Tine, Brian A. Van

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.

Abstract Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell therapy expressing a genetically modified T-cell receptor (TCR) to improve recognition of cancer cells expressing NY-ESO-1 and/or LAGE-1a. Next generation NY-ESO-1 TCR T-cell therapies, including GSK3901961 and GSK3845097, incorporate further genetic modifications to enhance anticancer activity. GSK3901961 co-expresses the CD8α chain to stabilize TCR-human leukocyte A (HLA) class I interactions on CD4+ T cells, enhancing T-cell persistence and increasing helper functions such as Type 1 T-helper anti-tumor responses. GSK3845097 co-expresses a dominant negative transforming growth factor-β (TGF-β) type II receptor to reduce TGF-β pathway activation and maintain T-cell proliferation, cytokine production, and cytotoxicity in the tumor microenvironment. A first-time-in-human master protocol (NCT04526509) will evaluate the safety, tolerability, and recommended Phase 2 dose (RP2D) of these two therapies and possible subsequent ones. Substudy 1 will assess GSK3901961 in patients with advanced non-small cell lung cancer (NSCLC) or synovial sarcoma (SS). Substudy 2 will assess GSK3845097 in patients with advanced SS. Methods: Each substudy includes a dose confirmation stage to assess RP2D and a dose expansion stage. Table 1 lists eligibility criteria. Primary endpoints are safety (adverse events) and tolerability (dose-limiting toxicities). Secondary endpoints include investigator-assessed overall response rate, duration of response, and maximum expansion/persistence and phenotype of infiltrating transduced T cells. Exploratory endpoints include laboratory parameters, overall survival, and anti-GSK3901961 and anti-GSK3845097 titers for the respective substudies. The substudies are open and recruiting. Funding: GSK (209012; NCT04526509) Initial screening criteriaInclusion criteriaExclusion criteriaSubstudies 1 and 2 (SS and NSCLC)≥18 years of agePrior malignancy that is not in complete remission or clinically significant systemic illnessMeasurable disease per RECIST v1.1 criteriaPrevious treatment with genetically modified NY-ESO-1-specific T cells, NY-ESO-1 vaccine, or NY-ESO-1 targeting antibodyExpression of HLA-A*02:01, A*02:05, or A*02:06Prior gene therapy using an integrating vectorExpression of NY-ESO-1/LAGE-1a in tumor archival or fresh biopsyPrevious allogeneic hematopoietic stem cell transplant within the last 5 years or solid organ transplantSubstudies 1 and 2 (SS only)Histologically confirmed advanced (metastatic or unresectable) SS diagnosisCentral nervous system metastasesPresence of t(X;18) translocation(Allowed for NSCLC participants on a case-by-case basis)Received, completed, or intolerant to treatment with anthracycline or anthracycline with ifosfamide for advanced (metastatic or unresectable) disease and has progressedSubstudy 1 (NSCLC only)Histologically or cytologically confirmed Stage IV NSCLCReceived or failed ≥3 lines of systemic therapyReceiving or previously received ≥1 prior line(s) of standard of care treatment including programmed death receptor-1/programmed death ligand-1 checkpoint blockade therapy, and received or be intolerant to doublet taxane and platinum chemotherapyPresence of actionable genetic aberration (activation epithelial growth factor receptor, anaplastic lymphoma kinase/c-ros oncogene 1) per NCCN guidelines Citation Format: Adam J. Schoenfeld, Mehmet Altan, Taofeek K. Owonikoko, Sandra D'Angelo, Brian H. Ladle, Jonathan Noujaim, Kai He, David Liebner, Adrian G. Sacher, John B.A.G. Haanen, Jeffrey Yachnin, Chao Huang, Brian A. Van Tine, Aisha Hasan, Thomas Faitg, Emily Butler, Aiman Shalabi, Steven Attia, Dejka M. Araujo. Master protocol to assess the safety and recommended Phase 2 dose of next generation NY-ESO-1-specific TCR T-cells in HLA-A*02 patients with synovial sarcoma and non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT219.

Abstract Background: Engineered toxin bodies (ETBs), composed of an engineered Shiga-like Toxin A subunit genetically fused to an antibody-binding domain, can force receptor internalization, induce potent cell-kill via enzymatic and permanent inactivation of ribosomes, and may not be subject to resistance mechanisms of other targeted agents. MT-5111, a de-immunized 55 kD ETB targeting HER2 in solid tumors, also binds to an epitope distinct from trastuzumab and pertuzumab, which may permit combination strategies with other HER2 targeting agents. Methods: The primary objective is to determine maximum tolerated dose (MTD) of MT-5111 monotherapy in adult patients (pts) with advanced HER2+ solid tumors. Secondary objectives are PK, efficacy, and immunogenicity. Using a modified 3+3 design, the dose-escalation part of the study includes the following 7 cohorts: 0.5, 1, 2, 3, 4.5, 6.75, and 10 µg/kg. Three dose-expansion cohorts will follow for HER2+ breast cancer, gastro-esophageal cancer, and any other HER2+ tumors. All pts will receive MT-5111 weekly as a 30-min IV infusion in each 21-d treatment (tx) cycle (C) until disease progression (PD), unacceptable toxicity, death, or withdrawn consent (NCT04029922). Results: As of the data cut in December 2020, 16 pts were treated; cancer types included breast (n=6), gastric (n=1), colon (n=1), gallbladder (n=5), and other solid tumors (n=3). Mean age was 64 years (range, 34-78); 37.5% were male. Pts received a median of 4 prior lines of systemic therapies (range, 1-8). No G4 or G5 TEAEs occurred. Six pts had 11 G3 TEAEs; the most common were increased AST and dyspnea (both n=2). Three pts had tx-emergent serious adverse events (abdominal distension [n=1]; dyspnea [n=2]). Tx-related TEAEs occurred in 8 (50%) pts; the most common was fatigue (n=5, 31.3%) and all were ≤ grade 2 in nature, except for one grade 3 event of dyspnea. No cardiac TEAEs, clinically significant changes in cardiac biomarkers (troponin, electrocardiogram, left ventricular ejection fraction), or cases of capillary leak syndrome were observed. Fifteen pts discontinued with PD; 1 pt in cohort 5 (4.5 µg/kg) is on tx with stable disease. To date, no DLTs have been observed and the MTD has not been reached. One pt in cohort 2 (1 µg/kg) had resolution of all hepatic lesions (sub-centimeter lesions pre-tx) at the end of C8; however, the pt came off study due to clinical progression at the end of C10. PK data for the first 5 cohorts matched simulations based on non-human primate studies. Conclusions: MT-5111 was well tolerated with no clinically significant cardiotoxicity. Continued dose escalations are ongoing. Citation Format: Zev A. Wainberg, Monica M. Mita, Minal A. Barve, Erika P. Hamilton, Andrew J. Brenner, Frances Valdes, Daniel Ahn, Joleen Hubbard, Jason Starr, Christine Burnett, Joshua Pelham, Eric T. Williams, Banmeet S. Anand, Thomas Strack, Andrés Machado Sandri, Brian A. Van Tine. Phase 1 study of the novel immunotoxin MT-5111 in patients with HER-2+tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT130.

As leiomyosarcoma patients are challenged by the development of metastatic disease, effective systemic therapies are the cornerstone of outcome. However, the overall activity of the currently available conventional systemic treatments and the prognosis of patients with advanced or metastatic disease are still poor, making the treatment of this patient group challenging. Therefore, in a joint effort together with patient networks and organizations, namely Sarcoma Patients EuroNet (SPAEN), the international network of sarcoma patients organizations, and the National LeioMyoSarcoma Foundation (NLMSF) in the United States, we aim to summarize state-of-the-art treatments for leiomyosarcoma patients in order to identify knowledge gaps and current unmet needs, thereby guiding the community to design innovative clinical trials and basic research and close these research gaps. This position paper arose from a leiomyosarcoma research meeting in October 2020 hosted by the NLMSF and SPAEN.

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.

AbstractBackgroundOutcomes data regarding advanced synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are limited, consisting primarily of retrospective series and post hoc analyses of clinical trials.MethodsIn this multi‐center retrospective study, data were abstracted from the medical records of 350 patients from nine sarcoma centers throughout the United States and combined into a registry. Patients with advanced/unresectable or metastatic SS (n = 249) or MRCL (n = 101) who received first‐line systemic anticancer therapy and had records of tumor imaging were included. Overall survival (OS), time to next treatment, time to distant metastasis, and progression‐free survival (PFS) were evaluated using the Kaplan‐Meier method and Cox regression.ResultsAt start of first‐line systemic anticancer therapy, 92.4% of patients with SS and 91.1% of patients with MRCL had metastatic lesions. However, 74.7% of patients with SS and 72.3% of patients with MRCL had ≥2 lines of systemic therapy. Median OS and median PFS from first‐line therapy for SS was 24.7 months (95% CI, 20.9‐29.4) and 7.5 months, respectively (95% CI, 6.4‐8.4). Median OS and median PFS from start of first‐line therapy for MRCL was 29.9 months (95% CI, 27‐44.6) and 8.9 months (95% CI 4.5‐12.0).ConclusionsTo the best of our knowledge, this is the largest retrospective study of patients with SS and MRCL. It provides an analysis of real‐world clinical outcomes among patients treated at major sarcoma cancer centers and could inform treatment decisions and design of clinical trials. In general, the survival outcomes for this selected population appear more favorable than in published literature.

11003 Background: ES is a rare soft tissue sarcoma that metastasizes in approximately 30% to 50% of cases. More than 90% of ES tumors lack expression of INI1, an important component of epigenetic regulation. Loss of INI1 function allows another epigenetic modifier, EZH2, to become an oncogenic driver in tumor cells. Tazemetostat, a first-in-class, selective, oral inhibitor of EZH2, has demonstrated tumor regression and favorable safety in phase 1/2 trials. Methods: Data from a phase 2 open-label, multicenter trial of pts with locally advanced or metastatic ES are reported. Efficacy was assessed with primary and secondary endpoints including objective response rate (ORR) by RECIST 1.1, disease control rate (DCR; objective confirmed response of any duration or stable disease [SD] lasting ≥32 weeks), duration of response (DOR), progression-free survival (PFS), overall survival (OS); safety and tolerability were also evaluated. Results: As of September 17, 2018, 62 INI1-negative ES pts were enrolled and treated with tazemetostat 800 mg BID. The median number of prior lines of therapy was 1 (range: 0-9). There were 9/62 (15%) confirmed partial responses (PRs) with an ORR of 15% and DCR of 26%. The DOR ranged from 7.1+ weeks to 103.0+ weeks (median: not reached) with a median OS of 82.4 weeks (95% CI: 47.4, not estimable) for all 62 pts. Tazemetostat was generally well tolerated. Treatment-emergent adverse events (TEAEs) were generally mild to moderate with the most commonly reported adverse events (AEs; ≥10% incidence) regardless of attribution being fatigue (24/62; 39%), nausea (22/62; 35%), and cancer pain (20/62; 32%). Any treatment-related TEAEs of grade ≥3 were reported in 10/62 (16%) pts. TEAEs grade ≥3 reported in ≥2 pts included anemia (6%) and decreased weight (3%). There were no drug-related deaths and a low discontinuation rate (1.7%). Conclusions: In the largest prospective clinical trial of ES to date, tazemetostat achieved disease control in 26% of pts with advanced ES who entered this study. Durable clinical response of the drug was documented. Tazemetostat demonstrated favorable safety with few pts with treatment-related AEs grade ≥3. Clinical trial information: NCT02601950.

Purpose. Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas. Combining Hsp90 inhibitors to enhance endoplasmic reticulum stress with mTOR inhibition results in dramatic MPNST shrinkage in a genetically engineered MPNST mouse model. Ganetespib is an injectable potent small molecule inhibitor of Hsp90. Sirolimus is an oral mTOR inhibitor. We sought to determine the safety, tolerability, and recommended dose of ganetespib and sirolimus in patients with refractory sarcomas and assess clinical benefits in patients with unresectable/refractory MPNSTs. Patients and Methods. In this multi-institutional, open-label, phase 1/2 study of ganetespib and sirolimus, patients ≥16 years with histologically confirmed refractory sarcoma (phase 1) or MPNST (phase 2) were eligible. A conventional 3 + 3 dose escalation design was used for phase 1. Pharmacokinetic and pharmacodynamic measures were evaluated. Primary objectives of phase 2 were to determine the clinical benefit rate (CBR) of this combination in MPNSTs. Patient-reported outcomes assessed pain. Results. Twenty patients were enrolled (10 per phase). Toxicities were manageable; most frequent non-DLTs were diarrhea, elevated liver transaminases, and fatigue. The recommended dose of ganetespib was 200 mg/m2 intravenously on days 1, 8, and 15 with sirolimus 4 mg orally once daily with day 1 loading dose of 12 mg. In phase 1, one patient with leiomyosarcoma achieved a sustained partial response. In phase 2, no responses were observed. The median number of cycles treated was 2 (1–4). Patients did not meet the criteria for clinical benefit as defined per protocol. Pain ratings decreased or were stable. Conclusion. Despite promising preclinical rationale and tolerability of the combination therapy, no responses were observed, and the study did not meet parameters for further evaluation in MPNSTs. This trial was registered with (NCT02008877).

Abstract Purpose: We recently reported a 17.5% objective RECIST 1.1 response rate in a phase II study of pembrolizumab in patients with advanced sarcoma (SARC028). The majority of responses occurred in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS). We sought to determine whether we can identify immune features that correlate with clinical outcomes from tumor tissues obtained pre- and on-treatment. Patients and Methods: Pretreatment (n = 78) and 8-week on-treatment (n = 68) tumor biopsies were stained for PD-L1 and multiplex immunofluorescence panels. The density of positive cells was quantified to determine associations with anti–PD-1 response. Results: Patients that responded to pembrolizumab were more likely to have higher densities of activated T cells (CD8+ CD3+ PD-1+) and increased percentage of tumor-associated macrophages (TAM) expressing PD-L1 pre-treatment compared with non-responders. Pre-treatment tumors from responders also exhibited higher densities of effector memory cytotoxic T cells and regulatory T cells compared with non-responders. In addition, higher density of cytotoxic tumor-infiltrating T cells at baseline correlated with a better progression-free survival (PFS). Conclusions: We show that quantitative assessments of CD8+ CD3+ PD-1+ T cells, percentage of TAMs expressing PD-L1, and other T-cell densities correlate with sarcoma response to pembrolizumab and improved PFS. Our findings support that multiple cell types present at the start of treatment may enhance tumor regression following anti–PD-1 therapy in specific advanced sarcomas. Efforts to confirm the activity of pembrolizumab in an expansion cohort of patients with UPS/DDLPS are underway.

PURPOSE:Olaratumab is a human monoclonal immunoglobulin G1 antibody against platelet-derived growth factor receptor-α. We report the nature and frequency of infusion-related reactions (IRRs) with olaratumab in clinical trials and postmarketing reports.METHODS:Data from patients exposed to olaratumab across nine clinical trials were reviewed for IRRs. Blood samples were also analyzed for pre-existing immunoglobulin E anti–galactose-α-1,3-galactose (anti–α-Gal) antibodies.RESULTS:In the clinical trials, IRRs were identified in 70 of 485 patients (14.4%). The most frequent symptoms included flushing, fever or chills, and dyspnea. For 68 of 70 patients (97.1%), the first IRR occurred during the first two cycles of treatment. Grade 3 or worse IRRs were reported in 11 patients (2.3%), all during the first infusion and usually within 15 minutes of the start of the infusion. One IRR-related fatality (0.2%) occurred in a nonpremedicated patient with grade 3 or worse cardiac comorbidities. There was an association between grade 3 or worse IRRs and pre-existing anti–α-Gal antibodies, with a trend toward higher IRR rates in US geographies known to have a higher prevalence of anti–α-Gal antibodies. IRRs in postmarketing reports were consistent in nature and severity with those in the clinical trials.CONCLUSION:Premedication with corticosteroids and antihistamines should occur in all patients before olaratumab infusion, as indicated in labels in the United States and the European Union. Patients receiving olaratumab should be monitored for IRRs in a setting where resuscitation equipment is available for the treatment of IRRs.