Diede, Scott J.

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.

AbstractBackgroundVorinostat combined with retinoids produces additive antitumor effects in preclinical studies of neuroblastoma. Higher systemic exposures of vorinostat than achieved in pediatric phase I trials with continuous daily dosing are necessary for in vivo increased histone acetylation and cytotoxic activity. We conducted a phase I trial in children with relapsed/refractory neuroblastoma to determine the maximum tolerated dose (MTD) of vorinostat on an interrupted schedule, escalating beyond the previously identified pediatric MTD.MethodsIsotretinoin (cis‐13‐retinoic acid) 80 mg/m2/dose was administered by mouth twice daily on days 1–14 in combination with escalating doses of daily vorinostat up to 430 mg/m2/dose (days 1–4; 8–11) in each 28‐day cycle using the standard 3 + 3 design. Vorinostat pharmacokinetic testing and histone acetylation assays were performed.ResultsTwenty‐nine patients with refractory or relapsed neuroblastoma were enrolled and 28 were evaluable for dose escalation decisions. Median number of cycles completed was two (range 1–15); 11 patients received four or more cycles. Three patients experienced cycle 1 dose‐limiting toxicities. A total of 18 patients experienced grade 3/4 toxicities related to study therapy. The maximum intended dose of vorinostat (430 mg/m2/day, days 1–4; 8–11) was tolerable and led to increased histone acetylation in surrogate tissues when compared to lower doses of vorinostat (P = 0.009). No objective responses were seen.ConclusionsIncreased dose vorinostat (430 mg/m2/day) on an interrupted schedule is tolerable in combination with isotretinoin. This dose led to increased vorinostat exposures and demonstrated increased histone acetylation. Prolonged stable disease in patients with minimal residual disease warrants further investigation.