Immune Checkpoint Inhibitors Nivolumab Research Articles

Stevens-Johnson Syndrome secondary to nivolumab in a patient with mixed cell variety classical Hodgkin Lymphoma

The immune checkpoint inhibitors (ICIs) nivolumab and pembrolizumab are some of the principal treatment options for relapsed or refractory classic Hodgkin lymphoma. However, immunotherapy has been related to dermatological adverse events (DAEs) and could lead to discontinuation of cancer treatment in severe cases. DAEs encompass entities such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), SJS/TEN-like reactions, drug reaction with eosinophilia and systemic symptoms (DRESS). We reported a case of a 46-year-old- female with classic mixed cellularity Hodgkin lymphoma, Lugano IV, who underwent a hematopoietic cell transplant and subsequent relapse, currently with Stevens-Johnson Syndrome secondary to nivolumab.

Abstract 4137177: A pharmacovigilance investigation from the FAERS database on patients using pembrolizumab and its association with cardiac arrhythmias

Background: Arrhythmia is always a concern in oncological treatments. The advent of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, enhancing the immune system's ability to combat malignancies. They are being more frequently used, revealing a range of immune-related adverse events (irAEs). This study aims to investigate the incidence of cardiac arrhythmias in patients receiving Pembrolizumab. Methods: We conducted a retrospective analysis of the FDA Adverse Event Reporting System (FAERS) database, focusing on reports submitted between 2006 to 2024. Cases involving patients treated with ICs were identified, and information related to cardiac arrhythmias was extracted using the Medical Dictionary for Regulatory Activities (MedDRA). Patients ≥ 18 years of age treated with ICIs were included in this study. A disproportionality analysis was conducted to identify arrhythmia events associated with pembrolizumab by comparing it with other immune checkpoint inhibitors (nivolumab, ipilimumab, and atezolizumab) and the entire FAERS database using the reporting odds ratio (ROR) and information component (IC). Results: A comprehensive analysis of 61,236 reported cases of pembrolizumab use revealed a total of 3,901 cases with cardiac complications. Among these, 672 cases (17.22 %) of arrhythmias were reported, with 452 individuals (67.26%) requiring hospitalization and 172 cases (25.59%) resulting in fatalities. Atrial fibrillation emerged as the most prevalent arrhythmia (49.7%). The occurrence of ventricular tachycardia with an ROR of 1.67 (1.18–2.35) and an IC of 0.44 (0.01–1.46) and complete atrio-ventricular block with an ROR of 1.57 (1.19–2.08) and an IC of 0.40 (0.04–1.24) were statistically significant. The reported arrhythmias associated with pembrolizumab are tabulated in Table 1 . The majority of events were reported in males, as shown in Figure 1 . Conclusion: This research offers significant insights into the connection between ICIs and cardiac arrhythmias, utilizing real-world data from the FAERS database. Healthcare providers should monitor cardiac events in patients receiving ICIs and aim to achieve a balance between anticancer effectiveness and cardiovascular safety. Further investigation is necessary to better understand the underlying mechanisms of arrhythmia and enhance risk stratification strategies for this specific patient group.

Role of immunohistochemical prognostic factors in various types of immunotherapy for metastatic melanoma: A retro-prospective study

Background. Anti-PD-1 immunotherapy (IT) is the standard of care for patients with metastatic melanoma. However, in the real world, IT is effective only in a fraction of patients. The lack of valid prognostic factors for various immunotherapy agents warrants a comprehensive and advanced study of this topic. Aim. To improve the outcomes of the first-line therapy for disseminated melanoma based on identifying immunohistochemical predictors of IT efficacy. Materials and methods. Data from 130 patients who were treated with immune checkpoint inhibitors nivolumab or prolgolimab in the first-line therapy for disseminated melanoma between 2017 and 2024 were analyzed. Results. The expression of PD-L110 on tumor cells was found to be a predictor of effective therapy: in the nivolumab group, the 2-year disease-free survival (DFS) with PD-L1 level 10% was high at 79% (95% confidence interval – CI 61–100); the 1-year DFS was 89% (95% CI 78–100) compared to 17% (95% CI 3.2–88) with a lower level of PD-L1 expression (p0.0001). In the prolgolimab group, the 2-year DFS with PD-L110% was also high at 78% (p0.0001; CI 54–100), the 1-year DFS was 94% (95% CI 84–100) compared to 35% (95% CI 17–73) with a lower level of PD-L1 expression (p0.0001). A less severe course of the disease was observed in patients with both peritumoral and intratumoral locations versus those with only peritumoral locations of the immune infiltrate. The study of the presence and form of lymphoid infiltration of the tumor showed the following direct relationship: in the nivolumab group, the 2-year DFS was 94% (95% CI 83–100) compared to 8.3% (95% CI 1.3–54), in the prolgolimab group, the 1-year DFS was 82% (95% CI 68–100) compared to 15% (95% CI 2.6–86); p0.0001. It was found that the predominance of CD8+ over CD4+ is associated with better results of IT: in the nivolumab group, the 2-year DFS was 87% (95% CI 74–100) compared to 19% (95% CI 4–91) in the absence of CD8+ predominance over CD4+; in the prolgolimab group, the 2-year DFS was 73% (95% CI 51–100) in patients with CD8+ predominance over CD4+ (p=0.0001). In patients without CD8 predominance over CD4, 2-year DFS was not achieved. The one-year DFS was 85% (95% CI 70–100) and 25% (95% CI 8.4–76), respectively; p=0.0001. Conclusion. The results of the study suggest that immunohistochemical characteristics such as a PD-L1 expression level 10%, the simultaneous presence of peri- and intratumoral lymphoid infiltration of the tumor, the ratio of the intensity of lymphoid infiltration with tumor-infiltrating lymphocytes (TILs), and the predominance of CD8+ over CD4+ can be considered predictors of IT efficacy with nivolumab and prolgolimab.

Quality of life under treatment with the immune checkpoint inhibitors ipilimumab and nivolumab in melanoma patients. Real-world data from a prospective observational study at the Skin Cancer Center Kiel

PurposeCombined immunotherapy (ipilimumab + nivolumab) has improved survival in stage IV melanoma patients, making Health-related Quality of Life (HrQoL) crucial due to potential immune-related adverse events (irAEs). Previous studies treated HrQoL as secondary/explorative endpoint, and no specific HrQoL questionnaire for melanoma patients on immune checkpoint inhibitor (ICI) therapy exists. This study aimed to gather specific HrQoL data during combined ICI therapy, tracking changes during and after treatment, and examining associations with gender, irAEs, and treatment response.Methods35 melanoma patients (22 males, 13 females) undergoing combined ICI were surveyed using the Short-form 36 questionnaire (SF-36), the Inflammatory Bowel Disease Questionnaire – Deutsch (IBDQ-D), and the distress thermometer (DT). HrQoL was evaluated during treatment, after six months, and at the onset of autoimmune colitis.ResultsirAEs occurred in 51.4% of patients, with colitis being the most common (26.1%). 45.7% had progressive disease. SF-36 showed stable HrQoL during treatment and follow-up. Women had worse HrQoL on the physical component scale than men (p = 0.019). Patients with progression showed worse HrQoL over time in physical (p = 0.015) and mental health scales (p = 0.04). IBDQ-D showed constant HrQoL throughout treatment and follow-up. Distress on DT remained constant, with women reporting higher levels of distress.ConclusionHrQoL remained stable during and after therapy. Female gender and disease progression negatively impacted HrQoL. The development of irAEs was not associated with HrQoL, though this may not apply to severe irAEs like colitis, which were not assessed.

A Review of Immunotherapy for Head and Neck Cancer

The introduction of immune checkpoint inhibitors (ICIs) to oncological care has transformed the management of various malignancies, including head and neck squamous cell carcinoma (HNSCC), offering improved outcomes. The first-line treatment of recurrent and malignant HNSCC for many years was combined platinum, 5-fluorouracil, and cetuximab. Recently, the ICI pembrolizumab was approved as a first-line treatment, with or without chemotherapy, based on tumor and immune cell percentage of programmed-death ligand 1 (PD-L1). Multiple head and neck (HN) cancer trials have subsequently explored immunotherapies in combination with surgery, chemotherapy, and/or radiation. Immunotherapy regimens may be personalized by tumor biomarker, including PD-L1 content, tumor mutational burden, and microsatellite instability. However, further clinical trials are needed to refine biomarker-driven protocols and standardize pathological methods to guide combined regimen timing, sequencing, and deescalation. Gaps remain for protocols using immunotherapy to reverse oral premalignant lesions, particularly high-risk leukoplakias. A phase II nonrandomized controlled trial, using the ICI nivolumab, showed a 2-y cancer-free survival of 73%, although larger trials are needed. Guidelines are also needed to standardize the role of dental evaluation and care before, during, and after immunotherapy, specifically in regard to oral immune-related adverse events and their impact on cancer recurrence. Standardized diagnostic and oral care coordination strategies to close these gaps are needed to ensure continued success of HN cancer immunotherapy.

Sequencing of Checkpoint or BRAF/MEK Inhibitors on Brain Metastases in Melanoma

BackgroundThe impact of the order of treatment with checkpoint inhibitors or BRAF/MEK inhibitors on the development of brain metastases in patients with metastatic unresectable BRAFV600-mutant melanoma is unknown. The SECOMBIT trial examined the impact of the order of receipt of these treatments in such patients.MethodsIn this three-arm trial, we reviewed patients without brain metastases who received the BRAF/MEK inhibitors encorafenib and binimetinib until they had progressive disease followed by the immune checkpoint inhibitors ipilimumab and nivolumab (arm A); or treatment with ipilimumab and nivolumab until they had progressive disease followed by encorafenib and binimetinib (arm B); or treatment with encorafenib and binimetinib for 8 weeks followed by ipilimumab and nivolumab until they had progressive disease followed by retreatment with encorafenib arm binimetinib (arm C).ResultsBrain metastases were discovered during the trial in 23/69 patients in arm A, 11/69 in arm B, and 9/68 in arm C. At a median follow-up of 56 months, the 60-month brain metastases–free survival rates were 56% for arm A, 80% for arm B (hazard ratio [HR] vs. A: 0.40, 95% confidence interval [CI] 0.23 to 0.58), and 85% for arm C (HR vs. A: 0.35, 95% CI 0.16 to 0.76).ConclusionsIn patients with unresectable metastatic melanoma, the treatment sequence of immune checkpoint inhibition followed by BRAF/MEK inhibitors was associated with longer periods of new brain metastases–free survival than the reverse sequence. A regimen in which immune checkpoint inhibition was sandwiched between BRAF/MEK inhibition also appeared to be protective against brain metastases. (ClinicalTrials.gov number NCT02631447.)

Efficacy and Safety of Immune Checkpoint Inhibitor Combination Therapy for Dysphagia in Patients with Advanced Esophageal Cancer.

Background/Objectives: Recently, pembrolizumab plus 5-fluorouracil and cisplatin (FP), nivolumab plus FP, and nivolumab plus ipilimumab have become the first-line treatments for patients with advanced esophageal cancer. However, the treatment efficacy in primary tumors has not been reported. We assessed the outcomes of these treatments in advanced esophageal cancer, specifically focusing on esophageal dysphagia improvements and the primary tumor response. Methods: This retrospective study was conducted between October 2021 and November 2023. We investigated 23 patients with esophageal cancer and dysphagia who received an immune checkpoint inhibitor (ICI) plus FP or nivolumab plus ipilimumab. Results: The median progression-free survival (PFS) was 10.6 months (95% confidence interval [CI]: 9.0-12.5), and the median overall survival was not reached (95%CI: 13.0-NA). Improvement in dysphagia was observed in 19/23 (82.6%) patients, with a median time to improvement of 26 days (range: 15-77 days) and a median dysphagia PFS of 12.6 months (range: 8.1-NA months). Ten patients experienced immune-related adverse events (irAEs): seven had interstitial pneumonia, and three had thyroid dysfunction, pituitary dysfunction, and rash, respectively. Conclusions: Although there was a high frequency of irAEs, ICI for esophageal cancer achieved high response rates and prolonged survival. The observed improvement in dysphagia suggests the potential efficacy of the treatment against primary tumors.

An update on the status of HSP90 inhibitors in cancer clinical trials.

The evolutionary conserved molecular chaperone heat shock protein 90 (HSP90) plays an indispensable role in tumorigenesis by stabilizing client oncoproteins. Although the functionality of HSP90 is tightly regulated, cancer cells exhibit a unique dependence on this chaperone, leading to its overexpression, which has been associated with poor prognosis in certain malignancies. While various strategies targeting heat shock proteins (HSPs) involved in carcinogenesis have been explored, only inhibition of HSP90 has consistently and effectively resulted in proteasomal degradation of its client proteins. To date, a total of 22 HSP90 inhibitors (HSP90i) have been tested in 186 cancer clinical trials, as reported by clinicaltrials.gov. Among these trials, 60% have been completed, 10% are currently active, and 30% have been suspended, terminated, or withdrawn. HSP90 inhibitors (HSP90i) have been used as single agents or in combination with other drugs for the treatment of various cancer types in clinical trials. Notably, improved clinical outcomes have been observed when HSP90i are used in combination therapies, as they exhibit a synergistic antitumor effect. However, as single agents, HSP90i have shown limited clinical activity due to drug-related toxicity or therapy resistance. Recently, active trials conducted in Japan evaluating TAS-116 (pimitespib) have demonstrated promising results with low toxicity as monotherapy and in combination with the immune checkpoint inhibitor nivolumab. Exploratory biomarker analyses performed in various trials have demonstrated target engagement that suggests the potential for identifying patient populations that may respond favorably to the therapy. In this review, we discuss the advances made in the past 5 years regarding HSP90i and their implications in anticancer therapeutics. Our focus lies in evaluating drug efficacy, prognosis forecast, pharmacodynamic biomarkers, and clinical outcomes reported in published trials. Through this comprehensive review, we aim to shed light on the progress and potential of HSP90i as promising therapeutic agents in cancer treatment.

Efficacy of adjuvant immune checkpoint inhibitors pembrolizumab or nivolumab in melanoma patients ≥ 75 years: results of a real-world cohort including 456 patients

BackgroundImmune checkpoint inhibitors (ICI) applied in patients with melanoma in an adjuvant setting have proven safety and efficacy in several studies, but data on elderly patients aged 75 years or more is scarce. Aim of this study was to investigate efficacy and safety of adjuvant ICI in patients aged ≥ 75 years compared to patients < 75 years in a real-world setting.MethodsWe retrospectively analyzed clinical data, including occurrence of immune-related adverse events (irAE) and outcome of 456 patients that had been treated with adjuvant ICI between January 1st, 2018 and December 20th, 2022. We then compared patients aged ≥ 75 years (n = 117) to patients < 75 years (n = 339) in terms of safety and disease-free survival (DFS).Results and conclusionICI were well tolerated in both groups, with no significant difference observed in the overall occurrence of irAE. However, within the elderly subgroup, there was a significantly higher proportion of skin or nephrological toxicity and colitis/diarrhea compared to the other group. In terms of efficacy, a significantly shorter DFS in patients aged ≥ 75 years was observed. Adjuvant ICI in patients ≥ 75 years was less effective and furthermore associated with an increased risk for skin, renal or bowel toxicity. Therefore, in elderly patients, adjuvant ICI should be used with precaution.

Immunohistochemical factors of prognosis of immunotherapy for metastatic melanoma: А prospective and retrospective study

Introduction. Anti-PD-1 immunotherapy (IT) is becoming the standard treatment for patients with metastatic melanoma. However, immune checkpoint inhibitors are only effective in a fraction of patients, and studies examining biological markers and their correlation with clinical efficacy are insufficient to draw unambiguous conclusions. Aim. To improve the outcomes of the first-line therapy for disseminated melanoma based on identifying clinical and immunohistochemical predictors of IT efficacy. Materials and methods. Data from 130 patients who were treated with immune checkpoint inhibitors (nivolumab or prolgolimab) in the first-line therapy for disseminated melanoma between 2017 and 2024 were analyzed. Results. Improvement was observed in 24 patients (18.4%): complete response in 18 patients (13.8%), partial response in 6 (4.6%), and stabilization in 71 (54.6%) patients. Progression was reported in 31 (24%) patients. Death occurred in 4 (3%) cases during IT with prolgolimab due to disease progression. The two-year disease-free survival (DFS) during IT was 53% (95% confidence interval [CI] 42–67), p=0.63; the median 2-year overall survival was not reached. In the immunohistochemical study, 47 (63.5%) patients had a predominance of tumor infiltration with CD8 lymphocytes over CD4, regardless of the IT type: 2-year DFS 82% (95% CI 70–96) vs 13% (95% CI 2.7–64) in the absence of CD8 predominance over CD4, p=0.0001; the median DFS was not reached in patients with the predominance of CD8 lymphocytes tumor infiltration over CD4 compared to the other group – 7.6 months in the absence of this feature (95% CI 5.8–0), p=0.001. The peritumoral location of the immune lymphoid infiltrate was observed in all 74 (100%) patients, and the intratumoral location was less common (52 patients, 70%). In the presence of both periand intratumoral location of the immune infiltrate, the 2-year DFS was 83% (95% CI 70–98) compared to the group of patients in whom no intratumoral location was detected – 5.5% (95% CI 0.8–36), p0.0001. The expression of programmed cell death ligand 1 (PD-L1) level 10% was observed in 47 (63.5%) patients. With this level of PD-L1 expression, the one-year DFS was 91% (95% CI 83–100) compared to 29% (95% CI 15–57) with a lower level of PD-L1 expression, p0.0001; the median DFS is reached, and in the group 2, DFS was only 6.6 months. In the case of PD-L110%, the 2-year DFS was high at 78% (95% CI 63–100), p0.0001. Conclusion. Based on the study's results, it can be assumed that immunohistochemical characteristics such as a PD-L1 expression level 10%, the simultaneous presence of periand intratumoral lymphoid tumor infiltration, and the predominance of CD8 over CD4 can be considered predictors of IT efficacy with nivolumab and prolgolimab.

Nivolumab Reaches Brain Lesions in Patients with Recurrent Glioblastoma and Induces T-cell Activity and Upregulation of Checkpoint Pathways.

Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis. Although immunotherapy is being explored as a potential treatment option for patients with GBM, it is unclear whether systemic immunotherapy can reach and modify the tumor microenvironment in the brain. We evaluated immune characteristics in patients receiving the anti-PD-1 immune checkpoint inhibitor nivolumab 1 week prior to surgery, compared with control patients receiving salvage resection without prior nivolumab treatment. We observed saturating levels of nivolumab bound to intratumorally and tissue-resident T cells in the brain, implicating saturating levels of nivolumab reaching brain tumors. Following nivolumab treatment, significant changes in T-cell activation and proliferation were observed in the tumor-resident T-cell population, and peripheral T cells upregulated chemokine receptors related to brain homing. A strong nivolumab-driven upregulation in compensatory checkpoint inhibition molecules, i.e., TIGIT, LAG-3, TIM-3, and CTLA-4, was observed, potentially counteracting the treatment effect. Finally, tumor-reactive tumor-infiltrating lymphocytes (TIL) were found in a subset of nivolumab-treated patients with prolonged survival, and neoantigen-reactive T cells were identified in both TILs and blood. This indicates a systemic response toward GBM in a subset of patients, which was further boosted by nivolumab, with T-cell responses toward tumor-derived neoantigens. Our study demonstrates that nivolumab does reach the GBM tumor lesion and enhances antitumor T-cell responses both intratumorally and systemically. However, various anti-inflammatory mechanisms mitigate the clinical efficacy of the anti-PD-1 treatment.

Hepatocellular Carcinoma: Beyond the Border of Advanced Stage Therapy.

Hepatocellular carcinoma (HCC) is the deadliest emergent health issue around the globe. The stronger oncogenic effect, proteins, and weakened immune response are precisely linked with a significant prospect of developing HCC. Several conventional systemic therapies, antiangiogenic therapy, and immunotherapy techniques have significantly improved the outcomes for early-, intermediate-, and advanced-stage HCC patients, giving new hope for effective HCC management and prolonged survival rates. Innovative therapeutic approaches beyond conventional treatments have altered the landscape of managing HCC, particularly focusing on targeted therapies and immunotherapies. The advancement in HCC treatment suggested by the Food and Drug Administration is multidimensional treatment options, including multikinase inhibitors (sorafenib, lenvatinib, regorafenib, ramucirumab, and cabozantinib) and immune checkpoint inhibitors (atezolizumab, pembrolizumab, durvalumab, tremelimumab, ipilimumab, and nivolumab), in monotherapy and in combination therapy to increase life expectancy of HCC patients. This review highlights the efficacy of multikinase inhibitors and immune checkpoint inhibitors in monotherapy and combination therapy through the analysis of phase II, and III clinical trials, targeting the key molecular pathways involved in cellular signaling and immune response for the prospective treatment of advanced and unresectable HCC and discusses the upcoming combinations of immune checkpoint inhibitors-tyrosine kinase inhibitors and immune checkpoint inhibitors-vascular endothelial growth factor inhibitors. Finally, the hidden challenges with pharmacological therapy for HCC, feasible solutions for the future, and implications of possible presumptions to develop drugs for HCC treatment are reported.

Binimetinib in combination with nivolumab or nivolumab and ipilimumab in patients with previously treated microsatellite-stable metastatic colorectal cancer with RAS mutations in an open-label phase 1b/2 study

BackgroundIn patients with previously treated RAS-mutated microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), a multicenter open-label phase 1b/2 trial was conducted to define the safety and efficacy of the MEK1/MEK2 inhibitor binimetinib in combination with the immune checkpoint inhibitor (ICI) nivolumab (anti–PD-1) or nivolumab and another ICI, ipilimumab (anti-CTLA4).MethodsIn phase 1b, participants were randomly assigned to Arm 1A (binimetinib 45 mg twice daily [BID] plus nivolumab 480 mg once every 4 weeks [Q4W]) or Arm 1B (binimetinib 45 mg BID plus nivolumab 480 mg Q4W and ipilimumab 1 mg/kg once every 8 weeks [Q8W]) to determine the maximum tolerable dose (MTD) and recommended phase 2 dose (RP2D) of binimetinib. The MTD/RP2D was defined as the highest dosage combination that did not cause medically unacceptable dose-limiting toxicities in more than 35% of treated participants in Cycle 1. During phase 2, participants were randomly assigned to Arm 2A (binimetinib MTD/RP2D plus nivolumab) or Arm 2B (binimetinib MTD/RP2D plus nivolumab and ipilimumab) to assess the safety and clinical activity of these combinations.ResultsIn phase 1b, 21 participants were randomized to Arm 1A or Arm 1B; during phase 2, 54 participants were randomized to Arm 2A or Arm 2B. The binimetinib MTD/RP2D was determined to be 45 mg BID. In phase 2, no participants receiving binimetinib plus nivolumab achieved a response. Of the 27 participants receiving binimetinib, nivolumab, and ipilimumab, the overall response rate was 7.4% (90% CI: 1.3, 21.5). Out of 75 participants overall, 74 (98.7%) reported treatment-related adverse events (AEs), of whom 17 (22.7%) reported treatment-related serious AEs.ConclusionsThe RP2D binimetinib regimen had a safety profile similar to previous binimetinib studies or nivolumab and ipilimumab combination studies. There was a lack of clinical benefit with either drug combination. Therefore, these data do not support further development of binimetinib in combination with nivolumab or nivolumab and ipilimumab in RAS-mutated MSS mCRC.Trial registrationNCT03271047 (09/01/2017).

Abstract 2361: A PD1-antibody-attenuated IL-2 fusion protein activates immune cells leading to the inhibition of tumor growth in ex vivo human 3D tumor models

Abstract IL-2 has been prescribed to effectively treat malignancies, mainly melanoma, for decades. Its use has waned in recent years due to significant toxicity and a narrow therapeutic index. To overcome the limitations of systemic administration of IL-2, we have generated a modified IL-2 (IL2Att) with specific substitutions to reduce the binding affinity with the IL-2R. The attenuated cytokine was fused to a high-affinity anti-PD1 antibody that does not block PD-1 binding with its ligands (PD-L1 and PD-L2). The resulting antibody-cytokine fusion, anti-PD1-IL2Att, allows selective delivery of IL-2 to tumor-reactive PD1+ T cells, with limited potential to activate PD1− cells. To evaluate the effect of anti-PD1-IL2Att in a human tumor microenvironment (TME), we established a unique human 3D multi-cellular cancer system. This model system includes neoplastic and somatic cells that make up the TME, further supplemented with peripheral blood mononuclear cells (PBMC). We found that the anti-PD1-IL2Att reduced tumor cell survival more effectively in several types of these 3D cancer models (melanoma, glioblastoma, ovarian and colon cancer) than standard immune checkpoint inhibitors pembrolizumab or nivolumab. Combination treatments of anti-PD1-IL2Att with either of these agents resulted in improved immune activation and tumor cell killing. Our findings suggest that tumor-targeted attenuated cytokines such as IL-2 can promote robust tumor killing while minimizing systemic toxicity. Citation Format: Ronit Satchi-Fainaro, Opal Avramoff, Anshika Katyal, Eilam Yeini, Anne Krinsky, Yulia Liubomirski, Shai Dulberg, Galia Tiram, Ayelet Kaminitz, Jason Gill, Jessica Pedersen, Dana Bar-On, Ayala Tamir, Paul Ayton, Tetsuya Taura, David Wilson, Asaf Madi. A PD1-antibody-attenuated IL-2 fusion protein activates immune cells leading to the inhibition of tumor growth in ex vivo human 3D tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2361.

DA-EPOCH-R for High Grade B-Cell Lymphoma Patients with MYC and BCL2 and/or BCL6 Rearrangements: Clinical Results of the Induction Phase of the HOVON-152 Trial

Introduction Patients (pts) with high grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 gene rearrangements (double hit and triple hit (DH/TH)) have poor outcomes to standard R-CHOP. Retrospective studies reported improved disease-free survival (DFS) through intensification with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R). This regimen was studied in a small prospective trial including 24 DH/TH and 19 single MYC rearranged (SH) lymphomas (Dunleavy, Lancet Haematol 2019). No prospective studies evaluating DA-EPOCH-R exclusively for pts with DH/TH HGBL have been reported. The HOVON-152 trial aimed to improve outcomes in untreated DH/TH HGBL pts by investigating the efficacy of the immune checkpoint inhibitor nivolumab as consolidation treatment in pts achieving complete metabolic response (CMR) after DA-EPOCH-R induction. Here, we present the efficacy and safety profile of the induction phase with DA-EPOCH-R. Methods HOVON-152 is a prospective, multi-center, single arm phase II trial. Inclusion criteria were pts with newly diagnosed HGBL-DH/TH (according to the WHO 2016 classification), age ≥ 18 years, WHO performance status (PS) 0-3 and Ann Arbor stage II-IV. During the screening period for rearrangement status, pts could receive 1 cycle of R-CHOP or DA-EPOCH-R, followed by 5 cycles of DA-EPOCH-R. All pts received intrathecal CNS prophylaxis. All diagnostic lymphoma samples were centrally reviewed. PET-CT scans were performed at diagnosis, after 3 cycles and at end-of-induction (local review, central review will be reported at the conference). Pts in CMR after induction treatment (Deauville 1-3 or a negative lymphoma biopsy in case of Deauville 4) proceeded to nivolumab consolidation (480 mg every 4 weeks for one year). The HOVON-152 aimed to improve 12 months DFS of pts in CMR after induction from an expected 70% to 85% with nivolumab consolidation. Secondary objectives included evaluation of response rates, overall survival (OS) and safety. With a power of 0.90 a sample size of 97 pts was calculated. Here, we report efficacy (CMR rate) and safety of DA-EPOCH-R induction treatment. Logistic univariate analysis is used to analyze baseline characteristics associated with response. Adverse events (AEs) were defined according to the common terminology criteria for adverse events (CTC AE 5.0), counted by the highest grade per system organ class per patient. Results From August 2018 - March 2022, 97 pts have been enrolled (study inclusion completed). One patient was excluded due to CNS localization. The median age was 62 years (range 35-79); 90 (83%) pts had stage III-IV disease and 52 (54%) had (intermediate-)high international prognostic index (IPI) (Table 1). Central pathology review confirmed DH/TH in all pts. 65 pts (67%) had a BCL2 DH, 11 (12%) a BCL6 DH and 16 (17%) a TH. Dose adjustments were performed conform protocol. The maximum dose-level (DL) achieved was DL1 in 41 (43%), DL2 in 22 (23%), DL3 in 25 (25%), DL4 in 7 (7%) and DL5 in 1 (1%) of the pts. Vincristine dose was reduced in 28/81 (35%) pts. After DA-EPOCH-R induction, 63/96 (66%, 95% CI 55-75%) pts achieved CMR. WHO PS 2-3 (odds ratio (OR) 0.15, 95% CI 0.03-0.85, p=0.03), elevated LDH (OR 0.24, 95%CI 0.10-0.59, p=0.002) and bulky disease defined as ≥10 cm mass (OR 0.23, 95%CI 0.09-0.56, p=0.001), were significantly associated with a lower chance of achieving CMR. During treatment, 7 (7%) pts experienced a grade 5 AE (ileus, intestinal perforation, multi-organ failure/sepsis). Thereof, 4 patients died during DA-EPOCH-R and 3 patients died after DA-EPOCH-R. 31 (32%) experienced a grade 4 AE (e.g. sepsis, perforation, hemorrhage, thrombocytopenia and neutropenia), 21 (22%) a grade 3 AE (e.g. anemia, mucositis, infections and electrolyte disturbances) and 16 (17%) pts a grade 2 AE. Conclusion We report the largest prospective series of DH/TH HGBL patients treated with DA-EPOCH-R. DA-EPOCH-R induction was feasible, with toxicity and dose adjustments as previously described. The observed CMR rate of 66% was lower than previously reported in a prospective cohort of mixed DH/TH and SH patients (74%). For patients achieving CMR, the nivolumab consolidation phase is ongoing. Translational side studies investigating predictive factors to identify patients not achieving CMR are ongoing. For these patients, novel strategies to improve first-line treatment are warranted.

Small molecule. Big biology. Dual phosphatase inhibitor enters the immunotherapy fray.

The advent and clinical success of immune checkpoint inhibitors Ipilimumab, Nivolumab and Pembrolizumab has had a seismic impact on our drug discovery focus and rationale. Novel extrinsic targets that enhance immune responses to cancer are actively being pursued, while tumor intrinsic targets that render cancer cells more sensitive to the immune system have joined traditional intrinsic targets (e.g. directly cytotoxic) in the drug discovery pipeline. The phosphatase PTPN2 (TC-PTP) and its paralog PTPN1 (PTP-1B) are negative regulators of several cytokine signaling pathways and Tcell receptor (TCR) signaling. In a recent publication, Baumgartner etal. demonstrate the pre-clinical efficacy of a first-in-class dual PTPN1/N2 active site inhibitor (ABBV-CLS-484/AC484) in cancer models.

P06.18.B OVERVIEW OF THE GLITIPNI TRIAL - LOCAL ADMINISTRATION OF IMMUNE CHECKPOINT INHIBITION AND/OR DENDRITIC CELLS FOLLOWING RESECTION OF RECURRENT GLIOBLASTOMA

Abstract BACKGROUND Intravenous (IV) administration of the Immune checkpoint inhibitor (ICI) nivolumab (NIVO) for recurrent glioblastoma (rGB) has proven mostly ineffective, and the combination of IV ipilimumab (IPI) plus nivolumab (NIVO) is associated with a high incidence of irAE. Combinatorial immunotherapy strategies are likely to be more effective, and direct Intracerebral (iCE) administration following the resection of rGB could be a more effective and safer alternative to iv-dosing METHODS We previously demonstrated that intra-operative intracerebral (iCE) administration of the Immune checkpoint inhibitors (ICI) ipilimumab (IPI) and nivolumab (NIVO) after resection of recurrent glioblastoma (rGB) is safe and resulted in encouraging survival. The adaptive phase I Glitipni trial was further expanded with more cohorts (C) exploring the implantation of an Ommaya reservoir for intracavitary (iCav) administration of escalating doses of ICI, complementary iCE injection of increasing numbers of myeloid dendritic cells (myDC). We provide an overarching overview of all patients included in the program. RESULTS 102 patients have been included in the Glitipni trial. In C1 and 2 (3 and 24 patients) iCE IPI and IPI+NIVO were followed by IV NIVO every two weeks. Next, we combined this peroperative backbone with postoperative iCav injection of NIVO 1-/5-/10 mg every two weeks through an Ommaya reservoir following stereotactic biopsy (C3, 16 patients) or resection (C4, 16 patients). No dose-related toxicity was seen for iCav NIVO. iCE injection of BDCA-1 and BDCA-3+ myDC (escalating from 1-/10- to 20.10E6) was added to the backbone of C3/4 with adjuvant 10mg iCav NIVO (resection in C5, 11 patients, biopsy in C6, 2 patients). In C7 (27+patients), patients had resection, iCE IPI+NIVO, and postoperative IV NIVO with iCav NIVO 10mg and IPI escalating 1/5/10mg. Dose limiting toxicity (aseptic neutrophilic pleocytosis) was encountered with iCav IPI (5-10mg Q2w). Median Overall Survival (mOS) was 38 weeks (C1/2), 23 weeks (C3), 42 weeks (C4), 44 weeks (C5/6) and 40 weeks (C7) CONCLUSION Peroperative iCer administration of IPI and NIVO is feasible and associated with an acceptable safety profile. A potential beneficial effect on overall survival was restricted to patients with resectable recurrences. Addition of myDC my improve PFS and OS. There is no indication for an additional benefit of adjuvant iCav IPI or NIVO. Further research will expand on iCer myDC administration and investigate complementary neo-adjuvant ICI administration.

Nivolumab plus Brentuximab vedotin +/- bendamustine combination therapy: a safe and effective treatment in pediatric recurrent and refractory classical Hodgkin lymphoma.

Classical Hodgkin lymphoma (cHL) is the most common pediatric lymphoma. Approximately 10% of patients develop refractory or recurrent disease. These patients are treated with intensive chemotherapy followed by consolidation with radiotherapy or high-dose chemotherapy and autologous stem cell reinfusion. Although this treatment is effective, it comes at the cost of severe long-term adverse events, such as reduced fertility and an increased risk of secondary cancers. Recently, promising results of inducing remission with the immune checkpoint inhibitor nivolumab (targeting PD-1) and the anti-CD30 antibody-drug conjugate Brentuximab vedotin (BV) +/- bendamustine were published. Here we describe a cohort of 10 relapsed and refractory pediatric cHL patients treated with nivolumab + BV +/- bendamustine to induce remission prior to consolidation with standard treatment. All patients achieved complete remission prior to consolidation treatment and are in ongoing complete remission with a median follow-up of 25 months (range: 12 to 42 months) after end-of-treatment. Only one adverse event of CTCAE grade 3 or higher due to nivolumab + BV was identified. Based on these results we conclude that immunotherapy with nivolumab + BV +/- bendamustine is an effective and safe treatment to induce remission in pediatric R/R cHL patients prior to standard consolidation treatment. We propose to evaluate this treatment further to study putative long-term toxicity and the possibility to reduce the intensity of consolidation treatment.

Angiogenesis inhibition in metastatic colorectal cancer continuum of care

Current treatment for most patients with metastatic colorectal cancer consists of sequential lines of different systemic therapies, including chemotherapy combinations (5-fluorouracil plus irinotecan or oxaliplatin) with the addition of molecular-targeted drugs, such as anti-angiogenic drugs (independently of the molecular characterisation of the tumour) or anti-epidermal growth factor receptor drugs (for patients whose tumours are wild type for KRAS and NRAS genes). More recently, for the subgroup of patients with high microsatellite instable or mismatch repair deficient tumours (approximately 5% of patients), immune checkpoint inhibitors (pembrolizumab or nivolumab plus ipilimumab) have been shown to be highly effective as first-line or second-line therapies. 1 Ciardiello F Ciardiello D Martini G Napolitano S Tabernero J Cervantes A Clinical management of metastatic colorectal cancer in the era of precision medicine. CA Cancer J Clin. 2022; 72: 372-401 Crossref PubMed Scopus (49) Google Scholar , 2 Cervantes A Adam R Roselló S et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023; 34: 10-32 Summary Full Text Full Text PDF PubMed Scopus (70) Google Scholar Furthermore, in patients whose tumours show HER2 gene amplification, BRAFV600E mutation, or KRASG12C mutation, current treatment options also incorporate the corresponding appropriate molecular-targeted drugs. 1 Ciardiello F Ciardiello D Martini G Napolitano S Tabernero J Cervantes A Clinical management of metastatic colorectal cancer in the era of precision medicine. CA Cancer J Clin. 2022; 72: 372-401 Crossref PubMed Scopus (49) Google Scholar , 2 Cervantes A Adam R Roselló S et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023; 34: 10-32 Summary Full Text Full Text PDF PubMed Scopus (70) Google Scholar Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 studyFruquintinib treatment resulted in a significant and clinically meaningful benefit in overall survival compared with placebo in patients with refractory metastatic colorectal cancer. These data support the use of fruquintinib as a global treatment option for patients with refractory metastatic colorectal cancer. Ongoing analysis of the quality of life data will further establish the clinical benefit of fruquintinib in this patient population. Full-Text PDF

Exploiting an Interleukin-15 Heterodimeric Agonist (N803) for Effective Immunotherapy of Solid Malignancies.

Identifying effective immunotherapies for solid tumors remains challenging despite the significant clinical responses observed in subsets of patients treated with immune checkpoint inhibitors. Interleukin-15 (IL-15) is a promising cytokine for the treatment of cancer as it stimulates NK and CD8+ lymphocytes. However, unfavorable pharmacokinetics and safety concerns render recombinant IL-15 (rIL-15) a less attractive modality. These shortcomings were addressed by the clinical development of heterodimeric IL-15 agonists, including N803. In preclinical tumor models, N803 elicited significant Th1 immune activation and tumor suppressive effects, primarily mediated by NK and CD8+ T lymphocytes. In addition, multiple clinical studies have demonstrated N803 to be safe for the treatment of cancer patients. The combination of N803 with the immune checkpoint inhibitor nivolumab demonstrated encouraging clinical responses in nivolumab-naïve and nivolumab-refractory patients with non-small cell lung cancer. In a recent Phase II/III clinical study, most Bacillus Calmette-Guerin (BCG)-refractory bladder cancer patients treated with N803 plus BCG experienced durable complete responses. Currently, N803 is being evaluated preclinically and clinically in combination with various agents, including chemotherapeutics, immune checkpoint inhibitors, vaccines, and other immuno-oncology agents. This report will review the mechanism(s) of action of N803 and how it relates to the preclinical and clinical studies of N803.