Checkpoint Inhibitors Nivolumab Research Articles

The role of cetuximab in treatment of squamous cell carcinoma of the head and neck

Squamous cell carcinoma of the head and neck (SCCHN) is one of the causes of cancer mortality. The mortality rate of patients within a year from the moment of diagnosis reaches 27% in patients with tumors of the oral cavity and 35.2% in patients with tumors of the pharynx. Despite the visual localization of SCCHN more than 50% of patients at the time of diagnosis are not subject to radical surgical treatment. More than half of the patients develop relapses of SCCHN within 3 years after the end of radical treatment. Most patients with SCCHN receive antitumor drug therapy either when an unresectable/metastatic tumor is detected or when a relapse develops after previously performed radical treatment. Epidermal growth factor receptor (EGFR) is expressed in almost 100% SCCHN and its expression is generally associated with decreased overall survival and progression-free survival. EGFR is a target receptor for targeted drugs. Cetuximab is a monoclonal antibody that blocks EGFR. The review examines the role of cetuximab in the treatment of recurrent and/or metastatic SCCHN in combination with chemotherapy and radiation therapy. The main undesirable phenomenon of cetuximab is dermatological toxicity: acne-like rash, dry skin, paronychia. Preventive therapy, including the antibiotic doxycycline, avoids the development of dermatological toxicity of 2–3 degrees. One of the most important biological processes involved in the progression of SCCHN is tumor escape from immune response associated with the expression of programmed death receptor 1 (PD-1), which inhibits the anti-tu mor immune response. Immunotherapy with checkpoint inhibitors pembrolizumab and nivolumab has shown a significant improvement in the survival of patients with progressing SCCHN after previously performed chemotherapy with the inclusion of cisplatin. Pembrolizumab in combination with cytostatics is an effective first-line therapy regimen for SCCHN in the presence of PD-L1 expression (CPS ≥ 1). In approximately 10–20% of patients, effective therapy changes due to poor tolerability. Timely prevention and relief of adverse events, control of disease manifestations, and a multidisciplinary approach to the patient make it possible to achieve optimal treatment results.

When to use stem cell transplantation for classical Hodgkin lymphoma.

Hodgkin lymphoma (HL) is a rare hematologic malignancy with a bimodal distribution of incidence, with most patients diagnosed between the ages of 15 and 30 years and another peak in patients older than 55 years. It is estimated that in 2023, almost 9000 people were diagnosed with HL in the United States. Most patients will be cured using conventional chemotherapy and radiotherapy. The treatment of HL has changed significantly over the past decade following the approval of highly effective novel therapies, including brentuximab vedotin and the checkpoint inhibitors (CPIs) nivolumab and pembrolizumab. The increasing use of these novel therapies has resulted in decreased utilization of both autologous and allogeneic hematopoietic cell transplantation (HCT) in patients with HL. In this review, we discuss the role of stem cell transplantation in patients with HL, with a particular focus on recent data supporting allogeneic HCT as a curative option in patients who progress on or are intolerant to CPI treatment.

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.

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.)

Classical chemotherapy, immunotherapy, or adjuvant radiotherapy-how to improve the oncologic outcome of radical cystectomy?

According to current guidelines, patients with muscle-invasive urothelial carcinoma (pT2-pt4a pN0) should be offered neoadjuvant cisplatin-containing chemotherapy before radical cystectomy. If not used neoadjuvantly, chemotherapy can be administered in the adjuvant setting (for > pT3 or pN+ disease). Both neoadjuvant and adjuvant therapy lead to improved overall survival. In the adjuvant setting, the checkpoint inhibitor nivolumab has also been approved for treatment of PD-L1-positive tumors (tumor proportion score [TPS] ≥ 1%). On the one hand, real-world evidence shows that cisplatin-fit patients often do not receive chemotherapy and, on the other hand, that arelevant proportion of patients are also not suitable for cisplatin-based chemotherapy. Further multimodal therapeutic strategies are hence urgently needed to improve the prognosis of affected patients. In particular, the use of antibody-drug conjugates and combination strategies involving checkpoint inhibitors are currently being intensively researched.

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.

The role of response adapted therapy in the era of novel agents

The optimal treatment of classic Hodgkin Lymphoma (cHL) requires an individualized approach, with therapy guided by pretreatment clinical risk stratification and interim response assessment with positron emission tomography (PET). The overall goal is to achieve high cure rates while minimizing acute toxicity and late therapy-related effects. Interim PET-adapted strategies (iPET) were initially developed with traditional chemotherapy, reducing intensity after interim complete response and escalating treatment for patients with iPET+ disease. Recently, novel agents including brentuximab vedotin and the checkpoint inhibitor immunotherapies (CPIs) pembrolizumab and nivolumab have been adopted into the front-line treatment of cHL, and PET-adapted approaches may be relevant for these drugs as well. In this review we discuss response-adapted strategies utilizing novel agents, consider challenges including indeterminate radiographic findings with CPIs, and address emerging techniques for response assessment including new PET-based imaging metrics and the role of circulating tumor DNA.

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.

Novel therapeutics for Hodgkin\'s lymphoma

Hodgkins LymphomaHL) was first described by Thomas Hodgkin in 1832., is a malignant disorder, a rare B cell lymphoma (mutant lymphocytes) with reasonable outcome due to the fair cure rates achieved by modern chemotherapy and/or radiotherapy. The incidence of HL is 2.6 cases per 100,000 people, accounts for 10% lymphoma cases. The Epstein–Barr virus (EBV) is detected in nearly 45% of HL patients Most of the affected patients are between ages 20 to 40 years. HL is uncommon in children &amp;#60; 5 years of age. The Reed-Sternberg (RS), large cells 50 micrometers in diameter which secrete cytokines to recruit reactive cells that include IL-5 and transforming growth factor-beta (TGF-beta). The RS cells are positive for CD 30 and CD15 &amp; sometimes for CD 20. They are negative for CD 45. The 5-year overall survival (OS) in stage 1 or stage IIa is approximately 90%;, the stage 4 disease has a 5-year OS of approximately 60%. More than 80 percent of all patients diagnosed with Hodgkin lymphoma can be cured by current treatment approaches. The cure rate is higher, approaching 90 percent, in younger patients and those with early-stage Hodgkins lymphoma (ESHL). Pragmatic therapeutic approach includes brief chemotherapy (ABVD- Adriamycin), bleomycin, vinblastine sulfate, and dacarbazine. For 3–4 cycles), For advanced-stage classic (CD30-positive) Hodgkin lymphoma, the combination of doxorubicin, vinblastine, dacarbazine, and brentuximab has emerged as a more effective, Patients with recurrent Hodgkin lymphoma would require high-dose chemotherapy followed by ASCT. Hodgkin lymphoma that recurs after ASCT would be managed by the checkpoint inhibitors nivolumab and pembrolizumab. Radiotherapy plays a role as a single modality in early stage lymphocyte-predominant HL. The role of autologous transplant was established decades ago by two randomized controlled trials demonstrating an improvement in PFS but not OS in patients with relapsed/refractory HL.

Nivolumab Plus 5-Azacitidine in Pediatric Relapsed/Refractory Acute Myeloid Leukemia (AML): Phase I/II Trial Results from the Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium

Improvements in survival have been made over the past two decades for childhood acute myeloid leukemia (AML), but the approximately 40% of patients who relapse continue to have poor outcomes. A combination of checkpoint-inhibitor nivolumab and azacitidine has demonstrated improvements in median survival in adults with AML. This phase I/II study with nivolumab and azacitidine in children with relapsed/refractory AML (NCT03825367) was conducted through the Therapeutic Advances in Childhood Leukemia &amp; Lymphoma consortium. Thirteen patients, median age 13.7 years, were enrolled. Patients had refractory disease with multiple reinduction attempts. Twelve evaluable patients were treated at the recommended phase II dose (established at dose level 1, 3 mg/kg/dose). Four patients (33%) maintained stable disease. This combination was well tolerated, with no dose-limiting toxicities observed. Grade 3–4 adverse events (AEs) were primarily hematological. Febrile neutropenia was the most common AE ≥ grade 3. A trend to improved quality of life was noted. Increases in CD8+ T cells and reductions in CD4+/CD8+ T cells and demethylation were observed. The combination was well tolerated and had an acceptable safety profile in pediatric patients with relapsed/refractory AML. Future studies might explore this combination for the maintenance of remission in children with AML at high risk of relapse.

Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial

No prospective data were available prior to 2021 to inform selection between combination BRAF and MEK inhibition versus dual blockade of programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) as first-line treatment options for BRAFV600-mutant melanoma. SECOMBIT (NCT02631447) was a randomized, three-arm, noncomparative phase II trial in which patients were randomized to one of two sequences with immunotherapy or targeted therapy first, with a third arm in which an 8-week induction course of targeted therapy followed by a planned switch to immunotherapy was the first treatment. BRAF/MEK inhibitors were encorafenib plus binimetinib and checkpoint inhibitors ipilimumab plus nivolumab. Primary outcome of overall survival was previously reported, demonstrating improved survival with immunotherapy administered until progression and followed by BRAF/MEK inhibition. Here we report 4-year survival outcomes, confirming long-term benefit with first-line immunotherapy. We also describe preliminary results of predefined biomarkers analyses that identify a trend toward improved 4-year overall survival and total progression-free survival in patients with loss-of-function mutations affecting JAK or low baseline levels of serum interferon gamma (IFNy). These long-term survival outcomes confirm immunotherapy as the preferred first-line treatment approach for most patients with BRAFV600-mutant metastatic melanoma, and the biomarker analyses are hypothesis-generating for future investigations of predictors of durable benefit with dual checkpoint blockade and targeted therapy.