Bifunctional Fusion Protein Targeting TGF-β Research Articles

Final analysis of the BIMES trial, a phase II single arm study assessing efficacy and safety of bintrafusp alfa in previously treated advanced malignant pleural mesothelioma (GECP 20/09).

8084 Background: Transforming growth factor β (TGF-β) is involved in tumor immune evasion and epithelial–mesenchymal transition (EMT). As TGF-β upregulation and EMT are associated with resistance to anti-PD1 therapy, we evaluated the efficacy of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in malignant pleural mesothelioma (MPM). Methods: Patients with advanced MPM who were previously treated with platinum-based chemotherapy were enrolled and received bintrafusp alfa 1200mg/m2 every 2 weeks until progression or for a maximum of two years. The primary objective was to determine the progression-free survival (PFS) by modified RECIST v1.1. assessed by the investigators. The expected median PFS was 4.5 months. Secondary objectives were overall response rate, duration of response, overall survival (OS) and safety. Results: Between October 2021 to March 2023, 47 patients were enrolled. Mean age was 70 years (41-84) and 36 (78.3%) were males. Most patients had epithelioid histology (82.9%) and had received only 1 prior line of therapy (84.8%). With a median follow-up of 11.5 months, 43 patients had disease progression and 24 patients died. The median number of doses administered was 4 (1-21) and reasons for treatment discontinuation were disease progression (82.6%), toxicity (6.5%), investigator decision (4.4%) and death (6.5%) by tumor progression. The median PFS was 1.9 months (95% CI 1.7 – 5.4) and the 6 month-PFS rate was 15.9%. Disease control rate was 34.8% (95% CI 22.2-49.9) consisting of 2 patients with partial response and 13 patients with stable disease as best response. The median OS was 11.9 months (95% CI 4.4 – not reached) and 6, 12 and 18-month OS rate was 65.3%, 46.5% and 26.6%, respectively. No significant differences in OS and PFS were observed based on MPM histological subtype. Grade 3-4 treatment-related adverse events occurred in 16 (34%) patients, anemia being the most common (n = 5); skin toxicity (n = 3); colitis (n = 2); adrenal insufficiency, acute kidney injury, allergic reaction, lipase, and amylase increased (n = 1 each). Conclusions: Bintrafusp alfa did not reach the expected efficacy in patients with advanced malignant pleural mesothelioma previously treated with platinum-based chemotherapy. Clinical trial information: NCT05005429 .

Efficacy, safety, and biomarker analyses of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with advanced non-small cell lung cancer

BackgroundBintrafusp alfa, a first-in-class bifunctional fusion protein targeting transforming growth factor-β (TGF-β) and programmed cell death ligand 1, has demonstrated encouraging efficacy as second-line treatment in patients with non-small cell...

511MO A phase I study of SHR-1701, a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with advanced non-small cell lung cancer (NSCLC)

511MO A phase I study of SHR-1701, a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with advanced non-small cell lung cancer (NSCLC)

A phase I study of bintrafusp alfa and NHS-IL12 (M9241) alone and in combination with stereotactic body radiation therapy (SBRT) in patients with metastatic genitourinary (GU) malignancies.

4571 Background: Bintrafusp alfa is a novel bifunctional fusion protein targeting PD-L1 and TGF-β which has demonstrated clinical efficacy in some tumor types and a manageable safety profile. M9241 is an immunocytokine that allows targeting of the pro-inflammatory IL-12 cytokine to exposed DNA in necrotic portions of tumors. SBRT can help promote anti-tumor responses and may potentially synergize with immunotherapy by inducing DNA damage. Methods: This is an open label, non-randomized, three arm phase I trial of bintrafusp alfa and M9241 combination therapy administered alone (Arm 1), or with either sequential (Arm 2), or concurrent (Arm 3) SBRT. Eligible patients must have metastatic non-prostate GU cancers with measurable disease. Bintrafusp alfa was used at a flat dose of 1200mg (q2w) for arms 1-3 and a fixed dose of SBRT (24Gy in 3 fractions) was used for arms 2-3. M9241 was administered at 16.8mcg/kg (q4w) for Arm 1 and decreased if side effects occur. Arm 1 used bintrafusp alfa and M9241 alone, with the maximum tolerated dose (MTD) of M9241 being dose level 1 (DL1) for Arm 2. Arm 2 used SBRT followed by bintrafusp alfa and M9241, with the MTD of M9241 being DL1 for Arm 3. Arm 3 used concurrent SBRT with bintrafusp alfa and M9241. The primary objective was to determine the safety and highest tolerable doses of each arm. Secondary objectives include objective response rate (ORR), progression free survival (PFS), and overall survival (OS). Results: Study enrollment began in 12/2019, with interim safety analyses performed quarterly. A total of 16 patients have enrolled, 12 in Arm 1, three in Arm 2, and one in Arm 3 at data cutoff 1/2/23. The first six patients enrolled in Arm 1 had no DLTs allowing Arm 2 to open, Arm 2 had no DLTs after 3 patients enrolled allowing Arm 3 to open. At data cut off four of 16 patients remained on treatment. The median age was 63 and 19% were female. The most frequent TRAEs were fatigue (grade 2, 38%), lipase increase (grade 2+3, 31%), and anemia (grade 2+3, 31%). Grade 3 hematuria occurred in 2 patients (13%); a grade 4 creatinine increase occurred in one (8%). There were no grade 5 TRAEs. Two (13%) patients had treatment discontinued and 5 (31%) had dose reductions due to AEs. Of the 16 patients enrolled on study, 11 were evaluable at data cutoff. Currently three patients (38%) on Arm 1 and one patient (50%) in Arm 2 had objective responses, corresponding to an ORR of 36.4% (4/11). All responses have been partial responses. On Arm 1 the responding patients included one with small cell carcinoma of the renal pelvis, one with Leydig cell tumor, and one with urothelial carcinoma. On Arm 2 the responding patient had a Sertoli cell tumor. Conclusions: The use of bintrafusp alfa and M9241 either alone or in combination with sequential or concurrent SBRT has shown clinical activity in pts with GU tumors and has not been associated with any DLTs. Clinical trial information: NCT04235777 .

Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-β and PD-L1, in Patients With Non-Small Cell Lung Cancer Resistant or Refractory to Immune Checkpoint Inhibitors.

Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor beta receptor II (a TGF-β "trap") fused to a human immunoglobulin G1 monoclonal antibody blocking programmed cell death 1 ligand 1 (PD-L1). We report the efficacy and safety in patients with non-small cell lung cancer (NSCLC) that progressed following anti-PD-(L)1 therapy. In this expansion cohort of NCT02517398-a global, open-label, phase I trial-adults with advanced NSCLC that progressed following chemotherapy and was primary refractory or had acquired resistance to anti-PD-(L)1 treatment received intravenous bintrafusp alfa 1200 mg every 2 weeks until confirmed progression, unacceptable toxicity, or trial withdrawal. The primary endpoint was best overall response (by Response Evaluation Criteria in Solid Tumors version 1.1 adjudicated by independent review committee); secondary endpoints included safety. Eighty-three eligible patients (62 [74.7%] treated with ≥3 prior therapies) received bintrafusp alfa. Four patients (3 primary refractory, 1 acquired resistant) had confirmed partial responses (objective response rate, 4.8%; 95% CI, 1.3%-11.9%), and 9 had stable disease. Tumor cell PD-L1 expression was not associated with response. Nineteen patients (22.9%) experienced grade ≥3 treatment-related adverse events, most commonly asthenia (3 [3.6%]) and fatigue, eczema, and pruritus (2 each [2.4%]). One patient had grade 4 amylase increased. One patient died during treatment for pneumonia before initiation of bintrafusp alfa. Although the primary endpoint was not met, bintrafusp alfa showed some clinical activity and a manageable safety profile in patients with heavily pretreated NSCLC, including prior anti-PD-(L)1 therapy. Tumor responses occurred irrespective of whether disease was primary refractory or had acquired resistance to prior anti-PD-(L)1 therapy.

Model-informed approach for risk management of bleeding toxicities for bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1

PurposeBintrafusp alfa (BA) is a bifunctional fusion protein composed of the extracellular domain of the transforming growth factor-β (TGF-β) receptor II fused to a human immunoglobulin G1 antibody blocking programmed death ligand 1 (PD-L1). The recommended phase 2 dose (RP2D) was selected based on phase 1 efficacy, safety, and pharmacokinetic (PK)–pharmacodynamic data, assuming continuous inhibition of PD-L1 and TGF-β is required. Here, we describe a model-informed dose modification approach for risk management of BA-associated bleeding adverse events (AEs).MethodsThe PK and AE data from studies NCT02517398, NCT02699515, NCT03840915, and NCT04246489 (n = 936) were used. Logistic regression analyses were conducted to evaluate potential relationships between bleeding AEs and BA time-averaged concentration (Cavg), derived using a population PK model. The percentage of patients with trough concentrations associated with PD-L1 or TGF-β inhibition across various dosing regimens was derived.ResultsThe probability of bleeding AEs increased with increasing Cavg; 50% dose reduction was chosen based on the integration of modeling and clinical considerations. The resulting AE management guidance to investigators regarding temporary or permanent treatment discontinuation was further refined with recommendations on restarting at RP2D or at 50% dose, depending on the grade and type of bleeding (tumoral versus nontumoral) and investigator assessment of risk of additional bleeding.ConclusionA pragmatic model-informed approach for management of bleeding AEs was implemented in ongoing clinical trials of BA. This approach is expected to improve benefit-risk profile; however, its effectiveness will need to be evaluated based on safety data generated after implementation.

Abstract 5538: Functional characterization of TU2218, ALK5 and VEGFR2 dual inhibitor, on in vitro tumor immunity-mimetic systems

Abstract High level of plasma TGF-β is significantly correlated with poor outcomes with approved immune-oncology therapeutics. Poor clinical results for ALK5 inhibitors and bifunctional fusion protein targeting TGF-β and PD-L1 are also being reported in several clinical trials. Therefore, a novel therapeutic with superior efficacy differentiated from previous TGF-β modulators will demonstrate significant clinical outcomes in combination with immuno-oncology therapeutics. In TME, TGF-β and VEGF synergistically induce eradication of immunogenic tumors. Therefore, a dual-inhibitor targeting both ALK5 and VEGFR2 has high potential to demonstrate effective clinical efficacy against TGF-β- and VEGF-enriched tumors as a single or combination treatment. TU2218 is a highly potent, orally available inhibitor against ALK5 and VEGFR2 with an IC50 of 1.2 nM and 4.9 nM respectively. In a human PBMC assay, 0.5-1 μM TU2218 treatment significantly enhanced IFN-γ production or IFN-γ-producing T lymphocytes number by TGF-β-driven immunosuppression, but vactosertib, galunisertib and TGF-β neutralizing antibody did not have significant effects. In a human regulatory T cells assay, CD4+CD25+ Tregs suppressed the proliferation of naïve CD4+CD25- T cells after TCR triggering. In contrast, 0.5 μM TU2218 treated Tregs completely reversed the TCR-mediated proliferation of CD4+CD25- T cells. In addition, the immunomodulatory activity of TU2218 was analyzed on the co-culture system of cancer cells with human PBMC. In this assay, MCF-7 and HT-1080 displayed strong inhibitory effects on IFN-γ secretion of human PBMC, but TU2218 completely restored IFN-γ production compared with the poor effect of either vactosertib or TGF-β neutralizing antibody. In an NK assay, TGF-β reduced the level of surface proteins of NKG2D and NKp30 on CD56dim and CD56bright human primary NK cells and NK92 cell lines. TU2218 treatment completely reversed not only the inhibitory effect of TGF-β on the expression of NKG2D but also TGF-β-driven impairment of NK cytolytic activity for K562 cell lines on the co-culture system. Results show TU2218 possesses potent anti-cancer immune activities through boosting T and NK immunity as well as blocking Treg activity, implicating the mechanism of overcoming immune tolerance and reversing immunosuppression in TME. These effects of TU2218 in human immune cells would be a basis for novel combination options to develop promising therapeutics for patients with advanced cancer. Citation Format: Nam-Hoon Kim, Seong-Ho Kang, Jihyun Lee, Seung-Hyun Kim, Chan-Hee Yu, Jae Won Choi, Soyoun Ahn, Jeongmin Seo, Hun-Taek Kim. Functional characterization of TU2218, ALK5 and VEGFR2 dual inhibitor, on in vitro tumor immunity-mimetic systems [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5538.

Phase II evaluation of the combination of PDS0101, M9241, and bintrafusp alfa in patients with HPV 16+ malignancies.

2518 Background: More than 630,000 cases of HPV related cancer occur worldwide annually. About 15-20% of cases respond to PD-(L)1 inhibitors and about 30% respond to dual PD-L1/TGF-β blockade including 10% of checkpoint refractory pts, but for the majority of pts with checkpoint refractory disease there is no effective standard therapy. Preclinical studies show that the combination of PDS0101, a therapeutic vaccine targeting HPV 16 E6/E7, M9241, a tumor-targeting IL-12 immunocytokine, and bintrafusp alfa (BA), a bifunctional fusion protein targeting TGF-β and PD-L1, resulted in maximum T cell infiltration and tumor reduction compared to any 1 or 2 of these agents alone. Prior clinical data suggests that the combination is preferentially active in HPV 16+ disease. Methods: 30 pts with advanced HPV 16+ cancer were treated with PDS0101, M9241 and BA (NCT04287868). Pts received BA at 1200 mg IV q2wks, M9241 at 16.8 mcg/kg SC q4wks or 8 mcg/kg SC q2wks, and PDS0101 as two 0.5 ml SC injections q4wks. Dose reductions or skipped doses for toxicities of BA and M9241 were allowed. 5 pts had surgical resection of tumor for disease control and were censored for PD but not survival. Results: 30 pts (9 cervical, 2 vaginal/vulvar, 6 anal, 13 oropharyngeal) were treated. 13/30 had grade 3 treatment related AEs including grade 3 anemia in 9 pts associated with grade 3 hematuria in 3 pts and grade 3 GI bleeding in 3 pts. 2 pts had grade 3 AST/ALT elevation. Grade 3 flu like symptoms and grade 3 hemophagocytic lymphohistiocytosis were each seen in 1 pt. One pt had grade 3 lymphopenia/leukopenia plus grade 4 neutropenia and one pt had grade 4 AST/ALT elevation. There were no grade 5 treatment related AEs. 7/8 (88%) pts with checkpoint naïve disease had objective responses (OR) including 1 delayed response after initial PD with 4/7 (57%) responses ongoing (median 17 months follow up). 10/22 (45%) with checkpoint refractory disease have had disease reduction including 6/22 (27%) with OR and 4/6 (67%) responses ongoing (median 12 months follow up). 6/8 (75%) pts with checkpoint naïve disease and 17/22 (77%) pts with checkpoint refractory disease are alive after a median of 17 and 12 months follow up respectively. For checkpoint refractory pts, M9241 dosing appears to affect response rates. 5/8 (63%) pts receiving M9241 at 16.8 mcg/kg had an OR compared to 1/14 (7%) who received M9241 at 8 mcg/kg with an OR. However, despite differences in response rates with higher vs lower M9241 dose, survival outcomes were similar irrespective of M9241 dose (p = 0.99 by Kaplan Meier analysis). Conclusions: The combination of PDS0101, M9241 and BA appears to have a manageable safety profile along with early evidence of clinical activity for pts with checkpoint naïve and refractory advanced HPV 16+ cancer. Moreover, growing data suggest that all 3 drugs in the combination contribute to the encouraging outcomes being observed. Clinical trial information: NCT04287868.

Phase I/IIa study of PM8001, a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with advanced tumors.

2512 Background: PM8001 is a bifunctional protein composed of the extracellular domain of the TGF-β RII receptor (a TGF-β “trap”) fused to a humanized anti-PD-L1 IgG1 single-domain antibody. This is the first dose escalation and expansion phase I/IIa study to evaluate the safety and preliminary anti-tumor activity of PM8001 in advanced tumors. Methods: This study is comprised of a standard 3+3 dose escalation (Part A: 1, 3, 10, 20, 30, and 45 mg/kg Q2W) followed by dose expansion (Part B). Primary endpoints include safety for Part A, and ORR per RECIST 1.1 for Part B. Secondary endpoints include pharmacokinetics (PK), immunogenicity, DCR, PFS, and OS. Results: As of 16 December, 2021, a total of 108 subjects had received at least 1 dose of PM8001 with 25 subjects in Part A (0.3 mg/kg [n = 1], 1 mg/kg [n = 3], 3 mg/kg [n = 3], 10 mg/kg [n = 4], 20 mg/kg [n = 7], 30 mg/kg [n = 3], and 45 mg/kg [n = 4]) and 83 subjects in Part B (10 mg/kg Q2W [n = 1], 20 mg/kg Q2W [n = 63], 20 mg/kg Q3W [n = 11]), and 30 mg/kg Q3W [n = 8]). In Part A, only 1 DLT occurred in the 20 mg/kg dose group. MTD was not reached. Finally, 20 mg/kg Q2W was recommended as the RP2D for Part B. Of the 108 subjects, the median duration of PM8001 exposure was 6.9 weeks (range, 1.4-71.9). Any-grade TRAEs occurred in 84 subjects (77.9%), with 18 subjects (16.7%) reported with ≥ Grade 3. The most commonly reported ≥ Grade 3 TRAEs were anemia and rash (3 subjects each). Any-grade irAEs occurred in 66 subjects (61.1%), with 13 subjects (12.0%) reported with ≥ Grade 3. The most commonly reported ≥ Grade 3 irAEs were anemia (3 subjects). PK analysis showed a nearly linear dose-exposure relationship with PM8001 dosing from 1 to 45 mg/kg. Pharmacodynamic analysis demonstrated close to 100% PD-L1 target occupancy on PBMCs from the 20 to 45 mg/kg groups after multiple doses. An adequate inhibition to below the limit of quantitation of TGF-β1 was observed in the 1 mg/kg and higher dose groups. Of the 108 enrolled subjects, 67 subjects completed at least one efficacy evaluation. The ORR per RECIST 1.1 by investigator was 10.4% (7/67; 95% CI, 4.3%-20.4%), with 7 subjects achieving PR; the DCR was 53.7% (36/67; 95% CI, 41.1%-66.0%). Four additional PRs were observed after the data cut-off date. Of the total 11 PRs, 4 PRs occurred in patients who previously progressed after anti-PD-1 treatment. Most responses (10/11) occurred within 6 infusions, which indicates a rapid response towards PM8001 treatment. To date, 8 responders are still on treatment. Conclusions: PM8001 showed an acceptable safety profile and promising anti-tumor activity in advanced solid tumors, especially in patients previously treated with checkpoint inhibitors, which supports further studies to explore the safety and efficacy of PM8001 as a monotherapy and in combination with other anti-tumor agents. Global Phase II monotherapy and combination studies are currently ongoing. Clinical trial information: ChiCTR2000033828.

A phase 1b/2 trial of SHR-1701 in combination with gemcitabine and nab-paclitaxel in patients with untreated locally advanced or metastatic pancreatic cancer.

e16264 Background: The current standard first-line therapy is nab-paclitaxel plus gemcitabine and prognosis of this patient population remains poor. Immune checkpoint inhibitors in combination with chemotherapy have shown substantial clinical activity in several metastatic malignancies, but evidences in pancreatic cancer are limited. This phase 1b/2 trial is designed to evaluate the antitumor activity and safety of SHR-1701 (a bifunctional fusion protein targeting PD-L1 and TGF-β) combined with chemotherapy in patients with untreated locally advanced or metastatic pancreatic cancer. Methods: Eligible patients had histologically or cytologically confirmed unresectable locally advanced or metastatic pancreatic adenocarcinoma and had never received systemic antitumor therapy for advanced or metastatic diseases. Patients received SHR-1701 (30 mg/kg) on day 1 plus gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on day 1 and 8 of each 3-week cycle by intravenous infusion. The primary endpoint of phase 1b part was recommended phase 2 dose (RP2D). In the phase 2 part, the primary endpoint was ORR per investigator according to RECIST v1.1. Results: No dose-limiting toxicities were observed among the first six patients; the RP2D of SHR-1701 was 30 mg/kg. From Dec 03, 2020 to Sep 17, 2021, a total of 56 patients were enrolled and received at least one dose of study drug treatment. As of data cutoff on Nov 19, 2021, with a median follow-up period of 4.2 months (range 0.2-10.6), 28 (50.0%) of the 56 patients were still on treatment. Of the 56 patients, ORR per investigator was 33.9% (95% CI 21.8-47.8; n = 19, with 13 patients confirmed) and DCR was 75.0% (95% CI 61.6-85.6; n = 42, all confirmed). Of the 52 patients who had at least one post-baseline radiographic assessment, the ORR was 36.5% (95% CI 23.6-51.0) and DCR was 80.8% (95% CI 67.5-90.4). 20 (35.7%) PFS events and 9 (16.1%) OS events occurred in the 56 patients as of data cutoff, and both PFS and OS data were immature. Treatment-related AEs of any grade or grade ≥3 were reported in 56 (100%) or 25 (44.6%) patients, respectively. The incidence of SHR-1701-related AEs was 92.9% (52 patients). Grade ≥3 SHR-1701-related AEs occurred in 13 (23.2%) patients, with increased gamma-glutamyltransferase (3 patients, 5.4%) and decreased white blood cell count (3 patients, 5.4%) as the most common ones. Serious SHR-1701-related AEs occurred in 6 (10.7%) patients and SHR-1701-related death occurred in 1 (1.8%, gastrointestinal hemorrhage) patient. Conclusions: Combination of SHR-1701 with gemcitabine and nab-paclitaxel showed preliminary antitumor activity in untreated locally advanced or metastatic pancreatic cancer. This combination therapy was well tolerated without unexpected safety signal. Further clinical investigations are warrant to confirm our results. Clinical trial information: NCT04624217.

A phase Ib study of SHR-1701, a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC).

6024 Background: Immune checkpoint inhibitors (ICIs) demonstrated favorable antitumor activity in RM-NPC. However, only a subset of patients derived benefits. Combining ICIs with agents blocking immunosuppressive pathway may expand the clinical benefit of ICIs to more patients. Transforming growth factor β (TGF-β) participates in tumor immune escape. SHR-1701 is a bifunctional fusion protein composed of a mAb against PD-L1 fused to the extracellular domain of TGF-β receptor II. Here, we report the safety and efficacy of SHR-1701 in RM-NPC patients. Methods: This is an ongoing, multicenter, open-label, phase Ib study (NCT04282070). Patients with confirmed RM-NPC who failed prior platinum-based chemotherapy (Arm 1) or both platinum-based chemotherapy and anti-PD-1/PD-L1 antibody treatment (Arm 2) were enrolled to receive SHR-1701 30 mg/kg intravenously once every three weeks until disease progression, unacceptable toxicity, or patient withdrawal. The primary endpoint was safety. The secondary endpoints were objective response rate (ORR), duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Results: 54 patients with RM-NPC were enrolled (Arm 1, n = 30; Arm 2, n = 24). All patients had stage IVb disease and 34 (63%) had received ≥2 lines prior therapies. At data cutoff on Nov 19, 2021, the median SHR-1701 exposure was 6.7 cycles (range 2-23) in Arm 1 and 2.1 cycles (range 1-17) in Arm 2. Grade ≥3 treatment-related adverse events (TRAEs) were observed in 10 patients (18.5%), with the most common being anemia (7.4%) and hemoptysis (3.7%). Two patients (3.7%) discontinued study treatment due to AEs (peripheral nerve injury and epistaxis, n = 1 each), and 10 patients (18.5%) had dose delay caused by AEs. Investigator reported immune related AEs (irAEs) of grade ≥3 occurred in five patients (9.3%). One death (1.9%) from unknown cause was observed, and the causality was deemed as not assessable. At data cutoff, the ORR was 33.3% (95% CI 17.3-52.8) in Arm 1 and 4.2% (95% CI 0.1-21.1) in Arm 2. Responses were ongoing in nine (90.0%) and no patients, respectively, and the median DoR was not reached in Arm 1 and 4.1 months in Arm 2. The DCR was 53.3% (95% CI 34.3-71.7) and 25.0% (95% CI 9.8-46.7), respectively. The median PFS was 5.3 months (95% CI 1.3-not reached) in Arm 1 and 1.4 months (95% CI 1.3-2.7) in Arm 2. At data cutoff, five patients (16.7%) in Arm 1 and eight patients (33.3%) in Arm 2 had died, and the median OS was not reached in both Arms. The 12-month OS rate was 79.9% (95% CI 53.2-92.3) and 71.9% (95% CI 47.6-86.4), respectively. Conclusions: SHR-1701 showed tolerable toxicity profile and promising antitumor activity in patients with RM-NPC who failed prior platinum-based chemotherapy. Clinical trial information: NCT04282070.

Co-targeting TGF-β and PD-L1 with radiation therapy: The Goldilocks principle

In the current issue of Cancer Cell, Lan et al.1 demonstrate that a bifunctional fusion protein targeting TGF-β and PD-L1 can synergize with radiation therapy to simultaneously augment tumor control and reduce normal tissue toxicity.

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

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.

1689P Adverse event management during treatment with bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1: Treatment guidelines based on experience in clinical trials

Bintrafusp alfa, an investigational, 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, has displayed clinical activity and manageable safety in patients with heavily pretreated solid tumors from two phase I studies (NCT02517398 and NCT02699515). Although bintrafusp alfa–associated adverse events (AEs) are mostly mild to moderate, effective management is essential to minimize disruptions in treatment and maintain quality of life (QOL).

1278P SHR-1701, a bifunctional fusion protein targeting PD-L1 and TGF-β, as first-line therapy for PD-L1+ advanced/metastatic NSCLC: Data from a clinical expansion cohort of a phase I study

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape of PD-L1+ advanced/metastatic NSCLC. SHR-1701, a novel bifunctional fusion protein composed of a mAb against PD-L1 fused with the extracellular domain of TGF-β receptor II, was designed to further improve the outcomes of ICIs.

776P SHR-1701, a bifunctional fusion protein targeting PD-L1 and TGF-β, for pretreated advanced cervical cancer: Data from a clinical expansion cohort of a phase I study

SHR-1701 is a novel bifunctional fusion protein composed of a mAb against PD-L1 fused with the extracellular domain of TGF-β receptor II. We initiated a phase I study (NCT03774979) to assess SHR-1701 in multiple cancer types. Here, the results from clinical expansion cohort 4 of cervical cancer are reported.

Evaluation of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in cervical cancer: Data from phase 1 and phase 2 studies.

5509 Background: The accelerated FDA approval of pembrolizumab validated the efficacy of anti–PD-(L)1 therapy for pts with recurrent/metastatic cervical cancer; however, the objective response rate (ORR) with pembrolizumab was 14.3% in pts with PD-L1 expressing tumors. HPV infection is implicated in > 95% of cervical cancers and is linked to upregulation of 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. We report pooled safety and efficacy in pts with immune checkpoint inhibitor–naive, recurrent/metastatic cervical cancer treated with bintrafusp alfa in phase 1 (INTR@PID 001; NCT02517398) and phase 2 (study 012; NCT03427411) studies. Methods: Pts with pretreated, immune checkpoint inhibitor–naive, recurrent/metastatic cervical cancer received bintrafusp alfa 0.3-30 mg/kg (phase 1 dose escalation) or 1200 mg Q2W (phase 1 expansion/phase 2) until progressive disease, unacceptable toxicity, or withdrawal. Treatment past progression was allowed. Primary endpoints were safety for the dose-escalation part of the phase 1 study and best overall response per RECIST 1.1 for the expansion part of phase 1 and phase 2 studies. Secondary endpoints for the expansion part of the phase 1 and 2 studies included safety. Results: As of May 15, 2020 (phase 1) and December 22, 2020 (phase 2), 39 pts had received bintrafusp alfa for a median duration of 2.8 months (range, 0.5-19.3). The median follow-up to data cutoff was 35.0 months and 24.1 months for the phase 1 and phase 2 studies, respectively. All pts had received prior anticancer therapy; 16 pts (41.0%) had received ≥3 prior anticancer regimens. There were 2 complete responses and 9 partial responses (PRs; ORR per RECIST 1.1, 28.2%). Median duration of response was 11.7 months (range, 1.4-41.2), and 5 pts (45.5%) had ongoing responses (duration 1.5-41.2 months). An additional delayed PR was observed (duration 23.7 months). Reponses occurred irrespective of tumor histology or prior bevacizumab or radiation treatment. Median overall survival (mOS) was 13.4 months (95% CI, 5.5 to not reached); 24-month OS rate was 33.2%. Any-grade treatment-related adverse events (TRAEs) occurred in 33 pts (84.6%). Grade 3 TRAEs occurred in 8 pts (20.5%; anemia, colitis, gastroparesis, upper gastrointestinal hemorrhage, keratoacanthoma, cystitis noninfective, hematuria, pneumonitis, rash macular [n = 1 each]); 1 patient (2.6%) had a grade 4 TRAE (asymptomatic hypokalemia related to the above grade 3 gastroparesis). No treatment-related deaths occurred. Conclusions: Bintrafusp alfa had a manageable safety profile and demonstrated clinical activity in pts with heavily pretreated, immune checkpoint inhibitor–naive recurrent/metastatic cervical cancer. Clinical trial information: NCT02517398 , NCT03427411.

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).

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]

First-in-human phase I/II trial of PRGN-2009 vaccine as monotherapy or with bintrafusp alfa in patients with recurrent/metastatic (R/M) human papillomavirus (HPV)-associated cancers (HPVC) and as neoadjuvant/induction therapy in locoregionally advanced (LA) HPV oropharyngeal (OP) and sinonasal (SN) squamous cell cancer (SCC).

TPS6092 Background: R/M HPVC (cervical, anal, oropharyngeal, etc.) are incurable by current therapies. For newly diagnosed LA HPV-OPSCC standard-of-care (SOC) is radiotherapy ± chemotherapy (C/RT) or surgery ± adjuvant C/RT, with considerable risk of relapse. Newly diagnosed LA SNSCC treatment follows the OPSCC paradigm, and detection of HPV appears to confer improved prognosis. Neoadjuvant PD-1 immune checkpoint blockade (ICB) before surgery may improve RFS and is being evaluated in a multicenter phase III clinical trial (Keynote-689). PRGN-2009 (P) is a novel gorilla adenovirus vaccine containing 35 non-HLA-restricted epitopes of HPV 16 and 18 shown to induce HPV specific responses (preclinical models). Bintrafusp alfa (BA) is a bifunctional fusion protein targeting TGF-β and PD-L1 with promising activity in HPVC. This trial will evaluate the safety and activity of P/ P + BA in patients with previously treated R/M HPVC and as neoadjuvant/induction therapy before SOC surgery or C/RT in newly diagnosed LA HPV-OPSCC and HPV-SNSCC. Methods: This is a first-in-human, investigator-initiated, single-center phase I/II trial. Pts with previously treated (incl. ICB) R/M HPVC are eligible for Phase I: P dose escalation arm (3+3 design, 6-12 patients) testing 2 dose levels (1x1011, 5x1011 viral particle units, SC Q2W three times, then Q4W), and combination arm (10 patients) testing P (recommended phase 2 dose (RP2D), same schedule) + BA (1200 mg IV Q2W). Treatment (both arms) will continue until disease progression, unacceptable toxicity, decision to withdraw. Primary endpoint is safety. Secondary endpoints include ORR (RECIST 1.1), PFS, and OS. For Phase II, patients with newly diagnosed stage II/III (AJCC Cancer Staging Manual, 8th ed.) HPV-OPSCC and stage II/III/IVA/IVB HPV-SNSCC planned for SOC C/RT or surgery will be eligible for two treatment arms of 20+2 patients each (sequential): P arm and P + BA, to evaluate the treatment activity. All patients will have pre-treatment biopsy, receive two cycles of the study treatment at the NCI Clinical Center two weeks apart, followed by post-treatment biopsy and SOC treatment (at the referring institution) 4 weeks after the first study treatment. Primary endpoint is post-treatment ≥2-fold increase in tumor-infiltrating CD3+ cells. Secondary endpoints include RFS, OS. Exploratory endpoints for both arms include analyses of immune subsets, soluble factors, and HPV-specific immune responses in peripheral blood and tissue where available, and in Phase II sequencing (exome, scRNA), immune spatial profiling with multiplex immunofluorescence, and salivary HPV DNA. Clinical trial registry: NCT04432597. Clinical trial information: NCT04432597.

Phase II evaluation of the triple combination of PDS0101, M9241, and bintrafusp alfa in patients with HPV 16 positive malignancies.

2501 Background: There are more than 630,000 cases of HPV associated malignancies including cervical, oropharyngeal and anal cancer worldwide annually. HPV 16 is responsible for the majority of these cases. About 15-20% of HPV associated malignancies respond to PD-(L)1 inhibitors, but for the overwhelming majority of patients who progress on these immunotherapies there is no effective standard of care therapy. Preclinical studies have shown that the triple combination of PDS0101 (Versamune-HPV), a liposomal multipeptide therapeutic vaccine targeting HPV 16 E6/E7, M9241, a tumor-targeting immunocytokine composed of IL-12 heterodimers fused to a monoclonal antibody targeting free DNA in necrotic tumor regions, and bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, resulted in maximum HPV-specific T cell responses, T cell tumor infiltration and tumor reduction as compared to any one or two of these agents alone. Methods: Fourteen pts with HPV 16+ relapsed or refractory advanced cancer were enrolled to the triple combination of PDS0101, M9241 and bintrafusp alfa (NCT04287868). Pts received bintrafusp alfa at 1200 mg flat dose i.v. every 2 weeks, M9241 at 16.8 mcg/kg s.c. every 4 weeks and PDS0101 given as two separate 0.5 ml s.c. injections every 4 weeks. Dose reductions of M9241 to 8 mcg/kg were allowed as well as skipped doses of any agent for ongoing toxicities. Results: Fourteen pts with advanced HPV 16+ cancers (5 cervical, 2 vaginal/vulvar, 4 anal, 3 oropharyngeal) were treated. 4/14 (28.6%) pts had a grade 3 treatment related toxicity including grade 3 hematuria in 2 pts with cervical ca and prior pelvic radiation and grade 3 AST/ALT elevation in 2 pts, one with anal ca and one with vaginal ca. For one patient with grade 3 AST/ALT elevation dose reduction of M9241 from 16.8 to 8 mcg/kg allowed for continued treatment with AST/ALT remaining at grade 1 or less. One additional patient had transient asymptomatic grade 4 neutropenia. No other treatment related grade 3 or greater toxicities were noted. 10/14 (71%) pts have had objective responses: 1 CR (anal ca) and 9 PRs (3 cervical, 2 vulvar/vaginal, 2 anal, 2 oropharyngeal) with 9/10 of these responses ongoing after a median 5 month of follow up. Of the 14 pts, 6 pts have checkpoint naïve disease and 8 pts have checkpoint refractory disease. 5/6 (83%) pts with checkpoint naïve disease and 5/8 (63%) pts with checkpoint refractory disease have had objective responses. Analyses of immune responses and other immune correlates are ongoing. Conclusions: Triple combination of PDS0101, M9241 and bintrafusp alfa appears to have a manageable safety profile along with early evidence of notable clinical activity for pts with both checkpoint naïve as well as checkpoint refractory HPV 16+ advanced malignancies. Clinical trial information: NCT04287868.