Okuno, Scott H.

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.

11005 Background: Pazopanib is approved for soft tissue sarcoma pts after failure of other therapy, but there are few subtype-specific data regarding kinase inhibitor activity. We report on a single arm, phase II trial of REGO in advanced EWS. Methods: EWS pts (age > 18, ECOG 0-2, good organ function) who had at least 1 line of therapy and had PD within 6 mo were eligible. Prior oral kinase inhibitors were not allowed. Initial REGO dose was 160 mg PO QD x21 q28d. Dose reductions were employed for toxicity and AEs. The primary endpoint was PFS at 8 weeks (PFS8w) employing RECIST 1.1. Sample size of 30 allowed determination of the difference between PFS8w of 50% vs 25% with alpha = 0.05 and power of 91%. Results: 30 pts (median age 32, range 19-65; M/F = 20/10; ECOG 0/1/2 = 16/13/1; bone, 12; soft tissue, 18; median prior treatments 5, range 1-10) enrolled at 14 US sites (09/2014-03/2016). Most common grade (G3) toxicities were hypophosphatemia (6), hypertension (2), high ALT (2) and 1 each: fatigue, abd pain, diarrhea, hypokalemia, oral mucositis, neutropenia and rash; no G4 toxicities were noted. 13 pts required ≥1 dose reduction, most commonly hypophosphatemia (n = 7); 2 stopped REGO for toxicity. There was 1 death in the 30 day post study period, not REGO related. Median dose at study end: 140 mg (3.5 tabs, range 80-160 mg) 3 wks on/1wk off. 18/30 pts were without PD at 8 wks. Median PFS: 3.6 mo (95%CI 2.8-3.8 mo). PFS8w by KM was 73% (95%CI 57-89%). Best responses: PR/SD/PD/not evaluable of 3/18/7/2, for RECIST RR 10%. Two pts with PR had EWSR1 translocation by FISH; a third had CIC-DUX4. Median duration of response: 5.5 mo (95%CI 2.9-8.0). Median OS is not reached. Conclusions: The substudy met its primary endpoint. REGO toxicity was similar to that seen previously. Enrollment continues in LPS and OGS cohorts, and is being expanded to further study variant EWS without EWSR1-FLI1 fusion. Study of the existing tissue may elucidate which EWS patients may benefit from REGO. Clinical trial information: NCT02048371.

e17529 Background: The immune system plays a major role in anti-tumor surveillance in healthy individuals. Immunosuppression after solid organ transplant prevents graft rejection, but leads to increased incidence of various malignancies including head and neck squamous cell carcinoma (HNSCC). Outcomes of patients (pts) with post-transplant HNSCC are unknown. Methods: After Institutional Review Board approval, we retrospectively identified pts who developed HNSCC after solid organ transplant between 1995 and 2010. Adults with pathology-proven HNSCC and good follow up were included. Cutaneous cancers were excluded. Median overall survival (mOS) and progression free survival (mPFS) were analyzed using the Kaplan–Meier method. The prognostic effect of variables was studied with Cox proportional hazards models. Results: 33 pts met study inclusion criteria. The median time to HNSCC after transplant was 5.9 years. The primary site was the oral cavity in 15 pts, the oropharynx in 10, the larynx in 3, the hypopharynx in 2, the parotid in 2 and unknown in 1 pt. 58% of pts presented with locally advanced disease, 39% with localized disease and one pt with metastatic disease. 87% underwent upfront surgical resection. Of those, 66% received adjuvant therapy (38% radiation alone and 28% chemoradiation). 6% of pts had definitive chemoradiation. After a median follow up of 10.5 years, the 5-year OS rate was 45% and 37% for localized and locally advanced disease respectively. 75% of pts with oropharyngeal tumors were HPV-positive and they had better outcomes (5-year OS rate of 67%). The mPFS for the cohort was 22.8 months (95% CI; 11.6-50.1) with a median time to relapse of 15.2 months. The pattern of relapse was local in 69% of pts, distant in 25% and local plus distant in 6%. In a multivariate analysis, age > 60 years was a negative predictor of survival (HR 2.7; 95% CI, 1.1 to 6.5; P = 0.03). Conclusions: This retrospective study evaluated the clinical course and outcomes of pts with non-cutaneous HNSCC after solid organ transplant. Pts had inferior survival compared to historical controls. older pts had poor prognosis. The risk of local and distant recurrence was high. HPV-positive oropharyngeal tumors continue to have better outcomes in this population.

6048 Background: The role of Human Papilloma Virus (HPV) infection in non-oropharyngeal squamous cell carcinoma (non-OPSCC) of the head and neck is unknown. Current available studies have yielded conflicting results due to limited number of patients. We present a large analysis from the National Cancer Database (NCDB) evaluating HPV-positive non-OPSCC. Methods: Using the NCDB registry, we included adults diagnosed with non-OPSCC from 2004-2012 with available HPV status. A cohort of patients with OPSCC was analyzed for HPV prevalence comparison. Survival analysis was performed using Kaplan-Meier method and stratified using HPV-status. The prognostic effect of variables was studied using Cox proportional hazards models. The JMP software was used for statistical analysis. Results: A total of 8726 non-OPSCC patients were identified and primary sites included the oral cavity (50%), larynx (41%) and hypopharynx (9%). 11% of non-OPSCC patients had evidence of infection with high-risk HPV strains compared to 61% of OPSCC patients. HPV-positive non-OPSCC patients presented at slightly younger age, had more advanced stage and higher tumor grade compared to HPV-negative patients (P < 0.01). HPV-positive non-OPSCC patients had better survival than HPV-negative patients (HR 0.82, 95% CI 0.72-0.93, P < 0.01) and this was most pronounced in patients with locally advanced disease (5-year survival 50% versus 40%, HR 0.69, 95% CI 0.6-0.8, P < 0.01). A univariate and multivariate analysis were performed adjusting for age, sex, race, stage, primary site, Charlson/Deyo comorbidity score, financial income, tumor grade, surgery, radiation and chemotherapy administration. Smoking history was unavailable. HPV positivity was an independent predictor of better survival in non-OPSCC in multivariate analysis (HR 0.69, 95% CI 0.59-0.8, P < 0.01). Conclusions: HPV infection is seen in a subset of patients with non-OPSCC head and neck cancer and these present with more advanced tumors. The survival of patients with HPV-positive non-OPSCC is significantly better than HPV-negative tumors. Routine HPV testing and enrollment in treatment de-intensification clinical trials similar to OPSCC might be appropriate for this patient population.

Background: Despite the plethora of chemotherapeutic remedies for advanced soft-tissue sarcomas, little evidence has developed to indicate that these efforts have been curative. No controlled comparison has yet proven that patients receiving multidrug regimens survive longer than those receiving doxorubicin alone. Methods: The authors review current systemic treatments and then discuss some investigational efforts now in progress. Also, they seek to demonstrate how the therapies currently available can be integrated with surgery and radiation therapy to accomplish more than might be anticipated from chemotherapy alone. Results: While working to develop better systemic therapies for advanced soft-tissue sarcomas, the integrated use of our best chemotherapy regimens in combination with selected surgical and radiotherapy efforts may provide patients with the best available therapy. Some recent observations involving the use of molgramostim plus chemotherapy have been intriguing. Conclusions: Progress in the systemic treatment of advanced soft-tissue sarcomas may be gradual, but it is real. Our daily challenge is to be certain that we offer each patient the best available multimodality treatment applicable to his or her clinical situation. Molgramostim should be made available for further study with chemotherapy in controlled clinical trials.