Reed, Damon R.

60 Background: The activity of the anti-PD-1 antibody P in pts with advanced STS was evaluated in a prospective multicenter Phase II study conducted by the Sarcoma Alliance for Research through Collaboration (SARC). SARC028 enrolled 40 patients with advanced soft tissue sarcoma. Pembro had an ORR of 19% and PFS rate at 12 weeks of 55%, suggesting clinical activity. We investigated biomarkers of response to P. Methods: The primary endpoint was Objective Response Rate (ORR) by RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival, and biomarkers of response in blood and tumor. Pre- and on-treatment biopsies were required and obtained from over 90% and 72% of pts respectively. Serum was obtained from all pts at baseline and at multiple time points on therapy (pre-, week 8, and every 12 weeks). Sera were examined for candidate circulating biomarkers by Affymetrix Luminex platform array, including PD-L2. To determine whether there is a statistically significant difference between different conditions, we used Mann-Whitney and two-tailed t tests. Log-rank p-values in Kaplan-Meier survival analyses were calculated using the "survival" R package. Results: Forty pts with STS were enrolled into 4 cohorts (10 each) based on histological subtype including undifferentiated pleomorphic sarcoma (UPS), dedifferentiated liposarcoma (LPS), synovial sarcoma (SS), and leiomyosarcoma (LMS). 4 pts with UPS, 2 pts with LPS, and one pt with SS achieved a response. Six of seven responses were durable at the time of this analysis. Circulating levels at baseline or after therapy of PD-1, PD-L1, 4-1BB, IDO, BTLA, CTLA-4, LAG-3, and TIM-3 did not correlate with outcome. However, pre-treatment and week 8 PD-L2 levels correlated best with clinical outcome: high PD-L2 levels were associated with better PFS (p=0.019) in STS. Conclusions: P has clinical activity in specific histologic subtypes of STS, namely UPS and LPS. Pre-treatment circulating PD-L2 levels correlated with progression-free survival and is a novel and promising predictor of improved clinical outcome of PD-1 therapy in STS.

PURPOSE SARC024 is a phase II clinical trial of the multikinase inhibitor regorafenib in specific sarcoma subtypes, including advanced osteosarcoma. We hypothesized that regorafenib would improve progression-free survival (PFS) in patients with sarcoma and report the results of the osteosarcoma cohort. PATIENTS AND METHODS This trial enrolled patients with progressive metastatic osteosarcoma with measurable disease by RECIST who had received at least one prior line of therapy. Patients were randomly assigned at a ratio of one to one to regorafenib or placebo. Crossover was allowed at time of disease progression. PFS was the primary end point of the study, which was powered to detect a difference of at least 3 months in median PFS. RESULTS Forty-two patients from 12 centers were enrolled between September 2014 and May 2018. Median age was 37 years (range, 18 to 76 years). Patients had received an average of 2.3 prior therapy regimens. Ten patients receiving placebo crossed over to active drug at time of progression. Study enrollment was stopped early, after a data safety monitoring committee review. Median PFS was significantly improved with regorafenib versus placebo: 3.6 months (95% CI, 2.0 to 7.6 months) versus 1.7 months (95% CI, 1.2 to 1.8 months), respectively (hazard ratio, 0.42; 95% CI, 0.21 to 0.85; P = .017). In the context of the crossover design, there was no statistically significant difference in overall survival. Fourteen (64%) of 22 patients initially randomly assigned to regorafenib experienced grade 3 to 4 events attributed to treatment, including one grade 4 colonic perforation. CONCLUSION The study met its primary end point, demonstrating activity of regorafenib in patients with progressive metastatic osteosarcoma. No new safety signals were observed. Regorafenib should be considered a treatment option for patients with relapsed metastatic osteosarcoma.

11008 Background: SARC028 is the first multicenter Phase II study of P monotherapy in patients (pts) with STS and BS. Designed to detect clinical efficacy signals in multiple histologies, the study collected blood & tissue samples on all pts. We report extended clinical follow-up and in-depth biomarker correlates of response. Methods: The primary endpoint was objective response rate (ORR) by RECIST 1.1. Secondary endpoints were safety, 12 wk progression-free survival (PFS), and overall survival (OS). The STS arm had 10 pts in each of 4 cohorts: undifferentiated pleomorphic sarcoma (UPS), dedifferentiated liposarcoma (DDLPS), synovial sarcoma (SS) and leiomyosarcoma (LMS). The BS arm included 40 pts with osteosarcoma (OS), Ewing sarcoma (ES) or dedifferentiated chondrosarcoma (CS). Pre- and on-P biopsies were required as well as blood at multiple time points. Tumor was assessed for PD-L1 expression (clone 22C3) and immune infiltrates by multi-color IHC (Vectra). Ongoing analyses include circulating cytokine and checkpoint levels and exome (DNA), transcriptome (RNA), and T-cell receptor (TCR) sequencing. Results: 86 pts were enrolled, 80 were evaluable for response. For STS, median follow-up was 14.5 months. The ORR in the overall STS cohort was 18% and the 12-wk PFS 55% [95% CI, 42-71]). Clinical activity was variable by histologic subtype with 40% ORR in UPS (1 CR and 3PR out of 10 evaluable pts), 2 PR/10 were seen in DDLPS, 1PR/10 in SS and 0/10 in LMS. For BS, median follow-up was 12.3 months (ORR 5%; 12-wk PFS 28% [95% CI, 14-41]), with 1PR/22 OS, 1PR/5 CS and 0/13 ES. 70 pre-P tissues were analyzed (11 excluded for insufficiency), with PD-L1+ in 3/70 (4%); all 3 were UPS. Of the 2 evaluable pts, 1 had CR and 1 PR. 2 OS were PD-L1+ on multi-color IHC, 1 had PR. All PD-L1+ samples had CD8+ T-cell infiltration. There were no post-P PD-L1+ samples. Conclusions: P has clinical activity in UPS and LPS, and expansion cohorts in those subtypes are planned. Pre-treatment PD-L1 expression was infrequent, but correlated with T-cell infiltration and response in UPS & OS. Ongoing biomarker analyses that may guide combination strategies are ongoing and will be presented at the meeting. Clinical trial information: NCT02301039.

Purpose TH-302, a prodrug of the cytotoxic alkylating agent bromo-isophosphoramide mustard, is preferentially activated in hypoxic conditions. This phase II study investigated TH-302 in combination with doxorubicin, followed by single-agent TH-302 maintenance therapy in patients with first-line advanced soft tissue sarcoma (STS) to assess progression-free survival (PFS), response rate, overall survival, safety, and tolerability. Patients and Methods In this open-label phase II study, TH-302 300 mg/m 2 was administered intravenously on days 1 and 8 with doxorubicin 75 mg/m 2 on day 1 of each 21-day cycle. After six cycles, patients with stable and/or responding disease could receive maintenance monotherapy with TH-302. Results Ninety-one patients initiated TH-302 plus doxorubicin induction treatment. The PFS rate at 6 months (primary efficacy measure) was 58% (95% CI, 46% to 68%). Median PFS was 6.5 months (95% CI, 5.8 to 7.7 months); median overall survival was 21.5 months (95% CI, 16.0 to 26.2 months). Best tumor responses were complete response (n = 2 [2%]) and partial response (n = 30 [34%]). During TH-302 maintenance (n = 48), five patients improved from stable disease to partial response, and one patient improved from partial to complete response. The most common adverse events during induction were fatigue, nausea, and skin and/or mucosal toxicities as well as anemia, thrombocytopenia, and neutropenia. These were less severe and less frequent during maintenance. There was no evidence of TH-302–related hepatic, renal, or cardiac toxicity. Conclusion PFS, overall survival, and tumor response compared favorably with historical outcomes achieved with other first-line chemotherapies for advanced STS. A phase III study of TH-302 is ongoing (NCT01440088).

The objective of this study was to determine the impact of lupus nephritis disease activity on maternal and foetal outcomes in pregnant patients with systemic lupus erythematosus (SLE). Medical records of all pregnant patients with SLE treated at our institution between 1976 and 2007 were reviewed. All patients met American College of Rheumatology classification criteria for SLE. Demographic data, history of lupus nephritis, nephritis disease activity and maternal and foetal outcomes of pregnancy were abstracted. Active lupus nephritis was defined as the presence of proteinuria >0.5 g/day and/or active urinary sediment with or without an elevation in serum creatinine (Cr). Quiescent lupus nephritis was confirmed in the presence of proteinuria <0.5 mg/day and inactive urinary sediment. We identified 58 patients with 90 pregnancies. Compared with pregnancies in SLE patients without renal involvement ( n = 47), pregnancies in patients with active lupus nephritis ( n = 23) were associated with a higher incidence of maternal complications (57% vs 11%, P < 0.001), whereas those with quiescent lupus nephritis ( n = 20) were not (35% vs 11%, P = 0.10). Women with active lupus nephritis were more likely to deliver preterm than women without lupus nephritis, median of 34 weeks vs 40 gestational weeks, respectively ( P = 0.002) and were more likely to suffer foetal loss (35% vs 9%, P = 0.031). Active, but not quiescent, lupus nephritis during pregnancy is associated with a higher incidence of maternal and foetal complications compared with pregnancies in SLE patients without renal involvement.