UNASSIGNED: Our study aimed to build a risk stratification system predicting the progression-free survival (PFS) to classify patients into diverse prognostic subgroups for advanced non-small-cell lung cancer patients treated with PD-(L)1 inhibitor.
UNASSIGNED: 404 patients from our center were enrolled in this study and 70% patients (n = 282) were randomly assigned into the training cohort and other 30% patients (n = 122) into the validation cohort. A testing cohort contained 81 patients from other centers were used to assess the generalizability of model. Cox regression analyses were used to identify the most significant clinical parameters. The model\'s performance was assessed by using concordance index (C-index), calibration curves, Decision Curve Analyses (DCAs), net reclassification improvement (NRI), integrated discrimination improvement (IDI) analyses, and survival curve.
UNASSIGNED: Five clinical parameters were identified as the most significant predictors by using cox regression. We then integrated them into a Nomogram to Evaluate the relative PFS of ICIs Treatment (NEPIT). The C-index of NEPIT in the training cohort, the validation cohort and testing cohort was 0.789 (95%CI: 0.750-0.828), 0.745 (95%CI: 0.706-0.784), and 0.766 (95%CI: 0.744-0.788), respectively. The calibration curves presented a good congruence between the predictions and actual observations. The Decision Curve Analyses (DCAs) reflected positive net benefits can be obtained for NEPIT. The results from NRI and IDI analyses showed that the NEPIT could improve predictive power of TPS. In addition, the further constructed risk stratification system could effectively categorize patients into different risk subgroups.
UNASSIGNED: The tools developed in this study would have value in guiding the optimal patient selection for precision care.

UNASSIGNED: In the study, patients with unresectable hepatocellular carcinoma (uHCC) were treated with either transcatheter chemoembolization (TACE) combined with lenvatinib and PD-(L)1 inhibitor (TACE-L-P) or TACE combined with lenvatinib (TACE-L). We compared the efficacy and safety of TACE-L-P with TACE-L, and analyzed factors affecting prognosis.
UNASSIGNED: A total of 122 patients were treated with either TACE-L-P (n = 64) or TACE-L (n = 58), and their data was collected and analyzed. We assessed tumor response, progression-free survival (PFS), prognostic factors for PFS and adverse events (AEs) to compare the efficacy and safety of TACE-L-P with TACE-L for patients with uHCC.
UNASSIGNED: TACE-L-P group\'s patients had a better objective response rate (ORR) (57.8% vs 41.4%, P = 0.047) and a better disease control rate (93.7% vs 81%, P = 0.013), as long as a longer median progression-free survival (PFS) (8 months vs 4.6 months, HR: 0.461; 95% CI: [0.314-0.675]; P = 0.001) than TACE-L group\'s patients. According to multivariate analysis, independent prognostic factors for PFS included treatment option (TACE-L-P / TACE-L; RH = 0.461; 95% CI [0.314-0.675]; P = 0.001), PVTT (Yes/No; RH =1 0.599;95% CI [1 0.095-2 0.336]; P=0 0.017), extrahepatic metastasis (Yes/No; RH=1 0.847;95% CI [1 0.176 -2 0.909]; P=0 0.008). AEs in TACE-L-P group was similar with TACE-L group.
UNASSIGNED: TACE-L-P has more promising clinical outcomes in patients with uHCC than TACE-L, and their safety is similar.

Biomarkers of systemic inflammation/nutritional status have been associated with outcomes in advanced-stage non-small-cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs). However, most of them were not tested in cohorts of patients treated with ICIs in combination with chemotherapy (CT) (ICI + CT) or with CT alone, making it impossible to discriminate a predictive from a prognostic effect. We conducted a single-center retrospective study to search for associations between various baseline biomarkers/scores that reflected the systemic inflammation/nutritional status (Lung Immune Prognostic Index, Modified Lung Immune Prognostic Index, Scottish Inflammatory Prognostic Score, Advanced Lung Cancer Inflammation Index, EPSILoN, Prognostic Nutritional Index, Systemic Immune-Inflammation Index, Gustave Roussy Immune Score, Royal Marsden Hospital Prognostic Score, Lung Immuno-oncology Prognostic Score 3, Lung Immuno-oncology Prognostic Score 4, score published by Holtzman et al., and Glasgow Prognostic Score) and outcomes in metastatic NSCLC treated in a first-line setting either with ICI in monotherapy (cohort 1; n = 75), ICI + CT (cohort 2; n = 56), or CT alone (cohort 3; n = 221). In the three cohorts, the biomarkers/scores were moderately associated with overall survival (OS) and progression-free survival (PFS). Their prognostic performance was relatively poor, with a maximum c-index of 0.66. None of them was specific to ICIs and could help to choose the best treatment modality. The systemic inflammation/nutritional status, associated with outcomes independently of the treatment, is therefore prognostic but not predictive in metastatic NSCLC.

The immune system plays an important role in controlling epithelial ovarian cancer (EOC). EOC is considered to be a \"cold tumour,\" a tumour that has not triggered a strong response by the immune system. However, tumour infiltrating lymphocytes (TILs) and the expression of programmed cell death ligand (PD-L1) are used as prognostic indicators in EOC. Immunotherapy such as PD-(L)1 inhibitors have shown limited benefit in EOC. Since the immune system is affected by behavioural stress and the beta-adrenergic signalling pathway, this study aimed to explore the impact of propranolol (PRO), a beta-blocker, on anti-tumour immunity in both in vitro and in vivo EOC models. Noradrenaline (NA), an adrenergic agonist, did not directly regulate PD-L1 expression but PD-L1 was significantly upregulated by IFN-γ in EOC cell lines. IFN-γ also increased PD-L1 on extracellular vesicles (EVs) released by ID8 cells. PRO significantly decreased IFN-γ levels in primary immune cells activated ex vivo and showed increased viability of the CD8+ cell population in an EV-immune cell co-incubation. In addition, PRO reverted PD-L1 upregulation and significantly decreased IL-10 levels in an immune-cancer cell co-culture. Chronic behavioural stress increased metastasis in mice while PRO monotherapy and the combo of PRO and PD-(L)1 inhibitor significantly decreased stress-induced metastasis. The combined therapy also reduced tumour weight compared to the cancer control group and induced anti-tumour T-cell responses with significant CD8 expression in tumour tissues. In conclusion, PRO showed a modulation of the cancer immune response by decreasing IFN-γ production and, in turn, IFN-γ-mediated PD-L1 overexpression. The combined therapy of PRO and PD-(L)1 inhibitor decreased metastasis and improved anti-tumour immunity offering a promising new therapy.

In recent years, immunotherapy has significantly changed the treatment of locally advanced/metastatic non-small-cell lung cancer (NSCLC). Conversely, the role of immunotherapy in NSCLC with uncommon histologies remains unclear, while in other rare thoracic malignancies, such as malignant pleural mesothelioma and thymic epithelial tumors, the use of immune checkpoint inhibitors is modifying therapeutic strategies with solid hopes for the future. However, larger prospective studies are urgently needed to define the best treatment strategies and the role of immunotherapy in these orphan tumors. This review provides a comprehensive overview of the emerging role of immunotherapy in the treatment of patients affected by these rare thoracic malignancies.

BACKGROUND: Locally advanced or metastatic squamous carcinoma of the anal canal (SCAC) has poor prognosis following platinum-based chemotherapy. Retifanlimab (INCMGA00012), a humanized monoclonal antibody targeting programmed death protein-1 (PD-1), demonstrated clinical activity across a range of solid tumors in clinical trials. We present results from POD1UM-202 (NCT03597295), an open-label, single-arm, multicenter, phase II study evaluating retifanlimab in patients with previously treated advanced or metastatic SCAC.
METHODS: Patients ≥18 years of age had measurable disease and had progressed following, or were ineligible for, platinum-based therapy. Retifanlimab 500 mg was administered intravenously every 4 weeks. The primary endpoint was overall response rate (ORR) by independent central review. Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.
RESULTS: Overall, 94 patients were enrolled. At a median follow-up of 7.1 months (range, 0.9-19.4 months), ORR was 13.8% [95% confidence interval (CI) 7.6% to 22.5%], with one complete response (1.1%) and 12 partial responses (12.8%). Responses were observed regardless of human immunodeficiency virus or human papillomavirus status, programmed death ligand 1 (PD-L1) expression, or liver metastases. Stable disease was observed in 33 patients (35.1%) for a DCR of 48.9% (95% CI 38.5% to 59.5%). Median DOR was 9.5 months (range, 5.6 months-not estimable). Median (95% CI) PFS and OS were 2.3 (1.9-3.6) and 10.1 (7.9-not estimable) months, respectively. Retifanlimab safety in this population was consistent with previous experience for the PD-(L)1 inhibitor class.
CONCLUSIONS: Retifanlimab demonstrated clinically meaningful and durable antitumor activity, and an acceptable safety profile in patients with previously treated locally advanced or metastatic SCAC who have progressed on or are intolerant to platinum-based chemotherapy.

In solid tumor Phase 1/2 trials (NCT02407990; NCT04068519), tislelizumab demonstrated clinical benefit, including in advanced gastroesophageal adenocarcinoma (GEA). However, the majority of patients with GEA did not respond, highlighting the need to understand mechanisms of resistance and identify predictive biomarkers for response.
All tislelizumab-treated patients with GEA from the Phase 1/2 trials were included (N = 105). Programmed death-ligand 1 (PD-L1) expression (Tumor Area Positivity [TAP] ≥ 5%), interferon gamma (IFNγ)-related gene signature, gene expression profile, tumor mutational burden (TMB), and gene hyperamplification (HA) were analyzed for correlation with tislelizumab.
A moderate association was observed between PD-L1 TAP ≥ 5%, IFNγ gene signature, TMB-high and efficacy. A potential correlation between hyperamplification (HA +) and worse outcomes with programmed cell death protein 1 (PD-1) inhibition was identified. Hyperamplified genes were mainly enriched in cancer progression pathways, including cell cycle and RTK-RAS-PI3K pathways. Joint PD-L1 TAP ≥ 5% and lack of hyperamplification showed the most favorable benefit with an objective response rate of 29.4%, and median progression-free survival and overall survival of 4.1 and 14.7 months, respectively. Tumors with TAP ≥ 5% and HA - had inflamed immune signatures with increased immune cell infiltration, enhanced anti-tumor cytotoxic activity and antigen presentation signatures. Findings were validated in two independent gastric and gastrointestinal cancer cohorts treated with immune checkpoint inhibitors.
In GEA, PD-L1 positivity, IFNγ-related gene signature and TMB-high status were positively associated with tislelizumab clinical benefit, whereas HA was associated with worse clinical outcomes. Combining PD-L1 positivity and HA - may help identify patients more likely to benefit from PD-1 blockade.

The safety of thoracic radiotherapy (TRT) after programmed death 1/programmed death ligand 1 (PD-(L)1) inhibitor treatment in patients with lung cancer was scarcely reported. This retrospective study was conducted to evaluate the incidence, severity, and risk factors of symptomatic treatment-related pneumonitis in patients with lung cancer who received this sequential combination.
We conducted a retrospective study of a cohort of patients with lung cancer who received TRT after at least two cycles of PD-(L)1 inhibitor treatment between January 2018 and August 2020. Treatment-related pneumonitis was evaluated and analyzed to illustrate the safety profile of this sequential combination. Potential risk factors were explored by univariate and multivariate logistic regression analyses.
Among the 828 patients with prior PD-(L)1 inhibitor treatment, 96 patients receiving subsequent TRT were included in the analysis. Of these, 49 patients (51%) received radical TRT while 47 patients (49%) received palliative TRT. The median total dose was 52 Gy (IQR 50-60 Gy). The median time from the initiation of PD-(L)1 inhibitor treatment to TRT was 4.8 months (1.6-14.1 months) with most of the patients (74%) administering no less than four cycles of PD-(L)1 inhibitor. During follow-up, 47 patients (48.96%) developed symptomatic treatment-related pneumonitis (grade 2 n = 28, grade ≥3 n = 19) while six patients (6.25%) suffered from fatal toxicity. The median time of pneumonitis onset after completion of TRT was 35 days (0-177 days) with six patients developing during TRT. Pulmonary emphysema and lung V20 were demonstrated to be independent risk factors of symptomatic pneumonitis (OR: 5.67, 95% CI: 1.66-19.37, p = 0.006; OR: 3.49, 95% CI: 1.41-8.66, p = 0.007, respectively).
TRT after PD-(L)1 inhibitor treatment resulted in significantly increased incidence and severity of treatment-related pneumonitis in patients with lung cancer. Intensive attention should be emphasized to the safety of this sequential combination in clinical practice.