Supplementary Figures S1 - S10. Supplementary Figure S1. Additional information for Patient 1. Supplementary Figure S2. Additional information for Patient 2. Supplementary Figure S3. Additional information for Patient 3. Supplementary Figure S4. Additional clinical information for Patient 4. Supplementary Figure S5. Characterization of EGFR-RAD51 in NR6 cells. Supplementary Figure S6. Relative stability of EGFR-WT, -L858R, and -RAD51. Supplementary Figure S7. Structural model of EGFR-RAD51 filaments. Supplementary Figure S8. On-target inhibition of EGFR-RAD51 by EGFR TKI. Supplementary Figure S9. Cetuximab inhibits ligand-induced activation of downstream signaling pathways in cells expressing EGFR-RAD51. Supplementary Figure S10. cDNA sequence of EGFR-RAD51.

Supplementary Tables S1 - S3. Supplementary Table S1. Summary of EGFR alterations in NSCLC identified by FoundationOne. Supplementary Table S2. Summary of genomic coordinates for the kinase fusions identified in this study. Supplementary Table S3. Results of MTT curve fitting from Prism.

Supplementary Methods, Supplementary References, Supplementary Table Legends, and Supplementary Figure Legends.

Abstract Here, we report that novel epidermal growth factor receptor (EGFR) gene fusions comprising the N-terminal of EGFR linked to various fusion partners, most commonly RAD51, are recurrent in lung cancer. We describe five patients with metastatic lung cancer whose tumors harbored EGFR fusions, four of whom were treated with EGFR tyrosine kinase inhibitors (TKI) with documented antitumor responses. In vitro, EGFR–RAD51 fusions are oncogenic and can be therapeutically targeted with available EGFR TKIs and therapeutic antibodies. These results support the dependence of EGFR-rearranged tumors on EGFR-mediated signaling and suggest several therapeutic strategies for patients whose tumors harbor this novel alteration. Significance: We report for the first time the identification and therapeutic targeting of EGFR C-terminal fusions in patients with lung cancer and document responses to the EGFR inhibitor erlotinib in 4 patients whose tumors harbored EGFR fusions. Findings from these studies will be immediately translatable to the clinic, as there are already several approved EGFR inhibitors. Cancer Discov; 6(6); 601–11. ©2016 AACR. See related commentary by Paik, p. 574. This article is highlighted in the In This Issue feature, p. 561

Dermatologic adverse events (dAEs) are common with the use of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. First- and second-generation agents (erlotinib, gefitinib, and afatinib) are frequently associated with acneiform rash, pruritus, xerosis, and paronychia; the incidence and characterization of these dAEs have been well described. However, there is evidence that the dAE profile is different with third-generation EGFR-TKIs. Herein, we describe the dAEs associated with third-generation EGFR-TKIs and our clinical experience with osimertinib, a third-generation EGFR-TKI approved by the U.S. Food and Drug Administration for the treatment of metastatic, EGFR T790M mutation-positive non-small cell lung cancer in patients whose disease has progressed on or after EGFR-TKI therapy. Case summaries of patients from two of our institutions who received osimertinib and were referred to a dermatologist for dAEs are also presented. Overall, the evidence suggests that osimertinib is associated with less severe and less frequent dAEs than first- and second-generation EGFR-TKIs and that therefore a different approach is warranted. Finally, we outline dAE management approaches for osimertinib in the context of those typically employed with first- and second-generation EGFR-TKIs.IMPLICATIONS FOR PRACTICE:Appropriate prevention and management of dermatologic adverse events (dAEs) associated with the use of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) may help patients to continue therapy and lessen any negative impact on their quality of life. EGFR-TKIs are frequently associated with acneiform rash, pruritus, xerosis, and paronychia; however, dAEs associated with third-generation EGFR-TKIs are lower in frequency and severity. Before therapy, health care providers should discuss the potential osimertinib-associated dAEs and encourage patients to report their dAEs. Patients should also be educated on prophylactic measures to minimize the severity of dAEs and the importance of adherence to the treatment regimen.

Chemotherapy, and now targeted therapies and immunotherapies, are widely used for the management of patients with all stages of lung cancer. Some challenges present when patients are receiving concomitant hemodialysis for various comorbid conditions. However, this should not immediately rule out a patient for treatment. Many drugs may be safely given to patients who are receiving hemodialysis with the proper dosing schedule and careful monitoring. This article will outline the current literature surrounding the use of these drugs in patients undergoing active hemodialysis while being treated for lung cancer.

ObjectivesEfficient 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.MethodsWe 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).Results175 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).ConclusionsIn 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.

In randomized trials of nivolumab in NSCLC, less than 10% of pts were ≥75 years old, and all had Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1. The effectiveness of nivolumab in elderly pts with NSCLC treated in routine practice has not been previously described. We conducted a retrospective cohort study of pts with advanced NSCLC treated with nivolumab outside of clinical trials at the University of Pennsylvania between March 2015 and March 2016. Logistic regression and Cox proportional hazards models were used to evaluate the association of age (≥75 vs. <75 years) with overall response rate (ORR), progression-free survival (PFS), and overall survival (OS), adjusting for ECOG PS (0-1 vs. ≥2), sex, smoking history [heavy (≥10 pack-years) vs. light/never (<10 pack-years)], and number of prior systemic therapies (1 vs. ≥2). Of 175 pts treated with nivolumab, 43 (25%) were ≥75 years old and 42 (24%) had ECOG PS ≥2. Ninety-five pts (54%) were female, 147 (84%) had heavy smoking history, and 81 (46%) had received ≥2 prior systemic therapies. ORR was 19.4%, with median PFS and OS of 2.1 and 6.5 months, respectively. Age ≥75 years was not associated with ORR (OR 1.0, 95% CI 0.4-2.5; p=0.97), PFS (HR 0.71, 95% CI 0.5-1.1; p=0.12), or OS (HR 0.8, 95% CI 0.5-1.4; p=0.4; Figure 1). ECOG PS ≥ 2 was associated with lower ORR (7.1% vs. 23.3%; OR 0.25, 95% CI 0.07 – 0.88; p=0.03), inferior PFS (median 1.8 vs. 2.3 months; HR 1.9, 95% CI 1.3 – 2.8; p=0.001), and inferior OS (median 3.6 vs. 7.8 months; HR 2.6, 95% CI 1.6 – 4.1; p<0.001). In a large NSCLC cohort treated outside of clinical trials, elderly pts gained similar benefit from nivolumab compared to younger pts. Pts with poor performance status had inferior outcomes regardless of age.

Thoracic oncology nursing is now entering over 10 years of experience with managing tyrosine kinase inhibitor (TKI) toxicities, most notably, epidermal growth factor receptor (EGFR) inhibitor associated rash. The three approved EGFR inhibitors used to treat non-small cell lung cancer (NSCLC) are afatinib, erlotinib, and gefitinib. Most recently, the drug Osimertinib, for EGFR mutation resistance known as T790M, has now been approved for use. Grading of the EGFRI rash has been difficult due to its inconsistency in comparison to non-EGFRI rashes in the general medical community and other oncologic rashes. Consensus guidelines for the management of EGFR inhibitor associated rash have been produced and disseminated in the oncology community.1,2 There is a correlation between EGFRI rash and overall survival in NSCLC patients, making it imperative to keep patients with rash on the EGFRI therapy.3,4 It remains a challenge for oncology nurses to understand and manage this sometimes severe rash (see figure 1). Figure 1. Other cutaneous toxicities such as scalp rash, paronychia, hypertrichosis- namely trichomegaly (see figure 2), fissuring, pruritis, and xerosis have all been reported. The Multinational Association for the Supportive Care in Cancer (MASCC) has produced recommendations for these toxicities as well.2 While they are often a minor annoyance, they can sometimes also become severe and cause dose reductions and a significant impact on activities of daily living (ADL’s). Identification, prevention, and management are important tasks for oncology nurses to master to allow patients to remain on therapy. Figure 2. Other classes of TKI toxicities include the Anaplastic Leukemia Kinase (ALK) inhibitors, where there are currently 3 drugs approved for use, alectinib, ceritinib, and crizotinib. Each of the ALK inhibitors carries different yet important toxicities, ranging from nausea/vomiting, diarrhea, edema, bradycardia, pneumonitis, myalgias with elevated CPK levels, and hepatotoxicity. Several other TKI’s are in development for potential use in lung cancer, such as HER2 inhibitors, BRAF inhibitors, and drugs targeting pathways dealing with RET, MET and KRAS (see table 1).5-7Tabled 1BRAF mutations•4% NSCLC•Most common is V600E•Drugs in trials: dabrafenib, vemurafenib, dasatinib,RET rearrangements•1-2% NSCLC•Highly associated with young, never-smokers•Drugs in trials: vandetanib, cabozantinib, sunitinib, ponatinibMET amplification•Drugs in trials: crizotinib, tivantinib, onartuzumab, MET inhibitorsHER2 mutations•Drugs in trials: trastuzumab, afatinib, dacomitinib, neratinibKRAS mutations•25-30% NSCLC, most common mutation•MEK, PI3K, FAK inhibitors Open table in a new tab It is important for thoracic oncology nurses to have a firm understanding of these drugs and their toxicities. Management strategies must be tailored to the patient’s symptoms and side effects, as well as to the specific drug and dosage. 1. Burtness B, Anadkat M, Basti S, et al (2009). NCCN task force report: management of dermatologic and other toxicities associated with EGFR inhibition in patients with cancer. JNCCN, 7(suppl 1):S5-S21. Available at http://www.nccn.org/JNCCN/PDF/2009_Derm_Tox_TF.pdf 2. Lacouture ME, Anadkat MJ, Bensadoun RJ, et al (2011). Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer, 19(8):1079-1095. http://dx.doi.org/10.1007/s00520-011-1197-6 3. Lee SM, Khan I, Upadhayay S, et al (2012). First-line erlotinib in patients with advanced non-small-cell lung cancer unsuitable for chemotherapy (TOPICAL): a double-blind, placebo-controlled, phase 3 trial. Lancet Oncol, 13(11):1161-1170. http://dx.doi.org/10.1016/S1470=2045(12)70412-6 4. Liu H, Wu Y, Lv T, et al (2013). Skin rash could predict the response to EGFR tyrosine kinase inhibitor and the prognosis for patients with non-small cell lung cancer: a systematic review and meta-analysis. PLOS One. http://dx.doi.org/10.1371/journal.pone.0055128 5. Cardarella S, Ogino A, Nishino M, et al. (2013). Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer. Clin Cancer Res. 2013; 19:4532-4540. 6. Tsuta K, Khono T, Yoshida A, et al. (2014). RET-rearranged non-small-cell lung carcinoma: a clinicopathological and molecular analysis. Br J Cancer. 110:1571-1578. 7. Awad MM, Oxnard GR, Jackman DM, et al. (2016). MET Exon 14 mutations in Non-small-cell lung cancer are associated with advanced age and stage dependent MET genomic amplification and c-MET overexpression. J Clin Oncol. 34(7):721-30. TKI toxicities, EGFR rash

INTRODUCTION As the official publication of the Advanced Practitioner Society for Hematology and Oncology (APSHO), JADPRO is pleased to offer Part 1 of an accredited educational activity based on the recently concluded APSHO Regional Lecture Series. Hosted in collaboration with major cancer centers around the country, the APSHO Regional Lecture Series brought case-based didactic presentations and skills workshops to advanced practitioners. In the spirit of JADPRO, three accredited Grand Rounds articles by Beth Eaby-Sandy, MSN, CRNP, OCN® (non-small cell lung cancer) and Sandra E. Kurtin, PhDc, ANP-C, AOCN® (multiple myeloma and chronic lymphocytic leukemia)-program chairs for the regional lecture series-offer the same practice-changing information and strategies for advanced practitioners. In this Grand Rounds article, essentials skills of interpreting pathology reports and imaging studies are reviewed. Images from patient cases supplement the article. Keep an eye out for Parts 2 and 3 in future issues of JADPRO, and be sure to check out apsho.org/lectures for information on registering for upcoming JADPRO Regional Lectures starting this spring.

Immune checkpoint inhibitors are associated with immune-related adverse events (irAEs). While the incidence of irAEs in routine practice and their effect on outcomes have been well characterized in melanoma, a similar analysis has not been previously reported in NSCLC pts treated with anti-programmed death 1 (PD-1) therapy. We conducted a retrospective cohort study of pts with advanced NSCLC who received nivolumab outside of clinical trials between March 2015 and March 2016 at the University of Pennsylvania. irAEs were graded using the Common Terminology Criteria for Adverse Events version 4.0. Data collected included demographics, timing and treatment of irAEs, and dates of disease progression and death or last follow-up. To analyze the effect of irAEs on progression-free survival (PFS) and overall survival (OS), landmark analyses were used beginning from 3 months after start of treatment. Pts who reached the PFS or OS endpoints prior to 3 months were excluded. Cox proportional hazards models were used to assess for differences in PFS and OS according to the occurrence of an irAE, adjusting for age, sex, and Eastern Cooperative Oncology Group Performance Status (ECOG PS). 175 pts received a median of 5 cycles of nivolumab (range, 1-24, IQR, 3-9). Median age was 68 years (range, 33-88, IQR, 60-74). Forty-six percent of pts were male; 5% had an ECOG PS ≥ 2. Twenty-eight pts (16%) experienced an irAE of any grade and 6 (3%) had a grade 3/4 irAE. Median time to onset of the irAE was 3 cycles (range, 1-18, IQR, 2-6). Of the pts who experienced an irAE, 14 (50%) were treated with systemic corticosteroids. The most common irAEs were hypothyroidism/hyperthyroidism (n=8), pneumonitis (n=6; three grade 4), colitis (n=4; one grade 3), dermatitis (n=4), and arthritis (n=2). Less common irAEs (n=1 each) included hepatitis (grade 4), aseptic meningitis (grade 3), immune thrombocytopenia, and severe hypoalbuminemia that improved with steroids. Overall response rate was 19.4% (34 of 175), and median PFS and OS were 2.1 and 6.5 months, respectively. After adjusting for age, sex, and ECOG PS, landmark analyses revealed no difference in PFS (HR 1.3, 95% CI 0.4-3.8, p=0.7) or OS (HR 0.9, 95% CI 0.3-2.7, p=0.9) stratified by the presence or absence of an irAE. In NSCLC pts treated with nivolumab in typical practice, irAEs of any grade were uncommon, and grade 3/4 irAEs were rare. The occurrence of irAEs was not associated with PFS or OS.

The NLR, a marker of systemic inflammation, has been associated with outcomes in multiple cancers. In patients (pts) with metastatic melanoma treated with ipilimumab, pre-therapy NLR < 5 has been associated with improved progression-free survival (PFS) and overall survival (OS). However, the utility of NLR as a marker of outcomes in pts with NSCLC treated with programmed-death 1 (PD-1) inhibitors is not known. We conducted a retrospective cohort study of pts with advanced NSCLC treated with nivolumab off clinical trials at the University of Pennsylvania between March 2015 and March 2016. NLR was calculated from complete blood counts obtained within two weeks of starting nivolumab. Pts were dichotomized based on a NLR <5 or ≥ 5. We calculated PFS and OS using the Kaplan-Meier method and used multivariate Cox proportional hazards models to adjust for sex, age, histology (squamous vs. non-squamous), Eastern Cooperative Oncology Group Performance Status (ECOG PS) (0-1 vs. ≥ 2), smoking history [heavy (≥10 pack-years) vs. light/never (<10 pack-years)], and number of prior systemic therapies (1 vs. ≥ 2). 175 pts received a median of 5 cycles of nivolumab (range, 1-24; IQR 3-9). Median age was 68 years (range 33-88, IQR 60-74), 46% of pts were male, 75% were white, 25% had an ECOG PS ≥ 2, and 46% had ≥ 2 prior systemic therapies. Eighty-four percent of pts had a ≥10 pack-year smoking history, and 76% had non-squamous histology. Median baseline NLR was 5.5 (IQR, 3.1 – 9.4), with NLR < 5 in 73 pts (42%) and NLR ≥ 5 in 102 patients (58%). Through the date of this analysis (June 1, 2016), disease progression had occurred in 124 pts (71%), and 92 pts (53%) had died, resulting in median PFS and OS of 2.1 and 6.5 months, respectively. After controlling for the aforementioned clinical and demographic factors, pts with baseline NLR<5 had significantly improved PFS (median 2.8 vs. 1.9 months; adjusted HR=0.70, 95% CI: 0.50-0.99; p = 0.04) and OS (median 8.4 vs. 5.5 months; adjusted HR=0.54, 95% CI: 0.34-0.84; p = 0.007) compared to pts with NLR ≥ 5. Pre-therapy NLR is independently associated with PFS and OS in advanced NSCLC pts treated with nivolumab. It is unclear whether this marker is predictive or prognostic. Prospective studies are warranted to determine the utility of NLR in predicting outcome in the context of other biomarkers of PD-1 therapy.

UNLABELLED:Here, we report that novel epidermal growth factor receptor (EGFR) gene fusions comprising the N-terminal of EGFR linked to various fusion partners, most commonly RAD51, are recurrent in lung cancer. We describe five patients with metastatic lung cancer whose tumors harbored EGFR fusions, four of whom were treated with EGFR tyrosine kinase inhibitors (TKI) with documented antitumor responses. In vitro, EGFR-RAD51 fusions are oncogenic and can be therapeutically targeted with available EGFR TKIs and therapeutic antibodies. These results support the dependence of EGFR-rearranged tumors on EGFR-mediated signaling and suggest several therapeutic strategies for patients whose tumors harbor this novel alteration.SIGNIFICANCE:We report for the first time the identification and therapeutic targeting of EGFR C-terminal fusions in patients with lung cancer and document responses to the EGFR inhibitor erlotinib in 4 patients whose tumors harbored EGFR fusions. Findings from these studies will be immediately translatable to the clinic, as there are already several approved EGFR inhibitors. Cancer Discov; 6(6); 601-11. ©2016 AACR.See related commentary by Paik, p. 574This article is highlighted in the In This Issue feature, p. 561.

Mr. T is a 78-year-old male who initially presented with stage IV oligometastatic non–small cell lung cancer (NSCLC) with adrenal metastasis. He is a retired pharmacist who comes to appointments with his wife. His medical history includes hypertension, emphysema, esophageal reflux, and hyperlipidemia. He initially presented with abdominal pain. Upon workup, a CT image of the chest and abdomen revealed a solitary adrenal metastasis and one lung lesion. He had laparoscopic resection of the adrenal metastasis. However, shortly afterward, he was found to have metastatic disease in the surgical bed and progression of the lung mass.

Radiation dermatitis (RD) results from radiotherapy and often occurs within the first 4 weeks of treatment, although late effects also occur. While RD may resolve over time, it can have a profound effect on patients' quality of life and lead to dose modifications. A study group of international, interdisciplinary experts convened to develop RD prevention and treatment guidelines based on evidence from randomized, controlled trials. Evidence-based recommendations were developed after an extensive literature review. Randomized, controlled trials with standardized measurement of outcomes were considered the best evidence, and a majority of the recommendations were formulated from this literature. The adoption of washing with water, with or without a mild soap, and allowing the use of antiperspirants is supported by randomized trials. Use of topical prophylactic corticosteroids (mometasone) is recommended to reduce discomfort and itching. There is some evidence that silver sulfadiazine cream can reduce dermatitis score. There is insufficient evidence to support, and therefore the panel recommends against the use of trolamine, topical sulcrate, hyaluronic acid, ascorbic acid, silver leaf dressing, light-emitting diode lasers, Theta cream, dexpanthenol, calendula, proteolytic enzymes, sulcralfate, oral zinc, and pentoxifylline. Moreover, there is no evidence to support the superiority for any specific intervention in a reactive fashion. For patients with established radiation-induced telangiectasia and fibrosis, the panel suggests the use of pulse dye laser for visual appearance, and the use of pentoxifylline and vitamin E for the reduction of fibrosis.