M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with heavily pretreated CRC: Preliminary results from a phase I trial.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 764-764 ◽  
Author(s):  
Scott Kopetz ◽  
Alexander I. Spira ◽  
Michael Wertheim ◽  
Edward Kim ◽  
Benjamin R. Tan ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Transforming Growth Factor ◽  
Molecular Subtype ◽  
Phase 1 ◽  
Unmet Need ◽  
Primary Objective ◽  
Open Label ◽  
Programmed Death ◽  
Heavily Pretreated ◽  
Bifunctional Fusion Protein

764 Background: Inhibiting the transforming growth factor β (TGF-β) pathway, which plays a key role in tumor immunosuppression, may enhance the response to programmed death 1/programmed death ligand 1 (PD-1/PD-L1) monoclonal antibodies (mAbs). M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a mAb against PD-L1 fused with the extracellular domain of TGF-β receptor II, which serves as a TGF-β “trap.” We report results in patients (pts) with heavily pretreated colorectal cancer (CRC), an area of high unmet need since these pts no longer respond to standard therapies. Methods: In this expansion cohort of the ongoing, phase 1, open-label trial NCT02517398, pts with heavily pretreated (≥3rd line) advanced CRC receive M7824 1200 mg q2w until confirmed progressive disease (PD), unacceptable toxicity or trial withdrawal. The primary objective is best overall response (BOR) per RECIST v1.1; secondary objectives include safety/tolerability. Results: As of 28 June 2017, 32 heavily pretreated pts with advanced CRC (87.5% had ≥3 prior therapies) received M7824 for a median duration of 7.1 (range: 2-38) weeks; 2 pts remained on treatment. Among the 29 evaluable pts, 1 had a confirmed partial response (PR; ongoing at 8 months), 1 had stable disease (SD) and 27 had PD as BOR per independent read. The pt with a PR had CRC that was microsatellite stable (MSS), consensus molecular subtype (CMS) 4, KRAS mutant (mt) and PD-L1+; this pt had the highest tumor cell PD-L1 expression in our cohort (20%; PD-L1 expression was generally low among the other 24 pts with available results). 4 pts (12.5%) experienced 5 different grade 3 treatment-related adverse events (AEs; adrenal insufficiency, anemia, blood bilirubin increased, enteritis [leading to discontinuation] and fatigue); there were no grade ≥4 treatment-related AEs or treatment-related deaths. Conclusions: In heavily pretreated pts with advanced CRC, 1 pt (MSS, CMS 4, KRAS mt and PD-L1+) had a durable PR, 1 had SD and 27 had PD as BOR. M7824 showed a manageable safety profile. Updated data – including PD-L1, TGF-β and CMS results – will be presented. A study in pts with CMS 4 is in preparation. Clinical trial information: NCT02517398.

M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in Asian patients with advanced solid tumors.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 762-762 ◽  
Author(s):  
Yutaka Fujiwara ◽  
Takafumi Koyama ◽  
Christoph Helwig ◽  
Morihiro Watanabe ◽  
Toshihiko Doi
Keyword(s):  
Fusion Protein ◽  
Solid Tumors ◽  
Transforming Growth Factor ◽  
Phase 1 ◽  
Gastroesophageal Junction ◽  
Advanced Solid Tumors ◽  
Asian Patients ◽  
Programmed Death ◽  
Heavily Pretreated ◽  
Bifunctional Fusion Protein

762 Background: Inhibiting the transforming growth factor β (TGF-β) pathway, which plays a key role in tumor immunosuppression, may enhance the response to programmed death 1/programmed death ligand 1 (PD-1/PD-L1) monoclonal antibodies (mAbs). M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a mAb against PD-L1 fused with the extracellular domain of TGF-β receptor II, which serves as a TGF-β “trap.” We report results in Asian patients (pts) with advanced solid tumors. Methods: NCT02699515 is a phase 1, open-label, 3 + 3 dose-escalation study. Pts receive M7824 at 3, 10 or 20 mg/kg q2w until confirmed progressive disease, unacceptable toxicity or trial withdrawal. The primary objective is to determine the safety and maximum tolerated dose (MTD); secondary objectives include pharmacokinetics (PK), immunogenicity and best overall response per RECIST v1.1. Results: As of 28 February 2017, 14 heavily pretreated pts (85.7% received ≥3 prior therapies) received M7824 for a median duration of 5.9 weeks (range: 2-40 weeks). Grade (gr) ≥3 treatment-related adverse events occurred in 3 pts (21.4%): 1 pt (3 mg/kg) had gr 4 hyponatremia and gr 3 hypopituitarism; 1 pt (20 mg/kg) had gr 3 intracranial tumor hemorrhage (dose-limiting toxicity; treatment discontinued [TD]); 1 pt (20 mg/kg) had gr 3 increased blood creatine phosphokinase, hyponatremia and hypoacusis (TD). PK data showed a dose-linear increase in exposure. Signs of efficacy were seen across all dose levels: 2 pts (colorectal cancer [CRC] associated with Lynch syndrome [3 mg/kg] and ovarian cancer [20 mg/kg]) achieved a confirmed partial response (PR) and 3 pts (gastric/gastroesophageal junction cancer [3 mg/kg], gastric cancer [3 mg/kg] and adenoid cystic carcinoma of the tongue [10 mg/kg]) achieved stable disease. Durations of response were 1.1+ months (ovarian; PR occurred after TD, with no further anticancer therapy) and 7.0+ months (CRC; treatment ongoing); both PRs were ongoing beyond the data cutoff. Conclusions: M7824 had a manageable safety profile in Asian pts with heavily pretreated advanced solid tumors; the MTD was not reached. Early signs of clinical efficacy are encouraging. Clinical trial information: NCT02699515.

scholarly journals Bintrafusp alfa (M7824) a bifunctional fusion protein targeting TGF-β and PD-L1: results from a phase 1 expansion cohort in patients with recurrent glioblastoma

2021 ◽  
Author(s):  
Mustafa Khasraw ◽  
Michael Weller ◽  
David Lorente ◽  
Kathryn Kolibaba ◽  
Chee Khoon Lee ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Disease Control ◽  
Protein Targeting ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Complete Response ◽  
Recurrent Glioblastoma ◽  
Open Label ◽  
Bifunctional Fusion Protein ◽  
Expansion Cohort

Abstract Background For patients with recurrent glioblastoma (rGBM), there are few options following treatment failure with radiotherapy plus temozolomide. 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 antibody blocking PD-L1. Methods In this phase 1, open-label expansion cohort, (NCT02517398), patients with rGBM that progressed after radiotherapy plus temozolomide received bintrafusp alfa 1200 mg Q2W until disease progression, unacceptable toxicity, or trial withdrawal. Response was assessed per RANO criteria. The primary endpoint was disease control rate (DCR); secondary endpoints included safety. Results As of August 24, 2018, 35 patients received bintrafusp alfa for a median of 1.8 (range, 0.5-20.7) months. Eight patients (22.9%) experienced disease control as assessed by an independent review committee: 2 had a partial response, 4 had stable disease, and 2 had non–complete response /non–progressive disease. Median progression-free survival (PFS) was 1.4 (95% CI, 1.2-1.6) months; 6- and 12-month PFS rates were 15.1% and 11.3%, respectively. Median overall survival (OS) was 5.3 (95% CI, 2.6-9.4) months; 6- and 12-month OS rates were 44.5% and 30.8%, respectively. The DCR (95% CI) was 66.7% (22.3-95.7%) for patients with IDH-mutant GBM (n=6) and 13.8% (3.9-31.7%) for patients with IDH–wild-type GBM (n=29). Disease control was seen regardless of PD-L1 expression. Twenty-five patients (71.4%) experienced treatment-related adverse events (grade ≥3; 17.1% [n=6]). Conclusions The percentage of patients achieving disease control and the manageable safety profile may warrant further investigation of bintrafusp alfa in GBM.

Efficacy and safety of vactosertib and pembrolizumab combination in patients with previously treated microsatellite stable metastatic colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3573-3573
Author(s):  
Tae Won Kim ◽  
Keun Wook Lee ◽  
Joong Bae Ahn ◽  
Jin Lee ◽  
Jiyeon Ryu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Molecular Subtype ◽  
Objective Response ◽  
Unmet Need ◽  
Transforming Growth Factor Β ◽  
Open Label ◽  
Drug Induced

3573 Background: Microsatellite stable metastatic colorectal cancer (MSS mCRC) represents a high unmet need since there are currently no approved immunotherapy options. Since the inhibition of the transforming growth factor-β (TGF-β) pathway is known to contribute to the enhancement of immunotherapy efficacy, here, we report the results of vactosertib, a potent and selective TGF-β receptor I kinase inhibitor, combined with pembrolizumab in patients with MSS mCRC. Methods: In this phase 2, open label trial, patients have received vactosertib (300 mg BID, 5 days on / 2 days off) and pembrolizumab (200 mg, every 3 weeks) until confirmed progressive disease (PD), unacceptable toxicity or consent withdrawal. Patients with histologically confirmed mCRC who had disease progression after treatment with all available therapies including fluoropyrimidine and oxaliplatin or irinotecan were enrolled. Eligible patients were ≥19 years old, had ECOG status ≤1, and had no prior exposure to immunotherapy. The objectives were to evaluate the safety and efficacy (objective response rate (ORR) per RECIST v1.1). Results: Thirty-three patients with MSS mCRC were enrolled. Median age was 60 (range 33-72), 55% were male, median number of previous lines of chemotherapy was 3 (range 1-7), and 82% were consensus molecular subtype (CMS) 4. The ORR was 15.2% including 5 partial responses (PRs), 7 stable diseases, and 17 PDs as best overall responses; 12 patients remain on treatment. Among 5 patients with PR, 3 patients had confirmed PR and median duration of response was not reached yet. As of 04 Jan 2021, the most common treatment related adverse events (AEs) were increased amylase (21.2%), pruritus (21.2%), rash (21.2%), and increased lipase (18.2%). There were 3 treatment-related SAEs reported; drug induced pneumonitis (3%), nausea (3%), and vomiting (3%). Conclusions: The combination treatment with vactosertib and pembrolizumab showed favorable safety profile with promising efficacy in patients with MSS mCRC. Updated data including pharmacodynamic markers will be presented at the meeting. Clinical trial information: NCT03724851.

Preliminary results from a phase 1 trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3006-3006 ◽  
Author(s):  
James L. Gulley ◽  
Christopher Ryan Heery ◽  
Jeffrey Schlom ◽  
Ravi Amrit Madan ◽  
Liang Cao ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Preliminary Data ◽  
Phase 1 ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Phase 1 Trial ◽  
Heavily Pretreated ◽  
Bifunctional Fusion Protein

3006 Background: M7824 (MSB0011359C) is a novel bifunctional fusion protein comprised of a fully human IgG1 monoclonal antibody against programmed death ligand 1 (PD-L1) fused to the soluble extracellular domain of transforming growth factor-β (TGF-β) receptor II, which acts as a TGF-β trap. We report preliminary data from a phase 1 trial of M7824 in patients (pts) with advanced solid tumors. Methods: NCT02517398 is a phase 1, open-label, 3+3 dose-escalation study. Eligible pts receive M7824 at 1, 3, 10, or 20 mg/kg Q2W until confirmed progressive disease, unacceptable toxicity, or trial withdrawal; treatment beyond progression is generally allowable. The primary objective is to determine the safety and maximum tolerated dose of M7824; secondary objectives include pharmacokinetics (PK), immunogenicity, and best overall response per RECIST v1.1. Results: 16 heavily pretreated pts with ECOG performance status 0-1 have received M7824. Our PK data show a dose-linear increase in exposure starting at a dose of 3 mg/kg; furthermore, M7824 saturates peripheral PD-L1 and sequesters any released plasma TGF-β1, -β2, and -β3 throughout the dosing period in a dose-dependent manner. Grade 3 drug-related treatment-emergent adverse events (TEAEs) occurred in 3 pts (skin infection secondary to grade 2 bullous pemphigoid [BP], lipase increased, and colitis with associated anemia); there were no grade 4-5 drug-related TEAEs. BP and colitis responded well to steroids. Colitis and its secondary events of anemia and rectal hemorrhage (in a previously radiated area) were considered dose limiting in 1 pt. There was preliminary evidence of efficacy across all dose levels, including 1 ongoing confirmed complete response (cervical), 1 durable partial response (pancreatic), a 25% reduction in the sum of diameters of target lesions after 2 doses of M7824 (cervical), and 2 cases of prolonged stable disease (pancreatic; carcinoid). Conclusions: Preliminary data from this phase 1 dose-escalation study suggest that M7824 has a manageable safety profile in pts with heavily pretreated advanced solid tumors. Early signs of clinical efficacy warrant further study. Clinical trial information: NCT02517398.

M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in Asian patients with pretreated recurrent or refractory gastric cancer: Preliminary results from a phase I trial.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 100-100 ◽  
Author(s):  
Yoon-Koo Kang ◽  
Toshihiko Doi ◽  
Shunsuke Kondo ◽  
Hyun-Choel Chung ◽  
Kei Muro ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Fusion Protein ◽  
Standard Therapy ◽  
Gastroesophageal Junction ◽  
Preliminary Results ◽  
Overall Response ◽  
Asian Patients ◽  
Programmed Death ◽  
Heavily Pretreated ◽  
Bifunctional Fusion Protein

100 Background: Inhibiting the transforming growth factor β (TGF-β) pathway, which plays a key role in tumor immunosuppression, may enhance the response to programmed death 1/programmed death ligand 1 (PD-1/PD-L1) monoclonal antibodies (mAbs). M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a mAb against PD-L1 fused with the extracellular domain of TGF-β receptor II, which serves as a TGF-β “trap.” We report preliminary results in Asian patients with heavily pretreated gastric cancer. Methods: In this expansion cohort of the ongoing, phase 1, open-label trial NCT02699515, patients with recurrent or refractory unresectable stage IV gastric or gastroesophageal junction adenocarcinoma for which no standard therapy exists or standard therapy has failed receive M7824 1200 mg q2w until confirmed progressive disease, unacceptable toxicity or trial withdrawal. The primary objective is safety; secondary objectives include best overall response (BOR) per RECIST v1.1. Results: As of 6 September 2017, 31 heavily pretreated patients with advanced gastric cancer (67.7% received ≥3 prior anticancer therapies) received M7824 for a median duration of 6.1 (range: 2-30) weeks (median number of M7824 infusions: 3 [range: 1-13]); 8 patients remained on treatment. Four patients (12.9%) experienced grade 3 treatment-related adverse events (anemia and diarrhea 1 each and 2 rash). No treatment-related grade 4 AEs occurred. One grade 5 event (total 5 doses received) was considered possibly treatment related, but suspected rupture of preexisting thoracic aortic aneurysm was cited as other probable cause by the investigator. There were 5 confirmed partial responses (4 ongoing after 4-6 months of follow-up) based on investigator assessment of BOR (overall response rate: 16.1%). This is an ongoing study; updated data will be presented. Conclusions: These preliminary data show that M7824 resulted in a manageable safety profile in heavily pretreated Asian patients with gastric cancer. Early signs of clinical efficacy are encouraging. Clinical trial information: NCT02699515.

scholarly journals A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors

2021 ◽  
Author(s):  
Noboru Yamamoto ◽  
Toshio Shimizu ◽  
Kan Yonemori ◽  
Shigehisa Kitano ◽  
Shunsuke Kondo ◽  
...  
Keyword(s):  
Liver Function ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Enzyme Inhibitor ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Phase 1 Study ◽  
Open Label Phase

SummaryBackground This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017

Long-term follow-up of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in advanced squamous cell carcinoma of the head and neck (SCCHN).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 6020-6020
Author(s):  
Byoung Chul Cho ◽  
Amaury Daste ◽  
Alain Ravaud ◽  
Sébastien Salas ◽  
Nicolas Isambert ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Safety Profile ◽  
Objective Response ◽  
Locally Advanced ◽  
Clinical Activity ◽  
Metastatic Setting ◽  
Heavily Pretreated ◽  
Bifunctional Fusion Protein

6020 Background: 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. A previous report of an expansion cohort from a phase 1 study (NCT02517398) suggested that bintrafusp alfa had a manageable safety profile and early signs of clinical activity in patients with heavily pretreated, advanced SCCHN after a median follow-up of 86.4 weeks. Here we report long-term efficacy and safety for this cohort. Methods: Patients with advanced SCCHN that progressed/recurred after platinum therapy in the recurrent/metastatic setting, or < 6 months after platinum therapy in the locally advanced setting, received bintrafusp alfa 1200 mg every 2 weeks until confirmed progressive disease, unacceptable toxicity, or trial withdrawal. The primary endpoint was confirmed best overall response assessed per RECIST 1.1 assessed by independent review committee (IRC); safety was a secondary endpoint. Results: As of May 15, 2020, 32 patients had received bintrafusp alfa for a median of 2.8 months (range, 0.5-29.9 months), no patient remained on treatment, and median follow-up to data cutoff was 41.7 months (range, 39.8-43.5 months). The objective response rate (ORR; 13%) was unchanged since the previous report; median duration of response (DOR) was increased at 21.4 months (95% CI, 5.5 months to not reached [NR]). While the clinical activity of bintrafusp alfa may be improved in patients with HPV-positive tumors (Table), outcomes were generally similar between PD-L1 subgroups (≥1% vs < 1% tumor cells). The overall safety profile was consistent with the previous report for this cohort, without grade 4 nor 5 treatment-related adverse events (TRAEs); no new TRAEs of grade 3 or that led to discontinuation of bintrafusp alfa were reported. Conclusions: With a median follow-up of over 3 years in patients with heavily pretreated advanced SCCHN, bintrafusp alfa showed sustained clinical activity and 3-year OS of 24.0%, which compares favorably to historical data. Clinical activity appeared to be greater in patients with HPV-positive tumors than those with HPV-negative tumors. The safety profile was manageable and consistent with earlier analysis. Further investigation of bintrafusp alfa in SCCHN and other HPV-associated cancers is ongoing. Clinical trial information: NCT02517398. [Table: see text]

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