Bifunctional Fusion Protein Targeting PD-L1 Research Articles

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 .

SHR-1701 in combination with platinum-based chemotherapy and BP102 (a bevacizumab biosimilar) for persistent, recurrent, or metastatic cervical cancer: Data from a phase 1b/3 study.

5529 Background: Platinum-based chemotherapy (chemo) ± bevacizumab is the standard first-line therapy for cervical cancer, regardless of PD-L1 expression. SHR-1701 is a novel bifunctional fusion protein targeting PD-L1 and TGF-βRII, and shows promising efficacy and controllable safety in pretreated patients (pts) with cervical cancer. This ongoing phase 1b/3 study aims to assess the addition of SHR-1701 to standard first-line therapy. Methods: In the phase 1b part, eligible pts had persistent, recurrent, or metastatic squamous-cell carcinoma, adenocarcinoma, or adenosquamous cell carcinoma of the cervix not previously treated with systemic chemo for recurrence or metastasis and not amenable to curative treatment. Prior chemo-radiotherapy was permitted for recurrence, if mono-chemo was used as sensitizer. Pts were given SHR-1701 (30 mg/kg), paclitaxel (175 mg/m2), cisplatin (50 mg/m2) / carboplatin (AUC 5), and BP102 (15 mg/kg) every 3 weeks. The primary endpoints were safety and ORR. Results: From Feb 26 to Aug 12, 2022, 31 pts were enrolled. Median age was 55 years (range, 27-71). 24 (77.4%) had squamous-cell carcinoma, and 7 (22.6%) had adenocarcinoma. 20 (64.5%) had metastatic disease, 7 (22.6%) had recurrent cervical cancer, and 4 (12.9%) had persistent cervical cancer. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 25 (80.6%) pts, with the most common being decreased neutrophil count (n=16, 51.6%), decreased white blood cell count (n=12, 38.7%), and anemia (n=8, 25.8%). TRAEs led to discontinuation of any study agent in 8 (25.8%) pts; of note, only 2 (6.5%) pts discontinued SHR-1701 due to TRAEs (grade 3 infusion reaction and grade 3 immune-mediated rash). No treatment-related deaths occurred. Efficacy outcomes are summarized in Table. ORR was 77.4%, with 4 CRs and 20 PRs; responses were ongoing in all 24 responders. DCR was 93.5%. Shrinkage in target lesions was observed in 30 (96.8%) pts. PFS rate at 6 months reached 93.5%. Conclusions: SHR-1701 plus platinum-based doublet chemo and BP102 provided a manageable safety profile and potent antitumor activity in pts with persistent, recurrent, or metastatic cervical cancer, supporting the subsequent randomized, double-blind, placebo-controlled phase 3 part. Clinical trial information: NCT05179239 . [Table: see text]

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.

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.

SHR-1701, a bifunctional fusion protein targeting PD-L1 and TGF-β, for advanced NSCLC with EGFR mutations: Data from a multicenter phase 1 study.

9055 Background: Despite the development of targeted therapies for advanced NSCLC harboring EGFR mutations ( EGFR+), acquired resistance remains inevitable. Immune checkpoint inhibitor as monotherapy has limited efficacy. Blockade of the TGF-β pathway which plays a key role in immune suppression may enhance the tumor response to anti-PD-1/PD-L1 antibodies. Here, we assessed SHR-1701, a novel bifunctional fusion protein composed of a mAb against PD-L1 fused with the extracellular domain of TGF-β receptor II, in advanced NSCLC pts including one separate EGFR+ cohort. Methods: This phase 1 study includes a 3+3 dose-escalation and dose-expansion period of pretreated advanced NSCLC and multiple clinical expansion cohorts of different tumor types, genetic aberrations, or prior therapies. During the dose-escalation and dose-expansion period, pathologically confirmed pts received SHR-1701 at 3, 10, or 20 mg/kg Q3W or 20 mg/kg Q2W by intravenous infusion. The primary objectives were to determine the safety profile, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of SHR-1701. In the EGFR+ NSCLC clinical expansion cohort, histologically or cytologically confirmed advanced pts after at least 1L standard EGFR TKI received SHR-1701 at RP2D, and the primary endpoint was objective response rate (ORR). Treatment beyond progression was allowed. Results: During the dose-escalation and dose-expansion period, 30 pts were recruited: all stage IV; 83.3% had ≥2 metastasis sites; 76.7% had received ≥2L prior systemic therapy. One dose-limiting toxicity (immune-mediated pneumonitis) in the 20 mg/kg Q2W group was observed, and the MTD was not reached. Population pharmacokinetics and exposure‐response analysis of SHR-1701 based on this study and another phase 1 study for advanced solid tumors (NCT03710265) demonstrated 30 mg/kg Q3W as the RP2D. In the EGFR+ NSCLC cohort, 27 pts were enrolled: all stage IV; 77.8% had ≥2 metastasis sites; 70.4% had received ≥2L prior systemic therapy; 29.6% had 19-Del, 14.8% 19-Del and T790M, 7.4% 20-ins, 29.6% L858R, 18.5% L858R and T790M. With a median SHR-1701 exposure of 8.7 weeks (range, 3.0-24.0), 4 of the 24 pts who had at least one post-baseline radiographic assessment achieved objective responses, including 3 ongoing confirmed and 1 unconfirmed partial response. ORR was 16.7% (95% CI, 4.7%-37.4%), and disease control rate was 50.0% (95% CI, 29.1%-70.9%). Grade 3 treatment-related adverse events (TRAEs) occurred in 2 (7.4%) pts, including anemia, hypokalemia, and asthenia (1 [3.7%] for each). There were no grade 4 or 5 TRAEs. No pts discontinued treatment due to TRAEs. Conclusions: 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. Clinical trial information: NCT03774979.

Phase 1 study of SHR-1701, a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with advanced solid tumors.

2503 Background: Dual inhibition of PD-1/PD-L1 and TGF-β pathways is a promising therapeutic strategy for multiple tumor types. SHR-1701 is a novel bifunctional anti-PD-L1/TGF-βRII agent. This dose escalation and expansion phase 1 study aimed to evaluated the safety and preliminary anti-tumor acitivity of SHR-1701 in refractory solid tumors. Methods: The dose escalation period was initiated by accelerated titration (1 mg/kg Q3W) and then switched to 3+3 scheme (3, 10, 20, and 30 mg/kg Q3W and 30 mg/kg Q2W). The dose expanded at doses of 10, 20, and 30 mg/kg Q3W and 30 mg/kg Q2W. The primary objectives were to determine the safety profile, MTD, and RP2D of SHR-1701. Results: 17 pts (1 mg/kg Q3W [n = 1]; 3, 10, 20 and 30 mg/kg Q3W [n = 3 each]; 30 mg/kg Q2W [n = 4]) were enrolled in dose escalation part. No DLT was observed and MTD was not reached. Another 32 pts (10 mg/kg Q3W [n = 8]; 20 and 30 mg/kg Q3W [n = 9 each]; 30 mg/kg Q2W [n = 6]) were enrolled in dose expansion part. Of 49 enrolled pts, 33 pts (67.3%) had received ≥2 lines of prior systemic therapy. As of data cutoff on Oct 30, 2020, the median duration of SHR-1701 exposure was 6.0 weeks (range, 2.0-78.6). The most common reported TRAEs were increased ALT/AST, anemia, hypothyroidism, and increased bilirubin/conjugated bilirubin, with incidence > 15%. The incidence of irAEs reported by the investigator was 46.9% and 4 pts received systemic corticosteroids. Hypothyroidism and rash were the most common irAEs with incidence > 10%. The incidence of Grade ≥3 TRAEs was 18.4%. The incidence of Grade ≥3 irAEs was 10.2%. 1 pt suffered early death for liver failure more likely caused by tumor progression. PK analysis showed a linear dose-exposure relationship with SHR-1701 dosing from 1 to 30 mg/kg. The peripheral PD-L1 target occupancy rate exceeded 90%, and nearly complete TGF-β1 trapping was detected in all dose groups. Of 49 enrolled pts, 45 pts completed at least once efficacy evaluation. The ORR was 17.8% (95% CI, 8.0%-32.1%), with 8 pts achieving PR (2 lung adenocarcinoma, 1 HCC, 1 ESCC, 1 dMMR-CRC, 1 renal cancer, 1 epiglottis cancer, and 1 pancreatic acinar cell carcinoma). The DCR was 40.0% (18/45; 95% CI, 25.7%-55.7%). Majority of responses (7/8) were still ongoing, and the median DoR had not been reached yet. Based on data of saftety, PK, PD, and efficacy, we recommended 30 mg/kg Q3W as the RP2D. Conclusions: SHR-1701 showed acceptable safety profile and encouraging antitumor activity in refractory solid tumors, establishing the foundation for further exploration. Clinical trial information: NCT03710265.

643P - M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with post-platinum esophageal adenocarcinoma (EAC): Preliminary results from a phase I cohort

643P - M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with post-platinum esophageal adenocarcinoma (EAC): Preliminary results from a phase I cohort

1048O - M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients (pts) with advanced SCCHN: Results from a phase I cohort

1048O - M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients (pts) with advanced SCCHN: Results from a phase I cohort

661P - Updated results from a phase I trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with pretreated recurrent or refractory gastric cancer

661P - Updated results from a phase I trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with pretreated recurrent or refractory gastric cancer

757P - M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in Asian patients with pretreated biliary tract cancer: Preliminary results from a phase I trial

757P - M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in Asian patients with pretreated biliary tract cancer: Preliminary results from a phase I trial

Safety and activity of M7824, a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with HPV associated cancers.

3007Background: Therapies targeting PD-1/L1 have produced response rates of 15-20% in patients (pts) with HPV associated cancers (HAC) including cervical (cerv), anal or head and neck squamous cell...

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.

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 pretreated recurrent or refractory gastric cancer: Preliminary results from a phase I trial.

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.

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

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.

Abstract 594: Dual targeting of TGFb and PD-L1 promotes potent anti-tumor efficacy in multiple murine models of solid carcinomas

Abstract Tumors evade host immune surveillance through multiple mechanisms, including promoting a tumor microenvironment able to effectively suppress immune effector functions. Secretion of cytokines such as TGFb and upregulation of immune checkpoint molecules are two main contributors to immune evasion and tumor progression. TGFb is an important immunosuppressive cytokine with pleiotropic actions in cancer, including promotion of epithelial to mesenchymal transition and metastasis. It promotes tumor immune evasion by impairing T and NK cell maturation, recruitment, and function. Tumors also inhibit antitumor immune responses through tumor cell-immune cell interaction, in which the negative regulatory checkpoint PD-L1/PD-1 interaction plays a major role. Therapies that independently target TGFb signaling or PD-L1/PD-1 interaction demonstrate limited clinical efficacy. Anti-PD-L1/TGFbTRAP (M7824) is a novel immunotherapeutic agent designed to simultaneously block the PD-L1 and TGFb immunosuppressive pathways. It is comprised of the extracellular domain of human TGFbRII (TGFbTRAP) linked to the C-terminus of human anti-PD-L1 heavy chain (anti-PD-L1). M7824 has shown potent anti-tumor activities in preclinical models1 and some evidence of clinical efficacy in a phase 1 study2. Here, we demonstrate that anti-PD-L1/ TGFbTRAP neutralizes murine TGFb-induced signaling and binds to murine PD-L1 in multiple murine breast and colon carcinoma models. In non-tumor bearing mice, anti-PD-L1/TGFbTRAP increases the number of CD8+ T cells in the lymph nodes, and elicits splenic CD8+ T and NK cells with a more active phenotype. Initial examination of peripheral immune subsets in tumor-bearing mice indicates that anti-PD-L1/TGFbTRAP induces CD8+ T cells and NK cells with a more active, less exhausted phenotype. Furthermore, dual targeting of PD-L1 and TGFb increases tumor expression of MHC-I, MHC-II, and PD-L1, suggesting additional immune effects in the tumor microenvironment. Importantly, anti-PD-L1/TGFbTRAP displays potent anti-tumor efficacy against various murine models of breast and colorectal carcinomas. This response is durable, preventing relapses up to 7 months. Anti-PD-L1/TGFbTRAP also decreases spontaneous metastasis in a murine model of triple-negative breast cancer. Taken together, these findings support the preclinical proof of concept for dual targeting of TGFb and PD-L1/PD-1 pathways with anti-PD-L1/ TGFbTRAP, its mode of action, and its potential clinical use as a monotherapy or in combination with other immunotherapies or standards of care. 1 Lan Y et al, Preclinical evaluation of M7824 (MSB0011359C), a novel bifunctional fusion protein targeting the PD-L1 and TGFb pathways. Keystone Symposium, Jan 2017. 2 Strauss J et al, Phase I trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGFb, in advanced solid tumors. Keystone Symposium, Jan 2017. Citation Format: Karin M. Knudson, Sofia R. Gameiro, Kin-Ming Lo, Jeffrey Schlom. Dual targeting of TGFb and PD-L1 promotes potent anti-tumor efficacy in multiple murine models of solid carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 594. doi:10.1158/1538-7445.AM2017-594