Dose-escalation part of Phase I study of single-agent mosunetuzumab in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma

Abstract

Objective

This dose-escalation part of an ongoing Phase I study assessed the tolerability, safety and pharmacokinetics of mosunetuzumab in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL).

Methods

Mosunetuzumab was administered intravenously, with step-up dosing in a 3 + 3 design, on Days 1, 8 and 15 of Cycle 1, and Day 1 of each subsequent 21-day cycle for up to 17 cycles to patients across five cohorts with different target doses (2.8, 6.0, 13.5, 27.0 or 60.0 mg).

Results

As of 5 July 2022, 23 patients had received mosunetuzumab. The median patient age was 63.0 years, 56.5% of patients were male, and 69.6% of patients had diffuse large B-cell lymphoma, 17.4% had transformed follicular lymphoma (FL) and 13.0% had FL. The median number of prior lines of therapy was 4. Mosunetuzumab was well tolerated and there were no deaths. The most common adverse events (any grade) were neutropenia/neutrophil count decreased (47.8%) and cytokine release syndrome (34.8%). Most cytokine release syndrome events were Grade 1/2 (one Grade 3), and most occurred within 24 hours of the first dose of mosunetuzumab. The apparent half-life of mosunetuzumab was 4.1–5.0 days. Two patients achieved a complete response, and 11 patients achieved a partial response.

Conclusions

This study demonstrated that mosunetuzumab has an acceptable safety profile and antitumor activity in Japanese patients with relapsed/refractory B-cell NHL. The recommended Phase II dose of 1.0/2.0/60.0/60.0/30.0 mg was tolerable and there were no new or different safety signals compared with the global Phase I study.

Single-agent mosunetuzumab demonstrates an acceptable safety profile and antitumor activity in Japanese patients with relapsed/refractory B-cell NHL and no new safety signals compared with the global Phase I study.

Introduction

The most common subtypes of non-Hodgkin lymphoma (NHL) worldwide are diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) (1). In Japan, the prevalence of DLBCL and FL, as a proportion of all NHL cases, have been reported to be approximately 38–45% and 14–16%, respectively (2,3), and are gradually increasing to be in line with the reported prevalence in Western countries (4). The prognosis of patients with newly diagnosed DLBCL has improved with the addition of novel agents such as rituximab and polatuzumab vedotin (5,6). Despite this improvement, around 20–50% of patients have relapsed or refractory (R/R) disease after first-line immunochemotherapy with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), depending on their International Prognostic Index (IPI) score (7), and the prognosis of patients with R/R DLBCL remains poor (8).

The current standard of care for fit patients with R/R DLBCL in Japan is salvage immunochemotherapy followed by high-dose chemotherapy in combination with autologous stem cell transplantation (ASCT) (9), but only a small proportion of patients achieve long-term progression-free survival (PFS) with this approach (10). Furthermore, there is no standard of care treatment for patients with R/R DLBCL who are ineligible for ASCT due to age, co-morbidities, or a lack of sensitivity to chemotherapy (11). Although there are several treatment options available for R/R FL, it is considered incurable and patients with early progression or histological transformation after immunochemotherapy have a poor prognosis (12). The introduction of CD19-targeted chimeric antigen receptor (CAR) T-cell therapy provided promising efficacy in patients with R/R DLBCL and FL (13–16); however, CAR T-cell therapy is not readily available and the median time between apheresis and infusion is 28–45 days (17), which may limit its applicability for patients with rapidly progressive disease or high tumor burden.

Mosunetuzumab is a CD20xCD3 T-cell engaging bispecific antibody that redirects T cells to engage and eliminate B cells, including those that cause malignant disease, via targeting of CD20 (18). In a dose-escalation study (NCT02500407) of patients with R/R B-cell NHL (B-NHL) enrolled in North America, Europe, Australasia and Asia, single-agent intravenous (IV) mosunetuzumab was administered using step-up dosing and demonstrated a manageable safety profile and durable complete responses (19). The maximum tolerated dose (MTD) was not reached and a recommended Phase II dose (RP2D) of 1.0/2.0/60.0/60.0/30.0 mg was selected for further study of IV mosunetuzumab treatment (19).

Based on a favorable efficacy-safety profile in the global Phase II trial (20), mosunetuzumab is being developed as an off-the-shelf, outpatient treatment. The IV formulation was approved by the European Medicines Agency in June 2022 and the Food and Drug Administration in December 2022, for the treatment of R/R FL in patients who have received two or more lines of prior therapy (21,22).

Despite the favorable outcomes reported in the global Phase I and II studies, limited numbers of Asian patients were enrolled in these studies (19,20). Therefore, it is important to determine whether the efficacy and safety outcomes in Japanese patients are consistent with those observed in the global Phase I study population.

Here, we report an analysis of the dose-escalation part of an ongoing Phase I study. The primary aim of this study was to assess the tolerability, safety and pharmacokinetics of mosunetuzumab monotherapy in Japanese patients with R/R B-NHL, including determination of the MTD, RP2D and dose-limiting toxicities (DLTs) of mosunetuzumab.

Patients and methods

Study design

JO40295 (JapicCTI-183 857; clinicaltrials.jp) is a multicenter, open-label, dose-escalation Phase I study with expansion cohorts. Mosunetuzumab was administered with Cycle 1 step-up dosing, as in group B of the global Phase I study (NCT02500407) (19). Dose escalation was carried out using a 3 + 3 design across five cohorts (Cohorts 1 and 5–8) with three to seven patients in each cohort (Supplementary Fig. 1). Based on the ongoing progress of the global Phase I study, and the reported tolerability of higher doses of mosunetuzumab, patients in pre-planned Cohorts 2–4 (previously selected doses: 0.8/2.0/4.2, 1.0/2.0/6.0 and 1.0/2.0/9.0 mg) were omitted from the study.

The protocol was approved by the relevant institutional review boards. The trial was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization guidelines for Good Clinical Practice, and applicable laws and regulations. All patients provided written informed consent.

Study population

Patients were aged ≥20 years with histologically confirmed CD20-positive B-NHL including DLBCL, FL, marginal zone lymphoma or mantle cell lymphoma, which had relapsed or was refractory to prior therapy. Patients had an Eastern Cooperative Oncology Group performance status of 0–1. Patients with a history of previous CAR T-cell therapy were excluded from the dose-escalation cohorts. For full details of inclusion and exclusion criteria, see the Supplementary Appendix.

Study treatment

Mosunetuzumab was administered intravenously, with low and intermediate step-up doses administered on Days 1 and 8 of Cycle 1, and the target dose administered on Day 15 of Cycle 1 and Day 1 of each subsequent 21-day cycle. The exception to this was Cohort 8 in which the loading dose was administered on Day 15 of Cycle 1 and Day 1 of Cycle 2, followed by administration of the target dose on Day 1 of Cycle 3 and Day 1 of each subsequent 21-day cycle (Supplementary Fig. 1). There were up to 17 cycles of treatment for each cohort (unless patients experienced disease progression or met discontinuation criteria) and in-patient monitoring was implemented for the dose-escalation cohorts from Cycle 1 Day 1 to 72 hours after Cycle 1 Day 15.

Premedication with corticosteroids (dexamethasone 20.0 mg IV or methylprednisolone 80.0 mg IV) was given to all patients 1 hour before administration of every mosunetuzumab dose until Cycle 3, where administration was optional. Patients also received premedication with oral acetaminophen (500.0–1000.0 mg) and antihistamines (e.g. diphenhydramine hydrochloride 50.0–100.0 mg) 1 hour before mosunetuzumab administration, at the discretion of the investigator.

Study objectives and outcome assessments

The primary objectives of the study were to evaluate the safety, tolerability, and pharmacokinetics of IV mosunetuzumab in Japanese patients with R/R B-NHL, and to determine the RP2D, MTD and DLTs. The secondary objectives were to assess the antitumor activity and immunogenicity of mosunetuzumab.

Safety endpoints of the study included adverse events (AEs), graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (v4.03), and serious AEs (SAEs). Cytokine release syndrome (CRS) was an AE of special interest and was graded according to the 2014 Lee criteria (23). DLTs, assessed during Cycle 1, were defined as Grade ≥ 3 treatment-related AEs (exceptions listed in the Supplementary Appendix), febrile neutropenia, aspartate aminotransferase/alanine aminotransferase >3 times the upper limit of normal, and bilirubin >2 times the upper limit of normal.

Mosunetuzumab pharmacokinetic parameters assessed included the area under the concentration-time curve (AUC), maximum concentration (C_max), time to maximum concentration (T_max) and half-life (t_1/2). Pharmacokinetic samples were taken according to the following schedule: Day 1 (pre-dose, end of infusion and 2 hours post-dose), Day 2, Day 4, Day 7, Day 8 (pre-dose, end of infusion and 2 hours post-dose), Day 9, Day 11, Day 15 (pre-dose, end of infusion and 2 hours post-dose), Day 16 and Day 18 in Cycle 1; Day 1 (pre-dose and end of infusion) and Day 8 in Cycles 2–4; and Day 1 pre-dose in Cycles 6, 8, 12 and 16.

Endpoints included clinical response rates (i.e. objective response and complete response rates based on best overall response), which were assessed by the investigator using the Revised Response Criteria for Malignant Lymphoma (24), as well as PFS and duration of response (DoR); however, PFS and DoR data will not be available until final analysis.

Tumor assessments, including computerised tomography scans, were performed at screening and every four cycles after the first mosunetuzumab infusion, until the end of treatment, with optional 18-fluorodeoxyglucose positron emission tomography.

Anti-drug antibodies (ADA) were measured in serum samples taken prior to dosing on Day 1 of Cycles 1–4, Day 1 of Cycles 6, 8, 12, and 16, and at the end-of-treatment visit (Supplementary Appendix).

Statistical analyses

The safety and efficacy evaluable populations included all patients who received ≥1 dose of mosunetuzumab. The pharmacokinetic analysis population included all patients who received ≥1 dose of mosunetuzumab and for whom ≥1 serum drug concentration measurement was available. All patients with ≥1 pre-dose and ≥ 1 post-dose ADA assessment were included in the analysis of immunogenicity. A sample size based on statistical power was not set for the study; a total of 15–30 patients were planned to be enrolled in five cohorts using a 3 + 3 design.

Rates of AEs and tumor response rates were summarised for each cohort. Changes over time in mean serum mosunetuzumab concentrations were represented graphically by dose level. Patient demographics, clinical characteristics, pharmacokinetic parameters of mosunetuzumab and immunogenicity data were summarised using descriptive statistics. A Clopper–Pearson estimate was used to provide 95% confidence intervals (CIs) for the objective response rates.

Results

Patients

As of 5 July 2022, 23 Japanese patients with R/R B-NHL had been enrolled in five cohorts at three sites in Japan. Nine patients completed treatment (Fig. 1). The median age of the patients across all cohorts was 63.0 years (range 41–85), 56.5% of patients were male, 69.6% of patients were diagnosed with DLBCL, 17.4% with transformed FL (tFL) and 13.0% with FL (Table 1). The median number of prior lines of therapy across all cohorts was 4 (range 1–9). All patients received premedication with corticosteroids, antihistamines and acetaminophen.

Figure 1.

Patient disposition.

Table 1.

Patient demographics and clinical characteristics (safety population)

No. of patients (%), unless stated	Overall   (N = 23)
Age (at screening), years  Median  Range	63.0 41–85
Male	13 (56.5)
ECOG PS  0  1	14 (60.9) 9 (39.1)
Ann Arbor stage at study entry  Stage I  Stage II  Stage III  Stage IV	3 (13.0) 5 (21.7) 5 (21.7) 10 (43.5)
Histological diagnosis  DLBCL  tFL  FL	16 (69.6) 4 (17.4) 3 (13.0)
Prior lines of therapy  Median  Range	4 1–9
Prior cancer therapy regimen  Surgery  Radiotherapy  Rituximab/obinutuzumab therapy  Other cancer therapy	3 (13.0) 5 (21.7) 23 (100.0) 11 (47.8)

DLBCL, diffuse large B-cell lymphoma; ECOG PS, Eastern Cooperative Oncology Group performance status; FL, follicular lymphoma; tFL, transformed follicular lymphoma.

Safety

The median duration of treatment across all cohorts was 148 days (range 1–366). The median number of mosunetuzumab doses administered was 10.0 (range 1.0–19.0), the median number of cycles received was 8.0 (range 1.0–17.0), and the median total cumulative dose was 104.8 mg (range 0.4–573.0). Corresponding median values for all cohorts are presented in Supplementary Table 1.

The safety profile of mosunetuzumab administered as a single agent is summarized by cohort in Table 2. The most common AEs (≥20% of patients) for all cohorts combined were neutropenia/neutrophil count decreased (47.8%), CRS (34.8%), leukopenia/white blood cell count decreased (30.4%), rash (30.4%), lymphopenia/lymphocyte count decreased (26.1%), insomnia (26.1%) and dry skin (21.7%; Table 3). The most common Grade 3/4 AE overall was neutropenia/neutrophil count decreased (39.1%; Table 3). Febrile neutropenia occurred in one patient (Grade 3, Cohort 8) and was considered by the investigator to be related to mosunetuzumab. There were no Grade 5 (fatal) AEs. AEs leading to mosunetuzumab discontinuation occurred in four patients (17.4%; Supplementary Table 2). AEs leading to mosunetuzumab discontinuation that were deemed related to mosunetuzumab by the investigator included Grade 3 viral hemorrhagic cystitis, Grade 3 viral pyelonephritis (both SAEs occurred in the same patient in Cohort 5), Grade 3 CRS and Grade 4 neutrophil count decreased (one patient each in Cohort 7; Supplementary Table 2). Discontinuation of mosunetuzumab in the patients with CRS and decreased neutrophil count was not based on the physician’s decision, but was in accordance with the study protocol, which specified that patients who experienced DLTs should be discontinued from the study. The patient with viral hemorrhagic cystitis and viral pyelonephritis complained of pain on urination 10 days after administration of mosunetuzumab on Cycle 5 Day 1 (6.0 mg) and adenovirus type 11 was subsequently detected in urine; the events resolved 66 days after onset. A total of 13 AEs resulted in an interruption or modification to the dose of mosunetuzumab; the most common of which were neutropenia, diarrhea and herpes zoster (each affecting two patients, 8.7%). Prophylactic administration for herpes zoster was not specified in the protocol; patients infected with herpes zoster did not receive prophylactic treatment (e.g. acyclovir).

Table 2.

Summary of AEs in Japanese patients treated with mosunetuzumab

No. of patients (%)	Cohort 1   0.4/1.0/2.8 mg   n = 4	Cohort 5   0.8/2.0/6.0 mg   n = 4	Cohort 6   1.0/2.0/13.5 mg   n = 5	Cohort 7   1.0/2.0/27.0 mg   n = 7	Cohort 8   1.0/2.0/60.0/60.0/30.0 mg   n = 3	All cohorts   N = 23
Any AE	4 (100.0)	3 (75.0)	4 (80.0)	7 (100.0)	3 (100.0)	21 (91.3)
SAE	1 (25.0)	1 (25.0)	0	1 (14.3)	2 (66.7)	5 (21.7)
Grade 3/4 AE	3 (75.0)	2 (50.0)	3 (60.0)	4 (57.1)	3 (100.0)	15 (65.2)
Grade 5 AE	0	0	0	0	0	0
DLT	0	0	0	2 (28.6)a	0	2 (8.7)
AEs leading to discontinuation of mosunetuzumab	0	1 (25.0)	0	2 (28.6)	1 (33.3)	4 (17.4)

AE, adverse event; CRS, cytokine release syndrome; DLT, dose limiting toxicity; SAE, serious adverse event.

^aGrade 4 neutropenia (resolved) and Grade 3 CRS (resolving at study discontinuation) occurred in two patients in Cohort 7.

Table 3.

Most common AEs (≥10% of patients; any grade and Grade 3/4) in Japanese patients treated with mosunetuzumab

No. of patients (%)	All cohorts (N = 23)
Any grade AEs
Neutropenia/neutrophil count decreased	11 (47.8)
CRS	8 (34.8)
Leukopenia/white blood cell count decreased	7 (30.4)
Rash	7 (30.4)
Lymphopenia/lymphocyte count decreased	6 (26.1)
Insomnia	6 (26.1)
Dry skin	5 (21.7)
Gamma-glutamyl transferase increased	4 (17.4)
Diarrhea	4 (17.4)
Nausea	4 (17.4)
Cystitis	4 (17.4)
Nasopharyngitis	4 (17.4)
Constipation	3 (13.0)
Anemia	3 (13.0)
Herpes zoster	3 (13.0)
Pyrexia	3 (13.0)
Aspartate aminotransferase increased	3 (13.0)
Alanine aminotransferase increased	3 (13.0)
Any Grade 3/4 AEs
Neutropenia/neutrophil count decreased	9 (39.1)
Lymphopenia/lymphocyte count decreased	6 (26.1)
Leukopenia/white blood cell count decreased	4 (17.4)
AEs related to mosunetuzumab (any grade)
Neutropenia/neutrophil count decreased	11 (47.8)
CRS	8 (34.8)
Leukopenia/white blood cell count decreased	7 (30.4)
Lymphopenia/lymphocyte count decreased	6 (26.1)
Rash	5 (21.7)
Dry skin	3 (13.0)
Herpes zoster	3 (13.0)

AE, adverse event; CRS, cytokine release syndrome.

Overall, AEs of any grade and Grade 3/4 AEs that were considered by the investigator to be related to mosunetuzumab were reported in 20 (87.0%) and 14 patients (60.9%), respectively. All SAEs were Grade 3 and were reported in five patients: sinusitis (one patient in Cohort 1), viral pyelonephritis, viral hemorrhagic cystitis (one patient each in Cohort 5), CRS (one patient in Cohort 7), cytomegalovirus (CMV) gastroenteritis and herpes zoster (one patient each in Cohort 8). Of these Grade 3 SAEs, the latter five were deemed by the investigator to be related to mosunetuzumab.

All CRS events were Grade 1/2 in severity (Table 4), with the exception of one Grade 3 CRS event in a patient from Cohort 7. This patient was aged >60 years with FL, an FL IPI score of 2, Ann-Arbor stage III and no bulky disease. The Grade 3 event initially occurred as a Grade 1 CRS event (16.4 hours after the first dose of mosunetuzumab [1.0 mg]) and was associated with Grade 1 fever and headache, before progressing to Grade 3 (4 hours later, 20.4 hours after the first dose) due to Grade 4 transaminitis. This event was considered Grade 3 according to the Lee 2014 criteria, as it was associated with Grade 4 transaminitis, although it was managed without the need for vasopressors or a high-flow nasal cannula. The patient withdrew from the study as per protocol specifications regarding DLTs. The event resolved following treatment with ursodeoxycholic acid and corticosteroids.

Table 4.

Summary of CRS events in Japanese patients treated with mosunetuzumab

No. patients (%)	Cohort 1   0.4/1.0/2.8 mg   n = 4	Cohort 5   0.8/2.0/6.0 mg   n = 4	Cohort 6   1.0/2.0/13.5 mg   n = 5	Cohort 7   1.0/2.0/27.0 mg   n = 7	Cohort 8   1.0/2.0/60.0/60.0/ 30.0 mg  n = 3	All cohorts   N = 23
Any grade CRSa Grade 1 Grade 2 Grade 3	0 0 0 0	1 (25.0) 1 (25.0) 0 0	1 (20.0) 1 (20.0) 0 0	4 (57.1) 2 (28.6) 1 (14.3) 1 (14.3)	2 (66.7) 0 2 (66.7) 0	8 (34.8) 4 (17.4) 3 (13.0) 1 (4.3)
Serious CRS event (any grade)	0	0	0	1 (14.3)	0	1 (4.3)
Median CRS duration, days (range) Cycle 1 Cycle 2	0 0	2.0 (2.0–2.0) 0	3.0 (3.0–3.0) 0	2.0 (2.0–8.0) 0	1.0 (1.0–3.0) 8.0 (8.0–8.0)	2.0 (1.0–8.0) 8.0 (8.0–8.0)
Median time to CRS onset, hours (range) Cycle 1 Cycle 2	NE NE	4.1 (4.1–4.1) NE	5.6 (5.6–5.6) NE	14.8 (4.2–20.3) NE	32.9 (9.9–53.3) 5.2 (5.2–5.2)	14.9 (4.1–53.3) 5.2 (5.2–5.2)
Tocilizumab for CRS management	0	0	0	0	1 (33.3)b	1 (4.3)b
Corticosteroids for CRS management	0	1 (25.0)	1 (20.0)	3 (42.9)	2 (66.7)	7 (30.0)
CRS resolved/resolvingc	0	1 (25.0)	1 (20.0)	4 (57.1)	2 (66.7)	8 (34.8)

CRS, cytokine release syndrome; NE, not evaluable.

^aIf a patient had more than one CRS event, only the event with the highest grade was reported

^bIn combination with corticosteroids

^cOne patient in Cohort 7 had a Grade 3 CRS event that was considered to be resolving at the time of study discontinuation.

CRS typically occurred during the first 24 hours following mosunetuzumab administration, with the exception of two events in Cohort 8 (time to onset of 45.2 and 53.3 hours). Most CRS events occurred in Cycle 1, and mainly on Day 1, with only one event occurring in Cycle 2 (Cohort 8; Fig. 2). Patients without a CRS event in Cycle 1 did not experience CRS in subsequent cycles. The CRS events on Day 8 and Day 15 of Cycle 1 occurred in the same patient; this patient and the patient who experienced a CRS event in Cycle 2 also experienced CRS events on Day 1 of Cycle 1. The median duration of CRS across all cohorts was 2.0 days (range 1.0–8.0) in Cycle 1 and 8.0 days (range 8.0–8.0) in Cycle 2 (Table 4).

Figure 2.

Onset of CRS events by grade and cycle. Most CRS events occurred on D1 of C1. There was one Grade 1 event after a dose of 0.8 mg and four Grade 1, two Grade 2, and one Grade 3 CRS event(s) after a dose of 1.0 mg. The CRS events on D8 and D15 of C1 occurred in the same patient in Cohort 8 who also experienced a CRS event on D1 of C1. The patient in Cohort 8 who experienced a CRS event in C2 previously reported CRS on D1 of C1. C, cycle; CRS, cytokine release syndrome; D, day.

The most common CRS symptoms (≥5% of patients) were pyrexia (34.8%), headache (8.7%), increased levels of alanine aminotransferase (8.7%) and increased levels of aspartate aminotransferase (8.7%; Supplementary Table 3). Of eight patients with a CRS event, six received corticosteroids alone for CRS management. One patient in Cohort 8 with a Grade 2 CRS event received tocilizumab as well as corticosteroids; no patients received tocilizumab alone (Supplementary Table 3).

Neurological AEs (defined based on the system organ class Nervous System Disorders or Psychiatric Disorders) were experienced by 10 patients (43.5%), and all were Grade 1. The most commonly reported event was insomnia (six patients, 26.1%); other neurological AEs included dizziness, dysgeusia, headache, hypoesthesia, and somnolence (all one patient each). Neurological AEs deemed mosunetuzumab-related by the investigator included dysgeusia (one patient in Cohort 8), headache (one patient in Cohort 7) and hypoesthesia (one patient in Cohort 5). Hematological AEs (all grades, Grade 3/4) included neutropenia/neutrophil count decreased (47.8%, 39.1%), leukopenia/white blood cell count decreased (30.4%, 17.4%), lymphopenia/lymphocyte count decreased (26.1%, 26.1%), anemia (13.0%, 8.7%) and thrombocytopenia (8.7%, 4.3%). Four patients received granulocyte colony-stimulating factor (G-CSF) for the management of neutropenia/neutrophil count decreased; no patients received G-CSF for prophylaxis.

In Cohort 7 (1.0/2.0/27.0 mg), two of seven patients experienced DLTs (Grade 4 neutrophil count decreased and Grade 3 CRS; Table 2) and discontinued mosunetuzumab as per protocol requirements. Grade 3 neutrophil count decrease occurred 2 days after administration of 27.0 mg, and this increased to Grade 4 after approximately 24 hours. The event decreased to Grade 2 at the time of the next laboratory test (conducted after 14 days; unscheduled in protocol) and resolved after 19 days from onset. The investigator judged that prolonged neutropenia was due to mosunetuzumab. The cause for prolonged neutropenia, other than mosunetuzumab, is unknown. Following this DLT, three additional patients were added to Cohort 7; the first patient developed a DLT of Grade 3 CRS after the first mosunetuzumab dose (1.0 mg) and discontinued the study without reaching the target dose (27.0 mg). The dose-escalation study continued with one additional patient in Cohort 7 following discussion with the data monitoring committee because the 1.0 mg dose had already been evaluated as tolerable in previous cohorts. The Cohort 7 dosing schedule was subsequently considered tolerable with the additional patient.

In Cohort 8 (1.0/2.0/60.0/60.0/30.0 mg), two of the three patients experienced multiple CRS events that were Grade 1 or 2 and considered manageable. One patient experienced Grade 2 CRS after administration of mosunetuzumab on Cycle 1 Day 1 (1.0 mg) that resolved with corticosteroid treatment. The other patient had Grade 2 CRS following the administration on Cycle 1 Day 15 (60.0 mg), which was treated with tocilizumab plus steroids and subsequently resolved. The previously determined RP2D in the global Phase I study of mosunetuzumab 1.0/2.0/60.0/60.0/30.0 mg was well tolerated in Cohort 8. The MTD was not reached.

Pharmacokinetics

The serum concentration of mosunetuzumab increased in an approximately dose-proportional manner over the doses administered to all cohorts (1.0–60.0 mg; Supplementary Fig. 3) and moderate pharmacokinetic variability was observed (Supplementary Table 4). The apparent t_1/2 for mosunetuzumab was 4.1–5.0 days across all cohorts. In Cohort 8 (dosing of 1.0/2.0/60.0/60.0/30.0 mg), the mean C_{max 0–42} (coefficient of variation [CV]%) following dosing on Day 1 of Cycle 2 was 33.0 μg/mL (28.4%; Supplementary Table 4). The AUC_0–42 in Cohort 8 was 295 day*μg/mL (19.4%).

Efficacy

Best overall responses are shown in Table 5. Two patients achieved a complete response (DLBCL, n = 1; tFL, n = 1), and 11 patients achieved a partial response (DLBCL, n = 7; tFL, n = 2; FL, n = 2). Four patients had stable disease (DLBCL, n = 3; FL, n = 1), and six patients had progressive disease (DLBCL, n = 5; tFL n = 1). Among 20 patients with aggressive B-NHL (DLBCL, n = 16; tFL, n = 4), 11 patients (55.0%) achieved an objective response (complete response, n = 2 [10.0%]; partial response, n = 9 [45.0%]). Out of three patients with FL, two patients (66.7%) achieved a partial response.

Table 5.

Best overall response with mosunetuzumab in Japanese patients with R/R B-NHL

No. of patients (%) [95% CI]	Cohort 1   0.4/1.0/2.8 mg   n = 4	Cohort 5   0.8/2.0/6.0 mg   n = 4	Cohort 6   1.0/2.0/13.5 mg   n = 5	Cohort 7   1.0/2.0/27.0 mg   n = 7	Cohort 8   1.0/2.0/60.0/60.0/ 30.0 mg  n = 3	All cohorts   N = 23
OR	2 (50.0) [6.8–93.2]	2 (50.0) [6.8–93.2]	4 (80.0) [28.4–99.5]	4 (57.1) [18.4–90.1]	1 (33.3) [0.8–90.6]	13 (56.5) [34.5–76.8]
CR	0 [0.0–60.2]	2 (50.0) [6.8–93.2]	0 [0.0–52.2]	0 [0.0–41.0]	0 [0.0–70.8]	2 (8.7) [1.1–28.0]
PR	2 (50.0) [6.8–93.2]	0 [0.0–60.2]	4 (80.0) [28.4–99.5]	4 (57.1) [18.4–90.1]	1 (33.3) [0.8–90.6]	11 (47.8) [26.8–69.4]
SD	1 (25.0) [0.6–80.6]	1 (25.0) [0.6–80.6]	0 [0.0–52.2]	1 (14.3) [0.4–57.9]	1 (33.3) [0.8–90.6]	4 (17.4) [5.0–38.8]
PD	1 (25.0) [0.6–80.6]	1 (25.0) [0.6–80.6]	1 (20.0) [0.5–71.6]	2 (28.6) [3.7–71.0]	1 (33.3) [0.8–90.6]	6 (26.1) [10.2–48.4]

B-NHL, B-cell non-Hodgkin lymphoma; CI, confidence interval; CR, complete response; OR, objective response; PD, progressive disease; PR, partial response; R/R, relapsed/refractory; SD, stable disease.

Immunogenicity

All patients were available for ADA assessment. No patients developed ADA antibodies against mosunetuzumab during treatment.

Discussion

This dose-escalation part of a Phase I study demonstrated the safety and preliminary efficacy of single-agent IV mosunetuzumab in 23 Japanese patients with R/R B-NHL. Mosunetuzumab demonstrated an acceptable safety profile and clinical activity in this patient population, in which the majority of patients had aggressive B-NHL (69.6% DLBCL and 17.4% tFL). The safety and efficacy data from this study were consistent with that previously reported in the global Phase I study (19).

Overall, the AE profile and severity of AEs were consistent with the known safety profile of mosunetuzumab (19). It is, however, difficult to compare with data from 197 patients in Group B of the global Phase I study, since there were 23 Japanese patients, and only three of them received the RP2D of 1.0/2.0/60.0/60.0/30.0 mg. AEs leading to discontinuation of mosunetuzumab occurred in four patients (17.4%), and there were 13 AEs that led to mosunetuzumab dose modification. There were no new or unexpected safety findings in this Japanese cohort.

CRS is a potentially serious inflammatory toxicity syndrome associated with T-cell-engaging immunotherapy (23); however, CRS events associated with bispecific antibodies are generally manageable with step-up dosing as demonstrated in the global Phase I study with mosunetuzumab (19) and the Phase II part of a Phase I/II study with glofitamab (25). Evaluation of the step-up dosing regimen in the Phase II portion of the global study, based on global Phase I dose-escalation results and exposure-response analysis, ensured optimal efficacy while minimising the risk for acute CRS (20).

In our study, CRS was commonly reported as an AE, but the events were mostly low grade (all Grade 1/2 in severity, with the exception of one Grade 3 CRS event). The proportion of patients who experienced CRS in our study and the global Phase I study were similar and both studies used the same CRS grading criteria (23). In our study, any grade CRS events were observed in eight patients (34.8%) and one patient experienced a Grade 3 CRS event (4.3%). This Grade 3 CRS event was considered Grade 3 according to the Lee 2014 grading criteria, used in both Phase I studies, as the event was associated with Grade 4 transaminitis. Although, when assessed using the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading (26), the event was equivalent to a Grade 2 CRS event as neither vasopressors nor a high-flow nasal cannula were used. In patients enrolled in Group B (step-up dosing group) of the global Phase I study, any grade CRS events were observed in 27.4% of patients and Grade 3 CRS events were observed in two patients (1.0%) (19). CRS onset occurred most often after Cycle 1 Day 1, and typically occurred during the first 24 hours (the median time to onset of all CRS events in Cycle 1 was 14.9 hours [range 4.1–53.3]) (19). In our study, patients without a CRS event in Cycle 1 Day 1 did not experience CRS in subsequent cycles, suggesting that step-up dosing was effective in mitigating CRS events in the majority of patients.

The most common treatment for CRS in our study was corticosteroids; seven patients with a CRS event were treated with corticosteroids, including one patient (4.3%) who received tocilizumab in combination with corticosteroids. No patients were treated with tocilizumab alone or vasopressors. In the global Phase I study, three patients (1.5%) received treatment with tocilizumab, one patient (0.5%) received vasopressors, and two patients (1.0%) were admitted to intensive care for CRS management (19). In our study and the global Phase I study, all CRS events resolved with management with corticosteroids and/or tocilizumab or other therapies (Supplementary Table 3) (19). The difference in CRS events and management of CRS events in our study compared with the global Phase I study was not deemed to be of clinical significance. The current safety monitoring guidance for mosunetuzumab in Europe or the USA, does not specify mandatory hospitalisation in clinical practice (21,22).

The only neurological AE reported in ≥10% of patients in our study was insomnia (26.1%). In contrast, headache (17.8%), insomnia (11.2%) and dizziness (10.2%) were reported in ≥10% of patients in the global Phase I study (19). In our study, dizziness, dysgeusia, headache, hypoesthesia, and somnolence all occurred in one patient each (4.3%). All neurological AEs in our study were Grade 1, whereas most neurological AEs in the global Phase I study were Grade 1/2; Grade 3 neurologic events occurred in 4.1% of patients, and there were no Grade 4/5 neurological AEs (19).

Of note, hematological AEs, with the exception of anemia, were more common in our study compared with the global Phase I study (leukopenia 30.4% vs 1.0%; lymphopenia 26.1% vs 2.0%; neutropenia 47.8% vs 28.4%; thrombocytopenia 8.7% vs 2.5%; anemia 13.0% vs 18.8%) (19). The reason for this difference may be because in our study, white blood cell count decreased and lymphocyte count decreased were included in the definitions of leukopenia and lymphopenia, respectively, whereas in the global Phase I study, the events were defined as separate terms (19). A higher number of prior systemic therapies may be associated with a higher frequency of hematological AEs in this study compared with that in the global Phase I study, yet the higher incidence of hematological AEs in our study did not lead to a higher incidence of infection or treatment discontinuations. Four Grade 3 infections related to mosunetuzumab were observed in this study (one patient each had viral hemorrhagic cystitis, viral pyelonephritis, herpes zoster and CMV gastroenteritis), but there was no clear association with the timing of decreased white blood cells/neutropenia; however, total lymphocyte count, CD4+ cell count and immunoglobulin G decreased in these three patients. This could have been related to prior treatment or prophylactic steroids. CMV gastroenteritis resolved without interruption or discontinuation of mosunetuzumab, and the other events resolved after interruption or discontinuation of mosunetuzumab. Therefore, the safety profile of mosunetuzumab in the current study was favorable and toxicities were generally manageable.

The serum concentration of mosunetuzumab increased in an approximately dose-proportional manner across all cohorts in our study as observed in the previous global Phase I study. The apparent t_1/2 in our study (4.1–5.0 days) was comparable with that reported for the global Phase I study (3.6–7.2 days) (27). In Cohort 8, the mean C_max (CV%) at the RP2D was 33.0 μg/mL (28.4%) compared with 17.9 μg/mL (49.6%) at the same RP2D in the global Phase I study (27). The AUC_0–42 in our study was 295 day*μg/mL (19.4%) versus 246 day*μg/mL (46.9%) in the global Phase I study. Since there were no safety concerns specific to Japanese patients in this study, the differences in the pharmacokinetic profile of mosunetuzumab versus the global Phase I study was not deemed to be of clinical significance.

The objective response rate in Japanese patients was in line with that reported in the global Phase I study. Baseline characteristics were generally comparable between our study and the global Phase I study, except more patients in the global Phase I study had stage III/IV disease (84.3% vs 65.2%, respectively) (19). Among 20 Japanese patients with aggressive B-NHL in our study, 11 patients (55.0%) achieved an objective response (complete response, n = 2 [10.0%]; partial response, n = 9 [45.0%]). In the global Phase I study, among 129 patients with aggressive B-NHL, 45 (34.9%) patients achieved an objective response (complete response, n = 25 [19.4%]; partial response, n = 20 [15.5%]) (19).

Limitations of our analysis include the lack of a control group and the small number of Japanese patients enrolled (N = 23) compared with the 197 patients evaluated for efficacy in Group B in the global Phase I study. Only three patients in our study received the suggested mosunetuzumab RP2D dose of 60.0 mg; however, there is an ongoing study with a dose-expansion cohort that is evaluating safety and efficacy of mosunetuzumab at the RP2D in Japanese patients.

Conclusions

In conclusion, the results of this study demonstrated that mosunetuzumab has an acceptable safety profile, including CRS severity and frequency, and shows antitumor activity in Japanese patients with R/R B-NHL. The mosunetuzumab RP2D identified in the global Phase I dose escalation study of 1.0/2.0/60.0/60.0/30.0 mg was tolerable in Japanese patients. The pharmacokinetic profile of mosunetuzumab was comparable with that reported in the global Phase I study, and there were no new or different safety signals observed.

Funding

This study was funded by Chugai, Pharmaceutical Co., Ltd. Third party medical writing assistance, under the direction of all authors, was provided by Martha Warren, MSci, and Louise Profit, PhD, of Ashfield MedComms, an Inizio company, and was funded by Chugai, Pharmaceutical Co., Ltd.

Conflict of Interest statement. Atsuko Kawasaki is employed by Chugai Pharmaceutical Co., Ltd.

Yuko Ishihara declares no conflicts of interest.

Takeshi Miyake is employed by Chugai Pharmaceutical Co., Ltd.

Toshihiro Nanki has received grants or contracts from Chugai Pharmaceutical Co., Ltd, Bristol-Myers K.K., Eisai Co.,Ltd, Ono Pharmaceutical Co., Ltd., Teijin Pharma Ltd., Asahikasei Pharma Corp., Mitsubishi-Tanabe Pharma Co., Ayumi Pharmaceutical Co., Nippon Kayaku Co., Ltd., AbbVie GK, Nippon Boehringer Ingelheim Co., Ltd., Taisho Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Eli Lilly, Japan K.K., Sanofi K.K., Abbott Japan LLC; has received consulting fees from UCB Japan Co., Ltd., Eisai Co., Ltd., Chugai Pharmaceutical Co.; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Chugai Pharmaceutical Co., Mitsubishi-Tanabe Pharma Co., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Astellas Pharma Inc., Taiho Pharmaceutical Co., Ltd., Eli Lilly, Japan K.K., Mylan N.V., AbbVie GK, UCB Japan Co. Ltd., Mochida Pharmaceutical Co., Ltd., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., Asahikasei Pharma Corp., AstraZeneca K.K., Nippon Boehringer Ingelheim Co., Ltd., Ayumi Pharmaceutical Co., Ono Pharmaceutical Co.,Janssen Pharmaceutical K.K., GlaxoSmithKline plc., Taisho Pharmaceutical Co., Ltd; and has received participation on a Data Safety Monitoring Board or Advisory Board Chugai Pharmaceutical Co.

Wataru Munakata has received grants or contracts from Chugai Pharmaceutical Co., Ltd; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Chugai Pharmaceutical Co., Ltd.

Yuko Mishima has received grants or contracts from Takeda Pharma Taiho, Bristol-Myers Squibb, Eisai,

Kyowa Kirin; has received consulting fees from Chugai Pharmaceutical, Roche Drug Safety committee; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Janssen, AstraZeneca, Takeda.

Yuzuru Kanakura declares no conflicts of interest.

Hirokazu Nagai has received grants or contracts from AstraZeneca, Celgene, Mundipharma, Zenyaku, Kogyo, Takeda, Chugai, Bayer, BMS, Janssen, Kyowa Kirin, Symbio, Ono, MSD, Abbvie, Esai, Nihon Shinyaku; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Eisai, Chugai, Takeda, Celgene, Mundipharma, Kyowa Kinin, Ono, AstraZeneca, Sanofi, BMS, Novartis, Janssen, Symbio, Chordia Therapeutics, Nihon Medi-Physics, Meiji Seika Pharma.

Koji Izutsu has received grants or contracts from Chugai, Abbvie, Genmab, Regeneron; has received consulting fees from Genmab; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bristol Myers Squibb, AstraZeneca, Eisai, Zenyaku, Kyowa Kirin, Takeda, Chugai, Novartis, MSD, SymBio, Nihon Shinyaku, Abbvie, Ono Pharmaceutical, Pfizer, Genmab, Eli, Lilly, Meiji Seika Pharma, Daiichi Sankyo.

Kenichi Ishizawa has received grants or contracts from any entity from SymBio, ZENYAKU, Otsuka, AbbVie, IQVIA, Novartis; has received consulting fees from SAWAI, Micron, KYOWAKIRIN; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Novartis, Takeda, BMS, Janssen, Ono, Chugai, Eisai.

Tatsuya Yoshinaga is employed by Chugai Pharmaceutical Co., Ltd.

Junji Suzumiya has received consulting fees from Chugai, Ootsuka, Kyowa-Kirin, SymBio, Janssen, Zenyaku, Abbvie; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Abbvie, Bristol Myers Squibb, Dainihon-Sumitomo, Eli, Lilly, Janssen, Kyowa-Kirin, Novartis, Ootsuka, SymBio, Takeda, Zenyaku, Tanabe-Mitsubishi.

Abbreviations

NHL

non-Hodgkin lymphoma

DLBCL

Diffuse large B-cell lymphoma

FL

Follicular lymphoma

R/R

Relapsed or refractory

R-CHOP

Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone

IPI

International Prognostic Index

ASCT

Autologous stem cell transplantation

PFS

Progression-free survival

CAR

Chimeric antigen receptor

B-NHL

B-cell non-Hodgkin lymphoma

IV

Intravenous

MTD

Maximum tolerated dose

RP2D

Recommended Phase II dose

DLT

Dose limiting toxicity

AE

Adverse event

SAE

Serious adverse event

CRS

Cytokine release syndrome

AUC

Area under the concentration-time curve

C _max

Maximum concentration

T _max

Time to maximum concentration

t _1/2

Half-life

DoR

Duration of response

ADA

Anti-drug antibodies

CI

Confidence interval

tFL

Transformed follicular lymphoma

CV

Coefficient of variation

ASTCT

American Society for Transplantation and Cellular Therapy

ECOG PS

Eastern Cooperative Oncology Group performance status

OR

Overall response

CR

Complete response

PR

Partial response

SD

Stable disease

PD

Progressive disease

CT

Computerized tomography

C

Cycle

D

Day

Data availability statement

Qualified researchers may request access to individual patient-level data through the clinical study data request platform (www.clinicalstudydatarequest.com). For further details on Chugai's Data Sharing Policy and how to request access to related clinical study documents, see www.chugai-pharm.co.jp/english/profile/rd/ctds_request.html.