Between May 20, 2020, and November 26, 2020, 25 patients were enrolled at the run-in stage; median age was 55.0 (range, 49–61) years and other baseline characteristics were found in Table S2.

Based on the results from the run-in stage, 121 patients from 41 sites in China were screened for stage 2 study from November 29, 2020, to June 18, 2022, of whom 82 were enrolled and included in the ITT and SS. As of the data cutoff (December 18, 2022), 41 (50.0%) patients were still on treatment; the majority (25/82, 30.5%) discontinued treatment due to disease progression (Fig. 1). Table 1 showed the baseline characteristics of 82 ITT populations. Median age was 52.5 (range, 32–76) years and 62.2% were male. Most patients (79/82, 96.3%) had ECOG PS of 0–1. The majority (64/82, 78.0%) had stage III-IV diseases, and median disease course of FL was 37.7 (range, 4.8-156.2) months. Forty-four (54.3%) were intermediate-/high-risk FL per Follicular Lymphoma International Prognostic Index 2 (FLIPI-2). All cases had received prior rituximab-based regimens, with R-CHOP/R-CDOP (76/82, 92.7%) being common; and 46 (56.1%) patients were refractory to last therapies. Median number of previous treatment lines was 3 (range, 2–7). No one received autologous/allogeneic stem cell transplants before the enrollment. Progression of disease within 24 months (POD24) at enrollment occurred in over half (73.2%).

Trial profile at stage 2. SS safety analysis set, PPS per-protocol set, ITT intent-to-treat

Median follow-up was 24.9 months at the run-in stage (cutoff date, December 18, 2022). Among 25 patients with evaluable efficacy, 6 (24.0%) patients achieved CR based on the IRC assessment (Table S3). The percentage of patients with the IRC-assessed objective response and disease control was 88.0% (95% CI, 68.8–97.5%) and 92.0% (95% CI, 74.0–99.0%), respectively. Median DOR was 11.8 (95% CI, 5.5-not estimable) months. Median PFS was 12.0 (95% CI, 7.3-not estimable) months; 24-month OS rate was estimated as 78.9% (95% CI, 56.4–90.6%) and median OS was not reached. The consistent results (ORR, 88.0%; CRR, 20.0%; DCR, 96.0%; median DOR, 14.8 months; median PFS, 10.9 months) assessed by the investigator were provided in Table S3.

Median follow-up at the stage 2 was 13.3 (95% CI, 10.1–18.9) months by the data cutoff (December 18, 2022). Of 82 patients, 28 (34.2%) achieved CR and 43 (52.4%) achieved PR, with IRC-assessed ORR of 86.6% (95% CI, 77.3–93.1%; Table S4). The study met its predefined primary endpoint, which significantly rejected the null hypothesis of ORR (≤40%). SD was attained in 7 (8.5%) patients and PD in 2 (2.4%) patients (Fig. 2a). As per IRC assessment in 82 patients, 70 (85.4%) achieved lesion reduction of at least 50% following TQ-B3525 treatment (Fig. 2b). Consistent with the IRC assessment, the investigator assessment showed an ORR of 87.8% (95% CI, 78.7–94.0%; Table S4). Also, ORR (IRC-assessed 88.6%; investigator-assessed, 89.9%) in the PPS yielded similar results to the analysis in the ITT (Table S5).

TQ-B3525 treatment and response outcomes in the ITT at stage 2. a Swimmer plot. b Waterfall plot of tumor change from baseline. PD progressive disease, SD stable disease, IRC independent review committee, PR partial response, NE not estimable, CR complete response

Responses for stage 2 were rapid and durable. For the ITT population, IRC-assessed median TTR was 1.8 (range, 0.2–9.3; Table S4) months, and DOR was not reached (95% CI, 9.2-not estimable; Fig. 3a). Investigator-assessed median TTR (1.8 months) and DOR (14.8 months) were similar to the above results (Table S4 and Fig. 3b). There were 26 (31.7%) PFS events as assessed by IRC; median PFS was 18.5 (95% CI, 10.2-not estimable; Fig. 3c) months, with both 58.3% of the patients remaining progression-free at 12 and 18 months. Investigator assessment also demonstrated similar PFS results (18.4 months; Fig. 3d). Median OS was not reached because of insufficient events (8 [9.8%] deaths; Fig. 3e); 12- and 24-month OS rates were respectively estimated as 91.8% (95% CI, 82.5–96.3%) and 86.1% (95% CI, 72.3–93.3%). A PPS analysis with DOR (IRC-assessed, not reached; investigator-assessed, 14.8 months), PFS (IRC-assessed, 18.5 months; investigator-assessed, 18.4 months), and OS (not reached) was consistent with these results in the ITT (Table S5 and Fig. S1).

Kaplan-Meier curves of DOR, PFS, and OS at stage 2 (ITT population). DOR as per IRC (a) and investigator assessments (b). PFS as per IRC (c) and investigator assessments (d). OS (e). DOR duration of response, mo months, OS overall survival, NR not reached, NE not estimable, CI confidence interval, IRC independent review committee, PFS progression-free survival

Subgroup analysis at stage 2 showed that response rates confirmed by IRC (ORR range, 76.2–96.8%; Fig. 4a) and investigator (ORR range, 77.8–-100.0%; Fig. 4b) in the ITT population were consistent across all patient subgroups including age, sex, histological grade, lines of prior systemic therapies, relapsed or refractory to last therapies, ECOG PS, POD24, bone marrow involvement, FLIPI, and Lugano stage. Favorable DOR, PFS, and OS were also observed in various subgroups (Fig. S2). Analysis in subpopulation with high-aggressive disease indicated by POD24 revealed that ORR assessed by IRC (90.9% vs. 85.0%) and investigator (95.5% vs. 85.0%) was numerically higher in non-POD24 than POD24 patients. Of note, patients who are clinically challenging to treat, such as those with POD24 (90.9%), refractory diseases to last therapies (84.8%), or Lugano stage III-IV (85.9%), exhibited a high IRC-assessed ORR exceeding 80.0%. Patients who underwent third-line or later treatments also have an ORR of 79.5% by IRC assessment. Patients with primary refractory disease attained an IRC-assessed ORR of 87.5%; besides, median DOR and PFS assessed by IRC and median OS were not reached.

Forest Plot of subgroup analysis for ORR in ITT at stage 2. Response rates were assessed by IRC (a) and investigator (b). ORR objective response rate, ITT intent-to-treatment, CI confidence interval, POD24 progression of disease within 24 months, IRC independent review committee, ECOG PS Eastern Cooperative Oncology Group Performance Score, FLIPI-2 Follicular Lymphoma International Prognostic Index 2

Median exposure with TQ-B3525 was 7.5 (range, 0.1–23.5) months and median exposure was 8.5 (range, 0–26) cycles (Table S6). Median actual and relative dose intensity (RDI), along with cumulative dose of TQ-B3525 were 480.7 (range, 310.6–615.4) mg/day, 79.0% (range, 51.0–100.0%), and 4050.0 (range, 80.0–14300.0) mg, respectively. Nearly half (46.3%) received 80–120% of RDI.

Any-grade treatment-related AEs (TRAEs) were observed in all 25 (100.0%) patients at the run-in stage, and mainly included hyperglycemia (19/25, 76.0%), neutropenia (16/25, 64.0%), diarrhea (15/25, 60.0%). Grade 3 or higher TRAEs were reported in 19 (76.0%) cases and primarily were neutropenia (9/25, 36.0%) and hyperglycemia (7/25, 28.0%). There were no deaths from any cause at the run-in stage (Table S7).

TRAE with an incidence of ≥10% at stage 2 was summarized in Table 2. All 82 patients in the SS experienced at least one treatment-related AE (TRAE) of any grade; frequent TRAEs were hyperglycemia (68/82, 82.9%), diarrhea (46/82, 56.1%), neutropenia (37/82, 45.1%), and leukopenia (31/82, 37.8%). Grade 3 or higher TRAEs occurred in 63 (76.8%) cases, with neutropenia (18/82, 22.0%), hyperglycemia (16/82, 19.5%), and diarrhea (11/82, 13.4%) being common. The grade 3 or higher TRAEs of special interest occurring in 61.0% of patients mainly included neutropenia (18/82, 22.0%), hyperglycemia (16/82, 19.5%), diarrhea (11/82, 13.4%), thrombopenia (7/82, 8.5%), lymphopenia (7/82, 8.5%), infectious pneumonia (6/82, 7.3%), and pneumonitis (5/82, 6.1%; Table S8). Serious TRAEs occurred in 39 (47.6%) patients and mainly included infectious pneumonia (8.5%), pneumonitis (7.3%), hyperglycemia (6.1%), diarrhea (6.1%), interstitial lung disease (3.7%), and upper respiratory infection (3.7%). Dosing of TQ-B3525 was reduced in 61 (74.4%) and interrupted in 60 (73.2%) patients due to TRAEs (Table S9). Eight (9.8%) patients discontinued TQ-B3525 as a result of a TRAE. Among 13 patients with pneumonitis, 3 dose reductions, 7 dose interruptions, and 2 treatment discontinuations were observed.

Only 1 death occurred and was considered possibly TQ-B3525 treatment related: a 56-year-old male with baseline ruptured neck mass experienced sepsis after approximately 1.5 months of first treatment and finally died following the discontinuation of TQ-B3525 and symptomatic treatment (Table S10).

All 82 patients experienced treatment-emergent AEs (TEAEs) at stage 2, of which 81.7% had grade 3 or higher events (Table S11). Commonly reported grade 3 or higher TEAEs included neutropenia (18/82, 22.0%), hyperglycemia (16/82, 19.5%), and diarrhea (13/82, 15.9%). Serious TEAEs occurred in 46 (56.1%) patients.