Background Off‐label drug prescribing is common in pediatric clinical medicine, though the extent and impact of this practice in pediatric oncology has not yet been characterized. Methods We completed a retrospective single‐institution cohort study evaluating prevalence, characteristics, and clinical outcomes of off‐label prescribing of 108 FDA‐approved targeted anticancer drugs in patients < 30 years old treated for cancer from 2007 to 2017. Dosing strategies were adjusted for body size and compared to FDA‐approved adult dosing regimen. A composite toxicity endpoint was defined as a patient having unplanned clinic visits, emergency department visits, or unplanned hospital admissions that were at least possibly related to the off‐label treatment. Results The overall prevalence of off‐label use of targeted therapies was 9.2% (n = 374 patients). The prevalence increased significantly over the study period (P < .0001). Patients treated off‐label were more likely to have neuro‐oncology diagnoses compared to patients not treated off‐label (46% vs 29%; P < .0001). Of the 108 potential agents, 38 (35%) were used by at least one patient. The median starting dose was below the FDA‐approved normalized dose for 44.4% of agents. Fifteen percent of patients had a complete response while receiving off‐label therapy, 38% experienced toxicity as defined, and 13% discontinued off‐label therapy due to toxicity. Conclusions In this real‐world evaluation of prescribing at a large pediatric cancer center, off‐label prescribing of FDA‐approved targeted therapies was common, increasing in prevalence, encompassed a broad sample of targeted agents, and was tolerable. Clinicians commonly start dosing below the equivalent FDA‐approved dose.

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Advanced hepatocellular carcinoma (HCC) is responsive to immune checkpoint inhibitors, but there are currently no known biomarkers to predict treatment benefit. Blood TMB (bTMB) estimation via circulating tumor DNA (ctDNA) profiling can provide a convenient means to estimate HCC TMB. Here we provide the first landscape of bTMB in advanced HCC using a commercially available next-generation sequencing assay, show that it is approximately three times as high as matched tissue TMB, and show that bTMB correlates with NAFLD cirrhosis etiology and the presence of genomic alterations in HTERT and TP53. These results lay the foundation for subsequent studies evaluating bTMB as an immune therapy predictive biomarker in HCC.

Background and Aims: Immunotherapies have altered the treatment paradigm in HCC. Surrogate and modified endpoints are used to assess early success in clinical studies and guide clinical practice. We sought to determine whether surrogate endpoints and modifications to the conventional criteria for tumor response (RECIST), including modified RECIST (mRECIST) and immune-modified RECIST (imRECIST), are valid measures to predict overall survival (OS) in HCC treated with immunotherapies. Approach and Results: We performed an individual-level post hoc analysis of patients treated with atezolizumab and bevacizumab in the IMbrave150 trial (N = 279) and a cross-sectional analysis of a multicenter real-world patient cohort treated with immunotherapy (N = 328). Landmark analyses showed that objective response rates by RECIST were associated with greater OS including among Child-Pugh A and B patients and among patients treated with immunotherapies in the first- or second-line setting (IMbrave150: HR 0.24, 95% CI, 0.17–0.33; RW: HR 0.25, 95% CI, 0.15–0.43). Objective response rates by mRECIST or imRECIST were not associated with the greater predictive power of OS benefit (mRECIST: HR 0.30, 95% CI, 0.22–0.42; imRECIST: HR 0.36, 95% CI, 0.30–0.51). Progression-free survival determined by RECIST was only moderately correlated with OS, and this association was not improved using mRECIST or imRECIST. Conclusions: Our results clarify the utility of surrogate and modified endpoints in HCC treated with immunotherapies and support the use of RECIST objective response rates as an appropriate signal-finding measure for the evaluation of emerging treatments. Contrary to their intended purpose, mRECIST and imRECIST did not provide meaningful improvements in predicting OS benefits.

Combination anti-PD-(L)1/CTLA-4 blockade is approved in patients with hepatocellular carcinoma (HCC) in the first-line setting or after sorafenib, but whether this treatment has efficacy after prior anti-PD-(L)1 therapy is unknown. We performed a multicenter retrospective review of patients with advanced HCC treated with ipilimumab plus nivolumab after prior anti-PD-(L)1 therapy, excluding patients with prior anti-CTLA-4 treatment. Of the 32 patients who met our inclusion criteria, prior anti-PD-(L)1 regimens included atezolizumab plus bevacizumab (50%, n=16), other anti-VEGF plus anti-PD-(L)1 combinations (31%, n=10), and anti-PD-(L)1 monotherapy (19%, n=6). The median number of prior systemic therapies was two (range 1-8). The objective response rate (ORR) with ipilimumab plus nivolumab by RECIST 1.1 was 22% (1 CR (3%), 6 PR (19%), 8 SD (25%), 16 PD (50%), and 1 NE (3%)), and objective response was associated with improved PFS and OS. Immune related adverse events were reported in 13 patients (41%), with no new safety signals. This study demonstrates that ipilimumab plus nivolumab has efficacy in patients with HCC who have received prior anti-PD-(L)1 therapy, suggesting that failure to respond to prior PD-(L)1 blockade should not preclude treatment with salvage ipilimumab plus nivolumab. Prospective studies are needed to define the optimal sequence of therapies.

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4091 Background: Combination PD-(L)1/CTLA-4 blockade is approved in patients with advanced hepatocellular carcinoma (HCC) in the first line or after treatment with sorafenib, but it is unclear if combination therapy has efficacy after treatment with anti-PD-(L)1 alone or in combination with a multikinase inhibitor. We evaluated responses to ipilimumab plus nivolumab in patients with advanced HCC who previously received anti-PD-(L)1 to assess the efficacy and safety of this regimen. Methods: We performed a multi-center retrospective review of patients 18 years of age or older with a diagnosis of HCC based on histology or imaging who had received at least one dose of anti-PD-(L)1 therapy prior to receiving ipilimumab plus nivolumab as a subsequent line of therapy. All patients had imaging and/or laboratory monitoring to monitor for disease progression. Results: Our cohort contained 32 patients, with a majority being male (88%, n = 28) and a median age of 67 years. All patients were Child Pugh A (66%, n = 21) or B (34%, n = 11) at the start of treatment, with most having an ECOG performance status of 0-1 (84%, n = 27). The median number of prior lines of therapy was 2 (range 1-8). Prior anti-PD-(L)1 containing regimens included atezolizumab plus bevacizumab (50%, n = 16), other VEGF plus anti-PD-(L)1 combination (31%, n = 10), and anti-PD-(L)1 monotherapy (19%, n = 6). The objective response rate (ORR) was 22% (1 CR, (3%), 6 PR (19%)), with remaining responses including 8 SD (25%), 16 PD (50%), and 1 NE (3%). Among patients who had an objective response to ipilimumab plus nivolumab, none had an objective response to prior anti-PD-(L)1 treatments. Response rates were similar across major clinical (obese vs. non-obese) and etiological (viral vs. non-viral) subsets of HCC. Response to ipilimumab plus nivolumab was associated with improved PFS and OS: median PFS for PD/SD/NE 2.4 months (95% CI: 2.1-NR) vs. PR/CR not reached (NR) (95% CI: 7.5-NR), p = 0.004, and OS for PD/SD/NE 5.9 months (95% CI: 3.1-NR) vs. PR/CR NR (95% CI: NR-NR), p = 0.02. Immune related adverse events (irAEs) were reported in 13 patients (41%), and 6 patients experienced grade 3-4 irAEs (19%). One patient in our cohort experienced a fatal irAE (autoimmune hepatitis), and 5 patients discontinued therapy due to irAEs. Conclusions: This study demonstrates that ipilimumab plus nivolumab has clinical activity in patients with advanced HCC who previously received anti-PD-(L)1 therapy with an acceptable safety profile, supporting this regimen as second line immune checkpoint inhibitor therapy in advanced HCC. Further studies are required to determine the optimal sequence of therapies in advanced HCC.