Joshua Bauml

Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: Results from a single-arm, phase II study

Purpose There are no approved treatments for recurrent/metastatic head and neck squamous cell carcinoma refractory to platinum and cetuximab. In the single-arm, phase II KEYNOTE-055 study, we evaluated pembrolizumab, an anti-programmed death 1 receptor antibody, in this platinum- and cetuximab-pretreated population with poor prognosis. Methods Eligibility stipulated disease progression within 6 months of platinum and cetuximab treatment. Patients received pembrolizumab 200 mg every 3 weeks. Imaging was performed every 6 to 9 weeks. Primary end points: overall response rate (Response Evaluation Criteria in Solid Tumors v1.1, central review) and safety. Efficacy was assessed in all dosed patients and in subgroups on the basis of programmed death ligand 1 (PD-L1) expression and human papillomavirus (HPV) status. Results Among 171 patients treated, 75% received two or more prior lines of therapy for metastatic disease, 82% were PD-L1 positive, and 22% were HPV positive. At the time of analysis, 109 patients (64%) experienced a treatment-related adverse event; 26 patients (15%) experienced a grade ≥ 3 event. Seven patients (4%) discontinued treatment, and one died of treatment-related adverse events. Overall response rate was 16% (95% CI, 11% to 23%), with a median duration of response of 8 months (range, 2+ to 12+ months); 75% of responses were ongoing at the time of analysis. Response rates were similar in all HPV and PD-L1 subgroups. Median progression-free survival was 2.1 months, and median overall survival was 8 months. Conclusion Pembrolizumab exhibited clinically meaningful antitumor activity and an acceptable safety profile in recurrent/metastatic head and neck squamous cell carcinoma previously treated with platinum and cetuximab.

Detection of therapeutically targetable driver and resistance mutations in lung cancer patients by next generation sequencing of cell-free circulating tumor DNA.

Purpose: The expanding number of targeted therapeutics for non–small cell lung cancer (NSCLC) necessitates real-time tumor genotyping, yet tissue biopsies are difficult to perform serially and often yield inadequate DNA for next-generation sequencing (NGS). We evaluated the feasibility of using cell-free circulating tumor DNA (ctDNA) NGS as a complement or alternative to tissue NGS. Experimental Design: A total of 112 plasma samples obtained from a consecutive study of 102 prospectively enrolled patients with advanced NSCLC were subjected to ultra-deep sequencing of up to 70 genes and matched with tissue samples, when possible. Results: We detected 275 alterations in 45 genes, and at least one alteration in the ctDNA for 86 of 102 patients (84%), with EGFR variants being most common. ctDNA NGS detected 50 driver and 12 resistance mutations, and mutations in 22 additional genes for which experimental therapies, including clinical trials, are available. Although ctDNA NGS was completed for 102 consecutive patients, tissue sequencing was only successful for 50 patients (49%). Actionable EGFR mutations were detected in 24 tissue and 19 ctDNA samples, yielding concordance of 79%, with a shorter time interval between tissue and blood collection associated with increased concordance (P = 0.038). ctDNA sequencing identified eight patients harboring a resistance mutation who developed progressive disease while on targeted therapy, and for whom tissue sequencing was not possible. Conclusions: Therapeutically targetable driver and resistance mutations can be detected by ctDNA NGS, even when tissue is unavailable, thus allowing more accurate diagnosis, improved patient management, and serial sampling to monitor disease progression and clonal evolution. Clin Cancer Res; 22(23); 5772–82. ©2016 AACR.

Pretreatment neutrophil-to-lymphocyte ratio as a marker of outcomes in nivolumab-treated patients with advanced non-small-cell lung cancer

OBJECTIVES Efficient use of nivolumab in non-small-cell lung cancer (NSCLC) has been limited by the lack of a definitive predictive biomarker. In patients with metastatic melanoma treated with ipilimumab, a pretreatment neutrophil-to-lymphocyte ratio (NLR)<5 has been associated with improved survival. This retrospective cohort study aimed to determine whether the pretreatment NLR was associated with outcomes in NSCLC patients treated with nivolumab. METHODS We reviewed the medical records of all patients with previously treated advanced NSCLC who received nivolumab between March 2015 and March 2016 outside of a clinical trial at the University of Pennsylvania. Patients were dichotomized according to pretreatment NLR<5 vs. ≥5. Multivariable logistic regression and Cox proportional hazards models were used to assess the impact of pretreatment NLR on overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). RESULTS 175 patients were treated. Median age was 68 (range, 33-88); 54% were female. Twenty-five percent of patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥2; 46% had received ≥2 prior systemic therapies. In multivariate analyses, pretreatment neutrophil-to-lymphocyte ratio (NLR) ≥5 was independently associated with inferior OS (median 5.5 vs. 8.4 months; HR 2.07, 95% CI 1.3-3.3; p=0.002) and inferior PFS (median 1.9 vs. 2.8 months; HR 1.43, 95% CI 1.02-2.0; p=0.04). CONCLUSIONS In a cohort of patients with NSCLC treated with nivolumab in routine practice, pretreatment NLR≥5 was associated with inferior outcomes. It is unclear whether this marker is predictive or prognostic. Prospective studies are warranted to determine the utility of NLR in the context of other biomarkers of programmed death-1 (PD-1) therapy.

Do attitudes and beliefs regarding complementary and alternative medicine impact its use among patients with cancer? A cross‐sectional survey

Complementary and alternative medicine (CAM) incorporates treatments used by cancer survivors in an attempt to improve their quality of life. Although population studies have identified factors associated with its use, to the best of the authors knowledge, assessment of why patients use CAM or the barriers against its use have not been examined to date.

Expectancy in Real and Sham Electroacupuncture: Does Believing Make It So?

BACKGROUND The large placebo effect observed in prior acupuncture trials presents a substantial challenge for interpretation of the efficacy of acupuncture. We sought to evaluate the relationship between response expectancy, a key component of the placebo effect over time, and treatment outcome in real and sham electroacupuncture (EA). METHODS We analyzed data from a randomized controlled trial of EA and sham acupuncture (SA) for joint pain attributable to aromatase inhibitors among women with breast cancer. Responders were identified using the Patient Global Impression of Change instrument at Week 8 (end of intervention). The Acupuncture Expectancy Scale (AES) was used to measure expectancy four times during the trial. Linear mixed-effects models were used to evaluate the association between expectancy and treatment response. RESULTS In the wait list control group, AES remained unchanged over treatment. In the SA group, Baseline AES was significantly higher in responders than nonresponders (15.5 vs 12.1, P = .005) and AES did not change over time. In the EA group, Baseline AES scores did not differ between responders and nonresponders (14.8 vs 15.3, P = .64); however, AES increased in responders compared with nonresponders over time (P = .004 for responder and time interaction term) with significant difference at the end of trial for responders versus nonresponders (16.2 vs 11.7, P = .004). CONCLUSIONS Baseline higher response expectancy predicts treatment response in SA, but not in EA. Divergent mechanisms may exist for how SA and EA influence pain outcomes, and patients with low expectancy may do better with EA than SA.

Survival outcome according to KRAS mutation status in newly diagnosed patients with stage IV non-small cell lung cancer treated with platinum doublet chemotherapy

Introduction Mutations (MT) of the KRAS gene are the most common mutation in non-small cell lung cancer (NSCLC), seen in about 20–25% of all adenocarcinomas. Effect of KRAS MT on response to cytotoxic chemotherapy is unclear. Methods We undertook a single-institution retrospective analysis of 93 consecutive patients with stage IV NSCLC adenocarcinoma with known KRAS and EGFR MT status to determine the association of KRAS MT with survival. All patients were treated between January 1, 2008 and December 31, 2011 with standard platinum based chemotherapy at the University of Pennsylvania. Overall and progression free survival were analyzed using Kaplan-Meier and Cox proportional hazard methods. Results All patients in this series received platinum doublet chemotherapy, and 42 (45%) received bevacizumab. Overall survival and progression free survival for patients with KRAS MT was no worse than for patients with wild type KRAS. Median overall survival for patients with KRAS MT was 19 months (mo) vs. 15.6 mo for KRAS WT, p = 0.34, and progression-free survival was 6.2 mo in patients with KRAS MT vs. 7mo in patients with KRAS WT, p = 0.51. In multivariable analysis including age, race, gender, and ECOG PS, KRAS MT was not associated with overall survival (HR 1.12, 95% CI 0.58–2.16, p = 0.74) or progression free survival (HR 0.80, 95% CI 0.48–1.34, p = 41). Of note, receipt of bevacizumab was associated with improved overall survival only in KRAS WT patients (HR 0.34, p = 0.01). Conclusions KRAS MT are not associated with inferior progression-free and overall survival in advanced NSCLC patients treated with standard first-line platinum-based chemotherapy.

Immunotherapy with VGX-3100 (HPV16 and HPV18 plasmids) + INO-9012 (DNA encoding IL-12) in human papillomavirus (HPV) associated head and neck squamous cell carcinoma (HNSCCa): interim safety and immunogenicity results

Meeting abstracts Oropharyngeal HNSCCa is frequently associated with HPV infection. DNA-based Immunotherapy with plasmids encoding HPV16 and HPV18 E6/E7 antigens has been shown to generate robust immune responses in women with HPV-driven high-grade cervical dysplasia. We hypothesize that HPV-

Transoral Robotic Surgery–Assisted Endoscopy With Primary Site Detection and Treatment in Occult Mucosal Primaries

Importance Management of cervical lymph node metastasis without a known primary tumor is a diagnostic and treatment challenge for head and neck oncologists. Identification of the occult mucosal primary tumor minimizes the morbidity of treatment. Objective To analyze the role of transoral robotic surgery (TORS) in facilitating the identification of a primary tumor site for patients presenting with squamous cell carcinoma of unknown primary (CUP). In addition, we assessed treatment deintensification by determining the number of patients who did not undergo definitive radiation therapy and chemotherapy. Design, Setting, and Participants In this retrospective case series from January 2011 to September 2015, 60 consecutive patients with squamous cell CUP who underwent TORS-assisted endoscopy and ipsilateral neck dissection were included from an academic medical center and studied to study the rate success rate of TORS identifying occult mucosal malignancy. Main Outcomes and Measures Success rate of identifying occult mucosal malignancy; usage of radiation therapy and chemotherapy. Results Overall, 60 patients (mean [SD] age, 55.5 [8.9] years) were identified; 48 of the 60 patients (80.0%) had a mucosal primary identified during their TORS-assisted endoscopic procedure. The mean (SD) size of the identified mucosal primary lesions was 1.3 (0.1) cm. All mucosal primaries, when found, originated in the oropharynx including the base of tongue in 28 patients (58%), palatine tonsil in 18 patients (38%), and glossotonsillar sulcus in 2 patients (4%). Among patients in this study, 40 (67%) did not receive chemotherapy, and 15 (25%) did not receive radiation therapy. Conclusions and Relevance Advances in transoral surgical techniques have helped identify occult oropharyngeal malignancies that traditionally have been treated with comprehensive radiation to the entire pharyngeal axis. We demonstrate the efficacy of a TORS-assisted approach to identify and surgically treat the primary tumor in patients presenting with CUP. In addition, patients managed with the TORS-assisted endoscopic approach benefit from surgical and pathological triage, which in turn results in deintensification of treatment by eliminating the need for chemotherapy in the majority of patients, as well as avoiding radiation therapy in select patients.

Capecitabine and lapatinib for the first‐line treatment of metastatic/recurrent head and neck squamous cell carcinoma

The combination of cisplatin, 5‐fluorouracil, and cetuximab is a standard treatment for patients with recurrent/metastatic head and neck cancer, with a high rate of toxicity. Identifying less toxic, equally effective regimens is imperative. Therefore, in the current study, the authors investigated first‐line treatment with an all‐oral regimen of capecitabine and lapatinib.

Radiologic Pseudoprogression during Anti–PD-1 Therapy for Advanced Non–Small Cell Lung Cancer

Introduction: Anti–programmed cell death protein 1 (PD‐1) therapy can lead to unconventional tumor responses, including radiologic pseudoprogression. Here we have determined the real‐world incidence of radiologic pseudoprogression in advanced NSCLC and compared radiologic response criteria for assessment of disease response. Methods: The electronic medical records of all patients with NSCLC who were receiving anti–PD‐1 therapy at our institution over a 3‐year period were retrospectively reviewed, and patients with clinically suspected radiologic pseudoprogression were identified. Patients without available follow‐up imaging or clinical data were excluded. Imaging examinations were then analyzed to determine whether progression was confirmed on subsequent reimaging. Assessments of tumor response by the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (RECIST 1.1), the unidimensional immune‐related response criteria (iRRC), and the iRECIST criteria for all patients were performed and compared. Results: A total of 228 consecutive patients began receiving anti–PD‐1 therapy over a 3‐year period. Of the 166 of these patients who were evaluable, most (80%) received nivolumab. Fifteen patients (9%) were clinically suspected of having radiologic pseudoprogression on account of tumor enlargement and/or development of new lesions on computed tomography images during the first 4 to 6 weeks of therapy, and they continued receiving anti–PD‐1 therapy. Three of these patients (2%) demonstrated evidence of radiologic pseudoprogression at first reimaging. The iRRC and immune RECIST criteria were more accurate in classifying radiologic pseudoprogression as nonprogression; none of the three cases were deemed progression by the iRRC or immune RECIST, whereas all three cases were determined to be progression according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Conclusions: Radiologic pseudoprogression is a clinical challenge but an uncommon occurrence in patients with NSCLC who are receiving anti–PD‐1 therapy.