retlirafusp alfa (SHR-1701)

P2, N=20, Not yet recruiting, Fudan University

P1, N=13, Terminated, Jiangsu HengRui Medicine Co., Ltd. | N=345 --> 13 | Recruiting --> Terminated; Sponsor R&D strategy adjustment

While preclinical data have demonstrated the great anti-tumorigenic potential of TGF-β inhibitors, the underwhelming results of ongoing and completed clinical trials highlight the difficulty actualizing these benefits into clinical practice. This topical review will discuss the relevant preclinical and clinical findings for TGF-β inhibitors in HNSCC and will explore the potential role of patient stratification in the development of this therapeutic strategy.

P2/3, N=81, Terminated, Suzhou Suncadia Biopharmaceuticals Co., Ltd. | N=896 --> 81 | Trial completion date: Dec 2027 --> Apr 2024 | Enrolling by invitation --> Terminated | Trial primary completion date: Jul 2027 --> Apr 2024; R&d strategy adjustment

P1/2, N=81, Completed, Suzhou Suncadia Biopharmaceuticals Co., Ltd. | Recruiting --> Completed | Trial completion date: Dec 2023 --> Mar 2024 | Trial primary completion date: Dec 2021 --> Mar 2024

The blocking effect of SHR-1701 on TGF-β1 was verified by inhibiting peritoneal metastases in xenografts. Collectively, the interplay of EGR1/TGF-β1/CD44s/STAT3 signaling between mesothelial cells and GC cells induces EMT and stemness phenotypes, offering potential as a therapeutic target for PM of GC.

P3, N=737, Active, not recruiting, Suzhou Suncadia Biopharmaceuticals Co., Ltd. | Recruiting --> Active, not recruiting

P1/2, N=56, Completed, Jiangsu HengRui Medicine Co., Ltd. | Active, not recruiting --> Completed | Trial completion date: Aug 2022 --> Feb 2023

Adverse events were limited and manageable. This is the first report of such a treatment regimen being applied in a clinical setting, suggesting that the SHR-1701 and famitinib combination may be a promising immunotherapeutic approach for patients with refractory advanced GBC.

P1/2, N=100, Recruiting, Chinese PLA General Hospital | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Mar 2023 --> Dec 2024

Conclusions SHR-1701 showed encouraging antitumor activity in all three cohorts. The safety profile was tolerable.

No grade ≥ 4 TRAEs occurred. Conclusions SHR-1701 plus TMZ showed promising antitumor activity in advanced melanoma pts, and was generally well tolerated.

Background The standard 1L therapies for mCRC involve a fluoropyrimidine with oxaliplatin and/or irinotecan, and a biologic agent. Median PFS was 10.3 months (95% CI, 8.3-13.7), and median OS was immature. Conclusions SHR-1701 in combination with BP102 and XELOX as 1L treatment provided a manageable safety profile and potent antitumor activity in pts with unresectable mCRC.

No grade 4/5 TRAEs were reported. Table: 1026MO Efficacy outcomes Variables GC/GEJC (1L) GC/GEJC (≥2L) nsqNSCLC All (n=19) CPS≥5 (n=15) All (n=27) CPS≥5 (n=9) All (n=10) Best overall response, n (%) CR 0 0 1 (3.7) 1 (11.1) 0 PR 4 (21.1) 4 (26.7) 8 (29.6) 6 (66.7) 1 (10.0) SD 7 (36.8) 5 (33.3) 5 (18.5) 1 (11.1) 5 (50.0) PD 7 (36.8) 5 (33.3) 12 (44.4) 1 (11.1) 3 (30.0) NE 1 (5.3) 1 (6.7) 1 (3.7) 0 1 (10.0) ORR, % (95% CI) 21.1 (6.1, 45.6) 26.7 (7.8, 55.1) 33.3 (16.5, 54.0) 77.8 (40.0, 97.2) 10.0 (0.3, 44.5) DCR, % (95% CI) 57.9 (33.5-79.7) 60.0 (32.3, 83.7) 51.8 (32.0, 71.3) 88.9 (51.8, 99.7) 60.0 (26.2, 87.8) mPFS, months (95% CI) 4.1 (1.3-NR) 4.1 (1.4-NR) 4.0 (1.4-NR) 10.3 (1.3-NR) 6.2 (1.3-9.9) Conclusions SHR-1701 plus BEV showed encouraging antitumor activity with a favorable safety profile in pts with advanced GC/GEJC and nsqNSCLC.

P1/2, N=100, Recruiting, Chinese PLA General Hospital | Not yet recruiting --> Recruiting

P1/2, N=100, Not yet recruiting, Chinese PLA General Hospital

P2, N=0, Withdrawn, Jiangsu HengRui Medicine Co., Ltd. | N=168 --> 0 | Not yet recruiting --> Withdrawn

P2, N=31, Recruiting, Yong Chen | Not yet recruiting --> Recruiting

P2, N=107, Active, not recruiting, Jiangsu HengRui Medicine Co., Ltd. | Not yet recruiting --> Active, not recruiting | Trial completion date: Mar 2023 --> Mar 2025 | Trial primary completion date: Mar 2023 --> Jul 2023

16 (100%) cHL pts had received prior anti-PD1/PD-L1 antibody therapy, and 15 ( 93.8%) prior epigenetic therapies, such as decitabine or chidamide. SHR-1701 combined with SHR2554 showed acceptable safety profile and encouraging antitumor activity in immunotherapy-pretreated cHL, establishing the foundation for further exploration. Clinical trial information: NCT04407741.

P1/2, N=100, Recruiting, Chinese PLA General Hospital | Trial completion date: Jun 2023 --> Dec 2023 | Trial primary completion date: Jun 2022 --> Mar 2023

SHR-1701 showed an acceptable safety profile and encouraging antitumor activity in pretreated advanced solid tumors, especially in gastric cancer, establishing the foundation for further exploration.

We investigated the safety and efficacy of famitinib, a tyrosine kinase inhibitor (TKI) of angiogenesis, combined with the bifunctional fusion protein SHR-1701 targeting PD-L1 and TGF-β in patients (Pts) with chemotherapy-refractory sarcoma. Pts were eligible if they were aged 12 years or older, and had histologically confirmed advanced or metastatic sarcomas; the presence of measurable disease according to RECIST 1.1; an ECOG performance status of 0-1; progressive disease after at least one line of adriamycin containing chemotherapy; MSI-H or TMB>5 or PD-L1≥1% except for alveolar soft-part sarcoma (ASPS) and undifferentiated pleomorphic sarcoma (UPS). Famitinib plus SHR-1701 has manageable toxicity and preliminary activity in pts with advanced sarcomas, warranting further investigation.

SHR-1701 exhibits encouraging antitumor activity and controllable safety in patients with recurrent or metastatic cervical cancer after platinum-based regimens, might providing another treatment option for this population.

SHR-1701 showed tolerable toxicity profile and promising antitumor activity in patients with RM-NPC who failed prior platinum-based chemotherapy.

Currently, a limited number of small molecular inhibitor and monoclonal antibody candidates that target TGF-β are in clinical development in combination with the following immune checkpoint inhibitors: SRK 181, an antibody inhibiting the activation of latent TGF-β1; NIS 793, a monoclonal antibody targeting TGF-β; and SHR 1701, a fusion protein consisting of an anti-PD-L1 monoclonal antibody fused with the extracellular domain of human TGF-β receptor II. Several small molecular inhibitors are also in development and are briefly reviewed: LY364947, a pyrazole-based small molecular inhibitor of the serine-threonine kinase activity of TGFβRI; SB-431542, an inhibitor targeting several TGF-β superfamily Type I activin receptor-like kinases as well as TGF-β1-induced nuclear Smad3 localization; and galunisertib, an oral small molecular inhibitor of the TGFβRI kinase. One of the most advanced agents in this area is bintrafusp alfa, a bifunctional fusion protein composed of the extracellular domain of TGF-β receptor II fused to a human IgG1 mAb blocking PD-L1. Bintrafusp alfa is currently in advanced clinical development and as an agent in this space with the most clinical experience, is a focused highlight of this review.

Lung cancer patients with poor lymphocyte recovery and suffering from persistent lymphopenia after previous chemotherapy are resistant to anti-PD-1/PD-L1 antibodies but might be sensitive to second-generation agents such as SHR-1701.

P3, N=920, Recruiting, Suzhou Suncadia Biopharmaceuticals Co., Ltd. | Not yet recruiting --> Recruiting

P3, N=561, Not yet recruiting, Suzhou Suncadia Biopharmaceuticals Co., Ltd.

P2, N=319, Recruiting, Fudan University | Not yet recruiting --> Recruiting | N=170 --> 319

SHR-1701 shows encouraging anti-tumor activity in treatment-naive PD-L1+ advanced/metastatic NSCLC pts, compared with the reported historical data of ICI monotherapy. Pts with PD-L1 TPS ≥50% have superior ORR.

SHR-1701 showed encouraging antitumor activity and manageable safety profile in pretreated r/r GC pts. PD-L1 might be a prognostic factor for SHR-1701, which needs further investigation.

Primary endpoint was ORR per RECIST v1.1. Totally, 32 eligible pts were recruited: squamous cell carcinoma, 100%; ≥2 metastasis sites, 68.8%; prior platinum-based chemotherapy, 87.5%; prior platinum-based chemotherapy plus bevacizumab, 12.5%; previous neoadjuvant or adjuvant therapy, 15.6%. SHR-1701 exhibits encouraging antitumor activity and controllable safety in pts with previously treated advanced cervical cancer after platinum-based regimens, might providing another treatment option for this population.

P3, N=920, Not yet recruiting, Suzhou Suncadia Biopharmaceuticals Co., Ltd.

SHR-1701 showed acceptable safety profile and encouraging antitumor activity in refractory solid tumors, establishing the foundation for further exploration.

SHR-1701 monotherapy shows a manageable safety profile and encouraging antitumor activity in advanced EGFR+ NSCLC pts after failure of at least 1L standard EGFR TKI . Further investigation of SHR-1701 combination therapy for EGFR+ NSCLC is warranted.

P1/2, N=100, Recruiting, Chinese PLA General Hospital | Not yet recruiting --> Recruiting

P1/2, N=100, Not yet recruiting, Chinese PLA General Hospital | Initiation date: Jun 2020 --> Sep 2020

P1/2, N=100, Not yet recruiting, Chinese PLA General Hospital

P2, N=170, Not yet recruiting, Fudan University