Richard Riedel

Overview:

Novel therapies for soft tissue and bone sarcomas

Positions:

Associate Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 2000

Thomas Jefferson University

Resident in Medicine, Medicine

Duke University

Fellow in Hematology-Oncology, Medicine

Duke University

Fellow in Hematology-Oncology, Medicine

Duke University

Grants:

An International, Multicenter, Open-label, Randomized, Phase 3 Study of BLU-285 vs Regorafenib in Patients with Locally Advanced Unresectable or Metastatic Gastrointestinal Stromal Tumor (GIST)

Administered By
Duke Cancer Institute
Awarded By
Blueprint Medicines Corporation
Role
Principal Investigator
Start Date
End Date

Dissecting Mechanisms of Metastasis Through Comparative Systems Genetics

Administered By
Radiation Oncology
Awarded By
National Institutes of Health
Role
Investigator
Start Date
End Date

A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Nirogacestat Versus Placebo in Adult Patients With Progressing Desmoid Tumors/Aggressive Fibromatosis (DT/AF)

Administered By
Duke Cancer Institute
Awarded By
SpringWorks Therapeutics
Role
Principal Investigator
Start Date
End Date

A Phase 3, Interventional, Randomized, Multicenter, Open-Label Study of DCC-2618 vs Sunitinib in Patients with Advanced Gastrointestinal Stromal Tumors after Treatment with Imatinib

Administered By
Duke Cancer Institute
Awarded By
Deciphera Pharmaceuticals, LLC
Role
Principal Investigator
Start Date
End Date

A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Determine the Efficacy and Safety of MB305 in Unresectable Locally-advanced or Metastatic NY-ESO-1+ Synovial Sarcoma Subjects Following First-line Systemic Anti-cancer Therapy

Administered By
Duke Cancer Institute
Awarded By
Immune Design Corp.
Role
Principal Investigator
Start Date
End Date

Publications:

Soft Tissue Sarcoma, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

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.
Authors
von Mehren, M; Kane, JM; Agulnik, M; Bui, MM; Carr-Ascher, J; Choy, E; Connelly, M; Dry, S; Ganjoo, KN; Gonzalez, RJ; Holder, A; Homsi, J; Keedy, V; Kelly, CM; Kim, E; Liebner, D; McCarter, M; McGarry, SV; Mesko, NW; Meyer, C; Pappo, AS; Parkes, AM; Petersen, IA; Pollack, SM; Poppe, M; Riedel, RF; Schuetze, S; Shabason, J; Sicklick, JK; Spraker, MB; Zimel, M; Hang, LE; Sundar, H; Bergman, MA
MLA Citation
von Mehren, Margaret, et al. “Soft Tissue Sarcoma, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.J Natl Compr Canc Netw, vol. 20, no. 7, July 2022, pp. 815–33. Pubmed, doi:10.6004/jnccn.2022.0035.
URI
https://scholars.duke.edu/individual/pub1526840
PMID
35830886
Source
pubmed
Published In
J Natl Compr Canc Netw
Volume
20
Published Date
Start Page
815
End Page
833
DOI
10.6004/jnccn.2022.0035

Large scale multiomic analysis suggests mechanisms of resistance to immunotherapy in leiomyosarcoma.

<jats:p> 11512 </jats:p><jats:p> Background: Leiomyosarcomas (LMS) have been reported to have immunohistochemical (IHC) and gene expression signatures suggestive of an immune-responsive tumor microenvironment. Despite this, immune checkpoint inhibitors have demonstrated minimal activity in LMS. We examined molecular profiles of LMS specimens from multiple institutions to explore mechanisms of immunotherapy (IO) resistance. Methods: LMS specimens (n = 1115), including 701 uterine (uLMS) and 414 soft tissue site (stLMS) samples, underwent next-generation sequencing (NGS) of DNA (592-gene panel or whole exome) and RNA (whole transcriptome, n = 537) at Caris Life Sciences (Phoenix, AZ). A threshold of 10 mut/Mb was used to identify high tumor mutational burden (TMB-H). IHC was performed for PD-L1 (SP142; 2+|5% positive). Deficient mismatch repair (dMMR)/high microsatellite instability (MSI-H) was tested by IHC and NGS, respectively. RNA expression was analyzed using Gene Set Enrichment Analysis and Microenvironment Cell Populations-counter, with results compared to melanoma (n = 1255) as a representative immunogenic tumor type. P-values were adjusted for multiple hypothesis testing. Results: TMB-H was observed in 3.8% (n = 41) of LMS specimens, with a median of 5 mut/Mb (IQR 3.3-6.7). dMMR/MSI-H was rarely detected (1.5%, n = 17), whereas 8.2% (n = 88) were positive for PD-L1 expression. uLMS and stLMS did not differ in TMB-H (3.4 vs 4.5%, p = 0.277), PD-L1 expression (8.6 vs 7.4%, p = 0.322), or dMMR/MSI-H (2.0 vs 0.7% p = 0.207). stLMS demonstrated upregulation of immune-related gene sets, including interferon γ (p = 0.035) and α (p = 0.033) response, inflammatory response (p = 0.038), interleukin-6/STAT3 signaling (p = 0.030), and TNFα signaling (p = 0.026) compared to uLMS. Immune cell infiltration was increased in stLMS over uLMS, most notably for CD8 T-cell and B-cell abundance ( &gt; 2-fold increase, p &lt; 0.0001). Compared to melanoma, all LMS had lower abundance of CD8 T cells, cytotoxic lymphocytes, and B-cells ( &gt; 2-fold decrease, p &lt; 0.0001). Fibroblasts were more prevalent in LMS relative to melanoma (3.2-fold increase, p &lt; 0.0001). Interestingly, while higher CD8 T-cell infiltration was positively associated with dMMR/MSI-H among LMS specimens (p = 0.032), TMB-H and PD-L1 expression were associated with lower CD8 T-cell infiltration (p &lt; 0.01). Conclusions: Only a small proportion of LMS are TMB-H or MSI-H, suggesting that the neoantigen burden in LMS may be insufficient to promote a robust anti-tumor response, even in the presence of PD-L1 positive tumor cells. Traditional predictive biomarkers of response to IO are unlikely to be useful in LMS. Furthermore, both uLMS and stLMS have an immune microenvironment characterized by a high fibroblast and low T cell abundance relative to melanoma. Future IO trials in LMS should focus on combination therapies that may reverse the observed T-cell exclusion/desmoplastic phenotype. </jats:p>
Authors
Lagos, G; Groisberg, R; Dizon, DS; Elliott, A; Copeland, T; Seeber, A; Gibney, GT; von Mehren, M; Cardona, K; Demeure, MJ; Riedel, RF; Florou, V; Chou, AJ; Kumar, A; Modiano, J; Khushman, MM; D'Amato, GZ; Espejo Freire, AP; Korn, WM; Trent, JC
MLA Citation
Lagos, Galina, et al. “Large scale multiomic analysis suggests mechanisms of resistance to immunotherapy in leiomyosarcoma.Journal of Clinical Oncology, vol. 39, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2021, pp. 11512–11512. Crossref, doi:10.1200/jco.2021.39.15_suppl.11512.
URI
https://scholars.duke.edu/individual/pub1502422
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
39
Published Date
Start Page
11512
End Page
11512
DOI
10.1200/jco.2021.39.15_suppl.11512

Multiomic analysis to reveal distinct molecular profiles of uterine and nonuterine leiomyosarcoma.

<jats:p> 11555 </jats:p><jats:p> Background: Leiomyosarcoma (LMS) is a rare group of mesenchymal malignancies found in the uterus, retroperitoneum, skin, or other soft-tissue sites. Treatment for LMS is extrapolated from trials including both uterine (uLMS) and non-uLMS subtypes, although whether they respond similarly and have similar outcomes from treatment is not clear. We examined the molecular composition of LMS by site of origin to better inform future drug development and trial design. Methods: We reviewed 1115 specimens with LMS histology tested by Caris Life Sciences for targeted exome (NextSeq, 592 gene panel), whole exome, and whole transcriptome sequencing (NovaSeq). Specimens were stratified into uLMS, rpLMS (retroperitoneal), and otherLMS (non-uterine/retroperitoneal) subgroups based on tumor origin sites. Genomic data was analyzed for mutations, copy number aberrations, and fusions. RNA expression profiling included evaluation of individual genes and gene set enrichment analysis (GSEA). P-value adjustment performed by the Benjamini-Hochberg procedure. Results: The study cohort was comprised of 62.9% uLMS (n = 701), 14.9% rpLMS (n = 166) and 22.2% otherLMS (n = 248) specimens. Overall, LMS specimens most frequently harbored TP53 (64%, n = 612), ATRX (30%, n = 219), RB1 (22%, n = 156), and MED12 (16%, n = 94) mutations, with these genes accounting for 74.4% (n = 1044) of all observed pathogenic/likely pathogenic mutations. RB1 mutations were significantly less common in uLMS (15%) compared to rpLMS (30%, p &lt; 0.05) and otherLMS (33%, p &lt; 0.01), whereas MED12 mutations were almost exclusive to uLMS (22% vs 1% rpLMS, 3% otherLMS, p &lt; 0.05). MAP2K4 copy number amplification were more common in rpLMS (22%, p &lt; 0.001) and otherLMS (14%, p &lt; 0.182) compared to uLMS (7%), with frequent co-amplification of nearby genes ( FLCN, GID4, SPECC1, GAS7, PER1, and AURKB) located at chr17p11-13. Actionable gene fusions involving ALK (2.1%, n = 11), FGFR1 (0.2%, n = 1), and NTRK1/2 (0.2%, n = 1 each) were rare overall, with similar prevalence across subtypes. Genomic alteration rates were not significantly different between rpLMS and otherLMS subtypes . RNA expression profiling identified significant upregulation of PI3K/AKT/mTOR, DDR, WNT/Beta-Catenin pathway genes in non-uLMS. GSEA indicated several immune-related gene sets were enriched in rpLMS and otherLMS compared to uLMS. Conclusions: Comprehensive molecular profiling suggests that LMS originating from the uterus represents a molecularly distinct disease compared to other primary sites of origin. We identified key genomic patterns which have potential for targeted therapy. These data provide insight for the framework of future clinical trials designed to separate uLMS from non-uLMS histologies, although further subdivision does not appear to be warranted. </jats:p>
Authors
Copeland, T; Groisberg, R; Dizon, DS; Elliott, A; Lagos, G; Seeber, A; von Mehren, M; Cardona, K; Demeure, MJ; Riedel, RF; Florou, V; Chou, AJ; Kumar, A; Modiano, J; Khushman, MM; D'Amato, GZ; Espejo Freire, AP; Korn, WM; Trent, JC
MLA Citation
Copeland, Tabitha, et al. “Multiomic analysis to reveal distinct molecular profiles of uterine and nonuterine leiomyosarcoma.Journal of Clinical Oncology, vol. 39, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2021, pp. 11555–11555. Crossref, doi:10.1200/jco.2021.39.15_suppl.11555.
URI
https://scholars.duke.edu/individual/pub1502423
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
39
Published Date
Start Page
11555
End Page
11555
DOI
10.1200/jco.2021.39.15_suppl.11555

Phase II study of atezolizumab in advanced alveolar soft part sarcoma (ASPS).

<jats:p> 11519 </jats:p><jats:p> Background: ASPS constitutes &lt; 1% of soft tissue sarcomas and frequently presents in adolescents and young adults. There are no approved therapies for ASPS. We are currently evaluating the clinical activity of atezolizumab (atezo), an anti-PD-L1 antibody, in patients (pts) with advanced ASPS. Methods: This is a multicenter, open-label, single-arm phase II study where atezo is administered at a fixed dose of 1200 mg in adults or 15 mg/kg (1200 mg max) in pediatric pts age ≥2 once Q21 days. The primary objective is to determine the objective response rate (ORR) of atezo using RECIST 1.1. Secondary objectives include duration of response and correlating response with the immune effects of atezo in blood and paired tumor biopsies (pre- and post-treatment). Tumor specimens were analyzed with multiplex immunofluorescence immuno-oncology panels to quantify CD8+, PD-1+, and PD-L1+ cells/mm<jats:sup>2</jats:sup> in the tumor microenvironment. CD8+ density was calculated as the total number of CD8+ cells divided by the entire area (mm<jats:sup>2</jats:sup>) of the tumor and invasive margins of the biopsy. Results: As of February 4, 2021, 44 pts have been enrolled. The median age in the study was 31 years (range, 12–70) with equal male: female distribution. 54.5% of pts were Caucasian. Baseline ECOG ≤1 was present in 97.7%. The median time on study was 11.5 months (range, 0.8–40.3 months). At data cutoff, response evaluation was available for 43 pts with an ORR of 37.2% (16/43). One pt experienced a complete response and 15 pts experienced a partial response (PR), of which 14 were confirmed. The median time to confirmed response was 3.5 months (range, 2.1–14.9 months). The median duration of confirmed response was 16.5 months (range, 4.9–38.1 months). Stable disease (SD) was present in 58.1% (25/43). One or more grade 3 adverse events potentially related to atezo were identified in 16.3% (7/43) pts. These include diarrhea, hypothyroidism, transaminitis, anemia, vertigo, extremity pain, myalgia, pneumonitis, rash, and stroke (n = 1 each). No grade 4 or 5 events have been reported. Among 8 cases with evaluable biopsy pairs, both baseline and C3D1 specimens in all cases demonstrated CD8+ T cell infiltration and PD-L1 expression. PD-1 expression was detected at baseline in 5 cases and at C3D1 in 7 cases. In 6 cases (3 SDs and 3 PRs), treatment did not change CD8+ cell density. In the other 2 cases (both PRs), CD8+ density increased &gt; 3x above baseline by C3D1. Analysis of T cell activation using pharmacodynamic response biomarkers, along with whole exome and RNA-seq to evaluate the genomic and transcriptomic landscape of ASPS, are ongoing. Conclusions: Atezo is well tolerated and demonstrates promising single agent activity with durable responses in advanced ASPS. Preliminary tumor biomarker analysis confirms the presence of multiple PD-1/PD-L1 immune checkpoint (IC) components, indicating that advanced ASPS is an ideal candidate for therapeutic IC inhibition. Funded by NCI Contract No HHSN261200800001E. Clinical trial information: NCT03141684. </jats:p>
Authors
Naqash, AR; O'Sullivan Coyne, GH; Moore, N; Sharon, E; Takebe, N; Fino, KK; Ferry-Galow, KV; Hu, JS; Van Tine, BA; Burgess, MA; Read, WL; Riedel, RF; George, S; Glod, J; Conley, AP; Foster, JC; Fogli, LK; Parchment, RE; Doroshow, JH; Chen, AP
MLA Citation
Naqash, Abdul Rafeh, et al. “Phase II study of atezolizumab in advanced alveolar soft part sarcoma (ASPS).Journal of Clinical Oncology, vol. 39, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2021, pp. 11519–11519. Crossref, doi:10.1200/jco.2021.39.15_suppl.11519.
URI
https://scholars.duke.edu/individual/pub1503015
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
39
Published Date
Start Page
11519
End Page
11519
DOI
10.1200/jco.2021.39.15_suppl.11519

P10015/SARC033: A phase 2 trial of trametinib in patients with advanced epithelioid hemangioendothelioma (EHE).

<jats:p> 11503 </jats:p><jats:p> Background: EHE is a rare vascular cancer arising in liver, lung, soft tissue and bone. The natural history of metastatic disease varies considerably from indolent growth over years to rapid growth with fatal outcome in months. Treatment of patients (pts) with metastatic EHE with antiangiogenic therapy induces tumor response in a minority of pts, and median PFS is 6-12 months. TAZ-CAMTA1 translocation results in activation of MAPK pathway and is an oncogenic driver in EHE. We sought to evaluate the effect of MEK inhibition using trametinib in pts with unresectable EHE. Methods: A phase 2 trial of trametinib 2 mg daily was conducted in pts with EHE though the Experimental Therapeutics Clinical Trials Network supported by NCI in collaboration with SARC. Additional support was provided by the EHE Rare Cancer Charity and the EHE Foundation. Pts had to have evidence of objective tumor progression or EHE-related pain requiring narcotics for relief prior to enrollment. Presence of TAZ-CAMTA1 translocation was analyzed by fusion-FISH after enrollment. Primary trial endpoint was objective response rate (ORR) per RECIST1.1 with at least 1 objective response required in the 1<jats:sup>st</jats:sup> 13 pts to expand enrollment to 27. The trial was amended after stage 1 to continue enrollment to 27 pts with TAZ-CAMTA1 detected by FISH with goal of &gt;4 objective responses in this group. Secondary objectives were PFS and OS rates, safety and change in pt-reported global health and pain scores per PROMIS questionnaires. Results: 43 pts were enrolled between 6/2017 – 9/2020 across 10 sites and 41 started therapy. TAZ-CAMTA1 fusion was detected in 26, not detected in 7, test failed in 5 and was not performed due to insufficient tumor in 5. Median pt age was 54 (range 22-81 yrs) and 11 were &gt;65 yrs; 25 were female; ECOG was 0 in 23, 1 in 16 and 2 in 3 pts. Most pts experienced reduction in tumor size. ORR per RECIST was 7% (3/41); in pts with TAZ-CAMTA1 detected, the ORR was 0% (0/26). Mean pain intensity and interference scores had a statistically significant improvement and global quality of life scores did not statistically change after 4 weeks of therapy. 17 pts remained on treatment &gt; 6 months and 7 &gt; 12 months. 25 pts stopped trametinib due to EHE progression, 6 died during treatment, 6 withdrew from treatment, 3 stopped drug due to adverse event and 1 is on treatment. The most common AEs related to trametinib were rash, fatigue, nausea/vomiting, diarrhea, alopecia and edema; Grade &gt;3 AEs included anemia, dyspnea, hypoxia, hypotension, syncope and dermatitis. Conclusions: To our knowledge, this is the largest prospective clinical study focused on pts with EHE. Although the trial did not meet the ORR goal, stable disease &gt; 6 months was seen in 40% of pts, and EHE-related pain improved on treatment. Trametinib was associated with expected cutaneous and GI adverse effects. Additional pt-reported outcomes and biomarkers of inflammation are undergoing analysis. Clinical trial information: NCT03148275. </jats:p>
Authors
Schuetze, S; Ballman, KV; Ganjoo, KN; Davis, EJ; Morgan, JA; Tinoco, G; Burgess, MA; Van Tine, BA; Choy, E; Shepard, DR; Kelly, CM; Riedel, RF; von Mehren, M; Siontis, BL; Attia, S; Schwartz, GK; Deshpande, HA; Kozlowski, E; Chen, HX; Rubin, B
MLA Citation
Schuetze, Scott, et al. “P10015/SARC033: A phase 2 trial of trametinib in patients with advanced epithelioid hemangioendothelioma (EHE).Journal of Clinical Oncology, vol. 39, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2021, pp. 11503–11503. Crossref, doi:10.1200/jco.2021.39.15_suppl.11503.
URI
https://scholars.duke.edu/individual/pub1503016
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
39
Published Date
Start Page
11503
End Page
11503
DOI
10.1200/jco.2021.39.15_suppl.11503