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.

NCCN Guidelines® Insights: Thyroid Carcinoma, Version 1.2025.

The NCCN Guidelines for Thyroid Carcinoma address the management of different types of thyroid carcinoma, including papillary, follicular, oncocytic, medullary, and anaplastic carcinoma. The NCCN Thyroid Carcinoma Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights focus on the panel's most recent recommendations regarding systemic therapies for thyroid carcinoma as well as the supporting clinical data.

Neoadjuvant and Adjuvant Pembrolizumab in Locally Advanced Head and Neck Cancer.

Background: The benefit of the addition of perioperative pembrolizumab to standard care with surgery and adjuvant therapy for patients with locally advanced head and neck squamous-cell carcinoma (HNSCC) is unclear.

Methods: In this phase 3, open-label trial, we randomly assigned participants with locally advanced HNSCC in a 1:1 ratio to receive 2 cycles of neoadjuvant pembrolizumab and 15 cycles of adjuvant pembrolizumab (both at a dose of 200 mg every 3 weeks) in addition to standard care (pembrolizumab group) or standard care alone (control group). Standard care was surgery and adjuvant radiotherapy with or without concomitant cisplatin.

LiGeR-HN phase III trials of petosemtamab + pembrolizumab and petosemtamab monotherapy in recurrent or metastatic HNSCC.

Patients with recurrent/metastatic (r/m) head and neck squamous cell carcinoma (HNSCC) have limited treatment options and a dismal prognosis, especially when their cancer is resistant to standard treatments like anti-programmed cell death protein 1 and platinum-based therapies. Petosemtamab - a human, common light chain, bispecific antibody with enhanced antibody-dependent cellular cytotoxicity targeting epidermal growth factor receptor (EGFR) and leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) - demonstrated antitumor activity in r/m HNSCC. In many tumor types, including HNSCC, EGFR is an oncogenic driver, while LGR5 is upregulated.

Navigating challenging patient factors in systemic therapy for head and neck cancer.

Patients with head and neck cancer often present with complex challenges due to a substantial comorbidity burden, including substance use disorders, and the tumor's location in regions that are both cosmetically and anatomically sensitive. These challenges can be categorized into 6 areas, that is, overall health (eg, performance status, biological age), physiological life stages (eg, aging), organ dysfunctions (including autoimmune comorbidities, organ transplants, and psychiatric disorders), previous and concurrent malignancies, previous and current therapies, and adherence to therapy. We provide a practical guide to help physicians understand and address the phenotypic multitude of potential complications in the management of these patients.

INTERLINK-1: A Phase III, Randomized, Placebo-Controlled Study of Monalizumab plus Cetuximab in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma.

Purpose: Treatment options for recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) after failure of immune checkpoint inhibitor treatment and platinum-based chemotherapy are limited. Preliminary data suggested that monalizumab plus cetuximab had clinical activity in R/M HNSCC.

Patients And Methods: INTERLINK-1 (NCT04590963) was a double-blind, phase III study.

STELLAR-305: phase II/III study of zanzalintinib plus pembrolizumab versus pembrolizumab alone in patients with HNSCC.

Tweetable Abstract: STELLAR-305: design of an ongoing phase III #clinicaltrial, assessing the multi-targeted tyrosine kinase inhibitor, zanzalintinib, in combination with pembrolizumab in previously untreated recurrent/metastatic #HNSCC.

Clinical Trial Registration: NCT06082167 (ClinicalTrials.gov).

Epigenetic therapy sensitizes anti-PD-1 refractory head and neck cancers to immunotherapy rechallenge.

BACKGROUNDImmune checkpoint blockade (ICB) is an effective treatment in a subset of patients diagnosed with head and neck squamous cell carcinoma (HNSCC); however, the majority of patients are refractory.METHODSIn a nonrandomized, open-label Phase 1b clinical trial, participants with recurrent and/or metastatic (R/M) HNSCC were treated with low-dose 5-azacytidine (5-aza) daily for either 5 or 10 days in combination with durvalumab and tremelimumab after progression on ICB. The primary objective was to assess the biologically effective dose of 5-aza as determined by molecular changes in paired baseline and on-treatment tumor biopsies; the secondary objective was safety.

Mutational Landscape of Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma and Association with Immune Checkpoint Inhibitor Outcomes.

Purpose: Understanding the mutational landscape of recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is important in identifying biomarkers to determine which patients may benefit from immune checkpoint inhibitors (ICI).

Experimental Design: The HAWK (NCT02207530), CONDOR (NCT02319044), and EAGLE (NCT02369874) studies evaluated R/M HNSCC treatment with durvalumab or durvalumab-tremelimumab. Tumor tissue samples pooled from HAWK/CONDOR (n = 153) and plasma cell-free DNA samples from EAGLE (n = 285) were analyzed to identify somatic alterations and association with survival.

Atezolizumab in High-Risk Locally Advanced Squamous Cell Carcinoma of the Head and Neck: A Randomized Clinical Trial.

Importance: Treating locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) involves any combination of surgery, radiation, and chemotherapy, followed by routine monitoring for local recurrence or distant metastases. Given the poor patient outcomes, a significant unmet clinical need for improved treatment options remains.

Objective: To evaluate efficacy and safety of maintenance atezolizumab in patients with LA SCCHN at high risk of disease progression after multimodal definitive treatment.

Phase I dose-escalation and pharmacodynamic study of STING agonist E7766 in advanced solid tumors.

E7766 is a novel stimulator of interferon genes (STING) agonist, capable of potent activation of immune cells and generating strong antitumor response in preclinical murine tumor models. Here we present the safety, efficacy, and biomarker results of the first-in-human phase I/Ib study of intratumoral E7766 in patients with advanced solid tumors. Eligible patients with relapsing/refractory cancers (n=24) were enrolled in dose-escalating cohorts to receive intratumoral injections of E7766 from 75 to 1000 µg.

NCCN Guidelines® Insights: Head and Neck Cancers, Version 2.2025.

The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses, as well as occult primary cancer, salivary gland cancer, and mucosal melanoma (MM). The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation of radiation, indications for systemic therapy). The NCCN Head and Neck Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations.

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.

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.

Dual Immune Checkpoint Inhibition in Patients With Aggressive Thyroid Carcinoma: A Phase 2 Nonrandomized Clinical Trial.

Importance: Aggressive thyroid carcinoma, including radioiodine refractory (RAIR) differentiated thyroid carcinoma (DTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC), are associated with significant morbidity and mortality and have limited therapeutic options. Distinct immune profiles have been identified in thyroid cancer subtypes suggesting they may be susceptible to immune checkpoint inhibition.

Objective: To evaluate the efficacy of anti-programmed cell death 1 nivolumab and anti-cytotoxic lymphocyte-associated protein 4 ipilimumab in patients with aggressive thyroid carcinoma.

A Phase I/II Trial of Sapanisertib in Advanced Anaplastic and Radioiodine Refractory Differentiated Thyroid Carcinoma.

Background: There are limited therapeutic options for patients with recurrent/metastatic anaplastic thyroid carcinoma (ATC) and radioiodine refractory (RAIR) differentiated thyroid carcinoma (DTC) refractory to multikinase inhibitors. This multicenter trial evaluated sapanisertib, a next-generation oral kinase inhibitor of mTOR complexes 1/2, in ATC and RAIR DTC.

Methods: A safety run-in phase I was followed by nonrandomized phase II trial in ATC, with an exploratory cohort in RAIR DTC.

Immunomethylomic profiles of long-term head and neck squamous cell carcinoma survivors on immune checkpoint inhibitors.

This study addresses the challenge of predicting the response of head and neck squamous cell carcinoma (HNSCC) patients to immunotherapy. Using DNA methylation cytometry, we analyzed the immune profiles of six HNSCC patients who showed a positive response to immunotherapy over a year without disease progression. There was an initial increase in CD8 T memory cells and natural killer cells during the first four cycles of immunotherapy, which then returned to baseline levels after a year.

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.

Revisiting TNM staging for EBV-related nasopharyngeal carcinoma.

Advances in imaging and novel treatment approaches might have outpaced the prognostic capabilities of the current AJCC/UICC TNM 8 edition for staging nasopharyngeal carcinoma (NPC). In this issue of Cancer Cell, Du et al. propose a new TNM-9 classification that incorporates these updates.

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.