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Cancer Immunol Immunother. 2024 May; 73(5): 89.
Published online 2024 Mar 30. doi:10.1007/s00262-024-03654-0
PMCID: PMC10981579
PMID: 38554156
Manish R. Patel,
1,2 Melissa Johnson,1,3 Ira Winer,4 Hendrik-Tobias Arkenau,5 Natalie Cook,6 Vanessa Samouëlian,7 Raid Aljumaily,1,8 Shigehisa Kitano,9,10 Christine Duffy,11 Miaomiao Ge,11 Mabrouk Elgadi,11 and Lillian L. Siu12
Author information Article notes Copyright and License information PMC Disclaimer
Associated Data
- Supplementary Materials
- Data Availability Statement
Abstract
Background
Ezabenlimab (BI 754091) is a humanised monoclonal antibody targeting programmed cell death protein-1. We report results from open-label, dose-escalation/expansion, Phase I trials that evaluated the safety, maximum tolerated dose (MTD), pharmaco*kinetics and antitumour activity of ezabenlimab at the recommended Phase II dose in patients with selected advanced solid tumours.
Study design
Study 1381.1 (NCT02952248) was conducted in Canada, the United Kingdom and the United States. Study 1381.4 (NCT03433898) was conducted in Japan. Study 1381.3 (NCT03780725) was conducted in the Netherlands. The primary endpoints were: number of patients experiencing dose-limiting toxicities (DLTs) in the first cycle (dose escalation parts), number of patients with DLTs during the entire treatment period and objective response (dose expansion part of Study 1381.1).
Results
Overall, 117 patients received ezabenlimab intravenously every 3weeks (80mg, n = 3; 240mg, n = 111; 400mg, n = 3). No DLTs were observed and the MTD was not reached. Fifty-eight patients (52.3%) had grade ≥ 3 adverse events, most commonly anaemia (10.8%) and fatigue (2.7%). In 111 assessed patients treated with ezabenlimab 240mg, disease control rate was 56.8% and objective response rate was 16.2%. Three patients had complete response; at data cut-off (November 2021) one remained in response and was still receiving ongoing treatment (duration of response [DoR]: 906days). Partial responses occurred across several tumour types; DoR ranged from 67 to 757days.
Conclusions
Ezabenlimab was well tolerated and associated with durable antitumour activity in multiple solid tumours, comparable to other immune checkpoint inhibitors in similar patient populations and treatment settings.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00262-024-03654-0.
Keywords: Ezabenlimab, Advanced solid tumours, PD-1 inhibitor, Phase I
Introduction
Immune checkpoint inhibitors have revolutionised the treatment of cancer over the last decade. Monoclonal antibodies that target programmed cell death protein-1 (PD-1; e.g. nivolumab and pembrolizumab) and its ligand, PD-L1 (e.g. atezolizumab and durvalumab), have been shown to be promising anticancer strategies and thus are approved for the treatment of a wide variety of solid tumours haematological malignancies [1]. Although anti-PD-1/PD-L1 therapies have achieved great success in treating cancers, only a subset of patients show clinical response [2–6]. Furthermore, a large group of responders develop acquired resistance after initial response and require alternative therapeutic approaches.
Ezabenlimab (BI 754091) is a humanised PD-1-targeting monoclonal antibody [7]. Here, we report safety, pharmaco*kinetic and efficacy results in patients with advanced solid tumours who received ezabenlimab monotherapy in three open-label, Phase I studies (Studies 1381.1 and 1381.4, and one patient from Study 1381.3), with a focus on patients who received ezabenlimab monotherapy at the recommended Phase II dose (RP2D) of 240mg given every 3weeks (Q3W).
Methods
Study design and patients
This manuscript reports data from three open-label, Phase I studies assessing ezabenlimab monotherapy in patients with advanced solid tumours. The international, multi-cohort Study 1381.1 (NCT02952248) was conducted in Canada, the United Kingdom and the United States and comprised dose escalation and dose expansion parts. Study 1381.4 (NCT03433898) was conducted in Japan and assessed ezabenlimab as monotherapy and in combination with BI 754111, a lymphocyte activation gene 3 (LAG3) inhibitor. Additionally, one patient from imaging study 1381.3 (NCT03780725), which was conducted in the Netherlands, was included [8]. The studies were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines. All patients provided written informed consent.
Eligible patients were aged ≥ 18years old, with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, and adequate organ function. For the dose-escalation/dose-finding parts of Studies 1381.1 and 1381.4, patients had a histologically or cytologically confirmed diagnosis of advanced, unresectable or metastatic solid tumours, and had disease progression on, were intolerant to, or not eligible for, standard therapies, including immune checkpoint inhibitors (anti-PD-1, anti-PD-L1, or cytotoxic T-lymphocyte–associated protein 4 inhibitors). In the dose expansion part of Study 1381.1, patients were enrolled into one of four cohorts: Cohort 1, seven solid tumour types (non-small cell lung cancer, bladder cancer, melanoma, gastric cancer, ovarian cancer, triple-negative breast cancer and renal cell carcinoma); Cohort 2, tumours with high tumour mutational burden (TMB; ≥ 10 mutations/MB) excluding those with high microsatellite instability; Cohort 3, squamous cell cervical, anal and skin tumours that were refractory to standard therapies; and Cohort 4, recurrent human papilloma virus-positive or -negative vagin*l or vulvar squamous cell carcinoma (VSCC) not amenable to surgery. All patients in the dose-expansion cohort of Study 1381.1 were required to have measurable lesions per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, have at least one tumour lesion amenable to biopsy, and be willing to undergo a biopsy before first treatment and after 6weeks of therapy. All patients had either progressed on conventional treatment, were not amenable to standard therapies, or there were no available therapies of proven efficacy.
Key exclusion criteria included: previous treatment with an anti-PD-1, anti-PD-L1, or cytotoxic T-lymphocyte–associated protein 4 inhibitor, requirement for chronic systemic steroid therapy, history of pneumonitis, and presence of untreated active brain metastases or active autoimmune disease or infections.
Treatment
The dose escalation part of Study 1381.1 was guided by a Bayesian Logistic Regression Model (BLRM) with overdose control, with cohorts of three patients sequentially enrolled at ezabenlimab doses of 80, 240, and 400mg (predetermined maximum administered dose) administered intravenously over 60min on Day 1 of 21-day cycles.
In the dose expansion part of Study 1381.1, part 1 of Study 1381.4 and in the one patient included from Study 1381.3, ezabenlimab was administered at 240mg Q3W (the RP2D established during dose escalation).
Treatment was continued for up to 1year, or until disease progression or unacceptable toxicity. Treatment could also be continued beyond 1year in patients with clinical benefit. Patients could remain on treatment at the investigator’s discretion following initial radiological progressive disease.
Endpoints and assessments
In the dose-escalation/dose-finding parts of Studies 1381.1 and 1381.4, the primary endpoint was the number of patients experiencing dose limiting toxicities (DLTs) in the first cycle. Secondary endpoints included pharmaco*kinetic parameters, DLTs in all cycles and objective response rate (ORR). For the dose expansion of Study 1381.1, the primary endpoints were number of patients with DLTs during the entire treatment period and ORR. Secondary endpoints included progression-free survival and safety.
Safety was assessed by descriptive analysis of incidence and severity of adverse events (AEs; graded per Common Terminology Criteria for Adverse Events version 5.0). Investigators indicated whether an AE was a potentially immune-related event. Immune-related AEs are AEs associated with immunotherapy treatments that appear to be associated with the immune therapy’s mechanism of action. In general, treatment of low grade immune-related AEs was left up to the discretion of the investigator. The protocol provided guidelines for management of potentially life-threatening AEs (such as pneumonitis, colitis, encephalitis, diabetes, hepatitis, etc.) consistent with international guidelines. The Phase I trial statistical analysis plan did not include specific analysis for time to resolution of low-grade AEs.
Blood samples were collected at pre-defined timepoints during each study to evaluate the presence of anti-drug antibodies (ADAs) using a validated immunoassay in a tiered approach. In Study 1381.1, biomarker assessments were performed in both blood samples (for PD-1 receptor occupancy in peripheral blood mononuclear cells in the dose escalation phase and cytokine analysis in the dose expansion phase) and tumour biopsies (for immunohistochemical analysis of PD-L1, PD-1, LAG-3 and CD-8). Tumour assessment was performed at baseline, every two cycles during the first 6months and every three cycles thereafter. Response was evaluated by the investigator per RECIST version 1.1 and iRECIST (modified RECIST version 1.1 for immune-based therapeutics).
Blood samples were also analysed to evaluate pharmaco*kinetics. Ezabenlimab plasma concentrations were evaluated using a validated immunoassay.
A population pharmaco*kinetic two-compartmental model was developed using the nonlinear mixed effects modelling approach. Data from 66 patients from BI Studies 1381.1 and 1381.2 (a Phase I dose-finding study of BI 754111 in combination with ezabenlimab) were used in the model. The predicted pharmaco*kinetic profile at steady state for ezabenlimab 240mg Q3W was compared with that of pembrolizumab 200mg Q3W.
Statistical analysis
The dose escalation part of Study 1381.1 was guided by a BLRM with overdose control. The estimated probability of a DLT at each dose level from the model was summarised using the following intervals: under dosing (0.00–0.16), targeted toxicity (0.16–0.33) and over toxicity (0.33–1.00). The BLRM recommended dose for the next cohort was the level with the highest posterior probability of the DLT rate falling in the target interval among the doses fulfilling escalation with overdose control criteria.
Maximum tolerated dose (MTD) was defined as the highest dose with a less than 25% risk of the true DLT rate being above 0.33. MTD was considered reached if at least one DLT was observed in the study and one of the following criteria was fulfilled: the posterior probability of the true DLT rate in that target interval of the MTD was above 0.50 or at least 15 patients had been treated in the study (of which at least six had been treated at the MTD).
DLTs observed during the first three weeks of treatment (the MTD evaluation period) of Study 1381.1 were considered for MTD determination, while the determination of the RP2D considered DLTs occurring in all treatment cycles of the study. For RP2D determination, the BLRM was re-run including the information from all cycles; the RP2D was selected after consideration of the BLRM estimates from the MTD evaluation period and the entire study period, as well as pharmaco*kinetic and other data obtained during the study.
Pharmaco*kinetic parameters were analysed by non-compartmental analysis.
Results
Patients and treatment
Between November 2016 and November 2021, 117 patients were enrolled and received ezabenlimab monotherapy. A total of 110 patients were treated in Study 1381.1 (nine in the dose escalation cohorts and 101 in dose expansion cohorts), six were treated in Study 1381.4, and one was treated in Study 1381.3 (Fig.1). Most patients (n = 111) received ezabenlimab 240mg Q3W, and three patients each received ezabenlimab 80mg and 400mg Q3W during the dose escalation part of Study 1381.1. At the data cut-off date (November 2021), 104 patients had discontinued treatment; the main reason for discontinuation was progressive disease. Seven patients remained on treatment (three patients in the high TMB cohort and four in the cervical/anal/skin cancer cohort).
Fig.1
Patient disposition. AE, adverse event; PD, progressive disease; Q3W, every 3weeks; TMB, tumour mutational burden
The median age of the population was 61years, the majority (73.5%) were female, and most (68.4%) had an ECOG PS of 1 (Table1). Patients had a range of tumour types, with the most common being cervical (13.7%), ovarian (10.3%), breast (9.4%), anal (8.5%) and VSCC (7.7%). Most patients had received prior systemic therapy (95.7%), with a median of two prior regimens (range 1–10; Table1).
Table1
Patient characteristics for the treated set
| Characteristic | N = 117 |
|---|---|
| Gender, n (%) | |
| Male | 31 (26.5) |
| Female | 86 (73.5) |
| Median age, years (range) | 61 (25–85) |
| Race, n (%) | |
| Asian | 8 (6.8) |
| Black/African American | 11 (9.4) |
| White | 94 (80.3) |
| Other | 4 (3.4) |
| Ethnicity, n (%) | |
| Hispanic/Latino | 7 (6.0) |
| Not Hispanic/Latino | 106 (90.6) |
| Unknown | 4 (3.4) |
| ECOG PS, n (%) | |
| 0 | 37 (31.6) |
| 1 | 80 (68.4) |
| Median number of metastatic sites at screening (range) | 2.5 (1–8) |
| Prior surgery, n (%) | 72 (61.5) |
| Prior radiotherapy, n (%) | 75 (64.1) |
| Prior systemic therapy, n (%) | 112 (95.7) |
| Median number of prior systemic therapies (range) | 2.0 (1–10) |
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ECOG PS, Eastern Cooperative Oncology Group performance status
Maximum tolerated dose
During dose escalation in Study 1381.1, patients received ezabenlimab at three dose levels: 80mg, 240mg and 400mg Q3W (n = 3 per dose level). During dose escalation, no DLTs were reported, and no MTD was reached. Per protocol, the maximum administered dose was 400mg Q3W. Ezabenlimab 240mg Q3W was selected as the RP2D based on an overall review of the pharmaco*kinetics, safety and pharmacometric modelling data from the dose escalation part of Study 1381.1.
In Part 1 of Study 1381.4, six patients received ezabenlimab 240mg Q3W. No DLTs were reported.
Safety and tolerability
As of the November 2021 data cut-off date, median duration of treatment for the treated patient population was 94.0days (range 20–1008). Across the treated set (N = 117), 114 (97.4%) patients had an AE and 72 (61.5%) patients had an investigator-defined treatment-related AE (TRAE). There were no fatal AEs.
Among those who received the RP2D dose of 240mg Q3W (n = 111), 108 (97.3%) had an AE and 67 (60.4%) had a TRAE. The most common AEs were fatigue (38.7%), nausea (29.7%) and anaemia (22.5%; Table2). TRAEs in patients who received 240mg Q3W are shown in Supplementary Table1; most TRAEs were grade 1 or 2 in severity. Seven (6.3%) patients had grade 3 TRAEs and there were no grade 4 TRAEs. A total of 42 (37.8%) patients who received ezabenlimab 240mg Q3W had serious AEs. Of these, three were considered treatment-related: grade 2 pyrexia, grade 3 drug-induced liver injury and grade 3 rash.
Table2
Most common any-cause AEs with ezabenlimab 240mg Q3W monotherapy during the on-treatment period (occurring in ≥ 10% of patients)
| All patients (N = 111) | |||||
|---|---|---|---|---|---|
| All grades | Grade 1 | Grade 2 | Grade 3 | Grade 4 | |
| Patients with any AE, n (%) | 108 (97.3) | 9 (8.1) | 41 (36.9) | 55 (49.5) | 3 (2.7)a |
| Fatigue | 43 (38.7) | 22 (19.8) | 18 (16.2) | 3 (2.7) | 0 |
| Nausea | 33 (29.7) | 24 (21.6) | 9 (8.1) | 0 | 0 |
| Anaemia | 25 (22.5) | 5 (4.5) | 8 (7.2) | 12 (10.8) | 0 |
| Decreased appetite | 23 (20.7) | 17 (15.3) | 5 (4.5) | 1 (0.9) | 0 |
| Diarrhoea | 20 (18.0) | 12 (10.8) | 7 (6.3) | 1 (0.9) | 0 |
| Cough | 20 (18.0) | 13 (11.7) | 5 (4.5) | 2 (1.8) | 0 |
| Constipation | 20 (18.0) | 13 (11.7) | 7 (6.3) | 0 | 0 |
| Abdominal pain | 18 (16.2) | 6 (5.4) | 10 (9.0) | 2 (1.8) | 0 |
| Vomiting | 17 (15.3) | 14 (12.6) | 3 (2.7) | 0 | 0 |
| Peripheral oedema | 17 (15.3) | 9 (8.1) | 8 (7.2) | 0 | 0 |
| Urinary tract infection | 17 (15.3) | 2 (1.8) | 14 (12.6) | 1 (0.9) | 0 |
| Pyrexia | 15 (13.5) | 9 (8.1) | 4 (3.6) | 2 (1.8) | 0 |
| Back pain | 15 (13.5) | 10 (9.0) | 5 (4.5) | 0 | 0 |
| Dyspnoea | 15 (13.5) | 10 (9.0) | 3 (2.7) | 2 (1.8) | 0 |
| Arthralgia | 14 (12.6) | 7 (6.3) | 6 (5.4) | 1 (0.9) | 0 |
| Headache | 14 (12.6) | 11 (9.9) | 2 (1.8) | 1 (0.9) | 0 |
| Rash | 13 (11.7) | 10 (9.0) | 1 (0.9) | 2 (1.8) | 0 |
| Pain in extremity | 13 (11.7) | 8 (7.2) | 4 (3.6) | 1 (0.9) | 0 |
| Hypokalaemia | 13 (11.7) | 11 (9.9) | 0 | 2 (1.8) | 0 |
| Weight decreased | 12 (10.8) | 6 (5.4) | 5 (4.5) | 1 (0.9) | 0 |
| Hypothyroidism | 12 (10.8) | 2 (1.8) | 10 (9.0) | 0 | 0 |
| Pruritus | 12 (10.8) | 10 (9.0) | 2 (1.8) | 0 | 0 |
| Insomnia | 11 (9.9) | 8 (7.2) | 3 (2.7) | 0 | 0 |
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aReported G4 adverse events (preferred terms) were: hypercalcaemia; sepsis; biliary sepsis
AE, adverse event; Q3W, every 3weeks
Immune-related AEs were reported in 31 (27.9%) patients who received ezabenlimab 240mg Q3W during the on-treatment period (in 33 [29.7%] patients when immune-related AEs were analysed during the entire study period). The most common immune-related AEs were hypothyroidism (8 patients; 7.2%), hyperthyroidism (5 [4.5%]), maculopapular rash (5 [4.5%]) and diarrhoea [5; 4.5%]). Most of these events were grade 1 or 2 in severity. There were no grade 4 or grade 5 immune-related AEs. Five patients had grade 3 immune-related AEs (preferred terms were maculopapular rash, rash, stomatitis, aspartate aminotransferase [AST] increased, weight increased and arthralgia). No infusion-related reactions were reported. Treatment of immune-related AEs usually involved the use of corticosteroids.
Five (4.5%) patients who received ezabenlimab 240mg Q3W had AEs leading to treatment discontinuation (grade 1 insomnia, grade 2 colitis, grade 2 AST increased, grade 2 pneumonitis and grade 3 drug-induced liver injury).
Antitumour activity
Among the 111 evaluable patients who received ezabenlimab 240mg Q3W, the ORR per investigator review as assessed by RECIST v1.1 was 16.2% (Table3). Three patients had a complete response (two patients with anal cancer and one with VSCC); one of the patients with anal cancer remained free of disease and was still receiving ezabenlimab at the data cut-off date (duration of response was 906days). Partial responses were observed in 15 patients across all Study 1381.1 cohorts (seven tumour types, high TMB, cervical/anal/skin (all n = 4), vulvar, dose escalation (all n = 1) and in Study 1381.4 (n = 1); duration of response ranged from 67 to 757days. Stable disease was seen in 45 patients across a range of tumour types. The disease control rate was 56.8%.
Table3
Best confirmed overall response in patients who received ezabenlimab monotherapy
| Study 1381.1 dose escalation | Study 1381.1 dose expansion (240mg Q3W) | Study 1381.4 and 1381.3a | Total | ||||||
|---|---|---|---|---|---|---|---|---|---|
| 80mg Q3W | 240mg Q3W | 400mg Q3W | Cohort 1 7 tumour types | Cohort 2 High TMB | Cohort 3 Cervical/anal/skin | Cohort 4 Vulvar | 240mg Q3W | ||
| Total treated, n | 3 | 3 | 3 | 30 | 27 | 31 | 13 | 7 | 117 |
| Post-baseline assessment, n | 3 | 3 | 3 | 29 | 24 | 31 | 12 | 6 | 111 |
| Objective response, n (%) | 0 | 1 (33.3)b | 0 | 4 (13.8)c | 4 (16.7)d | 6 (19.4) | 2 (16.7) | 1 (16.7)e | 18 (16.2) |
| Complete response, n (%) | 0 | 0 | 0 | 0 | 0 | 2 (6.5) | 1 (8.3) | 0 | 3 (2.7) |
| Partial response, n (%) | 0 | 1 (33.3) | 0 | 4 (13.8) | 4 (16.7) | 4 (12.9) | 1 (8.3) | 1 (16.7) | 15 (13.5) |
| Stable disease, n (%) | 2 (66.7) | 2 (66.7) | 1 (33.3) | 11 (37.9) | 9 (37.5) | 12 (38.7) | 5 (41.7) | 3 (50.0) | 45 (40.5) |
| Progressive disease, n (%) | 1 (33.3) | 0 | 2 (66.7) | 14 (48.3) | 10 (41.7) | 13 (41.9) | 5 (41.7) | 2 (33.3) | 47 (42.3) |
| Not evaluable, n (%) | 0 | 0 | 0 | 0 | 1 (4.2) | 0 | 0 | 0 | 1 (0.9) |
| Disease control, n (%) | 2 (66.7) | 3 (100) | 1 (33.3) | 15 (51.7) | 13 (54.2) | 18 (58.1) | 7 (58.3) | 4 (66.7) | 63 (56.8) |
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Percentages determined based on number of patients with post-baseline assessments. aOne patient from Study 1381.3 who received ezabenlimab included in the analysis; bTumour type: oesophageal; cTumour types: breast (n = 2), fallopian tube; renal cell carcinoma; dTumour types: angiosarcoma; breast; endometrial; left supraclavicular node; eTumour type: mesothelial
Q3W, every 3weeks; TMB, tumour mutational burden
In the 101 evaluable patients in the dose expansion part of Study 1381.1, progression-free survival was 2.6months.
Pharmaco*kinetic profile
The geometric mean ezabenlimab plasma concentration–time profiles of the three dose cohorts in the dose escalation part of Study 1381.1 and the 240mg dose cohort in the expansion part are shown in Fig.2. The profiles were at least biphasic, with a rapid distribution phase followed by a slower elimination phase. Pharmaco*kinetic profiles for the 240mg dose escalation and expansion cohorts were very similar.
Fig.2
Geometric mean plasma concentration–time profiles of ezabenlimab after the first intravenous infusion during dose escalation (80, 240 and 400mg Q3W) and dose expansion (240mg Q3W). Q3W, every 3weeks
Pharmaco*kinetic parameters of ezabenlimab in Studies 1381.1 and 1381.4 are shown in Supplementary Table2. Of note, there were no apparent differences in pharmaco*kinetic profiles between Japanese and Caucasian patients. ADAs occurred infrequently (in 10.2% of patients in Study 1381.1 and 0% in Study 1381.4) and did not impact the pharmaco*kinetic profile of ezabenlimab (data not shown).
Pharmacodynamic assessments
Preliminary data from nine patients in the 80mg, 240mg and 400mg dose groups in Study 1381.1 showed 100% PD-1 receptor occupancy in all on-treatment patient peripheral blood mononuclear cell samples versus baseline throughout the first treatment cycle. In the same treatment cycle, ezabenlimab treatment resulted in an increase in the pro-inflammatory cytokines interferon gamma (IFN-gamma), monokine induced by gamma (MIG) and interferon gamma-induced protein 10 kD (IP-10). The increases observed in the individual treatment cohorts were 1.3–7.3-fold for IFN-gamma, 1.8–4.3-fold for MIG and 1.8–3-fold for IP-10.
Discussion
The first-in-human studies show that ezabenlimab monotherapy was well tolerated and had clinical efficacy in patients with advanced solid tumours. Ezabenlimab 240mg Q3W was defined as the RP2D. Whilst no DLTs were observed during dose escalation (up to a dose of 400mg Q3W), the RP2D was selected based on an overall review of the pharmaco*kinetics, safety and pharmacometric modelling data from the dose escalation part of Study 1381.1.
Five (4.5%) patients discontinued treatment due to AEs. At the RP2D, the most common TRAEs with ezabenlimab were fatigue and nausea; this is consistent with the known profile of other PD-1 inhibitors (where fatigue is often the most common AE and other common AEs include gastrointestinal and skin toxicities) [2, 3, 9]. Given their mechanism of action, immune-related AEs are of interest for anti-PD-1 antibodies. Based on data from approved PD-1 antibodies, these AEs most commonly include endocrinological alterations (e.g. hypothyroidism and hyperthyroidism), and gastrointestinal (e.g. colitis) and skin toxicities (e.g. rash) [10]. Consistent with this, the most common immune-related AEs in these studies were hypothyroidism, hyperthyroidism, maculopapular rash and diarrhoea. These events were manageable and generally of low-grade intensity. However, immune-related AEs may differ depending on tumour type, underscoring the importance of monitoring during the treatment period.
Although these studies were not powered for efficacy, ezabenlimab demonstrated evidence of antitumour activity in multiple tumour types. Three confirmed complete responses were observed, in one patient with VSCC and two with anal cancer. One of the patients with anal cancer remained in complete response at 906days and was still receiving ezabenlimab at the data cut-off date. Partial responses and stable disease were observed across a range of tumour types. Durable responses were observed in several patients with various tumour types (response duration ranged from 67 to 906days) including seven patients remaining on treatment at the data cut-off date. Taken together, the data from these studies provide an indication of the broader application of ezabenlimab that is overall consistent with other PD-1 inhibitors [11–13].
The pharmaco*kinetic profile was as expected for an anti-PD-1 monoclonal antibody, with ezabenlimab showing an at least biphasic distribution. The small total volume of distribution was consistent with a limited extravascular disposition as expected for a therapeutic antibody. There were also no apparent differences in the pharmaco*kinetic profiles between Caucasian and Japanese patients. In the pharmacodynamic analyses, no induction of any of the measured cytokines by more than 50-fold was observed; as a result, there are no cytokine-related safety concerns with ezabenlimab. Limited pharmacodynamic analyses for the paired biopsies have been performed to date. Further pharmaco*kinetic and pharmacodynamic data will be published separately.
The application of PD-1/PD-L1 blockade has become a milestone of cancer immunotherapy. Although anti-PD-1/PD-L1 therapy has shown impressive efficacy in the treatment of a variety of solid tumours, durable sensitivity only occurs in a small proportion of patients and some responders develop acquired resistance or relapse after initial responses. While underlying mechanisms remain largely unknown and continue to be further investigated, combinations of PD-1/PD-L1 blockade with other therapies are currently being widely evaluated with the aim to overcome the lack of response and expand the spectrum of responders to anti-PD-1/PD-L1 therapy in the future through increasing the chance of success and postponing acquired resistance [14, 15]. In line with this approach, there are several ongoing studies evaluating ezabenlimab in combination with multiple novel anticancer drug candidates with different mechanism of actions (including, but not limited to, NCT05249426 [combination with the signal-regulatory protein α antagonist, BI 765063] and NCT03964233 [combination with the murine double minute 2-tumour protein p53 antagonist, brigimadlin, BI 907828]). Outcomes from these studies are awaited and may provide further information about new combinatorial treatment approaches for cancer patients.
In summary, data from these three Phase I studies provide evidence of safety, activity, and durability of response of ezabenlimab in multiple advanced solid tumours. Ezabenlimab shows a similar safety profile and response rate to that of other PD-1 inhibitors in comparable patient populations and treatment settings. Further development of ezabenlimab in combination with a variety of anti-cancer drug candidates is being pursued in multiple tumour types.
Supplementary Information
Below is the link to the electronic supplementary material.
Supplementary file1 (PDF 145 KB)(145K, pdf)
Acknowledgements
The authors thank the patients and their caregivers for making the study possible. This work was supported by Boehringer Ingelheim International GmbH. This research was supported by the NIHR Manchester Clinical Research Facility and a Manchester Experimental Cancer Medicine Centre award. Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Hannah Simmons MSc, of Ashfield MedComms, an Inizio Company, and funded by Boehringer Ingelheim. The authors received no direct payment for development of the manuscript.
Author contributions
Substantial contributions to the conception or design of the work: Melissa Johnson, Hendrik-Tobias Arkenau, Miaomiao Ge, Mabrouk Elgadi, Lillian Siu. Substantial contributions to the acquisition, analysis, or interpretation of data for the work: Manish Patel, Melissa Johnson, Ira Winer, Natalie Cook, Vanessa Samouëlian, Raid Aljumaily, Shigehisa Kitano, Christine Duffy, Miaomiao Ge, Mabrouk Elgadi, Lillian Siu. Drafting the work or revising it critically for important intellectual content: Manish Patel, Melissa Johnson, Ira Winer, Hendrik-Tobias Arkenau, Natalie Cook, Vanessa Samouëlian, Raid Aljumaily, Shigehisa Kitano, Christine Duffy, Miaomiao Ge, Mabrouk Elgadi, Lillian Siu. Final approval of the version to be published: Manish Patel, Melissa Johnson, Ira Winer, Hendrik-Tobias Arkenau, Natalie Cook, Vanessa Samouëlian, Raid Aljumaily, Shigehisa Kitano, Christine Duffy, Miaomiao Ge, Mabrouk Elgadi, Lillian Siu. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: Manish Patel, Melissa Johnson, Ira Winer, Hendrik-Tobias Arkenau, Natalie Cook, Vanessa Samouëlian, Raid Aljumaily, Shigehisa Kitano, Christine Duffy, Miaomiao Ge, Mabrouk Elgadi, Lillian Siu.
Funding
This work was supported by Boehringer Ingelheim International GmbH.
Data availiability
To ensure independent interpretation of clinical study results and enable authors to fulfil their role and obligations under the ICMJE criteria, Boehringer Ingelheim grants all external authors access to relevant clinical study data. In adherence with the Boehringer Ingelheim Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data, typically, one year after the approval has been granted by major Regulatory Authorities or after termination of the development program. Researchers should use the https://vivli.org/ link to request access to study data and visit https://www.mystudywindow.com/msw/datasharing for further information.
Declarations
Conflict of interest
Manish Patel: Leadership, ION Pharma; Honoraria Pfizer, Pharmacyclics, Bayer, Janssen Oncology, Genentech, Adaptive Biotechnologies; Consulting or advisory role, Pharmacyclics/Janssen, Pfizer/EMD Serono; Speakers Bureau, Exellxis, Genentech/Roche, Taiho Pharmaceutical, Celgene; Research funding (paid to institution), Adagene, Accutar Biotech, Acerta Pharma, ADC Therapeutics, Astellas, Agenus, Aileron Therapeutics, Artios, AstraZeneca, BioNTech AG, BioTheryX, Black Diamond Therapeutics, Blueprint Pharmaceuticals, Boehringer Ingelheim, Celgene, Checkpoint Therapeutics, CicloMed, Clovis Oncology, Compugen, Cyteir Therapeutics, Daiichi Sankyo, Lilly, EMD Serono, Evelo Therapeutics, FORMA Therapeutics, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, H3 Biomedicine, Hengrui Therapeutics, Hutchinson MediPharma, Ignyta, IgM Biosciences, Immugen, Incyte, Jacobio, Janssen, Klus Pharma, Kymab, Loxo, LSK Biopartners; Lycera, MabSpace Biosciences, Macrogenics, Merck, Millennium, Mirati Therapeutics, Moderna Therapeutics, NGM Biopharmaceuticals, Novartis, Nurix, Olema, ORIC, Pfizer, Placon, Portola Pharmaceuticals, Prelude Therapeutics, PureTech, Relay Therapeutics, Ribon Therapeutics, Samumed, Seven and Eight Biopharmaceuticals, Silicon Therapeutics, Syndax, Taiho Pharmaceutical, Takeda, TeneoBio, Tesaro, TopAlliance BioSciences Inc., Treadwell Therapeutics, Vigeo, Zymeworkds Melissa Johnson: Consulting fee (paid to institution), Abbvie, Amgen, Astellas, AstraZeneca, Axelia Oncology, Black Diamond, Calithera Biosciences, Checkpoint Therapeutics, CytomX Therapeutics, Daiichi Sankyo, EcoR1, Editas Medicine, Eisai, EMD Serono, G1 Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Ideaya Biosciences, iTeos, Janssen, Lilly, Merck, Mirati Therapeutics, Molecular Axiom, Novartis, Oncorus, Regeneron Pharmaceuticals, Ribon Therapeutics, Sanofi-Aventis, Turning Point Therapeutics, VBL Therapeutics; Grants or funds(paid to institution), Abbvie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Black Diamond, Boehringer Ingelheim, Calithera Biosciences, Carisma Therapeutics, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly, Elicio Therapeutics, EMD Serono, EQRx, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchison MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunocore, Impact, Incyte, Janssen, Kadmon Pharmaceuticals, Kartos Therapeutics, Loxo Oncology, Lycera, Memorial Sloan-Kettering, Merck, Merus, Mirati Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, OncoMed Pharmaceuticals, Palleon Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Rain Therapeutics, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, Y-mAbs Therapeutics. Ira Winer: Advisory board, Merck, GOG partners; Research grant, Oncoceutics. Hendrik-Tobias Arkenau declares no potential conflict of interest. Natalie Cook: Advisory council or committee, Roche, Cancer Research UK, RedX; Honoraria, Roche; Institutional research grants / funds: AstraZeneca, Orion, F. Hoffmann-La Roche Ltd, Taiho Pharmaceutical, GlaxoSmithKline, Novartis, Starpharma, Bayer, Eisai, UCB, Redx Pharmaceuticals, Stemline Therapeutics, Boehringer Ingelheim, Merck, AstraZeneca, Cancer Research UK. Vanessa Samouëlian: Consulting fee, Merck, GlaxoSmithKline. Raid Aljumaily declares no potential conflict of interest. Shigehisa Kitano: Honoraria: AstraZeneca, Pfizer, Regeneron Pharmaceuticals, Boehringer Ingelheim, Taiho Pharmaceutical, Novartis, MSD, Sumitomo Pharma, Eisai, Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb, Rakuten Medical, GlaxoSmithKline, Chugai, Merck Biopharma Co., Ltd, Takeda Pharmaceuticals; Consulting fee: ImmuniT Research Inc., United Immunity Co., Ltd.; Grants/Funds: Boehringer Ingelheim, Astellas, Gilead Sciences, Regeneron Pharmaceuticals, PACT Pharma, MSD, Eisai, Ono Pharmaceutical Co., Ltd., Takara Bio Inc., Daiichi-Sankyo, Chugai, AstraZeneca, Pfizer, Incyte, Takeda Pharmaceuticals. Christine Duffy: Employment, Boehringer Ingelheim. Miaomiao Ge: Employment, Boehringer Ingelheim. Mabrouk Elgadi: Employment, Boehringer Ingelheim. Lillian Siu: Ownership of stock/shares, Agios (spouse); Scientific Advisory Board/Consultancy (self), Merck, Pfizer, AstraZeneca, Roche, Symphogen, GlaxoSmithKline, Voronoi, Arvinas, Tessa, Navire, Relay, Janpix, Daiichi Sankyo, Coherus, Amgen, Marengo, InteRNA, Medicenna; Grants/Funds (institution, to conduct clinical trials), Novartis, Bristol-Myers Squibb, Pfizer, Boehringer-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca, Merck, Celgene, Astellas, Bayer, Abbvie, Amgen, Symphogen, Intensity Therapeutics, Mirati Therapeutics, Shattucks Lab; Other, cofounder of Treadwell Therapeutics (spouse).
Ethical approval
The studies were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines. All patients provided written informed consent.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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