Discussion
tumor, DLTs, toxicity, hepatocellular carcinoma, extensive-stage small-cell lung cancer, TRAEs
TUMOR, SOLID TUMORS, HEPATOCELLULAR CARCINOMA, SOFT TISSUE SARCOMA, MALIGNANT PLEURAL MESOTHELIOMA
In this first-in-human study of nofazinlimab, no DLTs were observed in part 1 phase 1a, and MTD was not reached at any of the escalating dose levels (1–10 mg/kg Q3W). TEAEs and TRAEs observed in patients did not reveal a clear dose-dependent increase in toxicity across doses. Preliminary anti-tumor activities were observed in 21 evaluable patients at dose of 3 mg/kg and above, including at 200 mg fixed dose. Receptor occupancy (RO) data from a separate phase 1 of nofazinlimab showed that the RO of PD-1 in peripheral T cells was close to saturation on C2D1 and remained saturated for at least 3 treatment cycles in 7 patients treated with 200 mg Q3W of nofazinlimab (the comprehensive data will be reported separately). Furthermore, the pharmacokinetic properties of nofazinlimab were comparable to those of other marketed anti-PD-1 mAbs, supporting the use of a flat dose and dosing interval of 3 weeks. In conclusion, the promising efficacy and safety of nofazinlimab from this phase 1a study, combined with a bridging study in China (separate manuscript in submission), led to selecting the recommended 200 mg Q3W dose (comparable to 3 mg/kg Q3W) as the RP2D. The ease of flat-dose administration further supports this choice.The safety profile of nofazinlimab observed in this study was consistent with those reported for other anti-PD-L1/anti-PD-1 mAbs therapeutics [The ORR in part 1 phase 1a and phase 1b in checkpoint inhibitor-naive patients with advanced solid tumors was 14.3% and 25.3%; the DCR was 47.6% and 56.3%, respectively. ORR was 20.0% and 14.3% in patients with soft tissue sarcoma (arm 1) and malignant pleural mesothelioma (arm 2), respectively. Specifically, ORR was 24.1% in arm 3 (200 mg Q3W) with three and four of 29 patients achieving CR and PR, respectively; while ORR was 32.3% in arm 4 (400 mg Q6W) with one and nine of 31 patients achieving CR and PR, respectively. Anti-tumor activity observed with nofazinlimab was comparable to that observed in studies of other single agent PD-1 inhibitors (e.g., nivolumab, pembrolizumab) in anti-PD-1/PD-L1-naïve populations with similar tumor types [Because of the limited number of patients with suitable tissue for analysis, the relationship between PD-L1 expression and clinical responses was only assessed in the phase 1b portion. Although a formal statistical assessment was not conducted, a trend towards higher ORR and longer PFS was observed in patients with high PD-L1 expression (TC ≥ 1%) versus those with low PD-L1 expression (TC < 1%). A previous meta-analysis comprising of 41 clinical trials of PD-1/PD-L1 inhibitors with available PD-L1 biomarker data showed that tumor and tumor-infiltrating immune cell with PD-L1 overexpression was significantly associated with higher response rates to immune checkpoint inhibitors across a range of solid tumors. The significant association with higher response rates remained when PD-L1 expression was evaluated using different immunohistochemistry (IHC) assays [The toxicity profile of nofazinlimab combined with regorafenib was substantially heightened compared to nofazinlimab monotherapy and consistent with that reported previously for nivolumab administered in combination with regorafenib [In part 2a, there were no responders among patients with mCRC, and DCR was 28.6%. This result is consistent with other PD-1/PD-L1 inhibitor and regorafenib combination therapies in MSS mCRC, indicating that combined treatment with PD-1 inhibitor and regorafenib has limited benefit in MSS mCRC patients [Nofazinlimab in combination with chemotherapy as first-line treatment in patients with extensive-stage small-cell lung cancer and in combination with lenvatinib as first-line treatment in patients with advanced hepatocellular carcinoma are currently being explored in a phase 1a/b study (NCT03809767) in mainland China. Additionally, a phase 3 randomized trial of nofazinlimab plus lenvatinib compared with placebo plus lenvatinib as first-line therapy in patients with advanced hepatocellular carcinoma is ongoing (NCT04194775) based on the promising anti-tumor activity observed in the phase 1 single-arm combination study (NCT03809767) [In conclusion, nofazinlimab was well tolerated and demonstrated preliminary anti-tumor activity in multiple tumor types at dose of 3 mg/kg and above. The fixed dose of 200 mg Q3W was determined as the RP2D based on all available data. An alternative dosing regimen of 400 mg Q6W showed comparable safety and efficacy, offering an additional and potentially more convenient option for patients and physicians, and could be further explored. Nofazinlimab 300 mg Q4W in combination with regorafenib at either 80 mg or 120 mg had a manageable safety profile, but no objective response was noted in a small cohort of heavily pretreated MSS mCRC patients.