Efficacy and safety of geptanolimab (GB226) for relapsed or refractory peripheral T cell lymphoma: an open-label phase 2 study (Gxplore-002)

Eligible individuals were patients aged 18 years and older with histologically confirmed PTCL, who had failed at least one prior systemic therapy. Additional criteria of enrolment included at least one bidimensionally measurable lesion according to investigator assessment as defined by Lugano criteria [28], an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1, life expectancy of at least 3 months and at least 4 weeks after ASCT or major operation. Patients were also required to have adequate organ functions: absolute neutrophil count ≥ 1.0 × 10⁹/L, platelet count ≥ 75 × 10⁹/L, hemoglobin ≥ 80 g/L, total bilirubin ≤ 1.5 × the upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN (if liver involvements are present, ALT and AST up to 5 × ULN), serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min (calculated by Cockcroft and Gault equation).

Patients were excluded if histologically classified as adult T cell leukemia/lymphoma (ATLL) or AITL; concomitant receipt of immunosuppressive therapy; prior exposure to any anti-PD-1/PD-L1 or anti-cytolytic T lymphocyte-associated antigen-4 (CTLA-4) antibody; treatment with systematic corticosteroids (> 10 mg daily prednisone equivalent) within 2 weeks; active or history of autoimmune disease except for type I diabetes, controllable hypothyroidism with replacement treatment, controllable skin disorders without systematic treatment, celiac disease within control; human immunodeficiency virus (HIV) infection, anti-treponema pallidum antibody (TP-Ab) positive or active hepatitis B or C; use of any investigational agent, biologics or devices within 30 days (or at least five periods of half-life) before study treatment. Pathological diagnosis was done by study site pathologists for study enrolment, and patient eligibility was determined by site investigators. Central pathology review was conducted retrospectively upon patient consent.

The study was done in accordance with the Declaration of Helsinki and International Council for Harmonisation (ICH) guidelines for Good Clinical Practice. The study protocol is available in Additional file 1. The protocol, protocol amendments and patient informed consent were reviewed and approved by the relevant independent ethics committee at each participating study site prior to implementation. Written informed consent was obtained from all patients prior to enrolment.

We conducted this open-label, single-arm, phase 2 study across 41 sites in China to evaluate the activity and safety profile of geptanolimab in r/r PTCL. Eligible patient received geptanolimab intravenously at a dose of 3 mg/kg every 2 weeks until disease progression, death, unacceptable toxicity, withdrawal of consent or end of the study (i.e., a maximum treatment duration of 2 years of the last subject, termination of treatment, consent withdrawal, lost to follow-up or death, whichever occurs first). Geptanolimab treatment was permitted to continue beyond the first assessment of progressive disease (PD) if the patient could benefit from the treatment with acceptable toxicity assessed by the investigator. Dose modification was not allowed. Patients with dose interruptions for more than 4 weeks should permanently discontinue the treatment.

Treatment response was assessed every 6 weeks until week 48 and every 12 weeks thereafter during the treatment phase. Treatment response was assessed using computed tomography (CT) or magnetic resonance imaging (MRI) and complementary information from positron emissions tomography and computed tomography (PET-CT). PET-CT was performed at baseline, week 13 and termination of treatment. All radiographic records of enrolled patients were provided to independent radiological review committee (IRRC). Efficacy was assessed based on individual best objective response by both investigators and IRRC according to the Lugano criteria [28]. Survival follow-up was done every 3 months until patient death, lost to follow-up or the end of the study.

The primary endpoint of this study was ORR, defined as the proportion of patients with a best overall response (including complete response [CR] and partial response [PR]) per the Lugano criteria and assessed by IRRC. The secondary outcomes included disease control rate (DCR), time to response (TTR), duration of response (DOR), PFS, OS, safety and immunogenicity of geptanolimab.

Safety was monitored for 30 days from the last dose of geptanolimab for all patients or before any anticancer therapy began. If no new anticancer treatment has commenced, the safety follow-up should be repeated as far as possible for  90 days after the last dose of geptanolimab. Adverse events (AEs) were assessed by National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE), version 4.03 and classified as related, possibly related, unlikely related, unrelated and uncertainly related to treatment assessed by investigator. Treatment-related AEs (TRAEs) were those AEs labeled related, possibly related, or uncertainly related to study drug. As an ICI, geptanolimab could cause a spectrum of immune-related adverse events (irAEs), which is recognized and managed according to National Comprehensive Cancer Network guideline for Management of Immunotherapy-Related Toxicities [29].

To provide roughly 85% power to reject the null hypothesis that the true proportion of patients achieving an objective response is 15% or fewer and given a one-sided alpha of 2.5%, 73 patients were required. Considering the possible drop-off rate of 15%, at least 86 patients were to be recruited.

Exact binominal confidence intervals (CIs) were calculated for response outcomes. PFS (from first geptanolimab administration to progression or death, whichever occurs first), OS (from first geptanolimab administration to death), DOR (from the date of first documented response to the date of first documented disease progression or death from any cause) and TTR (time from first geptanolimab administration to first documentation of response) were assessed using the Kaplan–Meier method. All statistical analyses were performed by using SAS version 9.4.

This trial was registered at the ClinicalTrials.gov (NCT03502629).

Immunogenicity was evaluated by the number of patients with antidrug antibody (ADA) positive. Serum samples were collected at baseline, week 1, 2, 6 and followed by every six weeks. An immunological ligand-binding assay (LBA) was developed and validated for the detection and quantitation of anti-geptanolimab antibodies in serum collected.

Archival tumor tissues were required from all patients prior to treatment. PD-L1 immunohistochemistry (IHC) was assessed on formalin-fixed paraffin-embedded (FFPE) tumor biopsy samples using Ventana PD-L1 (SP263; Roche) rabbit monoclonal primary antibody for exploratory analysis. Measure of PD-L1 expression built on the estimated percentage of PD-L1-stained cells. Genomic DNA was extracted from FFPE tumor samples using ReliaPrep FFPE gDNA Miniprep System (Promega) following the manufacturer’s instructions. Microsatellite instability (MSI) analysis using MSI Analysis System version 1.2 (Promega) and tumor mutation burden (TMB) assessed with hybridization capture of exons from 440 cancer-related genes were performed (Details in Additional file 1).

A total of 102 patients were recruited in this study at 41 sites in China from July 12, 2018, to August 15, 2019 (Additional file 1: Table S1). The average time for enrolled patients after the initial diagnosis of PTCL was 0.94 years (standard deviation: 1.53), and 58.8% of them had two or more prior treatments. At study entry, 84 (82.4%) patients had advanced disease and 13 (12.7%) patients had bone marrow involvement at baseline. All patients had received prior systematic treatment. For patients diagnosed with extranodal NK/T cell lymphoma, nasal type (ENKTL), 21 (91.3%) out of 23 patients received prior asparaginase-based chemotherapy. For other subtypes of PTCL except for ENKTL, 77 (97.5%) out of 79 patients were previously treated with anthracycline-containing chemotherapy. Twenty-four (23.5%) patients had received chidamide; 7 (6.9%) had undergone ASCT. Baseline characteristics of the 102 patients are shown in Table 1. Collectively, 89 patients with retrospectively histological confirmation per central pathology review were included in FAS (Additional file 1: Table S2). Of them, the most common histological subtypes were PTCL-NOS (n = 28 [31.5%]), ENKTL (n = 19 [21.3%]), anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (ALCL ALK-, n = 13 [14.6%]) and anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALCL ALK+, n = 7 [7.9%]). At the cutoff date, 54 (52.9%) deaths were recorded and 13 (12.7%) patients were still under treatment (Fig. 2a). Disease progression was the most common reason for patient withdrawal, occurring in 50 (49.0%) patients. Eleven (10.8%) patients discontinued for TRAEs including two platelet count decreased, two autoimmune hemolytic anemia and two pneumonitis (Additional file 1: Table S3). All 102 patients were included in safety analysis and 89 with histological confirmation of PTCL were in FAS for efficacy analysis (Fig. 1).

As of August 15, 2020, the median follow-up was 4.06 (range 0.30–22.9) months. Efficacy data in the total enrolled population (n = 102) and FAS (n = 89) are presented in Table 2, with no significant difference observed between the two sets. Of FAS population, 36 of 89 (40.4%, 95% CI, 30.2% to 51.4%) patients achieved an overall response by IRRC with a median TTR of 1.4 (95% CI, 1.4 to 1.5) months for responders; disease control was achieved in 53 (59.6%; 95% CI, 48.6% to 69.8%) patients. Assessed by investigators, 34 of 89 (38.2%, 95% CI, 28.1% to 49.1%) achieved an overall response (Table 2). The lower limit of the 95% CI (30.2%) of ORR by IRRC was above the prespecified threshold of response. Best reductions from baseline in tumor burden are shown in Fig. 2b.

Among the 36 patients who responded to geptanolimab, 13 (14.6%) patients achieved CR and 23 (25.8%) achieved PR. Among them, the majority of patients had an ongoing response with a median DOR of 11.4 (95% CI, 4.8 to not reached) months (Fig. 3a). The 12-month DOR was 48.5% (95% CI, 29.6% to 65.0%) (Table 2). Of FAS population, the median PFS was 2.7 (95% CI, 2.2 to 4.2; Fig. 3b) months with a range of 0 to 21.2 months, and the median OS was 14.6 (95% CI, 9.6 to not reached) months, with a range of 0.7 to 22.9 months. No significant difference was observed between efficacy result per IRRC and investigator (p = 0.356).

Subgroup analysis was performed on FAS population showing consistent response across different age, gender, clinical stage, baseline bone marrow involvement and prior ASCT. Elevated lactate dehydrogenase (LDH) level was adversely correlated with patient response (ORR, 49.0% vs. 28.9%, p = 0.081; DCR, 72.5% vs. 42.1%, p = 0.005) and OS (not reached vs 9.5 months, p = 0.012). Additionally, patients who were heavily treated (≥ 2 lines of systemic treatment) presented similar response (ORR 34.6% vs. 48.6%, p = 0.197) but shorter PFS (2.5 vs. 8.4 months, p = 0.001). Nevertheless, prior exposure to chidamide had no impact on patient response (p = 0.313). Among the 20 patients with previous failure of chidamide, response was observed in 6 patients (30.0%, 95% CI 11.9 to 54.3) (Additional file 1: Table S4). Among patients in FAS, the highest IRRC-assessed ORR was observed in ENKTL reaching 63.2% (12/19), followed by 53.8% (7/13) in ALCL ALK-, 42.9% (3/7) in ALCL ALK+ and 17.9% (5/28) in PTCL-NOS (Additional file 1: Table S5). Among the four patients classified as AITL according to the retrospectively central pathology review, two (50.0%) achieved PR and two (50.0%) achieved SD.

For 102 safety-evaluable patients, 94 (92.2%) patients experienced at least one AE during the study and 35 (34.3%) patients only had mild (grade 1–2) AEs. The most common AEs included white blood cell count decreased (n = 36, 35.3%), anemia (n = 34, 33.3%), fever (n = 27, 26.5%), platelet count decreased (n = 24, 23.5%), neutrophil count decreased (n = 20, 19.6%), lymphocyte count decreased (n = 17, 16.7%), hypokalemia (n = 16, 15.7%), AST increased (n = 16, 15.7%), cough (n = 16, 15.7%), upper respiratory infection (n = 15, 14.7%), anorexia (n = 15, 14.7%), weight loss (n = 14, 13.7%), ALT increased (n = 13, 12.7%) and pruritus (n = 13, 12.7%). According to investigator’s assessment, TRAEs occurred in 80.4% of patients (n = 82; Table 3). TRAEs occurring in ≥ 10% were white blood cell count decreased (n = 20, 19.6%), fever (n = 14, 13.7%) and anemia (n = 13, 12.7%). A total of 26 (25.5%) patients occurred grade 3 or above TRAEs. The most commonly reported grade 3 or above TRAEs were lymphocyte count decreased (n = 4, 3.9%), platelet count decreased (n = 3, 2.9%), white blood cell count decreased (n = 2, 2.0%), anemia (n = 2, 2.0%), lung infection (n = 2, 2.0%), upper respiratory infection (n = 2, 2.0%), abnormal liver function (n = 2, 2.0%), infection (n = 2, 2.0%) and autoimmune hemolytic anemia (n = 2, 2.0%). Severe adverse events (SAEs) were reported in 45 (44.1%) patients, and 26 SAEs were judged to be treatment related in 19 (18.6%) patients; the most common treatment-related SAE were platelet count decreased (n = 3, 2.9%) and pneumonitis (n = 3, 2.9%). There was no death attributed to the geptanolimab per investigator assessment.

irAE occurred in 36 (35.3%) patients with 9.8% (n = 10) of patients having grade 3 or above (Additional file 1: Table S6). The most common irAE was pruritus (n = 7, 6.9%), followed by hypothyroidism (n = 4, 3.9%), hyperthyroidism (n = 3, 2.9%), tri-iodothyronine free decreased (n = 3, 2.9%), tri-iodothyronine decreased (n = 3, 2.9%) and thyroid-stimulating hormone increased (n = 3, 2.9%). Of the 36 patients experiencing irAEs, the irAEs resolved without treatment or interruption of the geptanolimab in five patients. Twenty-two (21.6%) patients received treatment for their irAEs, and 12 (11.8%) of them received corticosteroids.

Of 94 patients with ADA samples available, two (2.1%) were tested positive for ADAs at baseline and one of them changed to be negative after geptanolimab administration. ADAs were detected in another four (4.3%) patients during treatment course. Archival FFPE tissue samples were obtained for TMB (n = 59) and MSI testing (n = 67). Most patients (n = 65, 97.0%) were microsatellite stable (MSS), and the median TMB was 1.2 (range 0–18.8) mutations/Mb.

Collectively, 91 patients had available tissue sample for PD-L1 testing. Of the 81 patients with available PD-L1 expression data in FAS, 80 (98.8%) had PD-L1 expression of 1% or greater. More than half of patients (45/81, 55.6%) had a PD-L1 ≥ 50%, and these patients derived more benefit from geptanolimab treatment compared to < 50% ones. Post hoc analysis showed ORRs were 53.3% (24/45, 95% CI 37.9% to 68.3%) in PD-L1 ≥ 50% patients and 25.0% (9/36, 95% CI 12.1% to 42.2%) in < 50% cases (p = 0.013) (Fig. 4a). Additionally, PD-L1 ≥ 50% patients showed longer median PFS (6.2 months, 95% CI, 2.7 to not reached vs. 1.5 months, 95% CI 1.3 to 2.7, p = 0.002; Fig. 4b) and OS (not reached, 95% CI, 9.5 to not reached vs. 10.2 months, 95% CI, 6.2 to 18.5, p = 0.043) than PD-L1 < 50% cases.