Background

Patients with metastatic NSCLC who are refractory/resistant (R/R) to anti-PD-(L)1 therapies have limited treatment options. Sitravatinib is a spectrum-selective tyrosine kinase inhibitor targeting TAM and VEGFR2 receptors, which can reduce the number of myeloid-derived suppressor cells, regulatory T cells, and increase the ratio of M1/M2 polarized macrophages, potentially augmenting antitumor immune responses. Tislelizumab, is an anti-PD-1 antibody engineered to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis, a potential mechanism of resistance. This phase 1b study assessed safety/tolerability and antitumor activity of sitravatinib + tislelizumab in solid tumors (NCT03666143). We report results from NSCLC cohorts.

Methods

Eligible patients had metastatic non-squamous (NSQ) or squamous (SQ) NSCLC with radiographic disease progression on/after anti-PD-(L)1 therapy as their most recent treatment. Patients with EGFR/BRAF mutations or ALK/ROS1 rearrangements were ineligible. Treatment included sitravatinib 120 mg orally QD and tislelizumab 200 mg IV Q3W. The primary endpoint was safety and tolerability. Key secondary endpoints included investigator-assessed objective response rate (ORR), duration of response (DoR), disease control rate (DCR) and progression-free survival (PFS).

Results

As of 13 Oct 2020, 47 patients with NSQ (n=24) and SQ (n=23) NSCLC were enrolled with a median study follow-up of 7.8 months (range: 0.4–18.1). Median age was 60 years (range: 25–79) and 72% of patients had ≥2 lines of prior therapies. All patients had a treatment-emergent adverse event (TEAE); 68% had a Grade ≥3 TEAE (most common: hypertension, 19%). Confirmed ORR was 14% (95% CI: 5.2–27.4) and DCR was 86% (95% CI: 72.7–94.8). Median DoR was 6.9 months (95% CI: 3.1–NE). Median PFS was 5.2 months (95% CI: 4.1–5.9). There was no association between PD-L1 expression and clinical response.

Conclusions

Sitravatinib plus tislelizumab demonstrated a manageable safety profile and promising antitumor activity in patients with PD-(L)1 antibody pretreated NSCLC. Further investigation of this combination in these pts is warranted.

Clinical trial identification

NCT03666143. Release date: October 13, 2020.

Editorial acknowledgement

Writing and editorial assistance was provided by Stephan Lindsey, PhD and Elizabeth Hermans, PhD (OPEN Health Medical Communications, Chicago, IL). Editorial support (in the form of editorial alignment with congress guidance) was provided by Louise Oakes, PhD, of Ashfield MedComms, an Ashfield Health company.

Legal entity responsible for the study

BeiGene, Ltd.

Funding

BeiGene, Ltd.

Disclosure

H. Li, J. Sun, J. Zhang, C. Fei,: Financial Interests, Institutional, Full or part-time Employment: BeiGene (Beijing) Co., Ltd. Y. Wu: Non-Financial Interests, Institutional, Sponsor/Funding: AstraZeneca; Non-Financial Interests, Institutional, Sponsor/Funding: Boehringer Ingelheim; Non-Financial Interests, Institutional, Sponsor/Funding: BMS; Non-Financial Interests, Institutional, Sponsor/Funding: Hengrui; Non-Financial Interests, Institutional, Sponsor/Funding: Pfizer; Non-Financial Interests, Institutional, Sponsor/Funding: Roche; Non-Financial Interests, Institutional, Advisory Role: AstraZeneca; Non-Financial Interests, Institutional, Advisory Role: Boehringer Ingelheim; Non-Financial Interests, Institutional, Advisory Role: Novartis; Non-Financial Interests, Institutional, Advisory Role: Merck; Non-Financial Interests, Institutional, Advisory Role: MSD; Non-Financial Interests, Institutional, Advisory Role: Roche; Non-Financial Interests, Institutional, Advisory Role: Takeda; Financial Interests, Institutional, Other, Honoraria: AstraZeneca; Financial Interests, Institutional, Other, Honoraria: Boehringer Ingelheim; Financial Interests, Institutional, Other, Honoraria: BMS; Financial Interests, Institutional, Other, Honoraria: Eli Lilly; Financial Interests, Institutional, Other, Honoraria: Hengrui; Financial Interests, Institutional, Other, Honoraria: MSD; Financial Interests, Institutional, Other, Honoraria: Pfizer; Financial Interests, Institutional, Other, Honoraria: Roche; Financial Interests, Institutional, Other, Honoraria: Sanofi. All other authors have declared no conflicts of interest.

Background

Patients (pts) with advanced NSCLC often develop progressive disease, with limited treatments for pts who are heavily pretreated with anti-PD-(L)1 antibodies and/or chemotherapy. Sitravatinib is a spectrum-selective tyrosine kinase inhibitor targeting TAM and VEGFR2 receptors, which can reduce the number of myeloid-derived suppressor cells, regulatory T cells, and increases the ratio of M1/M2 polarized macrophages, potentially augmenting antitumor responses. Tislelizumab, is an anti-PD-1 antibody engineered to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis, a potential mechanism of resistance. This phase 1b study assessed safety/tolerability and antitumor activity of sitravatinib + tislelizumab in solid tumors (NCT03666143). We report results from NSCLC cohorts.

Methods

Pts had confirmed metastatic nonsquamous (NSQ) or squamous (SQ) NSCLC treated with 1–3 lines of prior systemic therapy with/without an anti-PD-(L)1 inhibitor. Pts with EGFR/ BRAF mutations or ALK/ROS1 rearrangements were ineligible. Sitravatinib was given 120 mg orally QD and tislelizumab 200 mg IV Q3W. The primary endpoint was safety/tolerability. Secondary endpoints were objective response rate (ORR), duration of response (DoR), disease control rate (DCR), and progression-free survival (PFS).

Results

On 13 Oct 2020, 75 pts (NSQ, n=46; SQ, n=29) were treated; 47 pts were refractory/resistant (R/R) to PD-(L)1 therapy and 28 pts were PD-(L)1 naïve. Median age was 60 yrs (range: 25–79). Median study follow-up was 10.1 mo (range: 0.4–18.8). All pts had a treatment-emergent adverse event (TEAE); 73% of pts had a Grade ≥3 TEAE (most common: hypertension [n=12]). Confirmed ORR was 17% (95% CI: 9.1–27.7); DCR was 85% (95% CI: 74.0–92.0). Median DoR was 7.0 mo (95% CI: 2.9–not estimable). Median PFS was 5.5 mo (95% CI: 4.1–7.0). There was a trend toward higher ORR in pts with PD-L1 IC expression ≥10%. In R/R pts confirmed ORR was 14% (95% CI: 5.2–27.4).

Conclusions

Sitravatinib + tislelizumab had a manageable safety profile and demonstrated preliminary antitumor activity in pts with NSQ or SQ NSCLC who were pretreated or naïve to PD-(L)1 treatment. Further investigation in these pts is warranted.

Clinical trial identification

NCT03666143. Release date: October 13, 2020.

Editorial acknowledgement

Writing and editorial assistance was provided by Stephan Lindsey, PhD and Elizabeth Hermans, PhD (OPEN Health Medical Communications, Chicago, IL). Editorial support (in the form of editorial alignment with congress guidance) was provided by Louise Oakes, PhD, of Ashfield MedComms, an Ashfield Health company.

Legal entity responsible for the study

BeiGene, Ltd.

Funding

BeiGene, Ltd.

Disclosure

H. Li, J. Sun, J. Zhang, C. Fei: Financial Interests, Institutional, Full or part-time Employment: BeiGene (Beijing) Co., Ltd. Y. Wu: Non-Financial Interests, Institutional, Sponsor/Funding: AstraZeneca; Non-Financial Interests, Institutional, Sponsor/Funding: Boehringer Ingelheim; Non-Financial Interests, Institutional, Sponsor/Funding: BMS; Non-Financial Interests, Institutional, Sponsor/Funding: Hengrui; Non-Financial Interests, Institutional, Sponsor/Funding: Pfizer; Non-Financial Interests, Institutional, Sponsor/Funding: Roche; Non-Financial Interests, Institutional, Advisory Role: AstraZeneca; Non-Financial Interests, Institutional, Advisory Role: Boehringer Ingelheim; Non-Financial Interests, Institutional, Advisory Role: Novartis; Non-Financial Interests, Institutional, Advisory Role: Merck; Non-Financial Interests, Institutional, Advisory Role: MSD; Non-Financial Interests, Institutional, Advisory Role: Roche; Non-Financial Interests, Institutional, Advisory Role: Takeda; Financial Interests, Institutional, Other, Honoraria: AstraZeneca; Financial Interests, Institutional, Other, Honoraria: Boehringer Ingelheim; Financial Interests, Institutional, Other, Honoraria: BMS; Financial Interests, Institutional, Other, Honoraria: Eli Lilly; Financial Interests, Institutional, Other, Honoraria: Hengrui; Financial Interests, Institutional, Other, Honoraria: MSD; Financial Interests, Institutional, Other, Honoraria: Pfizer; Financial Interests, Institutional, Other, Honoraria: Roche; Financial Interests, Institutional, Other, Honoraria: Sanofi. All other authors have declared no conflicts of interest.

Background

PAUF plays a key role in PC tumour progression and metastasis by inducing cancer cell proliferation, angiogenesis and evasion of immune surveillance. PBP1510 developed by Prestige Biopharma Limited, is a novel humanized IgG1 mAb that binds to and neutralizes PAUF with high specificity and affinity. There are no targeted therapies against PAUF, making PBP1510 the first in this class.

Methods

Subcutaneous (SC) cell-derived xenograft (CDX), SC patient-derived xenograft (PDX) and orthotopic PDX studies were conducted in mice (Table). Efficacy was assessed by measuring tumour size and tumour growth inhibition (TGI). A 4-week repeated dose study was also conducted in mice for toxicity, toxicokinetic and immunogenicity analysis. Table: 3P

In vivo models to study PBP1510 efficacy

Results

Superior anti-tumour efficacy of PBP1510 treatment, compared to IgG control, was observed in all the three mouse models, particularly in PAUF-positive cancer models (Table). The SC PDX model derived from PAUF-negative sample did not respond to PBP1510, indicating specificity of treatment. No notable local or systemic toxicity was observed in mice receiving up to 40 mg/kg of PBP1510. Low immunogenic profile of PBP1510 was indicated by an absence of anti-PBP1510 antibodies.

Conclusions

The current efficacy and safety data, along with other pre-clinical data, support further clinical development of PBP1510 as a novel anti-cancer agent to treat PAUF-positive PC. As a result, PBP1510 was granted Orphan Drug Designation by EMA, US FDA and Korea MFDS. The pivotal step of advancing PBP1510 into initial human studies is now in progress.

Legal entity responsible for the study

Prestige Biopharma Limited.

Funding

Prestige Biopharma Limited.

Disclosure

S. Pradhan, Y.J. Kim, J. Kim, L. Jaison: Financial Interests, Institutional, Full or part-time Employment: Prestige Biopharma Limited. J. Park: Non-Financial Interests, Institutional, Full or part-time Employment: University of Ulsan College of Medicine. S. Jeong: Financial Interests, Institutional, Principal Investigator: University of Ulsan College of Medicine. S.S. Koh: Financial Interests, Institutional, Leadership Role: Prestige Biopharma Limited. K.D. Mandakhalikar: Non-Financial Interests, Institutional, Full or part-time Employment: Prestige Biopharma Limited.

Background

The overexpression of integrin αVβ3 enhances tumour development, metastasis, angiogenesis, treatment resistance, and clinical staging in breast cancer patients. As a result, inhibiting integrin αVβ3 might be a promising anti-cancer agent for breast cancer. Furthermore, dealing with a post-operative wound from breast cancer is difficult in cancer biology. The cancer-associated inflammatory proteins p70S6K and STAT3 are implicated in local recurrences of primary breast cancer in this regard. Hence, the present proposal is concerned with a new approach of integrin αVβ3-decorated nanocomposites for the intelligent subcellular targeted delivery of anticancer drugs and wound healing.

Methods

PEG-functionalized ZnO nanoparticles (ZnO NPs) were synthesized and characterized, providing the space for loading of both integrin αVβ3 antibody and DOX to specifically target tumor cells. The antitumor effect of DOX-αVβ3-ZnO NPs was evaluated in MDAMB- 231 cells in vitro and MDAMB- 231 xenograft mice models. Apoptotic and anti-apoptotic protein and mRNA (Bax, Bcl2, P53, caspase 3, 9 and cytochrome c) levels were examined. Cell proliferation assay and scratch test were performed to evaluate the anti-migratory effect of DOX-αVβ3-ZnO NPs in vitro.

Results

The in vitro and in vivo antitumor activities of DOX-αVβ3-ZnO NPs were evaluated against breast cancer. These DOX-αVβ3-ZnO NPs showed well-regulated DOX loading yields, enhanced cellular uptake properties, and excellent drug delivery output, which in vitro and in vivo cytotoxicity against breast cancer trough induced apoptosis. In MDAMB-231 xenograft mice models, DOX-αVβ3-ZnO NPs treatment significantly suppressed tumor weights and volumes. In the wound-healing process, DOX-αVβ3-ZnO NPs act as inhibitors of p70S6K protein expression through attenuating ERK phosphorylation, which will subsequently inhibit STAT3 protein expression for preventing re-growth and tumor metastasis.

Conclusions

DOX-αVβ3-ZnO NPs strongly inhibited tumor progression and suppress cell migration and proliferation. As a result, targeting certain integrins and integrin-binding proteins might open up new therapeutic avenues for breast cancer therapies.

Clinical trial identification

Periyar University Institutional Animal Ethical Committee (PUIAEC No. 1085/PO/Re/S/07/ CPCSEA/2023).

Legal entity responsible for the study

Periyar University.

Funding

UGC- Postdoctoral Fellowship (F.15-1/2016- 17/PDFWM-2015- 17-TAM- 36122), University Grant Commission New Delhi, India.

Disclosure

All authors have declared no conflicts of interest.

Background

RP-3500 is an oral ATR inhibitor (ATRi) in development for the treatment of patients (pts) with advanced solid tumors carrying alterations in ATRi-sensitizing genes. The dose-escalation portion of the TRESR study (NCT04497116) evaluated RP-3500 5–200 mg once daily (QD) or twice daily at defined intermittent schedules in 120 pts.

Methods

RP-3500 plasma levels were assessed and PK parameters were determined by non-compartmental analysis (Phoenix WinNonLin) in pts with evaluable plasma concentration-time points. To determine the effect of food on RP-3500 PK, 12 pts received a single dose of RP-3500 following a standard high-fat meal on Day -3 and after a 24-hr fast on Day 1. Serial blood samples were collected for PK analysis at baseline and after RP-3500 administration.

Results

120 pts had sufficient data on day 1, cycle 1, to report PK parameters. Overall, 323 plasma concentration-time profiles were collected. Plasma exposure was dose-linear with low within-pt variability and a T_½ of ∼6 hr. No accumulation of RP-3500 was observed after multiple doses were given. At therapeutic doses of 120 mg and 160 mg QD on day 1, cycle 1, mean AUC_0-24 was 33.6 and 48.2 μg٠hr/mL, respectively, and mean C_max was 5.74 and 7.64 μg/mL, respectively. Within the therapeutic dose range, median T_max was 2 hr (range 0.5–6). When administered with a high fat meal, RP-3500 median T_max was delayed by 3 hrs and mean C_max was reduced by 45% compared with fasting values within this cohort. Mean AUC_0-24 was 16% lower compared with AUC_0-24 in the fasted state. Importantly, the plasma levels required for the pharmacological activity of RP-3500 did not substantially differ between the fed and fasted states.

Conclusions

The PK profile of RP-3500 is predictable with low observed variability. RP-3500 given orally to pts at recommended doses of 120-160 mg QD on 3 days/week, with or without food, reaches or exceeds preclinically defined target exposure requirements (Roulston et al., Mol Cancer Ther. 2021). RP-3500 can be administered with or without food without affecting PK parameters relevant to tolerability and therapeutic window.

Clinical trial identification

NCT04497116.

Editorial acknowledgement

Editorial assistance was provided by Mike Zbreski, PharmD of Onyx Medica, London, UK, supported by Repare Therapeutics Inc.

Legal entity responsible for the study

Repare Therapeutics.

Funding

Repare Therapeutics.

Disclosure

S. Lheureux, S. Patel, R. Papp, S. May, D. Ulanet, M. Koehler: Financial Interests, Personal, Full or part-time Employment: Repare Therapeutics; Financial Interests, Personal, Stocks/Shares: Repare Therapeutics. D. Spigel: Financial Interests, Institutional, Research Grant: Aeglea Biotherapeutics; Financial Interests, Institutional, Research Grant: Agios; Financial Interests, Institutional, Research Grant: Apollomics; Financial Interests, Institutional, Research Grant: Arcus; Financial Interests, Institutional, Research Grant: Arrys Therapeutics; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Institutional, Research Grant: BeiGene; Financial Interests, Institutional, Research Grant: BIND Therapeutics; Financial Interests, Institutional, Research Grant: BioNTech; Financial Interests, Institutional, Research Grant: Blueprint Medicine; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Research Grant: Calithera; Financial Interests, Institutional, Research Grant: Celgene; Financial Interests, Institutional, Research Grant: Celldex; Financial Interests, Institutional, Research Grant: Clovis; Financial Interests, Institutional, Research Grant: Cyteir; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Denovo Biopharma; Financial Interests, Institutional, Research Grant: Eisai; Financial Interests, Institutional, Research Grant: Elevation Oncology; Financial Interests, Institutional, Research Grant: EMD Serono; Financial Interests, Institutional, Research Grant: Evelo Biosciences; Financial Interests, Institutional, Research Grant: G1 Therapeutics; Financial Interests, Institutional, Research Grant: Roche/Genentech; Financial Interests, Institutional, Research Grant: GlaxoSmithKline; Financial Interests, Institutional, Research Grant: GRAIL; Financial Interests, Institutional, Research Grant: Hutchinson MediPharma; Financial Interests, Institutional, Research Grant: ImClone System; Financial Interests, Institutional, Research Grant: Incyte; Financial Interests, Institutional, Research Grant: ImmunoGen; Financial Interests, Institutional, Research Grant: Ipsen; Financial Interests, Institutional, Research Grant: Janssen; Financial Interests, Institutional, Research Grant: Kronos Bio; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Research Grant: Loxo Oncology; Financial Interests, Institutional, Research Grant: MacroGenics; Financial Interests, Institutional, Research Grant: MedImmune; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Molecular Partner; Financial Interests, Institutional, Research Grant: Molecular Template; Financial Interests, Institutional, Research Grant: Nektar; Financial Interests, Institutional, Research Grant: Neon Therapeutics; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Novocure; Financial Interests, Institutional, Research Grant: Oncologie; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: PTC Therapeutics; Financial Interests, Institutional, Research Grant: PureTech Health; Financial Interests, Institutional, Research Grant: Razor Genomics; Financial Interests, Institutional, Research Grant: Repare Therapeutics; Financial Interests, Institutional, Research Grant: Rgenix; Financial Interests, Institutional, Research Grant: Takeda; Financial Interests, Institutional, Research Grant: Tizona Therapeutics; Financial Interests, Institutional, Research Grant: Transgene; Financial Interests, Institutional, Research Grant: UT Southwestern; Financial Interests, Institutional, Research Grant: Verastem; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Curio Science; Financial Interests, Personal, Advisory Role: EMD Serono; Financial Interests, Personal, Advisory Role: Evidera; Financial Interests, Personal, Advisory Role: Exelixis; Financial Interests, Personal, Advisory Role: GlaxoSmithKline; Financial Interests, Personal, Advisory Role: Intellisphere; Financial Interests, Personal, Advisory Role: Ipsen; Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Personal, Advisory Role: Jazz Pharmaceuticals; Financial Interests, Personal, Advisory Role: Lilly; Financial Interests, Personal, Advisory Role: Mirati Therapeutics; Financial Interests, Personal, Advisory Role: Molecular Template; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Novocure; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Puma Biotechnology; Financial Interests, Personal, Advisory Role: Regeneron; Financial Interests, Personal, Advisory Role: Roche/Genentech; Financial Interests, Personal, Advisory Role: Sanofi-Aventis. M. Højgaard: Other, Personal, Advisory Role: LingoMedical; Financial Interests, Personal, Stocks/Shares: Bavarian Nordic; Financial Interests, Personal, Stocks/Shares: Pacific Biosciences; Financial Interests, Personal, Stocks/Shares: Illumina Inc; Non-Financial Interests, Institutional, Principal Investigator: Amgen; Non-Financial Interests, Institutional, Principal Investigator: Incyte Cooperation; Other, Personal, Member of the Board of Directors: Danish Medicines Council. E. Fontana: Financial Interests, Personal, Full or part-time Employment: Hospital Corporation of America (HCA) International. N.B. Mettu: Financial Interests, Institutional, Research Grant: Repare Therapeutics; Financial Interests, Institutional, Research Grant: Genentech; Financial Interests, Institutional, Research Grant: Mereo BioPharma; Financial Interests, Institutional, Research Grant: OncoMed Pharmaceuticals; Financial Interests, Institutional, Research Grant: Amphivena Therapeutics; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Biomed Valley Discoveries; Financial Interests, Institutional, Research Grant: Erytech Pharma; Financial Interests, Institutional, Research Grant: Incyte Corporation; Financial Interests, Institutional, Research Grant: Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant: Revolution Medicines, Inc; Financial Interests, Institutional, Research Grant: Syros Pharmaceuticals; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Research Grant: Marc Lustgarten Pancreatic Cancer Foundation; Financial Interests, Institutional, Research Grant: Armo BioSciences/Eli Lilly; Financial Interests, Institutional, Research Grant: NIH; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb. P. Nejad, M. Wainszelbaum, P. Manley: Financial Interests, Personal, Full or part-time Employment: Repare Therapeutics. A.J. Fretland: Financial Interests, Personal, Full or part-time Employment: Repare Therapeutics. R. Plummer: Financial Interests, Personal, Advisory Board: Astex Therapeutics; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Biosceptre; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: CV6 Therapeutics; Financial Interests, Personal, Advisory Board: Cybrexa; Financial Interests, Personal, Advisory Board: Ellipses; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Pierre Faber; Financial Interests, Personal, Advisory Board: Sanofi Aventis; Financial Interests, Institutional, Royalties: Clovis Oncology; Financial Interests, Personal, Other, Honoraria as member of IDMC: Beigene; Financial Interests, Personal, Other, Honoraria as member of IDMC: SOTIO. T.A. Yap: Financial Interests, Institutional, Research Grant: Repare Therapeutics; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Artios; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Institutional, Research Grant: Beigene; Financial Interests, Institutional, Research Grant: BioNTech; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Research Grant: Clovis; Financial Interests, Institutional, Research Grant: Constellatior; Financial Interests, Institutional, Research Grant: Cyteir; Financial Interests, Institutional, Research Grant: Eli Lilly; Financial Interests, Institutional, Research Grant: EMD Serono; Financial Interests, Institutional, Research Grant: Forbius; Financial Interests, Institutional, Research Grant: F-Star; Financial Interests, Institutional, Research Grant: GlaxoSmithKline; Financial Interests, Institutional, Research Grant: Genentech; Financial Interests, Institutional, Research Grant: Haihe; Financial Interests, Institutional, Research Grant: ImmuneSensor; Financial Interests, Institutional, Research Grant: Ionis; Financial Interests, Institutional, Research Grant: Ipsen; Financial Interests, Institutional, Research Grant: Jounce; Financial Interests, Institutional, Research Grant: Karyopharm; Financial Interests, Institutional, Research Grant: KSQ; Financial Interests, Institutional, Research Grant: Kyowa; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Regeneron; Financial Interests, Institutional, Research Grant: Rubis; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Research Grant: Scholar Rock; Financial Interests, Institutional, Research Grant: Seattle Genetics; Financial Interests, Institutional, Research Grant: Tesaro; Financial Interests, Institutional, Research Grant: Vivace; Financial Interests, Institutional, Research Grant: Ribon Therapeutics; Financial Interests, Personal, Advisory Role: Repare Therapeutics; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Almac; Financial Interests, Personal, Advisory Role: Aduro; Financial Interests, Personal, Advisory Role: Artios; Financial Interests, Personal, Advisory Role: Athena; Financial Interests, Personal, Advisory Role: Atrin; Financial Interests, Personal, Advisory Role: Axiom; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Calithera; Financial Interests, Personal, Advisory Role: Clovis; Financial Interests, Personal, Advisory Role: Cybrexa; Financial Interests, Personal, Advisory Role: EMD Serono; Financial Interests, Personal, Advisory Role: F-Star; Financial Interests, Personal, Advisory Role: GLG; Financial Interests, Personal, Advisory Role: Guidepoint; Financial Interests, Personal, Advisory Role: Ignyta; Financial Interests, Personal, Advisory Role: I-Mab; Financial Interests, Personal, Advisory Role: ImmuneSensor; Financial Interests, Personal, Advisory Role: Jansen; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Schrodinger; Financial Interests, Personal, Advisory Role: Seattle Genetics; Financial Interests, Personal, Advisory Role: Varian; Financial Interests, Personal, Advisory Role: Zai Labs; Financial Interests, Personal, Advisory Role: Zielbio. All other authors have declared no conflicts of interest.

Background

RP-3500 is an oral inhibitor of ATR (ATRi) in development for the treatment of patients (pts) with advanced solid tumors carrying alterations in ATRi-sensitizing genes. We report popPK co-variates and effect on QT prolongation in 120 pts treated with RP-3500 in the phase 1 TRESR study (NCT04497116).

Methods

PK samples were collected from 120 pts on multiple days across doses and schedules during the dose-finding portion of the study. Pt demographics and baseline characteristics were collected at study enrollment. Triplicate electrocardiograms (ECGs) were collected prior to any drug administration and in conjunction with PK sampling at time points up to 4 hr post-RP-3500 dose. A popPK model was developed using Phoenix WinNonLin. PK co-variates were analyzed to assess the effect of age, sex, body weight (BW), body surface area (BSA), and renal/hepatic function on RP-3500 PK. Changes in ECG parameters were evaluated in an ER assessment.

Results

Plasma PK samples (N=2627) from 120 pts were analyzed; 85 pts were sampled on at least 3 different days. The PK data set encompassed an RP-3500 dose range of 5–200 mg QD and BID across 2 different weekly regimens: 5 days on/2 days off, 3 days on/4 days off. RP-3500 PK was well described using a 2-compartment model with a lag-time incorporated to accurately describe drug absorption. Preliminary co-variate analysis suggested some variation in RP-3500 PK according to BW and BSA. There was no significant impact on PK values in patients with mild renal or hepatic impairment. Among patients with moderate renal impairment, a small reduction in clearance was observed with limited impact on other compartmental PK values. Results of the initial ER assessment showed no RP-3500-related changes in QT intervals.

Conclusions

These popPK results from TRESR confirm a predictable RP-3500 PK profile with low variability. Importantly, the data indicate that RP-3500-induced changes in QT are unlikely, and strongly support further clinical development of RP-3500 with limited ECG evaluation. Further investigation into the potential need for moderate renal impairment-, BW- or BSA-adjusted RP-3500 dosing is ongoing.

Clinical trial identification

NCT04497116.

Editorial acknowledgement

Editorial assistance was provided by Mike Zbreski, PharmD of Onyx Medica, London, UK, supported by Repare Therapeutics Inc.

Legal entity responsible for the study

Repare Therapeutics.

Funding

Repare Therapeutics.

Disclosure

T.A. Yap: Financial Interests, Institutional, Research Grant: Repare Therapeutics; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Artios; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Institutional, Research Grant: Beigene; Financial Interests, Institutional, Research Grant: BioNTech; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Research Grant: Clovis; Financial Interests, Institutional, Research Grant: Constellatior; Financial Interests, Institutional, Research Grant: Cyteir; Financial Interests, Institutional, Research Grant: Eli Lilly; Financial Interests, Institutional, Research Grant: EMD Serono; Financial Interests, Institutional, Research Grant: Forbius; Financial Interests, Institutional, Research Grant: F-Star; Financial Interests, Institutional, Research Grant: GlaxoSmithKline; Financial Interests, Institutional, Research Grant: Genentech; Financial Interests, Institutional, Research Grant: Haihe; Financial Interests, Institutional, Research Grant: ImmuneSensor; Financial Interests, Institutional, Research Grant: Ionis; Financial Interests, Institutional, Research Grant: Ipsen; Financial Interests, Institutional, Research Grant: Jounce; Financial Interests, Institutional, Research Grant: Karyopharm; Financial Interests, Institutional, Research Grant: KSQ; Financial Interests, Institutional, Research Grant: Kyowa; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Regeneron; Financial Interests, Institutional, Research Grant: Rubius; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Research Grant: Scholar Rock; Financial Interests, Institutional, Research Grant: Seattle Genetics; Financial Interests, Institutional, Research Grant: Tesaro; Financial Interests, Institutional, Research Grant: Vivace; Financial Interests, Institutional, Research Grant: Ribon Therapeutics; Financial Interests, Personal, Advisory Role: Repare Therapeutics; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Almac; Financial Interests, Personal, Advisory Role: Aduro; Financial Interests, Personal, Advisory Role: Artios; Financial Interests, Personal, Advisory Role: Athena; Financial Interests, Personal, Advisory Role: Atrin; Financial Interests, Personal, Advisory Role: Axiom; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Calithera; Financial Interests, Personal, Advisory Role: Clovis; Financial Interests, Personal, Advisory Role: Cybrexa; Financial Interests, Personal, Advisory Role: EMD Serono; Financial Interests, Personal, Advisory Role: F-Star; Financial Interests, Personal, Advisory Role: GLG; Financial Interests, Personal, Advisory Role: Guidepoint; Financial Interests, Personal, Advisory Role: Ignyta; Financial Interests, Personal, Advisory Role: I-Mab; Financial Interests, Personal, Advisory Role: ImmuneSensor; Financial Interests, Personal, Advisory Role: Jansen; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Schrodinger; Financial Interests, Personal, Advisory Role: Seattle Genetics; Financial Interests, Personal, Advisory Role: Varian; Financial Interests, Personal, Advisory Role: Zai Labs; Financial Interests, Personal, Advisory Role: Zielbio. E. Fontana: Financial Interests, Personal, Full or part-time Employment: Hospital Corporation of America (HCA) International. D. Spigel: Financial Interests, Institutional, Research Grant: Aeglea Biotherapeutics; Financial Interests, Institutional, Research Grant: Agios; Financial Interests, Institutional, Research Grant: Apollomics; Financial Interests, Institutional, Research Grant: Arcus; Financial Interests, Institutional, Research Grant: Arrys Therapeutics; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Institutional, Research Grant: Beigene; Financial Interests, Institutional, Research Grant: BIND Therapeutics; Financial Interests, Institutional, Research Grant: BioNTech; Financial Interests, Institutional, Research Grant: Blueprint Medicine; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Research Grant: Calithera; Financial Interests, Institutional, Research Grant: Celgene; Financial Interests, Institutional, Research Grant: Celldex; Financial Interests, Institutional, Research Grant: Clovis; Financial Interests, Institutional, Research Grant: Cyteir; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Denovo Biopharma; Financial Interests, Institutional, Research Grant: Eisai; Financial Interests, Institutional, Research Grant: Elevation Oncology; Financial Interests, Institutional, Research Grant: EMD Serono; Financial Interests, Institutional, Research Grant: Evelo Biosciences; Financial Interests, Institutional, Research Grant: G1 Therapeutics; Financial Interests, Institutional, Research Grant: Roche/Genentech; Financial Interests, Institutional, Research Grant: GlaxoSmithKline; Financial Interests, Institutional, Research Grant: GRAIL; Financial Interests, Institutional, Research Grant: Hutchinson MediPharma; Financial Interests, Institutional, Research Grant: ImClone Systems; Financial Interests, Institutional, Research Grant: Incyte; Financial Interests, Institutional, Research Grant: ImmunoGen; Financial Interests, Institutional, Research Grant: Ipsen; Financial Interests, Institutional, Research Grant: Janssen; Financial Interests, Institutional, Research Grant: Kronos Bio; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Research Grant: Loxo Oncology; Financial Interests, Institutional, Research Grant: MacroGenics; Financial Interests, Institutional, Research Grant: MedImmune; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Molecular Partner; Financial Interests, Institutional, Research Grant: Molecular Template; Financial Interests, Institutional, Research Grant: Nektar; Financial Interests, Institutional, Research Grant: Neon Therapeutics; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Novocure; Financial Interests, Institutional, Research Grant: Oncologie; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: PTC Therapeutics; Financial Interests, Institutional, Research Grant: PureTech Health; Financial Interests, Institutional, Research Grant: Razor Genomics; Financial Interests, Institutional, Research Grant: Repare Therapeutics; Financial Interests, Institutional, Research Grant: Rgenix; Financial Interests, Institutional, Research Grant: Takeda; Financial Interests, Institutional, Research Grant: Tizona Therapeutics; Financial Interests, Institutional, Research Grant: Transgene; Financial Interests, Institutional, Research Grant: UT Southwester; Financial Interests, Institutional, Research Grant: Verastem; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Curio Science; Financial Interests, Personal, Advisory Role: EMD Sereno; Financial Interests, Personal, Advisory Role: Evidera; Financial Interests, Personal, Advisory Role: Exelixis; Financial Interests, Personal, Advisory Role: GlaxoSmithKline; Financial Interests, Personal, Advisory Role: Intellisphere; Financial Interests, Personal, Advisory Role: Ipsen; Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Personal, Advisory Role: Jazz Pharmaceuticals; Financial Interests, Personal, Advisory Role: Lilly; Financial Interests, Personal, Advisory Role: Mirati Therapeutics; Financial Interests, Personal, Advisory Role: Molecular Templates; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Novocure; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Puma Biotechnology; Financial Interests, Personal, Advisory Role: Regeneron; Financial Interests, Personal, Advisory Role: Roche/Genentech; Financial Interests, Personal, Advisory Role: Sanofi-Aventis. S. Lheureux: Financial Interests, Personal, Full or part-time Employment: Repare Therapeutics; Financial Interests, Personal, Stocks/Shares: Repare Therapeutics. N.B. Mettu: Financial Interests, Institutional, Research Grant: Repare Therapeutics; Financial Interests, Institutional, Research Grant: Genentech; Financial Interests, Institutional, Research Grant: Mereo BioPharma; Financial Interests, Institutional, Research Grant: OncoMed Pharmaceuticals; Financial Interests, Institutional, Research Grant: Amphivena Therapeutics; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Biomed Valley Discoveries; Financial Interests, Institutional, Research Grant: Erytech Pharma; Financial Interests, Institutional, Research Grant: Incyte Corporation; Financial Interests, Institutional, Research Grant: Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant: Revolution Medicines, Inc; Financial Interests, Institutional, Research Grant: Syros Pharmaceuticals; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Research Grant: Marc Lustgarten Pancreatic Cancer Foundation; Financial Interests, Institutional, Research Grant: Armo BioSciences/Eli Lilly; Financial Interests, Institutional, Research Grant: NIH; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb. R. Plummer: Financial Interests, Personal, Advisory Board: Astex Therapeutics; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Biosceptre; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: CV6 Therapeutics; Financial Interests, Personal, Advisory Board: Cybrexa; Financial Interests, Personal, Advisory Board: Ellipses; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Pierre Faber; Financial Interests, Personal, Advisory Board: Sanofi Aventis; Financial Interests, Institutional, Royalties: Clovis Oncology; Financial Interests, Personal, Other, Honoraria as member of IDMC: Beigene; Financial Interests, Personal, Other, Honoraria as member of IDMC: SOTIO. S. Patel, R. Papp, S. May, M. Koehler: Financial Interests, Personal, Full or part-time Employment: Repare Therapeutics; Financial Interests, Personal, Stocks/Shares: Repare Therapeutics. R. McDougall, P. Nejad, D. Ulanet, M. Wainszelbaum, P. Manley, A.J. Fretland: Financial Interests, Personal, Full or part-time Employment: Repare Therapeutics. M. Højgaard: Other, Personal, Advisory Board: LingoMedical; Financial Interests, Personal, Stocks/Shares: Bavarian Nordic; Financial Interests, Personal, Stocks/Shares: Pacific Biosciences; Financial Interests, Personal, Stocks/Shares: Illumina Inc; Non-Financial Interests, Institutional, Principal Investigator: Amgen; Non-Financial Interests, Institutional, Principal Investigator: Incyte Cooperation; Other, Personal, Member of the Board of Directors: Danish Medicines Council. All other authors have declared no conflicts of interest.

Background

Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) that regulate downstream target genes expression, and then promotes tumor cell proliferation, metastasis and drug resistance. Most of reported EZH2 inhibitors are S-adenosyle-methionine (SAM)-competitive inhibitor, and are less selective for EZH2 close homolog EZH1, which resulted in safety concerns and insufficient efficacy. To obtain irreversible EZH2 inhibitor, a novel covalent inhibitor was developed and characterized.

Methods

SKLB-0322 and its derivatives were designed, synthesized and confirmed as EZH2 covalent inhibitor by us. The mechanism of covalent binding of SKLB-0322 was confirmed by SAM competition experiments, mass spectrometry, and washing-out assays. Furthermore, the anti-tumor activities of SKLB-0322 were investigated by MTT assay, colony formation assay, flow cytometry, western blot assay, and xenograft model. The reversible analogue of SKLB-0322 (SKLB-0322') was used as negative control.

Results

SAM competition experiments, mass spectrometry, and washing-out assays confirmed SKLB-0322 could selectively covalently bind to the SAM pocket of EZH2, while exhibited weak activity against other histone methyltransferases. Nevertheless, the inhibitory activities of SKLB-0322' was reduced. Anti-proliferation activities of SKLB-0322 against different human cancer cells' result showed that ovarian cancer cell lines were most sensitive to SKLB-0322. Meanwhile, ovarian cancer cells treated with SKLB-0322 exhibited effects consistent with EZH2 protein expression. Besides, SKLB-0322 inhibited the proliferation of PA-1 and A2780 cells in a time- and concentration-dependent manner. Furthermore, SKLB-0322 induced A2780 and PA-1 cell apoptosis and reduced the expression level of H3K27me3 in a concentration-dependent manner, which was about 5-fold more active than the reversible negative control SKLB-0322'. Additionally, in a xenograft model of PA-1, oral administration of SKLB-0322 inhibited tumor growth in a dose-dependent manner without side effect.

Conclusions

Our data clarified that SKLB-0322 is an EZH2 covalent inhibitor for ovarian cancer therapy which is worthy of further evaluation.

Legal entity responsible for the study

The authors.

Funding

This study was supported by the Science and Technology Program of Sichuan Province [grant number 2021YFH0145], and the National Natural Science Foundation of China [grant number 82073687].

Disclosure

All authors have declared no conflicts of interest.

Background

Diffuse large B cell lymphomas (DLBCL) are aggressive tumours with frequent aberrations in epigenetic proteins. Histone deacetylase inhibitors (HDACi) are epigenetic agents with pre-clinical and clinical efficacy in lymphomas. Here we investigated the in vitro anti-lymphoma activities of eight novel HDAC6 inhibitors (HDAC6i) in DLBCL.

Methods

MTT assay was used to assess the anti-proliferative activities of HDAC6i: SS-2-08, SS-5-55, SW- 101, SW-113, SW-114, SW-115, SW-117 and WT-36-87, alone or combined with venetoclax or copanlisib (72 hours [h] ) in DLBCL cells: DOHH2, OCI-LY-18 (BCL2 and MYC translocated); SU-DHL-4, OCI-LY-1 (BCL2 translocated and MYC amplified). The Chou-Talalay combination index (CI) determined additive effect (CI 0.9-1.1), synergism (CI 0.3-0.9) and antagonism (CI > 1.1). For cell cycle analysis by flow cytometry, cells were fixed in 70% ethanol then stained with 7-AAD. Western blotting determined levels of acetylated α-tubulin.

Results

Median IC50 values for the eight HDAC6i ranged from 0.6 μM to 19.3 μM. SW-101, SW-117, SS-2-08 and WT-36-87 showed the strongest anti-proliferative activities. SW-117 was the most potent (range 0.2 - 2 μM; median 0.6 μM). DLBCLs treated with median IC50s of SW-101, SW-117, SS-2-08 and WT-36-87 for 72 h underwent G1 arrest and cell death. The most potent HDAC6i, SW-117 (with a potency of 0.3 nM for HDAC6), increased acetylated α-tubulin levels at 4 h and this upregulation persisted to 72 h. The three most active HDAC6i (SW-117, SW-101, WT-36-87), plus SW-113 that showed negligible activity as a single agent, were tested in combination with the PI3Kα/δ inhibitor copanlisib and the BCL2 inhibitor venetoclax, in DOHH2 and SU-DHL-4. All four HDAC6i showed enhanced anti-proliferative activity in at least one of the combinations tested. SW-117 and SW-101 showed similar benefit when combined with either copanlisib or venetoclax.

Conclusions

We observed robust in vitro anti-lymphoma activity of novel HDAC6i in DLBCL cells. Our results suggest that these agents are worthy of further pre-clinical investigation in DLBCL as single agents and in combination with other targeted anti-lymphoma drugs.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

W. Tueckmantel: Financial Interests, Personal, Member: Bright Minds Biosciences. A. Kozikowski: Financial Interests, Personal, Member of the Board of Directors: Bright Minds Biosciences. All other authors have declared no conflicts of interest.

Background

Circulating tumor DNA (ctDNA) represents a promising tool for diagnosis, prognosis and treatment monitoring of several malignant diseases. We aimed to investigate ctDNA as an early marker of response to treatment.

Methods

Liquid biopsy for ctDNA detection was prospectively obtained from patients with stage IV pancreatic ductal adenocarcinoma (PDAC, n=47) and colorectal cancer (CRC, n=64) prior to systemic treatment. Pretherapeutic detection rates and change of ctDNA levels undergoing palliative chemotherapy in serial measurements (digital droplet PCR) were evaluated for response according to RECIST.

Results

ctDNA was detectable in 57.4% of PDAC and 85.9% of CRC samples prior to treatment initiation. Furthermore, when detectable, median mutant allele fraction (MAF) was 10-fold higher (p<0.000) in CRC (11.80%, IQR 2.02-31.30) compared with PDAC (1.15%, IQR 0.26-6.48), despite comparable treatment lines (p=0.690). Progressive disease (PD) was detectable at a median of 15 days (IQR 9-21) (PDAC) and 28 days (IQR 14-43) (CRC) respectively. Non-progressive disease (non-PD) was displayed by ctDNA courses at a median of 15 days (IQR 12.25-24.5) (PDAC) and 24.5 days (IQR 14-29.75) (CRC). Thus, lead time was 15 days (16.7%) and 25 days (27.8%) compared with conventional computed tomography (after 3 months) in the course of clinical routine.

Conclusions

Apart from prediction of worse clinical outcome, ctDNA offers the potential early change of treatment within the first month of systemic chemotherapy by serial liquid biopsy in both pancreatic and colorectal cancer.

Legal entity responsible for the study

Holger Rumpold.

Funding

Vinzenzgruppe Austria, Krebshilfe Oberösterreich.

Disclosure

All authors have declared no conflicts of interest.

Background

Ewing sarcoma (EW) and Myxoid liposarcoma (ML) are characterized by the fusion of RNA-binding proteins EWSR1 or FUS with transcription factors. These fusion proteins aberrantly promote oncogenic gene expression profiles. The association of Lysine Specific Demethylase 1 (LSD1) with FET family oncogenic transcription factors is critical for FET-rearranged sarcoma development and progression. We aim to characterize the functional relationship of LSD1 and the oncogenic fusion proteins in EW and ML, as well as the anti-tumor effect of disrupting those interactions. SP-2577 is an oral, first-in-class, small molecule with reversible, noncompetitive inhibition of LSD1 demethylase activity (IC₅₀: 25–50 nM). SP-2509, an SP-2577 analog, demonstrates in vitro reversal of EWS/ETS mediated transcriptional regulation in EW. We previously reported that SP-2577 reduces the viability of EW and ML in vitro.

Methods

In this study, we set out to 1) evaluate the similarities of SP-2577-induced transcriptional alterations compared to published in vitro EWS/FLI or LSD1 knockdown and response to SP-2509 and 2) elucidate the changes in LSD1 protein-complexes following SP-2577 treatment. To evaluate the similarities of SP-2577-induced transcriptional alteration to published data, we treated A673 (EW), 1765-92 (ML), and 402-91 (ML) cells with SP-2577 at the established IC50 and IC90s for 24 and 48 hours and performed RNA-seq. Resulting transcriptional profiles were compared to A673 SP-2509, EWS/FLI knockout (KO), and LSD1 KO datasets published in Sankar, S. 2014, Sankar, S. 2013, and Pishas, K. et al 2018, respectively.

Results

The data reveal a concordance between SP-2577 and SP-2509 treatment, LSD1 KO, and EWS/FLI KO. To identify changes to LSD1-containing protein complexes, we performed Rapid Immunoprecipitation and Mass Spectrometry of Endogenous Proteins (RIME) in A673 after 48hrs of treatment at 2μM. Following SP-2577 treatment, LSD1 retained interactions with LCH, BHC, and NuRD complexes, but showed decreased interactions with multiple constituents of these complexes.

Conclusions

These data provide evidence for similar oncogenic transcriptional mechanisms controlled by LSD1 in FET-rearranged sarcomas and begin to define a signature of SP-2577 response.

Legal entity responsible for the study

Nationwide Children’s Hospital and Salarius Pharmaceuticals, Inc.

Funding

Salarius Pharmaceuticals, Inc; Cancer Prevention and Research Institute of Texas (grant ID: DP160014).

Disclosure

E. Theisen: Financial Interests, Institutional, Funding: Salarius Pharmaceuticals. A. Duncan, D. Santiesteban: Financial Interests, Personal, Full or part-time Employment: Salarius Pharmaceuticals. All other authors have declared no conflicts of interest.

Background

Oral squamous cell carcinoma (OSCC) is an aggressive disease that has substantial impacts on global health. RNA N6-Methyladenosine (m6A) modification is an emerging player in the posttranscriptional regulation of gene expression. m6A is a reversible modification and regulated by specific enzymes. METTL3 is a master regulator enzyme of m6A modification and its dysregulation is strongly associated with different types of cancer including OSCC. Here, we describe the development of STM2457, a new class of highly potent and selective, small-molecule inhibitor of METTL3 for OSCC treatment.

Methods

The expression and clinical implication of METTL3 were investigated in OSCC patients. The underlying mechanisms of METTL3 in OSCC were investigated using OSCC cell lines. Efficacy analysis of STM2457 against OSCC was elucidated in OSCC cell lines and patient-derived OSCC organoids.

Results

The m6A levels and METTL3 expression were increased in OSCC patients and OSCC cell lines. Clinically, increased expression of METTL3 indicated poor survival and adverse pathological features. Functionally, knockdown of the METTL3 gene in OSCC cells dramatically inhibited cellular proliferation, invasion and colony formation. Furthermore, STM2457 treatment exerted potential anti-tumorigenic and anti-metastatic activity in OSCC cells and patient-derived OSCC organoids through reduced m6A level, cell proliferation, cell viability and increased apoptosis.

Conclusions

Thus, we propose METTL3 inhibition as a novel and potent therapeutic option for OSCC.

Legal entity responsible for the study

The authors.

Funding

Indian Council of Medical Research (DHR-GIA, 2020-9530 to A. Paramasivam), Government of India.

Disclosure

All authors have declared no conflicts of interest.

Background

Avdoralimab (IPH5401) is a monoclonal antibody that inhibits the binding of the complement factor C5a to the receptor C5aR1. Preclinical analysis revealed that inhibition of C5a/C5aR1 axis limited myeloid derived suppressor cells (MDSCs) and increased CD8 T-cell tumor infiltration, promoting tumor reduction and limiting metastatic potential. Furthermore, the combined use of C5a/C5aR1 inhibition and anti-PD(L)1 therapy (IO) was shown to be superior to each modality alone in terms of reducing tumor volume and improving survival in several preclinical murine models.

Methods

This is a phase I, multicenter study of avdoralimab (15 mg/kg weekly) in combination with durvalumab (1500 mg every 4 weeks) to evaluate safety, preliminary anti-tumor activity according to RECIST1.1 and drug profile in patients (pts) with advanced NSCLC or HCC previously treated with 1 or 2 lines of standard systemic therapies, cohorts up to 40 pts were planned with a 2-stage design.

Results

As of May 27, 2021, 46 pts were enrolled in the expansion part, 21 NSCLC IO pretreated, 21 HCC IO naive and 4 HCC IO pretreated. Median age was 64 years (42-86), 76% were male, 61% had a performance score of 1. The most frequent adverse events (AEs) were asthenia (50%), cough (24%) and pruritus (24%), 11 pts (24%) reported AEs Grade 3 or higher, the most frequent was dyspnea (4%). A total of 31 (67%) pts experienced AE considered as related to avdoralimab, the most frequent were diarrhea, fatigue and pruritus (11% each). Serious related AEs were reported in 3 (6.5%) pts (colitis, liver injury, infusion related injection). Discontinuation rate due to an AE was 8.7%. In the HCC IO naïve cohort, the objective response rate was 4.8% (95% CI: 0.1-23.8) with a median duration of response of 8.3 months (6.5, 10.1). No responses were observed in the other cohorts. Stable disease was observed in 12 (57.1%) HCC IO naïve and 13 (61.9%) NSCLC IO pretreated pts. The median PFS was 3.4 (1.7-5.3) months for the HCC IO naïve cohort and 3.5 (1.9-5.6) months for the NSCLC cohort.

Conclusions

The combination of avdoralimab and durvalumab was well tolerated, minimal anti-tumor activity in the expansion cohorts led to early termination of the study. Further exploration of translational data is ongoing.

Clinical trial identification

NCT03665129.

Legal entity responsible for the study

Innate Pharma.

Funding

Innate Pharma.

Disclosure

J. Bennouna: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: F. Hoffmann-La Roche; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: MedImmune; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Research Grant: F. Hoffmann-La Roche; Financial Interests, Institutional, Research Grant: Innate Pharma; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Personal, Expert Testimony: AstraZeneca; Financial Interests, Personal, Expert Testimony: Bayer; Financial Interests, Personal, Expert Testimony: BMS; Financial Interests, Personal, Expert Testimony: F. Hoffmann-La Roche; Financial Interests, Personal, Expert Testimony: Merck; Financial Interests, Personal, Expert Testimony: MSD; Financial Interests, Personal, Expert Testimony: Daiichi Sankyo. Y. Touchefeu: Financial Interests, Personal, Advisory Board: AstraZeneca. F. Ghiringhelli: Other, Personal, Invited Speaker: F. Hoffmann-La Roche; Other, Personal, Invited Speaker: ASTRA; Other, Personal, Invited Speaker: MSD; Other, Personal, Invited Speaker: BMS; Financial Interests, Institutional, Research Grant: F. Hoffmann-La Roche; Financial Interests, Institutional, Research Grant: ASTRA; Financial Interests, Institutional, Research Grant: Amgen. F. Barlesi: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Eli Lilly Oncology; Financial Interests, Personal, Advisory Board: F. Hoffmann-La Roche; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Mirati Therapeutics; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Personal, Advisory Board: Pfizer P. Tomasini: Financial Interests, Personal, Expert Testimony: F. Hoffmann-La Roche; Financial Interests, Personal, Expert Testimony: AstraZeneca; Financial Interests, Personal, Expert Testimony: BI; Financial Interests, Personal, Expert Testimony: BMS; Financial Interests, Personal, Expert Testimony: Takeda; Financial Interests, Personal, Expert Testimony: Amgen; Financial Interests, Personal, Expert Testimony: AbbVie; Financial Interests, Personal, Expert Testimony: Daiichi Sankyo. P. Cassier: Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Personal, Advisory Role: ITeoas Therapeutics; Financial Interests, Personal, Advisory Role: Ose Immunitherapeutics; Financial Interests, Institutional, Funding: Novartis, Roche, Lilly, Bayer, Celgene, AbbVie, Plexxikon, BMS, Merck, Taiho, Toray, TransgeneLoxo, GlaxoSmithKline, Janssen; Financial Interests, Institutional, Funding: Innate Pharma; Financial Interests, Institutional, Funding: AstraZeneca. J. Edeline: Financial Interests, Personal, Expert Testimony: MSD; Financial Interests, Personal, Expert Testimony: Eisai Co.; Financial Interests, Personal, Expert Testimony: BMS; Financial Interests, Personal, Expert Testimony: AstraZeneca; Financial Interests, Personal, Expert Testimony: F. Hoffmann-La Roche; Financial Interests, Personal, Expert Testimony: Ipsen; Financial Interests, Personal, Expert Testimony: BASILEA; Financial Interests, Personal, Expert Testimony: Bayer; Financial Interests, Personal, Expert Testimony: Merck Serono; Financial Interests, Personal, Expert Testimony: INCYTE; Financial Interests, Personal, Expert Testimony: Servier; Financial Interests, Personal, Expert Testimony: BeiGene; Financial Interests, Institutional, Research Grant: BeiGene; Financial Interests, Institutional, Research Grant: BMS. S.M. Le Sourd: Financial Interests, Personal, Advisory Board: Servier; Financial Interests, Personal, Advisory Board: BTG; Financial Interests, Personal, Advisory Board: Ipsen. A.W. Tolcher: Financial Interests, Personal, Advisory Role: AbbVie; Financial Interests, Personal, Advisory Role: Aclaris Therapeutics; Financial Interests, Personal, Advisory Role: Agenus; Financial Interests, Personal, Advisory Role: Asana BioSciences; Financial Interests, Personal, Advisory Role: Ascentage Pharma; Financial Interests, Personal, Advisory Role: AxImmune; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: BluPrint Oncology; Financial Interests, Personal, Advisory Role: Daiichi Sankyo; Financial Interests, Personal, Advisory Role: Gilde Healthcare; Financial Interests, Personal, Advisory Role: HBM Partners; Financial Interests, Personal, Advisory Role: Immuneering; Financial Interests, Personal, Advisory Role: ImmunoMet Therapeutics; Financial Interests, Personal, Advisory Role: Impact Therapeutics US; Financial Interests, Personal, Advisory Role: Karma Oncology; Financial Interests, Personal, Advisory Role: Lengo Therapeutics; Financial Interests, Personal, Advisory Role: Mekanistic Therapeutics; Financial Interests, Personal, Advisory Role: Menarini Ricerche; Financial Interests, Personal, Advisory Role: Mersana; Financial Interests, Personal, Advisory Role: Nanobiotix; Financial Interests, Personal, Advisory Role: Ocellaris Pharma; Financial Interests, Personal, Advisory Role: Partner Therapeutics; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Pierre Fabre; Financial Interests, Personal, Advisory Role: Ryvu Therapeutics; Financial Interests, Personal, Advisory Role: Seattle Genetics; Financial Interests, Personal, Advisory Role: SK Life Science; Financial Interests, Personal, Advisory Role: Sotio Biotecnology; Financial Interests, Personal, Advisory Role: Spirea Limited; Financial Interests, Personal, Advisory Role: Sunshine Guojian Pharmaceutical; Financial Interests, Personal, Advisory Role: Transcenta Therapeutics; Financial Interests, Personal, Advisory Role: Trillium Therapeutics; Financial Interests, Personal, Advisory Board: Adagene; Financial Interests, Personal, Advisory Board: ARO Biotherapeutics; Financial Interests, Personal, Advisory Board: Bioinvent; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Deka Biosciences; Financial Interests, Personal, Advisory Board: Eleven Bio; Financial Interests, Personal, Advisory Board: Elucida; Financial Interests, Personal, Advisory Board: EMD Serono/Merck; Financial Interests, Personal, Advisory Board: Hiber Cell; Financial Interests, Personal, Advisory Board: Ikena Oncology; Financial Interests, Personal, Advisory Board: Immunome; Financial Interests, Personal, Advisory Board: Janssen Global Services; Financial Interests, Personal, Advisory Board: NBE Therapeutics; Financial Interests, Personal, Advisory Board: Pelican; Financial Interests, Personal, Advisory Board: Pieris Pharma; Financial Interests, Personal, Advisory Board: Pyxis Oncology; Financial Interests, Personal, Advisory Board: Vincerx; Financial Interests, Personal, Advisory Board: Zielbio; Financial Interests, Personal, Advisory Board: Zymeworks Biopharmaceuticals; Financial Interests, Personal, Expert Testimony: Mirati Therapeutics. D.B. Marie, J. Viotti, A. Boyer Chammard: Financial Interests, Personal, Full or part-time Employment: Innate Pharma. All other authors have declared no conflicts of interest.