Joseph, Richard W.

e21004 Background: Pembrolizumab (PEMBRO) and combination ipilimumab + nivolumab (IPI+NIVO) are FDA-approved immunotherapies for advanced melanoma (AM). HRQoL was better maintained with PEMBRO vs IPI in KEYNOTE-006. CheckMate-067 reported no clinically meaningful HRQoL differences with IPI+NIVO vs IPI. As randomized trial data are lacking, we compared HRQoL outcomes in AM between PEMBRO and IPI+NIVO in real-world clinical settings. Methods: A prospective, observational study was conducted with sponsor blinded to sites, and sites blinded to sponsor; nine oncologists from 9 US academic centers and affiliated satellite clinics enrolled AM patients (pts) age ≥18 years initiating first-line PEMBRO or IPI+NIVO between June 2017 – March 2018. The European Organization for the Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ C30) and EQ-5D-5L were administered at baseline and weeks 6, 12, 18, and 24 following therapy. Least squared (LS) mean changes in HRQoL scores from baseline were compared using mixed-effects models for repeated measures, adjusting for baseline covariates. Results: A total of 225 PEMBRO and 187 IPI+NIVO pts were enrolled, with > 95% questionnaire completion rates through week 24. At baseline, PEMBRO pts were more likely > age 65 (49% vs 37%, p = .011), stage IV disease (92% vs 85%; p = .002), and higher comorbidity index (1.0 vs 0.6; p < .001) compared with IPI+NIVO pts. Adjusted EORTC global health status/quality of life (GHS) LS mean changes from baseline showed greater improvement with PEMBRO vs. IPI+NIVO at 12, 18 and 24 weeks. At week 24, PEMBRO pts achieved a 3.3-point improvement (95% CI = 0.8, 5.7) and IPI+NIVO pts had no significant change (1.0, 95% CI = -1.6, 3.5), with a LS mean difference of 2.3 points (p = .037; 95% CI = 0.14, 4.51). At week 24, the EQ-5D visual analogue scale increased 1.0 (95% CI, -1.2, 3.2) for PEMBRO vs IPI+NIVO which decreased 0.9 (95% CI = -3.2, 1.3), with a statistically significant LS mean difference of 2.0 (95% CI = 0.4, 3.9; p = .045). Conclusions: Results from 2 measures suggest HRQoL was maintained vs. baseline in both PEMBRO and IPI+NIVO pts, with a significant between-group difference favoring PEMBRO in GHS over 24 weeks.

9532 Background: Both pembrolizumab (PEMBRO) and combination ipilimumab + nivolumab (IPI+NIVO) are FDA-approved immunotherapies for advanced melanoma (AM). These two treatment regimens have different toxicity profiles which may impact health care resource utilization (HCRU). Our aim was to compare real-world risk of hospitalization and emergency department (ED) visits within 12 months of starting the two treatment regimens. Methods: A retrospective cohort study was conducted in patients ≥18 years old with AM initiating PEMBRO or IPI+NIVO between Jan 1, 2016 – Dec 30, 2017. Patients were identified from 12 US academic medical centers and affiliated satellite clinics. Data were abstracted through chart review. All-cause hospitalizations or ED visits and the rates per patient per month (PPPM) through 12 months of follow-up were calculated. Utilization was compared between PEMRBO and IPI+NIVO using multivariate logistic regression analysis. Results: 400 patients were included, 200 each PEMBRO and IPI+NIVO with mean (SD) follow-up time of 10 (3) and 10 (4) months, respectively. The PEMBRO cohort had poorer Eastern Cooperative Group (ECOG) performance status at treatment start, 71% ECOG 0 or 1 vs 88% (p < .001); more diabetes, 21% vs 13% (p = .045); a trend towards more heart disease, 18% vs 12% (p = .067); were more likely to be PD-L1 expression positive, 77% vs 63% (p = .011); and less likely to harbor a BRAF mutation, 35% vs 50% (p = .003). The proportion with at least one hospitalization through 12 months was 17% PEMBRO vs 24% IPI+NIVO. Less than 2% of patients had more than one admission and none had more than two, regardless of cohort. Unadjusted mean (SD) PPPM hospitalizations were .016 (.037) for PEMBRO and .020 (.038) for IPI+NIVO. The adjusted odds ratio for any hospitalization with PEMBRO was 0.55 (95% CI .31, .97; p = .039) vs. IPI+NIVO. ED visits occurred in 18% vs 21% in PEMBRO and IPI+NIVO respectively, with no difference in covariate-adjusted analysis (p = .147). Conclusions: Patients receiving PEMBRO had a significantly lower probability of hospitalization and similar probability of ER visits compared with IPI+NIVO in the real world through 12 months.

4515 Background: The phase 2 IMmotion150 study showed improved PFS with atezo + bev vs sun in patients (pts) whose tumors were PD-L1+ and corroborated the activity of atezo monotherapy in previously untreated mRCC. This study offers an opportunity to evaluate PROs with immunotherapy and VEGF-directed therapy alone and in combination. Methods: Pts randomized to atezo 1200 mg IV q3w alone or with bev 15 mg/kg IV q3w, or sun 50 mg po qd for 4 wk on/2 wk off completed the MD Anderson Symptom Inventory (MDASI) and Brief Fatigue Inventory (BFI) q3w of each 6-wk cycle until progression (RECIST 1.1). Time to deterioration (TTD; first ≥ 2-point score increase over baseline [BL]) and change from BL (effect size [ES] ≥ 0.2 suggests a clinically important difference vs sun) in MDASI symptom severity and interference and BFI fatigue severity and interference scores are reported for all-comers. Results: Completion rates were > 90% at BL and ≥ 80% at most visits across arms. BL PRO scores indicating mild symptoms and interference were similar across arms. Delayed TTD of symptom severity and interference with daily life was seen with atezo vs sun and atezo + bev vs sun and was longest with atezo alone (Table). Pts reported milder symptoms and less interference during the first 6 cycles with atezo vs sun: ES mean (range) was 0.36 (0.07-0.68) for core symptom severity and 0.36 (0.04-0.83) for symptom interference. The 5 worst pt-reported symptoms during tx (dry mouth, fatigue, rash, drowsiness, lack of appetite) were all in the sun arm; all 16 symptoms measured were milder with atezo vs sun. Conclusions: PROs suggest that atezo alone or with bev maintained daily function with minimal symptom interference vs sun. Clinical activity, safety and PRO data for atezo support its investigation in adjuvant tx of high-risk RCC pts (IMmotion010; NCT03024996). Clinical trial information: NCT01984242. [Table: see text]

Abstract Background: The incidence of renal cell carcinoma (RCC) in the United States (U.S.) continues to rise and this trend cannot be fully attributed to incidental detection via increased use of abdominal imaging. Related to this, obesity rates have been rising steadily in the U.S. for several decades and obesity is one of the most widely accepted risk factors for the development of RCC. Interestingly, to date there are limited data regarding the molecular mechanisms that link obesity with an increased risk of RCC. Moreover, the few studies that have investigated the molecular underpinnings that link obesity and RCC have all used a candidate gene approach focusing exclusively on evaluation of germline genetic alterations (i.e., host genetics) and not somatic alterations in the tumor itself. Motivated by this, we used a multi-stage design to identify and validate genes that are associated with obesity-related clear cell RCC (ccRCC). Methods: We conducted a gene-expression microarray study of ccRCC and compared gene expression between 19 obese and 46 non-obese patients in both ccRCC tumors and patient-matched normal kidney tissues. Analyses were first stratified by smoking status, the other widely acceptable risk factor for RCC, and subsequently performed on the pooled cohort. To identify genes that are specific to obesity-related ccRCC, we identified Affymetrix probesets that had a tissue type-by-obesity status interaction p-value &lt;0.01 amongst non-smokers (stage 1), an interaction p-value &lt;0.05 in patients with a history of smoking (stage 2) and an interaction p-value&lt;0.01 in the pooled analysis (stage 3). Lastly, targeted validation was performed via RT-PCR on an independent cohort of 19 obese and 54 non-obese patients in both ccRCC tumors and patient-matched normal kidney tissues (stage 4). In addition to evaluating differential expression, an enrichment analysis was performed using DAVID and the results were compared to the Genetic Association Database. Results: From our microarray analyses, we identified two genes and one non-coding RNA as having candidate associations with obesity-related ccRCC: EFCAB6, ENRAGE and NCRNA00263, respectively. Using RT-PCR, we validated that while expression of ENRAGE is similar in normal kidney tissue across obese and non-obese subjects, ENRAGE is significantly over expressed in ccRCC tissues from obese patients compared to non-obese subjects. Others have shown that ENRAGE is a useful biomarker of inflammation and has a positive association with visceral fat adiposity, which provides further credence to our observations. As an alternative analysis approach, using the Genetic Association Database to identify medically-relevant somatic features, we also observed a putative relationship between GAL, IL6R, NMB and SORBS1 with obesity. Although the results of this alternative analysis approach are exploratory and thus need to be validated, there are some interesting relationships to note. Particularly, several variants in IL6R have been previously linked to obesity, diabetes and fat mass. Also, GAL is thought to play a role in drug resistance to chemotherapy in cell lines, warranting continued investigation to see if obese individuals with high or low expression show differential drug response. Conclusions: We provide evidence that overexpression of ENRAGE in ccRCC tumor tissue is an obesity-associated alteration. Up regulation of ENRAGE could lead to local, autocrine stimulation of the RAGE receptor and thus support cancer progression. Additionally, we show evidence of a putative relationship between GAL, IL6R, NMB and SORBS1 with obesity; however, these results need to be validated. Citation Format: Jeanette E. Eckel-Passow, Daniel J. Serie, Brian M. Bot, Richard W. Joseph, Steven N. Hart, John C. Cheville, Alexander S. Parker. Overexpression of ENRAGE is an obesity-related alteration in clear cell renal cell carcinoma. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr B42.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cutaneous melanoma have been significantly revised over the past few years in response to emerging data on immune checkpoint inhibitor therapies and BRAF-targeted therapy. This article summarizes the data and rationale supporting extensive changes to the recommendations for systemic therapy as adjuvant treatment of resected disease and as treatment of unresectable or distant metastatic disease.