Publications by authors named "Robert L Ferris"

382 Publications

The cost of cure: Examining objective and subjective financial toxicity in head and neck cancer survivors.

Head Neck 2021 Jul 8. Epub 2021 Jul 8.

Department of Otorhinolaryngology - Head and Neck Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Background: Little is documented regarding objective financial metrics and their impact on subjective financial toxicity in head and neck cancer (HNC) survivors.

Methods: In a cross-sectional analysis, 71 survivors with available claims data for HNC-specific out-of-pocket expenses (OOPE) completed a survey including patient-reported, subjective financial toxicity outcome tools: the Comprehensive Score for financial Toxicity (COST) and the Financial Distress Questionnaire (FDQ).

Results: Worse COST scores were significantly associated with lower earnings at survey administration (coefficient = 3.79; 95% CI 2.63-4.95; p < 0.001); loss of earnings after diagnosis (coefficient = 6.03; 95% CI 0.53-11.52; p = 0.032); and greater annual OOPE as a proportion of earnings [log10(Annual OOPE:Earnings at survey): coefficient = -5.66; 95% CI -10.28 to -1.04; p = 0.017]. Similar results were found with FDQ.

Conclusion: Financial toxicity is associated with particular socioeconomic characteristics which, if understood, would assist the development of pre-treatment screening tools to detect at-risk individuals and intervene early in the HNC cancer survivorship trajectory.
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http://dx.doi.org/10.1002/hed.26801DOI Listing
July 2021

NRG-HN003: Phase I and Expansion Cohort Study of Adjuvant Pembrolizumab, Cisplatin and Radiation Therapy in Pathologically High-Risk Head and Neck Cancer.

Cancers (Basel) 2021 Jun 9;13(12). Epub 2021 Jun 9.

Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA.

The anti-PD1 monoclonal antibody pembrolizumab improves survival in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Patients with locoregional, pathologically high-risk HNSCC recur frequently despite adjuvant cisplatin-radiation therapy (CRT). Targeting PD1 may reverse immunosuppression induced by HNSCC and CRT. We conducted a phase I trial with an expansion cohort (n = 20) to determine the recommended phase II schedule (RP2S) for adding fixed-dose pembrolizumab to standard adjuvant CRT. Eligible patients had resected HPV-negative, stage III-IV oral cavity, pharynx, or larynx HNSCC with extracapsular nodal extension or positive margin. RP2S was declared if three or fewer dose-limiting toxicities (DLT) occurred in a cohort of 12. DLT was defined as grade 3 or higher non-hematologic adverse event (AE) related to pembrolizumab, immune-related AE requiring over 2 weeks of systemic steroids, or unacceptable RT delay. A total of 34 patients enrolled at 23 NRG institutions. During the first cohort, only one DLT was observed (fever), thus RP2S was declared as pembrolizumab 200 mg every 3 weeks for eight doses, starting one week before CRT. During expansion, three additional DLTs were observed (wound infection, diverticulitis, nausea). Of the 34 patients, 28 (82%) received five or more doses of pembrolizumab. This regimen was safe and feasible in a cooperative group setting. Further development is warranted.
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http://dx.doi.org/10.3390/cancers13122882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230356PMC
June 2021

Patient selection for immunotherapy in head and neck cancer - Authors' reply.

Lancet Oncol 2021 07;22(7):e291-e292

Moores Cancer Center, UC San Diego Health, La Jolla, CA, USA.

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http://dx.doi.org/10.1016/S1470-2045(21)00339-9DOI Listing
July 2021

Bleeding complications in patients with squamous cell carcinoma of the head and neck.

Head Neck 2021 Jun 12. Epub 2021 Jun 12.

Head and Neck Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Hemorrhage in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) may be attributed to chemotherapy and local tumor irradiation. Evidence of the relationship between hemorrhage in R/M HNSCC and targeted therapies, including epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) inhibitors, or immune checkpoint inhibitors, is limited. We aimed to identify epidemiological and clinical data related to the occurrence of hemorrhage in R/M HNSCC and to explore its relationship with various therapies. We describe information obtained from literature searches as well as data extracted from a commercial database and a database from the author's institution (Istituto Nazionale dei Tumori of Milan). Evidence suggests that most bleeding events in R/M HNSCC are minor. Clinical trial safety data do not identify a causal association between hemorrhage and anti-EGFR agents or immune checkpoint inhibitors. In contrast, anti-VEGF agents are associated with increased, and often severe/fatal, hemorrhagic complications.
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http://dx.doi.org/10.1002/hed.26772DOI Listing
June 2021

Epidermal Growth Factor Receptor-Targeted Therapy for Head and Neck Cancer.

Otolaryngol Clin North Am 2021 Aug 9;54(4):743-749. Epub 2021 Jun 9.

Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, USA. Electronic address:

The epidermal growth factor receptor (EGFR) is an important therapeutic target in head and neck squamous cell carcinomas (HNSCCs). EGFR-targeted agents including monoclonal antibodies and tyrosine kinase inhibitors have shown mixed results in clinical trials. To date, only cetuximab, an anti-EGFR monoclonal antibody, is approved for use in local/regional advanced and recurrent or metastatic HNSCC. This article reviews the mechanism of action of cetuximab and its antitumor immune effects and the data to support its use in HNSCC. It additionally provides an overview of other EGFR monoclonal antibodies and small molecule tyrosine kinase inhibitors that have been studied.
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http://dx.doi.org/10.1016/j.otc.2021.04.005DOI Listing
August 2021

The Nasoseptal Flap for Reconstruction of Lateral Oropharyngectomy Defects: A Clinical Series.

Laryngoscope 2021 Jun 9. Epub 2021 Jun 9.

Department of Otolaryngology-Head and Neck Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, U.S.A.

Objectives/hypothesis: To study use of the nasoseptal flap (NSF) to reconstruct lateral transoral robotic surgery (TORS) oropharyngectomy defects.

Study Design: Retrospective case series.

Methods: A clinical series of six patients undergoing NSF reconstruction of lateral TORS oropharyngectomy defects was retrospectively studied. All patients underwent TORS for the treatment of intermediate-risk human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma of the lateral pharyngeal wall between January and June 2017. All patients underwent NSF reconstruction of lateral TORS defects with retrospective analysis of outcomes and complications.

Results: Six patients underwent NSF reconstruction of lateral TORS defects. Operative times decreased from 180 minutes to 90 minutes over the study period. There were two cases of partial flap dehiscence and partial necrosis. There were no major donor site complications. All patients had temporary nasal obstruction and crusting. Two experienced temporary aural fullness. In all patients, the lateral wall was mucosalized in 1-3 weeks. Cephalometric analysis of preoperative imaging revealed that patients with high-arched palates (>3 cm) and defect lengths that are longer than NSF flap lengths are poor candidates for this technique.

Conclusions: This NSF is a vascularized, locoregional rotational flap that can reconstruct lateral TORS defects in salvages cases or those where the parapharyngeal carotid or mandibular bone are exposed. Postoperative morbidity is limited to temporary nasal dyspnea, aural fullness, and crusting. Preoperative imaging can determine which patient will have successful defect coverage.

Level Of Evidence: 4 Laryngoscope, 2021.
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http://dx.doi.org/10.1002/lary.29660DOI Listing
June 2021

B cell signatures and tertiary lymphoid structures contribute to outcome in head and neck squamous cell carcinoma.

Nat Commun 2021 06 7;12(1):3349. Epub 2021 Jun 7.

Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.

Current immunotherapy paradigms aim to reinvigorate CD8 T cells, but the contribution of humoral immunity to antitumor immunity remains understudied. Here, we demonstrate that in head and neck squamous cell carcinoma (HNSCC) caused by human papillomavirus infection (HPV), patients have transcriptional signatures of germinal center (GC) tumor infiltrating B cells (TIL-Bs) and spatial organization of immune cells consistent with tertiary lymphoid structures (TLS) with GCs, both of which correlate with favorable outcome. GC TIL-Bs in HPV HNSCC are characterized by distinct waves of gene expression consistent with dark zone, light zone and a transitional state of GC B cells. Semaphorin 4a expression is enhanced on GC TIL-Bs present in TLS of HPV HNSCC and during the differentiation of TIL-Bs. Our study suggests that therapeutics to enhance TIL-B responses in HNSCC should be prioritized in future studies to determine if they can complement current T cell mediated immunotherapies.
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http://dx.doi.org/10.1038/s41467-021-23355-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184766PMC
June 2021

Neoadjuvant nivolumab for patients with resectable HPV-positive and HPV-negative squamous cell carcinomas of the head and neck in the CheckMate 358 trial.

J Immunother Cancer 2021 Jun;9(6)

Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.

Background: Head and neck squamous cell carcinomas (HNSCCs) are common malignancies caused by carcinogens, including tobacco and alcohol, or infection with human papillomavirus (HPV). Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1) pathway are effective against unresectable recurrent/metastatic HNSCC. Here, we explored the safety and efficacy of anti-PD-1 therapy in at-risk resectable HPV-positive and HPV-negative HNSCC in the neoadjuvant setting.

Methods: The phase I/II CheckMate 358 trial in virus-associated cancers assessed neoadjuvant nivolumab in patients with previously untreated, resectable HPV-positive or HPV-negative HNSCC. Patients received nivolumab 240 mg intravenously on days 1 and 15, with surgery planned by day 29. Safety/tolerability (primary endpoint) was assessed by monitoring adverse events (AEs) and surgical delays. Radiographic response was measured before surgery using RECIST v1.1, adapted for a single post-nivolumab evaluation. Pathologic specimens were examined for treatment response using immune-based criteria.

Results: From November 2015 to December 2017, 52 patients with AJCC (seventh edition) stage III-IV resectable HNSCC received neoadjuvant nivolumab (26 HPV-positive, 26 HPV-negative). Any-grade treatment-related AEs (TRAEs) occurred in 19 patients (73.1%) and 14 patients (53.8%) in the HPV-positive and HPV-negative cohorts, respectively; grade 3-4 TRAEs occurred in five (19.2%) and three patients (11.5%), respectively. No patient had a protocol-defined TRAE-related surgical delay (>4 weeks). Thirty-eight patients were reported as undergoing complete surgical resection, 10 had a planned post-nivolumab biopsy instead of definitive surgery due to a protocol misinterpretation, and four did not undergo surgery or biopsy, including two with tumor progression. Radiographic response rates in 49 evaluable patients were 12.0% and 8.3% in the HPV-positive and HPV-negative cohorts, respectively. There were no complete pathologic responses by site or central review in operated patients. Among 17 centrally evaluable HPV-positive tumors, one (5.9%) achieved major pathological response and three (17.6%) achieved partial pathologic response (pPR); among 17 centrally evaluable HPV-negative tumors, one (5.9%) achieved pPR.

Conclusions: Neoadjuvant nivolumab was generally safe and induced pathologic regressions in HPV-positive (23.5%) and HPV-negative (5.9%) tumors. Combinatorial neoadjuvant treatment regimens, and continued postoperative therapy for high-risk tumors, are warranted in future trials to enhance the efficacy of this approach.

Trial Registration Number: ClinicalTrials.gov NCT02488759; https://clinicaltrials.gov/ct2/show/NCT02488759.
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http://dx.doi.org/10.1136/jitc-2021-002568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183204PMC
June 2021

Treatment De-intensification for HPV-Positive Oropharynx Cancer: What Is Currently Acceptable?

J Clin Oncol 2021 May 27:JCO2100594. Epub 2021 May 27.

Anthony J. Cmelak, MD, Vanderbilt University Medical Center, Nashville, TN; Robert L. Ferris, MD, PhD, UPMC Hillman Cancer Center, Pittsburgh, PA; Allen M. Chen, MD, University of California Irvine, Irvine, CA; Tanguy Seiwert, MD, Johns Hopkins Medical Institutions, Johns Hopkins Medical Center, Baltimore, MD; and Barbara Burtness, MD, Yale School of Medicine, Yale University, New Haven, CT.

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http://dx.doi.org/10.1200/JCO.21.00594DOI Listing
May 2021

Tumor hypoxia is associated with resistance to PD-1 blockade in squamous cell carcinoma of the head and neck.

J Immunother Cancer 2021 May;9(5)

Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA

The majority of patients with recurrent/metastatic squamous cell carcinoma of the head and neck (HNSCC) (R/M) do not benefit from anti-PD-1 therapy. Hypoxia induced immunosuppression may be a barrier to immunotherapy. Therefore, we examined the metabolic effect of anti-PD-1 therapy in a murine MEER HNSCC model as well as intratumoral hypoxia in R/M patients. In order to characterize the tumor microenvironment in PD-1 resistance, a MEER cell line was created from the parental line that are completely resistant to anti-PD-1. These cell lines were then metabolically profiled using seahorse technology and injected into C57/BL6 mice. After tumor growth, mice were pulsed with pimonidazole and immunofluorescent imaging was performed to analyze hypoxia and T cell infiltration. To validate the preclinical results, we analyzed tissues from R/M patients (n=36) treated with anti-PD-1 mAb, via immunofluorescent imaging for number of CD8+ T cells (CD8), Tregs and the percent area (CAIX) and mean intensity (I) of carbonic anhydrase IX in tumor. We analyzed disease control rate (DCR), progression free survival (PFS), and overall survival (OS) using proportional odds and proportional hazards (Cox) regression. We found that anti-PD-1 resistant MEER has significantly higher oxidative metabolism, while there was no difference in glycolytic metabolism. Intratumoral hypoxia was significantly increased and CD8+ T cells decreased in anti-PD-1 resistant tumors compared with parental tumors in the same mouse. In R/M patients, lower tumor hypoxia by CAIX/I was significantly associated with DCR (p=0.007), PFS, and OS, and independently associated with response (p=0.028) and PFS (p=0.04) in a multivariate model including other significant immune factors. During PD-1 resistance, tumor cells developed increased oxidative metabolism leading to increased intratumoral hypoxia and a decrease in CD8+ T cells. Lower tumor hypoxia was independently associated with increased efficacy of anti-PD-1 therapy in patients with R/M HNSCC. To our knowledge this is the first analysis of the effect of hypoxia in this patient population and highlights its importance not only as a predictive biomarker but also as a potential target for therapeutic intervention.
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http://dx.doi.org/10.1136/jitc-2020-002088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126285PMC
May 2021

Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.

Lancet Oncol 2021 04;22(4):450-462

Moores Cancer Center, UC San Diego Health, La Jolla, CA, USA.

Background: Chemoradiotherapy is the standard of care for unresected locally advanced squamous cell carcinoma of the head and neck. We aimed to assess if addition of avelumab (anti-PD-L1) to chemoradiotherapy could improve treatment outcomes for this patient population.

Methods: In this randomised, double-blind, placebo-controlled, phase 3 study, patients were recruited from 196 hospitals and cancer treatment centres in 22 countries. Patients aged 18 years or older, with histologically confirmed, previously untreated, locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, larynx, or oral cavity (unselected for PD-L1 status), an Eastern Cooperative Oncology Group performance status score of 0 or 1, and who could receive chemoradiotherapy were eligible. Patients were randomly assigned (1:1) centrally by means of stratified block randomisation with block size four (stratified by human papillomavirus status, tumour stage, and nodal stage, and done by an interactive response technology system) to receive 10 mg/kg avelumab intravenously every 2 weeks plus chemoradiotherapy (100 mg/m cisplatin every 3 weeks plus intensity-modulated radiotherapy with standard fractionation of 70 Gy [35 fractions during 7 weeks]; avelumab group) or placebo plus chemoradiotherapy (placebo group). This was preceded by a single 10 mg/kg avelumab or placebo lead-in dose given 7 days previously and followed by 10 mg/kg avelumab or placebo every 2 weeks maintenance therapy for up to 12 months. The primary endpoint was progression-free survival by investigator assessment per modified Response Evaluation Criteria in Solid Tumors, version 1.1, in all randomly assigned patients. Adverse events were assessed in patients who received at least one dose of avelumab or placebo. This trial is registered with ClinicalTrials.gov, NCT02952586. Enrolment is no longer ongoing, and the trial has been discontinued.

Findings: Between Dec 12, 2016, and Jan 29, 2019, from 907 patients screened, 697 patients were randomly assigned to the avelumab group (n=350) or the placebo group (n=347). Median follow-up for progression-free survival was 14·6 months (IQR 8·5-19·6) in the avelumab group and 14·8 months (11·6-18·8) in the placebo group. Median progression-free survival was not reached (95% CI 16·9 months-not estimable) in the avelumab group and not reached (23·0 months-not estimable) in the placebo group (stratified hazard ratio 1·21 [95% CI 0·93-1·57] favouring the placebo group; one-sided p=0·92). The most common grade 3 or worse treatment-related adverse events were neutropenia (57 [16%] of 348 patients in the avelumab group vs 52 [15%] of 344 patients in the placebo group), mucosal inflammation (50 [14%] vs 45 [13%]), dysphagia (49 [14%] vs 47 [14%]), and anaemia (41 [12%] vs 44 [13%]). Serious treatment-related adverse events occurred in 124 (36%) patients in the avelumab group and in 109 (32%) patients in the placebo group. Treatment-related deaths occurred in two (1%) patients in the avelumab group (due to general disorders and site conditions, and vascular rupture) and one (<1%) in the placebo group (due to acute respiratory failure).

Interpretation: The primary objective of prolonging progression-free survival with avelumab plus chemoradiotherapy followed by avelumab maintenance in patients with locally advanced squamous cell carcinoma of the head and neck was not met. These findings may help inform the design of future trials investigating the combination of immune checkpoint inhibitors plus CRT.

Funding: Pfizer and Merck KGaA, Darmstadt, Germany.
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http://dx.doi.org/10.1016/S1470-2045(20)30737-3DOI Listing
April 2021

Reply to N. Hirshoren et al and D. Chakrabarti et al.

J Clin Oncol 2021 May 11;39(14):1600-1601. Epub 2021 Mar 11.

Stephen Y. Lai, MD, PhD, Departments of Head and Neck Surgery, Molecular and Cellular Oncology, and Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX and Robert L. Ferris, MD, PhD, Departments of Otolaryngology, Immunology, and Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA.

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http://dx.doi.org/10.1200/JCO.21.00027DOI Listing
May 2021

Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers.

PLoS Genet 2021 03 5;17(3):e1009254. Epub 2021 Mar 5.

University of Salzburg, Department of Biosciences and Cancer Cluster Salzburg, Salzburg, Austria.

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta<5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (Pmeta<5x10-7): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2). Gene-based association and gene set enrichment identified a set of 48 SqCC-related genes rel to DNA damage and epigenetic regulation pathways. Our study highlights the importance of cross-cancer analyses to identify pleiotropic risk loci of histology-related cancers arising at distinct anatomical sites.
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http://dx.doi.org/10.1371/journal.pgen.1009254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968735PMC
March 2021

Elective neck dissection versus positron emission tomography-computed tomography-guided management of the neck in clinically node-negative early oral cavity cancer: A cost-utility analysis.

Cancer 2021 Jun 26;127(12):1993-2002. Epub 2021 Feb 26.

Department of Otolaryngology-Head & Neck Surgery, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.

Background: In early oral cavity cancer, elective neck dissection (END) for the clinically node-negative (cN0) neck improves survival compared with observation. This paradigm has been challenged recently by the use of positron emission tomography-computed tomography (PET-CT) imaging in the cN0 neck. To inform this debate, we performed an economic evaluation comparing PET-CT-guided therapy with routine END in the cN0 neck.

Methods: Patients with T1-2N0 lateralized oral tongue cancer were analyzed. A Markov model over a 40-year time horizon simulated treatment, disease recurrence, and survival from a US health care payer perspective. Model parameters were derived from a review of the literature.

Results: The END strategy was dominant, with a cost savings of $1576.30 USD, an increase of 0.055 quality-adjusted life years (QALYs), a net monetary benefit of $4303 USD, and a 0.22 life-year advantage. END was sensitive to variation in cost and utilities in deterministic and probabilistic sensitivity analyses. PET-CT became the preferred strategy when decreasing occult nodal disease to 18% and increasing the negative predictive value (NPV) of PET-CT to 89% in 1-way sensitivity analyses. In probabilistic sensitivity analysis, assuming a cost effectiveness threshold of $50,000 USD/QALY, END was dominant in 64% of simulations and cost effective in 69.8%.

Conclusion: END is a cost-effective strategy compared with PET-CT in patients who have node-negative oral cancer. Although lower PET standardized uptake value thresholds would result in fewer false negatives and improved NPV, it is still uncertain that PET-CT would be cost effective, as this would likely result in more false positive tests.
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http://dx.doi.org/10.1002/cncr.33446DOI Listing
June 2021

Non-steroidal anti-inflammatory drugs induce immunogenic cell death in suppressing colorectal tumorigenesis.

Oncogene 2021 Mar 18;40(11):2035-2050. Epub 2021 Feb 18.

UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

Use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with reduced risk of colorectal cancer (CRC). However, the mechanism by which NSAIDs suppress colorectal tumorigenesis remains unclear. We previously showed that NSAIDs selectively kill emerging tumor cells via death receptor (DR) signaling and a synthetic lethal interaction mediated by the proapoptotic Bcl-2 family protein BID. In this study, we found NSAIDs induce endoplasmic reticulum (ER) stress to activate DR signaling and BID in tumor suppression. Importantly, our results unveiled an ER stress- and BID-dependent immunogenic effect of NSAIDs, which may be critical for tumor suppression. NSAID treatment induced hallmarks of immunogenic cell death (ICD) in CRC cells and colonic epithelial cells upon loss of APC tumor suppressor, and elevated tumor-infiltrating lymphocytes (TILs) in the polyps of APC mice. ER stress inhibition or BID deletion abrogated the antitumor and immunogenic effects of NSAIDs. Furthermore, increased ER stress and TILs were detected in human advanced adenomas from NSAID-treated patients. Together, our results suggest that NSAIDs induce ER stress- and BID-mediated ICD to restore immunosurveillance and suppress colorectal tumor formation.
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http://dx.doi.org/10.1038/s41388-021-01687-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981263PMC
March 2021

LincRNA-immunity landscape analysis identifies EPIC1 as a regulator of tumor immune evasion and immunotherapy resistance.

Sci Adv 2021 Feb 10;7(7). Epub 2021 Feb 10.

Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.

Through an integrative analysis of the lincRNA expression and tumor immune response in 9,626 tumor samples across 32 cancer types, we developed a lincRNA-based immune response (LIMER) score that can predict the immune cells infiltration and patient prognosis in multiple cancer types. Our analysis also identified tumor-specific lincRNAs, including , that potentially regulate tumor immune response in multiple cancer types. Immunocompetent mouse models and in vitro co-culture assays demonstrated that induces tumor immune evasion and resistance to immunotherapy by suppressing tumor cell antigen presentation. Mechanistically, lincRNA interacts with the histone methyltransferase EZH2, leading to the epigenetic silencing of , , , and MHC-I genes. Genetic and pharmacological inhibition of EZH2 abolish immune-related oncogenic effect and its suppression of interferon-γ signaling. The -EZH2 axis emerges as a potential mechanism for tumor immune evasion that can serve as therapeutic targets for immunotherapy.
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http://dx.doi.org/10.1126/sciadv.abb3555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875530PMC
February 2021

Characterizing postoperative physiologic swallow function following transoral robotic surgery for early stage tonsil, base of tongue, and unknown primary human papillomavirus-associated squamous cell carcinoma.

Head Neck 2021 05 5;43(5):1629-1640. Epub 2021 Feb 5.

Department of Otolaryngology - Head & Neck Surgery, Emory University School of Medicine, Atlanta, Georgia, USA.

Background: Data objectively evaluating acute post-transoral robotic surgery (TORS) swallow function are limited. Our goal was to characterize and identify clinical variables that may impact swallow function components 3 weeks post-TORS.

Methods: Retrospective cohort study. Pre/postoperative use of the Modified Barium Swallow Impairment Profile (MBSImP) and Penetration-Aspiration Scale (PAS) was completed on 125 of 139 TORS patients (2016-2019) with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma. Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) scores were retrospectively calculated. Uni/multivariate analysis was performed.

Results: Dysfunctional pre-TORS DIGEST scores were predictive of post-TORS dysphagia (p = 0.015). Pre-TORS MBSImP deficits in pharyngeal stripping wave, swallow initiation, and clearing pharyngeal residue correlated with airway invasion post-TORS based on PAS scores (p = 0.012, 0.027, 0.048, respectively). Multivariate analysis of DIGEST safety scores declined with older age (p = 0.044). Odds ratios (ORs) for objective swallow function components after TORS were better for unknown primary and tonsil primaries compared to base of tongue (BOT) (OR 0.35-0.91).

Conclusions: Preoperative impairments in specific MBSImP components, older patients, and BOT primaries may predict more extensive recovery in swallow function after TORS.
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http://dx.doi.org/10.1002/hed.26632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046724PMC
May 2021

Risk assessment for distant metastasis in differentiated thyroid cancer using molecular profiling: A matched case-control study.

Cancer 2021 Jun 4;127(11):1779-1787. Epub 2021 Feb 4.

Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.

Background: Risk stratification for patients with differentiated thyroid cancer (DTC) is based primarily on pathologic tumor characteristics. Accurate preoperative prognostication could allow for more informed initial surgical recommendations, particularly among patients at a higher risk for distant metastasis (DM). The objective of this study was to characterize the genetic profile of DTC with DM and to validate a molecular-based risk stratification.

Methods: A case-control study design was used to analyze patients who had DTC with DM (n = 62) and a propensity matched cohort of patients who had DTC without DM after at least 5 years of follow-up using the ThyroSeq version 3 targeted next-generation sequencing assay. The results were classified into high-risk, intermediate-risk, and low-risk of aggressive disease.

Results: Most patients who had DTC with DM (66%) had a late-hit mutation in TERT, TP53, or PIK3CA. After propensity matching by age, tumor size, and sex, the high-risk molecular profile had strong association with DM (high-risk vs intermediate-risk: odds ratio, 25.1; 95% CI, 3.07-204.4; P < .001; high-risk vs low-risk: odds ratio, 122.5; 95% CI, 14.5-1038.4; P < .001). Overall, molecular risk categories were associated with DM risk, with a concordance index of 0.836 (95% CI, 0.759-0.913), which remained consistent after internal validation. Within the range of 5% to 10% of DM observed in DTC, the expected probability of DM would be 0.2% to 0.4% for the low-risk molecular profile, 4.7% to 9.4% for the intermediate-risk molecular profile, and 19.3% to 33.5% for the high-risk molecular profile.

Conclusions: In this matched case-control study, genetic profiling using an available molecular assay provided accurate and robust risk stratification for DM in patients with DTC. The availability of preoperative prognostication may allow tailoring treatment for patients with DTC.
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http://dx.doi.org/10.1002/cncr.33421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113082PMC
June 2021

PET/CT Poorly Predicts AJCC 8th Edition Pathologic Staging in HPV-Related Oropharyngeal Cancer.

Laryngoscope 2021 07 11;131(7):1535-1541. Epub 2021 Jan 11.

Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

Objective: The American Joint Committee on Cancer (AJCC) 8th edition introduced distinct clinical and pathological staging paradigms for human papilloma virus positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC). Treatment planning for OPSCC often utilizes positron emission tomography/computed tomography (PET/CT) to assess clinical stage. We hypothesize that PET/CT will accurately predict final pathologic AJCC 8th edition staging in patients with HPV+ OPSCC.

Methods: All patients with primary HPV+ OPSCC with preoperative PET/CT who underwent transoral robotic surgery and neck dissection between 2011 and 2017 were identified. Data were collected via chart review. Two neuroradiologists performed blinded re-evaluation of all scans. Primary tumor size and cervical nodal disease characteristics were recorded and TNM staging was extrapolated. Cohen's kappa statistic was used to assess interrater reliability. Test for symmetry was performed to analyze discordance between radiologic and pathologic staging.

Results: Forty-nine patients met inclusion criteria. Interrater reliability was substantial between radiologists for nodal (N) and overall staging (OS) (κ = 0.715 and 0.715). Radiologist A review resulted in identical OS for 67% of patients, overstaging for 31%, and understaging for 2%. Radiologist B review resulted in 61% identical OS, 39% overstaging, and 0% understaging. In misclassified cases, the test of symmetry shows strong bias toward overstaging N stage and OS (P < .001). Radiologic interpretation of extracapsular extension showed poor interrater reliability (κ = 0.403) and poor accuracy.

Conclusion: PET/CT predicts a higher nodal and overall stage than pathologic staging. PET/CT should not be relied upon for initial tumor staging, as increased FDG uptake is not specific for nodal metastases. PET/CT is shown to be a poor predictor of ECE.

Level Of Evidence: 4 Laryngoscope, 131:1535-1541, 2021.
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http://dx.doi.org/10.1002/lary.29366DOI Listing
July 2021

Dose-response model for severe late laryngeal toxicity after stereotactic body radiation therapy for previously-irradiated head and neck cancer.

J Radiosurg SBRT 2020 ;7(2):89-94

Department of Radiation Oncology, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

We sought to evaluate the association between larynx dose and risk of severe late laryngeal toxicity in patients undergoing re-irradiation SBRT for recurrent HNC. Fifty-five patients with an intact larynx underwent re-irradiation SBRT to a median dose of 44 Gy in 5 fractions. Five (41.7%) patients treated for a laryngeal/hypopharyngeal recurrence experienced late grade ≥3 laryngeal toxicity, compared to 0.0-7.1% for other sites. Logistic dose-response models were created to predict risk of severe late laryngeal toxicity, including dysphagia and airway compromise. According to the model, the risk of severe laryngeal toxicity with a larynx D5cc of 5 Gy is 5.8% (95% CI 2.9-9.9%) and rises to 11.4% with a D5cc of 20 Gy and 25.3% with a D5cc of 40 Gy. In patients with a laryngeal/hypopharyngeal recurrence, SBRT planning should carefully assess the dose to laryngeal structures given these dose findings, and SBRT should be approached with significant caution in such patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717091PMC
January 2020

Defining best practices for tissue procurement in immuno-oncology clinical trials: consensus statement from the Society for Immunotherapy of Cancer Surgery Committee.

J Immunother Cancer 2020 11;8(2)

Department of Otolaryngology, Stanford University School of Medicine, Stanford, California, USA.

Immunotherapy is now a cornerstone for cancer treatment, and much attention has been placed on the identification of prognostic and predictive biomarkers. The success of biomarker development is dependent on accurate and timely collection of biospecimens and high-quality processing, storage and shipping. Tumors are also increasingly used as source material for the generation of therapeutic T cells. There have been few guidelines or consensus statements on how to optimally collect and manage biospecimens and source material being used for immunotherapy and related research. The Society for Immunotherapy of Cancer Surgery Committee has brought together surgical experts from multiple subspecialty disciplines to identify best practices and to provide consensus on how best to access and manage specific tissues for immuno-oncology treatments and clinical investigation. In addition, the committee recommends early integration of surgeons and other interventional physicians with expertise in biospecimen collection, especially in clinical trials, to optimize the quality of tissue and the validity of correlative clinical studies in cancer immunotherapy.
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http://dx.doi.org/10.1136/jitc-2020-001583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670953PMC
November 2020

HPV+ oropharyngeal squamous cell carcinomas from patients with two tumors display synchrony of viral genomes yet discordant mutational profiles and signatures.

Carcinogenesis 2021 02;42(1):14-20

Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA.

Human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma (HPV + OPSCC) is increasing in prevalence in the USA, as are cases of patients with multiple HPV + OPSCCs (mHPV + OPSCC). mHPV + OPSCCs present a unique opportunity to examine HPV + OPSCC mutation acquisition and evolution. We performed sequencing of the viral genome, somatic exome and somatic transcriptome from 8 patients each with 2 spatially distinct HPV + OPSCCs, and 37 'traditional' HPV + OPSCCs to first address if paired tumors are caused by the same viral isolate and next, if acquired alterations, and the underlying processes driving mutagenesis, are shared within pairs. All tumor pairs contained viral genomes from the same HPV type 16 sublineage and differed by 0-2 clonal single nucleotide polymorphisms (SNPs), suggesting infection with the same viral isolate. Despite this, there was significant discordance in expression profiles, mutational burden and mutational profiles between tumors in a pair, with only two pairs sharing any overlapping mutations (3/3343 variants). Within tumor pairs there was a striking discrepancy of mutational signatures, exemplified by no paired tumors sharing high APOBEC mutational burden. Here, leveraging mHPV + OPSCCs as a model system to study mutation acquisition in virally mediated tumors, in which the germline, environmental exposures, immune surveillance and tissue/organ type were internally controlled, we demonstrate that despite infection by the same viral isolate, paired mHPV + OPSCCs develop drastically different somatic alterations and even more strikingly, appear to be driven by disparate underlying mutational processes. Thus, despite a common starting point, HPV + OPSCCs evolve through variable mutational processes with resultant stochastic mutational profiles.
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http://dx.doi.org/10.1093/carcin/bgaa111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014522PMC
February 2021

Evolving Evidence in Support of Sentinel Lymph Node Biopsy for Early-Stage Oral Cavity Cancer.

J Clin Oncol 2020 12 14;38(34):3983-3986. Epub 2020 Oct 14.

Departments of Otolaryngology, Immunology, and Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA.

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http://dx.doi.org/10.1200/JCO.20.02716DOI Listing
December 2020

Safety and Clinical Activity of MEDI0562, a Humanized OX40 Agonist Monoclonal Antibody, in Adult Patients with Advanced Solid Tumors.

Clin Cancer Res 2020 10 14;26(20):5358-5367. Epub 2020 Aug 14.

UC San Diego Moores Cancer Center, La Jolla, California, USA.

Purpose: Immune checkpoint blockade has demonstrated clinical benefits across multiple solid tumor types; however, resistance and relapse often occur. New immunomodulatory targets, which are highly expressed in activated immune cells, are needed. MEDI0562, an agonistic humanized mAb, specifically binds to the costimulatory molecule OX40. This first-in-human study evaluated MEDI0562 in adults with advanced solid tumors.

Patients And Methods: In this phase I, multicenter, open-label, single-arm, dose-escalation (3+3 design) study, patients received 0.03, 0.1, 0.3, 1.0, 3.0, or 10 mg/kg MEDI0562 through intravenous infusion every 2 weeks, until confirmed disease progression or unacceptable toxicity. The primary objective evaluated safety and tolerability. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics.

Results: In total, 55 patients received ≥1 dose of MEDI0562 and were included in the analysis. The most common tumor type was squamous cell carcinoma of the head and neck (47%). Median duration of treatment was 10 weeks (range, 2-48 weeks). Treatment-related adverse events (TRAEs) occurred in 67% of patients, most commonly fatigue (31%) and infusion-related reactions (14%). Grade 3 TRAEs occurred in 14% of patients with no apparent dose relationship; no TRAEs resulted in death. Two patients had immune-related partial responses per protocol and 44% had stable disease. MEDI0562 induced increased Ki67 CD4 and CD8 memory T-cell proliferation in the periphery and decreased intratumoral OX40 FOXP3 cells.

Conclusions: MEDI0562 was safely administered at doses up to 10 mg/kg in heavily pretreated patients. On-target pharmacodynamic effects were suggested in this setting. Further evaluation with immune checkpoint inhibitors is ongoing.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3070DOI Listing
October 2020

Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding.

Sci Immunol 2020 07;5(49)

Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Mechanisms of resistance to cancer immunotherapy remain poorly understood. Lymphocyte activation gene-3 (LAG3) signaling is regulated by a disintegrin and metalloprotease domain-containing protein-10 (ADAM10)- and ADAM17-mediated cell surface shedding. Here, we show that mice expressing a metalloprotease-resistant, noncleavable LAG3 mutant (LAG3) are resistant to PD1 blockade and fail to mount an effective antitumor immune response. Expression of LAG3 intrinsically perturbs CD4 T conventional cells (T), limiting their capacity to provide CD8 T cell help. Furthermore, the translational relevance for these observations is highlighted with an inverse correlation between high LAG3 and low ADAM10 expression on CD4 T in the peripheral blood of patients with head and neck squamous cell carcinoma, which corresponded with poor prognosis. This correlation was also observed in a cohort of patients with skin cancers and was associated with increased disease progression after standard-of-care immunotherapy. These data suggest that subtle changes in LAG3 inhibitory receptor signaling can act as a resistance mechanism with a substantive effect on patient responsiveness to immunotherapy.
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http://dx.doi.org/10.1126/sciimmunol.abc2728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901539PMC
July 2020

A novel surgeon credentialing and quality assurance process using transoral surgery for oropharyngeal cancer in ECOG-ACRIN Cancer Research Group Trial E3311.

Oral Oncol 2020 11 14;110:104797. Epub 2020 Jul 14.

Winship Cancer Institute at Emory University, Atlanta, GA, United States.

Purpose: Understanding the role of transoral surgery in oropharyngeal cancer (OPC) requires prospective, randomized multi-institutional data. Meticulous evaluation of surgeon expertise and surgical quality assurance (QA) will be critical to the validity of such trials. We describe a novel surgeon credentialing and QA process developed to support the ECOG-ACRIN Cancer Research Group E3311 (E3311) and report outcomes related to QA.

Patients And Methods: E3311 was a phase II randomized clinical trial of transoral surgery followed by low- or standard-dose, risk-adjusted post-operative therapy with stage III-IVa (AJCC 7th edition) HPV-associated OPC. In order to be credentialed to accrue to this trial, surgeons were required to demonstrate active hospital credentials and technique-specific surgical expertise with ≥20 cases of transoral resection for OPC. In addition, 10 paired operative and surgical pathology reports from the preceding 24 months were reviewed by an expert panel. Ongoing QA required <10% rate of positive margins, low oropharyngeal bleeding rates, and accrual of at least one patient per 12 months. Otherwise surgeons were placed on hold and not permitted to accrue until re-credentialed using a new series of transoral resections.

Results: 120 surgeons trained in transoral minimally invasive surgery applied for credentialing for E3311 and after peer-review, 87 (73%) were approved from 59 centers. During QA on E3311, positive final pathologic margins were reported in 19 (3.8%) patients. Grade III/IV and grade V oropharyngeal bleeding was reported in 29 (5.9%) and 1 (0.2%) of patients.

Conclusions: We provide proof of concept that a comprehensive credentialing process can support multicenter transoral head and neck surgical oncology trials, with low incidence of positive margins and *grade III/V oropharyngeal bleeding.
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http://dx.doi.org/10.1016/j.oraloncology.2020.104797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771718PMC
November 2020

Neuropilin-1 is a T cell memory checkpoint limiting long-term antitumor immunity.

Nat Immunol 2020 09 13;21(9):1010-1021. Epub 2020 Jul 13.

Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Robust CD8 T cell memory is essential for long-term protective immunity but is often compromised in cancer, where T cell exhaustion leads to loss of memory precursors. Immunotherapy via checkpoint blockade may not effectively reverse this defect, potentially underlying disease relapse. Here we report that mice with a CD8 T cell-restricted neuropilin-1 (NRP1) deletion exhibited substantially enhanced protection from tumor rechallenge and sensitivity to anti-PD1 immunotherapy, despite unchanged primary tumor growth. Mechanistically, NRP1 cell-intrinsically limited the self-renewal of the CD44PD1TCF1TIM3 progenitor exhausted T cells, which was associated with their reduced ability to induce c-Jun/AP-1 expression on T cell receptor restimulation, a mechanism that may contribute to terminal T cell exhaustion at the cost of memory differentiation in wild-type tumor-bearing hosts. These data indicate that blockade of NRP1, a unique 'immune memory checkpoint', may promote the development of long-lived tumor-specific T that are essential for durable antitumor immunity.
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http://dx.doi.org/10.1038/s41590-020-0733-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442600PMC
September 2020

Two-year follow-up of a randomized phase III clinical trial of nivolumab vs. the investigator's choice of therapy in the Asian population for recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141).

Head Neck 2020 10 24;42(10):2852-2862. Epub 2020 Jun 24.

Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

Background: The present study evaluated the 2-year survival of the Asian population in the CheckMate 141 trial.

Methods: The CheckMate 141 trial included patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). In the present study, 34 Asian patients (nivolumab group: 23 patients; investigator's choice of therapy [IC] group: 11 patients) were analyzed.

Results: The median overall survival (OS) was 12.1 and 6.2 months for the nivolumab and IC groups, respectively. The estimated 2-year OS rates were 22.7% and 0% for the nivolumab and IC groups, respectively. In the nivolumab group, the patients with any treatment-related adverse events (TRAEs), including skin-related disorders, showed better OS than the patients without any TRAEs.

Conclusions: Nivolumab demonstrated prolonged OS benefits in the Asian population with platinum-refractory R/M SCCHN and a favorable safety profile. TRAEs, including skin-related disorders, may be favorable prognostic factors for nivolumab efficacy.

Clinical Trial Registration: NCT02105636.
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http://dx.doi.org/10.1002/hed.26331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540331PMC
October 2020

Phase I Study of Ficlatuzumab and Cetuximab in Cetuximab-Resistant, Recurrent/Metastatic Head and Neck Cancer.

Cancers (Basel) 2020 Jun 11;12(6). Epub 2020 Jun 11.

UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA.

Cetuximab, an anti-EGFR monoclonal antibody (mAb), is approved for advanced head and neck squamous cell carcinoma (HNSCC) but benefits a minority. An established tumor-intrinsic resistance mechanism is cross-talk between the EGFR and hepatocyte growth factor (HGF)/cMet pathways. Dual pathway inhibition may overcome cetuximab resistance. This Phase I study evaluated the combination of cetuximab and ficlatuzumab, an anti-HGF mAb, in patients with recurrent/metastatic HNSCC. The primary objective was to establish the recommended Phase II dose (RP2D). Secondary objectives included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Mechanistic tumor-intrinsic and immune biomarkers were explored. Thirteen patients enrolled with no dose-limiting toxicities observed at any dose tier. Three evaluable patients were treated at Tier 1 and nine at Tier 2, which was determined to be the RP2D (cetuximab 500 mg/m and ficlatuzumab 20 mg/kg every 2 weeks). Median PFS and OS were 5.4 (90% CI = 1.9-11.4) and 8.9 (90% CI = 2.7-15.2) months, respectively, with a confirmed ORR of 2 of 12 (17%; 90% CI = 6-40%). High circulating soluble cMet levels correlated with poor survival. An increase in peripheral T cells, particularly the CD8 subset, was associated with treatment response whereas progression was associated with expansion of a distinct myeloid population. This well-tolerated combination demonstrated promising activity in cetuximab-resistant, advanced HNSCC.
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http://dx.doi.org/10.3390/cancers12061537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352434PMC
June 2020