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LBA38 - Bexmarilimab, a novel macrophage re-programmer shows promising anti-tumour activity in phase I/II trial in several last line solid tumour types
- Petri Bono (Helsinki, Finland)
Abstract
Background
Bexmarilimab (FP-1305) is a novel humanized anti-CLEVER-1 IgG4-antibody capable of inducing a phenotypic M2 to M1 immune switch of tumor-associated macrophages.
Methods
MATINS (Macrophage Antibody To INhibit immune Suppression) trial is a three-part, first-in-human phase I/II study (NCT03733990) to assess safety and preliminary efficacy of Bexmarilimab in patients with advanced solid tumours. The Part I was recently completed (Bono et al., ESMO 2020). In Part II, 10 distinct solid tumour types were enrolled to assess tolerability, safety and preliminary efficacy (overall survival (OS), progression free survival (PFS), and disease control rate (DCR; PR+SD)).
Results
Between Dec 2018 and Jul 2021, 159 patients were enrolled into Part I (n=30; 0.1 - 10 mg/kg), and into Part II (n=129; 0.3 – 3.0 mg/kg), and received 1-12 doses (median 3) of Bexmarilimab every three weeks (q3w). Median follow-up was 2.1 months (range, 0.5 to 8.2). Total of 185 serious Treatment Emergent Adverse Events (TEAEs; 17.7% of all TEAEs) were reported. 13 were related to the study drug. The most common TEAEs were fatigue (31% of patients), abdominal pain (23%) and anaemia (21%). Part I and Part II fully enrolled 11 cancer cohorts (n=138 for tumor and survival analysis), the median PFS was 59 days (95% CI 58 - 61) and the median OS was 151 days (95% CI 118 - 190) at the data cut. DCR for Part II was 17.3% (19/110) at cycle 4 of treatment (by RECIST v.1.1). Six-month survival rate (based on the current Kaplan-Meier estimates) was 82.5% for DCR patients compared to 27.1% for non-DCR patients, with a similar length of prior therapy in both groups. Notably, 34% DCR at cycle 4 was seen in cutaneous melanoma (3/10), gastric cancer (3/10), cholangiocarcinoma (3/10), breast cancer (4/10) and hepatocellular cancer (4/10).
Conclusions
This phase I/II study with Bexmarilimab in patients with advanced solid tumours demonstrates good initial safety and tolerability, and promising anti-tumour activity as a monotherapy in several refractory metastatic solid tumours. Further expansion of the study will investigate optimal dosing, biomarkers of efficacy and Bexmarilimab’s potential for combination with earlier lines of therapy.
Legal entity responsible for the study
Faron Pharmaceuticals.
Funding
Faron Pharmaceuticals.
Disclosure
P. Bono: Financial Interests, Personal, Advisory Role: Faron Pharmaceuticals; Financial Interests, Personal, Stocks/Shares: TILT Biotherapeutics; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Oncorena; Financial Interests, Personal, Advisory Board: Herantis Pharma; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: Ipsen; Financial Interests, Personal, Stocks/Shares: Terveystalo. S. Shetty: Financial Interests, Personal, Advisory Board: Faron Pharmaceuticals. S. Jalkanen: Financial Interests, Personal, Ownership Interest: Faron Pharmaceuticals. M. Hollmen: Financial Interests, Personal, Ownership Interest: Faron Pharmacuticals. J. Mandelin: Financial Interests, Personal, Stocks/Shares: Faron Pharmaceuticals. M.K. Karvonen: Financial Interests, Personal, Stocks/Shares: Faron Pharmaceuticals. J.P. Koivunen: Financial Interests, Personal, Advisory Board: Faron Pharmaceuticals. All other authors have declared no conflicts of interest.
957O - Long-term follow-up of patients (pts) with human papillomavirus (HPV)–associated malignancies treated with bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1
- James Gulley (Bethesda, MD, United States of America)
Abstract
Background
Anti–PD(L)1 agents have activity in HPV-associated cancers (HAC), with median overall survival (mOS) of ≤12 months (mos). HPV infection has been linked to upregulation of tumor TGF-β signaling. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1. Previously we reported a post hoc pooled analysis of pts with HAC treated with bintrafusp alfa. Here we report longer follow-up of additional pts with HAC pooled from phase (Ph) 1 (INTR@PID 001; NCT02517398) and Ph 2 (study 012; NCT03427411) studies.
Methods
Pts with advanced, pretreated, immune checkpoint inhibitor (ICI)–naive HAC who had exhausted standard-of-care treatment received bintrafusp alfa 0.3-30 mg/kg (Ph 1 dose escalation) or 1200 mg Q2W (Ph 1 expansion/Ph 2) until progressive disease, unacceptable toxicity, or withdrawal. Treatment past progression was allowed. Primary endpoints were safety (Ph 1 dose escalation) and best overall response per RECIST v1.1 (Ph 1 expansion/Ph 2).
Results
As of 15 May 2020 (Ph 1) and 22 December 2020 (Ph 2), 75 pts with pretreated HAC (cervical 39, SCCHN 19, anal 9, other 8) had received bintrafusp alfa for a median duration of 3.2 mos (range, 0.5-29.9 mos) and been followed for a median of 33 mos; 3 pts remained on treatment. ORR was 28.0% [4 CRs; 17 PRs]; 3 more pts had a delayed PR, for a clinical response rate (RECIST response + delayed response) of 32.0%. Responses occurred in various HAC. Median duration of response (mDOR) was 17.3 (95% CI, 7.8-NE) mos. Median OS was 21.3 (95% CI, 10.8-NE) mos; 12- and 18-mo OS rates were 59.7% and 51.5%, respectively. The most common treatment-related adverse events (TRAEs) were pruritus (25.3%, all events grade 1), dermatitis acneiform (24.0%, all grade 1), and anaemia (18.7%, grade 3 [6.7%]); no deaths due to TRAEs were observed.
Conclusions
Bintrafusp alfa showed long-term efficacy (mDOR 17.3 mos, mOS 21.3 mos) and a manageable safety profile in pts with pretreated, ICI-naive HAC, a pt population with a high unmet need. Clinical trials of bintrafusp alfa in HAC are ongoing.
Clinical trial identification
INTR@PID 001: NCT02517398; Study 012: NCT03427411.
Editorial acknowledgement
Medical writing support was provided by Marci Daugherty, PharmD of ClinicalThinking, Inc, Hamilton, NJ, USA, and funded by Merck KGaA, Darmstadt, Germany, and GlaxoSmithKline.
Legal entity responsible for the study
Merck KGaA, Darmstadt, Germany.
Funding
Merck KGaA, Darmstadt, Germany, and GlaxoSmithKline.
Disclosure
J. Strauss: Financial Interests, Personal, Other, listed as a coinventor on an NIH patent: National Institutes of Health. B.C. Cho: Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: MOGAM Institute; Financial Interests, Institutional, Research Grant: Dong-A ST; Financial Interests, Institutional, Research Grant: Champions Onocology; Financial Interests, Institutional, Research Grant: Janssen; Financial Interests, Institutional, Research Grant: Yuhan; Financial Interests, Institutional, Research Grant: Ono; Financial Interests, Institutional, Research Grant: Dizal Pharma; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Abbvie; Financial Interests, Institutional, Research Grant: Medpacto; Financial Interests, Institutional, Research Grant: GIInnovation; Financial Interests, Institutional, Research Grant: Eli Lilly; Financial Interests, Institutional, Research Grant: Blueprint Medicines; Financial Interests, Institutional, Research Grant: Interpark Bio Convergence Corp; Financial Interests, Personal, Advisory Role: KANAPH Therapeutic Inc.; Financial Interests, Personal, Advisory Role: Bridgebio Therapeutics; Financial Interests, Personal, Advisory Role: Cryrus Therapeutics; Financial Interests, Personal, Advisory Role: Gaurdant Health; Financial Interests, Personal, Stocks/Shares: TheraCanVac Inc.; Financial Interests, Personal, Stocks/Shares: Gencurix Inc.; Financial Interests, Personal, Stocks/Shares: Bridgebio Therapeutics; Financial Interests, Personal, Stocks/Shares: KANAPH Therapeutic Inc.; Financial Interests, Personal, Stocks/Shares: Cyrus Therapeutics; Financial Interests, Personal, Stocks/Shares: Interpark Bio; Financial Interests, Personal, Stocks/Shares: Convergence Corp; Financial Interests, Personal, Other, Consulting Role: Novartis; Financial Interests, Personal, Other, Consulting Role: AstraZeneca; Financial Interests, Personal, Other, Consulting Role: Boehringer-Ingelheim; Financial Interests, Personal, Other, Consulting Role: Roche BMS; Financial Interests, Personal, Other, Consulting Role: Ono; Financial Interests, Personal, Other, Consulting Role: Yuhan; Financial Interests, Personal, Other, Consulting Role: Pfizer; Financial Interests, Personal, Other, Consulting Role: Eli Lilly; Financial Interests, Personal, Other, Consulting Role: Janssen; Financial Interests, Personal, Other, Consulting Role: Takeda; Financial Interests, Personal, Other, Consulting Role: MSD; Financial Interests, Personal, Other, Consulting Role: Medpacto; Financial Interests, Personal, Other, Consulting Role: Blueprint Medicines; Financial Interests, Personal, Other, Board of Director: Interpark Bio Convergence Corp.; Financial Interests, Personal, Royalties: Champions Oncology; Financial Interests, Personal, Other, Founder: DAAN Biotherapeutics. S. Salas: Financial Interests, Personal, Full or part-time Employment: Bristol-Myers Squibb; Financial Interests, Institutional, Research Grant: Merck & Co.; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Bristol-Myers Squibb. E. McClay: Financial Interests, Personal, Speaker’s Bureau: Bristol-Myers Squibb; Financial Interests, Personal, Speaker’s Bureau: Merck; Financial Interests, Personal, Speaker’s Bureau: Pfizer. E. Lamping: Financial Interests, Personal, Full or part-time Employment: NCI/NIH. G. Jehl: Financial Interests, Personal, Full or part-time Employment: Merck KGaA. L.S. Ojalvo: Financial Interests, Personal, Full or part-time Employment: EMD Serono Research & Development Institute, Inc.; Financial Interests, Personal, Other, IP/Patent holder: EMD Serono Research & Development Institute, Inc. J. Gulley: Financial Interests, Institutional, Other, NCI has a cooperative research and development agreement: EMD Serono / Merck KGaA. All other authors have declared no conflicts of interest.
958O - Coordinated activation of antitumor responses of g9d2 and CD8 T-cells by targeting BTN3A with ICT01 in patients with solid tumors: EVICTION trial
- Aurélien Marabelle (Villejuif, France)
Abstract
Background
g9d2 T-cells function at the crossroad of innate and adaptive antitumor immunity, infiltrate into most tumors, and are MHC-independent killers of tumors. Butyrophilin (BTN) 3A is an immune checkpoint molecule expressed on tumors and immune cells that is part of the stress response that activates g9d2 T-cells. ICT01, an anti-BTN3A mAb targeting all 3 isoforms of BTN3A, induces pAg-independent g9d2 T-cell activation and
Methods
EVICTION (EudraCT: 2019-003847-31) is a FIH, open-label, basket trial assessing safety, tolerability and activity of ICT01 monotherapy and in combination with pembrolizumab (200 mg IV Q3W), in advanced cancer patients with no available standard of care. Blood samples were collected for target occupancy (TO), immunophenotyping and cytokine analysis (IFNg, TNFa, IL-1b/2/4/6/8/10/12/13). Tumor biopsies (baseline, Day 28) were used for IHC of BTN3A and tumor-infiltrating lymphocytes, and gene expression profiling.
Results
Dose escalation from 20μg to 200mg IV ICT01 Q3W in solid tumor patients (n=32) and 2 dose cohorts of ICT01 (700μg, 2mg) plus Pembro (n=7) were completed without DLTs. First-dose fever and chills (Grade 1/2) were the most common AEs that increased in frequency but not severity with dose, and did not recur. BTN3A TO on circulating T-cells by ICT01 reached 100% within 30 minutes at doses ≥7 mg, which lasted at least 24h (20 mg) or 7 days (≥75 mg). ICT01 induced a >95% decrease from baseline of circulating γ9δ2 T-cells within 30 min post ICT01 (≥2 mg), which was sustained for 21 days at doses ≥75 mg. Transient, dose-dependent increases in serum cytokines at 30 min (TNFα) or 4h (IFNγ) post-dose were correlated with baseline γ9δ2 T-cell counts and led to activation and migration of NK and CD8 T-cells out of the blood at doses ≥7 mg. Paired tumor biopsies indicated that high baseline g9d2 T-cell counts were associated with significant ICT01-related intra-tumoral increases in γδ, CD3 and CD8 T-cells, and adaptive immunity using the Immunosign21 gene signature.
Conclusions
ICT01-activated g9d2 T-cells orchestrate a broad antitumor immune response that supports cohort expansion.
Clinical trial identification
NCT04243499; EudraCT: 2019-003847-31.
Legal entity responsible for the study
ImCheck Therapeutics.
Funding
ImCheck Therapeutics.
Disclosure
A. Marabelle: Financial Interests, Personal, Advisory Board: ImCheck. J. de Bono: Financial Interests, Personal, Advisory Board: ImCheck. P. Lorusso: Financial Interests, Personal, Advisory Board: ImCheck. D. Olive: Financial Interests, Personal, Stocks/Shares: ImCheck. P.A. Frohna: Financial Interests, Personal, Full or part-time Employment: ImCheck. All other authors have declared no conflicts of interest.
Invited Discussant LBA38, 957O and 958O
- Sebastian Kobold (Munich, Germany)
Q&A and live discussion
- Aurélien Marabelle (Villejuif, France)
959O - Gavocabtagene autoleucel (gavo-cel, TC-210) dose escalation in refractory mesothelin-expressing solid tumors
- David S. Hong (Houston, TX, United States of America)
Abstract
Background
The safety and activity of gavo-cel is being evaluated in a dose-escalation study in patients (pts) with refractory ovarian cancer, malignant mesothelioma (MPM), cholangiocarcinoma (ChoCa), or non-small cell lung cancer.
Methods
Dose escalation follows a 3+3 design. Autologous T-cells were transduced with a T-cell receptor fusion construct (TRuC™) encoding an anti-MSLN single domain antibody fused to the CD3ε subunit. The TRuC then integrates into native TCRs, allowing HLA-independent T-cell engagement to MSLN on cancer cells. Eligibility required central confirmation of 2+ or 3+ MSLN expression by IHC in ≥50% of tumor cells.
Results
As of April 28th, 2021, 17 pts (12 MPM, 4 ovarian, 1 ChoCa) had received a single IV dose of gavo-cel at 5x107/m2 either alone (dose level [DL] 0, n=1) or after lymphodepletion (LD) (DL1, n=6), at 1x108/m2 either alone (DL2, n=1) or after LD (DL3, n=5), or at 5x108/m2 either alone (DL4, n=1) or after LD (DL5, n=3). Median number of prior therapies was 5 (range, 2-9, immune checkpoint inhibitors 65%, anti-MSLN agents 33%). Bridging therapy was required by 53% of pts. Twelve pts were evaluable for safety and efficacy. One DLT (gr3 pneumonitis at DL1) and 2 gr3 CRS events were reported, both resolving with tocilizumab/corticosteroids. Median target lesion regression was 24% (range 5-75%). DCR was 92%. Two pts with ICI-refractory MPM and 1 with
Conclusions
The toxicity profile of gavo-cel was manageable. Activity was observed among pts with refractory MSLN-expressing solid tumors. Dose escalation is ongoing to determine the RP2D.
Clinical trial identification
NCT03907852.
Legal entity responsible for the study
TCR2 Therapeutics.
Funding
TCR2 Therapeutics.
Disclosure
D.S. Hong: Financial Interests, Institutional, Principal Investigator: TCR2 Therapeutics. S.L. SciMentum: Financial Interests, Institutional, Principal Investigator: TCR2 Therapeutics. J. Tanyi: Financial Interests, Institutional, Principal Investigator: TCR2 Therapeutics. L. MacMullen: Financial Interests, Personal, Full or part-time Employment: TCR2 Therapeutics. L. Jalbert: Financial Interests, Personal, Full or part-time Employment: TCR2 Therapeutics. V.P. Muzithras: Financial Interests, Personal, Full or part-time Employment: TCR2 Therapeutics. K. Zikaras: Financial Interests, Personal, Full or part-time Employment: TCR2 Therapeutics. R.E. O’Cearbhaill: Financial Interests, Institutional, Principal Investigator: TCR2 Therapeutics. A. Quintás-Cardama: Financial Interests, Personal, Full or part-time Employment: TCR2 Therapeutics. R. Hassan: Financial Interests, Institutional, Principal Investigator: TCR2 Therapeutics. All other authors have declared no conflicts of interest.
Invited Discussant 959O
- Alessandra Curioni (Zurich, Switzerland)
Q&A and live discussion
- Alessandra Curioni (Zurich, Switzerland)