Search

Platinum-based chemotherapy in combination with anti-PD-L1 antibodies has shown promising results in mesothelioma. However, the immunological mechanisms underlying its efficacy are not well understood and there are no predictive biomarkers to guide treatment decisions. Here, we combine time course RNA sequencing (RNA-seq) of peripheral blood mononuclear cells with pre-treatment tumor transcriptome data from the single-arm, phase 2 DREAM trial (N = 54). Single-cell RNA-seq and T cell receptor sequencing (TCR-seq) reveal that CD8 + T effector memory (TEM) cells with stem-like properties are more abundant in peripheral blood of responders and that this population expands upon treatment. These peripheral blood changes are linked to the transcriptional state of the tumor microenvironment. Combining information from both compartments, rather than individually, is most predictive of response. Our study highlights complex interactions between the tumor and immune cells in peripheral blood during objective tumor responses to chemoimmunotherapy. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12616001170415., Competing Interests: Declaration of interests W.J.L. declares consultancy for Douglas Pharmaceuticals and research funding from Douglas Pharmaceuticals, AstraZeneca, and ENA therapeutics. W.J.L. is a director of the Cancer Research Trust, which has funded parts of this work, but is not involved in any funding decisions, which are based on independent external peer review. W.J.L. is a founder and director of Setonix Pharmaceuticals, which is not related to the presented work. W.J.L. is an inventor on patent applications unrelated to the presented work. A.K.N. declares consultancy for Douglas Pharmaceuticals and Bristol-Myers Squibb, institutional research funding from AstraZeneca, and consultancy (unrelated to this work) from AstraZeneca., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) generally has a poor prognosis for patients with limited treatment options. While incorporating immune checkpoint inhibitors (ICIs) has now become the standard of care, the efficacy is variable, with only a subset of patients responding. The complexity of the tumor microenvironment (TME) and the role of tertiary lymphoid structures (TLS) have emerged as critical determinants for immunotherapeutic response., Methods: In this study, we analyzed two independently collected R/M HNSCC patient tissue cohorts to better understand the role of TLS in response to ICIs. Utilizing a multi-omics approach, we first performed targeted proteomic profiling using the Nanostring GeoMx Digital Spatial Profiler to quantify immune-related protein expression with spatial resolution. This was further characterized by spatially resolved whole transcriptome profiling of TLSs and germinal centers (GCs). Deeper single-cell resolved proteomic profiling of the TLSs was performed using the Akoya Biosciences Phenocycler Fusion platform., Results: Our proteomic analysis revealed the presence of T lymphocyte markers, including CD3, CD45, and CD8, expressing cells and upregulation of immune checkpoint marker PD-L1 within tumor compartments of patients responsive to ICIs, indicative of 'hot tumor' phenotypes. We also observed the presence of antigen-presenting cells marked by expression of CD40, CD68, CD11c, and CD163 with upregulation of antigen-presentation marker HLA-DR, in patients responding to ICIs. Transcriptome analysis of TLS and GCs uncovered a marked elevation in the expression of genes related to immune modulation, diverse immune cell recruitment, and a potent interferon response within the TLS structure. Notably, the distribution of TLS-tumor distance was found to be significantly different across response groups (H = 9.28, p = 0.026). The proximity of TLSs to tumor cells was found to be a critical indicator of ICI response, implying that patients with TLSs located further from tumor cells have worse outcomes., Conclusion: The study underscores the multifaceted role of TLSs in modulating the immunogenic landscape of the TME in R/M HNSCC, likely influencing the efficacy of ICIs. Spatially resolved multi-omics approaches offer valuable insights into potential biomarkers for ICI response and highlight the importance of profiling the TME complexity when developing therapeutic strategies and patient stratification., (© 2024. The Author(s).)

Background: Patients with unresectable advanced cutaneous squamous cell carcinoma (cSCC) are generally treated with palliative intent. Immune checkpoint blockade has significant activity in the palliative setting in patients with recurrent or metastatic cSCC. This single arm phase 2 prospective study aims to investigate the combination of curative intent chemoradiation and durvalumab (anti-PD-L1 checkpoint inhibitor) for this patient cohort., Methods: Patients with unresectable locally and or regionally advanced pathologically confirmed cSCC (stage III-IVa) deemed fit for CRIO by consensus of the Multidisciplinary meeting will be eligible. In the first stage of a two-stage minimax design, we aim to recruit a total of 15 patients. If fewer than 7 patients achieved a complete response in the first stage, we will conclude the treatment is not more effective than standard treatment. The co-primary endpoints of CRIO are the safety of treatment (acute and late toxicities) and the rate of complete response. Secondary endpoints would include overall survival, progression free survival, and locoregional control. Translational research endpoints including biomarkers (CD73, CD39, PD-1, PD-L1) will also be explored utilising multiplex immunohistochemistry on tumour biopsy samples obtained prior to commencing treatment and during treatment (week 2). In addition, the utility of CXCR-4 PET/CT scan will be explored., Discussion: CRIO is a novel trial evaluating the combination of curative intent chemoradiotherapy with concurrent and adjuvant durvalumab for patients with unresectable stage III-IVa cSCC., Trial Registration: Trial registered with the Australian New Zealand Clinical Trial Registry (ACTRN12618001573246).

Background: Studies suggest that combining radiotherapy (RT) with programmed cell death protein 1 (PD-1) blockade may elicit a synergistic antitumor response. We aimed to assess whether prior or concurrent RT was associated with improved disease control in patients with metastatic non-small cell lung cancer (NSCLC) treated with nivolumab., Methods: We conducted a retrospective study of patients receiving nivolumab as second or subsequent line therapy for metastatic NSCLC. Patients were categorized into those who received any RT for NSCLC prior to or during nivolumab therapy, and those with no history of RT for NSCLC., Results: A total of 85 patients received nivolumab between July 2015 and December 2016 and were followed up for a median of 15 months. Sixty-five patients (76.4%) received RT prior to or during nivolumab and 20 patients (23.6%) received nivolumab alone. Baseline characteristics of age, performance status, histology, smoking status and previous therapy were similar between the two groups. Prior or concurrent RT was associated with a superior PFS, median 2.8 months with RT versus 1.3 months without RT (Hazard Ratio (HR) = 0.494; 95% Confidence Interval (CI), 0.279-0.873; P = 0.02). The median OS of the group receiving RT was 6.4 months versus 4.2 months for the no RT group (P = 0.20). RT was not associated with an increase in toxicity., Conclusion: RT prior to or concurrent with nivolumab for metastatic NSCLC was associated with a modest improvement in PFS over nivolumab alone with no evidence of increase in adverse effects. RT may potentiate the effect of anti-PD-1 immunotherapy in NSCLC., (© 2019 John Wiley & Sons Australia, Ltd.)

Immune checkpoint inhibitors have recently emerged as an exciting new treatment paradigm across a broad spectrum of malignancies. This new class of agents also challenges oncologists with a unique set of immune-based toxicities. Early recognition and precise management of these toxicities can result in better outcomes, with minimization of toxicity and harm to the patient. This article provides a comprehensive review of immune-based toxicities caused by immune checkpoint inhibitors, including recommendations for their investigation and guidelines for specific management., (© 2017 John Wiley & Sons Australia, Ltd.)

In the phase 2 EMPOWER-CSCC-1 study (NCT02760498), cemiplimab demonstrated antitumor activity against metastatic cutaneous squamous cell carcinoma (mCSCC) and locally advanced cutaneous squamous cell carcinoma (laCSCC). To report final analysis of weight-based cemiplimab in mCSCC and laCSCC (groups 1 and 2), fixed-dose cemiplimab in mCSCC (group 3), and primary analysis of fixed-dose cemiplimab in mCSCC/laCSCC (group 6). Patients received cemiplimab (3 mg/kg intravenously every 2 weeks [groups 1 and 2]) or cemiplimab (350 mg intravenously [groups 3 and 6]) every 3 weeks. The primary end point was objective response rate (ORR). Duration of response (DOR) and progression-free survival (PFS) are presented per protocol, according to post-hoc sensitivity analyses that only include the period of protocol-mandated imaging assessments. At 42.5 months, ORR for groups 1-3 (n = 193) was 47.2%, estimated 12-month DOR was 88.3%, and median PFS was 26.0 months. At 8.7 months, ORR for group 6 (n = 165 patients) was 44.8%; median DOR and median PFS were not reached. Serious treatment-emergent adverse event rates (grade ≥3) were groups 1-3: 31.1% and group 6: 34.5%. Nonrandomized study, nonsurvival primary end point. EMPOWER-CSCC-1 provides the largest prospective data on long-term efficacy and safety for anti-programmed cell death-1 therapy in advanced CSCC. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the real‐world treatment patterns and outcomes for patients with pleural mesothelioma (PM) in the era of immunotherapy. Methods: This retrospective audit included patients with PM diagnosed within three tertiary referral centers in Queensland, Australia from January 2017 to July 2023. Patient and treatment characteristics and outcomes were recorded. Data was analyzed using descriptive statistics and the Kaplan‐Meier survival method. Results: A total of 90 patients were included: 84% were male, the median age was 75 years (range 70–79) and 85% had baseline Eastern Group Cooperative Group of 0–1. Subtypes included 54% epithelioid, 17% biphasic, 12% sarcomatoid, and 17% unspecified/unknown. First‐line treatment was received by 57/90 patients (63%) and 33/90 patients (37%) received the best supportive care (BSC). Chemotherapy was most used (63%) overall, but first‐line immunotherapy was more commonly used since ipilimumab/nivolumab was reimbursed by the Australian Pharmaceutical Benefits Scheme in July 2021. After first‐line treatment, only 40% received second‐line treatment and 60% received BSC. 12‐month overall survival (OS) and progression‐free survival for all patients were 53% (95% confidence interval [CI]: 43–65) and 25% (95% CI 15–40) respectively. 12‐month OS was 72%, 64%, and 29% for immunotherapy, chemotherapy, and BSC, respectively. There was no significant difference in survival between chemotherapy and immunotherapy (hazard ratio 1.28, 95% CI: 0.65–2.5, p = 0.5). Conclusion: In our unselected real‐world cohort, both chemotherapy and immunotherapy are active against PM, but the prognosis remains guarded. There remains a need for better treatment options, especially in the first‐line setting. Enrolment in clinical trials is crucial to improving outcomes in this debilitating disease. [ABSTRACT FROM AUTHOR]

Mucosal head and neck squamous cell carcinoma (HNSCC) are the seventh most common cancer, with approximately 50% of patients living beyond 5 years. Immune checkpoint inhibitors (ICIs) have shown promising results in patients with recurrent or metastatic (R/M) disease, however, only a subset of patients benefit from immunotherapy. Studies have implicated the tumor microenvironment (TME) of HNSCC as a major factor in therapy response, highlighting the need to better understand the TME, particularly by spatially resolved means to determine cellular and molecular components. Here, we employed targeted spatial profiling of proteins on a cohort of pre-treatment tissues from patients with R/M disease to identify novel biomarkers of response within the tumor and stromal margins. By grouping patient outcome categories into response or non-response, based on Response Evaluation Criteria in Solid Tumors (RECIST) we show that immune checkpoint molecules, including PD-L1, B7-H3, and VISTA, were differentially expressed. Patient responders possessed significantly higher tumor expression of PD-L1 and B7-H3, but lower expression of VISTA. Analysis of response subgroups indicated that tumor necrosis factor receptor (TNFR) superfamily members including OX40L, CD27, 4-1BB, CD40, and CD95/Fas, were associated with immunotherapy outcome. CD40 expression was higher in patient-responders than non responders, while CD95/Fas expression was lower in patients with partial response (PR) relative to those with stable disease (SD) and progressive disease (PD). Furthermore, we found that high 4-1BB expression in the tumor compartment, but not in the stroma, was associated with better overall survival (OS) (HR= 0.28, p-adjusted=0.040). Moreover, high CD40 expression in tumor regions (HR= 0.27, padjusted=0.035), and high CD27 expression in the stroma (HR= 0.2, p-adjusted=0.032) were associated with better survival outcomes. Taken together, this study supports the role of immune checkpoint molecules and implicates the TNFR superfamily as key players in immunotherapy response in our cohort of HNSCC. Validation of these findings in a prospective study is required to determine the robustness of these tissue signatures. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma (HNSCC) represents a heterogeneous group of tumors. While significant progress has been made using multimodal treatment, the 5‐year survival remains at 50%. Developing effective therapies, such as immunotherapy, will likely lead to better treatment of primary and metastatic disease. However, not all HNSCC tumors respond to immune checkpoint blockade therapy. Understanding the complex cellular composition and interactions of the tumor microenvironment is likely to lead to new knowledge for effective therapies and treatment resistance. In this review, we discuss HNSCC characteristics, predictive biomarkers, factors influencing immunotherapy response, with a focus on the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Aim: Hospital admissions secondary to immune‐related adverse events (irAE) arising from immune checkpoint inhibitors (ICI) are likely to increase with increasing use of this class of drug. We sought to determine the characteristics and outcomes of hospital admissions due to irAE. Methods: A retrospective analysis of patients treated with ICI at two tertiary hospitals in Queensland (Australia) was performed. Patients who received at least one dose of ICI for a nonhaematological malignancy between the 1st January 2016 and 1st January 2017 were included. All subsequent hospital admissions were analyzed. Results: A total of 140 patients were included, with the most common malignancies being non‐small‐cell‐cell lung cancer (41%) and melanoma (18%), and most patients received anti‐PD1 treatment (78%). A sum of 76 patients accounted for 116 admissions. Comparing admissions due to irAE and non‐irAE, those admitted for irAE had a significantly longer duration on ICI prior to admission (173 vs 105 days, P = 0.04) but durations of admissions were similar (9.0 vs 8.5 days, P = 0.85). Fifteen patients (11% overall cohort) accounted for 18 admissions attributable to 16 separate irAE. irAE was not considered as a differential diagnosis on admission in 7 patients (38%). In those patients, commencement of corticosteroids was delayed (1.5 days, P = 0.01) but this did not translate into adverse outcomes such as prolonged admissions, prolonged steroid use or long‐term complications. All patients with irAE were managed with high‐dose corticosteroids. One death resulted from irAE (pneumonitis). Conclusions: A sum of 11% patients receiving ICI required hospital admission for irAE. The relatively high rate of irAE as a missed differential diagnosis on admission suggests a need for improved cross‐discipline awareness, education, and institutional management guidelines. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICI) have shown durable and long-term benefits in a subset of head and neck squamous cell carcinoma (HNSCC) patients. To identify patient-responders from non-responders, biomarkers are needed which are predictive of outcome to ICI therapy. Cues in the tumor microenvironment (TME) have been informative in understanding the tumor-immune contexture. Methods: In this preliminary study, the NanoString GeoMx™ Digital Spatial Profiling (DSP) technology was used to determine the immune marker and compartment specific measurements in a cohort of HNSCC tumors from patients receiving ICI therapy. Results: Our data revealed that markers involved with immune cell infiltration (CD8 T-cells) were not predictive of outcome to ICI therapy. Rather, a number of immune cell types and protein markers (CD4, CD68, CD45, CD44, CD66b) were found to correlate with progressive disease. Cross platform comparison with the Opal Vectra (Perkin Elmer) for a number of markers across similar regions of interest demonstrated concordance for pan-cytokeratin, CD8, and PD-L1. Conclusion: This study, to our knowledge, represents the first digital spatial analysis of HNSCC tumors. A larger cohort of HNSCC will be required to orthogonally validate the findings. [ABSTRACT FROM AUTHOR]

Background: Studies suggest that combining radiotherapy (RT) with programmed cell death protein 1 (PD‐1) blockade may elicit a synergistic antitumor response. We aimed to assess whether prior or concurrent RT was associated with improved disease control in patients with metastatic non–small cell lung cancer (NSCLC) treated with nivolumab. Methods: We conducted a retrospective study of patients receiving nivolumab as second or subsequent line therapy for metastatic NSCLC. Patients were categorized into those who received any RT for NSCLC prior to or during nivolumab therapy, and those with no history of RT for NSCLC. Results: A total of 85 patients received nivolumab between July 2015 and December 2016 and were followed up for a median of 15 months. Sixty‐five patients (76.4%) received RT prior to or during nivolumab and 20 patients (23.6%) received nivolumab alone. Baseline characteristics of age, performance status, histology, smoking status and previous therapy were similar between the two groups. Prior or concurrent RT was associated with a superior PFS, median 2.8 months with RT versus 1.3 months without RT (Hazard Ratio (HR) = 0.494; 95% Confidence Interval (CI), 0.279–0.873; P = 0.02). The median OS of the group receiving RT was 6.4 months versus 4.2 months for the no RT group (P = 0.20). RT was not associated with an increase in toxicity. Conclusion: RT prior to or concurrent with nivolumab for metastatic NSCLC was associated with a modest improvement in PFS over nivolumab alone with no evidence of increase in adverse effects. RT may potentiate the effect of anti–PD‐1 immunotherapy in NSCLC. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors have recently emerged as an exciting new treatment paradigm across a broad spectrum of malignancies. This new class of agents also challenges oncologists with a unique set of immune-based toxicities. Early recognition and precise management of these toxicities can result in better outcomes, with minimization of toxicity and harm to the patient. This article provides a comprehensive review of immune-based toxicities caused by immune checkpoint inhibitors, including recommendations for their investigation and guidelines for specific management. [ABSTRACT FROM AUTHOR]

• Simultaneously targeting MET and PD-1 may offer enhanced clinical benefits in advanced NSCLC. • Capmatinib plus nivolumab exhibited clinical activity and manageable safety in pretreated advanced NSCLC patients. • This combination treatment demonstrated antitumor activity regardless of MET status. Dysregulated MET is an established oncogenic driver in non–small cell lung cancer (NSCLC). MET signaling may also suppress anticancer immune responses. Concomitant MET inhibition with capmatinib (a MET inhibitor) synergistically enhanced the efficacy of immunotherapies in murine cancer models, regardless of tumor dependency to MET signaling. Here, we report results of a multicenter, open-label, phase 2 study of capmatinib plus nivolumab (a PD-1 inhibitor) in patients with EGFR wild-type advanced NSCLC, previously treated with platinum-based chemotherapy. Patients were allocated into high-MET or low-MET groups according to MET expression determined by immunohistochemistry, MET gene copy number as assessed by fluorescence in-situ hybridization, and presence of MET exon 14 skipping mutation, then received capmatinib 400 mg, oral, twice daily in combination with nivolumab 3 mg/kg intravenously every 2 weeks. The primary endpoint was investigator-assessed 6-month progression-free survival (PFS) rate per RECIST v1.1. The primary endpoint was met in both the high-MET (N = 16) and low-MET (N = 30) groups. In the high-MET and low-MET groups, respectively, the estimated mean 6-month PFS rate (95 % credible interval) by Bayesian analysis was 68.9 % (48.5–85.7) and 50.9 % (35.6–66.4). The Kaplan-Meier median PFS (95 % CI) was 6.2 months (3.5–19.2) and 4.2 months (1.8–7.4). The overall response rate (95 % CI) was 25.0 % (7.3–52.4) and 16.7 % (5.6–34.7). Most frequent treatment-related adverse events (≥30 % any grade, N = 46) were nausea (52.2 %), peripheral edema (34.8 %), and increased blood creatinine (30.4 %). Capmatinib plus nivolumab showed clinical activity and manageable safety in pretreated patients with advanced EGFR wild-type NSCLC, independent of MET status. ClinicalTrials.gov NCT02323126. [ABSTRACT FROM AUTHOR]

Objectives: To assess health-related quality of life (HRQoL) with first-line pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) in the phase 3 KEYNOTE-048 trial (NCT02358031).Materials and Methods: HRQoL was measured using the European Organisation for Research and Treatment of Cancer 30-question quality-of-life (EORTC QLQ-C30), the EORTC 35-question quality-of-life head and neck cancer-specific module (EORTC QLQ-H&N35), and the EuroQol 5-dimension 3-level instruments (EQ-5D-3L). Secondary endpoints included mean change from baseline in EORTC QLQ-C30 global health status/quality of life (GHS/QoL) at week 15 and time to deterioration (TTD) in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing.Results: Of 882 enrolled participants, 844 received ≥ 1 dose of study treatment and completed ≥ 1 HRQoL assessment; adherence was ≥ 79% at week 15 across treatment groups. At week 15, EORTC QLQ-C30 GHS/QoL scores remained stable; no clinically meaningful between-group differences were observed (least squares mean difference, pembrolizumab vs cetuximab-chemotherapy, 0.24; 95% CI, -3.34 to 3.82; pembrolizumab-chemotherapy vs cetuximab-chemotherapy, 0.40; 95% CI, -3.46 to 4.26). Median TTD in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing scores was not reached over 51 weeks across groups, showing stable HRQoL. TTD was similar between groups for EORTC QLQ-C30 GHS/QoL (pembrolizumab vs cetuximab-chemotherapy: HR, 1.38; 95% CI, 0.95-2.00; pembrolizumab-chemotherapy vs cetuximab-chemotherapy: HR, 1.37; 95% CI, 0.94-2.00), as was TTD in EORTC QLQ-H&N35 pain and swallowing scores.Conclusions: Pembrolizumab monotherapy and pembrolizumab-chemotherapy extended OS while maintaining HRQoL, further supporting first-line use for R/M HNSCC. [ABSTRACT FROM AUTHOR]