A.D. Colevas

A Case Report of Unresectable Cutaneous Squamous Cell Carcinoma Responsive to Pembrolizumab, a Programmed Cell Death Protein 1 Inhibitor

At 1-month follow-up, the skin lesions had partially resolved, and resolution was greater by 2 months (Figure 1B). Initiation of isotretinoin therapy and discontinuation of leflunomide treatment resulted in complete lesional resolution by 3-month follow-up. The leg ulcers healed with continued conservative wound management. At 3 months, her isotretinoin dose was decreased to 20 mg/d without recurrence of additional lesions.

A Phase I Study of CUDC-101, a Multitarget Inhibitor of HDACs, EGFR, and HER2, in Combination with Chemoradiation in Patients with Head and Neck Squamous Cell Carcinoma

Purpose: CUDC-101 is a small molecule that simultaneously inhibits the epidermal growth factor receptor (EGFR), human growth factor receptor 2 (HER2), and histone deacetylase (HDAC) with preclinical activity in head and neck squamous cell cancer (HNSCC). The primary objective of this investigation is to determine the maximum tolerated dose (MTD) of CUDC-101 with cisplatin–radiotherapy in the treatment of HNSCC. Experimental Design: CUDC-101 monotherapy was administered intravenously three times weekly (Monday, Wednesday, Friday) for a one-week run-in, then continued with concurrent cisplatin (100 mg/m2 every 3 weeks) and external beam radiation (70 Gy to gross disease) over 7 weeks. Results: Twelve patients with intermediate or high-risk HNSCC enrolled. Eleven were p16INKa (p16)-negative. The MTD of CUDC-101–based combination therapy was established at 275 mg/m2/dose. Five patients discontinued CUDC-101 due to an adverse event (AE); only one was considered a dose-limiting toxicity (DLT), at the MTD. Pharmacokinetic evaluation suggested low accumulation with this dosing regimen. HDAC inhibition was demonstrated by pharmacodynamic analyses in peripheral blood mononuclear cells (PBMC), tumor biopsies, and paired skin biopsies. Paired tumor biopsies demonstrated a trend of EGFR inhibition. At 1.5 years of median follow-up, there has been one recurrence and two patient deaths (neither attributed to CUDC-101). The remaining nine patients are free of progression. Conclusions: CUDC-101, cisplatin, and radiation were feasible in intermediate-/high-risk patients with HNSCC, with no unexpected patterns of AE. Although the MTD was identified, a high rate of DLT-independent discontinuation of CUDC-101 suggests a need for alternate schedules or routes of administration. Clin Cancer Res; 21(7); 1566–73. ©2015 AACR.

A phase I dose-escalation study of aflibercept administered in combination with pemetrexed and cisplatin in patients with advanced solid tumours.

Background:To evaluate the safety, pharmacokinetics (PKs), and pharmacodynamics of aflibercept, and to identify the recommended phase II dose (RP2D) of aflibercept in combination with pemetrexed and cisplatin.Methods:Aflibercept was administered at escalating doses of 2, 4, or 6 mg kg−1 in combination with fixed doses of pemetrexed (500 mg m−2) plus cisplatin (75 mg m−2) every 3 weeks. Blood samples were collected for PK analyses. Serum antiaflibercept antibodies were quantified to assess their impact on systemic aflibercept concentrations.Results:Eighteen patients were enrolled. One patient dosed at 4 mg kg−1 experienced grade 3 hypophosphatemia (dose-limiting toxicity; DLT), which prompted a cohort expansion. No further DLTs were observed in the 4 mg kg−1 cohort or the 6 mg kg−1 dose cohort. Most common adverse events (AEs) of all grades included (%): fatigue (89), anaemia (89), nausea (83), hyponatremia (78), and neutropenia (72). Grade ⩾3 AEs consistent with anti-vascular endothelial growth factor therapy included (%): hypertension (22), pulmonary embolism (11), and deep vein thrombosis (6). Five patients (28%) experienced mild neurocognitive disturbance. No episodes of reversible posterior leukoencephalopathy syndrome (RPLS) were noted.Conclusion:The results of this phase I study allowed further evaluation of the combination of aflibercept with pemetrexed and cisplatin in a phase II study. The RP2D of aflibercept was 6 mg kg−1, to be administered intravenously every 3 weeks in combination with pemetrexed and cisplatin.

HIGHER INCIDENCE OF HEAD AND NECK CANCERS AMONG VIETNAMESE AMERICAN MEN IN CALIFORNIA

Our aim was to determine the incidence rates of head and neck cancer in Vietnamese Californians compared with other Asian and non‐Asian Californians.

Determination of Tumor Margins with Surgical Specimen Mapping Using Near-Infrared Fluorescence

For many solid tumors, surgical resection remains the gold standard and tumor-involved margins are associated with poor clinical outcomes. Near-infrared (NIR) fluorescence imaging using molecular agents has shown promise for in situ imaging during resection. However, for cancers with difficult imaging conditions, surgical value may lie in tumor mapping of surgical specimens. We thus evaluated a novel approach for real-time, intraoperative tumor margin assessment. Twenty-one adult patients with biopsy-confirmed squamous cell carcinoma arising from the head and neck (HNSCC) scheduled for standard-of-care surgery were enrolled. Cohort 1 (n = 3) received panitumumab-IRDye800CW at an intravenous microdose of 0.06 mg/kg, cohort 2A (n = 5) received 0.5 mg/kg, cohort 2B (n = 7) received 1 mg/kg, and cohort 3 (n = 6) received 50 mg. Patients were followed 30 days postinfusion and adverse events were recorded. Imaging was performed using several closed- and wide-field devices. Fluorescence was histologically correlated to determine sensitivity and specificity. In situ imaging demonstrated tumor-to-background ratio (TBR) of 2 to 3, compared with ex vivo specimen imaging TBR of 5 to 6. We obtained clear differentiation between tumor and normal tissue, with a 3-fold signal difference between positive and negative specimens (P < 0.05). We achieved high correlation of fluorescence intensity with tumor location with sensitivities and specificities >89%; fluorescence predicted distance of tumor tissue to the cut surface of the specimen. This novel method of detecting tumor-involved margins in surgical specimens using a cancer-specific agent provides highly sensitive and specific, real-time, intraoperative surgical navigation in resections with complex anatomy, which are otherwise less amenable to image guidance.Significance: This study demonstrates that fluorescence can be used as a sensitive and specific method of guiding surgeries for head and neck cancers and potentially other cancers with challenging imaging conditions, increasing the probability of complete resections and improving oncologic outcomes. Cancer Res; 78(17); 5144-54. ©2018 AACR.

Discordance in routine second opinion pathology review of head and neck oncology specimens: A single-center five year retrospective review

OBJECTIVES Second opinion review of pathology specimens is a common institutional practice, supported by large retrospective studies demonstrating significant histologic discordance. Since the most recent study of head and neck-specific pathology review was conducted, routine HPV and EBV testing is now recommended for certain specimens. We describe the frequency of and reasons for discordant reports and their potential impact on treatment recommendations and prognosis in a five-year retrospective cohort study at a single academic referral institution from 2005 to 2010. MATERIALS AND METHODS Following institutional review board review, 1003 cases referred to the Head and Neck Oncology Service were identified using a retrospective database search. Discordance between outside and second review pathology report was assessed by a board-certified medical oncologist. RESULTS 667 cases were included, of which 22% were discordant. Discordance was associated with adenocarcinomas (AOR [adjusted odds ratio] 0.09, 95% CI 0.03-0.31; p<0.001), poorly differentiated carcinomas (AOR 0.14, 95% CI 0.06-0.39; p<0.001), and specimens of uncommon histology (AOR 0.18, 95% CI 0.07-0.45; p<0.001) but not biopsy site in a multivariate model. The most common reasons for discordance included histology (61%), followed by the results of special studies (36%), and the presence or absence of stromal invasion (14%). Differences in tumor HPV status comprised 16% of discordant cases and were associated with better prognosis (p<0.001) following second opinion review. CONCLUSIONS Routine second opinion pathology review may lead to clinically significant differences in treatment recommendations and prognosis.

Stereotactic radiosurgery for retreatment of gross perineural invasion in recurrent cutaneous squamous cell carcinoma of the head and neck

Objectives:To report outcomes, failure patterns, and toxicity after stereotactic radiosurgery (SRS) for recurrent head and neck cutaneous squamous cell carcinoma with gross perineural invasion (GPNI). Methods:Ten patients who received SRS as part of retreatment for recurrent head and neck cutaneous squamous cell carcinoma with GPNI were included. All patients exhibited clinical and radiologic evidence of GPNI before SRS. Previous treatments included surgery alone in 3 patients and surgery with adjuvant external beam radiotherapy (EBRT) in 7 patients. Retreatment included SRS alone in 2 and EBRT boosted with SRS in 8 patients. Magnetic resonance images were obtained every 3 to 6 months after SRS to track failure patterns. Results:At a median 22-month follow-up, the 2-year progression-free and overall survival rates were 20% and 50%, respectively. Seven patients exhibited local failures, all of which occurred outside both SRS and EBRT fields. Five local failures occurred in previously clinically uninvolved cranial nerves (CNs). CN disease spreads through 3 distinct patterns: among different branches of CN V; between CNs V and VII; and between V1 and CNs III, IV, and/or VI. Five patients experienced side effects potentially attributable to radiation. Conclusions:Although there is excellent in-field control with this approach, the rate of out-of-field failures remains unacceptably high. We found that the majority of failures occurred in previously clinically uninvolved CNs often just outside treatment fields. Novel treatment strategies targeting this mode of perineural spread are needed.

Third party assessment of resection margin status in head and neck cancer

BACKGROUND Definitive assessment of primary site margin status following resection of head and neck cancer is necessary for prognostication, treatment determination and qualification for clinical trials. This retrospective analysis determined how often an independent reviewer can assess primary tumor margin status of head and neck cancer resections based on review of the pathology report, surgical operative report, and first follow-up note alone. METHODS We extracted from the electronic medical record pathology reports, operative reports, and follow-up notes from head and neck cancer resections performed at Stanford Hospital. We classified margin status as definitive or not. We labeled any pathology report clearly indicating a positive, negative, or close (<5mm) margin as definitive. For each non-definitive pathology report, we reviewed the operative report and then the first follow-up note in an attempt to clarify margin status. We also looked for associations between non-definitive status and surgeon, year, and primary site. RESULTS 743 unique cases of head and neck cancer resection were extracted. We discarded 255 as non-head and neck cancer cases, or cases that did not involve a definitive resection of a primary tumor site. We could not definitively establish margin status in 20% of resections by independent review of the medical record. There was no correlation between margin determination and surgeon, site, or year of surgery. CONCLUSION A substantial fraction (20%) of primary site surgical margins could not be definitively determined via independent EMR review. This could have implications for subsequent patient care decisions and clinical trial options.

Abstract B188: Pharmacokinetic assessment of drug-drug interaction potential when rosiglitazone or combined oral contraceptive is coadministered with vismodegib in patients with locally advanced or metastatic solid tumors.

Vismodegib is a first-in-class small molecule Hedgehog pathway inhibitor that is being developed for the treatment of advanced basal cell carcinoma. In a previous phase I study for patients with advanced malignancies, vismodegib was well tolerated and tumor regressions were seen in patients with advanced basal cell carcinoma and medulloblastoma. In vitro, vismodegib inhibits CYP2C8 with a Ki of 6.0 μM, which was the most potent relative to other CYP isoforms. With the average steady-state plasma concentration of total vismodegib being approximately 20 μM, inhibition of CYP2C8 by vismodegib may be important when patients are taking drugs known to be metabolized by CYP2C8. Furthermore, while vismodegib was not shown to induce CYP enzymes in vitro, it is a known teratogen. A DDI assessment with combined oral contraceptive (OC) was therefore conducted to ensure efficacious levels of OC would be maintained in patients taking vismodegib and OC in combination. This single-arm study consisted of two cohorts; 24 patients took 4 mg rosiglitazone (a known CYP2C8 substrate) and 27 patients took OC (norethindrone 1 mg/ethinyl estradiol 35 mcg, Ortho-Novum 1/35®). On Day 1 patients took rosiglitazone or OC followed by extensive PK sampling for 24 hrs. From Day 2 to Day 7 patients took 150 mg vismodegib once per day. On Day 8 patients took either vismodegib and rosiglitazone or vismodegib and OC followed by extensive PK sampling for 24 hrs. From Day 9 onward patients took vismodegib until disease progression or lack of benefit. The primary objective of this study was to evaluate the relative effect of vismodegib on AUC and Cmax for rosiglitazone and OC (ethinyl estradiol and norethindrone). The average steady state plasma concentration of total vismodegib (N=51) was 20.6 μM (range, 7.93 − 62.4 μM). There was no clinically meaningful difference in rosiglitazone PK parameters between Day 1 (without vismodegib) and Day 8 (with vismodegib) with a less than 10% difference in AUCinf and Cmax, on average. The geometric mean ratios (GMRs) for rosiglitazone AUC0−inf and Cmax were 93.1 and 93.4 with corresponding 90% confidence intervals (CIs) of (85.0, 102) and (89.4, 97.6), respectively. Concomitant administration of vismodegib with OC did not strongly impact the plasma concentrations of ethinyl estradiol or norethindrone, as evidenced by a less than 20% change in AUCinf and Cmax, on average, for both components. The GMRs for ethinyl estradiol AUC0−inf and Cmax were 99.3 and 106 with corresponding 90% CIs of (91.9, 107) and (94.8, 117), respectively while the GMRs for norethindrone AUC0−inf and Cmax were 124 and 112 with corresponding 90% CIs of (116, 132) and (101, 124), respectively. In the current study, the steady state plasma concentration of total vismodegib was above the in vitro Ki for CYP2C8. In addition, daily dosing of 150 mg vismodegib for 7 days should have been adequate to result in enzyme induction, if applicable. Overall, results from this study indicate that there was no clinically meaningful difference in AUC0−inf and Cmax for rosiglitazone, ethinyl estradiol, or norethindrone when co-administered with vismodegib. Taken together these results suggest that vismodegib can be co-administered with CYP substrates and combined oral contraceptive without the risk of a pharmacokinetic DDI. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B188.

Safety and clinical activity of atezolizumab in head and neck cancer: results from a phase I trial

Background Head and neck cancer (HNC) has a poor prognosis at advanced stages. Given the immunosuppressive tumor microenvironment in HNC, inhibition of the programmed death-ligand 1/programmed death-1 (PD-L1/PD-1) signaling pathway represents a promising therapeutic approach. Atezolizumab (anti-PD-L1) is efficacious against many tumor types. Here we report the clinical safety and activity from the HNC cohort of the phase Ia PCD4989g clinical trial. Patients and methods Patients with previously treated, advanced HNC received atezolizumab i.v. every 3 weeks for 16 cycles, up to 1 year or until loss of clinical benefit. Patients were monitored for safety and tolerability and evaluated for response at least every 6 weeks. Baseline PD-L1 expression level and human papillomavirus (HPV) status were evaluated. Results Thirty-two patients were enrolled; 7 patients (22%) had a primary tumor in the oral cavity, 18 (56%) in the oropharynx, 1 (3%) in the hypopharynx, 2 (6%) in the larynx, and 4 (13%) in the nasopharynx. Seventeen patients (53%) had ≥2 prior lines of therapy. Twenty-one patients (66%) experienced a treatment-related adverse event (TRAE), with three experiencing grade 3 TRAEs and one experiencing a grade 4 TRAE (per CTCAE v4.0). No grade 5 TRAEs were reported. Objective responses by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) occurred in 22% of patients, with a median duration of response of 7.4 months (range 2.8-45.8 months). Median progression-free survival was 2.6 months (range 0.5-48.4 months), and median overall survival was 6.0 months (range 0.5-51.6+ months). Responses showed no association with HPV status or PD-L1 expression level. Conclusions In this heavily pre-treated advanced HNC cohort, atezolizumab had a tolerable safety profile and encouraging activity, with responses observed regardless of HPV status and PD-L1 expression level. These findings warrant further investigation of atezolizumab in HNC. ClinicalTrials.gov number: NCT01375842.