BACKGROUND: 13‐Cis retinoic acid (13‐CRA) is a synthetic vitamin A derivative. High‐dose 13‐CRA in patients with squamous cell cancers of the head and neck (SCCHNs) reduces the incidence of second primary tumors (SPTs). The authors report long‐term results from a phase 3 randomized trial that compared treatment with low‐dose 13‐CRA versus placebo for patients who had early stage SCCHN, with a focus on the development of SPTs and overall survival (OS).METHODS: In total, 176 patients who received treatment for stage I/II SCCHN were randomized to receive either low‐dose 13‐CRA (weight‐based dose of 7.5 mg or 10 mg) or placebo for 2 years. A competing‐risk approach and the log‐rank test were used to compare the time to SPT and OS, respectively, between groups.RESULTS: 13‐CRA neither significantly reduced the cumulative incidence of SPT (P = .61) nor improved the time to SPT (hazard ratio [HR] for 13‐CRA/placebo; 0.86;P = .61). Despite limited power, there was a trend toward improved OS for the 13‐CRA arm (HR, 0.75;P = .14), particularly among patients whose index tumor was surgically excised (N = 26; HR, 0.50;P = .057) and among women (N = 39; HR, 0.44;P = .065) and never/former smokers (N = 129; HR, 0.61;P = .055), with a median follow‐up of 16 years. The main 13‐CRA related toxicities were dry skin and cheilitis.CONCLUSIONS: Treatment with low‐dose 13‐CRA for 2 years did not decrease the incidence of SPT; subset analysis indicates a potential survival advantage among patients who are women and never/former smokers. More targeted interventions based on clinical risk factors and molecular characterization of tumors may yield greater success in future prevention trials.Cancer2017;123:4653‐4662. ©2017 American Cancer Society.

Cancers of the head and neck region are among the leading causes of cancer-related mortalities worldwide. Oral leukoplakia and erythroplakia are identified as precursor lesions to malignancy. Patients cured of an initial primary head and neck cancer are also susceptible to developing second primary tumors due to cancerization of their mucosal field. Multi-step acquisition of genetic mutations leading to tumorigenesis and development of invasive cancer has been previously described. Recently, whole exome sequencing of tumor specimens has helped to identify driver mutations in this disease. For these reasons, chemoprevention or the use of systemic or biologic agents to prevent carcinogenesis is an attractive concept in head and neck cancers. Nonetheless, despite extensive clinical research in this field over the past couple decades, no standard of care option has emerged. This review article reports on targeted interventions that have been attempted in clinical trials to date, and focuses on novel molecular pathways and drugs in development that are worthy of being tested for this indication as part of future endeavors.

Human epidermal growth factor receptor 3 (HER3) is a receptor tyrosine kinase that is expressed in numerous solid tumors. Higher levels of HER3 expression in multiple tumor types are associated with adverse clinical outcomes, such as reduced survival. However, there is currently no HER3-directed antibody-drug conjugate approved for the treatment of any cancer. Improved treatment options are needed, in particular for patients who progress on standard therapies. HER3-DXd is an investigational HER3-directed antibody-drug conjugate composed of an anti-HER3 monoclonal antibody linked to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. In previous clinical trials, HER3-DXd demonstrated a manageable safety profile and durable efficacy in previously treated, advanced EGFR-mutated NSCLC and advanced breast cancer across a range of baseline tumor HER3 expression levels. HER3-DXd has also shown preclinical antitumor efficacy in HER3-expressing cancers including cutaneous melanoma, gastric cancer, and prostate cancer, among others. The aim of this global phase II HERTHENA-PanTumor01 multicohort study is to assess the efficacy and safety of HER3-DXd in patients with relapsed or refractory locally advanced or metastatic solid tumors including melanoma, head and neck squamous cell, gastric/gastroesophageal junction, ovarian, cervical, endometrial, bladder, esophageal squamous cell, pancreatic, and prostate cancers.Clinical trial registration: NCT06172478 (ClinicalTrials.gov); 2023-507641-29-00 (EudraCT); jRCT2031230575 (Japan Registry of Clinical Trials).

Overexpression of EGFR and MET occurs in a high proportion of recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Amivantamab, an EGFR-MET bispecific antibody with immune-cell directing activity, is approved in EGFR-mutated advanced non-small cell lung cancer and is being evaluated in phase 3 trials for other solid tumors. Cohort 1 of OrigAMI-4 (NCT06385080) enrolled adult participants with human papillomavirus-unrelated R/M HNSCC with disease progression on/after prior checkpoint inhibitor and platinum-based chemotherapy. Subcutaneous amivantamab was administered at 1600 mg (2240 mg for ≥ 80 kg body weight) on Cycle 1 Day 1 and 2400 mg (3360 mg for ≥ 80 kg body weight) thereafter. Primary end point was investigator-assessed objective response rate (ORR). As of July 1, 2025 (median follow-up, 3.5 months [range, 0-13.4]), 86 participants (median age, 63.5 years; 45 % Asian; 43 % White) received ≥ 1 dose of subcutaneous amivantamab. Subcutaneous amivantamab was well tolerated. Administration-related reactions were reported in 7 % (n = 6/86) of participants; no new safety signals were observed. In the efficacy population (n = 38; median follow-up, 8.3 months [range, 1.1-13.4]), confirmed ORR was 45 % (95 % CI, 29 %-62 %), median time to first response was 6.4 weeks (range, 5.7-18.3), and median duration of response was 7.2 months (95 % CI, 5.3-NE). The clinical benefit rate (responder or durable stable disease) was 76 % (95 % CI, 60 %-89 %). Median progression-free survival was 6.8 months (95 % CI, 4.2-9.0). Subcutaneous amivantamab as second-/third-line treatment among participants with R/M HNSCC demonstrated rapid and durable antitumor activity. The safety profile of subcutaneous amivantamab was consistent with previous studies.