PD-1 Inhibitors Research Articles

Concomitant Eruptive Squamous Atypia and Bullous Drug Eruption Associated with Pembrolizumab

This study involves the case of a rare eruptive squamous atypia (ESA) reaction and concurrent bullous eruption following pembrolizumab treatment for recurrent neck squamous cell carcinoma. This report aims to raise awareness to possible concurrent skin reactions related to PD-1 inhibitor treatment that has otherwise only been reported twice in melanoma patients.

Adjuvant chemoradiotherapy plus PD-1 inhibitor for pN3 gastric cancer: a randomized, multicenter, Phase III trial.

D2 surgery followed by adjuvant chemotherapy has been established as the standard of care for patients with locally advanced gastric cancer in Asian countries. However, its efficacy is still unsatisfactory, especially for pathological N3 disease. The RACING trial is a randomized, multicenter, Phase III trial designed to compare the efficacy and safety of chemotherapy alone versus chemotherapy in combination with PD-1 inhibitor and radiotherapy in patients with pN3 gastric or gastroesophageal junction adenocarcinoma. A total of 433 patients will be assigned at a 1:1 ratio to the two arms. The primary end point is the 3-year disease-free survival rate. The secondary end points include the 3-year overall survival rate, 3-year local recurrence-free survival rate, treatment-related adverse events and quality of life.Clinical Trial Registration: NCT04997837 (ClinicalTrials.gov).

Promising PD-1 antagonists for liver cancer: an evaluation of phase II and III results.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a significant cause of cancer-related morbidity and mortality. Limited treatment options for advanced stages emphasize the need for effective therapies. This review examines immune checkpoint inhibitors (ICIs), specifically PD-1, PD-L1, and CTLA-4 inhibitors, as novel treatments for advanced HCC. The review includes data from phase II and III clinical trials that evaluate ICI combinations with tyrosine kinase inhibitors (TKIs) and anti-angiogenic agents, as well as locoregional treatments such as Transarterial Chemoembolization (TACE). Clinical outcomes, including progression-free survival and overall response rates, were analyzed along with the incidence and management of immune-related adverse events (irAEs). A systematic literature review method was applied to ensure the inclusion of comprehensive, high-quality studies. ICI-based therapies and their combinations are reshaping the treatment landscape for advanced HCC by providing improved outcomes and potentially extending patient survival. Although promising, these therapies require further refinement to optimize sequencing and treatment selection, especially for patients with different levels of liver function and disease stages. Managing adverse effects effectively is essential for maximizing the benefits of these therapies in clinical practice. Continued research is needed to support the development of personalized approaches that can better tailor these treatments to individual patient needs, ultimately enhancing the overall effectiveness and safety of HCC management.

Present and prospect of transarterial chemoembolization combined with tyrosine kinase inhibitor and PD-1 inhibitor for unresectable hepatocellular carcinoma

Present and prospect of transarterial chemoembolization combined with tyrosine kinase inhibitor and PD-1 inhibitor for unresectable hepatocellular carcinoma

Factors Inducing Cutaneous Adverse Reactions in Cancer Patients Treated with PD-1 and PD-L1 Inhibitors: A Machine-Learning Algorithm Approach

Immune checkpoint inhibitors (ICIs) show promise in cancer treatment but can lead to immune-related adverse events (irAEs), notably affecting the skin. Understanding the factors behind these skin reactions is crucial for effective management during treatment. Hence, the aim of this study was to uncover associations between patient characteristics and cutaneous adverse reactions among cancer patients undergoing ICI treatment. The study involved 209 cancer patients receiving ICIs. Statistical methods, including the chi-square test, Fisher's exact test, and multivariable logistic regression, were employed to analyze variables such as hypertension, antihistamine use, cancer metastasis, diabetes, and opioid usage. Additionally, machine learning techniques, including logistic regression, elastic net, random forest, and support vector machines (SVM), were utilized to develop predictive models anticipating skin-related adverse events. Results highlighted significant associations between specific patient attributes and the incidence of skin reactions post-ICI treatment. Notably, patients using antihistamines or with cancer metastasis exhibited higher rates of skin adverse reactions, while those with diabetes or using opioids displayed lower incidence rates. Robust performance in forecasting these adverse events was observed, particularly in the predictive models employing logistic regression and elastic net. This pioneering study contributes crucial insights into predictive modeling for ICI-induced skin reactions, emphasizing the importance of personalized treatment strategies. By identifying risk factors and utilizing tailored predictive models, healthcare providers can proactively manage adverse events, optimizing the benefits of ICIs while mitigating potential side effects.

Entinostat in combination with nivolumab in metastatic pancreatic ductal adenocarcinoma: a phase 2 clinical trial.

Pancreatic ductal adenocarcinoma (PDA) is characterized by low cytotoxic lymphocytes, abundant immune-suppressive cells, and resistance to immune checkpoint inhibitors (ICI). Preclinical PDA models showed the HDAC inhibitor entinostat reduced myeloid cell immunosuppression, sensitizing tumors to ICI therapy. This phase II study combined entinostat with nivolumab (PD1 inhibitor) in patients with advanced PDA (NCT03250273). Patients received entinostat 5 mg orally once weekly for 14-day lead-in, followed by entinostat and nivolumab. The primary endpoint was the objective response rate (ORR) by RECIST v1.1. Secondary endpoints included safety, duration of response, progression free-survival and overall survival. Between November 2017 and November 2020, 27 evaluable patients were enrolled. Three showed partial responses (11% ORR, 95% CI, 2.4%-29.2%) with a median response duration of 10.2 months. Median progression-free survival (PFS) and overall survival (OS) were, respectively, 1.89 (95% CI, 1.381-2.301) and 2.729 (95% CI, 1.841-5.622) months. Grade ≥3 treatment-related adverse events occurred in 19 patients (63%), including decreased lymphocyte count, anemia, hypoalbuminemia, and hyponatremia. As exploratory analysis, peripheral and tumor immune profiles changes were assessed using CyTOF, mIHC, and RNA-seq. Entinostat increased dendritic cell activation and maturation. Gene expression analysis revealed an enrichment in inflammatory response pathways with combination treatment. Although the primary endpoint was not met, entinostat and nivolumab showed durable responses in a small subset of PDA patients. Myeloid cell immunomodulation supported the preclinical hypothesis, providing a basis for future combinatorial therapies to enhance clinical benefits in PDA.

Comment on ‘exploring prognostic factors for survival in patients with advanced pancreatic cancer undergoing PD-1 inhibitor immunotherapy’

Comment on ‘exploring prognostic factors for survival in patients with advanced pancreatic cancer undergoing PD-1 inhibitor immunotherapy’

CTIM-03. IMMUNE CHECKPOINT INHIBITOR NIVOLUMAB IN PEOPLE WITH RECURRENT SELECT RARE CNS CANCERS: RESULTS OF INTERIM ANALYSIS IN A NON-HEAVILY PRETREATED COHORT

Abstract BACKGROUND There is a paucity of salvage therapies for patients with rare CNS tumors. Nivolumab (PD-1 inhibitor) is approved for a variety of systemic cancers. We developed a multisite basket Phase II trial to evaluate Nivolumab for patients with recurrence of one of 12 selected rare CNS cancers. Efficacy is measured by Disease Control Rate (DCR; confirmed CR/PR or durable SD for ≥ 6 months) in 2 cohorts: heavily and non-heavily pretreated (≥ 3 prior therapies, vs. ≤ 2; including radiation and/or standard or experimental drugs). Cohort 1 has been completed. We report efficacy results and safety data of a preplanned interim analysis in Cohort 2 (non-heavily pretreated). METHODS In addition to progressive disease, eligibility includes available tumor tissue; age ≥ 18; KPS ≥ 70; no steroids at trial entry. Planned accrual: 75 in each cohort. Nivolumab dose: 240 mg IV every 2 weeks (4 doses), followed by 480 mg every 4 weeks (14 additional doses). Interim analysis was planned when the sample size reached 32 in each cohort. RESULTS As of December 1, 2023, among 27 evaluable patients treated in the non-heavily pretreated cohort, 10 achieved SD ≥ 6 months (DCR 37%; 95% CI 19.4%,57.6%) – 6 high-grade meningiomas; 1 each: myxopapillary ependymoma with lung metastases; solitary fibrous tumor, gliomatosis (astrocytoma IDH mutant WHO grade 2), chordoma. A total of 56 Grade 3-5 AEs occurred; 13 (Grade 3-4) related to nivolumab, including Grade 3 gait disturbance (3); cerebral edema, cognitive disturbance, colitis, headache, hypotension, hypoxia, lymphopenia, pain, and pruritus (1 each), and one Grade 4 cerebral edema. The three Grade 5 AEs were disease-related. CONCLUSION Preliminary efficacy analysis exceeded the “go” boundary (i.e., > 5 responders) in the non-heavily pretreated cohort. Nivolumab showed an acceptable safety profile. Cohort 2 will continue to complete a planned accrual of 75 patients.

CTIM-07. A PHASE II, OPEN LABEL, SINGLE ARM STUDY OF NIVOLUMAB FOR RECURRENT OR PROGRESSIVE IDH MUTANT GLIOMAS WITH PRIOR EXPOSURE TO ALKYLATING AGENTS

Abstract BACKGROUND Somatic mutations in isocitrate dehydrogenase 1 (IDH1) are an important prognostic factor in patients with gliomas. IDH-mutant gliomas are prone to develop hypermutation after exposure to alkylating agents; in other solid tumors, hypermutation may be a predictive biomarker for PD-1 inhibitor response. In this study, we hypothesize that this specific subgroup of patients would clinically benefit from nivolumab as measured by overall response rate (ORR), duration of response (DOR), median progression-free survival (PFS), and overall survival (OS). METHODS Patients aged 18 years and older with recurrent/progressive IDH-mutant (WHO Grades 2-4) gliomas and prior exposure to alkylating agents were included. Nivolumab was given 240 mg q2w for 8 cycles, then 480 mg q4w until progression, toxicity, study withdrawal, or completion at 2 years. Efficacy was evaluated by ORR of partial (PR) and complete responses (CR) per RANO criteria; low-grade glioma RANO criteria was used for patients with non-enhancing disease. Secondary endpoints included median PFS, median OS, DOR. Toxicity and survival were followed every 3 months until death/study completion. RESULTS Thirty-three patients (66.7% male) were evaluable at study completion. Histology consisted of oligodendroglioma (N=11; 55% Grade 3) and astrocytoma (N=22; 36% Grade 3, 32% Grade 4). Median number of prior lines of systemic therapy was 1 (range 1-6). Median dexamethasone dose at screening was 0 mg (range 0-4). ORR was 9% with two PR and one CR, median DOR 33 months. 11 (32%) patients had stable disease (7 stable for 6+ months) with median PFS 2.2 months and median OS 29.1 months. There were two treatment-related Grade 3 adverse events (lymphopenia and hypotension). One patient discontinued treatment for Grade 2 transaminitis. CONCLUSIONS Though the primary endpoint was not met, three patients have ongoing CR and PR at 54+, 33+ and 24+ months. Future combination therapies with PD-1 inhibitors may increase efficacy in recurrent IDH-mutant gliomas.

CTIM-06. OUTCOME OF PATIENTS WITH RECURRENT MEDULLOBLASTOMA AND EPENDYMOMA TREATED WITH PEMBROLIZUMAB, AN IMMUNE CHECKPOINT INHIBITOR: A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY (PBTC045)

Abstract BACKGROUND Children with recurrent medulloblastoma and ependymoma typically have a dismal prognosis. Immune checkpoint blockade has revolutionized treatment of some resistant cancers. PBTC045 is a safety and preliminary efficacy study of pembrolizumab, a PD-1 inhibitor, in children with recurrent/progressive brain tumors. Here we present the strata that included children with recurrent/progressive ependymoma and medulloblastoma. METHODS Eligibility included patients aged 1-21 years old with recurrent/progressive ependymoma or medulloblastoma and with functional scores ≥70, no greater than physiologic steroid usage and standard washout periods, among other eligibility criteria. Pembrolizumab was administered at 2mg/kg IV every three weeks. Tumor tissue (if available) and serum were collected for correlative studies. Primary endpoints included toxicity and response, and two stages were planned requiring objective responses for potential expansion. RESULTS Patients with progressive ependymoma (Stratum D, n=13) or medulloblastoma (Stratum E, n=14, one ineligible) were enrolled. The median age at diagnosis was 3.37 years (range, 1-12.7) and 7 years (range, 2.2-13.1), respectively. The median age at study entry was 8.5 years and 11.4 years, respectively. There were no first-stage objective responses in either stratum, and thus the expansion arms were not initiated. Grade 3 or greater treatment-related adverse events included rash (n=1), anemia (n=1) and neutropenia (n=2), with no dose-limiting toxicities. The median progression-free survival (PFS) for ependymoma and medulloblastoma were 1.38 months (range, 1.08-1.51) and 1.41 months (range, 1.22-3.45), respectively. Immune correlative analyses are ongoing. CONCLUSIONS Immune checkpoint inhibition holds potential for CNS cancer treatment, and as a single agent, is well tolerated. However, in the current study, checkpoint inhibition monotherapy does not appear to significantly prolong survival or induce radiographic responses in children with recurrent/progressive ependymoma or medulloblastoma. Potential incorporation of checkpoint inhibitors into treatment for these patients will likely require combinatorial approaches that may be informed by the correlative science.

NCMP-07. ADVERSE NEUROLOGIC COMPLICATIONS FOLLOWING IMMUNE CHECKPOINT INHIBITORS FOR TREATMENT OF MELANOMA: COMPARATIVE ANALYSIS OF PD-1 INHIBITOR MONOTHERAPY TO COMBINATION THERAPY WITH CTLA-4 INHIBITORS

Abstract In the past decade, FDA approval of several novel immune checkpoint inhibitors (ICI) has revolutionized treatment of advanced melanoma. However, severe immune-related adverse events (irAEs) from these medications have been reported. This study examines whether PD-1/CTLA-4 inhibitor combination immunotherapy confers increased incidence of neurologic irAEs in melanoma patients compared to PD-1 inhibitor monotherapy. A retrospective, multicenter cohort study performed using TriNetX research platform identified adult patients diagnosed with melanoma. Cohort 1 (n=9,105) included melanoma patients treated with PD-1 inhibitor monotherapy (pembrolizumab or nivolumab). Cohort 2 (n=4,727) included melanoma patients treated with PD-1/CTLA-4 inhibitor combination therapy (PD-1 inhibitor + ipilimumab). Propensity Score Matching generated final cohorts (n=4,667) using covariates: gender, race, age at diagnosis, and history of nervous system disorders. Odds ratios (OR) were determined for the occurrence of neurologic irAEs at 3 years and 5 years following therapy initiation. Kaplan Meier analysis estimated survival probabilities for each irAE subtype, as defined by the 2021 Neuro irAE Disease Definition Panel. At 3 years post-diagnosis, there was increased risk of meningitis [OR: 2.8, 95% CI: (1.8, 4.2)], encephalitis [OR: 3.1, 95% CI: (1.9, 5.1)], demyelinating syndromes [OR: 2.7, 95% CI: (1.4, 5.2)], vasculitis [OR: 1.2, 95% CI: (0.5, 2.8)], peripheral neuropathy [OR: 1.3, 95% CI (1.1, 1.5)], neuromuscular junction disorders [OR: 1.1, 95% CI: (0.7, 1.8)], and myopathy [OR: 1.4, 95% CI: (1.1, 1.9)] in melanoma patients receiving combination immunotherapy compared to those receiving anti-PD-1 monotherapy. Increased incidence of neurologic irAEs corresponded with marginally lower, yet statistically significant decreases in survival probability (p<0.01), except for vasculitis (p=0.2) and neuromuscular junction irAEs (p=0.3). At 5 years following therapy initiation, these trends persisted. Melanoma patients receiving anti-PD-1/CTLA-4 combination therapies are at greater risk of neurologic irAEs than patients on anti-PD-1 monotherapy. Incidence of neurologic irAEs may confer worsened survival prognosis for these patients.

IMMU-12. TRANSLATING COMBINED PD1 AND LAG3 INHIBITION FROM PRECLINICAL MODELS TO PATIENTS WITH REFRACTORY, DNA REPLICATION REPAIR DEFICIENT (RRD) GLIOBLASTOMA: AN IRRDC STUDY

Abstract BACKGROUND AND AIMS RRD-glioblastoma harbour high tumor mutation burden (TMB) and respond to anti-PD1 immune-checkpoint inhibition (ICI). However, not all respond, and the majority progress, highlighting the need for combinatorial therapies for sustained immune-surveillance. METHODS We performed transcriptomic analyses of human RRD-glioblastoma specimens for immune checkpoint expression, and accordingly, tested combined ICI in immunocompetent murine models. Based on these preclinical data, we treated refractory patients using a combination of anti-PD1+anti-LAG3 through single-patient trial/compassionate access. Complimentary immuno-genomic biomarker analyses including circulating tumor DNA (ctDNA) were performed to investigate mechanisms and track responses. RESULTS Human RRD-glioblastoma (n=80) demonstrated high LAG3 expression, providing a strong rationale for therapeutic targeting. We tested combined anti-PD1+anti-LAG3 inhibition in three immunocompetent RRD-glioblastoma murine models. In the anti-PD1-responsive (Nestin-CreMSH2LoxP/LoxP-POLES459F/+) model, anti-PD1+anti-LAG3 resulted in universal tumor response and superior survival to ICI-monotherapy. In the anti-PD1 resistant models (Mlh1-/-/NestinCre+/Trp53LoxP/LoxP and therapy-induced hypermutant ENU/Trp53-/- gliomas), anti-PD1+antiLAG3 improved survival, overcoming the lack of response to ICI-monotherapy. Biologically, high LAG3 expression and immune-exhaustion observed in CD8 T-cells after treatment with anti-PD1 was ablated following the addition of anti-LAG3. Serially transplanted, post-anti-PD1 treated tumors showed response, confirming, in-vivo, that resistance to anti-PD1 could be abrogated by anti-PD1+anti-LAG3. Seven children with refractory RRD-glioblastoma who had progressed after anti-PD1 treatment were treated using anti-PD1+anti-LAG3, resulting in objective radiological responses and prolonged ongoing survival. Tolerability was better than a previous study of combined CTLA4 and PD1 inhibition for similar patients. Paired immuno-genomic tumor analyses, serial blood flow-cytometry, T-cell receptor clonotype, and CSF ctDNA analyses provided novel insights into the mechanisms of immunological invigoration and first-in-human, radiological responses. CONCLUSIONS LAG3 is an effective target in refractory RRD-glioblastoma. Combined inhibition with anti-PD1 inhibition demonstrated radiological response, prolonged survival and manageable toxicities in patients, and unearthered mechanisms of immune-responses. The combination will now be tested in biomarker-driven clinical trials in RRD-glioblastoma and other immune-inflamed solid tumors.

EXTH-75. IMMUNOVIROTHERAPY WITH PP2A AND PD-1 INHIBITION IN PEDIATRIC HIGH-GRADE GLIOMA

Abstract Pediatric high-grade gliomas (HGGs) represent a significant clinical challenge with poor survival rates. Engineered oncolytic herpes simplex virus (oHSV) has shown potential in several clinical trials at targeting HGGs through their direct lytic effect and induction of an immune response. We have learned from our clinical trial experience (NCT02457845) that a critical barrier to more durable response is augmenting and sustaining the anti-tumor immune response generated by oHSV. LB-100, a protein phosphatase 2A (PP2A) inhibitor, is known to enhance T-cell activity. We hypothesized that LB-100 with anti-PD-1 therapy would overcome the immunosuppressive barriers, enhancing the immunotherapeutic effects of oHSV and improve survival in an immunocompetent murine model. We investigated the therapeutic impact of clinically available, next-generation oHSV, M002, which expresses murine interleukin-12, combined with LB-100 and PD-1 inhibition compared to M002 with LB-100 or anti-PD-1 antibody, each therapy alone, or control by measuring median survival and changes in the tumor immune microenvironment. The triple combination of M002, LB-100, and anti-PD-1 antibody significantly extended median survival compared to control (45 days vs 22.5 days, P=0.001) or each treatment alone, and compared to M002 and LB-100 (44 days vs 28 days, P=0.017) or M002 and anti-PD-1 (45.5 days vs 41 days, P=0.023). This increase in survival was correlated with a robust increase in CD45+ immune cell infiltration and a reduction in T-regulatory cells. We will further investigate the changes in the tumor microenvironment to better understand the specific contributions of different immune cell populations. These data support the hypothesis that LB-100 enhances the efficacy of oHSV by amplifying T-cell-mediated immune responses against tumor cells. This combination therapy demonstrates a promising strategy that warrants further exploration and potential clinical application, emphasizing the critical role of targeting multiple aspects of immune regulation to enhance the efficacy of oncolytic virotherapy in pediatric tumors.

IMMU-61. THE LAST OF US: A FUNGI BASED DENDRITIC CELL VACCINE

Abstract BACKGROUND Glioblastoma (GBM) is the most prevalent primary malignant brain tumor in adults. The current standard treatment for newly diagnosed GBM involves maximal surgical resection followed by radiotherapy and temozolomide. Despite these interventions, the median overall survival for GBM patients remains approximately 15 months, highlighting the critical need for innovative therapeutic approaches. OBJECTIVE Our laboratory has previously developed a subcutaneous autologous tumor vaccine incorporating irradiated (IR) tumor cells with phagocytosis-stimulating ligands (Mannan-BAM), toll-like receptor (TLR) agonists, and an immunostimulant anti-CD40 antibody (collectively termed MBT). This combination has shown efficacy in mouse models of colon carcinoma, breast cancer, melanoma, and, more recently, gliomas. Our study aimed to create a dendritic cell (DC) vaccine using this strategy. METHODS To evaluate whether MBT could induce the maturation of DCs in vitro, we harvested BMDCs from mice and co-cultured them in the presence of MBT-tagged irradiated tumor cells. We then analyzed the maturation markers using flow cytometry and assessed cytokine production via ELISA. To test the efficacy of this approach in vivo, we utilized two different murine glioma models (SB28 and GL261). RESULTS Using flow cytometry, we observed a significant upregulation of important co-stimulatory molecules. Additionally, ELISA analysis demonstrated that MBT-treated DCs significantly increased the secretion of Type 1 cytokines while limiting the secretion of the regulatory cytokine IL-10. MBT-primed DCs combined with immune checkpoint inhibitor PD-1 increased mouse survival in a glioma model compared to WT mice. However, mice eventually succumbed to cerebral edema. Histology demonstrated significant treatment effects. CONCLUSION Our results demonstrate that MBT effectively matures DCs ex-vivo. Further research is required to immunophenotype the response to vaccination in glioma models and explore ways to overcome resistance.

An opinion on advanced cancer immunotherapy through innovations in PD-1 inhibitor delivery systems

An opinion on advanced cancer immunotherapy through innovations in PD-1 inhibitor delivery systems

Differences in immune-related toxicity between PD-1 and PD-L1 inhibitors: a retrospective cohort study in patients with advanced cancer

Immunotherapy with PD-1 or PD-L1 inhibitors has become an essential treatment strategy for a growing number of malignancies. These treatments have a risk for immune-related adverse events (IRAEs). Pooled analyses based on clinical trials show a favorable toxicity profile for treatment with PD-L1 compared to PD-1 inhibitors. This study aimed to investigate differences in IRAEs between patients with advanced solid malignances treated with PD-L1 and PD-1 inhibitors in a real-world setting. We conducted a retrospective cohort study at four Swedish Regions. Patients (n = 605) treated for advanced cancer with a PD-L1 or PD-1 inhibitor in monotherapy between June 2016 and August 2022 were included. Non-small cell lung cancer (NSCLC) was the most common malignant disease (n = 251; 41.5%), followed by malignant melanoma (n = 173; 28.6%), renal cell carcinoma (n = 71; 11.7%) and urothelial carcinoma (n = 35; 5.8%). Among patients receiving PD-L1 inhibitors, NSCLC (94.4%) was the predominant malignancy, whereas for those treated with PD-1 inhibitor, malignant melanoma constituted the most prevalent malignancy (34.5%). Discontinuation of treatment due to IRAEs overall and IRAEs grade ≥ 2 were significantly less common in patients treated with PD-L1 compared to PD-1 inhibitors [Odds Ratio (OR): 0.38 (95% Confidence Interval (CI) 0.16–0.88) and OR: 0.63 (95% CI 0.35–0.98) respectively]. Any grade IRAE, IRAE grade ≥ 3 and multiple IRAEs were numerically more frequent in patients treated with PD-1 inhibitors.In conclusion, our study of patients with advanced solid malignancies in a real-world setting supports the results from clinical trials demonstrating a favorable toxicity profile for PD-L1 inhibitors versus PD-1 inhibitors.

Neoadjuvant and adjuvant toripalimab for locoregionally advanced nasopharyngeal carcinoma: a randomised, single-centre, double-blind, placebo-controlled, phase 2 trial

Patients with locoregionally advanced nasopharyngeal carcinoma with a high pretreatment plasma concentration of Epstein-Barr virus (EBV) DNA remain at high risk for recurrence after concurrent chemoradiotherapy. This study aimed to compare the efficacy and safety of neoadjuvant-adjuvant treatment with the PD-1 inhibitor toripalimab and concurrent chemoradiotherapy versus placebo and concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma. This randomised, single-centre, double-blind, placebo-controlled, phase 2 trial was conducted at Sun Yat-sen University Cancer Centre in Guangzhou, China. Adult patients (aged 18-65 years) with newly diagnosed high-risk stage III-IVa locoregionally advanced nasopharyngeal carcinoma, with a pretreatment plasma EBV DNA concentration of at least 1500 copies per mL and an Eastern Cooperative Oncology Group performance score of 0-1, were eligible. Patients were randomly assigned (2:1) using an interactive web response system (block size of six), stratified by TNM stage (III vs IVa), to neoadjuvant toripalimab (240 mg intravenously) or placebo once every 2 weeks for two cycles, followed by concurrent cisplatin (100 mg/m2 intravenously) on days 1, 22, and 43 during intensity-modulated radiotherapy and adjuvant toripalimab (240 mg intravenously) or placebo once every 3 weeks for up to eight cycles. The primary endpoint was 2-year progression-free survival in the intention-to-treat population. This study was registered with ClinicalTrials.gov, NCT03925090, and is closed to enrolment; follow-up is ongoing. Between Dec 6, 2019, and Dec 9, 2021, 150 patients were enrolled and randomly assigned to the toripalimab group (n=100) or placebo group (n=50). 115 (77%) patients were male and 35 (23%) were female. As of data cutoff (May 31, 2024), median follow-up for progression-free survival was 37·8 months (IQR 34·2-46·5) for the intention-to-treat population analyses. 2-year progression-free survival was higher in the toripalimab group (92·0% [95% CI 86·7-97·3]) than in the placebo group (74·0% [61·8-86·2]; stratified hazard ratio 0·40 [95% CI 0·18-0·89]; log-rank p=0·019). The most common grade 3 or worse acute adverse events (occurring within 1 year of randomisation) were leukopenia (40 [40%] of 99 patients in the toripalimab group vs 22 [44%] of 50 patients in the placebo group), mucositis (28 [28%] vs ten [20%]), neutropenia (17 [17%] vs nine [18%]), anaemia (16 [16%] vs five [10%]), and weight loss (12 [12%] vs six [12%]). The most common grade 3 or worse late adverse events (occurring >1 year after randomisation) was auditory or hearing loss (eight [8%] vs four [8%]). Immune-mediated adverse events of grade 3 or worse occurred in ten (10%) patients only in the toripalimab group. One (2%) of 50 patients in the placebo group died due to septic shock caused by bacteraemia considered not treatment related. There were no treatment-related deaths in the toripalimab group. Our findings suggested that a so-called sandwich approach involving toripalimab (in the neoadjuvant and adjuvant phases) combined with concurrent chemoradiotherapy could be a highly promising therapy for the treatment of locoregionally advanced nasopharyngeal carcinoma. Phase 3 non-inferiority trials are warranted comparing neoadjuvant and adjuvant toripalimab versus cisplatin plus gemcitabine neoadjuvant chemotherapy combined with concurrent chemoradiotherapy. National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Basic and Applied Basic Research Foundation, Science and Technology Program of Guangzhou, Sun Yat-sen University Clinical Research 5010 Program, Innovative Research Team of High-level Local Universities in Shanghai, Postdoctoral Innovative Talent Support Program, Planned Science and Technology Project of Guangdong Province, Key Youth Teacher Cultivating Program of Sun Yat-sen University, and Fundamental Research Funds for the Central Universities. For the Chinese translation of the abstract see Supplementary Materials section.

Phase II trial of multi-tyrosine kinase inhibitor ESK981 in combination with PD-1 inhibitor nivolumab in patients with metastatic castration-resistant prostate cancer.

Increasing the response rates of immune checkpoint inhibitors in patients with metastatic castration-resistant prostate cancer (mCRPC) presents a significant challenge. ESK981 is a multi-tyrosine kinase and PIKfyve lipid kinase inhibitor that augments immunotherapeutic responses. In this phase II study, ESK981 was combined with the PD-1 blocking monoclonal antibody nivolumab to test for potentially improved response rates in patients with mCRPC who have progressed on androgen receptor (AR)-targeted agents and chemotherapy. Eligible patients received ESK981 orally once daily for five consecutive days, followed by a two-day break. Patients were also treated with nivolumab intravenously on Day 1 of each 28-day cycle. The primary endpoints were a 50% reduction in prostate-specific antigen (PSA50), and safety. Secondary endpoints included radiographic progression free survival (rPFS) and overall survival (OS). Additional investigations included whole exome sequencing in patients. Ten patients were enrolled. The maximum PSA decline from baseline of 14% was achieved in only one patient. Grade 3 treatment-related adverse events (AEs) included fatigue, anemia, and lymphopenia. There were no Grade 4 events. The median rPFS was 3.7 months (95% CI, 1.6-8.4). The median OS was 9.6 months (95% CI, 1.8-22.4). The study was terminated due to futility after 10 patients. Whole exome sequencing identified AR amplification in 63% of patients (5/8). ESK981 + nivolumab showed no antitumor activity in patients with AR-positive (AR+) mCRPC. Further evaluation of ESK981 combined with the PD-1 inhibitor nivolumab in AR + mCRPC patients is not warranted. (Trial registration: ClinicalTrials.gov NCT04159896. Registration date: November 12, 2019.).

Sex Disparities in Cancer Immunotherapy: A Review

Cancer immunotherapy has revolutionized cancer treatment, particularly through immune checkpoint inhibitors (ICIs) targeting proteins like PD-1, PD-L1, and CTLA-4. While these therapies have shown significant survival benefits across various cancers, sex-based disparities in treatment response and outcomes have emerged. This review explores the mechanisms behind these differences, focusing on genetic, hormonal, and immune system variations between male and female patients. Women tend to exhibit stronger immune responses due to the presence of two X chromosomes and the immunostimulatory effects of estrogen, which enhances immune activity. Conversely, men’s single X chromosome and the immunosuppressive effects of testosterone contribute to a less vigorous immune response. These biological differences manifest in clinical outcomes, with men generally experiencing better overall survival rates from ICIs, while women are more prone to immune-related adverse events (irAEs), including autoimmune toxicities. However, in certain cases, women may demonstrate more robust long-term survival benefits from treatments such as CTLA-4 inhibitors, despite higher toxicity risks. Beyond ICIs, sex disparities also extend to adoptive cell therapies (ACT) and cancer vaccines, where female patients often display stronger immune responses but face increased risks of side effects, necessitating personalized approaches to therapy. The review also discusses emerging research on the tumor microenvironment (TME), gut microbiome, and sex-specific pharmacokinetics and pharmacodynamics as contributing factors to these disparities. Understanding these mechanisms is critical for improving cancer immunotherapy outcomes for both sexes. Future research should focus on investigating the role of sex hormones, the microbiome, and developing biomarkers to better predict responses to immunotherapy. Clinically, the findings highlight the need for tailored treatment strategies that account for sex-specific differences, aiming for more equitable and effective cancer care. Keywords: Cancer immunotherapy, Immune checkpoint inhibitors (ICIs), Sex-based disparities, PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors

Feasibility and Tolerability of Anlotinib Plus PD-1 Inhibitors for Previously-Treated Advanced Non-Small Cell Lung Cancer: A Retrospective Exploratory Study.

Anlotinib demonstrated encouraging therapeutic activity as third-line treatment for patients with advanced non-small cell lung cancer (NSCLC). Programmed cell death protein 1 (PD-1) inhibitors also exhibited promising and durable response against previously-treated advanced NSCLC. Therefore, the present study aimed to determine the feasibility and safety of anlotinib plus PD-1 inhibitors for previously-treated NSCLC in clinical practice. This retrospective study included 56 patients with advanced NSCLC treated with systemic treatment previously. Patients included were treated with anlotinib plus PD-1 inhibitors in clinical practice. Therapeutic outcomes of the patients were evaluated radiologically using target lesions, and the prognostic outcomes were generated by follow-up. Adverse reactions experienced throughout the treatment were documented and analyzed. Between August 2018 and November 2022, 56 patients with advanced NSCLC were eligible to participate in this study consecutively. Therapeutic outcomes resulted in an overall response rate of 28.6% [95% confidence interval (CI): 17.3%-42.2%] and a disease control rate of 91.1% (95% CI: 80.4%-97.0%). Furthermore, this combination regimen among the 56 patients yielded a median progression-free survival (PFS) of 6.5 months (95% CI: 4.81-8.19) and a median overall survival (OS) of 15.8 months (95% CI: 10.23-21.37), respectively. And the median duration of response (DoR) among patients who responded was 8.3 months (95% CI: 4.38-12.22). Additionally, adverse reactions of all grades throughout the treatment were observed in 50 patients (89.3%), and adverse reactions of grade ≥3 were detected in 23 patients (41.1%). Fatigue, hypertension, diarrhea, nausea, and vomiting were the most common adverse reactions. Association analysis between PFS and baseline characteristic subgroups indicated that ECOG score and number of metastatic lesions might be potential predictors of PFS in the exploratory analysis. Anlotinib plus PD-1 inhibitors demonstrated a tolerable safety profile and encouraging therapeutic activity as subsequent-line therapy in patients with advanced NSCLC. This conclusion should be confirmed in prospective large-scale clinical trials subsequently.