A phase 1, dose escalation/dose-expansion study of QLF31907, a bispecific antibody (BsAb) targeting PD-L1 and 4-1BB, in patients with advanced solid tumors and lymphoma.
Authors: Lin Tongyu , Liu Bin , Pu Xingxiang , Wu Lin , Du Xiaobo , Mo Ning , Song Zhengbo , Zhou Liwei , Duan Xianlin , Zhu Yanan , Kang Xiaoyan 
Published: June 2024

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Background: Clinical development of agonistic 4-1BB mAbs is limited by their narrow therapeutic window or unsatisfactory efficacy. Development of novel molecules with improved efficacy and restricted 4-1BB activation to tumor microenvironment is crucial. QLF31907 is a BsAb targeting PD-L1 and 4-1BB and showed restricted activation of 4-1BB in preclinical studies. Here we present the results from an ongoing phase 1 study of QLF31907 in patients (pts) with advanced solid tumors and relapsed/refractory (r/r) lymphoma. Methods: This study consisted of dose-escalation and dose-expansion phases. Pts were enrolled if with histologically confirmed solid tumors or r/r lymphoma; failed in or intolerable to standard therapy; and with ≥ 1 measurable lesion. Pts received QLF31907 intravenously once every 2 weeks (Q2W) at 0.026 and 0.1 mg/kg (accelerated titration design), and 0.3, 1, 3, 10, 20, and 30 mg/kg (i3+3 design) in the dose-escalation phase. The DLT evaluation window was 28 days. Pts received QLF31907 10 mg/kg and 20 mg/kg Q2W in the dose-expansion phase. The primary endpoint was dose-limiting toxicity (DLT). Results: As of 30 Nov 2023, 38 pts were enrolled from 5 centers across China. Median age was 58 years and 52.6% patients had an ECOG PS of 1. Five (13.2%) pts had r/r lymphoma. 36 (94.7%) pts had stage IV disease. 31.6% pts previously received ≥3 therapies and 57.9% pts previously received PD-1/PD-L1 therapy. DLTs were observed in 1 pt (20 mg/kg): myalgia and platelet count decreased. All pts experienced TEAEs (treatment-related, 92.1%). The most common TEAE was anemia (73.7%), followed by hypertriglyceridemia (50.0%). Twenty-four (63.2%) pts experienced Gr≥3 TEAEs (treatment-related, 31.6%). The most common Gr≥3 TEAE was pneumonia (13.2%). TEAEs leading to treatment discontinuation occurred in 6 (15.8%) pts (treatment-related, 7.9%). Serious TEAEs occurred in 20 (52.6%) pts (treatment-related, 26.3%). Six (15.8%) pts had PRs and 3 PRs were confirmed. SD was observed in 20 (52.6%) pts. DCR was 60.5% (23/38). PR was observed in 3 patients who previously received PD-1/PD-L1 therapy. The median DoR was not reached and the 6 month DoR rate was 60.0% (95% CI, 12.6-88.2). Two patients had PRs lasting for more than 1 year: 1 with PD-1/PD-L1 naïve cervical cancer (PR>18 months) and 1 with PD-1/PD-L1 treated melanoma (PR>13 months). In the dose range of 0.026-30 mg/kg, the exposure increased proportionally with dose increase. At 10mg/kg Q2W and above, PD-L1 and 4-1BB receptor occupancy indicated by PBMCs stabilized >80% during the treatment period. Conclusions: QLF31907 showed an acceptable safety profile and preliminary clinical activity in heavily pretreated patients with advanced solid tumors and lymphoma. Encouraging clinical activity was observed in patients who have failed PD-1/PD-L1 therapy and further research on the mechanism is ongoing. Clinical trial information: NCT05150405 .