Maki, Robert G.

9514 Background: We sought to compare the response of metastatic STS to G vs. G+D in a phase III study using a novel Bayesian adaptive randomization strategy. Methods: Entry criteria included non-GIST STS diagnosis, age > 10, measurable disease, ≤ 3 prior regimens, normal organ function, and Grade (Gr) ≤ 1 neuropathy. Pts were stratified by histology (leiomyosarcoma [LMS] vs. other), and history of prior pelvic radiation (PPR) or not, yielding 4 diagnostic subgroups. Therapy was G 1200 mg/m2 (over 120 min, d1+d8) or G 900 mg/m2 (over 90 min, d1+d8) and docetaxel (100 mg/m2 d8) q21d; all pts received (peg)-filgrastim starting d9. 25% dose reductions were employed for PPR or toxicity. The primary endpoint was tumor response (CR, PR, or 24+ weeks stable), using a double-blind Bayesian adaptive randomization procedure to incrementally assign more pts to the superior treatment arm, while accounting for possible treatment-subgroup interactions. Although this study is not based on a 1:1 randomized phase III design, enrolling ∼120 pts would show a difference between a response rate (RR) of 10% for G and 30% with G+D with a power of 0.8 and two-sided alpha of 0.05. Results: 122 pts were randomized; 119 pts had evaluable outcomes. Median number of prior regimens was 1; median number of cycles was 4 (range 1–26). 49 pts were adaptively randomized to G and 73 to G+D, indicating superiority of G+D. Of 119 evaluable pts, 27% (G) and 32% (G+D) showed response as defined. The odds of pts with LMS receiving G+D instead of G increased from 1:1 at the start of the study to ∼6:1 at its completion. RR was 10% (G) vs. 16% (G+D) (p=0.15, Fisher exact test). Consistent with the RR outcomes, progression free survival (PFS) was 6.2 m (G+D, K-M 95%CI 3.6–8.8) vs. 2.6 m (G, 95%CI 2.0–3.2). Overall survival (OS) was 18.0 m (G+D, K-M 95%CI 11.7–24.1) vs. 11.2 m (G, 95%CI 6.8–15.5). Pts receiving G+D had a higher rate of discontinuation due to toxicity than those receiving G (p<0.01, log rank). Conclusions: We observed substantial clinical activity in this pre-treated STS population. G+D yields superior PFS and OS to G, but at the price of increased toxicity. Adaptive randomization is an effective method that substantively reduces the number of pts receiving inferior therapy. [Table: see text]

11015 Background: Immune checkpoint inhibitors have demonstrated activity in multiple tumor types but their activity in soft tissue sarcomas remains limited. In the multicenter phase II study, SARC028, the anti-PD-1 antibody, P demonstrated objective responses that were largely restricted to UPS and LPS subtypes. We now report outcomes from 2 expansion cohorts of SARC 028 in advanced UPS and LPS. Methods: To further confirm the clinical activity of P in UPS and LPS, we enrolled an additional 30 pts in each of 2 expansion cohorts for a total of 40 UPS and 40 LPS pts. Primary endpoint was investigator-assessed response by RECIST v1.1. Secondary endpoints were safety, progression-free survival (PFS), 12-week PFS rate, and overall survival (OS). An ORR of 25% was considered clinically meaningful and < 10% was considered to show lack of efficacy. P was to be considered a success if 8 or more of 40 enrolled patients had a PR or better (1-sided α = 0.042, 82% power). Pts age ≥18 with advanced, refractory UPS or LPS received 200 mg of P IV every 3 weeks until progression or unacceptable toxicity. Results: Preliminary results from the first 10 pts in each of the UPS and LPS cohorts have been reported. We now present summary data after enrolling an additional 30 pts in each cohort. The ORR in the UPS cohort was 23% (9/40), with an additional 5/30 PRs observed in the expansion cohort (total 2 CRs, 7 PRs). In the LPS cohort, the ORR was 10% (4/39 evaluable pts), with an additional 2/30 PRs observed (total 4 PRs). Median PFS for the UPS group was 3 months [95% CI: 2, 5] and 2 months [95% CI: 2, 4] for the LPS group. 12-week PFS rate was 50% in UPS [95% CI: 35, 65] and 44% in LPS [95% CI: 28, 60]. The UPS group had a median OS of 12 months [95% CI: 7, 34] and 13 months [95% CI: 8, NR] for the LPS group. P was well tolerated with no unexpected toxicities. Conclusions: The UPS cohort achieved its primary endpoint, however the activity of P in UPS deserves further evaluation in a randomized study. The activity of P was not confirmed in the LPS cohort. Ongoing biomarker analyses may direct better patient selection and guide future combination strategies. Clinical trial information: NCT02301039.

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.

Background Ontuxizumab, a humanized monoclonal antibody, targets endosialin (tumor endothelial marker 1 [TEM‐1] or CD248), which is expressed on sarcoma cells and is believed to be involved in tumor angiogenesis. This is the first trial to evaluate ontuxizumab in patients with sarcoma. Methods Part 1 was an open‐label, dose‐finding, safety lead‐in: 4, 6, or 8 mg/kg with gemcitabine and docetaxel (G/D; 900 mg/m 2 gemcitabine on days 1 and 8 and 75 mg/m 2 docetaxel on day 8). In part 2, patients were randomized in a double‐blind fashion in 2:1 ratio to ontuxizumab (8 mg/kg) or a placebo with G/D. Randomization was stratified by 4 histological cohorts. Results In part 2 with 209 patients, no significant difference in progression‐free survival between ontuxizumab plus G/D (4.3 months; 95% confidence interval [CI], 2.7‐6.3 months) and the placebo plus G/D (5.6 months; 95% CI, 2.6‐8.3 months) was observed ( P = .67; hazard ratio [HR], 1.07; 95% CI, 0.77‐1.49). Similarly, there was no significant difference in median overall survival between the 2 groups: 18.3 months for the ontuxizumab plus G/D group (95% CI, 16.2‐21.1 months) and 21.1 months for the placebo plus G/D group (95% CI, 14.2 months to not reached; P = .32; HR, 1.23; 95% CI, 0.82‐1.82). No significant differences between the treatment groups occurred for any efficacy parameter by sarcoma cohort. The combination of ontuxizumab plus G/D was generally well tolerated. Conclusions Ontuxizumab plus G/D showed no enhanced activity over chemotherapy alone in soft‐tissue sarcomas, whereas the safety profile of the combination was consistent with G/D alone.

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.