma (mRCC) remains unclear in the immuno-oncology (IO) era. The results of two randomized trials, CARMENA and SURTIME, questioned the role and timing of CN. However, despite the latest advances in the systemic treatment of mRCC, previous trials have only used targeted therapy, and no studies have fully investigated the role of CN in immune checkpoint inhibitor (CPI) settings, and there is an urgent need for future studies to better define the role and timing of CN.MethodsThis study is an open-label, multi-center, parallel, prospective, randomized, interventional clinical study to evaluate the efficacy of CN in combination with CPIs in mRCC patients with International mRCC Database Consortium (IMDC) intermediate- and poor-risk. Synchronous mRCC patients with ≤ 3 IMDC risk features will be randomly allocated to three groups (1, upfront CN; 2, deferred CN; and 3, systemic therapy [ST] only). For ST, the nivolumab plus ipilimumab combination regimen, one of the standard regimens for intermediate- and poor-risk mRCC, is chosen. The primary endpoint is overall survival. The secondary endpoints are progression-free survival, objective response rate, number of participants with treatment-related adverse events, and number of participants with surgical morbidity. We will analyze the genetic mutation profiles of the tumor tissue, circulating tumor DNA, urine tumor DNA, and tumor-infiltrating lymphocytes. The gut and urine microbial communities will be analyzed. The study will begin in 2022 and will enroll 55 patients.DiscussionThis study is one of the few prospective randomized trials to evaluate the benefit of CN in the treatment of synchronous mRCC in the IO era. The SEVURO-CN trial will help identify the role and timing of CN, thereby rediscovering the value of CN.Trial registrationClinicalTrials.gov, NCT05753839. Registered on 3 March 2023.

Quality of life and patient-reported toxicities in patients with advanced Merkel cell carcinoma treated with combined nivolumab and ipilimumab with or without stereotactic body radiation therapy.

Merkel cell carcinoma is a rare skin cancer associated with poor survival. Based on a previous Phase II trial of adults with advanced Merkel cell carcinoma by Kim and colleagues (2022), there is now a strong rationale for combination therapy (i.e., nivolumab and ipilimumab) to become a treatment option for patients with advanced Merkel cell carcinoma. The goal of this paper was to report on the secondary outcome of quality of life (QOL) among patients on this trial. Patients receiving combined nivolumab and ipilimumab, with or without stereotactic body radiation therapy (SBRT), completed the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 prior to starting treatment and every 2 weeks thereafter. Changes in QOL during treatment and post-treatment were evaluated using piecewise random-effects mixed models. Exploratory analyses compared changes in QOL between study arms. The original trial was registered with ClinicalTrials.gov (NCT03071406). Study participants (n = 50) reported no changes in overall QOL (ps > 0.05), but emotional functioning improved during treatment (p = 0.01). Cognitive and social functioning worsened post-treatment (ps < 0.01). In general, patients treated with combination therapy only (n = 25) reported no change in QOL over time, whereas patients also treated with SBRT (n = 25) consistently demonstrated worsening QOL post-treatment. QOL is generally preserved in patients treated with combination therapy, but the addition of SBRT may worsen QOL. Combined with clinical efficacy data published previously, results support the use of combination therapy with nivolumab and ipilimumab as a treatment option for patients with advanced Merkel cell carcinoma.

Real-World efficacy and safety of combination nivolumab plus ipilimumab for Untreated, Unresectable, pleural Mesothelioma: The Meso-Immune (GFPC 04–2021) trial

BackgroundFirst-line standard-of-care for unresectable, pleural mesothelioma (PM) changed with the phase 3 CheckMate 743 study results, showing that nivolumab plus ipilimumab (Nivo + Ipi) significantly extended overall survival (OS) versus platinum + pemetrexed chemotherapy for PM (median OS 18.1 versus 14.1 months; hazard ratio: 0.74; p = 0.002). Efficacy and safety data in real-world (rw) settings are needed to confirm these results. MethodsThis French multicenter, retrospective cohort study was undertaken to assess the outcomes of treatment-naïve PM patients given Nivo + Ipi via an early-access program (EAP). The primary objective was investigator-assessed real world −progression-free survival (PFS). The secondary objectives were the combination’s −overall survival (OS) and safety. ResultsFrom 1 April 2021 to 15 Feb 2022, the analysis included 201 of the 305 EAP-enrolled patients treated in 63 centers (79.6 % men; median age: 75 years; 91.8 % Eastern Cooperative Oncology Group performance status (ECOG-PS) 0/1; 74.5 % epithelioid histology). With median (95 % CI) follow-up for all patients of 18.4 (17.7–19.2) months, −PFS and OS were 6.3 (5.3–7.5) and 18.9 (17.6–not reached (NR)) months, with 1-year OS at 66.4 % (60.1–73.3 %). Median OS and 1-year survival rates were 21.0 (18.7–NR) and 70.8 % (63.9 %-780.6 %), and 14.1 (10.9–21.0) months and 54.9 % (42.8 %–70.4 %) for epithelioid and non-epithelioid PM subgroups, respectively. PFS was equal between the two subgroups. Grade 3–4 adverse events occurred in 23.3 % of patients and three deaths were treatment-related. ConclusionsFor this unselected PM population, efficacy and safety outcomes compared favorably with CheckMate 743 trial results.

Clinical Association Between Immune-related Adverse Events and Treatment Efficacy in Patients With Non-small-cell Lung Cancer Treated With Nivolumab-Ipilimumab-based Therapy.

Nivolumab and ipilimumab combination therapy has been extensively explored for the treatment of advanced non-small-cell lung cancer (NSCLC) through the pivotal phase III trials CheckMate 227 and CheckMate 9LA. However, the relationship between immune-related adverse events (irAEs) and the effectiveness of nivolumab plus ipilimumab-based therapy in a real-world clinical setting remains uncertain. We performed a retrospective analysis of 28 patients with advanced or recurrent NSCLC who underwent treatment with nivolumab plus ipilimumab, with or without platinum-doublet chemotherapy, from February 2021 to January 2023. The primary objective was to elucidate the clinical association between irAEs and treatment efficacy associated with nivolumab plus ipilimumab-based therapy. Among the 28 patients, 22 (78.6%) experienced irAEs. The median progression-free survival (PFS) was significantly longer for patients with irAEs than for those without (p=0.0158), as was overall survival (OS) (p=0.000394). The severity of irAEs had no significant influence on PFS or OS. The objective response rate tended to be higher in patients with irAEs than in those without (50.0% versus 0.0%, respectively; p=0.0549). Multivariate analysis indicated that irAE occurrence was an independent factor for improved PFS (hazard ratio=0.2084, p=0.01383) and OS (hazard ratio=0.0857, p=0.001588). Interstitial lung disease was inferior to other irAE profiles for both PFS and OS. Patients with advanced NSCLC experiencing irAEs demonstrated superior clinical outcomes when treated with nivolumab plus ipilimumab-based therapy compared with those without irAEs. However, immune-related interstitial lung disease may be less linked with PFS and OS than other irAE profiles.

A combination of 5-azacytidine and nivolumab is a potentially effective rescue therapy in relapsed/refractory AITL.

Angioimmunoblastic T-cell lymphoma (AITL) is a peripheral T-cell lymphoma characterized by a T follicular helper cell phenotype expressing PD-1 (programmed cell death-1). AITL exhibits a poor response to conventional chemotherapy, with a median 5-year overall survival of 44% and a progression-free survival of 32%. Relapse is common, resulting in a median overall survival of 6 months. Recurrent mutations are detected in genes regulating DNA methylation, including TET2, DNMT3A, and IDH2 variants, along with the prevalent RHOA G17V mutation. In this context, patients treated with the hypomethylating agent 5-azacytidine achieved overall response and complete response rates of 75% and 41%, respectively. We hypothesized that targeted therapies combining anti-PD-1 checkpoint blockers with hypomethylating agents could be efficient in AITL patients and less toxic than standard chemotherapy. Here, we report the efficacy of a regimen combining 5-azacytidine and nivolumab in nine relapsed or refractory AITL patients. This regimen was well-tolerated, especially in elderly patients. The overall response rate was 78%, including four partial responses (44%) and three complete responses (33%). Allogeneic hematopoietic stem cell transplantation was performed in two patients who reached complete response. These preliminary favorable results may serve as a basis for further investigation in prospective studies.

Treatment approaches for older Hodgkin lymphoma patients.

Hodgkin lymphoma (HL) occurs at two age peaks around 25 and 60 years of age. Due to varying fitness and co-morbidities older patients are a heterogeneous group that has relatively poor treatment outcomes. The evolving therapeutic landscape for older HL is summarized herein. Due to lack of data from larger trials and approval of novel drugs, first-line treatment of limited-stage HL (i.e. early-stage favourable and unfavourable) remains largely A(B)VD and radiotherapy based. For patients with advanced-stage HL, the anti-CD30 antibody-drug conjugate brentuximab vedotin is approved in combination with AVD chemotherapy (BV-AVD). Due to toxicities such as febrile neutropenia or polyneuropathy and lack of improvement in progression-free and overall survival in the older subgroup, fully concomitant BV-AVD is however not used widely. More recently, promising early data was reported with the combination of nivolumab and AVD (N-AVD) in patients >60 years with advanced-stage HL. Second-line treatment depends on fitness and might include high-dose chemotherapy and autologous stem-cell transplantation for selected patients. For unfit or multiply relapsed patients, anti-PD1 antibodies are the preferred treatment option. The increasing number of older HL patients constitutes a therapeutic challenge despite recent advances and the increased usage of targeted agents.

Comparison of FDG-PET/CT and CT for evaluation of tumor response to nivolumab plus ipilimumab combination therapy and prognosis prediction in patients with unresectable malignant pleural mesothelioma.

Results for malignant pleural mesothelioma (MPM) patients following first-line treatment with nivolumab plus ipilimumab obtained with immunotherapy-modified PERCIST (imPERCIST), shown by [18F]fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT), and modified RECIST (mRECIST), shown by CT, were compared for response evaluation and prognosis prediction. imPERCIST indicated nine progressive metabolic disease (PMD), eight stable metabolic disease (SMD), four partial metabolic response (PMR), and five complete metabolic response (CMR) cases. mRECIST showed nine with progressive disease (PD), nine stable disease (SD), seven partial response (PR), and one complete response (CR). Although high concordance was noted (κ = 0.827), imPERCIST correctly judged a greater percentage with CMR (15.4%). Following a median 10.0 months, 15 patients showed progression and eight died from MPM. With both, progression-free survival (PFS) and overall survival (OS) were significantly longer in patients without progression (CMR/PMR/SMD, CR/PR/SD, respectively) as compared to PMD/PD patients (imPERCIST p < 0.0001 and p = 0.015, respectively; mRECIST p < 0.0001 and p = 0.015, respectively). Twenty-six patients (23 males, 3 females; median 73.5 years) with histologically proven MPM and no curative surgery received nivolumab plus ipilimumab combination therapy. FDG-PET/CT and diagnostic CT scanning at the baseline, and after 2-4 cycles (2 in three, 3 in 17, 4 in six patients) were performed. Therapeutic response findings evaluated using imPERCIST and mRECIST were compared. PFS and OS analyses were done using log-rank and Cox methods. For unresectable MPM patient examinations, FDG-PET and CT provide accurate findings for evaluating tumor response and also prognosis prediction following first-line nivolumab plus ipilimumab immunotherapy (approximately three cycles).

A current comprehensive role of immune-checkpoint inhibitors in resectable non-small cell lung cancer: A narrative review.

The objective of this article is to review the efficacy, safety, and evidence for current use and potential future uses of immune-checkpoint inhibitors (ICIs) in the management of resectable non-small cell lung cancer (NSCLC). A literature review was carried out through PubMed to identify completed and ongoing clinical trials evaluating the use, efficacy, and safety of ICIs in the management of resectable NSCLC. To date, four phase 3 trials have emerged that have changed our treatment practice concerning the utilization of ICIs during the adjuvant and neoadjuvant settings. The IMpower010 and KEYNOTE-091 trials examined the application of adjuvant atezolizumab and pembrolizumab, respectively, following surgical resection and adjuvant chemotherapy. In the CheckMate 816 trial, the combination of nivolumab and chemotherapy as a neoadjuvant therapy received approval for patients with resectable NSCLC. Also, for patients with resectable NSCLC, the use of a pembrolizumab and chemotherapy combination as a perioperative therapy received approval based on the results of the KEYNOTE-671 trial. Apart from these trials, there are numerous phase 2 and phase 3 trials, some of which have been published while others are still in progress. Despite the promising outcomes from these trials there remain several unanswered questions. In this review, we will assess clinical trials involving adjuvant, neoadjuvant, and perioperative ICIs, aiming to address the unresolved questions related to these therapeutic approaches.

Ipilimumab and nivolumab plus UV1, an anticancer vaccination against telomerase, in advanced melanoma.

LBA9519 Background: The combination of ipilimumab (IPI) and nivolumab (NIVO) remains a standard of care for patients with advanced melanoma, especially those with poor prognostic factors, albeit with a significant risk of toxicity. Therapeutic cancer vaccines are ideally positioned to improve outcomes without significantly increasing toxicity. UV1 is a therapeutic cancer vaccine generating T-cell responses against the universal cancer antigen telomerase. In a Phase I trial in melanoma (N = 30), UV1 plus pembrolizumab demonstrated a tolerable safety profile, a complete response rate of 33%, median PFS of 18.9 months, and 2-year OS rate of 73.3%. Recently, results from a randomized Phase II trial indicated a longer overall survival and a higher response rate for previously treated patients with advanced mesothelioma receiving UV1 in combination with IPI-NIVO (1). Methods: In this Phase II, open-label, multicenter study, we randomly assigned treatment-naïve patients with unresectable or metastatic melanoma (stage IIIb-IIId or IV) to IPI 3mg/kg + NIVO 1mg/kg for 4 cycles, followed by NIVO 480 mg as maintenance, with or without 8 intradermal injections of 300 µg UV1 (+GM-CSF). The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR) according to RECIST 1.1. Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response, and safety. Results: A total of 156 patients underwent randomization; 78 patients were assigned to the IPI-NIVO-UV1 arm and 78 patients to the IPI-NIVO arm. The median age was 60, 48% had M1C or D disease, 38% had LDH &gt;upper limit of normal, and 42% had a positive BRAF mutation status. With a minimum follow-up of 18 months, the 12-month PFS rate was 57% in both arms (HR 0.95, 95% CI 0.59-1.55, p value 0.845). The ORR was similar with IPI-NIVO-UV1 compared to IPI-NIVO, at 60% vs 59%, respectively (Odds ratio 1.12, 95% CI 0.58-2.16, p value 0.867). The 12-month OS rate was 87% and 88%, respectively (HR 1.15, 95% CI 0.60-2.20, p value 0.674). The occurrence of grade &gt;3 adverse events was similar in both treatment arms. Conclusion: UV1 did not improve on outcomes of IPI-NIVO, in terms of PFS. Longer follow-up is required for the accurate assessment of OS. No significant toxicity increases were observed with the addition of UV1. Data from a biomarker driven cohort are awaited. 1. Helland et al, Eur J Cancer 2024. Clinical trial information: NCT04382664 .

Characterization of complete responders to nivolumab + gemcitabine-cisplatin vs gemcitabine-cisplatin alone and patients with lymph node–only metastatic urothelial carcinoma from the CheckMate 901 trial.

4509 Background: In the CheckMate 901 trial, combination nivolumab (NIVO) + gemcitabine-cisplatin (GC) demonstrated significant improvements in overall survival (OS) and progression-free survival (PFS) with compelling objective response rates (ORR; 57.6% with NIVO+GC vs 43.1% with GC alone) and deep, durable complete responses (CR; 21.7% with NIVO+GC vs 11.8% with GC alone) in patients (pts) with previously untreated unresectable or metastatic urothelial carcinoma (mUC). Lymph node (LN)-only metastatic disease is a favorable prognostic factor in pts with mUC and a subset of pts achieve durable disease-free, treatment-free survival with GC +/- surgical consolidation. We conducted a post hoc analysis to characterize the subset of pts with CR, with further analysis of pts with LN-only mUC. Methods: In the global, open-label, randomized, phase 3 CheckMate 901 (NCT03036098) trial, cisplatin-eligible pts received NIVO 360 mg + GC every 3 wk for ≤6 cycles followed by NIVO 480 mg every 4 wk until disease progression/unacceptable toxicity or up to a maximum of 2 yrs, or GC every 3 wk for ≤6 cycles. Primary endpoints were OS and PFS by blinded independent central review (BICR). ORR per BICR and safety were exploratory endpoints. These post hoc analyses evaluated treatment outcomes in complete responders and in pts with LN-only disease. Results: Of the 608 pts randomized, 102 (16.8%) achieved a CR. Baseline disease characteristics of these pts are shown in the Table. As pts with LN-only mUC were enriched in the CR group, additional analysis of this subgroup was performed. Of all randomized pts, 54 treated with NIVO+GC and 56 treated with GC had LN-only mUC. In these pts, the ORR and CR rate was 81.5% (95% CI 68.6-90.7) and 63.0% versus 64.3% (50.4-76.6%) and 33.9% for NIVO+GC and GC, respectively. Median OS (95% CI) in LN-only pts was 46.3 (24.0-NE) mos with NIVO+GC vs 24.9 (21.4-29.9) with GC (HR, 0.58, 95% CI 0.34-1.00), and median PFS (95% CI) was 30.5 (9.6-NE) mos with NIVO+GC vs 8.8 (7.5-10.9) mos with GC (HR 0.38, 95% CI 0.22-0.66). Conclusions: NIVO+GC generated deep responses in CheckMate 901 with a fixed duration of chemotherapy and up to 2 years NIVO. Exploratory characterization of pts with CR identified a group of pts enriched with LN-only disease.In pts with LN-only mUC, NIVO+GC induced durable disease control and clinically meaningful improvements in OS and PFS vs GC alone. These results provide additional support for NIVO plus cisplatin-based chemo as a first-line treatment option for pts with mUC. Clinical trial information: NCT03036098 . [Table: see text]

Correlation of ctDNA and radiographic imaging features derived from 18F-FDG PET/CT for patients with metastatic melanoma treated with immunotherapy.

3057 Background: 18F-FDG PET/CT scans are used to assess tumor response for patients undergoing immunotherapy for metastatic melanoma (MM). Evaluating the relationship between features derived from quantitative medical image analysis and markers in blood samples such as circulating tumor DNA (ctDNA) may present an opportunity to discover imaging and blood biomarkers that can influence future patient care. This study evaluates the correlation of ctDNA and radiographic imaging features derived from FDG PET/CT. Methods: Whole-body FDG PET/CT scans from MM patients between 2014-2020 were retrospectively collected under IRB-approved protocol. Patients received pembrolizumab (n=20), ipilimumab (n=4), nivolumab (n=7), or a combination of ipilimumab and nivolumab (n=19). TRAQinform IQ software (AIQ Solutions) identified and quantified regions of interest suspicious of cancer (lesion-ROI), enabling extraction of imaging features including SUVmax, SUVmean, and SUVtotal in baseline (BL) and follow-up (FU) images and change. Plasma ctDNA concentration (copies/ml) and frequency abundance (FA) were evaluated for the first sample (1) after immunotherapy had started (between baseline and first on-treatment scan), and the next available sample (2). Patients were further grouped by ctDNA mutation for analysis. Correlation between imaging features and ctDNA features was assessed using Spearman coefficient (ρ). Results: The patient cohort included 32 males and 19 females with average age of 62 years (range 23-83). For all 51 patients, moderate correlation was observed in SUVmax,BL with ctDNA copies/ml1 (ρ = 0.48, p&lt;&lt; 0.001) and ctDNA FA1 (ρ = 0.49, p &lt;&lt; 0.001) and in SUVtotal,BL with ctDNA FA1 (ρ= 0.41, p &lt; 0.001). In BRAF mutation patients (N=32), moderate correlations existed between SUVmax,BL with ctDNA copies/ml1 (ρ = 0.49, p = 0.0041 and ctDNA FA1 (ρ = 0.05, p = 0.0035), and SUVtotal,BL with ctDNA copies/ml2 (ρ = 0.42, p = 0.017), ctDNA FA1 (ρ = 0.40, p = 0.023), and ctDNA FA2 (ρ = 0.43, p = 0.012). All the other combinations displayed weak correlations (ρ &lt; 0.39, p &gt; 0.05). Conclusions: This study shows that in patients with MM receiving immunotherapy, quantitative features from blood biomarkers such as ctDNA correlate with FDG PET/CT imaging features. Combining blood biomarkers with imaging features that are spatially localizable may strengthen prognostication in this patient group. Further analysis is being performed with more types of ctDNA mutations.

An update on SOC-1882: A phase 2 study using talimogene laherparepvec, nivolumab, and trabectedin for advanced leiomyosarcoma.

e23570 Background: Intratumoral injection of Talimogene Laherparepvec (TVEC) has a local oncolytic effect and evokes a cytotoxic immune response. The combination of Trabectedin (T) and Nivolumab (N) is a safe and effective therapy in soft tissue sarcoma (STS). Here, we report an update on an ongoing Phase 2 study that aims to determine the efficacy and safety of adding TVEC to the combination of T and N in advanced leiomyosarcoma (LMS). Objectives: Primary: To assess progression-free survival (PFS). Secondary: (1) To evaluate the best overall response, (2) PFS rate at 6 and 9 months, (3) Overall survival (OS) rate at 6, 9, and 12 months, (4) Incidence of conversion from unresectable to the resectable tumor, and (5) Incidence of treatment-related adverse events (TRAEs). Patients and Methods: Eligible patients included patients ≥ 18 years of age with locally advanced unresectable or metastatic LMS, measurable disease by RECIST v1.1, and at least one accessible tumor for TVEC intratumoral injection. N (3 mg/kg q2 weeks), T (1.2 mg/m2 q3 weeks), and TVEC (1x108 PFU/ml q 2 weeks depending on tumor size) were administered. A starting dose of TVEC (1x106 PFU/ml) was initially given, followed by a total dose of 1x108 PFU/ml q 2 weeks depending on tumor size) three weeks later. Results: Efficacy: Per protocol, there were 17 evaluable subjects (Modified Intention to Treat [mITT] patients who had completed at least one treatment cycle and had a follow-up CT scan). The median number of prior lines of therapy was 4 (range 1-9). The disease control rate (PR+SD) was 94% with 1 PR, and 15 SD. The median PFS was 8.0 months (95% CI:4.8-11.28) with a 6-month PFS rate of 71%; median OS 19.2 months (95% CI:12.7- 25.7); 6-month OS rate, 82%. Safety: 22 patients (Intention to treat [ITT] who had received at least one-time drug administration) were evaluated for safety analysis. The &gt; Grade 3 TRAEs include anemia (n = 3), thrombocytopenia (n = 3), neutropenia (n = 1), increased ALT (n = 1), increased GGT (n = 1), decreased LVEF (n = 1), dehydration (n = 1), hyponatremia (n = 1). There were no new safety signals noted in this study. Conclusions: Taken together, the data confirms our previous report that (1) the combination regimen using Talimogene laherparepvec, Nivolumab &amp; Trabectedin may be more effective and treatment for previously treated patients with advanced leiomyosarcoma with manageable toxicity, and (2) The best responders are patients with HR+ uterine LMS. Clinical trial information: NCT03886311 .

Mucosal melanoma treatment patterns and outcomes in real clinical practice: Single institution experience.

e21571 Background: Mucosal melanoma (MM) is a challenging malignancy to diagnose and treat, even with the advent of modern drug therapies. There is a lack of established surgical, radiological, or pharmacological treatment approaches for locally advanced or metastatic mucosal melanoma. This study analyzes the treatment practices and clinical outcomes at a single institution over a five-year period to understand real-world clinical practices. Methods: A сomprehensive, continuous, retrospective study analyzed medical records of adults with histologically confirmed MM at the N.N. Blokhin Russian Cancer Research Center from January 2018 to December 2023. Data was digitized into an electronic questionnaire, with patient follow-up conducted via telephone. Results: A total of 87 patients were identified, comprising 72 females (82.8%) from 31 regions of Russia. The median age was 67.8 years (ranging from 29.5 to 90.1 years). The patient breakdown was as follows: 6 with head&amp;neck MM (6.9%), 41 with vulvovaginal MM (47.1%), 5 with penile MM (5.7%), 27 with anorectal MM (31.0%), and 8 with gastrointestinal MM (9.2%). A significant portion of the patients presented with locally advanced (22.9%) or metastatic disease (67.8%), while 9.2% of the patients had undergone surgery and were being considered for adjuvant treatment. The most common sites of metastasis were regional lymph nodes (23%), liver (14%), and lungs (11.5%), with one patient having CNS metastasis. Mutational status was determined for 48 of the 87 patients, revealing driver mutations in 12 patients (Table). The majority of patients were initially treated with immunotherapy. The most frequently used therapies included monotherapy with anti-PD-1 agents (nivolumab or pembrolizumab, accounting for 41.6%) and a combination of ipilimumab and nivolumab (33.3%). After a median follow-up of 17.7 months, the median overall survival (OS) for the entire cohort was 18.1 months (with a 95% confidence interval ranging from 6.8 to 23.2 months), showing no significant statistical differences in outcomes based on the location of the mucosal melanoma or the type of treatment received. Conclusions: Mucosal melanoma remains an under-researched malignancy. There is a critical need for prospective, randomized trials to explore more effective treatment options for patients with this condition. [Table: see text]

CVM-1118: A potent oral anti-vasculogenic mimicry (VM) agent in combination with nivolumab in patients with unresectable advanced hepatocellular carcinoma (HCC)—A phase IIa study.

e16150 Background: CVM-1118 is a potent anti-tumor new chemical entity with multiple mechanisms of action including induction of apoptosis, cell cycle arrest, and inhibition of VM network formation. This study evaluated the anti-tumor effect and safety profile of CVM-1118 plus nivolumab in patients with progressive unresectable advanced HCC following the first-line therapy with TKIs. Methods: Eligible pts had unresectable advanced HCC and were refractory to prior systemic therapy (e.g., sorafenib, lenvatinib, regorafenib, and/or ramucirumab), with the exception of prior immunotherapy. Patients received oral CVM-1118 at 200 mg BID (400 mg daily) in combination with intravenous nivolumab at 240 mg Q2W in 28-day cycles. The primary endpoint of objective response rate was evaluated using mRECIST. The secondary endpoints were overall response rate (ORR) (per RECIST 1.1), progression free survival (PFS), disease control rate (DCR), and duration of overall response (DoR). Results: A total of 31 evaluable pts were enrolled (25 M/6 F; median age 65 y, range 44–80 y). All patients were Child Pugh A, BCLC stage B (13%, n = 4) or C (87%, n = 27) at the start of treatment. The median number of prior lines of therapy was 1 (range 1–2). The duration of CVM-1118 and nivolumab treatment ranged from 1.5–15.0 mos (median 3.1 mos) with 5/31 (16%) pts remaining on treatment for ≥ 4.6 mos (range 4.67–15.0 mos). The best ORR was 19.4% (mRECIST) (2 CR (6%), 4 PR (13%)), with remaining responses including 11 SD (36%) and 14 PD (45%). The DCR was 54.8% (95% CI 37.3–72.3%), the median PFS was 3.53 mos (95% CI 1.9–5.4 mos) and the median DoR was 10.4 mos (95% CI 2.8–13.7 mos). The most common treatment-related AEs ³ grade 3 included AST increased (12.9%), neutrophil count decreased (9.7%), anemia (6.5%), and WBC decreased (6.5%). As opposed to therapy with atezolizumab plus bevacizumab, gastrointestinal hemorrhage and hypertension were not observed in this study. Pharmacokinetics data demonstrated that CVM-1118 was rapidly metabolized to CVM-1125 in all pts following administration. On Day 1, the mean drug exposure of CVM-1125 was Cmax 564 ng/mL and the AUC0-24 was 2154 ng·hr/mL. Intersubject variability of drug exposure appeared to be high; the T1/2 of CVM-1125 was ~1.7 hr. Conclusions: CVM-1118 combined with nivolumab demonstrated clinical activity in advanced HCC pts with a safety profile that appears favorable compared to atezolizumab plus bevacizumab. These data support further development of the combination of CVM-1118 and nivolumab in pts with unresectable advanced HCC. Clinical trial information: NCT05257590 .