Chemotherapy combined with regorafenib and immune checkpoint inhibitors as a first-line treatment for patients with advanced biliary tract cancer: a single arm phase II trial.

Objective: This study aimed to investigate the efficacy, long-term prognosis and safety of combining chemotherapy with regorafenib and immune checkpoint inhibitors as first-line treatment for patients with advanced biliary tract carcinoma (BTC). Methods: In this single arm phase II trial, twenty-nine patients with advanced BTC were included, all of whom received gemcitabine-based chemotherapy combined with regorafenib and immune checkpoint inhibitors as the first-line treatment. And the study analyzed anti-tumor efficacy, long-term prognosis, and adverse reactions. Results: Among the patients, 0 patient achieved complete response, 18 patients (62.1%) achieved partial response, 8 patients (27.6%) had stable disease, and 3 patients (10.3%) experienced progressive disease. The corresponding objective response rate (ORR) was 18/29 (62.1%), and the disease control rate (DCR) was 26/29 (89.7%). The median overall survival (OS) was 16.9 months (95% confidence interval [CI]: 12.0 -21.8) and the median progress free survival (PFS) was 10.2 months (95% CI: 7.8- 12.6). The 1-year OS and PFS were 65% (95% CI: 0.479-0.864) and 41% (95% CI: 0.234-0.656), respectively. The incidence of adverse reactions was 27/29 (93.1%), and the incidence of grade III/IV adverse reactions was 5/29 (17.2%). Conclusion: The combination of chemotherapy, regorafenib, and immune checkpoint inhibitors as a first-line treatment for patients with advanced BTC may has good anti-tumor efficacy without causing serious adverse reactions, and can significantly improve the long-term prognosis.

Risk factors for relapse of immune-related pneumonitis after 6-week oral prednisolone therapy: a follow-up analysis of a phase II study.

BACKGROUND: Immune-related pneumonitis (irP) is one of the most important immune-related adverse events caused by immune checkpoint inhibitors (ICIs). After corticosteroid therapy irP frequently relapses, which can interfere with cancer therapy. However, risk factors for irP relapse are unknown. METHODS: This study was a follow-up analysis of a phase II study that evaluated 56 patients with grade ≥ 2 irP treated with oral prednisolone, 1 mg/kg/day, tapered over 6 weeks. Clinical factors including patient characteristics, blood test findings, and response to prednisolone therapy were assessed to identify risk factors for irP relapse using the Fine-Gray test. RESULTS: Among 56 patients with irP, 22 (39.3%) experienced irP relapse after 6 weeks of prednisolone therapy during the follow-up observation period. Radiographic organising pneumonia (OP) pattern and duration to irP onset ≥ 100 days from ICI initiation were determined to be significant risk factors for irP relapse in a multivariate Fine-Gray test (hazard ratio [HR] = 3.17, 95% CI 1.37-7.32, p = 0.007, and HR = 2.61, 95% CI 1.01-6.74, p = 0.048, respectively). Other patient characteristics, blood test findings, irP severity, and response to prednisolone therapy were not associated with irP relapse. CONCLUSIONS: In irP patients treated with 6-week prednisolone tapering therapy, OP pattern and duration to irP onset ≥ 100 days were associated with relapse risk. Assessment of the risk factors for irP relapse will be helpful for irP management.

Efficacy analysis of HAIC combined with lenvatinib plus PD1 inhibitor vs. first-line systemic chemotherapy for advanced intrahepatic cholangiocarcinoma.

This research was intended to compare the clinical efficacy of hepatic arterial infusion chemotherapy (HAIC) in conjunction with lenvatinib and PD1 inhibitors to first-line systemic chemotherapy for advanced intrahepatic cholangiocarcinoma(ICC). The research enrolled advanced ICC patients who underwent HAIC plus lenvatinib and PD1 inhibitor(n = 51) or first-line systemic chemotherapy(cisplatin + gemcitabine, n = 39) between July 2020 to January 2023 in Zhongshan People's Hospital.Their clinical outcomes were assessed through measurement of parameters encompassing objective response rate (ORR), disease control rate (DCR), median overall survival (mOS), median progression-free survival (mPFS), median duration of response (mDOR), and treatment-related adverse events (TRAEs). In accordance with the RECIST1.1, the ORR in the HAIC + L + P and SC groups was 43.1% and 20.5%, while the DCR was 90.2% and 69.2%, respectively (P = 0.04 and = 0.02, respectively). The change in the maximum diameter of intrahepatic target lesions in patients before and after treatment and the diameter of intrahepatic tumors in the HAIC + L + P group were sharply smaller versus the SC group ( P < 0.001). The HAIC + L + P group had prolonged mOS (16.8 months vs. 11.0 months, P = 0.01) and mPFS (12.0 months vs. 6.9 months, P < 0.01) in comparison with the SC group. Compared to first-line systemic chemotherapy(cisplatin + gemcitabine), HAIC plus lenvatinib and PD-1 inhibitors contributes to improvement of tumor response and prolongation of OS and PFS in advanced ICC patients.

Dynamics of tumor in situ fluid circulating tumor DNA in recurrent glioblastomas forecasts treatment efficacy of immune checkpoint blockade coupled with low-dose bevacizumab.

PURPOSE: Immune checkpoint blockade (ICB) therapies have shown efficacy in various tumors, but long-term responses in glioblastoma are less than 10%. Quantifying tumor in situ fluid circulating tumor DNA (TISF-ctDNA) and therapeutic dynamics may enable real-time GBM disease burden evaluation. This study explores the potential of tumor in situ fluid circulating tumor DNA (TISF-ctDNA) dynamics in predicting treatment efficacy. METHODS: TISF and peripheral blood samples were collected from patients with recurrent glioblastoma (rGBM) undergoing tislelizumab (a programmed death 1 inhibitor) combined with low-dose bevacizumab (an anti-vascular endothelial growth factor antibody) treatment before and during each immunotherapy cycle. Biomarkers evaluated included TISF-ctDNA, measured using Next Generation Sequencing (NGS), and host inflammation markers such as the platelet-to-lymphocyte ratio (PLR). RESULTS: All 32 patients received tislelizumab plus low-dose bevacizumab regularly. The median progression-free survival (PFS) was 4.0 months, and overall survival (OS) was 22.3 months. An analysis of 19 patients with continuous evaluable TISF showed baseline TISF-ctDNA abundance did not correlate with OS (p = 0.23) or PFS (p = 0.23). However, a change in TISF-ctDNA maximal Somatic Variant Allelic Frequency (MVAF) after six treatment cycles predicted both PFS (p = 0.02) and OS (p < 0.0001). Lower baseline PLR also correlated with better survival outcomes. CONCLUSION: The combination of tislelizumab and low-dose bevacizumab therapy appears to be effective in extending both OS and PFS in rGBM patients. Continuous TISF-ctDNA testing shows potential utility in complementing radiological monitoring. The temporal change pattern of TISF MVAF is more predictive of immunotherapy response than imaging. PLR before immunotherapy can screen patients likely to benefit from tislelizumab plus low-dose bevacizumab therapy. TRIAL REGISTRATION: The trial registration number: NCT05502991; Date of registration: 2022-08-14.

Efficacy and safety of lenvatinib combined with anti-PD-1 antibodies plus GEMOX chemotherapy as non-first-line systemic therapy in advanced gallbladder cancer.

BACKGROUND: Lenvatinib, programmed cell death 1 (PD-1) antibodies, and gemcitabine and oxaliplatin (GEMOX) chemotherapy have shown significant antitumor activity as first-line therapy against biliary tract cancer. This study evaluated their efficacy and safety as non-first-line therapy in advanced gallbladder cancer (GBC). METHODS: Patients with advanced GBC who received lenvatinib combined with anti-PD-1 antibodies and GEMOX chemotherapy as a non-first-line therapy were retrospectively analyzed. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR) and safety. RESULTS: A total of 36 patients with advanced GBC were included in this study. The median follow-up time was 11.53 (95% confidence interval (CI): 2.2-20.9) months, and the ORR was 36.1%. The median OS and PFS were 15.1 (95% CI: 3.2-26.9) and 6.1 (95% CI: 4.9-7.2) months, respectively. The disease control rate (DCR) and clinical benefit rate (CBR) were 75% and 61.1%, respectively. Subgroup analysis demonstrated that patients with programmed cell death-ligand 1 (PD-L1) expression had significantly longer PFS and OS than those without PD-L1 expression. Additionally, patients with a neutrophil-lymphocyte ratio (NLR) < 5.57 had a longer OS than those with an NLR ≥ 5.57. All patients experienced adverse events (AEs), with 61.1% experiencing grade 3 or 4 AEs, including myelosuppression (13.9%) and fatigue (13.3%), alanine transaminase or aspartate transaminase levels (8.3%), and diarrhea (8.3%). No grade 5 AEs were reported. CONCLUSION: Anti-PD-1 antibodies combined with lenvatinib and GEMOX chemotherapy are effective and well-tolerated as a non-first-line therapy in advanced GBC. PD-L1 expression and baseline NLR may potentially predict treatment efficacy.

Gut microbiome influences efficacy of Endostatin combined with PD-1 blockade against colorectal cancer.

The combination of anti-angiogenic drugs and immune checkpoint inhibitors (ICIs) in the treatment of tumors is emerging as a way to improve ICIs-resistant tumor therapy. In addition, gut microbes (GMs) are involved in angiogenesis in the tumor microenvironment and are also associated with the antitumor function of immune checkpoint inhibitors. However, it is unclear whether gut microbes have a role in anti-tumor function in the combination of anti-angiogenic drugs and immune checkpoint inhibitors for cancer treatment. Endostatin, an angiogenesis inhibitor, has been widely used as an antiangiogenic therapy for cancer. We showed that combined therapy with an adenovirus encoding human endostatin, named Ad-E, and PD-1 blockade dramatically abrogated MC38 tumor growth. The structure of intestinal microbes in mice was changed after combination treatment. We found that the antitumor function of combination therapy was inhibited after the elimination of intestinal microbes. In mice with depleted microbiota, oral gavage of Bacteroides fragilis salvaged the antitumor effects of combination Ad-E and αPD-1 monoclonal antibody (mAb) to a certain extent. Further, Bacteroides fragilis could improve CD3+T cells, NK cells, and IFNγ+CD8+ T cells in the tumor microenvironment to inhibit tumor growth. Besides, Bacteroides fragilis might restore antitumor function by down-regulating isobutyric acid (IBA). Our results suggested that GMs may be involved in the combination of Ad-E and αPD-1 mAb for cancer treatment, which has oncological implications for tumor growth dynamics and cancer immune surveillance.

Sequential vs. concurrent systemic therapies in combination with FOLFOX-HAIC for locally advanced hepatocellular carcinoma: a single-center, real-world cohort study.

BACKGROUND: Tri-combination therapy based on hepatic arterial infusion chemotherapy (HAIC) of infusion fluorouracil, leucovorin, and oxaliplatin (FOLFOX-HAIC) plus immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) for the locally advanced hepatocellular carcinoma (HCC) patients have been proven effective. However, whether it was best for these HCC patients to start with the most potent therapeutic pattern was still under debate. This retrospective study evaluated the efficacy and safety of FOLFOX-HAIC combined with systemic therapies in the patterns of sequential and concurrent schedules. METHODS: This real-world study included 117 unresectable HCC patients who initially received either FOLFOX-HAIC monotherapy (HAIC group, n = 44) or concurrent ICIs and TKIs (ConHAIC group, n = 73) from March 2020 and June 2022, during the period of FOLFOX-HAIC monotherapy in HAIC group, patients in the HAIC group (n = 30) experienced progressive disease (PD) would have their treatment pattern converted from the FOLFOX-HAIC monotherapy to the combination of FOLFOX-HAIC plus ICIs and TKIs sequentially (SeqHAIC group). The progression-free survival (PFS) and overall survival (OS), as primary outcomes, were compared between patients in the SeqHAIC and ConHAIC groups. RESULTS: The median follow-up time of the SeqHAIC group was 24.92 months (95% CI, 12.74-37.09 months) and of the ConHAIC group was 17.87 months (95% CI, 16.85-18.89 months) and no significant difference was observed in both PFS (HR, 1.572; 95% CI, 0.848-2.916; p = 0.151) and OS (HR, 1.212; 95% CI, 0.574-2.561; p = 0.614) between the SeqHAIC and the ConHAIC groups. As for the tumor responses, there was no significant difference between the two groups regarding tumor responses, overall response rates (p = 0.658) and disease control rates (p = 0.641) were 50.0%, 45.2%, and 83.3%, 89.0% for the SeqHAIC and the ConHAIC groups, respectively. CONCLUSION: Our study revealed that sequential systemic ICIs and TKIs in combination with FOLFOX-HAIC provides similar long-term prognosis and better tolerability compared to concurrent therapy for locally advanced HCC patients. Prospective studies with a larger sample size and longer follow-up are required to validate these findings.

Current immunotherapy techniques in meningioma.

INTRODUCTION: Although meningiomas are the most common primary brain tumor, there are limited treatment options for recurrent or aggressive lesions. Compared to other brain tumors, meningiomas may be uniquely amenable to immunotherapy by virtue of their location outside the blood-brain barrier. AREAS COVERED: This review describes our current understanding of the immunology of the meninges, as well as immune cell infiltration and immune signaling in meningioma. Current literature on meningioma immunology and immunotherapy was comprehensively reviewed and summarized by a comprehensive search of MEDLINE (1/1/1990-6/1/2024). Further, we describe the current state of immunotherapeutic approaches, as well as potential future targets. Potential immunotherapeutic approaches include immune checkpoint inhibition, CAR-T approaches, tumor vaccine therapy, and immunogenic molecular markers. EXPERT OPINION: Meningioma immunotherapy is in early stages, as no immunotherapies are currently included in treatment guidelines. There is substantial heterogeneity in immune cell infiltration, immunogenicity, and immune escape across tumors, even within tumor grade. Furthering our understanding of meningioma immunology and tumor classification will allow for careful selection of tumors and patient populations that may benefit from primary or adjunctive immunotherapy for meningioma.

Real-world efficacy and safety of durvalumab-tremelimumab as second-line systemic therapy after atezolizumab-bevacizumab in unresectable hepatocellular carcinoma.

The efficacy and safety of immune-checkpoint inhibitors (ICI) for the treatment of unresectable hepatocellular carcinoma are known. We explored ICI rechallenges with direct switching from 1 ICI regimen to another. This retrospective study included 16 patients who received atezolizumab-bevacizumab (Atezo+Bev) and durvalumab-tremelimumab (Dur+Tre) as the first-line and second-line combination therapy, respectively, at Hiroshima University Hospital. The radiological response and adverse event were evaluated in all patients. Of the 16 patients, 12 were male, and the median age at Atezo+Bev induction was 71 years. The reasons for medication changes were disease progression in 11 patients and adverse events in 5 patients. With Atezo+Bev and Dur+Tre initiation, the Barcelona-Clinic Liver-Cancer stage (A/B/C) progressed in 9/6/3 and 3/4/9 patients and the Child-Pugh classification (A/B/C) progressed in 12/4/0 and 9/6/3 patients, respectively. The disease control rate and overall response rate of Atezo+Bev were 87.5% and 58.3%, respectively, and of Dur+Tre were 62.5% and 0%, respectively. The most common immune-related adverse event in both the Atezo+Bev and Dur+Tre groups was colitis; 3 of the 5 patients with colitis on Atezo+Bev treatment had colitis with Dur+Tre, and 2 had exacerbations. Regarding liver function, ALBI score significantly decreased during Atezo+Bev, but not Dur+Tre, treatment. In patients with colitis following Atezo+Bev, subsequent Dur+Tre treatment may induce colitis recurrence or exacerbation. For immune-related adverse events other than colitis, Dur+Tre could provide relatively safe disease control while maintaining liver function.

Circulating tumor DNA-based stratification strategy for chemotherapy plus PD-1 inhibitor in advanced non-small-cell lung cancer.

Stratification strategies for chemotherapy plus PD-1 inhibitors in advanced non-small-cell lung cancer (NSCLC) are critically demanded. We performed high-throughput panel-based deep next-generation sequencing and low-pass whole genome sequencing on prospectively collected circulating tumor DNA (ctDNA) specimens from 460 patients in the phase 3 CHOICE-01 study at different time points. We identified predictive markers for chemotherapy plus PD-1 inhibitor, including ctDNA status and genomic features such as blood-based tumor mutational burden, intratumor heterogeneity, and chromosomal instability. Furthermore, we established an integrated ctDNA-based stratification strategy, blood-based genomic immune subtypes (bGIS) scheme, to distinguish patients who benefit from the addition of PD-1 inhibitor to first-line chemotherapy. Moreover, we demonstrated potential applications for the dynamic monitoring of ctDNA. Overall, we proposed a potential therapeutic algorithm based on the ctDNA-based stratification strategy, shedding light on the individualized management of immune-chemotherapies for patients with advanced NSCLC.

Efficacy and safety of transarterial chemoembolization plus lenvatinib combined with PD-1 inhibitors versus transarterial chemoembolization plus lenvatinib for unresectable hepatocellular carcinoma: a meta-analysis.

Background: Locoregional treatment combined with systemic therapy is expected to play a synergistic anticancer role. We conducted this systemic meta-analysis to examine the efficacy and safety of transarterial chemoembolization (TACE) plus lenvatinib with or without programmed cell death protein-1 (PD-1) inhibitors (TLP group) compared with TACE + lenvatinib (TL group) for unresectable hepatocellular carcinoma (uHCC). Methods: From the inception date to April 2024, the data from PubMed, EMBASE, the Cochrane Library, Ovid, Web of Science, and Clinical Trials. gov were used for meta-analysis. All clinical outcomes of interest included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). The hazard ratio (HR) and risk ratio (RR) with 95% confidence intervals (CI) were used to measure the pooled effect. Results: This study included 10 retrospective cohort studies, including 1128 patients. The OS (HR=0.51; 95% CI: 0.43-0.60, P < 0.05), PFS (HR=0.52; 95% CI: 0.45-0.61, P < 0.05), ORR (RR = 1.58; 95% CI: 1.37-1.83; P < 0.05) and DCR (RR = 1.31; 95% CI: 1.20-1.43; P < 0.05) were significantly higher in TLP group than in the TL group. The incidence of AEs was acceptable. Prognostic factor analysis identified that ECOG PS (1/0), Child-Pugh class (B/A), BCLC stage (C/B) and main portal vein invasion (yes/no) were independent prognostic factors for OS. BCLC stage (C/B) and main portal vein invasion (yes/no) were independent prognostic factors for PFS. Conclusion: The TLP group had better efficacy for uHCC than that of the TL group, with acceptable safety. Systematic review registration: PROSPERO, identifier (CRD42023420093).

Tivozanib plus nivolumab versus tivozanib monotherapy in patients with renal cell carcinoma following an immune checkpoint inhibitor: results of the phase 3 TiNivo-2 Study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor receptor tyrosine kinase inhibitors are cornerstones of first-line treatment for advanced renal cell carcinoma; however, optimal treatment sequencing after progression is unknown. This study aimed to assess clinical outcomes of tivozanib-nivolumab versus tivozanib monotherapy in patients with metastatic renal cell carcinoma who have progressed following one or two lines of therapy in the post-ICI setting. METHODS: TiNivo-2 is a multicentre, randomised, open-label, phase 3 trial at 190 sites across 16 countries, in Australia, Europe, North America, and South America. Patients with advanced renal cell carcinoma and progression during or after one to two previous lines of therapy (including one ICI) were randomised 1:1 to tivozanib (0·89 mg per day, orally) plus nivolumab (480 mg every 4 weeks, intravenously) or tivozanib (1·34 mg per day, orally). Randomisation was stratified by immediate previous therapy (ICI or non-ICI) and International Metastatic Renal Cell Carcinoma Database Consortium risk category. The primary endpoint was progression-free survival (PFS), defined as the time from randomisation to first documentation of objective progressive disease according to RECIST 1·1 or death from any cause, whichever came first, by independent radiology review. Efficacy was evaluated in the intention-to-treat population, and safety was assessed in patients who received one or more doses of the study drug. This trial was registered on ClinicalTrials.gov (NCT04987203) and is active and not recruiting. FINDINGS: From Nov 4, 2021, to June 16, 2023, 343 patients were randomly assigned to tivozanib-nivolumab (n=171) or tivozanib monotherapy (n=172). Median follow-up was 12·0 months. Median PFS was 5·7 months (95% CI 4·0-7·4) with tivozanib-nivolumab and 7·4 months (5·6-9·2) with tivozanib monotherapy (hazard ratio 1·10, 95% CI 0·84-1·43; p=0·49). Among those with an ICI as their immediate previous therapy (n=244), median PFS was 7·4 months (95% CI 5·6-9·6) with tivozanib-nivolumab and 9·2 months (7·4-10·0) with tivozanib monotherapy. With non-ICIs as the most recent therapy, lower median PFS was observed, with no difference between groups (tivozanib-nivolumab 3·7 months [95% CI 2·7-5·4] and with tivozanib monotherapy 3·7 months [1·9-7·2]). Serious adverse events occurred in 54 (32%) of 168 patients receiving tivozanib-nivolumab and 64 (37%) of 171 patients receiving tivozanib monotherapy. One (<1%) treatment-related death occurred (tivozanib group). INTERPRETATION: These data further support that ICI rechallenge should be discouraged in patients with advanced renal cell carcinoma. Furthermore, these data suggest that tivozanib monotherapy has efficacy in the post-ICI setting. FUNDING: Aveo Pharmaceuticals.

The short-term efficacy of neoadjuvant SOX versus SOX plus immune checkpoint inhibitor following laparoscopic gastrectomy for locally advanced gastric cancer: a multicenter retrospective cohort study in China.

BACKGROUND: This study aims to evaluate the short-term efficacy for locally advanced gastric cancer (LAGC) who accepted laparoscopic gastrectomy (LG) after neoadjuvant SOX versus SOX plus immune checkpoint inhibitors (ICIs). METHODS: LAGC patients who accepted LG after neoadjuvant SOX (SOX-LG, n = 169) and SOX plus ICIs (SOX + ICIs-LG, n = 140) in three medical centers between Jan 2020 and Mar 2024 were analyzed. We compared the tumor regression, treatment-related adverse events (TRAEs), perioperative safety between two groups, and explored the risk factors of postoperative complications (POCs) for LG after neoadjuvant therapy. RESULTS: The baseline characteristics were comparable between two groups (P > 0.05). SOX + ICIs-LG group acquired a higher proportion of objective response (63.6% vs. 46.7%, P = 0.003), major pathological response (43.6% vs. 31.4%, P = 0.001), and pathological complete response (17.9% vs. 9.5%, P = 0.030). There were no significant differences in the TRAEs rates, operation time, R0 resection, retrieved lymph nodes, postoperative first flatus, and hospitalized days, overall and severe POCs between two groups (P > 0.05). Patients in the SOX-ICIs-LG group had lower estimated blood loss (EBL) compared with SOX-LG (P = 0.001). Multivariate analysis showed that more EBL (P = 0.003) and prognostic nutritional index (PNI) < 40 (P = 0.005) were independent risk factors of POCs for LG after neoadjuvant therapy. CONCLUSION: Neoadjuvant SOX plus ICIs brings better tumor regression and similar TRAEs compared with SOX alone for LAGC. SOX + ICIs-LG is safe and feasible to conduct with less EBL. Surgeons should focus on the perioperative management to control POCs for patients with PNI < 40 and more EBL.

Optimizing inpatient care for lung cancer patients with immune checkpoint inhibitor-related pneumonitis using a clinical care pathway algorithm.

PURPOSE: Immune checkpoint inhibitor-related pneumonitis (ICI-P) is a condition associated with high mortality, necessitating prompt recognition and treatment initiation. This study aimed to assess the impact of implementing a clinical care pathway algorithm on reducing the time to treatment for ICI-P. METHODS: Patients with lung cancer and suspected ICI-P were enrolled, and a multimodal intervention promoting algorithm use was implemented in two phases. Pre- and post-intervention analyses were conducted to evaluate the primary outcome of time from ICI-P diagnosis to treatment initiation. RESULTS: Of the 82 patients admitted with suspected ICI-P, 73.17% were confirmed to have ICI-P, predominantly associated with non-small cell lung cancer (91.67%) and stage IV disease (95%). Pembrolizumab was the most commonly used immune checkpoint inhibitor (55%). The mean times to treatment were 2.37 days in the pre-intervention phase, 3.07 days (p = 0.46), and 1.27 days (p = 0.40) in the post-intervention phases 1 and 2, respectively. Utilization of the immunotoxicity order set significantly increased from 0 to 27.27% (p = 0.04) after phase 2. While there were no significant changes in ICU admissions or inpatient mortality, outpatient pulmonology follow-ups increased statistically significantly, demonstrating enhanced continuity of care. The overall mortality for patients with ICI-P was 22%, underscoring the urgency of optimizing management strategies. Notably, all patients discharged on high-dose corticosteroids received appropriate gastrointestinal prophylaxis and prophylaxis against Pneumocystis jirovecii pneumonia infections at the end of phase 2. CONCLUSION: Implementing a clinical care pathway algorithm for managing severe ICI-P in hospitalized lung cancer patients standardizes practices, reducing variability in management.

Steroid-refractory immune checkpoint inhibitor (ICI) hepatitis and ICI rechallenge: A systematic review and meta-analysis.

BACKGROUND: In recent years, the use of immune checkpoint inhibitors (ICIs) has become a cornerstone in cancer treatment. However, this has also resulted in the emergence of immune-related adverse events, notably ICI hepatitis, posing a significant clinical challenge. While steroids are the primary treatment, there are increasing cases of steroid-refractory ICI hepatitis. Our objective is to investigate the management of ICI hepatitis and its response to steroid treatment. METHODS: PubMed/MEDLINE, EMBASE, and CENTRAL databases were searched in July 2023 based on keywords including ICIs (anti-Programmed cell death protein 1/Programmed Death-Ligand 1, anti-CTLA-4, and anti-LAG3) and hepatitis. RESULTS: A total of 4358 studies were screened, and 44 studies were included in this systematic review. One thousand eight hundred fifty-six patients with ICI hepatitis were included (grade 1-2: 31.7%, grade 3-4: 56.0%, and unknown: 12.3%) with 1184 patients who received corticosteroid treatment. The duration of treatment and dosage varied considerably across the studies. Mycophenolate mofetil was the predominant agent used in 68 out of 82 cases (82.9%), followed by infliximab and azathioprine. A summary estimate of the proportion of steroid-refractory hepatitis in a random effects model was 16% (95% CI: 11%-23%). An estimated 40% (95% CI: 30%-51%) of patients of all patients with ICI hepatitis were rechallenged with an ICI, and of those rechallenged, there was an estimated 22% (95% CI: 15%-30%) recurrence. CONCLUSIONS: Corticosteroids are the primary treatment for ICI hepatitis, with mycophenolate mofetil used as a secondary option for steroids-refractory cases. Current practices mostly rely on expert consensus, highlighting the need for further research to validate and optimize these treatments, particularly for steroid-resistant cases.

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

BACKGROUND: The 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. METHODS: In 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). RESULTS: Brain 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). CONCLUSIONS: In 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.).

Functional co-delivery nanoliposomes based on improving hypoxia for increasing photoimmunotherapy efficacy of cold tumors.

Cold tumors lack T cells infiltration and have low immunogenicity, resulting insufficient immunotherapy response. Therefore, how to realize the transformation from cold tumor to hot tumor is an urgent problem to be solved. Photodynamic therapy can induce immunogenic death of tumor cells (ICD) and activate T lymphocytes to produce tumor immune response. However, hypoxia in the cold tumor microenvironment limits the effectiveness of photodynamic therapy. So in this article, MET-HMME/CAT-HMME@Nlip as a functional co-delivery nanoliposomes was constructed based on overcoming the above problems. Firstly, the oxygen-deficient state could be improved by the following two ways, one is catalase loaded in CAT-HMME@Nlip can decompose high concentration hydrogen peroxide to produce oxygen, and the other is metformin loaded in MET-HMME@Nlip can decrease oxygen consumption by inhibiting of mitochondrial respiration. And then with the increase of substrate oxygen concentration, the sensitivity of photodynamic therapy can be greatly improved and the anti-tumor immune response by PDT-induced ICD can also be enhanced obviously. In addition, metformin could act as a small molecule immune checkpoint inhibitor to reduce the expression of PD-L1 on the surface of tumor cells, thereby effectively improving the specific killing ability of cytotoxic T cells to tumor cells which could not only erasing the primary tumor, but also inhibiting the growth of simulated distant tumors through the immune memory function. This study provides a new idea for improving the clinical treatment effect of hypoxic cold tumors, especially for tumors that could not benefit from immunotherapy due to low or no expression of PD-L1 protein on the surface of tumor cells.

Immune-Related Adverse Events Can Predict Progression-Free and Overall Survival In Patients With Metastatic Renal Cell Carcinoma Treated With Immune Checkpoint Inhibitors.

BACKGROUND: Different combination therapies using anti - PD-1 / PD-L1 or CTLA-4 immune checkpoint inhibition (ICI) are widely used in patients with metastatic renal cell carcinoma (mRCC). In the absents of established biomarkers, immune-related adverse events (irAEs) have been discussed as potential predictors of response. METHODS: In this retrospective cohort study, data of 134 patients with mRCC undergoing ICI treatment (Nivolumab, Ipilimumab and Nivolumab, Pembrolizumab and Axitinib or Avelumab and Axitinib) between 2015 and 2021 were analyzed. To examine the utility of irAEs as predictors of overall survival (OS) and progression-free survival (PFS), separate Kaplan-Meier analyses and Cox proportional regression analyses were applied. Landmark analysis was conducted after 12 weeks to reduce immortal time bias. RESULT: irAEs were observed in 85 patients (63.4%). Cutaneous (n = 52, 38.8%), endocrine (n = 33, 24.6%) and hepatic (n = 19, 14.2%) irAEs were most commonly observed. In Kaplan-Meier analysis, patients experiencing irAEs showed favorable median PFS (15 months, 95% CI, 9.91-20.09) compared to the non-irAE group (5 months, 95% CI, 3.56-6.44, P < .001). The median OS was 25 months (95% CI, 16.79-33.21) in the non-irAE group, while it was not reached in the irAE group (P = .002). In multivariable analysis, the presence of any irAE was associated with favorable PFS (HR 0.46 [95% CI, 0.26-0.82] P = .008) and OS (HR: 0.28 [95% CI, 0.12-0.63] P = .002), respectively. Landmark analysis after 12 weeks showed mixed results depending on the classification of the irAE group at the landmark time. CONCLUSION: The presence of irAEs under ICI therapy in patients with mRCC is associated with better PFS and OS. Thus, manageable irAEs should not be cause for premature discontinuation of ICI therapy, as they seem to indicate favorable outcomes. Considering the time-dependent nature of irAEs is crucial estimating their value as predictive markers.

Anti-PD-L1 checkpoint inhibitor combined with nanocarrier-mediated cisplatin codelivery system for effective treatment of pancreatic cancer.

Immune checkpoint inhibitor-based cancer immunotherapy has shown promise as a potential treatment in the clinic. It has been reported that anti-PD-L1 combined with cisplatin treatment can improve the antitumor effect. However, the therapeutic outcome is limited due to the abundance of tumor stroma in pancreatic cancer (PC), which prevented the penetration of cisplatin and anti-PD-L1 into tumor regions, thus impeding the effectiveness in the treatment of PC. In this study, a nanocarrier-mediated codelivery system of hyaluronidase and cisplatin was constructed, which can degrade the stroma and promote cisplatin and anti-PD-L1 to penetrate the tumor stroma into the deep tumor, so as to suppress PC effectively. When combined the cisplatin nanocarrier system BPEI-SS-Pt/HAase@CaP (BSP/H@CaP) with an immune checkpoint inhibitor to overcome the poor therapeutic outcome of PC, the results indicated that the therapeutic effect of BSP/H@CaP combined with anti-PD-L1 was better than that of BSP/H@CaP and single anti-PD-L1 group. Because the stroma is degrading, a higher amount of BPEI-SS-Pt and anti-PD-L1 can enter the tumor stroma and reach the inner depths of the tumor for immune stimulation, leading to a synergistically augmented chemotherapy and immunotherapy for PC. The above combination therapy is useful for clinical translation to overcome the treatment resistance of matrix-rich PC.

Effect of neoadjuvant chemoradiotherapy with or without PD-1 antibody sintilimab in pMMR locally advanced rectal cancer: A randomized clinical trial.

Neoadjuvant chemoradiotherapy (NACRT) was the standard treatment for patients with locally advanced rectal cancer (LARC) with proficient mismatch repair (pMMR) proteins. In this randomized phase 2 trial (ClinicalTrial.gov: NCT04304209), 134 pMMR LARC patients were randomly (1:1) assigned to receive NACRT or NACRT and the programmed cell death protein 1 (PD-1) antibody sintilimab. As the primary endpoint, the total complete response (CR) rate is 26.9% (18/67, 95% confidence interval [CI] 16.0%-37.8%) and 44.8% (30/67, 95% CI 32.6%-57.0%) in the control and experimental arm, respectively, with significant difference (p = 0.031 for chi-squared test). Response ratio is 1.667 (95% CI 1.035-2.683). Immunohistochemistry shows PD-1 ligand 1 (PD-L1) combined positive score is associated with the synergistic effect. The safety profile is similar between the arms. Adding the PD-1 antibody sintilimab to NACRT significantly increases the CR rate in pMMR LARC, with a manageable safety profile. PD-L1 positivity may help identify patients who might benefit most from the combination therapy.