Haddad, Robert I.

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.

TPS6111 Background: Human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) has surpassed cervical cancer as the most common HPV-related cancer in the US, with the majority being caused by HPV16. Persistent expression of HPV16 oncoproteins E6 and E7 by host genome may promote HNSCC. HPV16-positive HNSCC may be associated with poor clinical outcomes in the recurrent/metastatic (R/M) setting. PDS0101 (Versamune HPV) is an HPV16-immunotherapy that generates a potent, targeted T cell attack against HPV16 E6 & E7. In a Phase 2 study, PDS0101 plus pembrolizumab has shown encouraging safety and survival benefit in patients with HPV16-positive R/M HNSCC. (Weiss J et al. ESMO 2024. Poster 879P. NCT04260126). Methods: VERSATILE-003 is a global Phase 3, randomized, controlled, open-label study evaluating PDS0101 plus pembrolizumab vs. pembrolizumab in patients with HPV16-positive R/M HNSCC with PD-L1 positive disease (CPS ≥1). Key eligibility criteria include age ≥18-years-old, histologically- or cytologically-confirmed diagnosis of R/M HNSCC with primary tumor location of oropharynx, oral cavity, hypopharynx, or larynx and no prior systemic anticancer treatment in the R/M setting, HPV16 tumor positivity (centrally tested), PD-L1 positivity defined as CPS ≥ 1 using FDA-approved PD-L1 IHC 22C3 pharmDx kit, and measurable disease based on RECIST 1.1 confirmed by blinded independent central review (BICR). Patients will be randomized 2:1 to receive pembrolizumab 200 mg IV Q3W with PDS0101 1 mL SC administered concurrently during Cycles 1, 2, 3, 4, and 12 (investigational arm), or pembrolizumab 200 mg IV Q3W alone (control arm). The primary objective is to compare overall survival (OS) between the investigational and control arms. Secondary objectives include objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and progression-free survival (PFS) using RECIST 1.1 and assessed by BICR. Exploratory objectives include tumor response assessed by investigator and by irRECIST, PFS2, quality of life as assessed by EQ-5D, QLQ-C30, and QLQ H&N35, and assessment of ctHPVDNA. Updated enrollment data will be provided. Clinical trial information: NCT06790966 .

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. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding management of nasopharynx cancer and ongoing research in this area.

Differentiated thyroid carcinomas is associated with an excellent prognosis. The treatment of choice for differentiated thyroid carcinoma is surgery, followed by radioactive iodine ablation (iodine-131) in select patients and thyroxine therapy in most patients. Surgery is also the main treatment for medullary thyroid carcinoma, and kinase inhibitors may be appropriate for select patients with recurrent or persistent disease that is not resectable. Anaplastic thyroid carcinoma is almost uniformly lethal, and iodine-131 imaging and radioactive iodine cannot be used. When systemic therapy is indicated, targeted therapy options are preferred. This article describes NCCN recommendations regarding management of medullary thyroid carcinoma and anaplastic thyroid carcinoma, and surgical management of differentiated thyroid carcinoma (papillary, follicular, Hürthle cell carcinoma).

The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses. Occult primary cancer, salivary gland cancer, and mucosal melanoma (MM) are also addressed. 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. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding management of HPV-positive oropharynx cancer and ongoing research in this area.

PURPOSEMutations in the HRAS (m HRAS) proto-oncogene occur in 4%-8% of patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Tipifarnib is a farnesyltransferase inhibitor that disrupts HRAS function. We evaluated the efficacy of tipifarnib in patients with R/M m HRAS HNSCC.METHODSWe enrolled 30 patients with R/M HNSCC in a single-arm, open-label phase II trial of tipifarnib for m HRAS malignancies; one additional patient was treated on an expanded access program. After an ad hoc analysis of the first 16 patients with HNSCC with m HRAS variant allele frequency (VAF) data, enrollment was limited to those with a m HRAS VAF of ≥ 20% (high VAF). The primary end point was objective response rate. Secondary end points included assessing safety and tolerability. Patients received tipifarnib 600 or 900 mg orally twice daily on days 1-7 and 15-21 of 28-day cycles.RESULTSOf the 22 patients with HNSCC with high VAF, 20 were evaluable for response at the time of data cutoff. Objective response rate for evaluable patients with high-VAF HNSCC was 55% (95% CI, 31.5 to 76.9). Median progression-free survival on tipifarnib was 5.6 months (95% CI, 3.6 to 16.4) versus 3.6 months (95% CI, 1.3 to 5.2) on last prior therapy. Median overall survival was 15.4 months (95% CI, 7.0 to 29.7). The most frequent treatment-emergent adverse events among the 30 patients with HNSCC were anemia (37%) and lymphopenia (13%).CONCLUSIONTipifarnib demonstrated encouraging efficacy in patients with R/M HNSCC with HRAS mutations for whom limited therapeutic options exist ( NCT02383927 ).

Treatment is complex for patients with head and neck (H&N) cancers with specific site of disease, stage, and pathologic findings guiding treatment decision-making. Treatment planning for H&N cancers involves a multidisciplinary team of experts. This article describes supportive care recommendations in the NCCN Guidelines for Head and Neck Cancers, as well as the rationale supporting a new section on imaging recommendations for patients with H&N cancers. This article also describes updates to treatment recommendations for patients with very advanced H&N cancers and salivary gland tumors, specifically systemic therapy recommendations.

Abstract Background: This Phase 2 study (NCT02383927) is a multi-institutional, open-label trial to determine the efficacy and safety of tipifarnib in patients (pts) with locally advanced/unresectable and/or metastatic solid tumors that carry HRAS missense mutations. HRAS is a proto-oncogene that is overexpressed and mutated in head and neck squamous cell carcinomas (HNSCC) and other SCCs. Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase, a critical enzyme for HRAS activity. Methods: Pts received tipifarnib at a starting dose of 600 – 900 mg orally twice daily on days 1-7 and 15-21 of 28-day cycles. Disease assessments were conducted according to RECIST v1.1 criteria. Null hypothesis and objective response of interest were respectively 10% and 30%. Prior to its completion, this study met its primary objective and, based on preliminary efficacy results (Ho, et. al, ESMO 2018), was amended to continue enrolling only pts with HNSCC (Cohort 2) and other SCC tumors (Cohort 3) carrying HRAS missense mutations at a high variant allele frequency (VAF >35% or ≥20% if baseline serum albumin is >3.5 g/dL). Results: As of May 1, 2019, 23 pts with HNSCC and 10 pts with tumors with other SCC histologies have been treated with tipifarnib. Pts had relapsed/refractory disease with a median of 2 prior regimens. Of note, no objective partial responses were observed on their last therapy prior to study entry, including platinum, immunotherapy and cetuximab +/- chemotherapy. In 15 HNSCC pts meeting the HRAS mutation high VAF inclusion criteria, a 53% overall response rate (ORR) was observed, with 8 confirmed partial responses (PR) and 5 disease stabilizations (SD). Two pts await first on-study tumor response assessment. Overall median progression free survival (PFS) was 5.4 mos (95% CI 4.5 to 19.5 mos, N=15); 19 mos (95% CI 5.3 to 19.5 mos) for pts experiencing a PR and 4.5 mos (95% CI 1.6 to 5.4 mos) for those experiencing SD. Median PFS on last prior therapy was 3.2 mos. All pts had at least 1 treatment-emergent adverse event (TEAE). The most frequently observed drug-related Grade >3 TEAEs occurring in ≥10% pts were blood and lymphatic system disorders, gastrointestinal disorders and renal disorders. Conclusions: Encouraging activity of tipifarnib was observed in HRAS mutant HNSCC. Based on these data, a pivotal study (AIM-HN and SEQ-HN Study, NCT03719690) evaluating the efficacy of this agent in HRAS mutant HNSCC (AIM-HN) and the impact of HRAS mutations on first line therapy of HNSCC (SEQ-HN) has been initiated. Citation Format: Alan Ho, Irene Brana, Robert Haddad, Jessica Bauman, Keith Bible, Laurence Faugeras, Sjoukje Oosting, Deborah J Wong, Myung-Ju Ahn, Valentina Boni, Caroline Even, Jerome Fayette, Maria Jose Flor, Kevin Harrington, Sung-Bae Kim, Lisa Licitra, Ioanna Nixon, Nabil F Saba, Cyrus Sayehli, Pol Specenier, Francis Worden, Binaifer Balsara, Jeanne Britt, Vishnu Mishra, Catherine Scholz, Antonio Gualberto. Preliminary results from a phase 2 trial of tipifarnib in squamous cell carcinomas (SCCs) with HRAS mutations [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr PR08. doi:10.1158/1535-7163.TARG-19-PR08