Immune-mediated Adverse Events Research Articles

Abstract PO1-03-10: Differential microbial metabolic pathways associated with resistance to neoadjuvant immunotherapy in locally advanced triple negative breast cancer

Abstract Differential microbial metabolic pathways associated with resistance to neoadjuvant immunotherapy in locally advanced triple negative breast cancer Background: It has previously been shown that microbial metabolic pathways are differentially activated in immunotherapy resistance, hence can serve as potential targets for therapeutic intervention. With the advent of Immune Checkpoint Blockers in the neoadjuvant setting of locally advanced (LA) TNBC, we hypothesized that similar microbial metabolite mediated resistance may be at play. We are presenting the real world data for neoadjuvant treatment in early TNBC along with a subset of tumor metabolite analysis. Method: 35 patients who received neoadjuvant pembrolizumab and chemotherapy for LA TNBC were identified at Moffitt Cancer Center between July 2019 to January 2023. These included 22 Caucasian, 5 African American, 2 Hispanic and 6 patients with undisclosed race. The age range was 33-78 years. The weight and Body Mass Index range was 55.3 kg-127.3 kg and 20.96-45.43 kg/m2 respectively. Nine patients had stage III disease while 24 had stage II breast cancer. The response was assessed in 33 patients; 20 patients (60.6%) achieved pathological complete response (pCR) and 13 (39.4%) had residual disease (RD). 1 patient developed severe immune mediated toxicity with colitis, hepatitis, myasthenia gravis leading to death while 1 patient had disease progression leading to drug discontinuation. Six patients developed immune mediated adverse events. We conducted untargeted metabolomic profiling on 24 patients to identify differentially abundant metabolites associated with pCR (ypT0/is ypN0) vs RD; 16 vs 8 patients respectively. Formalin fixed paraffin embedded (FFPE) slides from tumor tissue vs tumor bed were retrieved and histopathological evaluation of tumor cells was performed. 20 μm sections of FFPE block were used for untargeted metabolomics via liquid chromatography/mass spectrometry. Among the 200 metabolites detected, 63 were differentially abundant between pCR and tumor samples with RD. After correcting for false discovery rate, we observed striking differential activation of two microbial metabolic pathways. Samples with RD had significantly elevated kynurenine (OR-3.64 X1034, P-1.94 X 10-74 and kynurenine/Tryptophan ratio). The tryptophan, kynurenine pathway has been known to be overexpressed in patients resistant to immunotherapy and modulated by the microbiome. Similarly, the purine metabolic pathway, specifically microbiota-derived immunostimulatory metabolites- inosine, hypoxanthine, uric acid were significantly depleted in patients with RD (Inosine OR-0.54, p-0.007, Hypoxanthine OR-0.5, p-0.00039, uric acid OR: 0.41, P-0.003). Previously Inosine has been shown to increase the anti-tumor effects of immune checkpoint blockade by enhancing CD8+ effector T-cell function. Hence depletion of inosine, hypoxanthine and uric acid signals lack of an effector CD8 T cell response. Conclusion: Despite being a small study, it corroborates pCR rates noted in KEYNOTE 522 in the real world setting but shows significant concern for serious immune mediated adverse effects. This highlights the importance of stratifying patients who might be resistant to ICB or develop significant toxicities, thus deriving little to no benefit from standard neoadjuvant treatment. This underscores the need to develop precision-based treatment algorithms. The study represents one of the first investigations of differential abundance of microbial metabolites with immunotherapy resistance in LA TNBC. Our results highlight two microbially mediated mechanisms that could be targeted to improve pCR rates in LA TNBC. We are working to identify microbial metabolic pathways associated with immune mediated toxicity. Citation Format: Humaira Sarfraz, Brian Czerniecki, Zena Jameel, Michael Jaglal, Mostafa Eysha, Turkan Ozkul, Jameel Muzaffar, Aditi Saha, Sara Sarfraz, Fatima Zahra, Min Liu, Khushali Jhaveri, Melissa Sur, Adrianna Bagos-Estevez, Shahla Bari. Differential microbial metabolic pathways associated with resistance to neoadjuvant immunotherapy in locally advanced triple negative breast cancer [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 PO1-03-10.

Abstract PO5-03-11: Ultra-low dose nivolumab added to dose-dense, cisplatin-based neoadjuvant chemotherapy in locally advanced, borderline operable triple negative breast cancer: A matched case-control study

Abstract Background In India, the majority of patients with triple negative breast cancer(TNBC) present with locally advanced and often inoperable disease due to lack of screening, awareness, and social stigma. This makes pathological complete response(pCR) after neoadjuvant chemotherapy(NAC) less likely, leading to early recurrence and poor survival outcomes. Immune checkpoint inhibitors(ICI) in addition to platinum agents have improved both pCR and disease-free survival(DFS). However, these are accessible only to a very small proportion(< 3%) of patients in LMICs due to exorbitant costs. The activity and cost-effectiveness of low dose ICI has been demonstrated in head and neck. The efficacy of low dose ICI in the neoadjuvant setting for TNBC has not been studied. We examined our outcomes with ultra-low dose nivolumab(< 0.6 mg/kg every 2 weeks) added to NAC for locally advanced and borderline operable TNBC. Methods A retrospective analysis of 132 patients with TNBC who received NAC with the ddDCEP regimen(Docetaxel 75mg/m2 and Cyclophosphamide 600 mg/m2 alternating with Epirubicin 90mg/m2 and Cisplatin 60mg/m2 every 2 weeks for 8 cycles) or ddDCEP plus low dose nivolumab(< 0.6mg/kg/2 weeks) and underwent mastectomy at our centre between 2018-2023 was carried out. 105 and 27 patients received ddDCEP alone and ddDCEP + low dose nivolumab respectively. Using rigorous exact matching, 26 matched pairs(52 patients) were obtained based on tumour grade and AJCC TNM stage. pCR in the surgical specimen was the principal outcome assessed. Survival data, adverse events and cost were also analysed. Results The median age of cases and controls was 42 and 40 years respectively. Tumour histology was ductal carcinoma most patients. Across both groups the stage distribution was the same with nearly 85% stage III(IA 3.8%;IIB 7.7%; IIIA 23.1%;IIIB 43.2%;IIIC 19.2%). 92% of cases and 85% of controls had node positive disease. 62% of cases and 46% of controls had T4 disease. At a median follow up of 9 months, there were no recurrences or deaths among the cases. The most common immune mediated adverse event was hypothyroidism seen in 11.5% of cases. The rates of grade 3/4 anaemia, thrombocytopenia and febrile neutropenia were approximately 38%, 10% and 3.8% across cases and controls respectively. The median dose of nivolumab was 0.27mg/kg/2weeks as opposed to the approved dose of 3mg/kg/2weeks for most indications. The range of doses varied from 0.07 to 0.58mg/kg/2weeks. In the overall cohort, the addition of nivolumab did not have any apparent effect on the pCR rates which were identical at 42.3% in both cases and controls. However, there was a positive correlation between the total dose of nivolumab/kg(body weight) and the likelihood of pCR(coefficient 0.34; p-value 0.046). Patients who received higher than the median dose of nivolumab had a significantly higher likelihood of attaining pCR than those who received lower doses (69.2% pCR vs.15.4%;p-value 0.015). The cost of nivolumab at 0.6 mg/kg for 4 doses is approximately USD2000 compared to USD34400 for 8 doses of pembrolizumab in the neoadjuvant component of the KEYNOTE-522 regimen. Conclusion In this cohort with locally advanced/inoperable TNBC, the addition of ultra-low dose nivolumab did not improve pCR overall compared to a matched control set who did not receive ICI. However, in the subset of patients who received between 0.27-0.58 mg/kg/2weeks, the pCR rates were significantly higher at 69%. This presents a promising and cost-effective approach for TNBC management in LMICs. This effect needs verification in larger phase II/III trials. Table. Citation Format: Zachariah Thomas, Josh Georgy, Ashish Singh, Anjana Joel, Divya Thumaty, Ajoy John, Jerryes Wisely, Grace Rebekah, Elanthenral Sigamani, Anish Cherian, Deepak Abraham, Paul Jacob, Rajesh Balakrishnan, Patricia Solomon, Selvamani Backianathan, Raju Chacko. Ultra-low dose nivolumab added to dose-dense, cisplatin-based neoadjuvant chemotherapy in locally advanced, borderline operable triple negative breast cancer: A matched case-control study [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 PO5-03-11.

Nivolumab, Pomalidomide, and Elotuzumab Combination Regimens for Treatment of Relapsed and Refractory Multiple Myeloma: Results from the Phase 3 CheckMate 602 Study

BackgroundPreclinical studies suggest that combining nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor, with pomalidomide/dexamethasone (Pd) with or without elotuzumab, an anti-signaling lymphocytic activation molecule F7 monoclonal antibody, may improve multiple myeloma (MM) treatment efficacy. Patients and MethodsThe phase 3 CheckMate 602 study (NCT02726581) assessed the efficacy and safety of nivolumab plus pomalidomide/dexamethasone (NPd) and NPd plus elotuzumab (NE-Pd). Eligible patients (aged ≥ 18 years) had measurable MM after ≥ 2 prior lines of therapy, that included an immunomodulatory drug (IMiD) and proteasome inhibitor (PI), each for ≥ 2 consecutive cycles, alone or combined, and were refractory to their last line of therapy. Patients were randomized 3:3:1 to receive NPd, Pd, or NE-Pd. The primary endpoint was progression-free survival (PFS); overall response rate (ORR) was a key secondary endpoint. ResultsAt a median follow-up of 16.8 months, PFS was similar between treatment arms (Pd, 7.3 months [95% CI, 6.5–8.4]; NPd, 8.4 months [95% CI, 5.8–12.1]; NE-Pd, 6.3 months [95% CI, 2.4–11.1]). ORR was similar in the Pd (55%), NPd (48%), and NE-Pd (42%) arms. Nivolumab-containing arms were associated with a less favorable safety profile versus Pd, including a higher rate of thrombocytopenia (NPd, 25.0%; NE-Pd, 16.7%; Pd, 15.7%), any-grade immune-mediated adverse events (NPd, 13.9%; NE-Pd, 16.7%; Pd, 2.9%), and adverse events leading to discontinuation (NPd, 25.0%; NE-Pd, 33.3%; Pd, 18.6%). No new safety signals were identified. ConclusionCheckMate 602 did not demonstrate clinical benefit of nivolumab (+/- elotuzumab) plus Pd versus Pd for patients with relapsed/refractory MM (RRMM). MicroAbstractPrior preclinical studies suggest combining nivolumab with pomalidomide/dexamethasone (NPd) +/- elotuzumab (NE-Pd) may increase multiple myeloma (MM) treatment efficacy. In this study, patients with RRMM were randomized 3:3:1 to receive NPd (n=75), Pd (n=71), or NE-Pd (n=24). The three treatment arms had similar PFS, ORR, and OS outcomes. Nivolumab-containing arms were associated with a less favorable safety profile versus Pd.

Pembrolizumab-Induced Pancytopenia: A Case Report

Introduction: Immunotherapy is increasingly acknowledged as an effective treatment for metastatic melanoma. Hematological immune-mediated adverse events are rarely reported. In this article, we report a case of a patient who developed pancytopenia following administration of pembrolizumab. Case Report: A 63 -year-old woman, followed for a scalp melanoma with pulmonary metastasis developed severe pancytopenia after receiving 4 cycles of pembrolizumab. Outcome and Management: Following the appearance of the adverse effect, Pembrolizumab was stopped. A series of blood tests were performed in order to get the reasons of this event. The patient received high-dose of corticosteroids with tapering the dose over 6 weeks, and blood transfusion was required. Discussion: Checkpoint inhibitors (ICI) stimulate both humoral and cellular immune responses against tumor antigens, potentially resulting in immune-related adverse effects, including hematological issues like pancytopenia. Due to the substantial morbidity and mortality linked to ICI-induced pancytopenia, further data is essential to formulate evidence-based management guidelines.

Abstract CT024: A DNA plasmid melanoma cancer vaccine, SCIB1, combined with nivolumab + ipilimumab in patients with advanced unresectable melanoma: Efficacy and safety results from the open-label Phase 2 SCOPE Trial

Abstract Background Targeting melanoma by T cells drives anti-tumor responses. We previously showed that a DNA vaccine, SCIB1, incorporating T cell epitopes from TRP-2/gp100 into an antibody framework to allow Fc targeting of activated dendritic cells, was successfully evaluated as a monotherapy in a phase 1/2 in stage 3/4 melanoma patients. Unresectable melanoma patients showed a 60% ORR and 88% of patients treated with SCIB1 post tumor resection, remained disease free for 5 years [1]. The current SCOPE trial tests the hypothesis that unresectable patients may have an improved response when SCIB1 is combined with checkpoint inhibitors (CPI). Methods Patients were treated with nivolumab with ipilimumab and SCIB1 (8mg) i.m. using needle-free injection at a fixed dosing schedule for a total of 10 doses over 24 months. The CPI therapy was administered i.v. in accordance with their respective SmPC. ORR as measured by RECIST 1.1 in the overall intention-to-treat population was the primary endpoint. The study is designed using Simon's two stage methodology with 80% power when the true response rate is 70% with an overall type I error of 5%. In the first stage, 15 patients will be enrolled and if there are eight or fewer clinical responses (RECIST 1.1 objective response [CR or PR] within 25 weeks of the first dose of SCIB1), further recruitment will be stopped. The null hypothesis will be rejected if 27 or more responses are observed in 43 patients. Results 19 patients received the combination of SCIB1 with nivolumab and ipilimumab. At study entry, all patients were stage IV. 13 patients had reached the first imaging timepoint at 13 weeks, and the objective response rate is 85%. 9/9 responses were confirmed in a subsequent scan. Patients showed a 40-95% reduction in tumor volume between 13 and 25 weeks. Most of the SCIB1-related adverse events were Grade 1/2. Only 1 patient reported a Grade 3 rash. No enhancement of immune-mediated adverse events was observed when SCIB1 was added to nivolumab with ipilimumab. Conclusions SCIB1 in combination with nivolumab and ipilimumab as first line treatment for unresectable melanoma improved the ORR to 85% without an increase in clinically meaningful adverse events. These results if confirmed in a larger patient cohort provide confidence in initiating a randomized registration program in unresectable melanoma patients with the novel DNA plasmid technology Citation Format: Heather Shaw, Poulam Patel, Miranda Payne, Satish Kumar, Martin Highley, Kellati Prasad, Ruth Board, Clare Barlow, Sarah Danson, Robert Miller, Georgia Goodhew, Fayaz Master, Lindy Durrant. A DNA plasmid melanoma cancer vaccine, SCIB1, combined with nivolumab + ipilimumab in patients with advanced unresectable melanoma: Efficacy and safety results from the open-label Phase 2 SCOPE Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT024.

Real-World Multicenter Study of PD-1 Blockade in HIV-Associated Classical Hodgkin Lymphoma Across the United States

BackgroundDespite a higher risk of classical Hodgkin lymphoma (cHL) in people with HIV and the demonstrated safety and efficacy of PD-1 blockade in cHL, there are limited data on the use of these agents in HIV-associated cHL (HIV-cHL). Patients/MethodsWe retrospectively identified patients with HIV-cHL from the “Cancer Therapy using Checkpoint inhibitors in People with HIV-International (CATCH-IT)” database who received nivolumab or pembrolizumab, alone or in combination with other agents, and reviewed records for demographics, disease characteristics, immune-mediated adverse events (imAEs), and treatment outcomes. Changes in CD4+ T-cell counts with treatment were measured via Wilcoxon signed-rank tests. Overall response rate (ORR) was defined as the proportion of patients with partial or complete response (PR/CR) per 2014 Lugano classification. ResultsWe identified 23 patients with HIV-cHL who received a median of 6 cycles of PD-1 blockade: 1 as 1st-line, 6 as 2nd-line, and 16 as ≥3rd-line therapy. Seventeen (74%) patients received monotherapy, 5 (22%) received nivolumab plus brentuximab vedotin, and 1 received nivolumab plus ifosfamide, carboplatin, and etoposide. The median baseline CD4+ T-cell count was 155 cells/µL, which increased to 310 cells/µL at end-of-treatment (P = .009). Three patients had grade 3 imAEs; none required treatment discontinuation. The ORR was 83% with median duration of response of 19.7 months. The median progression-free survival was 21.2 months and did not differ between patients with <200 versus ≥200 CD4+ cells/µL (P = .95). ConclusionOur findings support the use of PD-1 blockade in HIV-cHL for the same indications as the general population with cHL.

Body mass index as a possible predictor of the development of endocrine immune-mediated adverse events during immune checkpoint inhibitors therapy

BACKGROUND: Overweight and obesity have a significant impact on the course and results of treatment of many diseases, including cancer. One of the modern types of antitumor therapy is immune checkpoint inhibitors. Taking into account the high effectiveness of immune checkpoint inhibitors for various types of tumors, it seems interesting to study the initial anthropometric data of patients and assess the possible influence of nutritional status on the development of endocrine immune-mediated adverse events.AIM: To compare groups of patients with different starting body mass index (BMI) before the first administration of the immune checkpoint inhibitors drug and analyze the risk of developing endocrine immune-mediated adverse events in the future.MATERIALS AND METHODS: The single-center study included 172 patients who were recommended antitumor therapy immune checkpoint inhibitors at the N.N. Blokhin National Medical Research Center of Oncology and Moscow City Oncology Hospital №62 in 2020–2022. Measurement of height and body weight with further calculation of BMI was carried out before the first administration of the drug immune checkpoint inhibitors.Depending on the subsequent occurrence of immune-mediated adverse events, patients were divided into groups: those with developed immune-mediated adverse events (any, cutaneous, thyroid) and those without immune-mediated adverse events (any, cutaneous, thyroid).RESULTS: According to the results of our study, in 38 patients (37.3%) out of 102, for whom data on the presence/absence of any immune-mediated adverse events were obtained, the following were recorded: thyropathies (n=13, 12.7%), skin lesions (n=13, 12.7%), gastrointestinal toxicity (n=7, 6.9%), hepatotoxicity (n=4, 3.9%), hypophysitis (n=2, 2%), nephritis (n=2, 2%), diabetes mellitus (DM) (n=1, 1%), hematological toxicity (n=1, 1%), pneumonitis (n=1, 1%), Guillain-Barré syndrome (n=1, 1%). At the same time, in most patients only one immune-mediated adverse event was encountered (n=31, 81.6%), two immune-mediated adverse events were detected significantly less frequently (n=7, 18.4%).When conducting a comparative analysis of groups of patients with developed immune-mediated adverse events, including dermatological ones, or their absence, a statistical trend in differences in BMI was obtained. Using ROC analysis, a BMI cut-off point was determined equal to 28.16 kg/m² for all immune-mediated adverse events and 25.39 kg/m² for skin immune-mediated adverse events, below which, contrary to the available data, the risk of developing immune-mediated adverse events increased, but the diagnostic sensitivity (DS) and diagnostic specificity (DS) turned out to be low.CONCLUSION: We identified a statistical trend in the risk of developing immune-mediated adverse events (primarily dermatological) with a lower BMI before the start of antitumor immunotherapy immune checkpoint inhibitors. More research is required to find a more reliable relationship.

Low-dose Paclitaxel with Pembrolizumab Enhances Clinical and Immunologic Responses in Platinum-refractory Urothelial Carcinoma.

Single-agent checkpoint inhibition is effective in a minority of patients with platinum-refractory urothelial carcinoma; therefore, the efficacy of combining low-dose paclitaxel with pembrolizumab was tested. This was a prospective, single-arm phase II trial with key inclusion criteria of imaging progression within 12 months of platinum therapy and Eastern Cooperative Oncology Group ≤1. Treatment was pembrolizumab 200 mg day 1 and paclitaxel 80 mg/m2 days 1 and 8 of a 21-day cycle for up to eight cycles unless progression or unacceptable adverse events (AE). The primary endpoint was overall response rate (ORR) with overall survival (OS), 6-month progression-free survival (PFS), and safety as key secondary endpoints. Change in circulating immune cell populations, plasma, and urinary miRs were evaluated. Twenty-seven patients were treated between April 2016 and June 2020, with median follow-up of 12.4 months. Baseline median age was 68 years, with 81% men and 78% non-Hispanic White. ORR was 33% by intention to treat and 36% in imaging-evaluable patients with three complete responses. Six-month PFS rate was 48.1% [95% confidence interval (CI): 28.7-65.2] and median OS 12.4 months (95% CI: 8.7 months to not reached). Common ≥ grade 2 possibly-related AEs were anemia, lymphopenia, hyperglycemia, and fatigue; grade 3/4 AEs occurred in 56%, including two immune-mediated AEs (pneumonitis and nephritis). Responding patients had a higher percentage of circulating CD4+IFNγ+ T cells. Levels of some miRs, including plasma miR 181 and miR 223, varied in responders compared with nonresponders. The addition of low-dose paclitaxel to pembrolizumab is active and safe in platinum-refractory urothelial carcinoma. We found that combining pembrolizumab with low-dose paclitaxel may be effective in patients with urothelial carcinoma progressing on platinum chemotherapy, with favorable safety profiles.

Immune checkpoint inhibitors and risk of immune-mediated adverse events: a cohort study comparing extended versus standard interval administration

The COVID-19 pandemic precipitated the implementation of extended interval immune checkpoint inhibitors (ICIs) in an effort to limit hospital visits, but few studies have examined their safety. This study aimed to compare in oncology outpatients, immune-mediated adverse events (IMAEs) in terms of total number, incidence, severity, and time to occurrence, based on exposure to standard or extended interval ICIs. A retrospective cohort study was conducted in patients who received at least one dose of an ICI between 2015 and 2021. Data were collected from patient records and pharmacy software. Adjusted logistic, Poisson, and Cox regression models were estimated. A total of 310 patients with a mean age of 67.1 years were included, 130 of whom had the extended interval. No statistically significant differences were observed between the groups. With the standard and extended intervals, the mean total number of IMAE per participant was 1.02 and 1.18, respectively; the incidence of an IMAE was 62% and 64%. Of the 147 IMAE episodes in the standard interval group, 14 (9.5%) were grade 3 or higher, while there were 15 (12.4%) among the 121 IMAE episodes in the extended interval group. Compared with standard interval, the use of extended interval did not increase the risk of having a first IMAE (adjusted hazard ratio 0.92 (95% CI 0.67–1.26)). This study suggests that the administration of an ICI according to extended interval is as safe as the administration according to standard interval in oncology outpatients.

Atezolizumab Plus Carboplatin and Etoposide in Patients with Untreated Extensive-Stage Small-Cell Lung Cancer: Interim Results of the MAURIS Phase IIIb Trial.

MAURIS is an Italian multicenter, open-label, phase IIIb ongoing trial, aiming at evaluating the safety and effectiveness of atezolizumab + carboplatin/etoposide in patients with newly diagnosed, extensive-stage small-cell lung cancer (ES-SCLC). The primary objective is the safety evaluation. Patients received atezolizumab + carboplatin/etoposide Q3W for 4-6 cycles in the induction phase, followed by atezolizumab maintenance Q3W. We presented the interim analysis on safety (referring to the induction phase) and clinical effectiveness, in all patients (N = 154) and in subgroups that received ≤3 (N = 23), 4 (N = 43), and 5-6 cycles (N = 89) of induction. At a median follow-up of 10.5 months, 139 patients (90.3%) discontinued treatment. Serious adverse events occurred in 29.9% of patients overall, and the rate was lower in patients with 5-6 cycles (19.1%) than in those with 4 (34.9%) or ≤3 (63.6%) cycles. Immune-mediated adverse events were reported in 14.9%, 15.7%, 11.6%, and 18.2% of patients, overall and by subgroup, respectively. The median overall survival and progression-free survival were 10.7 and 5.5 months, respectively. Overall, 111 patients (71.6%) had a tumor response. Interim results provide further evidences about safety and efficacy profile of atezolizumab + carboplatin/etoposide treatment in a ES-SCLC patient population closer to that observed in clinical practice. Eudract No. 2019-001146-17, NCT04028050.

Clinical and Real-World Effectiveness of Mogamulizumab: A Narrative Review.

Mogamulizumab (MOG) is an antibody targeting the CCR4 receptor, authorized for relapsed or refractory peripheral T-cell (PTCL) and cutaneous T-cell lymphomas (CTCL). Its adoption in guidelines and endorsement by FDA and EMA established it as a systemic treatment, especially for advanced disease stages due to its comparatively lower toxicity. Clinical trials and real-world evidence have underscored its efficacy in advanced CTCLs, including mycosis fungoides and Sézary syndrome; PTCLs; and adult T-cell leukemia/lymphoma (ATLL), showcasing positive outcomes. Notably, the drug has demonstrated significant response rates, disease stability, and extended periods of progression-free survival, suggesting its applicability in cases with multiple treatment lines. Its safety profile is generally manageable, with adverse events (AEs) primarily related to the skin, infusion-related reactions, drug eruptions, autoimmune diseases, and skin disorders. The latter seem to appear as CCR4 can promote the skin-specific homing of lymphocytes, and MOG is directed against this receptor. While combination with immunostimulatory agents like interferon alpha and interleukin 12 has shown promising results, caution is urged when combining with PD1 inhibitors due to the heightened risk of immune-mediated AEs. The introduction of MOG as a systemic treatment implies a significant advancement in managing these diseases, supported by its favorable safety profile and complementary mechanisms.

ZSAB-TOP: A phase 2 trial of tislelizumab (TIS) and ociperlimab (OCI) combined with gemcitabine and cisplatin (GemCis) as the first-line treatment for advanced biliary tract cancer (BTC).

475 Background: GemCis has long been the standard-of-care for advanced BTC, however the prognosis remains poor. Combinations with immunotherapy and GemCis are being explored in BTC. This study aimed to evaluate the efficacy and safety of TIS (an anti-PD-1 antibody) and OCI (a TIGIT inhibitor) combined with GemCis as the first-line treatment for advanced BTC. Herein, the primary analysis results of this study were reported. Methods: In this open-label, single-arm, multicenter phase 2 study, systematic treatment-naïve pts with unresectable advanced BTC received TIS (200 mg, day1, Q3W), OCI (900 mg, day1, Q3W), and GemCis (Gem 1000 mg/m2 and Cis 25 mg/m2 on days 1 and 8 Q3W, up to 8 cycles). The primary endpoint was investigator-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. A binomial exact test with a one-sided α of 0.05 was performed in the analysis of the primary endpoint to test the historical ORR of 25% with GemCis. If p≤0.05, the statistical superiority of the study treatment would be claimed. Results: A total of 45 pts were enrolled, with 75.6% having intrahepatic cholangiocarcinoma and 60.0% metastatic disease. As of 24 Aug 2023 (median follow-up, 8.0 months), 24.4% (11/45) pts remained on study treatment. Among the 41 pts in efficacy analysis set, confirmed ORR (cORR) was 48.8% (20/41, 95% CI, 32.9-64.9, p=0.0009), with 1 complete response. The statistical superiority was achieved. The subgroups of TIGIT+ pts tended to have numerically higher cORR (Table). Median PFS was 7.7 months, with 6-month PFS rate of 67.6%. Median OS was not reached, and 6-month OS rate was 86.2%. Grade ≥3 treatment-related adverse events rate was 60% (27/45). Immune-mediated adverse events rate was 37.8% (17/45), which were mostly grade 1 and 2. Conclusions: The combination of TIS and OCI plus GemCis showed promising anti-tumor activity with manageable safety as the first-line treatment for advanced BTC. Clinical trial information: NCT05023109 . [Table: see text]

Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study

Checkpoint inhibitors are standard adjuvant treatment for stage IIB-IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma. We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB-IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881. From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309-1·017]; two-sided p=0·053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69·0-85·6) versus 62% (46·9-74·3). Most treatment-related adverse events were grade 1-2. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4-5 events. Immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups. Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting. Moderna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Efficacy and safety of nurulimab+prolgolimab with continued prolgolimab therapy compared to prolgolimab alone as first-line therapy in patients with unresectable or metastatic melanoma: final results of the phase II OBERTON clinical study

Background. In an era of breakthroughs in cancer immunotherapy, CheckMate 067 studies declared the combination of PD-1 and CTLA-4 inhibitors a new standard of care for patients with metastatic melanoma (MM). A significant limitation of the widespread use of the combination of ipilimumab and nivolumab in routine clinical practice is the high risk of severe immune-mediated adverse events. Prolgolimab and nurulimab are a combination of fixed doses of original monoclonal antibodies (manufactured by JSC "BIOCAD," Russia) to the PD-1 receptor (prolgolimab) and the CTLA-4 receptor (nurulimab) (3:1 ratio). This paper presents the results of an international, multicenter, double-blind, placebo-controlled, comparative, randomized, phase II OBERTON clinical study to investigate the efficacy and safety of nurulimab + prolgolimab combination therapy with continued prolgolimab therapy compared to prolgolimab alone as first-line therapy in patients with unresectable melanoma (uRM) or MM (NCT03913923).&#x0D; Materials and methods. The study included patients with uRM or MM who were not previously treated for metastatic disease. The patients were randomized into two groups (1:1). Patients in group 1 were treated with a nurulimab (1 mg/kg) and prolgolimab (3 mg/kg) combination at a dose of 0.2 mL/kg (equivalent to 1 mg/kg of nurulimab and 3 mg/kg of prolgolimab) once every 3 weeks during the first 4 blinded infusions. Patients in group 2 received prolgolimab monotherapy at a dose of 3 mg/kg once every 3 weeks during the first 4 blinded infusions. Starting from infusion 5, patients in both groups received open prolgolimab 1 mg/kg once every 2 weeks. The primary endpoint of the study was progression-free survival (PFS). The study is registered on ClinicalTrials.gov under the number NCT05732805 and is currently ongoing, but recruitment of new patients has been completed.&#x0D; Results. One hundred seventeen patients were randomized and received at least one dose of the study therapy. At a median follow-up of 16.79 months, the median PFS was 12.2 (4.9; not achieved) months in the nurulimab + prolgolimab group and 2.8 (1.5; 4.7) months in the prolgolimab monotherapy group (95% confidence interval 0.36-0.90, hazard ratio 0.57). PFS at 24 months was 41% in the nurulimab + prolgolimab group and 25.4% in the prolgolimab monotherapy group. In both groups, the therapy was well tolerated. Grade 3-4 immune-mediated adverse events were reported in 15.5% of patients who received nurulimab + prolgolimab, compared with 1.7% of those who received prolgolimab alone. The most frequent grade 3-4 treatment-related adverse events in both treatment groups were increased alanine aminotransferase and aspartate aminotransferase and asthenia. Overall, the safety profile was favorable, as expected for the class of immune checkpoint inhibitors, anti-CTLA-4, and anti-PD-1 monoclonal antibodies.&#x0D; Discussion. The results demonstrate a favorable safety profile in both the nurulimab + prolgolimab combination and prolgolimab monotherapy groups as the first-line treatment for uRM or MM. The assessment of the primary endpoint, PFS, showed the benefit of combination immunotherapy followed by switching to prolgolimab compared to prolgolimab alone.&#x0D; Conclusion. Combination immunotherapy with the CTLA-4 inhibitor nurulimab and the PD-1 inhibitor prolgolimab, available as a combination of solutions of two drugs in a single vial, with a further switch to monotherapy with prolgolimab, can fill an important niche in the treatment of patients with uRM or MM. Confirmation of the obtained data on the efficacy and safety of the combined regimen of nurulimab + prolgolimab in comparison with PD-1 inhibitor monotherapy is expected from the ongoing phase III BCD-217-2 OCTAVA study (NCT05732805).

The safety and efficacy of tislelizumab, alone or in combination with chemotherapy, for the treatment of non-small cell lung cancer: a systematic review of clinical trials

BackgroundTislelizumab is an anti-programmed death-1 (PD-1) monoclonal antibody with a construction that enables it to have a higher affinity to its target. We aimed to evaluate tislelizumab’s safety and efficacy for treating non-small cell lung cancer (NSCLC).MethodsEmbase, Scopus, PubMed, Web of Science, and Google Scholar were searched up to December 20, 2022. The review only included randomized controlled trials (RCTs) that evaluated the safety or efficacy of tislelizumab for treating patients with lung cancer. The revised Cochrane risk-of-bias tool (RoB2) was utilized to evaluate study quality.ResultsThere were four RCTs identified, which included 1565 patients with confirmed locally advanced or metastatic squamous and/or non-squamous types of NSCLC. Treatment with tislelizumab was associated with better progression-free survival (PFS) and objective response rate (ORR), particularly when used in combination with chemotherapy. Almost all patients in both arms reported at least one treatment-emergent adverse event (TEAE). Decreased hematologic indexes accounted for more than 20% of the grade ≥ 3 TEAEs in the tislelizumab plus chemotherapy group. The proportion of TEAE that led to death in the tislelizumab plus chemotherapy arms ranged from 3.2 to 4.2%. Hypothyroidism, pneumonitis, and hyperglycemia were the most frequently noted immune-mediated adverse events in the tislelizumab group.ConclusionsTislelizumab, whether used alone or in combination with chemotherapy, seems to demonstrate both a safety and efficacy as a treatment for NSCLC.

Gut Microbiota Is Associated with Onset and Severity of Type 1 Diabetes in Nonobese Diabetic Mice Treated with Anti-PD-1.

Our bodies are home to individual-specific microbial ecosystems that have recently been found to be modified by cancer immunotherapies. The interaction between the gut microbiome and islet autoimmunity leading to type I diabetes (T1D) is well described and highlights the microbiome contribution during the onset and T1D development in animals and humans. As cancer immunotherapies induce gut microbiome perturbations and immune-mediated adverse events in susceptible patients, we hypothesized that NOD mice can be used as a predictive tool to investigate the effects of anti-PD-1 treatment on the onset and severity of T1D, and how microbiota influences immunopathology. In this longitudinal study, we showed that anti-PD-1 accelerated T1D onset, increased glutamic acid decarboxylase-reactive T cell frequency in spleen, and precipitated destruction of β cells, triggering high glucose levels and pancreatic islet reduction. Anti-PD-1 treatment also resulted in temporal microbiota changes and lower diversity characteristic of T1D. Finally, we identified known insulin-resistance regulating bacteria that were negatively correlated with glucose levels, indicating that anti-PD-1 treatment impacts the early gut microbiota composition. Moreover, an increase of mucin-degrading Akkermansia muciniphila points to alterations of barrier function and immune system activation. These results highlight the ability of microbiota to readily respond to therapy-triggered pathophysiological changes as rescuers (Bacteroides acidifaciens and Parabacteroides goldsteinii) or potential exacerbators (A. muciniphila). Microbiome-modulating interventions may thus be promising mitigation strategies for immunotherapies with high risk of immune-mediated adverse events.

Efficacy and Safety of Pembrolizumab and Chemotherapy in Newly-Diagnosed, Early Unfavorable or Advanced Classic Hodgkin Lymphoma: The Phase 2 Keynote-C11 Study

Introduction: The phase 2 KEYNOTE-C11 study (NCT05008224) evaluates the safety and efficacy of pembrolizumab (pembro) followed by AVD chemotherapy (chemotherapy) and pembro consolidation in patients with untreated, early unfavorable or advanced-stage cHL without radiotherapy. The criteria for study continuation were met at the pre-specified interim futility analysis after pembrolizumab induction and 2 cycles of AVD, with approximately 3 months of follow-up. We present results of an analysis of efficacy and safety in all enrolled patients with an additional 8 months of follow-up. Methods: Patients aged ≥18 years with newly-diagnosed, early unfavorable or advanced stage cHL, received induction with pembrolizumab 200 mg IV on d1 Q3W for 3 cycles, followed by a PET2 to determine response. All patients then received 2 cycles standard dose AVD on d1 and 15 for 2 cycles (chemotherapy phase 1) followed by PET3. Patients who were PET3-negative (Deauville score 1-3) received 2-4 additional cycles AVD based on bulk. Patients aged ≤60 years who were PET3-positive (Deauville score 4-5) received 2-4 cycles of escalated bleomycin plus etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (escBEACOPP, chemotherapy phase 2). All patients then received consolidation pembrolizumab 400 mg Q6W for 4 cycles followed by a PET4 assessment. The primary endpoint for this analysis was investigator assessed PET3-negativity response in all treated patients. A posthoc PET analysis was also performed in the actuarial population of all treated patients who reached PET2 or PET3. Results: At data cut-off (Apr 5, 2023), the median (range) follow-up was 11.8 months (9.7-17.6). A total of 146 patients with untreated cHL were enrolled. Median (range) age was 34.5 years (18-78); 32 (22%) patients had bulky disease, 84 (57%) and 62 (43%), respectively, had advanced and early unfavorable disease. Of 146 patients, 137 (94%) had completed pembrolizumab monotherapy, 130 of 136 (96%) who proceeded to chemotherapy phase 1 completed chemotherapy phase 1, and 127 of 130 (98%) completed chemotherapy phase 2 (111 [AVD]; 16 [BEACOPP]). The PET2-negativity rate was 29% and 31% in all treated patients (N=146) and the actuarial population (n=137), respectively. The PET3-negativity rate was 70% and 78% in all treated patients (N=146) and the actuarial population (n=131), respectively. The ORR at end of PET2 and PET3 was 78% and 88%, respectively. Grade ≥3 drug related adverse events (AEs) were reported in 23 of 146 (16%) patients who received pembrolizumab alone or at consolidation, 94 of 136 (69%) patients who received AVD, and in 10 of 17 (59%) patients who received escBEACOPP. Immune mediated AEs were reported in 37 (25%) patients who received pembrolizumab alone and consolidation, most commonly hyperthyroidism (10%) and hypothyroidism (6%). There were no deaths due to study drug related or immune-mediated AEs. Conclusion: Pembrolizumab induction followed by chemotherapy continued to be well tolerated in patients with newly-diagnosed, early unfavorable, or advanced-stage cHL, with 70% achieving a PET3-negative response as assessed by investigator after the initial chemotherapy phase. There were no new safety concerns and study is ongoing.

Safety and Preliminary Efficacy of Sabestomig (AZD7789), an Anti-PD-1 and Anti-TIM-3 Bispecific Antibody, in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma Previously Treated with Anti-PD-(L)1 Therapy

Background Immunotherapies targeting the PD-1/PD-L1 pathway have been shown to induce high response rates in patients with relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). However, most responses are partial and not durable. T cell immunoglobulin and mucin domain-containing protein-3 (TIM-3) is implicated as a resistance mechanism following anti-PD-1 therapy, and increased TIM-3 expression has been observed on T cells of patients with cHL post anti-PD-1 therapy. Therefore, we hypothesized that dual targeting of PD-1 and TIM-3 may reinvigorate immune responses and lead to more durable antitumor activity. Sabestomig is a monovalent, bispecific, humanized IgG1 monoclonal antibody that binds PD-1 and a unique epitope in the TIM-3 IgV domain without blocking phosphatidylserine binding, eliciting differential functionality. In preclinical mouse models, sabestomig was more effective at inhibiting growth of solid tumors than treatment targeting only PD-1, and sequential sabestomig after anti-PD-1 therapy increased antitumor responses. Here we report preliminary data from the ongoing dose escalation portion of a Phase I/II, open-label, multicenter study to assess the safety and preliminary efficacy of sabestomig in patients with r/r cHL (NCT05216835). Methods Eligible patients are aged ≥16 years with r/r cHL, an Eastern Cooperative Oncology Group performance status 0-1, at least one positron emission tomography-avid measurable lesion according to modified Lugano Criteria, and exposure to at least 2 prior lines of systemic therapy including a minimum of 3 cycles of an anti-PD-(L)1-based therapy. Sabestomig is intravenously infused over 1 hour following pretreatment with diphenhydramine and acetaminophen every 3 weeks, with planned doses ranging from 2 to 2000 mg across 8 cohorts (A1-A8); cohorts A1 to A4 (2, 7, 22.5 or 75 mg) follow an accelerated titration design with a single patient treated at each dose level, while cohorts A5 to A8 (225-2000 mg) follow a modified toxicity probability interval-2 algorithm. The primary endpoint of the dose escalation part of the study is safety, including dose-limiting toxicities (DLTs). Secondary endpoints include efficacy, pharmacokinetics, and immunogenicity. Data cutoffs were May 17, 2023 for safety and June 20, 2023 for efficacy. Results As of May 17, 2023, 14 patients were treated across the first 6 cohorts (A1-A6; 2-750 mg). They were predominantly male (64.3%) with Stage IV disease (85.7%) and a median age of 41.5 years (range, 25-77). Patients received a median of 6 prior lines of therapy (range, 3-13). Baseline disease characteristics are summarized in Table 1. Four patients received sabestomig 2-75 mg in cohorts A1-A4 (n=1 each), 5 patients received 225 mg in cohort A5, and 5 patients received 750 mg in cohort A6. Median duration of exposure to sabestomig was 8.9 weeks (range, 3.0-34.3) with a median of 3 cycles received (range 1-12). Sabestomig was well tolerated with no Grade ≥3 treatment-related adverse events (AEs) (Table 2). One Grade ≥3 AE occurred, which was fatal (sepsis secondary to gastric ulcer rupture, not related to sabestomig but deemed a DLT by the safety review committee). No immune-mediated AEs were reported, and no AEs led to treatment discontinuation. At the safety data cutoff, treatment was ongoing for 6 patients (42.9%). As of June 20, 2023, 11 patients had their first disease assessment and 4/11 had an objective response based on modified Lugano Criteria: 1 patient in cohort A3 (22.5 mg, a partial response [PR]) and all 3 patients who had their first disease assessment in cohort A6 (750 mg, 2 CRs and 1 PR). Two of these 4 responders (both in cohort A6) had experienced a best overall response of progressive disease during prior anti-PD-1 therapy; the other two initially had a response (1 CR [cohort A6] and 1 PR [cohort A3]) but subsequently progressed on anti-PD-1 therapy. Sustained PD-1 receptor occupancy (≥90%) was observed in peripheral blood at doses ≥225 mg. Conclusions Sabestomig was well tolerated with a manageable safety profile. Early efficacy data at 750 mg is encouraging with objective responses in 3/3 patients who had their first disease assessment, including those who were anti-PD-1 refractory or who relapsed on treatment. Updated data will be presented from ongoing and subsequent patients treated during dose escalation with doses of up to 2000 mg.

Keynote-B68: Updated Efficacy and Safety of Pembrolizumab Every Six Weeks in Relapsed/Refractory Classical Hodgkin Lymphoma or Primary Mediastinal B-Cell Lymphoma

Background: Pembrolizumab 200 mg Q3W demonstrated robust antitumor activity and manageable safety in relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) and R/R primary mediastinal B-cell lymphoma (PMBCL), resulting in FDA approval. Recently, the FDA granted accelerated approval of pembrolizumab 400 mg Q6W in all approved indications based on data in solid tumors. The global Phase 2 KEYNOTE-B68 trial (NCT04875195) evaluates the efficacy and safety of pembrolizumab 400 mg Q6W in patients (pts) with R/R cHL or R/R PMBCL. We previously reported ORR of 65% for pts with R/R cHL, and 50% for pts with R/R PMBCL with approximately 9 months (mo) of follow up. Here we present data from 66 patients (pts) with an additional 6 mo of follow up. Methods: In this nonrandomized, open-label trial, pts aged ≥18 years with PD-1 inhibitor naïve R/R cHL or PMBCL received 400 mg pembrolizumab Q6W for ≤ 18 cycles, until progression, unacceptable toxicity, or withdrawal. Eligible pts with cHL must have relapsed or failed to respond after ≥1 prior lines of therapy or relapsed or failed to respond after ≥1 prior multiagent lines of therapy, or autologous stem cell transplant (ASCT). Eligible pts with PMBCL must have relapsed or failed to respond after ≥2 prior lines of therapy including rituximab and relapsed or failed to respond to or were ineligible for ASCT. The primary endpoint was ORR per Lugano criteria by investigator. Secondary endpoints were DOR per Lugano criteria by investigator and safety. Exploratory endpoints were PFS per Lugano criteria by investigator and OS. Data cut-off date was May 15, 2023. Results: At data cut-off, 66 pts (60 R/R cHL, 6 R/R PMBCL) were enrolled. Pts had a median age of 32.5 years (range, 19 to 85), and 35 (53%) were female. Overall, 47 (71%) pts discontinued treatment, 34 (52%) due to progressive disease, 8 (12%) due to ASCT, 2 (3%) due to adverse events (AE), 2 (3%) withdrawals and 1 (2%) due to physician decision. A total of 57 pts with cHL and 5 with PMBCL had ≥2 prior lines of therapy. The median follow-up was 15.7 mo (range, 7.8 -22.7) for pts with R/R cHL and 17.5 mo (range, 12.0 - 22.2) with R/R PMBCL. The ORR was 66.7% (95% CI, 53.3 -78.3 [35.0% CR; 31.7% PR]) for pts with R/R cHL, and 50% (95% CI, 11.8 -88.2 [33.3% CR; 16.7% PR]) for R/R PMBCL. The median DOR was 16.6 mo (range, 1.6 -17.0) for pts with R/R cHL and 9.7 mo (range, 2.6 -9.7) for R/R PMBCL. Treatment-related AEs occurred in 26 pts with R/R cHL and 2 with R/R PMBCL. The most common treatment-related AEs were hypothyroidism in 8 pts with R/R cHL and 1 with R/R PMBCL, and neutropenia in 3 pts with R/R cHL and 1 with R/R PMBCL. Grade ≥3 treatment-related AEs occurred in 3 (5%) pts with R/R cHL and 1 (17%) with R/R PMBCL. No grade 5 treatment-related AE occurred. Immune-mediated AEs occurred in 14 (23%) pts with R/R cHL and 1 (17%) with R/R PMBCL. Grade 3 infusion-related reactions and immune-mediated AE of toxic epidermal necrolysis occurred in 2 (3%) pts and 1 (2%) pt, respectively, with R/R cHL. No grade 4-5 immune-mediated AEs occurred in pts with R/R cHL and no grade ≥3 immune-mediated AEs occurred in pts with R/R PMBCL. Antitumor activity is summarized in the Table. Conclusions: Following 15 months of follow-up the ORR and PFS rates in the cHL patient population have increased, further highlighting the consistency to pembrolizumab 200 mg Q3W as observed in KN-087 and KN-204 patient populations. Additionally, no new safety concerns occurred in either cHL or PMBCL patient populations. This KEYNOTE-B68 trial further demonstrates the continued antitumor activity in patients and confirms the acceptability of Q6W dosing in heme indications.

Brentuximab Vedotin, Nivolumab, Doxorubicin, and Dacarbazine for Advanced Stage Classical Hodgkin Lymphoma: Efficacy and Safety Results from the Single Arm Phase 2 Study

Introduction: Brentuximab vedotin (BV) is an antibody-drug conjugate approved for multiple cancer types, including previously untreated stage III or IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine (AVD) in adults. The combination of BV and nivolumab are both individually active and well tolerated in patients with cHL and have distinct and complementary mechanisms of action. BV and nivolumab have been previously studied in combination and with multiagent chemotherapy as BV+AD (omitting vinblastine) and N+AVD. It was hypothesized that the combination of BV and nivolumab with doxorubicin and dacarbazine (AN+AD) would result in high response rates and a well-tolerated safety profile with potentially less toxicity than vinblastine-containing regimens. SGN35-027 (NCT03646123; EudraCT Number 2020-004027-17; Part B) is an open-label, multiple-part, multicenter, phase 2 clinical trial. Preliminary results of this study showed promising efficacy (objective response rate [ORR] 93%; complete response [CR] rate 88% at end of therapy [EOT]) with no cases of febrile neutropenia or grade 5 adverse events (AEs) (Lee ASCO 2022). Of the patients with stage III or IV cHL who relapse, most will relapse within 18 to 24 months of treatment initiation. Methods: Part B enrolled patients with stage II bulky mediastinal disease (≥10 cm), stage III, or stage IV cHL. Patients received up to 6 cycles of AN+AD (BV 1.2 mg/kg [A], nivolumab 240 mg [N], doxorubicin 25 mg/m 2 [A], and dacarbazine 375 mg/m 2 [D]). The primary efficacy endpoint was CR rate at EOT. Key secondary endpoints included safety and tolerability, ORR, duration of response (DOR), duration of complete response (DOCR), and progression-free survival (PFS). Disease response and progression were assessed by investigator using Lugano Classification Revised Staging System for malignant lymphoma, incorporating Lymphoma Response to Immunomodulatory Therapy Criteria for nodal non-Hodgkin and Hodgkin lymphomas. Results: Fifty-eight patients were enrolled; all but 1 patient received ≥1 dose of study drug (data cutoff 22 May 2023). Median age was 35 years (range, 19-78 years). Among efficacy evaluable patients (n = 56), ORR (CR+ PR) at EOT was 95% (95% CI: 85.1, 98.9); CR rate was 89% (95% CI: 78.1, 96.0) (Table 1). A total of 88.3% (95% CI: 75.7, 94.6) of responders had a DOR of at least 24 months, and 88.4% (95% CI: 76.0, 95.0) of responders had a DOCR of at least 24 months. Seven patients (12%) had a PFS event: 6 with disease progression and 1 who died (sepsis, outside safety reporting period). The estimated PFS rate at 24 months was 88.3% (95% CI: 75.7, 94.6) (Figure 1). Median follow-up was 24.2 months (95% CI: 23.4, 26.9). The most common treatment-related AEs of any grade were nausea (37 patients [65%]), fatigue (28 patients [49%]), and peripheral sensory neuropathy (25 patients [44%]). Of the patients with treatment-related peripheral sensory neuropathy, most (23 of 25 patients [92%]) were grade 1 or 2; the remaining 2 patients had grade 3 peripheral sensory neuropathy. Dose modifications due to peripheral sensory neuropathy occurred in 9 patients (16%). Grade ≥3 treatment-related AEs occurred in 19 patients (33%) (most common: alanine aminotransferase increased in 6 [11%] and neutropenia in 5 [9%]). No febrile neutropenia or Grade 5 AEs occurred. Treatment-related serious AEs (SAEs) occurred in 8 patients (14%). Seven patients (12%) had a treatment-emergent AE that led to discontinuation of BV. Treatment-emergent immune-mediated AEs (IMAEs) occurred in 19 patients (33%); treatment-emergent IMAEs that occurred in ≥5% of patients were hypothyroidism (5 patients [9%]) and pneumonitis and rash maculopapular (3 patients [5%] each). All cases of pneumonitis resolved. Conclusions: The use of 2 active, targeted agents with distinct and complementary mechanisms of action for the frontline treatment of advanced stage cHL resulted in promising efficacy, safety, and tolerability. These results demonstrate continued tolerability of AN+AD with no new safety signals observed. AN+AD may provide a future first-line treatment option for patients with advanced stage cHL; long-term follow-up is ongoing.