PF-08634404（一种在研的抗PD-1和抗VEGF双特异性抗体）的剂量优化和暴露-反应（ER）分析

Introduction: Despite advances in therapy for non-small cell lung cancer (NSCLC) and colorectal cancer (CRC), patients ultimately progress and some do not respond, underscoring the need for innovative agents. Given the role of PD-1 and VEGF pathways in tumor growth via evading the immune system and promoting angiogenesis, PF-08634404, formerly SSGJ-707, is designed as a bispecific antibody that inhibits both targets. PF-08634404 demonstrated a manageable safety profile and encouraging activity across multiple tumor types and across a wide dose range. Here, we present integrated ER analyses that informed dose optimization and supported the selection of the recommended phase 3 doses (RP3D) based on results from the phase 1 and phase 2 clinical studies in NSCLC and CRC. Experimental Procedures: One Ph 1 study (SSGJ-707-ST-I-01-CN-Ib), two Ph 2 studies (SSGJ-707-NSCLC-II-01, SSGJ-707-NSCLC-II-02), and one Ph 2 study (SSGJ-707-CRC-II-01) evaluated PF-08634404 monotherapy or combination with chemotherapy as 1L treatment for advanced NSCLC and metastatic CRC, respectively. In both NSCLC and CRC, doses of 5 and 10 mg/kg were selected for further dose optimization. A population PK model was used to derive exposure metrics. Logistic regression was conducted to assess the relationship between exposure and the efficacy endpoint confirmed overall response (cOR) using data from the 5 and 10 mg/kg Q3W dose levels for participants with NSCLC. ER-safety analysis assessed the relationship between exposure and Grade ≥3 treatment-emergent AE (TEAEs) using data from 5 to 30 mg/kg Q3W in NSCLC. In NSCLC, a Clinical utility index (CUI) was developed to evaluate the tradeoff between efficacy and safety. A tumor growth inhibition (TGI) model was developed to characterize the time course of tumor size change from baseline. Result Summary: In NSCLC, higher exposure was associated with higher probability of Grade ≥3 TEAE and confirmed overall response rate (cORR). The estimated probabilities of Grade ≥3 TEAE at the median exposure were 47.4% and 61.6% for 5 mg/kg and 10 mg/kg Q3W, respectively. The estimated probabilities of cORR at the median exposure were 42.3% and 58.6% for 5 and 10 mg/kg Q3W, respectively. TGI model-based simulation showed median reduction in tumor size from baseline of 28% and 40% for 5 and 10 mg/kg Q3W, respectively. Based on the CUI, 10 mg/kg Q3W had a greater clinical utility vs 5 mg/kg Q3W in patients with 1L NSCLC. Data from the CRC-II-01 study showed consistent efficacy and safety between the 5 and 10 mg/kg Q2W or Q3W regimens (~20 participants/group). Collectively, the ER analyses from the larger NSCLC studies support the 10 mg/kg Q2W dose in combination with chemotherapy in the 1L CRC setting. Conclusions: These analyses support that the 10 mg/kg dose of PF-08634404 provides a favorable balance of safety and efficacy. The 10 mg/kg dose was selected for further evaluation for both NSCLC (Q3W) and CRC (Q2W) in their respective Phase 3 studies.