Background

AL102 is a potent, orally available, selective gamma secretase inhibitor (GSI) under investigation as an antineoplastic agent. GSIs have antitumor activity against DT, including AL101 (2 confirmed PRs >3.5 years and >1 year; 1 stable disease for 1 year). There remains an unmet need for effective systemic therapy in DT, associated with durable tolerability, tumor regression, and symptom improvement.

Methods

RINGSIDE is a Phase 2/3 randomized study in patients with progressing DT. Part A (Phase 2) is an open-label part with safety as the primary endpoint. Patients are randomized to three dosing regimens: 1.2 mg QD, 2 mg intermittent BIW (2 days on 5 days off), or 4 mg intermittent BIW. Part B is a Phase 3 double-blind, placebo-controlled study with PFS as primary endpoint. The dose for part B will be determined based on the totality of data collected in part A. We report descriptive statistics for Part A. A Food Effect/PK (FE) substudy was also performed.

Results

As of Feb 22, 2022, 31 patients enrolled in Part A and 30 were still on study (the first 18 patients for ≥4 weeks). Mean age was 40 years, and 74% were women. The table shows treatment-emergent adverse events (TEAEs) by dose. There were no deaths or life-threatening TEAEs. Four patients had Grade 3 TEAEs (2 study-drug related: anemia, diarrhea; 2 unrelated: vomiting, pleural effusion). Four patients had dose reductions and one discontinued AL102 due to TEAEs. One serious TEAE (pleural effusion) was unrelated to AL102 per investigator. The most common AEs were diarrhea, rash, nausea, fatigue and stomatitis. No clinically significant ECG findings were noted. The FE substudy revealed that food had no significant effect on PKs. Table: 1488MO

Summary of Treatment-emergent Adverse Events (TEAEs) by Patient

Conclusions

Safety findings to date show no indication for discontinuing any of the three dosing cohorts. Efficacy, patient reported outcome and additional safety data will be presented at the conference.

Clinical trial identification

NCT04871282.

Editorial acknowledgement

Professional medical writing support provided by Laurie LaRusso, MS, ELS (Walpole, MA, USA) funded by Ayala Pharmaceuticals, Inc.

Legal entity responsible for the study

Ayala Pharmaceuticals.

Funding

Ayala Pharmaceuticals.

Disclosure

M.M. Gounder: Financial Interests, Personal, Other, Honoraria: Flatiron Health, PER, Medscape, Guidepoint Global, touchIME, Med Learning Group, More Health; Financial Interests, Personal, Advisory Role: Daiichi Sankyo, Karyopharm Therapeutics, Epizyme, Bayer, Springworks Therapeutics, Boehringer Ingelheim, Ayala Pharmaceuticals, Rain Therapeutics; Financial Interests, Personal, Advisory Role, Ayala Pharmaceuticals: TYME; Financial Interests, Personal, Speaker’s Bureau: Amgen, Karyopharm Therapeutics, Boehringer Ingelheim; Financial Interests, Personal, Other, Patents, Royalties, Other Intellectual Property: UpToDate; Financial Interests, Institutional, Other, Patents, Royalties, Other Intellectual Property: GODDESS PRO Desmoid Tumor; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Epizyme; Financial Interests, Personal, Other, Other Relationship: Desmoid Tumor Research Foundation; Non-Financial Interests, Personal, Other: Foundation Medicine, Athenex. R.L. Jones: Financial Interests, Personal, Expert Testimony, I worked as a consultant: Adaptimmune, Bayer, Boehringer Ingelheim, Blueprint, Clinigen, Eisai, Epizyme, Daiichi, Deciphera, Immunedesign, Lilly, Springworks, Tracon, Upto Date, PharmaMar; Financial Interests, Personal, Advisory Board, I worked as a consultant: Athenex; Financial Interests, Institutional, Research Grant, Research grant for a clinical trial: MSD. R. Chugh: Financial Interests, Institutional, Funding, Research Funding: Ayala Pharmaceuticals, SpringWorks; Financial Interests, Personal, Advisory Board: Ipsen, Deciphera, Jazz Pharmaceuticals. M. Agulnik: Financial Interests, Personal, Advisory Board: Lilly, Adaptimmune, Regeneron, AstraZeneca; Financial Interests, Personal, Invited Speaker: Bristol-Myers Squibb, Bayer, Deciphera; Financial Interests, Institutional, Research Grant: Exelixis. A. Singh: Financial Interests, Personal, Other, Consultant: Daiichi Sankyo, Deciphera; Financial Interests, Institutional, Other, Support for Clinical Trial: Deciphera, RAIN Therapeutics, Ayala Pharmaceuticals, Tracon; Financial Interests, Personal, Member of the Board of Directors: Certis Oncology Solutions; Financial Interests, Personal, Stocks/Shares: Certis Oncology Solutions. B.A. Van Tine: Financial Interests, Personal, Invited Speaker, Educational Speaker: Targeted Oncology; Financial Interests, Personal, Advisory Board, Also, Travel paid to conference to present abstract: Adaptimmune Limited; Financial Interests, Personal, Invited Speaker, Also attended an Ad Board meeting. Travel was paid to present abstract at conference: GSK; Financial Interests, Personal, Other, Consulting. Also attended and Ad Board meeting. Travel was paid to attend an Ad board meeting.: Epizyme; Financial Interests, Personal, Other, Consulting- ADRx working on a cancer project and they are requesting my expertise.: ADRx; Financial Interests, Personal, Advisory Board, tenosynovial giant cell tumors (TGCT): Ayala Pharmaceuticals; Financial Interests, Personal, Other, Consulting/Advisor: Cytokinetics Inc; Financial Interests, Personal, Other, Consulting: Bayer; Financial Interests, Personal, Other, 60 minute interview regarding Synovial Sarcoma.: Bionest Partners; Financial Interests, Personal, Other, OncLive Virtual Workshop: Intellisphere LLC; Financial Interests, Personal, Advisory Board, Attended Advisory Board Meeting: Apexigen Inc; Financial Interests, Personal, Advisory Board, Attended an Advisory Board Meeting: Daiichi Sankyo, Deciphera Pharmaceuticals, Inc; Financial Interests, Personal, Advisory Board, Attended an advisory board meeting: Novartis; Financial Interests, Personal, Advisory Board: lilly, PTC Therapeutics; Financial Interests, Personal, Invited Speaker, Sigma-2 Receptor Ligands and Therapeutic uses therefor (006766), Modular Platform for Targeted Therapeutic Delivery (006755), Sigma-2 Receptor Ligand Drug Conjugates as Antitumor Compounds, Methods of synthesis and Uses Thereof (014229): Accuronix Therapeutics; Financial Interests, Institutional, Research Grant: Pfizer, Merck, Tracon Pharm, GSK; Non-Financial Interests, Invited Speaker: Polaris. E. Choy: Financial Interests, Institutional, Invited Speaker, Participated in RINGSIDE study as local PI. Support for the study was given to the institution: Ayala Pharma; Non-Financial Interests, Member: Connective Tissue Oncology Society, ASCO, SARC. R. Ratan: Financial Interests, Personal, Advisory Board: Epizyme; Financial Interests, Personal, Invited Speaker: Epizyme; Financial Interests, Institutional, Invited Speaker: Ayala Pharmaceuticals, Springworks Therapeutics, C4 Therapeutics. J.B. Kaplan: Financial Interests, Personal, Full or part-time Employment: Ayala Pharmaceuticals. J. Yovell: Financial Interests, Personal, Full or part-time Employment: Ayala Pharmaceuticals; Financial Interests, Personal, Stocks/Shares: Ayala Pharmaceuticals. G. Gordon: Financial Interests, Personal, Full or part-time Employment: Ayala Pharmaceuticals. B. Kasper: Financial Interests, Personal, Advisory Board: Bayer, Blueprint, Boehringer Ingelheim, Springworks, GSK, PharmaMar, Ayala; Financial Interests, Institutional, Invited Speaker: PharmaMar, Springworks, Ayala; Non-Financial Interests, , Leadership Role, Chair of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG): European Organisation for Research and Treatment of Cancer (EORTC). All other authors have declared no conflicts of interest.

Background

Currently approved agents in metastatic GIST focus on targeted suppression of KIT or PDGFRA oncogenic activation. However, their clinical benefit after imatinib (IM) progression is still modest, suggesting the co-operation of KIT/PDGFRA-independent mechanisms in GIST cell survival. Selinexor is an oral, selective inhibitor of XPO1-mediated nuclear export, and preclinical studies evidenced antitumoral activity in GIST as single agent and in combination with IM in both IM-sensitive and IM-resistant models.

Methods

IM-resistant, advanced GIST patients (pts) were treated in two sequential cohorts: Cohort A studied IM 400 mg daily plus weekly selinexor at dose levels (DL) 1 (60 mg), DL2 (80 mg) and DL3 (100 mg) using a standard 3+3 dosing schema to determine the recommended phase II dose (RP2D) of the combination. Cohort B studied selinexor 60 mg twice weekly. Investigator-assessed response was evaluated every 8 weeks using RECIST 1.1.

Results

As of Feb 10, 2022, 30 pts were enrolled, 12 in Cohort A and 18 in Cohort B. Median age 57 (range 36-77), male 70%, mean prior therapies 4 (range 1-7). One dose limiting toxicity (DLT) occurred at DL3 (G3 nausea) in Cohort A. Other non-DLT G3/4 toxicities were fatigue (2/12 pts), anemia, neutropenia and vomiting (1 pt each). Common G1/2 toxicities (>4 pts) were nausea, vomiting and neutropenia. Grade 3/4 toxicities in Cohort B were fatigue (2/18 pts), neutropenia, thrombocytopenia, and GGT elevation (1 pt each). Common G1/2 toxicities (> 6 pts) were nausea, anemia, thrombocytopenia and fatigue. No unexpected toxicities were observed. All pts were evaluable for response. Clinical benefit rate (CBR = CR, PR, SD) ≥ 16 weeks was 42% (95% CI 0.181-0.685) in Cohort A and 28% (95% CI 0.213-0.354) in Cohort B. Two partial responses were observed in Cohort A (17%) vs. none in Cohort B. Median progression free survival was 3.3 months (95% CI 1.7-4.3) in Cohort A and 2.9 months (95% CI 1.8-5.6) in Cohort B.

Conclusions

Both schedules using selinexor as single agent and in combination with IM show manageable toxicity and clinical activity. At RP2D, selinexor + IM show encouraging antitumor activity in IM-resistant GIST (NCT04138381).

Clinical trial identification

NCT04138381.

Legal entity responsible for the study

Spanish Sarcoma Research Group (GEIS).

Funding

Karyopharm.

Disclosure

C. Serrano: Financial Interests, Personal, Advisory Board: Deciphera Pharmaceuticals, Blueprint Medicines, Immunicum AB; Financial Interests, Institutional, Invited Speaker: Blueprint Medicines, Bayer AG; Financial Interests, Personal, Invited Speaker: PharmaMar; Financial Interests, Institutional, Research Grant: Deciphera Pharmaceuticals, Pfizer, Bayer AG; Financial Interests, Personal and Institutional, Invited Speaker: AROG Pharmaceuticals, Karyopharm; Non-Financial Interests, , Invited Speaker: Spanish Group for Sarcoma Research (GEIS), Spanish Society of Medical Oncology (SEOM); Other, Travel Grant: PharmaMar, Pfizer, Bayer AG. C.M. Valverde Morales: Financial Interests, Personal, Advisory Board: PharmaMar, Bayer, GSK, Mundipharma, Lilly, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Invited Speaker: Adaptimmune, Karyopharm, Lilly; Non-Financial Interests, Invited Speaker, President 2018-ongoing: GEIS- Spanish Sarcoma Group for Research. J. Cruz Jurado: Financial Interests, Personal, Advisory Board: PharmaMar, Roche, Lilly, Pfizer, Novartis, Gilead, AstraZeneca, Daiichii, Seagen, GSK, Bayer; Financial Interests, Personal, Invited Speaker: PharmaMar, Roche, Lilly, Pfizer, Novartis, Eisai, Gilead, Astra Zeneca, Daiichi, Seagen, Esteve, Roche. J. Martinez Trufero: Financial Interests, Personal, Advisory Board, Advisory Board meeting: PharmaMar, Eisai; Financial Interests, Personal, Invited Speaker: Roche, Eisai, Merck, Medicamenta; Financial Interests, Institutional, Invited Speaker, Clinical trial: RAIN Therapeutics, Blueprint, Lilly, Kariopharm Therapeutics, Syneos Health; Non-Financial Interests, Invited Speaker, Spanish Group of Sarcoma Research: GEIS Group; Non-Financial Interests, Invited Speaker, Spanish Group of Head and Neck cancer Research: TTCC Group. M. Giuppi: Financial Interests, Personal, Full or part-time Employment: PharmaMar. B. Suarez: Financial Interests, Personal, Full or part-time Employment: Merk. All other authors have declared no conflicts of interest.

Background

It is well established that CSF1 action at the CSF1R mediates the formation and expansion of TGCT – a benign but locally aggressive neoplasm. Indeed, oral or intravenous administration of CSF1R inhibitors may yield tumor regression over weeks to months of repeat dosing. With these systemic exposures, on-target side effects such as liver enzyme elevation and facial edema often present and may complicate the treatment paradigm. We hypothesized that administration of a potent, inhibitory anti-CSF1R antibody, AMB-05X, into the affected synovium could yield sustained, high local concentrations with low systemic exposures and thus enable tumor regression with minimal pharmacologic side effects.

Methods

8 TGCT patients with confirmed TGCT of the knee were enrolled in a Phase 2 study wherein AMB-05X was administered intra-articular (IA) at a dose of 150 mg every 2 weeks over a 12-week treatment period. The synovial and serum pharmacokinetics of AMB-05X were monitored. CSF1 levels in the joint and serum were also quantitated as a pharmacodynamic marker since inhibitor action at the CSF1R interferes with native and tumor-derived CSF1 elimination.

Results

The clearance of antibodies administered intra-articular is not well characterized and, in fact, has often been regarded as short-lived. The unique formulation of AMB-05X administered at the dose and regimen employed in this proof-of-concept study yielded high local concentrations that were sustained beyond expectations such that accumulation over the dosing period was extensive (>5-fold). Importantly, systemic exposures were consistently approximately 1/5 that of the synovial concentrations. Moreover, pharmacodynamic elevation of CSF1 levels was approximately 20-fold greater in synovial fluid vs serum. CSF1 levels in both compartments achieved a plateau, indicative of full receptor engagement, early in the treatment period.

Conclusions

The AMB-05X PK and PD results support expansion of the clinical development of AMB-05X in TGCT with IA treatment at a comfortable interval of once-monthly or less.

Clinical trial identification

AMB-051-01.

Legal entity responsible for the study

AmMax Bio.

Funding

AmMax Bio.

Disclosure

M. Huang: Financial Interests, Personal, Stocks/Shares: AmMax Bio. L. Alani: Financial Interests, Personal, Full or part-time Employment: AmMax Bio. T. Huang: Financial Interests, Personal, Member: AmMax Bio. L. Hsu: Financial Interests, Personal, Member of the Board of Directors: AmMax Bio. K. Johnson: Financial Interests, Personal, Officer: AmMax Bio. All other authors have declared no conflicts of interest.

Background

Chordoma is a rare bone tumor with an unmet therapeutic need. In chordoma cell lines and patient biopsies, the p16 (cyclin-dependent kinase inhibitor 2a, encoded by CDKN2A) tumor suppressor is consistently inactivated, resulting in aberrant cyclin D-CDK4/6-RB pathway activity, which can be efficiently inhibited by the CDK4/6 inhibitor palbociclib (PMID 26183925).

Methods

Patients (pts) ≥18 years (yrs) with locally advanced or metastatic chordoma, at least one measurable tumor lesion per RECIST 1.1, ECOG PS 0–2, adequate organ function, loss of p16 (by immunohistochemistry [IHC]) or CDKN2A (by genomic analysis) and presence of CDK4/6 and RB1 (by IHC or RNA-seq) and not amenable to curative surgery or radiotherapy, are eligible. Palbociclib 125 mg q.d. is given in a 21-days-on/7-days-off schedule. Based on a Simon optimal 2-stage design, disease control rate (DCR) is the primary endpoint. Response is defined as complete response (CR), partial response (PR), or stable disease (SD) per RECIST 1.1 after 6 cycles. For sample size calculation, a poor or good response were assumed to be 10% and 25%, respectively (α, 5 %; β, 20%), resulting in a 1^st stage of 18 pts and, if ≥3 pts respond, study continuation to a total of 43 pts.

Results

Between 12/2017 and 04/2022, 26 pts (female, n=6; median age, 59 yrs [range, 31–84]) were enrolled. Primary chordoma sites were sacrococcygeal (n=14), skull base (n=4), and other parts of the spine (n=8). Palbociclib was well tolerated. Adverse events were mostly mild (CTC-AE °1–2) cytopenias; one CTC-AE °5 was recorded (neutropenic sepsis). The interim analysis revealed 6/18 pts (33%) with SD and none with PR or CR. Recruitment was continued in 11/2021 as initially planed. Median progression-free survival was 5.75 months (95% confidence interval [CI], 3.55–not reached), and the median number of applied cycles was 6 (range, 2–42). Overall survival after 2 yrs was 74% (95% CI, 56–97%). Correlative biomarker studies, including WGS/WES and RNA-seq, are ongoing.

Conclusions

This is the 1^st proof-of-concept trial in chordomas using a genomic marker to predict palbociclib activity. Therapy with palbociclib resulted in a DCR of 33% with manageable toxicity. Although no PR or CR were yet achieved, single-agent palbociclib showed anti-tumor activity.

Clinical trial identification

NCT03110744.

Legal entity responsible for the study

The authors.

Funding

Pfizer, National Center for Tumor Diseases Heidelberg.

Disclosure

R.W. Hamacher: Other, Personal, Other: Lilly, Novartis; Financial Interests, Personal, Other: Lilly; Financial Interests, Personal, Invited Speaker: PharmaMar. S. Bauer: Financial Interests, Personal, Advisory Board, Recurring Advisory Role since 2017 in the context of clinical trial development: Deciphera; Financial Interests, Personal, Advisory Board, Advisory role in the context of clinical trial development: Blueprint Medicines; Financial Interests, Personal, Advisory Board, Advisory role for clinical trial development: Lilly; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board, Clinical trial developemnt: Daiichi-Sankyo; Financial Interests, Personal, Advisory Board, 2017: Plexxikon; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker, CME-related presentations: PharmaMar; Financial Interests, Personal, Advisory Board, Advisory role drug development: Roche; Financial Interests, Personal, Advisory Board, Advisory role drug development,: GSK; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Invited Speaker, PI for Enliven trial: Daiichii-Sankyo; Financial Interests, Institutional, Invited Speaker, Local PI for Avelumab Phase I trial: Roche; Financial Interests, Institutional, Invited Speaker, PI for Intrigue, Invictus and DCC-2618-Phase I trial; Lead PI for INtrigue trial, Scientific Committee for Invictus and Intrigue: Deciphera; Financial Interests, Institutional, Invited Speaker, PI for JGDJ trial Phase I Olaratumab plus Doxo/Ifos: Lilly; Financial Interests, Institutional, Invited Speaker, PI for Phase I trials cCGM097, HDM201, STI571-2103: Novartis; Financial Interests, Institutional, Invited Speaker, Local PI und national PI for Voyager and Navigator trial (BLU-285 / Avapritinib): Blueprint Medicines; Financial Interests, Institutional, Invited Speaker, PI (national) for Relatlimab (BMS-CA224-020): BMS; Financial Interests, Institutional, Invited Speaker, PI for IIT with ponatinib in GIST; research Grant (institutional for IIT): Incyte; Non-Financial Interests, , Advisory Role, Off-label committee: BfArm; Non-Financial Interests, , Invited Speaker, Founding Member of German Sarcoma Foundation: Deutsche Sarkomstiftung (German SarcomaFoundation). S. Fröhling: Financial Interests, Personal, Advisory Board: Bayer, Illumina, Roche; Financial Interests, Personal, Invited Speaker: Amgen, Eli Lilly, Illuminna, PharmaMar, Roche. R.F. Schlenk: Financial Interests, Institutional, Invited Speaker, Webinar: Astellas; Financial Interests, Personal, Advisory Board, Presentation: Pfizer; Financial Interests, Personal, Other, DMC: BergenBiO; Financial Interests, Personal, Advisory Board, Ad Board: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker, Speaker: Abbvie; Financial Interests, Institutional, Advisory Board: Jazz; Financial Interests, Institutional, Funding, GnG Study: Pfizer; Financial Interests, Institutional, Funding, Q-HAM StudyQ-SOC Study: Daiichi Sankyo; Financial Interests, Institutional, Funding, TOP-ART Study: AstraZeneca, PharmaMar; Financial Interests, Institutional, Funding, PMO-1604 Study: Boehringer Ingelheim; Financial Interests, Institutional, Funding, PMO-1601 study: Pfizer. All other authors have declared no conflicts of interest.

Background

Recently, we performed a meta-analysis for leiomyosarcoma (Kantidakis et al., EJC 2021) based on a literature review for advanced or metastatic soft-tissue sarcoma (STS) to update long-standing reference values for STS trials (van Glabbeke et al., EJC 2002). Our work is now extended for LPS and SS patients.

Methods

Study endpoints were progression-free survival rates (PFSRs) at 3 and 6 months. Whenever information could not be retrieved from publications, first authors and/or sponsors were contacted. Data collection has been completed. Trial-specific estimates were pooled per treatment line (first-line or pre-treated) with random effects meta-analyses. The choice of the therapeutic benefit to target in future trials was guided by the ESMO Magnitude of Clinical Benefit Scale (ESMO–MCBS).

Results

Information was acquired for 1030 LPS patients (25 trials; 7 first-line, 17 pre-treated, 1 both) and 348 SS patients (13 trials; 3 first-line, 10 pre-treated). For LPS, the overall pooled PFSRs at 3 and 6 months were 69% (95%-CI 60-77%) / 56% (95%-CI 45-67%) for first-line and 49% (95%-CI 40-57%) / 28% (95%-CI 22-34%) for >1 lines, respectively. For SS, first-line PFSRs were 74% (95%-CI 58-86%) / 56% (95%-CI 31-78%) at 3 and 6 months and pre-treated rates were 45% (95%-CI 34-57%) / 25% (95%-CI 16-36%). ESMO–MCBS recommends a hazard ratio of at least 0.65 for PFS. The table summarizes what this translates to for parameters P₀ (null hypothesis) and P₁ (alternative hypothesis) of a study under the assumption of an exponential PFS curve. Table: 1491MO

Conclusions

New benchmarks are proposed for advanced/metastatic LPS or SS to design future histology-specific phase II trials. Minimum values to target in first-line at 3 and 6 months are 79% and 69% for LPS, 82% and 69% for SS. For pre-treated patients, recommended PFSRs at 3- and 6-months suggesting drug activity are 63% and 44% for LPS, 60% and 41% for SS.

Legal entity responsible for the study

EORTC Soft Tissue and Bone Sarcoma Group.

Funding

EORTC.

Disclosure

All authors have declared no conflicts of interest.

Background

To allow for infinite proliferation, tumor cells need to activate mechanisms for telomere maintenance, such as alternative lengthening of telomeres (ALT). ALT is linked to the loss of ATRX or DAXX. Current evidence supports that sarcomas predominantly use ALT for telomere elongation, at a prevalence rate of 20-60%. However, in our dataset, only 12.3% of sarcomas harbored ATRX/DAXX alterations. Thus, we sought to investigate genomic determinants of high telomeric content beyond the canonical ATRX/DAXX alterations.

Methods

Our sarcoma dataset consisted of 14277 samples across 80 sarcoma types, sequenced as a part of routine clinical care on the FoundationOne® Heme platform. Using TelomereHunter, a tool for the estimation of telomeric content from sequencing data, we determined the telomeric content of sarcoma samples in our cohort and investigated the enrichment of genetic alterations associated with high telomeric content.

Results

Telomeric content varied by sarcoma disease type. We observed a median telomeric content of 622.3 TRPM (telomeric reads per million reads) across all sarcoma types and a range of 787.4. In agreement with previous studies, telomeric content was significantly higher in ATRX-altered sarcomas. We further identified that alterations in 3 genes, RAD51B, GID4, and POT1, were enriched in sarcomas with high telomeric content, specifically within uterus leiomyosarcoma for RAD51B, soft tissue sarcoma for GID4, and soft tissue angiosarcoma samples for POT1. Overall, 84% of RAD51B alterations were deletions, mostly spanning the ATPase domain. In ATRX-mutated uterus leiomyosarcoma, RAD51B alterations exerted an additive effect on telomeric elongation. All detected GID4 alterations were amplifications and we identified the minimal amplified region associated with high telomeric content to be chr17p11.2. All POT1 alterations were short variant mutations. Furthermore, our results demonstrated that RAD51B and POT1 alterations were mutually exclusive with ATRX and DAXX alterations, suggestive of a redundancy between alterations in these genes.

Conclusions

Our results suggest a role played by RAD51B, GID4, and POT1 in telomere elongation in sarcomas and open research opportunities for agents aimed at targeting this pathway.

Legal entity responsible for the study

Foundation Medicine, Inc.

Funding

Foundation Medicine, Inc.

Disclosure

R. Sharaf: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche. D.X. Jin: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche. G.M. Frampton: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche. L.A. Albacker: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche. D. Thomas: Financial Interests, Personal, Officer, CEO: Omico; Financial Interests, Personal and Institutional, Other, Commercial and academic partnership: Roche, Pfizer, Eisai, AstraZeneca, Amgen, Foundation Medicine, Inc, Microba, Merck, GMDx, Biotessellate, InterVenn; Financial Interests, Personal and Institutional, Other, Commercial and academic partnership partnership: Abbvie, Eli Lilly, BeiGene, Bayer, Illumina; Financial Interests, Personal, Advisory Role: Health Futures Fund of Australian unity, Maine Cancer Genome Initiative. M. Montesion: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche. All other authors have declared no conflicts of interest.

Background

The interactions with immune system and influence on the tumor microenvironment (TME) of L + E remain elusive. The LEADER study (NCT03526679) investigated the efficacy of L + E in advanced LMS and LPS and immune-related biomarkers were examined.

Methods

Pre- and post-treatment (2 cycles) samples were analyzed using the nCounter Platform by Nanostring PanCancer Immune Profiling Panel including 760 genes associated with immune cells and regulations. Analyses were based on gene expression levels and immune cells, which was estimated by transcriptomic-based methods (MCP-Counter or Danaher et al. 2017).

Results

32 samples (11 pre-post paired) had adequate quality for analysis; there were 4 and 15 pts, with PR and SD as best response; 13 pts had PFS ≥ 6 months. Based on pretreatment samples, higher endothelial cells were significantly associated with PR (p = 0.027). Bundled pre (n = 19) vs post (n=13)-treatment samples analysis showed a significant increase in dendritic cells after L + E (p = 0.037). In paired samples, patients with PFS longer than 6 months had significantly increased dendritic cells (p = 0.031), Th1 cells (p = 0.031), macrophages (p = 0.016), cytotoxic cells (p = 0.047), and exhausted CD8 (p = 0.047). Results of differential gene expression of paired samples also suggested a similar pattern of transformation into an active immune TME after L +E: mRNA levels of TNFSR14 (p = 0.03) and CCL19 (p = 0.03), both are molecules associated with tertiary lymphoid structure, were significantly increased.

Conclusions

L+E may have the ability to adjust the TME. A pre-treatment immune-suppressive TME was associated with worse clinical efficacy, but pts with a transformed immune-active post-treatment TME after L + E were associated with better outcome.

Clinical trial identification

NCT03526679.

Legal entity responsible for the study

T.W-W. Chen.

Funding

National Taiwan University Hospital Clinical Trial Center, Eisai.

Disclosure

T.W-W. Chen: Financial Interests, Personal, Speaker’s Bureau: Eisai; Financial Interests, Personal and Institutional, Research Grant: Eisai. All other authors have declared no conflicts of interest.

Background

Recurrences are common after resection of DDLPS and UPS. We conducted a neoICB trial in resectable UPS and DDLPS pts and assessed peripheral immune biomarkers.

Methods

DDLPS (n=17) and UPS (n=10) patients (pts) were treated with neoICB; UPS pts received concurrent radiation. We performed RNA sequencing of peripheral blood mononuclear cells (PBMCs) and tumor specimens collected at baseline, on treatment and at surgery and single sample gene set enrichment analysis (ssGSEA) to quantify 30 immune cell types/signatures. The peripheral TCR repertoire (richness, clonality, density) was assessed by TCR-sequencing of DNA extracted from PBMCs. Correlation between peripheral and tumor immune scores were calculated by Spearman correlation test. Longitudinal comparisons between variables were done using ANOVA tests. Progression-free survival (PFS) was defined from time of neoICB start to progression on neoICB or relapse after surgery. Survival curves were compared using log-rank tests.

Results

Median follow-up was 30 months from start of ICB treatment. Median PFS was 20 months (DDLPS: 18 months; UPS: Not Reached), with 15 progression events (12 DDLPS, 3 UPS). None of the peripheral ssGSEA scores correlated with their tumor counterparts at any time point. There was no significant change in any peripheral ssGSEA score nor TCR richness or clonality upon ICB treatment. Peripheral TCR density decreased with ICB treatment (p<0.001; DDLPS: p=0.0037; UPS: p=0.0027). Pts with higher peripheral TCR densities (above median) on treatment had improved PFS (p=0.049). Higher peripheral TCR richness (above median) at baseline showed a trend towards better PFS (p=0.1) and was also seen on treatment (p=0.08) but not at surgery (p=0.81).

Conclusions

In UPS and DDLPS patients undergoing neoICB, we were unable to identify a correlation between peripheral and tumor immune cells and signatures. However, peripheral TCR richness and density at baseline and during treatment may identify pts with better prognosis.

Clinical trial identification

NCT03307616.

Legal entity responsible for the study

The authors.

Funding

BMS.

Disclosure

A. Reuben: Financial Interests, Personal, Advisory Board: Adaptive Biotechnologies. All other authors have declared no conflicts of interest.