Publications by authors named "Ranee Mehra"

88 Publications

Impact of the Novel Coronavirus 2019 (COVID-19) Pandemic on Head and Neck Cancer Care.

Otolaryngol Head Neck Surg 2021 Mar 30:1945998211004544. Epub 2021 Mar 30.

Department of Otorhinolaryngology, University of Maryland School of Medicine, Baltimore, Maryland, USA.

Objective: The study aimed to assess the impact of the coronavirus disease 2019 (COVID-19) pandemic on head and neck oncologic care at a tertiary care facility.

Study Design: This was a cross-sectional study conducted between March 18, 2020, and May 20, 2020. The primary planned outcome was the rate of treatment modifications during the study period. Secondary outcome measures were tumor conference volume, operative volume, and outpatient patient procedure and clinic volumes.

Setting: This single-center study was conducted at a tertiary care academic hospital in a large metropolitan area.

Methods: The study included a consecutive sample of adult subjects who were presented at a head and neck interdepartmental tumor conference during the study period. Patients were compared to historical controls based on review of operative data, outpatient procedures, and clinic volumes.

Results: In total, 117 patients were presented during the review period in 2020, compared to 69 in 2019. There was an 8.4% treatment modification rate among cases presented at the tumor conference. There was a 61.3% (347 from 898) reduction in outpatient clinic visits and a 63.4% (84 from 230) reduction in procedural volume compared to the prior year. Similarly, the operative volume decreased by 27.0% (224 from 307) compared to the previous year.

Conclusion: Restrictions related to the COVID-19 pandemic resulted in limited treatment modifications. Transition to virtual tumor board format observed an increase in case presentations. While there were reductions in operative volume, there was a larger proportion of surgical cases for malignancy, reflecting the prioritization of oncologic care during the pandemic.
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http://dx.doi.org/10.1177/01945998211004544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010374PMC
March 2021

Parotid Salivary Duct Carcinoma With a Prominent Squamous Component: Immunohistochemical Profile, Diagnostic Pitfalls, and Therapeutic Implications.

Int J Surg Pathol 2021 Mar 8:10668969211001952. Epub 2021 Mar 8.

12264University of Maryland School of Medicine, Baltimore, MD, USA.

Salivary duct carcinoma of the parotid gland is a highly aggressive epithelial malignancy morphologically resembling high-grade, invasive, and in situ breast carcinoma. It can occasionally present with variable morphology making it diagnostically challenging in cases with unusual morphological components. Ancillary testing, particularly androgen receptor (AR) positivity on immunohistochemistry, can be very helpful in cases that demonstrate extensive squamous morphology, since AR positivity is uncommon in both the primary salivary gland and metastatic squamous cell carcinomas to the parotid. In this report, we describe a case of salivary duct carcinoma that showed only a squamous cell carcinoma component on the initial primary tumor site biopsy, as well as in subsequent contralateral neck lymph node and skin metastases. Apart from the variable morphology, the typical salivary duct and squamous cell carcinoma tumor components also showed significant immunohistochemical differences, including differential staining of human epidermal growth factor receptor 2/neu. The associated diagnostic pitfalls, distinct immunoprofiles of the tumor components, helpful adjuncts for making the correct diagnosis, and associated therapeutic implications are discussed.
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http://dx.doi.org/10.1177/10668969211001952DOI Listing
March 2021

Cost-Effectiveness of Durvalumab After Chemoradiotherapy in Unresectable Stage III NSCLC: A US Healthcare Perspective.

J Natl Compr Canc Netw 2021 02 2;19(2):153-162. Epub 2021 Feb 2.

AstraZeneca Pharmaceuticals LP, Gaithersburg, Maryland.

Background: Durvalumab was approved by the FDA in February 2018 for patients with unresectable stage III NSCLC that has not progressed after platinum-based concurrent chemoradiotherapy (cCRT), and this regimen is the current standard of care. The objective of this study was to examine the cost-effectiveness of durvalumab following cCRT versus cCRT alone in patients with locally advanced, unresectable stage III NSCLC.

Methods: A 3-state semi-Markov model was used. Modeling was performed in a US healthcare setting from Medicare and commercial payer perspectives over a 30-year time horizon. Clinical efficacy (progression-free and post progression survival) and utility inputs were based on PACIFIC study data (ClinicalTrials.gov identifier: NCT02125461; data cutoff March 22, 2018). Overall survival extrapolation was validated using overall survival data from a later data cutoff (January 31, 2019). The main outcome was the incremental cost-effectiveness ratio (ICER) of durvalumab following cCRT versus cCRT alone, calculated as the difference in total costs between treatment strategies per quality-adjusted life-year (QALY) gained.

Results: In the base-case analysis, durvalumab following cCRT was cost-effective versus cCRT alone from Medicare and commercial insurance perspectives, with ICERs of $55,285 and $61,111, respectively, per QALY gained. Durvalumab was thus considered cost-effective at the $100,000 willingness-to-pay (WTP) threshold. Sensitivity analyses revealed the model was particularly affected by variables associated with subsequent treatment, although no tested variable increased the ICER above the WTP threshold. Scenario analyses showed the model was most sensitive to assumptions regarding time horizon, treatment effect duration, choice of fitted progression-free survival curve, subsequent immunotherapy treatment duration, and use of a partitioned survival model structure.

Conclusions: In a US healthcare setting, durvalumab was cost-effective compared with cCRT alone, further supporting the adoption of durvalumab following cCRT as the new standard of care in patients with unresectable stage III NSCLC.
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http://dx.doi.org/10.6004/jnccn.2020.7621DOI Listing
February 2021

Survivin expression and impact on head and neck cancer outcomes.

Oral Oncol 2021 01 19;112:105049. Epub 2020 Nov 19.

Fox Chase Cancer Center, United States. Electronic address:

Introduction: Survivin is an inhibitor of apoptosis that is proposed as a target for anti-cancer therapy because of its high expression in cancer cells. It has potential as a prognostic and predictive biomarker of response to radiation and systemic therapies. We report its expression in head and neck squamous cell carcinoma (HNSCC) and its correlation with treatment response and survival.

Methods: We measured survivin protein expression in tumor specimens from 96 patients with HNSCC treated at Fox Chase Cancer Center, of whom 21 were p16+. Quantitative automated immunofluorescence was employed to score nuclear and cytoplasmic survivin in 5 tissue microarrays (TMAs) consisting of 316 H&N tumor cores and 107 control tissue cores. Survivin levels were then correlated to therapy response and survival outcomes.

Results: Using the median score as the cutoff, overall survival (OS) was significantly shorter for the group expressing higher survivin in nuclear (p = 0.013), cytoplasmic (p = 0.018) and total compartments (p = 0.006). No correlation was seen between survivin expression and patient sex or grade of tumor, T or N stage, or p16 status. Survivin expression in metastases did not significantly differ from that in primary tumors. Levels of p53 expression showed a significant positive correlation with higher survivin expression in the cytoplasm (p = 0.0264) and total compartments (p = 0.0264), but not in the nucleus (p = 0.0729).

Conclusions: Survivin expression above the median is associated with shorter overall survival in HNSCC, including for patients treated with chemotherapy or radiation. p16 expression did not correlate with survivin levels.
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http://dx.doi.org/10.1016/j.oraloncology.2020.105049DOI Listing
January 2021

Development of autoimmune diabetes with severe diabetic ketoacidosis and immune-related thyroiditis secondary to durvalumab: a case report.

Transl Lung Cancer Res 2020 Oct;9(5):2149-2156

Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.

Immune-mediated endocrinopathies are among the most frequent immune-related adverse events (irAEs) with immune checkpoint inhibitors (ICIs) targeting programmed death-ligand 1 (PD-L1)/PD-1. However, the development of auto-immune diabetes is an uncommon event during PD(L)-1 blockade, either as monotherapy or in combination therapy. Here we report a case of a 75-year-old male with a mediastinal recurrence from a stage IA squamous cell carcinoma of the lung previously treated with stereotactic body radiotherapy (SBRT) who early developed a severe diabetic ketoacidosis (DKA) caused by new-onset auto-immune diabetes, with positive glutamic acid decarboxylase (GAD65) autoantibodies, during durvalumab consolidation therapy after concurrent chemoradiation. The patient had no personal or family history of diabetes or auto-immune diseases and was admitted after the second cycle of durvalumab to the intensive care unit (ICU) with severe DKA. During his hospitalization, insulin and fluid therapy were started and the patient had a favorable clinical course. Durvalumab treatment was interrupted and thyroiditis was verified during follow-up, without anti-thyroid antibodies, that progressed to subsequent hypothyroidism with need of thyroid hormone replacement therapy. This case highlights the rare irAE of autoimmune type 1 diabetes during anti-PD(L)-1 therapy, which can be life-threatening and requires adequate patient education and prompt medical treatment within a multidisciplinary team, including endocrinology and emergency medicine. Besides its low incidence, this case show how irAE must be taken in account about decision of ICI treatment, especially in curative setting, as they can be potentially fatal and impair overall survival. Furthermore, as reported in the present case, multiple endocrine irAEs can occur in the same patient either simultaneously or sequentially, suggesting that active surveillance is needed in those who develop endocrinopathies as a result of ICI treatment. Immune-mediated endocrinopathies are generally irreversible and cause life-long morbidity, which must be taken into consideration when deciding on further lines of treatment.
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http://dx.doi.org/10.21037/tlcr-20-408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653143PMC
October 2020

Emerging immune checkpoint inhibitors for the treatment of head and neck cancers.

Expert Opin Emerg Drugs 2020 12 17;25(4):501-514. Epub 2020 Dec 17.

University of Maryland Medical Center, Greenebaum Comprehensive Cancer Center , Baltimore, MD, USA.

: The benefits of immune checkpoint inhibitors (ICIs) in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) have been demonstrated through multiple studies to improve overall survival (OS) with decreased side effects when compared to the standard of care (SOC) treatment regimens in place for decades, leading to the approval of two ICIs, nivolumab and pembrolizumab. There has been a subsequent influx in the development of novel immunotherapy agents for the treatment of HNSCC. : Data for anti-programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) antibodies in treatment of R/M HNSCC will be reviewed. Emerging immune checkpoint inhibitors as well as combined therapies in HNSCC will be discussed. The role of predictive biomarkers, HPV-status, PD-L1 expression, and challenges related to treating patients with ICIs will be summarized. : A shift toward ICIs as SOC for the treatment of R/M HNSCC will continue as emerging immune checkpoints and combination therapies are evaluated. Response rates are variable in this patient population underlying the importance of identifying predictive biomarkers to aid in patient selection for ICI treatment.
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http://dx.doi.org/10.1080/14728214.2020.1852215DOI Listing
December 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

Quality of Life With Pembrolizumab for Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: KEYNOTE-040.

J Natl Cancer Inst 2021 02;113(2):171-181

Moores Cancer Center at UC San Diego Health, University of California San Diego, La Jolla, CA, USA.

Background: Head and neck squamous cell carcinoma (HNSCC) affects health-related quality of life (HRQoL); few treatments have demonstrated clinically meaningful HRQoL benefit. KEYNOTE-040 evaluated pembrolizumab vs standard of care (SOC) in patients with recurrent and/or metastatic HNSCC whose disease recurred or progressed after platinum-containing regimen.

Methods: Patients received pembrolizumab 200 mg or SOC (methotrexate, docetaxel, or cetuximab). Exploratory HRQoL analyses used European Organisation for Research and Treatment of Cancer (EORTC) 30 quality-of-life, EORTC 35-question quality-of-life head and neck cancer-specific module, and EuroQoL 5-dimensions questionnaires.

Results: The HRQoL population comprised 469 patients (pembrolizumab = 241, SOC = 228). HRQoL compliance for patients in the study at week 15 was 75.3% (116 of 154) for pembrolizumab and 74.6% (85 of 114) for SOC. The median time to deterioration in global health status (GHS) and QoL scores were 4.8 months with pembrolizumab and 2.8 months with SOC (hazard ratio = 0.79, 95% confidence interval [CI] = 0.59 to 1.05). At week 15, GHS / QoL scores were stable for pembrolizumab (least squares mean [LSM] = 0.39, 95% CI = -3.00 to 3.78) but worsened for SOC (LSM = -5.86, 95% CI = -9.68 to -2.04); the LSM between-group difference was 6.25 points (95% CI = 1.32 to 11.18; nominal 2-sided P = .01). A greater difference in the LSM for GHS / QoL score occurred with pembrolizumab vs docetaxel (10.23, 95% CI = 3.15 to 17.30) compared with pembrolizumab vs methotrexate (6.21, 95% CI = -4.57 to 16.99) or pembrolizumab vs cetuximab (-1.44, 95% CI = -11.43 to 8.56). Pembrolizumab-treated patients had stable functioning and symptoms at week 15, with no notable differences from SOC.

Conclusions: GHS / QoL scores were stable with pembrolizumab but declined with SOC in patients at week 15, supporting the clinically meaningful benefit of pembrolizumab in recurrent and/or metastatic HNSCC.
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http://dx.doi.org/10.1093/jnci/djaa063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850527PMC
February 2021

Concurrent Definitive Immunoradiotherapy for Patients with Stage III-IV Head and Neck Cancer and Cisplatin Contraindication.

Clin Cancer Res 2020 08 5;26(16):4260-4267. Epub 2020 May 5.

Division of Hematology and Oncology, Lineberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill, North Carolina.

Purpose: Although cisplatin plus radiotherapy is a standard treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC), cisplatin contraindication is common. Radiation elicits and promotes tumor-directed immune stimulation, which may potentiate anti-PD-1 therapy. We provide the first efficacy report of combined pembrolizumab and definitive radiotherapy in LA-HNSCC.

Patients And Methods: This single-arm, multi-institution, phase II study (NCT02609503) enrolled 29 cisplatin-ineligible patients. Patients received radiotherapy concurrently with three cycles of pembrolizumab 200 mg every 3 weeks followed by three adjuvant cycles. The primary endpoint was a progression-free survival (PFS) of ≥16 months. Correlative studies included peripheral blood flow cytometry and Luminex cytokine profiling.

Results: Reasons for cisplatin ineligibility included otopathy (69.0%), nephropathy (20.7%), and neuropathy (6.9%). With median follow-up of 21 months, estimated 24-month PFS and overall survival rates were 71% (95% confidence interval, 49%-84%) and 75% (51%-88%). The primary PFS endpoint has exceeded the hypothesis and its median has not been reached. Toxicities were typical of radiotherapy; however, high rates of grade 3/4 lymphopenia (58.6%) were observed. Flow cytometry revealed a relative decline in CD4 T cells and B cells, but not CD8 T cells. Upon treatment, frequencies of transitional B cells and tissue-like memory B cells increased, while resting memory B cells decreased. Patients with progression had greater percentages of baseline naïve B cells and fewer marginal zone B cells.

Conclusions: Pembrolizumab and radiotherapy is efficacious in LA-HNSCC and should be evaluated in a randomized trial. The observed changes in B-cell markers deserve further study both as potential biomarkers and as therapeutic targets.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968114PMC
August 2020

Potential of Pembrolizumab in Metastatic or Recurrent Head and Neck Cancer: Evidence to Date.

Onco Targets Ther 2020 9;13:3047-3059. Epub 2020 Apr 9.

University of Maryland Medical Center, Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA.

Relapsed and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is a heterogeneous disease previously associated with poor prognosis and limited treatment options until the advent and implementation of immune checkpoint inhibitors (ICIs). The fully humanized monoclonal antibody pembrolizumab alone, or in combination with chemotherapy, was shown to have significantly improved overall survival (OS) when compared to the standard of care (SOC) EXTREME regimen consisting of the monoclonal antibody cetuximab combined with a platinum and 5-fluorouracil. Pembrolizumab with or without chemotherapy will soon supplant the EXTREME regimen that has been in use for over a decade. Given the fast-approaching significant change in the treatment algorithm for R/M HNSCC and the novelty of ICIs in general, it is important to review the literature to date to understand how this rapidly growing treatment class has come about and explore potential areas of research for the plethora of questions that remain unanswered in selecting patients appropriate for treatment with ICIs in the R/M setting. In this review, we explore the landmark trials leading to the use of ICIs for R/M HNSCC with a particular focus on pembrolizumab, the most well-studied ICI in this setting. We also provide an overview of the rationale behind the use of ICIs in relation to the immune system and challenges surrounding tumor heterogeneity and PD-L1 expression status, human papilloma virus (HPV) and the efficacy of ICI, potential of radiation therapy for enhancement of ICI response, and complications of immune-related adverse events (irAEs).
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http://dx.doi.org/10.2147/OTT.S196252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153996PMC
April 2020

Immunotherapy in Lung Cancer: From a Minor God to the Olympus.

Adv Exp Med Biol 2020 ;1244:69-92

University of Maryland Medical Center, Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA.

Over the last decade, we have witnessed a paradigm shift in cancer treatment, with the advent of novel therapeutic approaches that target or manipulate the immune system, also known as immunotherapy. Blocking immune checkpoints has emerged as an effective strategy with unprecedented results in several solid tumors, including lung cancer. Since 2012 when PD(L)-1 inhibitors showed first clinical signals of activity in lung cancer, immune checkpoint blockade (ICB) has emerged as a novel effective therapeutic strategy in different settings, determining a dramatic change in the therapeutic landscape of both non-small cell lung cancer (NSCLC) and, more recently, small cell lung cancer (SCLC). Although the benefit from this novel therapeutic approach is undeniable, several open questions still remain unanswered. Herein, we summarize the major breakthroughs in the immunotherapy journey in lung cancer and how it is changing our clinical practice.
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http://dx.doi.org/10.1007/978-3-030-41008-7_4DOI Listing
July 2020

New Targets in Lung Cancer (Excluding EGFR, ALK, ROS1).

Curr Oncol Rep 2020 04 16;22(5):48. Epub 2020 Apr 16.

Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 22 S Greene Street Rm. N9E08, Baltimore, MD, 21201, USA.

Purpose Of Review: Over the last two decades, the identification of targetable oncogene drivers has revolutionized the therapeutic landscape of non-small cell lung cancer (NSCLC). The extraordinary progresses made in molecular biology prompted the identification of several rare molecularly defined subgroups. In this review, we will focus on the novel and emerging actionable oncogenic drivers in NSCLC.

Recent Findings: Recently, novel oncogene drivers emerged as promising therapeutic targets besides the well-established EGFR mutations, and ALK/ROS1 rearrangements, considerably expanding the list of potential exploitable genetic aberrations. However, the therapeutic algorithm in these patients is far less defined. The identification of uncommon oncogene drivers is reshaping the diagnostic and therapeutic approach to NSCLC. The introduction of novel highly selective inhibitors is expanding the use of targeted therapies to rare and ultra-rare subsets of patients, further increasing the therapeutic armamentarium of advanced NSCLC.
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http://dx.doi.org/10.1007/s11912-020-00909-8DOI Listing
April 2020

Real-world treatment patterns for patients with metastatic head and neck squamous cell carcinoma treated with immuno-oncology therapy.

Head Neck 2020 08 9;42(8):2030-2038. Epub 2020 Mar 9.

IQVIA, Cambridge, Massachusetts, USA.

Background: Real-world use of immuno-oncology (IO) therapies (nivolumab and pembrolizumab) in metastatic head and neck squamous cell carcinoma (mHNSCC) has not been well studied.

Methods: mHNSCC patients treated with an IO therapy were identified from a large US claims database from 2016 to 2017. Treatment patterns before and after initiation of IO therapy (index date) were described.

Results: Among 416 mHNSCC patients, 85% had ≥1 regimen prior to IO therapy. Ninety-seven percent of patients initiated IO as monotherapy and 3% initiated IO combined with another systemic treatment. One hundred seventeen (28%) patients had a subsequent regimen, usually chemotherapy (n = 58, 50%) or IO monotherapy (n = 27, 23%), of which 22 patients restarted the same IO therapy and 5 switched to another IO monotherapy.

Conclusion: The majority of mHNSCC patients initiated IO as a monotherapy. Approximately half of patients with a subsequent regimen received chemotherapy and one-fourth received IO monotherapy.
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http://dx.doi.org/10.1002/hed.26126DOI Listing
August 2020

Assessing Outcomes of Patients Treated With Re-Irradiation Utilizing Proton Pencil-Beam Scanning for Primary or Recurrent Malignancies of the Esophagus and Gastroesophageal Junction.

J Thorac Oncol 2020 06 4;15(6):1054-1064. Epub 2020 Mar 4.

Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland.

Introduction: Re-irradiation (re-RT) for locoregionally recurrent esophageal and gastroesophageal junction (GEJ) cancer and de novo esophageal + GEJ cancer arising in-field after a course of prior radiation poses considerable treatment challenges given the sensitivity of surrounding organs at risk (OARs). Guidelines for treatment of this presentation are not well established. Pencil-beam scanning (PBS) proton therapy has the ability to decrease radiation dose to OARs relative to photon plans. We present the first published series to date of re-RT with PBS for esophageal + GEJ malignancies and hypothesize that re-RT with proton PBS will be feasible and improve the safety profile of re-RT for this cohort of patients.

Methods: Consecutive esophageal + GEJ cancers treated with PBS re-RT within a single institution were analyzed. Comparative volumetric-modulated arc therapy photon plans were generated. A total of 17 patients were included for analysis.

Results: At a median follow-up of 11.6 months, 1-year local control was 75.3% and overall survival was 68.9%. There were five (27.8%) grade 3 or higher late toxicities. When matched for clinical target volume coverage, proton PBS plans delivered significantly lower doses to the spinal cord, lungs, liver, and heart (all p < 0.05); five volumetric-modulated arc therapy plans would have been undeliverable on the basis of physician-specified OAR constraints.

Conclusions: Re-RT for de novo or recurrent malignancies of the esophagus + GEJ, when delivered with PBS proton therapy, yields high rates of local control with acceptable acute and late toxicities in a high-risk population and decreased radiation dose to OARs relative to comparative photon plans. This is the largest series of proton re-RT for esophageal malignancies and the first that exclusively used PBS.
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http://dx.doi.org/10.1016/j.jtho.2020.01.024DOI Listing
June 2020

RET fusions in solid tumors.

Cancer Treat Rev 2019 Dec 30;81:101911. Epub 2019 Oct 30.

Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address:

The RET proto-oncogene has been well-studied. RET is involved in many different physiological and developmental functions. When altered, RET mutations influence disease in a variety of organ systems from Hirschsprung's disease and multiple endocrine neoplasia 2 (MEN2) to papillary thyroid carcinoma (PTC) and non-small cell lung cancer (NSCLC). Changes in RET expression have been discovered in 30-70% of invasive breast cancers and 50-60% of pancreatic ductal adenocarcinomas in addition to colorectal adenocarcinoma, melanoma, small cell lung cancer, neuroblastoma, and small intestine neuroendocrine tumors. RET mutations have been associated with tumor proliferation, invasion, and migration. RET fusions or rearrangements are somatic juxtapositions of 5' sequences from other genes with 3' RET sequences encoding tyrosine kinase. RET rearrangements occur in approximately 2.5-73% of sporadic PTC and 1-3% of NSCLC patients. The most common RET fusions are CDCC6-RET and NCOA4-RET in PTC and KIF5B-RET in NSCLC. Tyrosine kinase inhibitors are drugs that target kinases such as RET in RET-driven (RET-mutation or RET-fusion-positive) disease. Multikinase inhibitors (MKI) target various kinases and other receptors. Several MKIs are FDA-approved for cancer therapy (sunitinib, sorafenib, vandetanib, cabozantinib, regorafenib, ponatinib, lenvatinib, alectinib) and non-oncologic disease (nintedanib). Selective RET inhibitor drugs LOXO-292 (selpercatinib) and BLU-667 (pralsetinib) are also undergoing phase I/II and I clinical trials, respectively, with preliminary results demonstrating partial response and low incidence of serious adverse events. RET fusions provide a viable therapeutic target for oncologic treatment, and further study is warranted into the prevalence and pathogenesis of RET fusions as well as development of current and new tyrosine kinase inhibitors.
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http://dx.doi.org/10.1016/j.ctrv.2019.101911DOI Listing
December 2019

Liquid biopsy tracking of lung tumor evolutions over time.

Expert Rev Mol Diagn 2019 12 16;19(12):1099-1108. Epub 2019 Oct 16.

Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.

: The rise of the personalized era in lung cancer prompted the evaluation of novel diagnostic tools to overcome some of the limits of traditional tumor genotyping. Liquid biopsy refers to a multitude of minimally invasive techniques that can allow a real-time biomolecular characterization of the tumor through the analysis of human body fluids.: Herein we provide a comprehensive overview of the role of liquid biopsy in lung cancer, mainly focusing on the most studied members of the liquid biopsy family, cell-free DNA (cfDNA) and circulating tumor cells (CTCs).: Among the different components of the large liquid biopsy family, cfDNA is the most studied and widely adopted source for tumor genotyping in lung cancer, already entered clinical practice for detection of both sensitizing and resistance EGFR mutations. However, the impressive technological advances made in the last few years are expanding its potential applications, allowing a more comprehensive plasma genotyping through next-generation sequencing and moving from advanced/metastatic disease to novel frontiers, such as early detection and minimal residual disease evaluation.
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http://dx.doi.org/10.1080/14737159.2020.1680287DOI Listing
December 2019

How I treat ALK-positive non-small cell lung cancer.

ESMO Open 2019 20;4(Suppl 2):e000524. Epub 2019 Jul 20.

University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, Maryland, USA. Electronic address:

Since the discovery of anaplastic lymphocyte kinase (ALK) rearrangement in non-small cell lung cancer (NSCLC) and subsequent development of increasingly effective and central nervous system (CNS)-penetrant first-generation, second-generation and third-generation ALK tyrosine kinase inhibitors (TKIs), the landscape of resistance mechanisms and treatment decisions has become increasingly complex. Tissue and/or plasma-based molecular tests can identify not only the rearrangement proper but also common resistance mechanisms to guide decision-making for further lines of treatment. However, frequently encountered questions exist regarding how to diagnosis ALK rearrangement, how to select a first-line ALK TKI, how to diagnose and manage ALK TKI resistance, how to control CNS disease and how to handle failure of ALK inhibition. Herein, we attempt to answer these questions through the evidence-based interpretation of studies on ALK-rearranged NSCLC combined with experience gained from our institution. The authors also propose a therapeutic algorithm for the management of this complex and highly treatable disease to assist clinicians globally in the treatment of patients with ALK-positive NSCLC.
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http://dx.doi.org/10.1136/esmoopen-2019-000524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677959PMC
July 2019

Immune-Related Adverse Events Requiring Hospitalization: Spectrum of Toxicity, Treatment, and Outcomes.

J Oncol Pract 2019 09 6;15(9):e825-e834. Epub 2019 Aug 6.

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD.

Purpose: Immune checkpoint inhibitors (ICIs) cause immune-related adverse events (irAEs). The proportion of patients who are hospitalized for irAEs and their spectrum, management, and outcomes are not well described.

Methods: We report the proportion of hospitalized patients in an academic center who were treated with ICIs from May to December 2017. Patient characteristics, toxicities, management, and outcomes for confirmed irAE admissions are reported. Associations between patient features and irAE hospitalizations are examined.

Results: Twenty-three percent (n = 100) of 443 patients who were admitted to an academic oncology center over 6 months had ever received ICIs. Of these patients, 41% were admitted for suspected irAEs and 23% were confirmed irAEs. IrAEs accounted for 5% of all oncology hospitalizations (n = 23). Ninety-one percent of patients with confirmed irAEs prompted a medicine subspecialist consultation, most commonly gastroenterology (22%). Fifteen patients (65%) had their irAEs improve/resolve, seven (30%) had worsening irAEs, and three (13%) died of their irAEs. The majority of patients (n = 20; 87%) discontinued ICIs after discharge. Among ICI-treated patients who required admission, an increased likelihood of irAE-related hospitalization was associated with patient age older than 65 years (odds ratio, 5.4; 95% CI, 1.6 to 17.8) and receipt of combination immunotherapy (OR, 6.8; 95% CI, 2.0 to 23.2).

Conclusion: A notable proportion of ICI-treated patients are hospitalized for irAEs, and these patients have a high demand for multidisciplinary management. Older age and combination ICI treatment were associated with an increased risk of irAE-related hospitalization. Whereas these data are from an academic center and include patients in clinical trials, with expanding use of ICIs, these data have important implications for inpatient service planning and risk stratification.
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http://dx.doi.org/10.1200/JOP.18.00703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743220PMC
September 2019

Pembrolizumab for the treatment of head and neck squamous cell cancer.

Expert Opin Biol Ther 2019 09 19;19(9):879-885. Epub 2019 Jul 19.

b Department of Oncology, University of Maryland School of Medicine , Baltimore , MD , USA.

: Groundbreaking progress in cancer immunotherapy in the recent years has revolutionized the field of oncology with unprecedented survival rates in multiple cancer types. Head and neck cancers comprise the sixth most common cancer type in the United States with estimated 14,620 deaths in 2019. Two checkpoint inhibitors, e.g. antibodies against programmed cell death protein 1 (PD-1), are currently FDA approved for second-line therapy of recurrent and/or metastatic head and neck squamous cell carcinomas (HNSCC). Pembrolizumab is one of the two approved anti-PD-1 antibodies and under active investigation of its role in managing HNSCCs. : This review provides an in-depth discussion of pembrolizumab's structural features, pharmacokinetics, pharmacodynamics, efficacy data, toxicity profile, ongoing studies, and competing agents including the standard of care options in the context of treating HNSCCs. : Immune checkpoint inhibitor therapy is already an integral part of HNSCC management, especially in the recurrent and/or metastatic stage, and is preferable to conventional cytotoxic therapies due to a generally more favorable toxicity profile. Pembrolizumab's role in treating HNSCC is highly anticipated to expand over to other contexts such as definitive combination therapy and neoadjuvant therapy for locally advanced HNSCC.
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http://dx.doi.org/10.1080/14712598.2019.1644315DOI Listing
September 2019

Circulating tumor cell and cell-free RNA capture and expression analysis identify platelet-associated genes in metastatic lung cancer.

BMC Cancer 2019 Jun 19;19(1):603. Epub 2019 Jun 19.

Protocol Support Laboratory, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.

Background: Circulating tumor cells (CTC) and plasma cell-free RNA (cfRNA) can serve as biomarkers for prognosis and treatment response in lung cancer. One barrier to the selected or routine use of CTCs and plasma cfRNA in precision oncology is the limited quantity of both, and CTCs are only seen in metastatic disease. As capture of CTCs and plasma cfRNA presents an opportunity to monitor and assess malignancies without invasive procedures, we compared two methods for CTC capture and identification, and profiled mRNA from CTCs and plasma cfRNA to identify potential tumor-associated biomarkers.

Methods: Peripheral blood was collected from ten patients with small cell lung cancer (SCLC), ten patients with non-small cell lung cancer (NSCLC) and four healthy volunteers. Two methods were used for CTC capture: the standard epithelial cell adhesion molecule (EpCam) CellSearch kit (unicapture) and EpCAM plus HER2, EGFR and MUC-1 specific combined ferrofluid capture (quadcapture). For the quadcapture, anti-cytokeratin 7 (CK7) was additionally used to assist in CTC identification. NanoString analysis was performed on plasma cfRNA and on mRNA from combined ferrofluid isolated CTCs. Expression data was analyzed using STRING and Reactome.

Results: Unicapture detected CTCs in 40% of NSCLC and 60% of SCLC; whereas, quadcapture/CK7 identified CTCs in 20% of NSCLC and 80% of SCLC. Bioinformatic analysis of NanoString data identified high expression of a platelet factor 4 (PF4)-related group of transcripts.

Conclusions: Quadcapture ferrofluid reagent did not significantly improve CTC capture efficacy. NanoString analysis based on CTC and plasma cfRNA data highlighted an intriguing PF-4-centric network in patients with metastatic lung cancer.
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http://dx.doi.org/10.1186/s12885-019-5795-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582501PMC
June 2019

Targeting phosphoinositide 3-kinase (PI3K) in head and neck squamous cell carcinoma (HNSCC).

Cancers Head Neck 2018 4;3. Epub 2018 Jun 4.

2Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 201 N Broadway, Baltimore, MD USA.

The landscape of head and neck squamous cell carcinoma (HNSCC) has been changing rapidly due to growing proportion of HPV-related disease and development of new therapeutic agents. At the same time, there has been a constant need for individually tailored treatment based on genetic biomarkers in order to optimize patient survival and alleviate treatment-related toxicities. In this regard, aberrations of PI3K pathway have important clinical implications in the treatment of HNSCC. They frequently constitute 'gain of function' mutations which trigger oncogenesis, and PI3K mutations can also lead to emergence of drug resistance after treatment with EGFR inhibitors. In this article, we review PI3K pathway as a target of treatment for HNSCC and summarize PI3K/mTOR inhibitors that are currently under clinical trials. In light of recent advancement of immune checkpoint inhibitors, consideration of PI3K inhibitors as potential immune modulators is also suggested.
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http://dx.doi.org/10.1186/s41199-018-0030-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460806PMC
June 2018

PTEN loss is associated with resistance to cetuximab in patients with head and neck squamous cell carcinoma.

Oral Oncol 2019 04 4;91:69-78. Epub 2019 Mar 4.

Department of Medicine, Yale University School of Medicine and Yale Cancer Center, United States. Electronic address:

Introduction: Cetuximab, a monoclonal antibody to the epidermal growth factor receptor (EGFR), extends survival in combination with standard therapy in head and neck squamous cell carcinoma (HNSCC). However, as effects are modest, and patients experience side effects, a biomarker to predict resistance and personalize therapy is needed. Activation of signaling pathways downstream from receptor tyrosine kinases predicts resistance to such therapies in other cancers. The most common abnormalities downstream from EGFR in HNSCC are in the PI3K pathway, activated via loss of expression of the regulator PTEN, or via PI3K mutation. We studied whether PTEN and/or PI3K abnormalities predict resistance to cetuximab.

Methods: Tumor PTEN and PIK3CA/PI3K p110α were analyzed in samples from subjects treated on two trials of cetuximab-based therapy for patients with metastatic or recurrent HNSCC: E5397, a randomized trial of cisplatin plus placebo versus cisplatin plus cetuximab; and NCI-8070, a randomized trial of cetuximab plus sorafenib versus cetuximab. In situ quantification of PTEN and PI3K p110 α was performed using the AQUA™ method of quantitative immunofluorescence. PI3KCA hot spot mutations were determined with BEAMing.

Results: For E5397, in multivariable analysis, PTEN expressing/PIK3CA WT patients tended to improve PFS with cetuximab compared to placebo (N = 48; HR = 0.54, Wald p = 0.0502). High PTEN expression was significantly associated with superior PFS among patients treated on NCI-8070 (N = 37; HR = 0.35, p = 0.008).

Conclusion: Loss of PTEN expression may be associated with lack of benefit from cetuximab. This analysis is limited by small sample size, and PTEN as a potential predictive biomarker merits validation in larger sample sets.
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http://dx.doi.org/10.1016/j.oraloncology.2019.02.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855599PMC
April 2019

Combined Aurora Kinase A (AURKA) and WEE1 Inhibition Demonstrates Synergistic Antitumor Effect in Squamous Cell Carcinoma of the Head and Neck.

Clin Cancer Res 2019 06 12;25(11):3430-3442. Epub 2019 Feb 12.

Section of Medical Oncology, Department of Internal Medicine and Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut.

Purpose: Human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCC) commonly bear disruptive mutations in , resulting in treatment resistance. In these patients, direct targeting of p53 has not been successful, but synthetic lethal approaches have promise. Although Aurora A kinase (AURKA) is overexpressed and an oncogenic driver, its inhibition has only modest clinical effects in HPV-negative HNSCC. We explored a novel combination of AURKA and WEE1 inhibition to overcome intrinsic resistance to AURKA inhibition. AURKA protein expression was determined by fluorescence-based automated quantitative analysis of patient specimens and correlated with survival. We evaluated treatment with the AURKA inhibitor alisertib (MLN8237) and the WEE1 inhibitor adavosertib (AZD1775), alone or in combination, using and HNSCC models.

Results: Elevated nuclear AURKA correlated with worse survival among patients with p16(-) HNSCC. Alisertib caused spindle defects, G-M arrest and inhibitory CDK1 phosphorylation, and cytostasis in mutant HNSCC FaDu and UNC7 cells. Addition of adavosertib to alisertib instead triggered mitotic entry and mitotic catastrophe. Moreover, in FaDu and Detroit 562 xenografts, this combination demonstrated synergistic effects on tumor growth and extended overall survival compared with either vehicle or single-agent treatment.

Conclusions: Combinatorial treatment with adavosertib and alisertib leads to synergistic antitumor effects in and HNSCC models. These findings suggest a novel rational combination, providing a promising therapeutic avenue for mutated cancers.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548643PMC
June 2019

Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study.

Lancet 2019 01 30;393(10167):156-167. Epub 2018 Nov 30.

The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, National Institute of Health Research Biomedical Research Centre, London, UK.

Background: There are few effective treatment options for patients with recurrent or metastatic head-and-neck squamous cell carcinoma. Pembrolizumab showed antitumour activity and manageable toxicity in early-phase trials. We aimed to compare the efficacy and safety of pembrolizumab versus standard-of-care therapy for the treatment of head-and-neck squamous cell carcinoma.

Methods: We did a randomised, open-label, phase 3 study at 97 medical centres in 20 countries. Patients with head-and-neck squamous cell carcinoma that progressed during or after platinum-containing treatment for recurrent or metastatic disease (or both), or whose disease recurred or progressed within 3-6 months of previous multimodal therapy containing platinum for locally advanced disease, were randomly assigned (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive pembrolizumab 200 mg every 3 weeks intravenously or investigator's choice of standard doses of methotrexate, docetaxel, or cetuximab intravenously (standard-of-care group). The primary endpoint was overall survival in the intention-to-treat population. Safety was analysed in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT02252042, and is no longer enrolling patients.

Findings: Between Dec 24, 2014, and May 13, 2016, 247 patients were randomly allocated to pembrolizumab and 248 were randomly allocated to standard of care. As of May 15, 2017, 181 (73%) of 247 patients in the pembrolizumab group and 207 (83%) of 248 patients in the standard-of-care group had died. Median overall survival in the intention-to-treat population was 8·4 months (95% CI 6·4-9·4) with pembrolizumab and 6·9 months (5·9-8·0) with standard of care (hazard ratio 0·80, 0·65-0·98; nominal p=0·0161). Fewer patients treated with pembrolizumab than with standard of care had grade 3 or worse treatment-related adverse events (33 [13%] of 246 vs 85 [36%] of 234). The most common treatment-related adverse event was hypothyroidism with pembrolizumab (in 33 [13%] patients) and fatigue with standard of care (in 43 [18%]). Treatment-related death occurred in four patients treated with pembrolizumab (unspecified cause, large intestine perforation, malignant neoplasm progression, and Stevens-Johnson syndrome) and two patients treated with standard of care (malignant neoplasm progression and pneumonia).

Interpretation: The clinically meaningful prolongation of overall survival and favourable safety profile of pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma support the further evaluation of pembrolizumab as a monotherapy and as part of combination therapy in earlier stages of disease.

Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co.
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http://dx.doi.org/10.1016/S0140-6736(18)31999-8DOI Listing
January 2019

Pattern of planned systemic therapy usage in newly diagnosed, nonmetastatic squamous cell carcinoma of the head and neck in a commercially insured population in the United States.

Head Neck 2018 12 13;40(12):2612-2620. Epub 2018 Nov 13.

Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

Background: We analyzed systemic therapy plans submitted for commercially insured patients with untreated, newly diagnosed squamous cell carcinoma of the head and neck (SCCHN) to investigate patterns of practice.

Methods: Consecutive chemotherapy treatment plans were submitted using Eviti Connect (https://www.marylandphysicianscare.com/content/dam/centene/maryland/pdfs/evitiConnectFactSheet.pdf) portal for preauthorization between June 1, 2011, and June 30, 2015, were analyzed.

Results: A total of 387 treatment plans were submitted for 340 patients; 68 and 272 patients were from academic centers and community practices, respectively. Single agent cisplatin (57%), cetuximab (18%), and carboplatin (9%) were the most commonly proposed regimens concurrent with definitive radiotherapy (RT). The frequency of cetuximab use was not significantly different between academic centers and community practices. A clinical trial was proposed in only 15% of patients.

Conclusion: Among commercially insured patients with newly diagnosed, nonmetastatic SCCHN, the choice of systemic therapy in initial treatment plans was not significantly different between academic centers and community practices. Clinical trials are underutilized and should be encouraged.
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http://dx.doi.org/10.1002/hed.25333DOI Listing
December 2018

Association between pretreatment lymphocyte count and response to PD1 inhibitors in head and neck squamous cell carcinomas.

J Immunother Cancer 2018 08 31;6(1):84. Epub 2018 Aug 31.

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 401 N Broadway, 1550 Orleans St., CRB2 5M44, Baltimore, MD, 21287, USA.

Background: Low absolute lymphocyte count (ALC) has previously been established as a marker of poor prognosis in multiple cancer types. There is growing evidence that ALC may also be associated with response to immunotherapy. This study explores whether response to PD1 inhibitors in recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is associated with pretreatment ALC.

Methods: Thirty-four R/M HNSCC patients who received either nivolumab or pembrolizumab between January 2014 and May 2018 at Johns Hopkins were identified retrospectively. Pretreatment blood counts in patients with and without clinical benefit from PD1 inhibitors were compared. Time-to-progression analyses were performed by dichotomizing the study cohort with the threshold of ALC 600 cells/μl, which is approximately 1.5 standard deviations away from treatment-naïve baseline mean.

Results: Patients with lower ALC appeared to have significantly less clinical benefit from anti-PD1 therapy. Those patients with pretreatment ALC < 600 cells/μl also had shorter PFS than patients with pretreatment ALC ≥ 600 cells/μl (median PFS 60 days vs. 141 days, p < 0.05). These results were consistent with multivariate proportional hazards analyses demonstrating significant association with progression. These observations were further supported by an expansion cohort analysis incorporating additional fourteen R/M HNSCC patients who received other checkpoint immunotherapy regimens at our institution.

Conclusions: This study for the first time demonstrates that pretreatment ALC is significantly associated with response to PD1 inhibitors in R/M HNSCC patients.
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http://dx.doi.org/10.1186/s40425-018-0395-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117944PMC
August 2018

Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma: pooled analyses after long-term follow-up in KEYNOTE-012.

Br J Cancer 2018 07 29;119(2):153-159. Epub 2018 Jun 29.

Dana-Farber Cancer Institute, Boston, MA, USA.

Background: Second-line treatment options for advanced head and neck squamous cell carcinoma (HNSCC) are limited. The phase Ib KEYNOTE-012 study evaluated the safety and the efficacy of pembrolizumab for the treatment of HNSCC after long-term follow-up.

Methods: Multi-centre, non-randomised trial included two HNSCC cohorts (initial and expansion) in which 192 patients were eligible. Patients received pembrolizumab 10 mg/kg every 2 weeks (initial cohort; N = 60) or 200 mg every 3 weeks (expansion cohort; N = 132). Co-primary endpoints were safety and overall response rate (ORR; RECIST v1.1; central imaging vendor review).

Results: Median follow-up was 9 months (range, 0.2-32). Treatment-related adverse events (AEs) of any grade and grade 3/4 occurred in 123 (64%) and 24 (13%) patients, respectively. No deaths were attributed to treatment-related AEs. ORR was 18% (34/192; 95% CI, 13-24%). Median response duration was not reached (range, 2+ to 30+ months); 85% of responses lasted ≥6 months. Overall survival at 12 months was 38%.

Conclusions: Some patients received 2 years of treatment and the responses were ongoing for more than 30 months; the durable anti-tumour activity and tolerable safety profile, observed with long-term follow-up, support the use of pembrolizumab as a treatment for recurrent/metastatic HNSCC.
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http://dx.doi.org/10.1038/s41416-018-0131-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048158PMC
July 2018

Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy.

Nat Commun 2018 02 21;9(1):741. Epub 2018 Feb 21.

Department of Otolaryngology-Head and Neck Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.

A majority of cancers fail to respond to immunotherapy with antibodies targeting immune checkpoints, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed death-1 (PD-1)/PD-1 ligand (PD-L1). Cancers frequently express transforming growth factor-β (TGFβ), which drives immune dysfunction in the tumor microenvironment by inducing regulatory T cells (Tregs) and inhibiting CD8 and T1 cells. To address this therapeutic challenge, we invent bifunctional antibody-ligand traps (Y-traps) comprising an antibody targeting CTLA-4 or PD-L1 fused to a TGFβ receptor II ectodomain sequence that simultaneously disables autocrine/paracrine TGFβ in the target cell microenvironment (a-CTLA4-TGFβRIIecd and a-PDL1-TGFβRIIecd). a-CTLA4-TGFβRIIecd is more effective in reducing tumor-infiltrating Tregs and inhibiting tumor progression compared with CTLA-4 antibody (Ipilimumab). Likewise, a-PDL1-TGFβRIIecd exhibits superior antitumor efficacy compared with PD-L1 antibodies (Atezolizumab or Avelumab). Our data demonstrate that Y-traps counteract TGFβ-mediated differentiation of Tregs and immune tolerance, thereby providing a potentially more effective immunotherapeutic strategy against cancers that are resistant to current immune checkpoint inhibitors.
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http://dx.doi.org/10.1038/s41467-017-02696-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821872PMC
February 2018

NSD1- and NSD2-damaging mutations define a subset of laryngeal tumors with favorable prognosis.

Nat Commun 2017 11 24;8(1):1772. Epub 2017 Nov 24.

Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.

Squamous cell carcinomas of the head and neck (SCCHN) affect anatomical sites including the oral cavity, nasal cavity, pharynx, and larynx. Laryngeal cancers are characterized by high recurrence and poor overall survival, and currently lack robust molecular prognostic biomarkers for treatment stratification. Using an algorithm for integrative clustering that simultaneously assesses gene expression, somatic mutation, copy number variation, and methylation, we for the first time identify laryngeal cancer subtypes with distinct prognostic outcomes, and differing from the non-prognostic laryngeal subclasses reported by The Cancer Genome Atlas (TCGA). Although most common laryngeal gene mutations are found in both subclasses, better prognosis is strongly associated with damaging mutations of the methyltransferases NSD1 and NSD2, with findings confirmed in an independent validation cohort consisting of 63 laryngeal cancer patients. Intriguingly, NSD1/2 mutations are not prognostic for nonlaryngeal SCCHN. These results provide an immediately useful clinical metric for patient stratification and prognostication.
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http://dx.doi.org/10.1038/s41467-017-01877-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701248PMC
November 2017

Lymph-node-positive cutaneous nonmelanoma skin cancer: A poor-prognosis disease in need of treatment intensification.

Ear Nose Throat J 2017 Jul;96(7):E12-E18

Department of Radiation Oncology, 333 Cottman Ave., Philadelphia, PA 19111-2497, USA.

Locoregionally advanced nonmelanoma skin cancer (NMSC) has an aggressive clinical course characterized by high rates of treatment failure and poor survival compared with localized skin cancers. Our goal was to investigate multimodal therapy for lymph-node-positive NMSC. Data from patients with lymph-node-positive NMSC who underwent surgery and adjuvant therapy at a single tertiary center from 2002 to 2012 were retrospectively reviewed. Median follow-up was 1.8 years (range: 0.5 to 8.5). Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. The chi-square test and logistic regression were used to determine the association between locoregional control (LRC) and the following variables: evidence of extracapsular extension, number of lymph nodes positive, largest involved lymph node, presence of a positive margin, and use of concurrent chemoradiation (CRT). Forty-six patients were evaluated, 13 (28%) of whom received adjuvant CRT. CRT patients were younger (p < 0.001) and had a significantly greater number of positive lymph nodes (p = 0.016) than patients who received adjuvant radiation alone. At 5 years, LRC was 76%, PFS was 65%, and OS was 49%. Univariate analysis demonstrated that CRT (p = 0.006), largest lymph node measurement (p = 0.039), and ≥3 involved lymph nodes (p = 0.001) predicted local recurrence. CRT (p = 0.035, odds ratio [OR] 0.20 [95% confidence interval 0.05 to 0.90]) and ≥3 involved lymph nodes (p = 0.017, OR 0.07 [95% confidence interval 0.01 to 0.62]) remained significant on multivariate analysis. CRT was well tolerated. No grade ≥3 toxicities were observed except for 1 asymptomatic grade-4 thrombocytopenia. Patients with lymph-node-positive NMSC do poorly. Patient selection for intensification of adjuvant therapy needs clarification.
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http://dx.doi.org/10.1177/014556131709600703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549076PMC
July 2017
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