MEK/ERK signaling is a critical regulator of high-risk human papillomavirus oncogene expression revealing therapeutic targets for HPV-induced tumors.

Intracellular pathogens have evolved to utilize normal cellular processes to complete their replicative cycles. Pathogens that interface with proliferative cell signaling pathways risk infections that can lead to cancers, but the factors that influence malignant outcomes are incompletely understood. Human papillomaviruses (HPVs) predominantly cause benign hyperplasia in stratifying epithelial tissues. However, a subset of carcinogenic or "high-risk" HPV (hr-HPV) genotypes are etiologically linked to nearly 5% of all human cancers. Progression of hr-HPV-induced lesions to malignancies is characterized by increased expression of the E6 and E7 oncogenes and the oncogenic functions of these viral proteins have been widely studied. Yet, the mechanisms that regulate hr-HPV oncogene transcription and suppress their expression in benign lesions remain poorly understood. Here, we demonstrate that EGFR/MEK/ERK signaling, influenced by epithelial contact inhibition and tissue differentiation cues, regulates hr-HPV oncogene expression. Using monolayer cells, epithelial organotypic tissue models, and neoplastic tissue biopsy materials, we show that cell-extrinsic activation of ERK overrides cellular control to promote HPV oncogene expression and the neoplastic phenotype. Our data suggest that HPVs are adapted to use the EGFR/MEK/ERK signaling pathway to regulate their productive replicative cycles. Mechanistic studies show that EGFR/MEK/ERK signaling influences AP-1 transcription factor activity and AP-1 factor knockdown reduces oncogene transcription. Furthermore, pharmacological inhibitors of EGFR, MEK, and ERK signaling quash HPV oncogene expression and the neoplastic phenotype, revealing a potential clinical strategy to suppress uncontrolled cell proliferation, reduce oncogene expression and treat HPV neoplasia.

The impact of socioeconomic and geographic factors on access to transoral robotic/endoscopic surgery for early stage oropharyngeal malignancy.

OBJECTIVE: To evaluate the role of social and geographic factors on the likelihood of receiving transoral robotic surgery (TORS) or non-robotic transoral endoscopic surgery treatment in early stage oropharyngeal squamous cell carcinoma (OPSCC). MATERIALS AND METHODS: The National Cancer Database was queried to form a cohort of patients with T1-T2 N0-N1 M0 OPSCC (AJCC v.7) who underwent treatment from 2010 to 2016. Demographics, tumor characteristics, treatment type, social, and geographic factors were all collected. Univariate analysis and multivariate logistic regression were then performed. RESULTS: Among 9267 identified patients, 1774 (19.1%) received transoral robotic surgery (TORS), 1191 (12.9%) received transoral endoscopic surgery, and 6302 (68%) received radiation therapy. We found that lower cancer stage, lower comorbidity burden and HPV- positive status predicted a statistically significant increased likelihood of receiving surgery. Patients who reside in suburban or small urban areas (>1 million population), were low-to- middle income, or rely on Medicaid were less likely to receive surgery. Patients that reside in Medicaid-expansion states were more likely to receive TORS (p > .0001). Patients that reside in states that expanded Medicaid January 2014 and after were more likely to receive non-robotic transoral endoscopic surgery (p > .0001). CONCLUSIONS: Poorer baseline health, lower socioeconomic status and residence in small urban areas may act as barriers to accessing minimally invasive transoral surgery while residence in a Medicaid-expansion state may improve access. Barriers to accessing robotic surgery may be greater than accessing non-robotic surgery.

Precision and Immunoprevention Strategies for Tobacco-Related Head and Neck Cancer Chemoprevention.

OPINION STATEMENT: To date, there is no FDA-approved chemoprevention approach for tobacco-related HNSCC. Effective chemoprevention approaches validated in sufficiently powered randomized trials are needed to reduce the incidence and improve survival. In this review, we recap the challenges encountered in past chemoprevention trials and discuss emerging approaches, with major focus on green chemoprevention, precision prevention, and immunoprevention. As our current depth of knowledge expands in the arena of cancer immunotherapy, the field of immunoprevention is primed for new discoveries and successes in cancer prevention.

A randomized phase 2 network trial of tivantinib plus cetuximab versus cetuximab in patients with recurrent/metastatic head and neck squamous cell carcinoma.

BACKGROUND: MET signaling is a well described mechanism of resistance to anti-EGFR therapy, and MET overexpression is common in head and neck squamous cell carcinomas (HNSCCs). In the current trial, the authors compared the oral MET inhibitor tivantinib (ARQ197) in combination with cetuximab (the TC arm) versus a control arm that received cetuximab monotherapy (C) in patients with recurrent/metastatic HNSCC. METHODS: In total, 78 evaluable patients with cetuximab-naive, platinum-refractory HNSCC were enrolled, including 40 on the TC arm and 38 on the C arm (stratified by human papillomavirus [HPV] status). Patients received oral tivantinib 360 mg twice daily and intravenous cetuximab 500 mg/m2 once every 2 weeks. The primary outcome was the response rate (according to Response Evaluation Criteria in Solid Tumors, version 1.1), and secondary outcomes included progression-free and overall survival. After patients progressed on the C arm, tivantinib monotherapy was optional. RESULTS: The response rate was 7.5% in the TC arm (N = 3; 1 complete response) and 7.9% in the C arm (N = 3; not significantly different [NS]). The median progression-free survival in both arms was 4 months (NS), and the median overall survival was 8 months (NS). Both treatments were well tolerated, with a trend toward increased hematologic toxicities in the TC arm (12.5% had grade 3 leukopenia). The response rate in 31 HPV-positive/p16-positive patients was 0% in both arms, whereas the response rate in HPV-negative patients was 12.7% (12.5% in the TC arm and 13% in the C arm). Fifteen patients received tivantinib monotherapy, and no responses were observed. CONCLUSIONS: Combined tivantinib plus cetuximab does not significantly improve the response rate or survival compared with cetuximab alone but does increase toxicity in an unselected HNSCC population. Cetuximab responses appear to be limited to patients who have HPV-negative HNSCC. MET-aberration-focused trials for HNSCC and the use of higher potency, selective MET inhibitors remain of interest.

Long term follow-up of neoadjuvant chemotherapy for non-small cell lung cancer (NSCLC) investigating early positron emission tomography (PET) scan as a predictor of outcome.

BACKGROUND: Neoadjuvant chemotherapy is effective in improving survival of resectable NSCLC. Based on findings in the adjuvant and metastatic setting, FDG positron emission tomography (PET) scans may offer early prognostic or predictive value after one cycle of induction chemotherapy. METHODS: In this phase II non-randomized trial, patients with AJCC version 6 stage IB to IIIB operable NSCLC were treated with 3 cycles of cisplatin and pemetrexed neoadjuvant chemotherapy. Patients underwent FDG-PET scanning prior to and 18 to 21 days after the first cycle of chemotherapy. Investigators caring for patients were blinded to results, unless the scans showed evidence of disease progression. FDG-PET response was defined prospectively as a ≥ 20% decrease in the SUV of the primary lesion. RESULTS: Between October 2005 and February 2010, 25 patients enrolled. Fifty two percent were female, 88% white, and median age was 62 years. Histology was divided into adenocarcinoma 66%, not otherwise specified (NOS) 16%, squamous cell 12%, and large cell 4%. Stage distribution was: 16% IB, 4% IIB, and 79% IIIA. Treatment was well tolerated and only one patient had a grade 4 toxicity. The median follow up was 95 months. The 5 year progression free survival (PFS) and overall survival (OS) for the entire population were 54 and 67%, respectively. Eighteen patients had a baseline FDG-PET scan and a repeat scan at day 18-21 available for comparison. Ten patients (56%) were considered metabolic responders on the day 18-21 FDG-PET scan. Responders had a 5 year PFS and OS of 60 and 70%, respectively, while the percentage for non-responders was 63 and 75% (p = 0.96 and 0.85). CONCLUSIONS: This phase II trial did not demonstrate that a PET scan after one cycle of chemotherapy can predict survival outcomes of patients with NSCLC treated with neoadjuvant chemotherapy. TRIAL REGISTRATION: NCT00227539 registered September 28th, 2005.

Phase 1 study of EGFR-antisense DNA, cetuximab, and radiotherapy in head and neck cancer with preclinical correlatives.

BACKGROUND: Cetuximab combined with radiation therapy (RT) is an evidence-based treatment for locally advanced head and neck squamous cell carcinoma (HNSCC); however, locoregional failure remains the primary cause of cancer-related death in this disease. Intratumoral injection of epidermal growth factor receptor (EGFR)-antisense plasmid DNA (EGFR-AS) is safe and has been associated with promising lesional responses in patients who have recurrent/metastatic HNSCC. For the current study, the authors investigated the antitumor effects of cetuximab and EGFR-AS in preclinical HNSCC models and reported their phase 1 experience adding intratumoral EGFR-AS to cetuximab RT. METHODS: Antitumor mechanisms were investigated in cell line and xenograft models. Phase 1 trial eligibility required stage IVA through IVC HNSCC and a measurable lesion accessible for repeat injections. Patients received standard cetuximab was for 9 weeks. EGFR-AS was injected weekly until they achieved a lesional complete response. RT was delivered by conventional fractionation for 7 weeks, starting at week 3. Research biopsies were obtained at baseline and week 2. RESULTS: When added to cetuximab, EGFR-AS decreased cell viability and xenograft growth compared with EGFR-sense control, partially mediated by reduced EGFR expression. Six patients were enrolled in the phase 1 cohort. No grade 2 or greater EGFR-AS-related adverse events occurred. The best lesional response was a complete response (4 patients), and 1 patient each had a partial response and disease progression. EGFR expression decreased in 4 patients who had available paired specimens. CONCLUSIONS: In preclinical models, dual EGFR inhibition with cetuximab and EGFR-AS enhanced antitumor effects. In a phase 1 cohort, intratumoral EGFR-AS injections, cetuximab, and RT were well tolerated. A phase 2 trial is needed to conduct an extended evaluation of safety and to establish efficacy.

Immunotherapy of head and neck cancer: Emerging clinical trials from a National Cancer Institute Head and Neck Cancer Steering Committee Planning Meeting.

Recent advances have permitted successful therapeutic targeting of the immune system in head and neck squamous cell carcinoma (HNSCC). These new immunotherapeutic targets and agents are being rapidly adopted by the oncologic community and hold considerable promise. The National Cancer Institute sponsored a Clinical Trials Planning Meeting to address the issue of how to further investigate the use of immunotherapy in patients with HNSCC. The goals of the meeting were to consider phase 2 or 3 trial designs primarily in 3 different patient populations: those with previously untreated, human papillomavirus-initiated oropharyngeal cancers; those with previously untreated, human papillomavirus-negative HNSCC; and those with recurrent/metastatic HNSCC. In addition, a separate committee was formed to develop integrative biomarkers for the clinical trials. The meeting started with an overview of key immune components and principles related to HNSCC, including immunosurveillance and immune escape. Four clinical trial concepts were developed at the meeting integrating different immunotherapies with existing standards of care. These designs were presented for implementation by the head and neck committees of the National Cancer Institute-funded National Clinical Trials Network. This article summarizes the proceedings of this Clinical Trials Planning Meeting, the purpose of which was to facilitate the rigorous development and design of randomized phase 2 and 3 immunotherapeutic trials in patients with HNSCC. Although reviews usually are published immediately after the meeting is held, this report is unique because there are now tangible clinical trial designs that have been funded and put into practice and the studies are being activated to accrual. Cancer 2017;123:1259-1271. © 2016 American Cancer Society.

Subsets of salivary duct carcinoma defined by morphologic evidence of pleomorphic adenoma, PLAG1 or HMGA2 rearrangements, and common genetic alterations.

BACKGROUND: The authors hypothesized that histogenetic classification of salivary duct carcinoma (SDC) could account for de novo tumors and those with morphologic or molecular evidence (pleomorphic adenoma gene 1 [PLAG1], high-mobility group AT hook 2 [HMGA2] rearrangement, amplification) of pleomorphic adenoma (PA). METHODS: SDCs (n = 66) were reviewed for morphologic evidence of PA. PLAG1 and HMGA2 alterations were detected by fluorescence in situ hybridization (FISH). PLAG1-positive tumors were tested by FISH for fibroblast growth factor receptor 1 (FGFR1) rearrangement. Thirty-nine tumors were analyzed using a commercial panel for mutations and copy number variations in 50 cancer-related genes. RESULTS: On the basis of combined morphologic and molecular evidence of PA, 4 subsets of SDC emerged: 1) carcinomas with morphologic evidence of PA but intact PLAG1 and HMGA2 (n = 22); 2) carcinomas with PLAG1 alteration (n = 18) or 3) HMGA2 alteration (n = 12); and 4) de novo carcinomas, without morphologic or molecular evidence of PA (n = 14). The median disease-free survival was 37 months (95% confidence interval, 28.4-45.6 months). Disease-free survival and other clinicopathologic parameters did not differ for the subsets defined above. Combined Harvey rat sarcoma viral oncogene homolog/phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit α (HRAS/PIK3CA) mutations were observed predominantly in de novo carcinomas (5 of 8 vs 2 of 31 tumors; P = .035). Erb-B2 receptor tyrosine kinase 2 (ERBB2) copy number gain was not observed in de novo carcinomas (0 of 8 vs 12 of 31 tumors; P = .08). Tumor protein 53 (TP53) mutations were more common in SDC ex pleomorphic adenomas than in de novo carcinomas (17 of 31 vs 1 of 8 tumors; P = .033). CONCLUSIONS: The genetic profile of SDC varies with the absence or presence of pre-existing PA and its cytogenetic signature. Most de novo SDCs harbor combined HRAS/PIK3CA mutations and no ERBB2 amplification. Cancer 2016;122:3136-44. © 2016 American Cancer Society.

Upregulation of the ATR-CHEK1 pathway in oral squamous cell carcinomas.

The ATR-CHEK1 pathway is upregulated and overactivated in Ataxia Telangiectasia (AT) cells, which lack functional ATM protein. Loss of ATM in AT confers radiosensitivity, although ATR-CHEK1 pathway overactivation compensates, leads to prolonged G(2) arrest after treatment with ionizing radiation (IR), and partially reverses the radiosensitivity. We observed similar upregulation of the ATR-CHEK1 pathway in a subset of oral squamous cell carcinoma (OSCC) cell lines with ATM loss. In the present study, we report copy number gain, amplification, or translocation of the ATR gene in 8 of 20 OSCC cell lines by FISH; whereas the CHEK1 gene showed copy number loss in 12 of 20 cell lines by FISH. Quantitative PCR showed overexpression of both ATR and CHEK1 in 7 of 11 representative OSCC cell lines. Inhibition of ATR or CHEK1 with their respective siRNAs resulted in increased sensitivity of OSCC cell lines to IR by the colony survival assay. siRNA-mediated ATR or CHEK1 knockdown led to loss of G(2) cell cycle accumulation and an increased sub-G(0) apoptotic cell population by flow cytometric analysis. In conclusion, the ATR-CHEK1 pathway is upregulated in a subset of OSCC with distal 11q loss and loss of the G(1) phase cell cycle checkpoint. The upregulated ATR-CHEK1 pathway appears to protect OSCC cells from mitotic catastrophe by enhancing the G(2) checkpoint. Knockdown of ATR and/or CHEK1 increases the sensitivity of OSCC cells to IR. These findings suggest that inhibition of the upregulated ATR-CHEK1 pathway may enhance the efficacy of ionizing radiation treatment of OSCC.

Integrating novel therapeutic monoclonal antibodies into the management of head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) is an immunosuppressive malignancy. Interest in developing novel immunotherapies in HNSCC has been reawakened by the success of cetuximab, a therapeutic monoclonal antibody (mAb) against the epidermal growth factor receptor, which likely relies on immune as well as antisignaling mechanisms. This review focuses on novel therapeutic mAbs in current clinical development against established mechanisms of immune evasion in HNSCC, targeting: 1) tumor antigens, with resultant potential to induce antibody-dependent cell-mediated cytotoxicity and T cell activation; 2) immunosuppressive cytokines; 3) costimulatory tumor necrosis factor-family receptors; and 4) coinhibitory immune checkpoint receptors. Clinical trials of immunotherapeutic mAbs as monotherapy, in combination with cytolytic standard therapies exposing tumor antigens or in combination with other immunomodulatory mAbs, are urgently needed in HNSCC.

A clinical algorithm for fine-needle aspiration molecular testing effectively guides the appropriate extent of initial thyroidectomy.

OBJECTIVE: To test whether a clinical algorithm using routine cytological molecular testing (MT) promotes initial total thyroidectomy (TT) for clinically significant thyroid cancer (sTC) and/or correctly limits surgery to lobectomy when appropriate. BACKGROUND: Either TT or lobectomy is often needed to diagnose differentiated thyroid cancer. Determining the correct extent of initial thyroidectomy is challenging. METHODS: After implementing an algorithm for prospective MT of in-house fine-needle aspiration biopsy specimens, we conducted a single-institution cohort study of all patients (N = 671) with nonmalignant cytology who had thyroidectomy between October 2010 and March 2012, cytological diagnosis using 2008 Bethesda criteria, and 1 or more indications for thyroidectomy by 2009 American Thyroid Association guidelines. sTC was defined by histological differentiated thyroid cancer of 1 cm or more and/or lymph node metastasis. Cohort 2 patients did not have MT or had unevaluable results. In cohort 1, MT for a multigene mutation panel was performed for nonbenign cytology, and positive MT results indicated initial TT. RESULTS: MT guidance was associated with a higher incidence of sTC after TT (P = 0.006) and a lower rate of sTC after lobectomy (P = 0.03). Without MT results, patients with indeterminate (follicular lesion of undetermined significance/follicular or oncocytic neoplasm) cytology who received initial lobectomy were 2.5 times more likely to require 2-stage surgery for histological sTC (P < 0.001). In the 501 patients with non-sTC for whom lobectomy was the appropriate extent of surgery, lobectomy was correctly performed more often with routine preoperative MT (P = 0.001). CONCLUSIONS: Fine-needle aspiration biopsy MT for BRAF, RAS, PAX8-PPARγ, and RET-PTC expedites optimal initial surgery for differentiated thyroid cancer, facilitating succinct definitive management for patients with thyroid nodules.

Salivary duct carcinoma and the concept of early carcinoma ex pleomorphic adenoma.

AIMS: The data on the histological type of carcinomatous component and the extent of extracapsular invasion for salivary carcinomas ex pleomorphic adenoma (PA) are conflicting. We aimed to determine the prognostic value of extracapsular invasion in salivary duct carcinomas (SDC) ex PA. METHODS AND RESULTS: A total of 117 patients with SDC were identified retrospectively; 44 cases involving major salivary glands had pre-existing PA (44 of 117, 37%). The morphological spectrum of SDC ex PA was characterized. The primary endpoint was overall survival (OS). Most SDC ex PA were widely invasive at presentation (27 of 44; 61%). Five patients with intracapsular SDC ex PA experienced no disease progression. The assessment of extracapsular invasion was precluded in eight cases (e.g. positive margins of resection). The rate of lymph node involvement was similar in cases with extracapsular invasion of ≤2 mm (two of three) and >7 mm (22 of 26). Only pT correlated with OS [116 months, 95% confidence interval (CI) 22-210 months for pT1 versus 20 months (95% CI 6-34) for pT4; P = 0.013]. CONCLUSIONS: Intracapsular SDC ex PA are potentially indolent. SDC ex PA with extracapsular invasion of ≤2 mm are rare, and appear to be clinically aggressive. Several histological parameters preclude assessment of extracapsular invasion.

Novel targets in HPV-negative head and neck cancer: overcoming resistance to EGFR inhibition.

Cancers of the head and neck that arise from habitual exposure to carcinogens have lower cure rates than those that arise from infection with human papillomavirus (HPV), and intensification of cytotoxic chemotherapy and radiation has not improved outcomes. HPV-negative head and neck cancers abundantly express EGFR, and the monoclonal antibody cetuximab, directed against EGFR, is the only targeted therapy that has improved disease survival so far. However, response rates to single-agent cetuximab are lower than 15%, and cetuximab given with chemotherapy or radiation leads to only a modest effect on survival. Thus, investigating the mechanisms of resistance to EGFR inhibition in HPV-negative head and neck cancer might help identify novel and active therapies. In this Review, we focus on therapies in development that target redundant receptor tyrosine kinases (eg, HER2 and MET), reduce or abrogate nuclear functions of EGFR, affect cellular trafficking by inhibition of histone deacetylase, or treatments that might address resistance that arises in the EGFR signalling stream (eg, aurora-kinase inhibitors and STAT decoys).

Durvalumab in combination with chemoradiotherapy in patients with head and neck squamous cell carcinoma: Results from the Phase 1 CLOVER study.

BACKGROUND: The Phase 1 CLOVER study (NCT03509012) assessed durvalumab in combination with concurrent chemoradiotherapy (cCRT) in patients with advanced solid tumors; we report results from the head and neck squamous cell carcinoma (HNSCC) cohort. METHODS: Patients with histologically/cytologically confirmed locally advanced HNSCC, eligible for definitive cCRT and not considered for primary surgery, received durvalumab plus cisplatin and concurrent external beam radiation. Objectives were to assess safety/tolerability and preliminary efficacy. RESULTS: Eight patients were enrolled. The most frequent any-cause adverse events (AEs) were nausea and radiation skin injury (each n = 5); most frequent grade 3/4 AEs were lymphopenia and stomatitis (each n = 3). No patients had dose-limiting toxicities. Objective response rate was 71.4% (5/7 patients; four complete responses, one partial response); disease control rate was 85.7% at 18 weeks and 83.3% at 48 weeks. CONCLUSIONS: Durvalumab plus cCRT was tolerable and active in patients with unresected, locally advanced HNSCC.

Durvalumab in combination with chemoradiotherapy for patients with unresectable stage III non-small-cell lung cancer: Results from the phase 1 CLOVER study.

INTRODUCTION: For patients with unresectable, stage III non-small-cell lung cancer (NSCLC), current standard of care is concurrent chemoradiotherapy (cCRT) followed by consolidation durvalumab. However, earlier initiation of durvalumab simultaneously with cCRT may increase antitumor activity relative to initiation after cCRT. The phase 1 CLOVER study (NCT03509012) evaluated durvalumab combined with cCRT in patients with advanced solid tumors; we report findings from the NSCLC cohort. METHODS: CLOVER comprised a dose-limiting toxicity (DLT) assessment part, followed by an expansion part. In the NSCLC cohort, patients with previously untreated, unresectable, stage III NSCLC were enrolled in three treatment arms: durvalumab every 4 weeks (Q4W) + cisplatin + etoposide + radiotherapy (Arm 1); durvalumab Q4W + carboplatin + paclitaxel + radiotherapy (Arm 2); or durvalumab Q4W + carboplatin or cisplatin + pemetrexed + radiotherapy (non-squamous histology only; Arm 3). Patients received durvalumab until disease progression or unacceptable toxicity. The primary endpoint was safety and tolerability. RESULTS: Sixty-four patients were enrolled: 21, 22, and 21 in Arms 1, 2, and 3, respectively. One patient in Arm 1 had DLT (grade 3 aspartate aminotransferase increase and grade 4 alanine aminotransferase increase); no DLTs were observed in Arms 2 or 3. Grade 3/4 adverse events occurred in 76.6 % of patients overall; the most common were neutropenia (51.6 %), leukopenia (20.3 %), and anemia (17.2 %). In a post-hoc analysis, 7.8 % of patients had grade 3 pneumonitis/radiation pneumonitis (grouped term) events. Overall, the objective response rate was 60.9 % (95 % confidence interval [CI], 47.9-72.9); median duration of response was 15.8 months (95 % CI, 9.0-not estimable [NE]). Median progression-free survival was 13.4 months (95 % CI, 8.8-20.1) and median overall survival was not reached (95 % CI, 21.9-NE). CONCLUSION: Durvalumab in combination with cCRT was well tolerated, with a manageable safety profile and showed encouraging antitumor activity in patients with unresectable, stage III NSCLC.

T Cell Responses to Individualized Neoantigen Therapy mRNA-4157 (V940) Alone or in Combination With Pembrolizumab in the Phase 1 KEYNOTE-603 Study.

mRNA-4157 (V940) is an individualized neoantigen therapy (INT) targeting up to 34 patient-specific tumor neoantigens to induce T cell responses and potentiate anti-tumor activity. We report mechanistic insights into the immunogenicity of mRNA-4157 via characterization of T cell responses to neoantigens from the first-in-human phase 1, KEYNOTE-603 study (NCT03313778) in patients with resected non-small cell lung cancer (Part A: 1mg mRNA-4157, n = 4) or resected cutaneous melanoma (Part D: 1mg mRNA-4157 + 200mg pembrolizumab, n = 12). Safety, tolerability, and immunogenicity were assessed. All patients experienced ≥1 treatment-emergent adverse event (AE); there were no grade 4/5 AEs or dose-limiting toxicities. mRNA-4157 alone induced consistent de novo, and strengthened pre-existing, T cell responses to targeted neoantigens. Following combination therapy, sustained mRNA-4157-induced neoantigen-specific T cell responses and expansion of cytotoxic CD8 and CD4 T cells were observed. These findings show the potential of a novel mRNA INT approach in oncology.

Integrating Immunotherapy into Multimodal Treatment of Head and Neck Cancer.

Patients with locally advanced head and neck squamous cell carcinoma (HNSCC) have a poor prognosis, with a significant risk of progression or death despite multimodal treatment with surgery, chemotherapy, and radiotherapy. Immune checkpoint inhibitors targeting the programmed death receptor-1 (PD1) have dramatically changed the treatment landscape for recurrent/metastatic disease, improving overall survival in both the first- and second-line palliative settings. This success has driven the investigation of treatment strategies incorporating immunotherapy earlier into the multimodal curative-intent or salvage treatment of both locally advanced and recurrent/metastatic HNSCC. This review encompassed the following three subjects, with a focus on recently reported and ongoing clinical trials: (1) the use of neoadjuvant immunotherapy prior to surgery for locally advanced HNSCC, (2) the use of immunochemoradiotherapy for locally advanced head and neck cancers, and (3) novel uses of immunotherapy in the salvage of recurrent/metastatic HNSCC via a combined modality, including reirradiation paradigms. The results of these studies are eagerly awaited to improve patient outcomes in this challenging disease.

Feasibility of 5-fluorouracil and imiquimod for the topical treatment of cervical intraepithelial neoplasias (CIN) 2/3.

OBJECTIVES: To determine the feasibility (as measured by tolerability and safety) and efficacy of topical 5-fluorouracil (5-FU) and imiquimod for the treatment of cervical intraepithelial neoplasia (CIN) 2/3. METHODS: This pilot prospective study was conducted in women aged 18-45 years with p16+ CIN 2/3. Participants underwent an 8-week alternating regimen of self-applied 5% 5-FU on weeks 1, 3, 5, and 7 and physician-applied imiquimod on weeks 2, 4, 6, and 8. Adverse events (AEs) were collected by symptom diary and clinical exam. Feasibility was measured by tolerability and safety (AEs) of the study intervention. Tolerability was assessed as the number of participants able to apply 50% or more of the treatment doses. The safety outcome was calculated as the number of participants who experienced "specified AEs" defined as possibly, probably, or definitely related grade 2 or worse AE or grade 1 genital AEs (blisters, ulcerations, or pustules) lasting more than 5 days. The efficacy of the intervention was determined by histology and high-risk human papillomavirus (hrHPV) testing was done after treatment. RESULTS: The median age of the 13 participants was 27 ± 2.9 years. Eleven (84.61%) participants applied 50% or more of the treatment. All participants reported grade 1 AEs; 6 (46.15%) reported grade 2 AEs; and 0 reported grade 3/4 AEs. Three (23.08%) participants had specified AEs. Histologic regression to normal or CIN 1 among those completing 50% or more of the treatment doses was observed in 10 (90.91%) participants, and 7 (63.63%) tested negative for hr-HPV at the end of the study. CONCLUSIONS: Topical treatment for CIN 2/3 with 5-FU/imiquimod is feasible, with preliminary evidence of efficacy. Topical therapies need further investigation as adjuncts or alternatives to surgical therapy for CIN 2/3.

Immunotherapy and Biomarker Testing in Recurrent and Metastatic Head and Neck Cancers: ASCO Guideline.

PURPOSE: To provide evidence-based recommendations for practicing physicians and other health care providers on immunotherapy and biomarker testing for head and neck cancers. METHODS: ASCO convened an Expert Panel of medical oncology, surgical oncology, radiation oncology, radiology, pathology, and patient advocacy experts to conduct a literature search, including systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 2000 through 2022. Outcomes of interest included survival, overall response, and locoregional control. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS: The literature search identified 28 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS: When possible, evidence-based recommendations were developed to address biomarker testing, first-line treatment regimens based on programmed death ligand-1 scores, immunotherapy in platinum-refractory recurrent or metastatic head and neck squamous cell carcinoma, immunotherapy in nasopharyngeal carcinoma, and radiation therapy in combination with immunotherapy for treatment of local recurrence.Additional information is available at www.asco.org/head-neck-cancer-guidelines.

Randomized Phase II Trial of Ficlatuzumab With or Without Cetuximab in Pan-Refractory, Recurrent/Metastatic Head and Neck Cancer.

PURPOSE: Primary or acquired resistance to cetuximab, an antiepidermal growth factor receptor monoclonal antibody (mAb), minimizes its utility in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Aberrant hepatocyte growth factor/cMet pathway activation is an established resistance mechanism. Dual pathway targeting may overcome resistance. PATIENTS AND METHODS: This multicenter, randomized, noncomparative phase II study evaluated ficlatuzumab, an antihepatocyte growth factor mAb, with or without cetuximab in recurrent/metastatic HNSCC. The primary end point was median progression-free survival (PFS); an arm met significance criteria if the lower bound of the 90% CI excluded the historical control of 2 months. Key eligibility criteria were HNSCC with known human papillomavirus (HPV) status, cetuximab resistance (progression within 6 months of exposure in the definitive or recurrent/metastatic setting), and resistance to platinum and anti-PD-1 mAb. Secondary end points included objective response rate (ORR), toxicity, and the association of HPV status and cMet overexpression with efficacy. Continuous Bayesian futility monitoring was used. RESULTS: From 2018 to 2020, 60 patients were randomly assigned and 58 were treated. Twenty-seven versus 33 patients were allocated to monotherapy versus combination. Arms were balanced for major prognostic factors. The monotherapy arm closed early for futility. The combination arm met prespecified significance criteria with a median PFS of 3.7 months (lower bound 90% CI, 2.3 months; P = .04); the ORR was 6 of 32 (19%), including two complete and four partial responses. Exploratory analyses were limited to the combination arm: the median PFS was 2.3 versus 4.1 months (P = .03) and the ORR was 0 of 16 (0%) versus 6 of 16 (38%; P = .02) in the HPV-positive versus HPV-negative subgroups, respectively. cMet overexpression was associated with reduced hazard of progression in HPV-negative but not HPV-positive disease (P interaction = .02). CONCLUSION: The ficlatuzumab-cetuximab arm met significance criteria for PFS and warrants phase III development. HPV-negative HNSCC merits consideration as a selection criterion.