Xevinapant or Placebo Plus Platinum-Based Chemoradiotherapy in Unresected Locally Advanced Squamous Cell Carcinoma of the Head and Neck (TrilynX): A Randomized, Phase III Study.

Purpose: TrilynX was a randomized, double-blind, phase III study evaluating the addition of xevinapant (an inhibitor of apoptosis proteins inhibitor) or placebo to chemoradiotherapy (CRT) in patients with unresected locally advanced squamous cell carcinoma of the head and neck (LA SCCHN).

Methods: Patients with unresected LA SCCHN (oropharynx [p16-negative only], hypopharynx, or larynx) were randomly assigned 1:1 to six cycles of oral xevinapant 200 mg/day or matched placebo (once daily on Days 1-14 of a 21-day cycle) plus CRT for the first three cycles (cisplatin [100 mg/m once on Day 2 of every cycle] plus intensity-modulated radiotherapy [70 Gy; 35 fractions of 2 Gy/day, 5 days/week]). The primary end point was event-free survival (EFS) assessed by the blinded independent review committee.

Stereotactic MRI Guided Adaptive Radiotherapy: a pooled analysis of a master prospective trial.

Background: Master clinical trial protocol structures offer administrative, procedural and statistical advantages but have not been applied in assessing new radiotherapy devices. Herein, we report on a pooled analysis from a first-of-kind master trial evaluating stereotactic MRI-guided adaptive radiotherapy (SMART).

Methods: Subjects were enrolled on a prospective master protocol evaluating SMART for multiple oncologic indications.

Artificial Intelligence Measured Tumor Burden and Pre-Treatment Circulating Tumor DNA in Human Papilloma Virus-Associated Oropharynx Cancer.

Background: Artificial intelligence (AI)-based imaging analysis and circulating tumor-associated DNA (ctDNA) are both being used diagnostically in HPV-driven oropharynx squamous cell carcinoma (HPV-OPSCC). We evaluated associations between AI-measured tumor burden and ctDNA.

Methods: We analyzed 170 patients treated definitively for HPV-OPSCC.

Proceedings of the National Cancer Institute Workshop on combining immunotherapy with radiotherapy: challenges and opportunities for clinical translation.

Radiotherapy both promotes and antagonises tumour immune recognition. Some clinical studies show improved patient outcomes when immunotherapies are integrated with radiotherapy. Safe, greater than additive, clinical response to the combination is limited to a subset of patients, however, and how radiotherapy can best be combined with immunotherapies remains unclear.

International Expert-Based Consensus Definition, Classification Criteria, and Minimum Data Elements for Osteoradionecrosis of the Jaw: An Interdisciplinary Modified Delphi Study.

Purpose: Osteoradionecrosis of the jaw (ORNJ) is a severe iatrogenic disease characterized by bone death after radiation therapy to the head and neck. With >9 published definitions and at least 16 classification systems, the true incidence and severity of ORNJ are obscured by lack of a standard for disease definition and severity assessment, leading to inaccurate estimation of incidence, reporting ambiguity, and likely underdiagnosis worldwide. This study aimed to achieve consensus on an explicit definition and phenotype of ORNJ and related precursor states through data standardization to facilitate effective diagnosis, monitoring, and multidisciplinary management of ORNJ.

A Prospective Trial of Biomarker-Guided Surveillance for HPV-Positive Oropharynx Cancer Using Plasma Tumor Tissue-Modified Viral HPV DNA.

Purpose: Observational studies suggest circulating tumor human papillomavirus (HPV) DNA may facilitate early detection of recurrent HPV-positive oropharynx cancer. We prospectively investigated whether biomarker-guided surveillance detects recurrence earlier than the standard-of-care methods.

Patients And Methods: We enrolled patients evaluated for HPV-positive oropharynx cancer at a single center from November, 2020, to April, 2023, undergoing curative-intent treatment in a single-arm cohort study.

Next-Generation Sequencing-Based MSI Scoring Predicts Benefit in Mismatch Repair-Deficient Tumors Treated with Nivolumab: Follow-up on NCI-MATCH Arm Z1D.

Purpose: Mismatch repair-deficient (dMMR) tumors have demonstrated favorable responses to immune checkpoint inhibition targeting PD-1. However, more in-depth identification of predictors of response could further refine patient selection for immunotherapy treatment.

Patients And Methods: We undertook integrated evaluation performed on samples collected from 28 of 42 patients enrolled on the NCI-Molecular Analysis for Therapy Choice arm Z1D trial that evaluated PD-1 inhibition treatment with nivolumab in patients with noncolorectal dMMR tumors.

T cell dynamics with neoadjuvant immunotherapy in head and neck cancer.

Immune-checkpoint inhibitors (ICIs) are being tested as neoadjuvant therapies in various solid tumours, including in patients with head and neck squamous cell carcinoma (HNSCC), with promising results. Key findings thus far include that this approach is well-tolerated with favourable clinical outcomes including promising pathological response rates in initial studies. Pathological responses are likely to be increased by combining other agents with anti-PD-(L)1 antibodies.

Overall Survival, Treatment Duration, and Rechallenge Outcomes With ICI Therapy for Recurrent or Metastatic HNSCC.

Importance: Immune checkpoint inhibition (ICI) is a frontline treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), but questions remain surrounding optimal duration of therapy, benefits and risks of ICI rechallenge, and efficacy in first vs subsequent lines of therapy.

Objectives: To estimate survival in US patients receiving ICI-based treatment for R/M HNSCC, compare outcomes associated with treatment discontinuation vs continuation at 1 or 2 years, and assess outcomes after immunotherapy rechallenge.

Design, Setting, And Participants: This retrospective, population-based cohort study included adult patients in the Flatiron Health nationwide oncology database treated with immunotherapy for R/M HNSCC from 2015 to 2023.

Changes in Merkel cell oncoprotein antibodies after radiation therapy in curatively treated Merkel cell carcinoma and association with recurrence.

Background: Serum antibodies to the Merkel oncoprotein (AMERK) are detectable in approximately 50% of patients with Merkel cell carcinoma (MCC) and can be used to monitor for recurrence. The objective of this study was to characterize AMERK levels in patients receiving curative-intent radiation therapy (RT) for MCC and identify associations between AMERK and recurrence.

Methods: This was a retrospective study of patients with MCC who had baseline AMERK measurements before they received curative-intent RT from 2010 to 2020.

Evasion of apoptosis and treatment resistance in squamous cell carcinoma of the head and neck.

Combinations of surgery, radiotherapy and chemotherapy can eradicate tumors in patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN), but a significant proportion of tumors progress, recur, or do not respond to therapy due to treatment resistance. The prognosis for these patients is poor, thus new approaches are needed to improve outcomes. Key resistance mechanisms to chemoradiotherapy (CRT) in patients with LA SCCHN are alterations to the pathways that mediate apoptosis, a form of programmed cell death.

Personalized ctDNA for Monitoring Disease Status in Head and Neck Squamous Cell Carcinoma.

Purpose: Many patients with locoregionally advanced human papillomavirus-negative head and neck squamous cell carcinoma (HNSCC) relapse. ctDNA has the potential to identify minimal residual disease, but its clinical utility for virus-negative HNSCC is not well understood.

Experimental Design: We retrospectively evaluated a personalized, commercial ctDNA assay (Signatera, Natera) during clinical care of patients treated for predominantly newly diagnosed human papillomavirus-negative HNSCC.

Multicenter Evaluation of Radiation and Immune Checkpoint Inhibitor Therapy in Mucosal Melanoma and Review of Recent Literature.

Purpose: Optimal integration of local therapy and systemic immune therapy for patients with mucosal melanoma (MM) is uncertain. We evaluated treatment patterns and outcomes following radiation therapy (RT) in combination with immune checkpoint inhibition (ICI) in MM.

Methods And Materials: Thirty-seven patients with localized (n = 32, 87%) or node-positive (n = 5, 14%) MM were treated across 4 institutions with RT to the primary tumor with or without oncologic resection (n = 28, 76%) and ICI from 2012 to 2020.

Xevinapant plus radiotherapy in resected, high-risk, cisplatin-ineligible LA SCCHN: the phase III XRay Vision study design.

There is a significant unmet need and lack of treatment options for patients with resected, high-risk, cisplatin-ineligible locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). Xevinapant, a first-in-class, potent, oral, small-molecule IAP inhibitor, is thought to restore cancer cell sensitivity to chemotherapy and radiotherapy in clinical and preclinical studies. We describe the design of XRay Vision (NCT05386550), an international, randomized, double-blind, phase III study.

The Next Chapter in Immunotherapy and Radiation Combination Therapy: Cancer-Specific Perspectives.

Immunotherapeutic agents have revolutionized cancer treatment over the past decade. However, most patients fail to respond to immunotherapy alone. A growing body of preclinical studies highlights the potential for synergy between radiation therapy and immunotherapy, but the outcomes of clinical studies have been mixed.

AGuIX nanoparticle-nanobody bioconjugates to target immune checkpoint receptors.

This article presents bioconjugates combining nanoparticles (AGuIX) with nanobodies (VHH) targeting Programmed Death-Ligand 1 (PD-L1, A12 VHH) and Cluster of Differentiation 47 (CD47, A4 VHH) for active tumor targeting. AGuIX nanoparticles offer theranostic capabilities and an efficient biodistribution/pharmacokinetic profile (BD/PK), while VHH's reduced size (15 kDa) allows efficient tumor penetration. Site-selective sortagging and click chemistry were compared for bioconjugation.