Association between neutrophil-to-eosinophil ratio (NER) and efficacy outcomes in the JAVELIN Renal 101 study.

4549 Background: Baseline NER has been reported to be associated with outcomes of immuno-oncology based combination treatment in advanced renal cell carcinoma (aRCC). We report outcomes by baseline NER of patients with aRCC in the JAVELIN Renal 101 trial who received avelumab + axitinib (A + Ax) or sunitinib (S). Methods: We calculated the median NER (mNER) for patients in the A + Ax and the S arms at the data cutoff (April 20, 2020) for the 3rd interim analysis (IA3). Progression-free survival (PFS), overall survival (OS), and objective response (OR) by NER are reported. Multivariate Cox regression analyses of PFS and OS were also conducted. Results: At the IA3 cutoff date, the mNERs for the A + Ax arm (n = 383) and S arm (n = 396) were 29.2 and 27.0, respectively. OR, PFS and OS for both arms are summarized in the table below. Better observed treatment outcomes in OR (63.9% vs 55.2%) and median PFS (15.5 vs, 11.1 months) were observed for patients with a NER < median vs. NER ≥ median in the A + Ax arm, while there were not major differences in outcome based on NER in the S arm. The stratified hazard ratio (HR) for PFS in patients with a NER < median compared with those with a NER ≥ median in the A + Ax arm was 0.81 (95% CI, 0.630-1.035) and 0.93 (95% CI, 0.728-1.181) in the S arm. Patients with a NER < median had improved OS compared with those with a NER ≥ median in the A + Ax arm (stratified HR, 0.67; 95% CI, 0.481-0.940) and the S arm (stratified HR, 0.57; 95% CI, 0.424-0.779). Multivariate analysis showed that a low NER was associated with longer PFS and OS by treating baseline NER as either a continuous variable or a binary variable (dichotomized by median). Conclusions: Baseline NER may be predictive of OR and PFS in aRCC patients treated with A + Ax, and prognostic for overall survival regardless of therapy. Clinical trial information: NCT02684006. [Table: see text]

Effect of pembrolizumab (pembro) on hepatitis B viral (HBV) load and aminotransferase (ALT) levels in patients (pts) with advanced hepatocellular carcinoma (aHCC) in KEYNOTE-224 and KEYNOTE-240.

4587 Background: The effect of PD-1 inhibition on HBV infection is unclear, and pts with HBV are often excluded from trials. This analysis evaluated HBV viral load and liver function (ALT levels) in pts with HBV infection in 2 trials of pembro: KEYNOTE-224 and KEYNOTE-240. Methods: Eligible pts with aHCC post first-line sorafenib and controlled HBV received pembro 200 mg IV Q3W until progression. Pts with active HBV (HBsAg positive and/or HBV DNA detectable) and inactive HBV (anti-HBc positive, HBsAg negative, and HBV DNA not detectable) at baseline (BL) were included. Results: Of 104 pts in KEYNOTE-224 and 413 pts in KEYNOTE-240, 8 (7.7%) and 101 (24.5%) had active HBV and 13 (12.5%) and 102 (24.7%) had inactive HBV, respectively. All pts with HBV received nucleos(t)ide analogs. In KEYNOTE-240, 2 (2.8%) pts with active HBV in the pembro arm and 1 (3.4%) in placebo (pbo) had a > 1 log increase (incr) of HBV DNA and 1000 IU/mL over BL; none in the pembro arm were associated with ALT elevation. No pts with inactive HBV in KEYNOTE-240 and no pts in KEYNOTE-224 had a > 1 log incr and 1000 IU/mL over BL. No pts in KEYNOTE-224 and 28 (38.9%) with active HBV and 1 (1.4%) with inactive HBV in the pembro arm, and 8 (27.6%) with active HBV and 0 with inactive HBV in the pbo arm in KEYNOTE-240 had a > 1 log decrease (decr) in HBV DNA. Conclusions: Few pts with aHCC and HBV had viral load incr with pembro. In KEYNOTE-240 no clinically meaningful differences between pembro and pbo were observed. ALT elevation was not associated with viral load incr with pembro. These data suggest that pembro is unlikely to significantly affect underlying HBV infection in pts with aHCC receiving HBV antiviral therapy. Clinical trial information: KEYNOTE-224, NCT02702414; KEYNOTE-240, NCT02702401 . [Table: see text]

The Changing Face of Adrenoleukodystrophy

Adrenoleukodystrophy (ALD) is a rare X-linked disorder of peroxisomal oxidation due to mutations in ABCD1. It is a progressive condition with a variable clinical spectrum that includes primary adrenal insufficiency, myelopathy, and cerebral ALD. Adrenal insufficiency affects over 80% of ALD patients. Cerebral ALD affects one-third of boys under the age of 12 and progresses to total disability and death without treatment. Hematopoietic stem cell transplantation (HSCT) remains the only disease-modifying therapy if completed in the early stages of cerebral ALD, but it does not affect the course of adrenal insufficiency. It has significant associated morbidity and mortality. A recent gene therapy clinical trial for ALD reported short-term MRI and neurological outcomes comparable to historical patients treated with HSCT without the associated adverse side effects. In addition, over a dozen states have started newborn screening (NBS) for ALD, with the number of states expecting to double in 2020. Genetic testing of NBS-positive neonates has identified novel variants of unknown significance, providing further opportunity for genetic characterization but also uncertainty in the monitoring and therapy of subclinical and/or mild adrenal insufficiency or cerebral involvement. As more individuals with ALD are identified at birth, it remains uncertain if availability of matched donors, transplant (and, potentially, gene therapy) centers, and specialists may affect the timely treatment of these individuals. As these promising gene therapy trials and NBS transform the clinical management and outcomes of ALD, there will be an increasing need for the endocrine management of presymptomatic and subclinical adrenal insufficiency. (Endocrine Reviews 41: 1 – 17, 2020)