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Immune checkpoint inhibitor (ICI) therapy improves outcomes in several cancers. Unfortunately, many patients experience grade 3-4 treatment-related adverse events, including gastrointestinal (GI) toxicities which are common. These GI immune-related adverse events (irAEs) induced by ICIs present significant clinical challenges, require prompt intervention, and result in treatment delays or discontinuations. The treatment for these potentially severe and even fatal GI irAEs which include enterocolitis, severe diarrhea, and hepatitis may interfere with the anti-cancer approach. Sargramostim (glycosylated, yeast-derived, recombinant human GM-CSF) is an agent that has been used in clinical practice for more than 30 years with a well-recognized safety profile and has been studied in many therapeutic areas. The mechanism of action of sargramostim may treat moderate-to-severe GI irAEs without impairing the anti-cancer therapy. Some early data also suggest a potential survival benefit. Through the differentiation/maturation of monocytes, macrophages, and neutrophils and induction of anti-inflammatory T cell responses, GM-CSF aids in GI homeostasis, mucosal healing, and mucosal immunity. GM-CSF knockout mice are susceptible to severe colitis which was prevented with murine GM-CSF administration. For some patients with GI mucosa and immune cell function impairment, e.g., Crohn's disease, sargramostim reduces disease severity. In a prospective, randomized study (ECOG 1608), advanced melanoma patients had a reduction in grade 3-5 GI irAEs and less frequent colonic perforation in the sargramostim plus ipilimumab arm compared to ipilimumab alone. Sargramostim continues to be studied with ICIs for the prophylactic management of irAEs while also potentially providing a survival benefit.

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Background: In the contemporary era of cancer treatment, lung cancer (LC) holds the unenviable position of being the primary contributor to cancer-induced mortality worldwide. Although immunotherapy has expanded the therapeutic landscape for metastatic non-small cell lung cancer (NSCLC), the advent of immune checkpoint inhibitors has been accompanied by a concomitant increase in immune-related adverse events (irAEs). Timely detection of irAEs is pivotal for efficacious management and enhanced patient outcomes. Diagnostic imaging, encompassing x-ray and CT scans, can facilitate the identification and supervision of irAEs, thereby ensuring the prompt recognition of associated patterns and alterations for expeditious treatment. Methods: The present inquiry undertook a systematic exploration of multiple databases, incorporating a diverse array of studies such as randomized controlled trials and observational analyses. Patient demographics, imaging outcomes, and risk of bias were extracted from the data. Meta-analysis was executed utilizing R Statistical Software, with the results of the risk of bias assessment summarized accordingly. Findings: The analysis unveiled a higher prevalence of irAEs in patients receiving first-line treatment for NSCLC compared to those receiving subsequent treatments, with a statistically significant distinction observed for both high- and low-grade irAEs (p < 0.001). Pneumonitis, thyroiditis, and colitis emerged as the most frequently reported irAEs, whereas hepatitis and pancolitis were less commonly documented. This investigation signifies a crucial advancement in elucidating the function of imaging in the treatment of NSCLC with PD-1/PD-L1 inhibitors and emphasizes the imperative for ongoing research in this domain.

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Background: Concurrent programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors with sequential chemoradiotherapy (SCRT) have been reported in only a limited number of studies involving patients with unresectable stage III non-small-cell lung cancer (NSCLC). A retrospective study was conducted to systematically analyze the efficacy and safety of the emerging therapy among Chinese patients. Materials and methods: We included patients with unresectable, stage III NSCLC who received concurrent sintilimab with chemotherapy or chemotherapy alone for 3-6 cycles, followed by radical radiotherapy at the First Hospital of Jilin University from Dec 15, 2019, to Jul 15, 2022. The primary end point was the objective response rate (ORR). The secondary end points included progression-free survival (PFS), overall survival (OS), 12-month and 18-month PFS rates, the duration of response (DoR), and safety. Results: The retrospective study involved 77 patients, of which 49 receiving concurrent sintilimab with SCRT were assigned to cohort A, and 28 receiving SCRT alone were assigned to cohort B. The ORR was significantly higher in cohort A (79.6%, 95% CI 65.7-89.8) than in cohort B (35.7%, 95% CI 18.6-55.9) (p<0.001). Median PFS was significantly longer in cohort A than in cohort B (NR [95% CI 21.4-NR] vs. 16.0 months [13.0-22.5]; HR 0.375, 95% CI 0.192-0.735; p=0.003). The PFS rates at 12 and 18 months were 84.8% (95% CI 75.0-95.9) and 71.3% (95% CI 58.7-86.7) in cohort A and 75.0% (95% CI 60.6-92.9) and 38.3% (95% CI 23.7-61.7) in cohort B, respectively. Grade 3 or 4 adverse events (AEs) were reported in 19 patients (38.8%) and seven patients (25.0%) in two cohorts, respectively. Grade 3 or 4 pneumonitis or immune-mediated pneumonitis, radiation pneumonitis, and pneumonia occurred in five (10.2%), four (8.2%), and two (4.1%) cohort A patients, and zero, two (7.1%), and two (7.1%) cohort B patients, respectively. Only cohort A reported AE leading to death in one (2.0%) patient (immune-mediated pneumonitis). Conclusion: Concurrent sintilimab with SCRT resulted in a significantly better ORR and longer PFS than SCRT alone, with manageable safety profiles in Chinese patients with unresectable stage III NSCLC.

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WHAT IS KNOWN AND OBJECTIVE: Although immune checkpoint inhibitors (ICIs) have shown clinical benefit for patients with non-small cell lung cancer (NSCLC), the efficacy of the combination of ICIs targeting different pathways is still unclear. We performed this meta-analysis to explore the efficacy of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor plus programmed cell death 1 receptor (PD-1)/programmed cell death receptor ligand 1 (PD-L1) inhibitor therapy (CP) for NSCLC IIIB/IV patients. METHODS: We systematically searched the main databases for relevant studies. The main outcomes were overall survival (OS) and progression-free survival (PFS). RESULTS AND DISCUSSION: We identified 3526 articles, including 5 randomized controlled trials (RCTs) (4377 patients), in our meta-analysis. We conducted two comparisons of CP versus chemotherapy or PD1/PDL1 inhibitor (P). Compared with chemotherapy, CP was more effective, with better OS (hazard ratio [HR]: 0.77, 95% CI [confidence interval]: 0.66-0.91; p = 0.001), better PFS (HR: 0.77, 95% CI: 0.70-0.85; p < 0.00001) and comparable objective response rate (ORR) (risk ratio [RR]: 1.27, 95% CI: 0.98-1.65; p = 0.07); in terms of toxicity, CP was comparable to chemotherapy across all-grade adverse events (AEs) (RR: 0.87, 95% CI: 0.73-1.03; p = 0.11) and grade 3-5 AEs (RR: 0.85, 95% CI: 0.63-1.14; p = 0.27). Compared with P, CP had no superiority in efficacy in terms of the OS (HR: 1.04, 95%CI: 0.86-1.24; p=0.70), PFS (HR: 0.95, 95%CI: 0.75-1.22; p = 0.70) and the ORR (RR: 1.07, 95% CI: 0.95-1.21; p = 0.27) but CP was more effective than P when PD-L1 expression was <1% (RR: 0.77,95%CI: 0.60-0.98; p = 0.04); in terms of toxicity, CP was associated with increased all-grade AEs (RR:1.07, 95% CI: 0.97-1.19; p = 0.18) and grade 3-5 AEs (RR:1.58, 95% CI: 1.21-2.07; p = 0.0008). WHAT IS NEW AND CONCLUSION: CP is a beneficial therapeutic schedule with longer PFS and OS than chemotherapy and has an acceptable, manageable grade 3-4 AE rate in IIIB/IV NSCLC. However, compared with P, CP results in better OS only in patients with PD-L1 expression <1%.

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Immune-checkpoint inhibitor mediated hepatobiliary injury is an emerging concern in cancer treatment. Most of these adverse reactions are attributed to nivolumab and are characterized by panlobular hepatitis. Large duct cholangiopathy related to these drugs is extremely rare. We present a case of adenocarcinoma of lung treated with pembrolizumab who developed biochemical and imaging features consistent with cholangiopathy characterized by common bile duct dilatation, wall enhancement, and gallbladder wall edema. On follow-up in the fourth month, the imaging features persisted despite the normalization of liver enzymes. To the best of our knowledge, this is the first description of diagnosis and follow-up imaging of pembrolizumab-related cholangiopathy in imaging literature.

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AIM: In this meta-analysis, we evaluated several predictors of benefit to single-agent immune checkpoint inhibitors (ICIs) in metastatic non-small-cell lung cancer (NSCLC). PATIENTS & METHODS: Using the random-effect model, we assessed the comparative efficacy of ICIs over chemotherapy according to age, gender, smoking history, PD-L1 status and CNS involvement. RESULTS: Eight randomized trials were selected. In comparison to chemotherapy, ICIs demonstrated significant progression-free survival (PFS) superiority in ever-smoker, male and PD-L1 positive subgroups. Never-smoker was an unfavorable factor for ICIs. Female and PD-L1 nonexpressing patients demonstrated similar PFS between ICIs and chemotherapy. ICI's PFS benefit wasn't influenced by age or CNS involvement. The overall survival (OS) benefit of ICIs was consistent across all subgroups, except for never-smokers. CONCLUSION: Male, ever-smoker and positive PD-L1 are indicative of benefit to ICIs in metastatic non-small-cell lung cancer.

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BACKGROUND: Immunotherapy targeting the checkpoint PD1 (programmed cell death protein 1) or PDL1 (programmed death ligand 1) has led to advances in the treatment of melanoma and non-small cell lung cancer (NSCLC). The use of such therapies has also been introduced into the treatment of other malignancies, including head and neck cancer. The combined effects of checkpoint inhibitors and anti-PD1(L1) antibodies and radiation therapy have not yet been sufficiently investigated. CASE PRESENTATION: We report a case of locally relapsed non-resectable oral cavity squamous cell carcinoma, with excellent local control after pembrolizumab (MK3475) followed by radiotherapy. CONCLUSION: T cell activation induced by checkpoint inhibition may dramatically improve tumor response to radiation. More data are needed to identify the toxicity and efficacy of sequential or concurrent checkpoint inhibitors and radiotherapy.

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