Agulnik, Mark

Gastrointestinal stromal tumors (GIST) are the most common type of soft tissue sarcoma that occur throughout the gastrointestinal tract. Most of these tumors are caused by oncogenic activating mutations in the KIT or PDGFRA genes. The NCCN Guidelines for GIST provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with these tumors. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised systemic therapy options for unresectable, progressive, or metastatic GIST based on mutational status, and updated recommendations for the management of GIST that develop resistance to specific tyrosine kinase inhibitors.

Abstract Background Regorafenib is one of several FDA‐approved cancer therapies targeting multiple tyrosine kinases. However, there are few subtype‐specific data regarding kinase inhibitor activity in sarcomas. We report results of a single arm, phase II trial of regorafenib in advanced Ewing family sarcomas. Methods Patients with metastatic Ewing family sarcomas (age ≥ 18, ECOG 0–2, good organ function) who had received at least one line of therapy and experienced progression within 6 months of registration were eligible. Prior kinase inhibitors were not allowed. The initial dose of regorafenib was 160 mg oral days 1–21 of a 28‐day cycle. The primary endpoint was estimating progression‐free rate (PFR) at 8 weeks employing RECIST 1.1. Results Thirty patients (median age, 32 years; 33% women [10 patients]; bone primary, 40%; extraskeletal primary, 60%) enrolled at 14 sites. The most common grade 3 or higher toxicities were hypophosphatemia (5 grade 3, 1 grade 4), hypertension (2 grade 3), elevated ALT (2 grade 3). Sixteen patients required dose reductions, most often for hypophosphatemia ( n = 7 reductions in 6 patients); two stopped regorafenib for toxicity. There was one death unrelated to treatment in the 30‐day post‐study period. Median progression‐free survival (PFS) was 14.8 weeks (95% CI 7.3–15.9); PFR at 8 weeks by Kaplan–Meier analysis was 63% (95% CI 46–81%). The RECIST 1.1 response rate was 10%. Median OS was 53 weeks (95% CI 37–106 weeks). Conclusions Regorafenib has modest activity in the Ewing family sarcomas. Toxicity was similar to that seen in approval studies.

Soft tissue sarcomas (STS) are rare malignancies of mesenchymal cell origin that display a heterogenous mix of clinical and pathologic characteristics. STS can develop from fat, muscle, nerves, blood vessels, and other connective tissues. The evaluation and treatment of patients with STS requires a multidisciplinary team with demonstrated expertise in the management of these tumors. The complete NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Soft Tissue Sarcoma provide recommendations for the diagnosis, evaluation, and treatment of extremity/superficial trunk/head and neck STS, as well as retroperitoneal/intra-abdominal STS, desmoid tumors, and rhabdomyosarcoma. This portion of the NCCN Guidelines discusses general principles for the diagnosis and treatment of retroperitoneal/intra-abdominal STS, outlines treatment recommendations, and reviews the evidence to support the guidelines recommendations.

AbstractBackgroundSarcomas are rare diagnoses but are seen with relative frequency in adolescents and young adults and thus can present in pregnancy. We sought to study the administration of anthracyclines and/or ifosfamide in pregnancy‐associated sarcomas.Patients and MethodsWe conducted a multi‐institutional retrospective study, identifying sarcoma patients who received anthracyclines and/or ifosfamide during pregnancy. Chart review identified variables related to demographics, cancer diagnosis, therapies, and outcome of the patient and fetus. Wilcoxon rank‐sum test compared two independent samples.ResultsWe identified 13 patients at seven institutions with sarcoma who received anthracyclines and/or ifosfamide during pregnancy, including four bone sarcomas and nine soft tissue sarcomas diagnosed at a mean gestational age of 16.7 ± 5.9 weeks. Only nine patients had live births (9/13, 69.2%), with mean gestational age of 30.8 ± 3.8 weeks at delivery. The four patients with pregnancy loss all received both doxorubicin and ifosfamide, with chemotherapy initiated at 15.5 weeks as compared with 21.3 weeks for those patients with live births (p = 0.016).ConclusionIn this multi‐institutional study of sarcoma chemotherapy regimens administered during pregnancy, we found a high rate of fetal demise that was seen only in patients receiving both doxorubicin and ifosfamide and statistically more likely with chemotherapy initiation earlier in the second trimester. While limited by a small sample size, our study represents the largest study of sarcoma patients that received anthracyclines and/or ifosfamide in pregnancy thus far reported and supports development of an international registry to study concerns raised by our study.

PURPOSE CMB305 is a heterologous prime-boost vaccination regimen created to prime NY-ESO-1–specific CD8 T-cell populations and then activate the immune response with a potent TLR-4 agonist. This open-label randomized phase II trial was designed to investigate the efficacy and safety of adding the CMB305 regimen to atezolizumab (anti–programmed death ligand-1 therapy) in comparison with atezolizumab alone in patients with synovial sarcoma or myxoid liposarcoma. PATIENTS AND METHODS Patients with locally advanced, relapsed, or metastatic synovial sarcoma or myxoid liposarcoma (any grade) were randomly assigned to receive CMB305 with atezolizumab (experimental arm) or atezolizumab alone (control arm). The primary end points were progression-free survival (PFS) and overall survival (OS) analyzed using the Kaplan-Meier method. Safety and immune responses were assessed. RESULTS A total of 89 patients were enrolled; 55.1% had received ≥ 2 prior lines of chemotherapy. Median PFS was 2.6 months and 1.6 months in the combination and control arms, respectively (hazard ratio, 0.9; 95% CI, 0.6 to 1.3). Median OS was 18 months in both treatment arms. Patients treated with combination therapy had a significantly higher rate of treatment-induced NY-ESO-1–specific T cells ( P = .01) and NY-ESO-1–specific antibody responses ( P < .0001). In a post hoc analysis of all dosed patients, OS was longer (36 months) in the subset who developed anti-NY-ESO-1 T-cell immune response (hazard ratio, 0.3; P = .02). CONCLUSION Although the combination of CMB305 and atezolizumab did not result in significant increases in PFS or OS compared with atezolizumab alone, some patients demonstrated evidence of an anti-NY-ESO-1 immune response and appeared to fare better by imaging than those without such an immune response. Combining prime-boost vaccines such as CMB305 with anti–programmed death ligand-1 therapies merits further evaluation in other clinical contexts.

11505 Background: AL3818 (Catequentinib, Anlotinib) is a novel, orally administered, small molecule tyrosine kinase inhibitor. The primary objective of this Phase 3 study is to evaluate the efficacy of AL3818 monotherapy in patients (pts) with synovial sarcoma (SS) comparing with dacarbazine in randomization setting. Methods: Patients with a diagnosis of synovial sarcoma requiring second line or further line treatment were eligible for enrollment. The regimen was a 21-day cycle with oral AL3818 administered on 14 days on and 7 days off. This phase 3 trial is randomized in 2:1 ratio of AL3818 comparing to dacarbazine with option of crossover after PD of dacarbazine treatment. Progression free survival (PFS) with Log Rank test is the primary endpoint and this trial for SS is currently completed enrolled in US and Italy. Results: Total 79 pts initiated treatment and are evaluable, 52 received AL3818 as treatment arm (T), and 27 received dacarbazine (D) as control arm (C). Arms T/C median ages were 40.5/42.0 years (range: 18-70+) and 20/16 (38.5%/59.3%) were male. Overall, PFS was 2.89 months (95% CI: 2.73 – 6.87) for AL3818 and 1.64 (95% CI: 1.45 – 2.70) for D. The PFS of study met the primary endpoint with a p-value of 0.0015 and a HR of 0.449 (95% CI: 0.270– 0.744). At the month 4, 6, and 12, the percentages of progression free patients for AL3818 were 48.1%, 42.3% and 26.9%; and for D were 14.85%, 11.1% and 3.7%. For grade 3 treatment-related adverse events, 12(23.1%) of pts experienced for AL3818 and 7(25.9%) of pts experienced for D. The most common AL3818 related grade 3 AEs were diarrhea (5.8%) and hypertension (3.8%). Conclusions: This phase III trial demonstrates improved disease control and superior progression free survival for AL3818 vs dacarbazine in advanced SS. In addition, the study further confirms the acceptable benefit-risk profile of AL3818 from the prior randomized Phase 2b soft tissue sarcoma study (NCT02449343). AL3818 is a meaningful treatment option for pts with advanced SS. Clinical trial information: NCT 03016819 Clinical trial information: NCT03016819.

10522 Background: The limited therapeutic options and dismal prognosis for patients (pts) with angiosarcomas (AS) provide a strong rationale for the evaluation of new therapies. Preclinical studies in AS tumor models have shown antitumor effects of antiangiogenic agents. We conducted a phase II study to determine the antitumor effect of bevacizumab in AS. Methods: The study was a two-stage design in which patients with newly diagnosed or relapsed/refractory AS and epithelioid hemangioendotheliomas were treated with bevacizumab 15 mg/kg IV every 3 weeks. Treatment was continued until progression or unacceptable toxicity. Response was assessed by RECIST criteria. Results: To date, of 29 pts enrolled, 28 received treatment. Baseline data on 29 pts are: M:F= 12:17 and median age 62 (range 18–94). Three pts are not evaluable (1 too early, 2 full treatment not given). Among 26 pts evaluable for response so far: 3 have PR (range 3–16 cycles), 13 have SD (3–32 cycles) and 10 have PD. ORR 3/26 (12%). After 141 cycles of therapy, only 1 grade 4 adverse event occurred (thrombocytopenia) and 5 patients experienced a grade 3 adverse event (anemia, pleural effusion, congestive heart failure, pain, headache, and nausea). Conclusions: Bevacizumab monotherapy for AS resulted in a response rate of 12% and tumor stabilization achieved by 62% of pts. Further studies with bevacizumab in combination with chemotherapy should be explored in this disease. No significant financial relationships to disclose.

Although checkpoint inhibitors have been approved in multiple cancers, they are still under investigation in soft tissue sarcoma (STS). We conducted a retrospective review to report the safety, efficacy, and prognostic factors related to checkpoint inhibitors in STS. A sequential cohort of metastatic STS patients from four institutions treated with checkpoint inhibitors was assembled. Logistic and Cox regression models were applied to determine the effect of patient characteristics, prior treatment, and baseline factors on achieving the best overall response of complete response (CR), partial response (PR), or stable disease (SD) as determined by the treating physician. Eighty-eight patients with two median prior therapies received checkpoint inhibitors. Treatments included pembrolizumab in 47, nivolumab in 6, ipilimumab in 1, combination ipilimumab/nivolumab in 27, and other combination immunotherapies in 7 patients. Immunotherapy was discontinued in 54 patients—72.2% for progression, 16.7% for toxicity, and 11.1% for other reasons. Median progression-free survival (PFS) was 4.1 months and median overall survival was 19.1 months. One patient with undifferentiated pleomorphic sarcoma (UPS) achieved a CR, while 20 patients had a PR, including 7 UPS, 9 leiomyosarcoma (LMS), and 1 each with alveolar soft part sarcoma, fibroblastic sarcoma, sclerosing epithelioid fibrosarcoma, and myxofibrosarcoma. Forty-five percent (9 of 20) of LMS patients achieved a PR. Twenty-eight patients had SD. Our results confirm the activity and safety of anti-PD-1 therapy in metastatic STS. A notable response rate was observed in UPS and LMS subtypes. This study expands the knowledge base beyond what is currently available from clinical trials involving checkpoint inhibitors in metastatic STS.

11564 Background: Epithelioid sarcoma (ES) is a rare, aggressive soft tissue sarcoma characterized by loss of inhibitor of integrase 1 (INI1), allowing enhancer of zeste homologue 2 (EZH2) to repress cell differentiation and promote tumorigenesis. Tazemetostat (TAZ) is a selective inhibitor of EZH2 approved by the FDA for treatment of patients (pts) aged ≥16 years with metastatic or locally advanced ES ineligible for complete resection. Methods: This open-label, multicenter, multi-cohort phase 2 study (NCT02601950) evaluated safety and efficacy of TAZ in pts with INI1-negative tumors. ES pts were enrolled in Cohorts 5 and 6; pts in Cohort 6 underwent mandatory pre-dose (at screening) and post-dose biopsies (at Day 1 of cycle 2). Herein, we report the interim efficacy and safety data from Cohort 6. Results: As of July 31 2019, 44 pts were enrolled into Cohort 6 and treated with TAZ 800 mg BID. The objective response rate (ORR) was 11.4%; 4 pts (9.1%) had a partial response and 1 pt (2.3%) had a complete response (Table). Another 17 pts (38.6%) had stable disease (SD). 18 pts had progressive disease; 13 of these pts remained on study beyond progression. Progression-free survival (PFS) and overall survival (OS) at 56 weeks were 19.4% and 59.4%, respectively. In a pooled posthoc analysis of 106 ES pts from Cohorts 5 (n = 62), and 6, ORR was 13.2%. Grade 3–4 adverse events (AEs) were reported in 16 pts (36.4%), most commonly anemia (6.8%; n = 3) and tumor pain (6.8%; n = 3). 3 pts (6.8%) experienced grade 3–4 treatment-related AEs. One pt discontinued study drug and there were no treatment-emergent dose reductions or treatment-related deaths. These safety data from Cohort 6 are consistent with previously reported data from Cohort 5. 19 paired biopsies were included for translational endpoint analyses. Preliminary RNA seq and pathway analyses are currently ongoing and updated data, including additional biomarker data will be presented. Conclusions: Consistent with previously reported data from the completed Cohort 5, TAZ demonstrated clinically meaningful, durable, single agent activity in ES pts. Efficacy data from Cohort 6 continue to mature with 8 patients still on treatment. TAZ was well tolerated with a low incidence of treatment related AEs. Clinical trial information: NCT02601950 . [Table: see text]

11562 Background: Soft tissue sarcoma (STS) is a heterogeneous malignancy of connective tissue. Although mTOR is implicated in STS pathogenesis, clinical activity from mTORC1 inhibitors is modest. M, a potent selective mTORC1/mTORC2 inhibitor, was more effective in STS preclinical models than inhibitors of mTORC1, IGF1R and mTORC1+IGF1R, owing to more complete suppression of PI3K/AKT/mTOR and abrogation of feedback AKT activation. P, an oral multikinase inhibitor, is approved for non-adipocytic STS and often used after progression (PD) on chemotherapy. In phase 1, the RP2D of M was 30 mg weekly. A091304 was to evaluate M as a novel targeted therapy for STS. Methods: In A091304, pts were randomized 1:1 to M 30 mg weekly or P 800 mg daily. Eligibility required Eastern Cooperative Oncology Group PS ≤ 1, progression on ≥ 1 prior chemotherapy and specific STS subtypes (cohort 1: UPS; 2: LMS; 3: MPNST, SS). Crossover to M was allowed after PD on P. 1° endpoint was progression-free survival (PFS). Assuming median PFS of P was 4.6 months (mo), 98 pts yielded 80% power to detect a hazard ratio of 0.66 favoring M [1-sided test, alpha = 0.15] and including 1 planned futility analysis. 2° endpoints were response rate, clinical benefit rate (CBR) at 4 mo and safety. After 4 of the first 12 pts randomized to P experienced ≥ grade (gr) 3 toxicity, the study was amended to begin at P 400 mg, allowing titration to 800 per investigator discretion. Results: After protocol amendment, 114 pt underwent randomization (M: 56, P: 58), and 111 initiated treatment. Median PFS was 2 mo for M and 2.1 mo for P (HR = 1.47; 1-sided 85% upper confidence boundary = 1.85), with 2 partial responses in each arm. CBR was 5.4% for M and 13.8% for P. Median OS was 10.7 mo for M and 13.9 mo for P (HR = 1.41; 95% CI 0.80-2.49). 26/43 pt with PD on P crossed over to M. Median PFS after crossover was 1.8 mo (95% CI 1.5-3.5). Gr 3 drug-related adverse events (AEs) occurred in 36% on M and 41% on P; gr 4 toxicity was rare. AEs were consistent with known effects of M and P. Conclusions: P at 400 mg daily (allowing escalation to 800 mg per investigator discretion) demonstrated a shorter PFS as compared prior randomized studies with P. Despite this, M failed to demonstrate superior clinical activity as compared to P at the interim analysis. Further work will examine activity within histology-specific cohorts and evaluate available tissue samples for evidence of pharmacodynamic activity. Support: U10CA180821, U10CA180882, U10CA180888, UG1CA233324 (SWOG); https://acknowledgments.alliancefound.org . Clinical trial information: NCT02601209 .